fumarates and Hypertension

Aliskiren is a newly developed medicine. As one of the effective renin-angiotensin-aldosterone system inhibitors, its role in lowering blood pressure has been recognised. However, its safety and tolerability still remain controversial. The aim of the paper is to systematically summarise the published studies about the clinical efficacy and side effects of aliskiren monotherapy.. A comprehensive review of PubMed, Embase and Cochrane Library databases published from inception until June 2019 will be conducted. The selected articles are meta-analyses that integrated the randomised controlled studies, which evaluated efficacy, safety and tolerability of aliskiren monotherapy. Two people will select eligible articles and extract data independently. Any disputes will be resolved by discussion or the arbitration of a third person. The quality of reporting evidence will be assessed using the AMSTAR 2 tool. Study selection process will be presented using a flowchart. We will re-analyse each outcome with the random effect methods if necessary. If possible, we will also calculate 95% prediction intervals for each random effect estimate, by using Egger's test to evaluate if the reporting bias existed.. Ethical approval is not required for the study, as we only collected data from available published materials. This umbrella review will be also submitted to a peer-reviewed journal for publication after completion.. CRD42019142141.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Tolerance; Fumarates; Humans; Hypertension; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that has a critical role in maintaining the normotensive state and electrolyte balance of the organism. The RAAS also has an important influence in the development of various pathophysiological conditions especially those concerning the renal system, cardiovascular system and hypertension. One of the consequences of the RAAS system is an increase in the generation of the reactive oxygen species (ROS) that causes an increase in oxidative stress, which may play a role in the development or exacerbation of such pathological conditions. Blocking this system at multiple points has been advantageous in the clinical management of these disorders. The key blockers that had gained predominant clinical use for such manifestations were angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. However, their prolonged use caused a compensatory increase in renin and angiotensin I levels. The blocking of the system at the initial stages by blocking renin was of advantage to overcome such compensation. Such a renin blocker that gained widespread use was aliskiren. It is the first oral renin inhibitor that was approved for use in 2007. Although the opinions are varied about the use and future of renin inhibitors as antihypertensive agents, aliskiren has been well documented to have antioxidant effects. Aliskiren functions as an antioxidant by lowering the increase in ROS that are produced by the RAAS system at doses independent of decreasing the blood pressure. In the present review we discuss the antioxidant properties of aliskiren independent of its blood pressure lowering property.

Topics: Amides; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Fumarates; Humans; Hypertension; Reactive Oxygen Species

The role of the direct renin inhibitor aliskiren in hypertension is not fully established and use of aliskiren in diabetic patients is especially controversial. A systematic review investigating both short-term diastolic and systolic blood pressure (DBP and SBP) reduction and long-term cardiovascular outcomes has not been conducted. Therefore, we aimed to fill this gap by investigating BP reduction, major cardiovascular outcomes, and mortality of aliskiren compared to other antihypertensive therapy. We searched PubMed and Embase databases for relevant randomized controlled trials (RCTs). Using a random-effects model, weighted mean difference (WMD) and relative risk (WRR) with 95% confidence interval (CI) were used to measure the effect of aliskiren therapy in the management of hypertension and major cardiovascular outcomes. Thirty seven RCTs with a total of 35,916 patients were included. Aliskiren induced slightly greater DBP and SBP reductions than other antihypertensive agents (WMD -0.77 mmHg, 95% CI [-2.01;0.46 mmHg] and WMD -1.14 mmHg, 95% CI [-2.78;0.50 mmHg], respectively). Aliskiren did not reduce total mortality or cardiovascular death. In patients with diabetes, aliskiren add-on therapy may have the potential to increase total mortality and cardiovascular death (WRR 1.06, 95% CI [0.88;1.28] and WRR 1.09, 95% CI [0.94;1.24], respectively). Despite superior BP-reducing effect, aliskiren is not recommended as first-line treatment in hypertensive patients as it does not reduce mortality and major cardiovascular outcomes. Dual renin-angiotensin-aldosterone system inhibition with aliskiren should be avoided in diabetic patients, while the use of aliskiren monotherapy remains to be investigated.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Risk Factors; Signal Transduction; Treatment Outcome

Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration-related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14-6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83-12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=-0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=-2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design.

Topics: Amides; Antihypertensive Agents; Benzimidazoles; Benzopyrans; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Control Groups; Double-Blind Method; Drug Resistance; Eplerenone; Ethanolamines; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Nebivolol; Oxadiazoles; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Regression Analysis; Research Design; Spironolactone; Sympathectomy; Tetrazoles; Treatment Outcome

The two major classes of drugs that target the RAS are the angiotensin-converting enzyme (ACE) inhibitors and the selective AT1 receptor blockers (ARBs). Although both of these drug classes target angiotensin II, the differences in their mechanisms of action have implications for their effects on other pathways and receptors that may have therapeutic implications. Both ACEIs and ARBs are effective antihypertensive agents that have been shown to reduce the risk of cardiovascular and renal events. Direct inhibition of renin -the most proximal aspect of the RAS -became clinically feasible from 2007 with the introduction of aliskiren. This latter drug has been shown to be efficacious for the management of hypertension. Combined therapy of direct renin-inhibitors with ACEIs or ARBs has been tested in some clinical situations as congestive HF and proteinuria with diverse results. This article tries to offer an updated review of current knowledge on the use of RAS blocking drugs in clinical settings.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, a direct renin inhibitor, is effective for reducing blood pressure (BP) in patients with hypertension when combined with amlodipine or hydrochlorothiazide (HCTZ). However, the efficacy and tolerability of the 2 combinations are unclear. We performed a meta-analysis of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ for hypertension.. The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and the Novartis clinical trial database were searched through December 2012 for reports of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ vs. monotherapy in patients with hypertension. The main outcome measures were reduction in systolic BP and diastolic BP from baseline and rates of therapeutic response and BP control. Tolerance of aliskiren/amlodipine and aliskiren/HCTZ was also analyzed. Outcomes were initially pooled by standard random-effects methods, producing a weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs). The pooled estimates were then used for adjusted indirect comparisons.. We selected 19 reports of trials involving 13,614 participants. Aliskiren/amlodpine and aliskiren/HCTZ were more effective than monotherapy in controlling BP. Aliskiren/amlodipine was significantly more effective than aliskiren/HCTZ in reducing systolic BP (WMD = -3.36 mm Hg; 95% CI = -4.64 to 2.07 mm Hg) and diastolic BP (WMD = -3.49 mm Hg; 95% CI = -4.34 to 2.63 mm Hg). As compared with aliskiren/HCTZ, alikiren/amlodipine was associated with higher rate of therapeutic response (RR = 1.23; 95% CI = 1.14-1.33) and BP control (RR = 1.24; 95% CI = 1.11-1.39). Number of adverse events and withdrawals due to adverse events were similar with aliskiren/amlodipine and aliskiren/HCTZ.. BP control is better with aliskiren combined with amlodipine or HCTZ than with monotherapy, with aliskiren/amlodipine being more effective than aliskiren/HCTZ.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Renin

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials.

Topics: Adolescent; Amides; Child; Child, Preschool; Fumarates; Humans; Hypertension; Infant; Infant, Newborn; Kidney Diseases; Renin; Renin-Angiotensin System

Renin-angiotensin-system (RAS) is an enzymatic cascade that plays a pivotal role in the development of arterial hypertension, kidney disease and cardiovascular disease. Inhibition of the RAS with angiotensin converting enzyme (ACE) inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) has proved to be a successful strategy for the treatment of hypertension and related cardiovascular disorders. However, by reducing feedback inhibition of renin release, the effects of ACE-Is and ARBs lead to an increase in plasma renin concentration (PRC) and activity (PRA), limiting a complete inhibition of the RAS. Consequently the effects of a different pharmacological strategy that completely blocks the RAS upstream has been assessed in the last years. In this context, aliskiren is the first representative of a new class of non-peptide orally active renin inhibitor that blocks the RAS at its rate-limiting step and induces a net reduction in PRA, angiotensin II and aldosterone levels. Aliskiren effectively reduces blood pressure as a monotherapy as well in combination therapy. In addition, aliskiren has a placebo-like tolerability profile at the licensed doses of 150 mg and 300 mg. Aliskiren also exhibits additive effects on blood pressure reduction when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE-Is or ARBs. In previous studies, aliskiren showed beneficial effects in patients with arterial hypertension and associated clinical conditions. However, later trials indicated that the use of aliskiren should be avoided in patients with renal failure or receiving ACE-Is or ARBs. The main aim of this review is to summarize the available data on its efficacy and safety profile, highlighting clinical implications from recent trials.

Topics: Amides; Animals; Antihypertensive Agents; Atherosclerosis; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin

The renin-angiotensin system (RAS) affects vascular tone, cardiac output and kidney function. By these means the RAS plays a key role in the pathogenesis of arterial hypertension. As a result, RAS inhibition is highly effective not only in lowering blood pressure but also in reducing kidney disease progression (particularly when associated with proteinuria) and cardiovascular events. Among RAS blocking agents, direct renin inhibitors have shown not only excellent efficacy in hypertension control but also pharmacologic tolerance that is comparable with other renin-angiotensin suppressors. Indeed, aliskiren, the only direct renin inhibitor available is effective in controlling blood pressure as monotherapy or in combination with other antihypertensive drugs, irrespective of patient's age, ethnicity or sex. It is also effective in patients with metabolic syndrome, obesity and diabetes. Long-term studies comparing 'hard endpoints' of aliskiren therapy versus treatment with other RAS inhibitors, including cardiac and kidney protection, are currently ongoing. Combined with other antihypertensive agents, aliskiren not only improves their hypotensive response but may also lessen the adverse effects of other drugs. In high-risk patients, however, precautions should be taken when combining two or more renin-angiotensin inhibiting agents, as tissue perfusion may be highly renin-dependent in these patients and serious adverse side effects could take place.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) has long been established as a key pathway in the regulation of blood pressure and body fluid volume. The aspartic protease renin is responsible for the initial and rate-limiting step of the RAAS; hence inhibition of renin would favor an upstream blockade or modulation of the RAAS. Direct renin inhibitors (DRIs) are therefore considered attractive agents for the treatment of hypertension. However, the identification of orally bioavailable, efficacious and safe low molecular weight DRIs has proven very challenging. To date, aliskiren is the only DRI that has reached FDA approval as a hypertension therapy option.. The present review summarizes the recent scientific accounts describing the design of new non-peptidic DRIs published between 2009 and 2012. The author also presents a number of chemical structures in addition to preclinical ADMET obtained from public scientific literatures and patent filings. Furthermore, the author discusses the results of early clinical trials of new candidate DRIs.. The vast medicinal chemistry efforts on structure-based design of non-peptidic DRIs, over the past 10 years, have presented new chemical spaces for tight binding to renin as well as gaining a proper balance between the physicochemical properties, potency, efficacy and safety. However, the criteria for candidate selection has become increasingly demanding; and new antihypertensives are expected to demonstrate a clear difference in their clinical profile beyond lowering blood pressure compared with established drug treatment paradigms.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Design; Drug Discovery; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines.. Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data.. We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = -10.42, 95% CI -13.03∼-7.82, P<0.00001; DBP: WMD = -6.60, 95% CI -7.22∼-5.97, P<0.00001) or amlodipine (SBP: WMD = -4.85, 95% CI -6.88∼-2.81, P<0.00001; DBP: WMD = -2.91, 95% CI -3.85∼-1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66∼0.92, P = 0.004; RR = 0.51, 0.27∼0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m(2)) hypertensive and non-obese (body mass index <30 kg/m(2)) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups.. We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Obesity; Publication Bias; Randomized Controlled Trials as Topic

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renal Insufficiency, Chronic; Renin

To investigate the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs and placebo in patients with hypertension, a meta-analysis was performed of studies published between 1950 and 2012. A systematic literature search of MEDLINE and the Cochrane Library was conducted for randomized controlled trials. Weighted mean differences and relative risk with 95% confidence intervals were calculated for continuous and dichotomous data, respectively. In all, 14 studies with 6741 participants were included in the present meta-analysis. Nine studies included trial arms with placebo, four included angiotensin (Ang) AT1 receptor blockers (ARBs), three included Ang-converting enzyme inhibitors (ACEIs), two included calcium channel blockers (CCBs), one included a β-blocker, and one included hydrochlorothiazide (HCTZ). We found that aliskiren, which lowered blood pressure (BP) effectively in patients with mild-to-moderate hypertension, was similar to HCTZ but inferior to CCBs in BP reduction, response rates and control rates. Furthermore, aliskiren was superior to ACEIs in lowering diastolic BP (DBP), while it had similar effects to ACEIs on systolic BP (SBP) reduction, response rates and control rates. Additionally, the present meta-analysis showed the superiority of atenolol over aliskiren in DBP reduction and BP response but showed that atenolol was inferior in SBP reduction and BP control. No difference was found in the rates of therapeutic response between aliskiren and ARBs, while more patients achieved BP control with aliskiren. Further studies will be needed to determine the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Fumarates; Humans; Hypertension; Treatment Outcome

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.

Topics: Arginine; Argininosuccinate Lyase; Argininosuccinic Acid; Argininosuccinic Aciduria; Child, Preschool; Citrulline; Cognition Disorders; Diet, Protein-Restricted; Fumarates; Genetic Testing; Glucose; Humans; Hyperammonemia; Hypertension; Infant; Infant, Newborn; Lipids; Liver Diseases; Liver Transplantation; Neonatal Screening; Phenylbutyrates; Sodium Benzoate

Cardiovascular-related morbidity and mortality is linked to hypertension with proportional gains in cardiovascular risk factor reduction with the lowering of blood pressure. Clinical trial data has shown that attaining goal blood pressure requires, for most patients, at least two antihypertensive medications, with a significant proportion requiring regimens of three or more medications. Single-pill triple combinations have returned to the market following results of increased efficacy and adherence over dual- and mono-therapy. The combination of aliskiren, amlodipine and hydrochlorothiazide is a rational choice for combination therapy and recent studies suggest that it is safe and effective in lowering blood pressure in patients who fail dual combination therapy.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Treatment Outcome

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Agonists; Catheter Ablation; Cerebrovascular Circulation; Chronic Disease; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Kidney Diseases; Randomized Controlled Trials as Topic; Tetrazoles; Valine; Valsartan

High blood pressure (BP) is a major risk factor for cardiovascular and renal complications. A majority of treated hypertensive patients still complain of high BP. The renin-angiotensin aldosterone system (RAAS) has been a centre-stage target for all the cardiovascular and cardio-renal complications. Aliskiren, is the first direct renin inhibitor (DRI) to be approved by the US FDA. Renin controls the rate-limiting step in the RAAS cascade and hence is the most favorable target for RAAS suppression.. This review article strives to summarize the pharmacokinetic, preclinical and clinical studies done so far pertaining to the efficacy of aliskiren. Further, the pharmacology of aliskiren has been comprehensively dealt with to enhance understanding so as to further research in this unfathomed area in the multitude of cardiovascular disorders and renal diseases.. Aliskiren has been shown to have comparable BP-lowering effects to other RAAS inhibitors. Recent clinical trials have indicated that it might contribute significantly in combination with other agents for the protection of end-organ diseases.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Aliskiren is the first orally active direct renin inhibitor approved for the treatment of hypertension. Aliskiren's inhibitory effect on angiotensin I generation, through renin blockade, is highly specific and long-lasting (24 hours). This feature differentiates aliskiren from traditional antihypertensive drugs.. This paper reviews the results of various clinical trials which investigate the safety and efficacy of aliskiren on blood pressure (BP) reduction and clinical end points.. Aliskiren is suitable for once-daily administration. Its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses. The tolerability profile of aliskiren is placebo-like at the licensed doses of 150 and 300 mg. In particular, the discontinuation of therapy due to clinical adverse events occurs similarly among patients treated with either aliskiren or placebo. Aliskiren is not recommended in association with ACE-inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and renal impairment. Pending disclosure of full results, the early termination of the ALTITUDE seems to confirm previous concerns about the safety of the dual pharmacological blockade of the renin-angiotensin system in these patients. Aliskiren is a well-tolerated antihypertensive drug that may help to achieve the recommended targets of BP control.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Costs; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects.. This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions.. Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin-angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Treatment Outcome

Aliskiren is a novel antihypertensive agent and the first direct renin inhibitor (DRI) in clinical use. Several clinical trials have compared DRI with angiotensin receptor blockers (ARBs) in the management of essential hypertension. However, systematic comparison of efficacy and safety between DRIs and ARBs is still lacking. We reviewed randomized controlled trials (RCTs) comparing aliskiren with ARBs for net reduction of blood pressure from baseline, achieved rate of control, and incidences of common and serious adverse events. Weighted mean differences (WMD) and relative risk (RR) with 95% confidence intervals (CI) were calculated for continuous and dichotomous data, respectively. Seven RCTs with 5488 patients were included in this meta-analysis. We compared the efficacy of aliskiren and ARBs in reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP). No differences were found between the two groups. Aliskiren combined with ARBs was superior to aliskiren monotherapy at the maximum recommended dose on SBP and DBP reduction. (WMD -4.80, 95% CI -6.22-- -3.39, p < 0.0001; WMD -2.96, 95% CI -4.63-- -1.28, p = 0.0001; respectively). Similar results were found with aliskiren combined with ARBs versus ARB monotherapy (WMD -4.43, 95% CI -5.91-- -2.96, p < 0.0001; WMD -2.40; 95% CI -3.41-- -1.39, p < 0.0001; respectively). No differences were found in adverse events between the aliskiren and ARB groups. Similar results were found with aliskiren and ARB combination therapy and its respective monotherapy. We conclude that aliskiren's BP-lowering capabilities were comparable to those of ARBs. Aliskiren and ARB combination therapy provided more effective BP reduction than each respective monotherapy without increasing adverse events.

Topics: Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Aliskiren, a drug which inhibits the initial and rate-limiting step of the renin angiotensin aldosterone system (RAAS), recently approved for the treatment of hypertension, may become a reasonable therapeutic choice in a broad number of clinical conditions sharing an increased cardiovascular risk, where the inhibition of the RAAS has been shown to be beneficial.. The present review summarizes the pharmacokinetic and pharmacodynamic properties of aliskiren along with the clinical trials that took into account the effects of aliskiren on blood pressure control and on a number of renal and cardiovascular end points. The specific effects of aliskiren on different populations (e.g., elderly hypertensives, patients with diabetes and hypertension, patients with hypertension and renal impairment) are discussed.. The review discusses the most recent discoveries of the cardiovascular and renal effects of aliskiren, including a comprehensive discussion of the ongoing trials and of the areas of remaining uncertainty.. Aliskiren is a promising drug that may become a convenient choice in several clinical conditions. The full spectrum of the beneficial effects of aliskiren will be fully elucidated when the results of the large ongoing trials become available.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Drug Evaluation; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Hypertension is one of the most important risk factor and cause of cardiovascular diseases (CVD). Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors such aliskiren offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity; by contrast, ACEI and ARBs increase plasma renin activity. The efficacy of aliskiren in the reduction of major clinical events is being tested in large ongoing clinical trials. This review examines the efficacy, safety, and tolerability of aliskiren, and considers the evidence for the potential organ protection benefits of this treatment.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Heart; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Aliskiren, a newly discovered renin inhibitor, blocks the renin-angiotensin system (RAS) from the top of the enzyme cascade and therefore, might provide comparable or even superior clinical efficacy of blood pressure (BP) control than angiotensin receptor blockers (ARBs). With this meta-analysis, we aimed to compare the efficacy and tolerability of aliskiren and ARBs in the treatment of hypertension in the short-term treatment period.. Reports of randomized controlled trials (RCTs) comparing aliskiren and ARBs in patients with hypertension were selected by a search of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. The main outcome measures were reduction in diastolic BP (DBP) and systolic BP (SBP) and rates of therapeutic response and BP control. We also compared the tolerability of aliskiren and ARBs. Revman v5.0 was used to obtain the pooled estimates.. We analyzed data from 10 reports of trials involving 3,732 participants. DBP and SBP reduction did not differ between aliskiren and ARBs (weighted mean difference (WMD), -0.18; 95% confidence interval (CI), -1.07 to 0.71, and WMD, 0.15; 95% CI, -1.38 to 1.69, respectively). Aliskiren and ARB treatment did not differ in rates of BP control or therapeutic response. Moreover, aliskiren and ARB treatment led to a similar number of adverse events, severe adverse events, and withdrawal due to adverse events.. Aliskiren is as effective as ARBs (losartan, valsartan, and irbesartan) in controlling BP and does not differ from ARBs in risk of adverse events.

Topics: Amides; Angiotensin Receptor Antagonists; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic

Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.. We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.. We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).. In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Research Design; Treatment Refusal

Optimal antihypertensive therapy requires a multimodal approach based on lifestyle modification and, for most individuals, combination drug therapy. Recommendations from experts suggest that a combination of an agent that blocks the renin-angiotensin system (RAS), together with a vasodilator (generally a calcium-channel blocker or a thiazide-type diuretic), is most likely to control blood pressure and provide the widest overall cardiovascular protection. Understanding the opportunities afforded by the combination of RAS blockade with a calcium-channel blocker requires a discussion of basic and clinical science data. One new concept is that of 'global' or total RAS blockade. The impact of the RAS can be diminished or blocked by several different classes of drugs (central sympatholytics, β-blockers, renin inhibitors, ACE inhibitors or ARBs); what is most important is how effectively the overall impact of angiotensin II is blunted. A second new concept is that the complementary actions of RAS blockers and calcium-channel blockers are best explained on the basis of diminished intracellular calcium availability in excitable tissue (sympathetic neurons and vascular smooth muscle cells) via parallel actions that reduce angiotensin II type-1 receptor stimulation and L-channel-mediated calcium flux. Aliskiren is the first of the direct renin inhibitors, the newest subclass of RAS blockers. In both short- and long-term studies, aliskiren has been shown to be similar in efficacy and tolerability compared with other RAS blockers, with the added benefit that its effects persist longer. Outcome studies with aliskiren are currently underway.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Treatment Outcome

Topics: Amides; Amlodipine; Animals; Drug Approval; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Tablets; United States

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Hypertension, Pregnancy-Induced; Pregnancy

To provide an educational update for the nurse practitioner (NP) on the care of patients with hypertension, particularly in high-risk populations. Barriers to reaching blood pressure goals are reviewed in the context of identifying and addressing the sequelae of uncontrolled hypertension. Available antihypertensive agents are reviewed, including a description of direct renin inhibition with aliskiren, the newest agent and antihypertensive class available. Treatment recommendations are discussed in light of recent clinical trial data demonstrating improved cardiovascular (CV) outcomes, including myocardial infarction, stroke, and death.. Clinical studies and state-of-the-art articles indexed on PubMed. Current hypertension guidelines provide detailed management strategies, particularly for patients at high risk for CV events. NPs may help improve CV outcomes through careful diagnosis, risk stratification, and disease management, including improved patient education of the benefits of rational and sustained management of hypertension.. Early diagnosis, evidence-based treatment, and ongoing disease management of hypertension can be expected to improve CV outcomes. Treatment initiation with combination therapy, preferably with single-pill combinations that incorporate an agent that modulates the renin-angiotensin-aldosterone system, provides an approach that is safe, effective, and well tolerated and which can be tailored to the needs of the individual patient.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Practice Guidelines as Topic; Renin; Renin-Angiotensin System; United States

In the current context of renin-angiotensin-aldosterone system (RAAS) blockade, angiotensin (Ang) converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), or their combination, have proved to be effective in providing cardiovascular and renal protection. However, renin inhibition has long been recognized as the preferred site for blockade of the RAAS because renin represents the first, highly-regulated and rate-limiting step of the system. Up to now, the first orally active renin inhibitors initially tested in humans did not meet the necessary all the criteria (specificity, potency, and pharmacokinetic profile) to become clinically useful drugs. The synthesis of aliskiren, a potent alkane carboxamide renin inhibitor, now provides an orally active compound which, according to its pharmacological profile in normotensive subjects and in patients with hypertension, diabetic nephropathy or heart failure suggests that this drug may be of value for the treatment of patients with cardiovascular and renal disorders. However, long-term studies are needed to demonstrate the efficacy of aliskiren in these clinical settings. The results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Disease Endpoints (ALTITUDE) trial which has already included 8600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk and compared the effects of aliskiren vs. a placebo on a composite endpoint including renal and cardiovascular morbidity and mortality should be provided in 2012.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

While it may seem at first that antihypertensive drug combinations run counter to the desire to 'personalize' the management of hypertension, the best combinations have predictable efficacy in different individuals and subpopulations. Race is probably not a valid surrogate for clinically meaningful genetic variation or guide to therapy. Most guidelines suggest similar blood pressure goals for different races but drug treatment recommendations have diverged. In the United States, race is not considered to be a major factor in drug choice, but in England and other countries, initial therapy with renin-angiotensin system blocking drugs is not recommended in Blacks. In this review we: (1) examine new trends in race-based research; (2) emphasize the weaknesses of race-based treatment recommendations; and (3) explore the effects of a new combination, renin inhibition (aliskiren) and amlodipine, in African Americans.

Topics: Amides; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Patient Selection; Practice Guidelines as Topic; Precision Medicine; Treatment Outcome; United States

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

Topics: Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Fumarates; Humans; Hypertension; Myocardial Infarction; Neoplasms

Combinations of the direct renin inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from 9 short-term (8-week) and 4 longer-term (26- to 52-week) randomized controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared with component monotherapies. In short-term studies, overall AE rates were similar for patients receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2%-39.8%) and those receiving the component monotherapies (30.0%-39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients taking combination therapies vs monotherapy. The safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic, is similar to aliskiren, ARBs, or diuretics alone.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Sodium Chloride Symporter Inhibitors; Treatment Outcome

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Renin

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Aliskiren, the sole oral renin inhibitor approved by the US Food and Drug Administration, is indicated for the treatment of hypertension, either as monotherapy or in combination, with reductions in blood pressure similar to other agents. •  Early evidence suggests that aliskiren confers additional benefit in patients with diabetic nephropathy. Data are not yet available to determine whether protection will extend to cardiovascular disease. •  No initial dosage adjustment is required in elderly patients or for patients with mild to severe renal impairment; however, clinical experience is limited in patients with significant renal impairment, and with renal artery stenosis. •  It appears rational to combine aliskiren with agents that otherwise increase plasma renin activity, including thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. •  While there is a reactive rise in renin in response to aliskiren, probably larger than that induced by angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, there is no evidence that this rise is harmful. •  In placebo-controlled studies, the incidence of edema anywhere in the body was 0.4% with aliskiren compared with 0.5% with placebo. It is unknown whether angioedema rates are higher in blacks with aliskiren. •  Aliskiren is associated with a slight increase in cough, with rates of about one third to one half seen with angiotensin-converting enzyme inhibitors. •  Increases in serum potassium >5.5 meq/L were infrequent in patients with essential hypertension treated with aliskiren alone (0.9% compared with 0.6% with placebo).

Topics: Amides; Antihypertensive Agents; Cough; Edema; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Nowadays, social and economic burden related to cardiovascular and renal diseases still remains extremely high, although there has been a dramatic improvement of diagnostic options and therapeutic strategies reported in the last 30 years. The progressively higher attention towards integrated pharmacological strategies, which are able to interfere with different pathophysiological mechanisms, has certainly led to better control of cardiovascular and renal diseases. In view of the large involvement of the renin-angiotensin system (RAS) in the vast majority of pathophysiological mechanisms leading to the development and progression of cardiovascular and renal diseases, it can be easily understood why it has been long viewed as the 'ideal' target for the pharmacological treatment of several clinical conditions. Recently, besides the well known therapeutic approaches for RAS blockade, based on the use of ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and aldosterone antagonists, both the scientific and medical community have focused their attention on a novel therapeutic option. In 2007, aliskiren, the first compound of a new drug class, the direct renin inhibitors (DRIs), has become available for clinical use, being a novel and innovative therapeutic option. Aliskiren is able to interfere with the enzymatic activity of renin by blocking the catalytic site of the molecule and inducing an 'upstream' RAS blockade. This leads to a modulation of the biological properties of renin, thus resulting in the missed cleavage of angiotensinogen to angiotensin I. Aliskiren has demonstrated antihypertensive efficacy comparable or even superior to that of other classes of antihypertensive drugs, both in monotherapy and in combination therapies. Its safety and tolerability are comparable with those of other antihypertensive drug classes and almost similar to placebo. In addition, it has been demonstrated to reduce progression of cardiac and renal organ damage in addition to ACE inhibitors or ARBs. An ambitious and large clinical trial programme specifically designed for this innovative antihypertensive drug will evaluate the efficacy of aliskiren in terms of reduced incidence of major cardiovascular and renal outcomes in patients with hypertension and cardiovascular disease, besides the use of optimal (standard) therapeutic strategies, including ACE inhibitors and ARBs.

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus; Diffusion of Innovation; Drug Design; Fumarates; Heart Diseases; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System; Translational Research, Biomedical

Hypertension (HTN) affects an estimated 76.4 million US adults. Despite improvements in blood pressure (BP) control rates and the availability of effective antihypertensive agents, only 50% of these individuals achieve BP control. It is now recognized that many patients will require ≥ 2 antihypertensive agents to achieve BP control. Both the current US and reappraisal of the 2007 European guidelines include dual-combination regimens among recommended treatments for initial HTN therapy. For patients requiring 3 drugs, the combination of agents with complementary mechanisms of action (ie, renin-angiotensin-aldosterone system blocker, calcium channel blocker, and diuretic) has been recognized as rational and effective. Three single-pill triple-drug combinations have recently been approved for use in HTN in the United States: valsartan (VAL)/amlodipine (AML)/hydrochlorothiazide (HCTZ); olmesartan medoxomil (OM)/AML/HCTZ; and aliskiren (ALI)/VAL/HCTZ. Triple-combination regimens have resulted in a greater proportion of patients achieving BP control compared with dual-combination regimens, with significantly lower BP levels documented after only 2 weeks at maximum doses. Single-pill combinations offer convenience to address barriers to BP control such as poor adherence to therapy and therapeutic inertia. Additional benefits of combining antihypertensive agents from different classes include improved efficacy, safety, and reduction of cardiovascular risk. In patients with essential HTN for whom dual therapy is inadequate, single-pill triple-drug therapy can offer a simplified and effective treatment strategy.

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Drug Design; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Medication Adherence; Olmesartan Medoxomil; Practice Guidelines as Topic; Practice Patterns, Physicians'; Tetrazoles; Valine; Valsartan

Angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics all cause reactive rises in plasma renin concentration, but particularly high levels have been reported with aliskiren. This prompted speculation that blockade of plasma renin activity with aliskiren could be overwhelmed, leading to paradoxical increases in blood pressure. This meta-analysis of data from 4877 patients from 8 randomized, double-blind, placebo- and/or active-controlled trials examined this hypothesis. The analysis focused on the incidence of paradoxical blood pressure increases above predefined thresholds, after > or =4 weeks of treatment with 300 mg of aliskiren, angiotensin receptor blockers (300 mg of irbesartan, 100 mg of losartan, or 320 mg of valsartan), 10 mg of ramipril, 25 mg of hydrochlorothiazide, or placebo. There were no significant differences in the frequency of increases in systolic (>10 mm Hg; P=0.30) or diastolic (>5 mm Hg; P=0.65) pressure among those treated with aliskiren (3.9% and 3.1%, respectively), angiotensin receptor blockers (4.0% and 3.7%), ramipril (5.7% and 2.6%), or hydrochlorothiazide (4.4% and 2.7%). Increases in blood pressure were considerably more frequent in the placebo group (12.6% and 11.4%; P<0.001). None of the 536 patients with plasma renin activity data who received 300 mg of aliskiren exhibited an increase in systolic pressure >10 mm Hg that was associated with an increase in plasma renin activity >0.1 ng/mL per hour. In conclusion, the incidence of blood pressure increases with aliskiren was similar to that during treatment with other antihypertensive drugs. Blood pressure rises on aliskiren treatment were not associated with increases in plasma renin activity. This meta-analysis found no evidence that aliskiren uniquely causes paradoxical rises in blood pressure.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Renin; Treatment Outcome

Arterial hypertension is an important risk factor for the development and progression of cardiovascular disease (CVD). The renin angiotensin aldosterone system (RAAS) plays a crucial role in the pathophysiology of hypertension and associated complications. Direct renin inhibitors (DRIs) are novel antihypertensive drugs which inhibit the first step of RAAS. Aliskiren is the first orally active DRI approved as monotherapy or in combination with other antihypertensive agents for the treatment of hypertension.. This article reviews the efficacy and safety of aliskiren as monotherapy and in combination with other antihypertensive agents and comments on its potential role in clinical practice.. Relevant articles were identified through a PubMed search (up to 17 August 2009).. Aliskiren, used alone or in combination with other antihypertensive agents, has a favourable effect on blood pressure (BP). Specifically, aliskiren is equally effective with other RAAS inhibitors and probably superior to hydrochlorothiazide in the reduction of systolic and diastolic BP. The combination of aliskiren with other antihypertensive drugs seems to be an effective and safe therapeutic option. In addition, aliskiren may have favourable effects in terms of ameliorating several microvascular and macrovascular complications of hypertension and diabetes.. Aliskiren appears to be an effective and safe antihypertensive drug. Whether the BP lowering effect of aliskiren is associated with improvements in cardiovascular outcomes remains to be elucidated.

Topics: Amides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Signal Transduction; Treatment Outcome

Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP) ≥95 and <110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; P<0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose-dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Renin; Sex Factors; Time Factors; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren - alone or in combination - might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.. Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 - 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.. An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.. The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi-ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Design; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Male; Rats

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Humans; Hypertension; Kidney Diseases; Prorenin Receptor; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System

Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the 'escape' phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete 'upstream' inhibition of the renin-angiotensin-aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13-17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.

Topics: Aging; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Fumarates; Half-Life; Humans; Hypertension; Ramipril; Renin-Angiotensin System

ACE inhibitors and angiotensin receptor blockers confer renal protection in proteinuric nephropaties, but recently worsening of renal outcomes has been reported in non-proteinuric patients treated with a combination of ramipril and telmisartan, compared to ramipril only. In view of these apparently contradictory data, the review wants to shed light on treatment modalities of patients with hypertension and chronic kidney disease.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diuretics; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Failure, Chronic; Meta-Analysis as Topic; Natriuresis; Proteinuria; Randomized Controlled Trials as Topic; Water-Electrolyte Imbalance

Hypertension is the most prevalent and important risk factor for cardiovascular and renal disease worldwide. Despite the large armamentarium of available blood pressure-lowering agents, the need remains for safer and more effective antihypertensive treatment. Based on current target levels of < 140/90 mm Hg, only one-third of hypertensive Americans have achieved goal blood pressure. Several strategies can help address these challenges, including increasing public awareness, and improving physician awareness of evidence-based therapeutic guidelines. There also remains a need for new therapeutic options. This review examines new developments among those agents having inhibitory activity on the renin-angiotensin-aldosterone system (RAAS). All currently available RAAS blockers cause a reactive increase in plasma renin concentration. However, the direct renin inhibitors are the only class that diminishes plasma renin activity, an effect that may provide additional cardiovascular and/or renoprotective benefit. Aliskiren is the first clinically available direct renin inhibitor that has been shown to be effective and well tolerated both as monotherapy and in combination with other established agents in hypertensive patients. Randomized clinical trials are underway to explore the extent to which direct renin inhibition provides additive protection against cardiovascular and renal disease events.

Topics: Aged; Amides; Antihypertensive Agents; Diabetes Complications; Drug Therapy, Combination; Fumarates; Healthy People Programs; Heart Failure; Humans; Hypertension; Middle Aged; Obesity; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) is a major factor for the development and maintenance of hypertension and a major cause for cardiovascular remodeling and cardiovascular complications through its active peptide angiotensin (Ang) II. Blockade of RAAS with ACE inhibitors (ACEIs) results in suppression of Ang II levels, which eventually return to baseline levels after prolonged ACEI administration. This leads to an escape phenomenon through generation of Ang II from enzymes other than ACE and led to the hypothesis that dual blockade of RAAS with an ACEI/Ang receptor blocker (ARB) combination could lead to total blockade of RAAS, since ARBs block the action of Ang II at the AT1 receptor level, irrespective of the mechanism of Ang II generation and will have an additive blood pressure (BP)-lowering effect. However, this hypothesis has not materialized clinically, as the ACEI/ARB combination produces modest BP reductions that are not significantly greater than monotherapy with the component drugs, and is frequently associated with higher incidence of side effects. A new dual RAAS blockade with the direct renin inhibitor aliskiren and the ARB valsartan produces greater BP reductions than monotherapy with the component drugs and is safe and well tolerated. The combination of aliskiren with valsartan, and with other antihypertensive drugs is discussed.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure and mediator of hypertension-related complications, is a prime target for cardiovascular drug therapy. Angiotensin-converting enzyme inhibitors (ACEIs) were the first drugs to be used to block the RAAS. Angiotensin II receptor blockers (ARBs) have also been shown to be equally effective for treatment. Although these drugs are highly effective and are widely used in the management of hypertension, current treatment regimens with ACEIs and ARBs are unable to completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior than to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes, but dual RAAS blockade with the combination of an ACEI and an ARB is sometimes associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The recent introduction of the direct renin inhibitor, aliskiren, has made available new combination strategies to obtain a more complete blockade of the RAAS with fewer adverse events. Renin system blockade with aliskiren and another RAAS agent has been, and still is, the subject of many large-scale clinical trials and furthermore, is already available in some countries as a fixed combination.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Hypertension is one of the most important risk factors and causes of cardiovascular disease (CVD). From some years, renin-angiotensin-aldosterone system (RAAS) inhibitors such angiotensin converting enzyme (ACE) and angiotensin receptor blockade (ARB) have been of interest, not only for better blood pressure (BP) control but also for their involvement in the mechanisms of various organ functions.. The aim of this review is to focus on the effectiveness and safety of aliskiren beyond the treatment of hypertension.. Aliskiren, the first approved renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic non-peptide molecule that blocks angiotensin I generation. Because of its mechanism of action, aliskiren may offer the additional opportunity to inhibit progression of atherosclerosis at tissue level and the potential to be useful in a wide spectrum of conditions. However, we will discuss how it might become a reasonable therapeutic choice also in a broad number of clinical conditions, sharing an increased cardiovascular risk as stable coronary artery disease (CAD), microvascular and cardio-renal disease, diabetes, and peripheral arterial disease (PAD).. Therapy of hypertension through a better blockade of RAAS may be the first step in also achieving interesting results in the complications that hypertension causes in several organs.

Topics: Amides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Disease Progression; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Rats; Renin; Renin-Angiotensin System

Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS) are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA), a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI) to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic

Aliskiren, the first orally active direct renin inhibitor, is an effective antihypertensive drug with distinctive characteristics, including good blockade of the renin-angiotensin system, a prolonged duration of action, pharmacologic effects that persist after drug discontinuation, and favorable tolerability comparable with placebo. The blood pressure-lowering effect of aliskiren monotherapy is similar, if not superior, to that of other first-line antihypertensive agents, and is greatly enhanced when aliskiren is combined with various other antihypertensive medications, without any adverse drug interactions. Aliskiren is also an effective and well tolerated therapy in special populations, including diabetic, obese, and elderly hypertensives. Beyond its blood pressure-lowering efficacy, results from experimental and clinical trials suggest that aliskiren has positive effects on markers of cardiovascular and renal damage. The ASPIRE (Aliskiren Study in Post-MI patients to Reduce rEmodelling) HIGHER clinical trials program is further assessing whether the promising pharmacologic properties of aliskiren translate into reduced risk of adverse cardiovascular and renal outcomes.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Agents that block the renin-angiotensin-aldosterone system (RAAS) are the cornerstones of antihypertensive therapy in patients at high risk for cardiovascular or renal disease. Recently, it was shown that activation of RAAS may occur through alternate pathways not inhibited by angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs), and that ACEIs, ARBs, or MRAs may actually cause a reactive increase in plasma renin concentration and activity. While these agents, alone or in combination, decrease blood pressure and cardiovascular events to varying degrees, the direct renin inhibitor is a new class of RAAS blocking agent. Aliskiren is the first US Food and Drug Administration-approved direct renin inhibitor with good oral bioavailability. ASPIRE HIGHER is an ongoing series of clinical trials designed to investigate the effect of aliskiren on cardiovascular/renal surrogate endpoints and morbidity/mortality in patients with hypertension and high risk for cardiovascular or renal disease.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biological Availability; Fumarates; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System

The paper covers current problems in the treatment of arterial hypertension. Renin is an important and promising therapeutic target. The direct renin inhibitor aliskiren (Rasilez) is a promising current effective antihypertensive agent that has cardio- and nephroprotective effects. The paper considers a number of clinical studies that have proven the antihypertensive effect of aliskiren and revealed its benefits versus other drugs recommended for blood pressure lowering. It is assumed that this agent may be used in combinations with angiotensin-converting enzyme inhibitors, thiazide or thiazide-like diuretics, and calcium antagonists. Moreover, aliskiren neutralizes the effect of feedback in the compensatory increase in the activity of plasma renin.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Reninangiotensinaldosterone system is a key link in regulation of blood pressure and causes the target organ damage in hypertensive patients. For many years is not lost interest in the pharmacological blockade of RAAS in order to achieve target levels of BP and prevent damage target organs, particularly kidneys. Most recently recommended for clinical application of direct rennin inhibitor--aliskiren, a number of researcher have proven expressed nephroprotective effect. However, at present there is no unequivocal answer to the question whether there are advantages in combined RAAS blockade in hypertensive patients with use of aliskiren and angiotensinconverting enzyme inhibitor or angiotensin receptor blocker.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Kidney; Kidney Diseases; Renin-Angiotensin System

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) have been shown to be effective drugs in the management of hypertension and to have beneficial effects along the cardiovascular continuum. However, due to compensatory mechanisms, both of these types of agent increase plasma renin activity, which has been reported to have deleterious effects on patient outcomes. Aliskiren is the first nonpeptide orally administered direct renin inhibitor available on the market. Reported data have shown that aliskiren effectively reduces BP alone or in combination with other antihypertensive agents, and has a good tolerability profile. Moreover, this agent reduces plasma renin activity, which in theory could have additional clinical benefits. However, clinical trials analyzing the effects of aliskiren on mortality are still ongoing.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Suppressed baseline plasma renin activity (PRA) levels or large reactive increases in renin secretion are two possible reasons for treatment failure with antirenin system drugs.. To investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren.. Aliskiren failed to lower systolic blood pressure (SBP) by at least 10 mm Hg in half of all patients. It was very effective in two-thirds of medium- to high-renin patients (-19 mm Hg). But BP did not fall in most low-renin patients, or in 30% of medium- to high-renin patients. BP actually rose by >10 mm Hg in 5% of patients taking aliskiren and in >10% of patients when aliskiren was added to an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI). PRA changed in parallel with BP. Although PRA fell in most patients, it actually rose in 5% and in up to 30% when aliskiren was added to an ARB or ACEI.. There are two reasons for treatment failure with aliskiren. Many hypertensive patients have large BP falls. But, BP does not fall in most low-renin patients or in medium- to high-renin patients whose PRA levels do not fall sufficiently. If the concept of that treatment resistance is caused by excessive reactive increases in renin secretion is confirmed, then a PRA determination during treatment could be used to guide subsequent addition or subtraction of either natriuretic or antirenin drug types, to thereby correct BP and reduce cardiovascular risk.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin; Treatment Failure

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966-March 2008), EMBASE (1988-March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, -2.9 (-4.6, -1.3)/-2.3 (-3.3, -1.3) mm Hg; aliskiren 150 mg, -5.5 (-6.5, -4.4)/-3.0 (-3.7, -2.3) mm Hg; aliskiren 300 mg, -8.7 (-9.7,-7.6)/-5.0 (-5.6, -4.3) and aliskiren 600 mg, -11.4 (-13.5, -9.2)/-6.6 (-7.9, -5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP -3.0 (-4.0, -2.0) and DBP -1.7 (-2.3, -1.0) as compared to aliskiren 150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Blood Pressure; Cough; Dose-Response Relationship, Drug; Fumarates; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Treatment Outcome; Young Adult

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Complications; Drug Approval; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; United States

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Proteinuria; Treatment Outcome

Diabetes mellitus is an independent risk factor for cardiovascular disease (CVD) and current opinion holds that hyperglycemia directly damages smaller blood vessels, resulting in microvascular complications of nephropathy, retinopathy, and neuropathy. In a patient with diabetes, hypertension compounds and greatly increases the risk of microvascular complications, and thus the risk of end-stage kidney disease, vision loss, and nontraumatic limb amputations. Hypertension and hyperglycemia directly damage the microvasculature, leading to small vessel dysfunction that manifests as the clinical disease states of diabetic retinopathy and nephropathy. Early recognition and treatment of both hyperglycemia and hypertension may prevent vision loss and chronic kidney disease, the devastating outcomes of these microvascular complications. One of the pathogenic mechanisms for microvascular dysfunction is upregulation of the angiotensin II type 1 receptor, the most physiologically common receptor for the vasoconstrictor properties of angiotensin II. In patients with diabetic retinopathy and nephropathy, tight control of blood pressure (BP) (< 130/80 mm Hg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. Aggressive treatment with 2 or more antihypertensive agents, selected from different drug classes, is often needed to reach the optimal BP target level. A PubMed search was conducted to identify randomized controlled trials that evaluated hypertension control and microvascular outcomes in patients with diabetes. Several clinical trials have yielded promising data with renin-angiotensin-aldosterone system (RAAS) inhibitors (the direct renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). Attainment of BP control with RAAS inhibitors reduces the risk for CVD, nephropathy, and retinopathy. In addition, RAAS inhibitors have demonstrated renoprotective effectiveness independent of the BP reduction achieved. This review will examine the results of clinical trials in the context of BP control, diabetes, and the microvascular complications of retinopathy and nephropathy.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Microvessels

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin; Renin-Angiotensin System; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

Aliskiren is the first direct renin inhibitor for the treatment of hypertension. Clinical experience from studies in over 14,000 patients has shown that aliskiren, alone or in combination with other antihypertensive therapies, provides effective blood pressure lowering with a good safety and tolerability profile.The ultimate aim of antihypertensive therapy, however, is to reduce the risk of adverse cardiovascular and renal outcomes.The effect of aliskiren on surrogate markers of organ damage and clinical outcomes is being assessed in the ongoing ASPIRE HIGHER programme, the largest clinical trials programme in the cardio-renal disease area. Results from the ALOFT, AVOID and ALLAY studies suggest that aliskiren has positive effects on markers of cardiovascular and renal damage in patients with type 2 diabetes and nephropathy, heart failure and left ventricular hypertrophy.ASPIRE HIGHER also includes four large-scale studies assessing the potential outcome benefits of aliskiren, and the results of these trials will help define the clinical utility of aliskiren in the treatment of cardiovascular and renal diseases. In this article, we review the antihypertensive efficacy of aliskiren and explore its potential in the management of cardiovascular and renal risk.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Renin; Renin-Angiotensin System

The overall purpose of hypertension treatment is 2-fold. First, patients often have symptoms that are related to their high blood pressure and although subtle in many instances may be improved dramatically by blood pressure control. The main reason for blood pressure treatment, however, is to reduce the burden of cardiovascular complications and end organ damage related to the condition. This may be considered the ultimate goal of blood pressure treatment. In this respect, actual blood pressure measurements may be seen as surrogate end points as the organ protective effects of two antihypertensive agents may differ significantly even though their blood pressure lowering effects are similar. Thus beta-blockers, once seen as first-line treatment of hypertension for most patients, now are considered as third- or fourthline agents according to the latest NICE guidelines (National Institute for Health and Clinical Excellence, www.nice.org.uk/CG034). On the other hand, agents that inhibit the activity of the renin-angiotensin-aldosterone system (RAAS) system are being established as safe, effective and end organ protective in numerous clinical trials, resulting in their general acceptance as first-line treatment in most patients with stage 2 hypertension. This shift in emphasis from beta-blockers and thiazide diuretics is supported by numerous clinical trials and has proven safe and well tolerated by patients. The impact of this paradigm shift will have to be established in future long-term randomized clinical trials. The optimal combination treatment with respect to end organ protection has yet to be determined. Most combinations will include either a RAAS active agent and calcium channel blocker or two separate RAAS active agents working at different levels of the cascade. In this respect direct renin inhibitors and angiotensin receptor blockers seem particularly promising but the concept awaits evaluation in upcoming randomized clinical trials. Although safety data from the randomized clinical trials to date have been promising, we still lack data on the long-term effect of aliskiren on mortality and there still are patient groups where the safety of aliskiren is unexplored.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin-Angiotensin System; United States

The number of well-controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti-remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate-binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high-risk hypertensives, for hypertensives with LVH, and possibly for high-risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin-angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events.

Topics: Amides; Animals; Antihypertensive Agents; Chronotherapy; Circadian Rhythm; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Melatonin

Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high. For some years renin-angiotensin system inhibitors such as angiotensin-converting enzyme (ACE) and angiotensin receptor blockade have been objects of interest for treatment of cardiovascular disease. Aliskiren, the first approved renin inhibitor to reach the market, is a low molecular weight, orally active, hydrophilic nonpeptide molecule, which blocks angiotensin I generation. However it might also become a reasonable therapeutic choice in a broad number of clinical conditions, as stable coronary artery disease, cerebrovascular and cardiorenal disease, diabetes, and peripheral arterial disease. The aim of this review is to describe the effectiveness and safety of aliskerin in the treatment of hypertension.

Topics: Amides; Animals; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

Despite the last three decades of progress in improving cardiovascular outcomes via renin-angiotensin-aldosterone system (RAAS) blockade in hypertensive patients, substantial residual morbidity/mortality remains. Attempts to improve clinical outcomes by combining angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have yielded mixed results. Adverse effects of RAAS blockade with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may relate to compensatory increases in plasma renin activity (PRA). The first-in-class direct renin inhibitor, aliskiren, blocks the RAAS at its point-of-activation, suppressing PRA and attenuating increases associated with other antihypertensives. Aliskiren (with or without other agents) provides significant and prolonged blood pressure reductions in a broad range of hypertensive patients and is well tolerated. Initial results from organ-protection studies are promising. Long-term outcomes studies should yield valuable information regarding the significance of direct renin inhibition in clinical practice.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, the first orally effective direct renin inhibitor, is an effective antihypertensive agent with distinctive properties including placebo-like tolerability, pharmacologic effects that persist after drug discontinuation, and a unique mechanism of action. When combined with agents that inhibit the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, additional blood pressure reduction reflects more complete RAAS blockade. Concern that marked elevation in plasma renin concentration following aliskiren administration might lead to RAAS-induced paradoxical blood pressure increases appears unfounded, based upon analyses of patients participating in clinical trials. Studies in animals and humans indicate that aliskiren accumulates in renal tissue, blocks the intrarenal RAAS, and interferes with deleterious cellular effects of angiotensin II by mechanisms that may include enzymatic blockade of renin and prorenin at the site of the (pro)renin receptor. In patients with diabetic nephropathy, adding aliskiren to losartan resulted in an additional 20% reduction in urinary protein excretion. In patients with heart failure, aliskiren reduced brain natriuretic peptide levels when added to other RAAS inhibitors, suggesting an additional hemodynamic effect. The ASPIRE HIGHER clinical trials program is assessing whether the promising pharmacologic properties of aliskiren translate into long-term clinical benefits.

Topics: Amides; Animals; Antihypertensive Agents; Disease Models, Animal; Fumarates; Humans; Hypertension; Rats; Renin

The renin-angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Fumarates; Heart Failure; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Psoriasis, a chronic common immune-mediated disease with frequent remitting/relapsing courses, has a high negative impact on the quality of life, especially in patients moderately or severely affected by the disease. It is also associated with various co-morbidities resulting in a decreased life expectancy and remarkable socioeconomic costs. At least one third of the patients who suffer from it has moderate or severe psoriasis and require continuous treatment to control disease activity. The therapeutic approach in daily practice is usually determined by the severity of the disease. Whether the definition of disease severity is not always clear, there is a considerable number of patients requiring systemic treatment to control the symptoms of psoriasis. The treatment options available for the management of moderate-severe psoriasis have dramatically increased over the past decade, and now range from phototherapy to traditional systemic treatments to biologics. Available data from clinical trials and growing number of patients treated with biologics shows that this new agent are effective and relatively safe to control psoriasis, and are coupled with improved tolerability, convenience and improvement in quality of life. This review shortly presents the characteristics, safety and efficacy profile of the conventional and newer systemic drugs used in moderate-to-severe psoriasis.

Topics: Abnormalities, Drug-Induced; Alefacept; Antibodies, Monoclonal; Clinical Trials as Topic; Contraindications; Cyclosporine; Etanercept; Female; Fumarates; Hematologic Diseases; Humans; Hypertension; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Male; Methotrexate; Photochemotherapy; Pregnancy; Pregnancy Complications; Psoriasis; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Retinoids; Severity of Illness Index; Tumor Necrosis Factor-alpha

Arterial hypertension is an independent risk factor for cardiovascular diseases and one of the major causes for mortality worldwide. Drugs, that control hypertension effectively are therefore needed to reduce hypertension induced morbidity and mortality. The inhibition of the renin-angiotensin-aldosterone-system (RAAS) is one target to control blood pressure in these patients. The new direct renin inhibitor aliskiren is one new substance on the market to inhibit the RAAS effectively by suppression of the plasma renin activity, which inhibits the RAAS at its rate-limiting step. Therefore, aliskiren in monotherapy and in combination might yield beneficial effects for the patients. Nevertheless, blood pressure lowering has to be combined with a reduction of target organ damage for all drug classes prescribed to patients with hypertension. Therefore, we review here the major effects of this new drug not only in regard to hypertension but also in regard to target organ damage reduction and possible changes in morbidity and mortality, which future trials will investigate.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biphenyl Compounds; Cardiovascular Diseases; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Europe; Fumarates; Germany; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Japan; Prevalence; Prorenin Receptor; Protein Precursors; Randomized Controlled Trials as Topic; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; World Health Organization

The three main causes of Chronic Kidney Diseases [CKD] are diabetes mellitus, chronic glomerulonephritis and hypertension. CKD is an increasing burden in the community as more patients fall prey to kidney failure. Both dialysis and renal transplantation are expensive modalities of treatment for end stage renal failure [ESRF]. Through the years many clinical trials have been performed to retard the progression of CKD to ESRF. Most of the trials focus on three main strategies which aim at renal retardation, namely, control of hypertension, treatment of proteinuria and control of hypercholesterolaemia. More recently, investigators have been exploring the role of high dose ARBs as well as the use of Aliskiren, a renin inhibitor. Early therapeutic intervention is necessary as it will contribute to better chances of minimising glomerular damage and in the case of some, even lead to the improvement of renal function with regression of glomerulosclerosis.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy, Combination; Fumarates; Humans; Hypercholesterolemia; Hypertension; Kidney Failure, Chronic; Losartan; Proteinuria; Renal Replacement Therapy

The importance of renin-angiotensin aldosterone system (RAAS) in cardiovascular and renal diseases has long ago been recognized. However despite the availability of many effective drugs, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, RAAS blockade is incomplete in several patients with consequent uncontrolled high blood pressure and not efficacy cardiovascular and renal protection. Aliskiren is a new renin inhibitor that block the RAAS at its origin. Recent studies suggest that Aliskiren reduces blood pressure, inhibits plasma renin activity and attenuates renal damage in diabetic patients with nephropathy. This review summarized the results of the more important studies performed in hypertensive and diabetic patients in which Aliskiren showed to be a safe and effective antihypertensive agent that can be used in monotherapy or in combination with other drugs to provide additional options to improve blood pressure control.

Topics: Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Tetrazoles; Valine; Valsartan

The renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA). This is the main point of action of aliskiren, making it completely different from ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. However, the question concerning its real role in the management of heart failure and its place in the existing therapeutic schemes with ACE inhibitors, ARBs, beta blockers and antagonists of aldosterone receptor, will be answered by numerous ongoing studies and clinical trials. Aliskiren shows renoprotective and antiproteinuric effects similar to those of ACE inhibitors and ARBs. The available results demonstrate that aliskiren provides a new approach to the antagonism of the RAS, offering possibilities of a more efficacious and effective treatment of hypertension, heart failure and proteinuria in diabetic patient.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin-Angiotensin System

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that

Topics: Administration, Oral; Amides; Antihypertensive Agents; Biological Availability; Drug Interactions; Fumarates; Humans; Hypertension; Renin

The US Food and Drug Administration's approval in March 2007 of aliskiren, the first commercially available direct renin inhibitor, for the treatment of hypertension met with great enthusiasm. Clinical trials have demonstrated it to be as effective as other commonly prescribed antihypertensive agents with few side effects. Preclinical studies in genetically manipulated rats have shown it to be effective in reversing angiotensin II-induced cardiac and renal damage. Despite the notable absence of human clinical data for this agent, many clinicians have touted aliskiren as the ideal agent to achieve additional suppression of the renin-angiotensin-aldosterone system (RAAS) as a means to reduce the morbidity and mortality of chronic diseases of the cardiovascular and renal systems. Clinical studies are ongoing and future studies are planned to prove its effectiveness in several chronic diseases known to be related to RAAS activation.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Drug Evaluation, Preclinical; Fumarates; Humans; Hypertension; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System

The direct renin inhibitor aliskiren has recently been approved for the treatment of hypertension in humans. The potential for these newer agents having an advantage over the existing renin-angiotensin-aldosterone system (RAAS) antagonists in the treatment of hypertension and related target organ damage has drawn the interest of several investigators. In this review, we discuss the potential advantages and disadvantages of this newest antihypertensive class over other available RAAS antagonists.. The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. These studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade.. The potential advantages and disadvantages of aliskiren therapy versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Risk Factors

Direct renin inhibitors such as aliskiren offer a novel way of treating hypertension and its co-morbidities, conditions with a considerable prevalence, morbidity, and mortality worldwide.. The burden of hypertension worldwide and the role of the renin-angiotensin-aldosterone system in this disease will be reviewed. Current treatments for hypertension and its co-morbidities that work by manipulating this system will be discussed. The development of, and clinical trials involving, direct renin inhibitors will be reviewed, with a focus on aliskiren.. PubMed was utilized to search the most recent literature on the topics of the renin-angiotensin-aldosterone system, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone and aliskiren.. The direct renin inhibitors, including aliskiren, are new agents with great promise for the treatment of hypertension and its co-morbid conditions, including renal and cardiovascular disease.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren is the first renin inhibitor to be licensed for use as an antihypertensive drug in both the United States and Europe. Opinions vary considerably concerning the future of aliskiren and renin inhibition. Some experts argue that renin inhibitors should only be prescribed when less expensive blockers of the renin-angiotensin system (RAS), with established effects on morbidity and mortality, are not tolerated or have failed to reduce blood pressure effectively. Others propose that because renin is a highly specific catalyst for the rate-limiting step of the RAS, renin inhibitors have the potential to supersede angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the preferred inhibitors of the cascade in patients with particular pathologies and/or genotypes. It has also been suggested that dual blockade of the RAS might be particularly advantageous. This review discusses the currently available evidence, and concludes with speculation concerning the future of direct renin inhibition.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

To systematically analyze the efficacy and safety of aliskiren for the treatment of hypertension in comparison to placebo, other monotherapy, and various combination therapies.. A PubMed database (1966-June 2008) search was conducted with aliskiren as a search term with limits of humans, written in English, and in title only. Phase III pivotal clinical studies retrieved by PubMed database and resources such as printed labeling, approval letter, pharmacology reviews, and medical reviews posted in Drug@FDA website were evaluated with regard to study design and outcomes of efficacy and safety.. Six Phase III pivotal clinical studies compared various doses of aliskiren to placebo and some studies compared aliskiren to treatment with other monotherapies or combinations. Aliskiren in doses of 300 mg showed a statistically significant reduction in both systolic and diastolic blood pressure versus placebo. Comparison to other antihypertensive treatments suggest that aliskiren doses of 150 and 300 mg may induce blood pressure changes similar to those seen with moderate doses of hydrochlorothiazide or angiotensin receptor blockers. Aliskiren in combination with angiotensin receptor blockers or hydrochlorothiazide showed additional blood pressure reduction only when higher doses of aliskiren were used. Aliskiren appears to be well tolerated, with diarrhea being the only statistically significant adverse event.. Aliskiren is a novel antihypertensive that exerts its effects through the direct inhibition of renin. Although the drug is well tolerated, its modest effects on blood pressure and the present lack of evidence of impact on objective cardiovascular outcomes appear to limit its utility in the general treatment of hypertension at this time.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase III as Topic; Diarrhea; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. The renin-angiotensin-aldosterone system is an important target site for five antihypertensive drug classes: beta blockers, renin inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs) and aldosterone inhibitors. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors prevent the formation of both angiotensin I and angiotensin II . Renin inhibitors do not affect kinin metabolism and may produce fewer adverse effects than ACE inhibitors such as dry cough or angioedema.. To quantify the dose-related blood pressure lowering efficacy of renin inhibitors versus placebo in the treatment of primary hypertension.. We searched the following databases for randomised, double blind, placebo-controlled trials of renin inhibitors: Medline (1966-March 2008), EMBASE (1988-March 2008), Cochrane CENTRAL, and bibliographic citations from retrieved references. No language restrictions were applied.. Study design had to meet the following criteria: double-blinded, placebo-controlled; random allocation to a specific dose of renin inhibitor group and parallel placebo group; duration of follow-up of at least three weeks.. Two reviewers independently extracted data and assessed trial quality using risk of bias tables. Disagreements were resolved by discussion or a third reviewer. Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5. Data for continuous variables were combined using a weighted mean difference method. Dichotomous variables were analysed using relative risk.. Six trials (N=3694) met the inclusion criteria for this review. Aliskiren was the only renin inhibitor studied in these studies. The meta-analysis shows that aliskiren has a dose-related both systolic/diastolic blood pressure lowering effect as compared to placebo: aliskiren 75 mg -2.9/-2.3 mmHg, aliskiren 150 mg -5.5/-3.0 mmHg, aliskiren 300 mg -8.7/-5.0, aliskiren 600 mg -11.4/-6.6 mmHg. Aliskiren 300 mg significantly lowered both SBP and DBP as compared to aliskiren 150 mg (SBP:-2.97 (95% CI -3.99, -1.95) and DBP: -1.66 (95% CI -2.32, -1.0). Aliskiren has no effect on blood pressure variability. No data was available to assess the effect of aliskiren on heart rate and pulse pressure. This review found weak evidence that with short- term use, aliskiren does not increase withdrawals due to adverse effects as compared to placebo.. Aliskiren has a dose-related blood pressure lowering effect better than placebo. This effect is similar to that determined for ACE inhibitors and ARBs.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

Arterial hypertension is one of the major risk factors for the development of cardiovascular diseases such as heart failure, ischemic heart disease, chronic kidney disease and cerebrovascular events. Adequate blood pressure control is vital for the management of patients with vascular disease. New therapeutic alternatives are appearing on the horizon to improve the degree of blood pressure control in these patients, such as direct renin inhibitors, beta-blockers with additional properties, carotid receptor- stimulating devices and vaccination against arterial hypertension. Direct renin inhibitors are a new family of antihypertensive drugs that have so far shown a good antihypertensive effect and an additive effect on reduction of proteinuria in patients with diabetic nephropathy. Recent meta-analyses suggest that betablockers used as first-line treatment for uncomplicated arterial hypertension could have a less beneficial effect on the development of cardiovascular disease than other antihypertensive drugs. However, the emergence of new subtypes of beta-blockers with other hemodynamic and metabolic properties could change this conception. Carotid receptor-stimulating devices and vaccination against arterial hypertension, although not totally new therapies, are being revitalized, with preliminary results that suggest that they could be used for the treatment of arterial hypertension in patients with a specific profile. Although scientifically stimulating, the long-term beneficial effects of these new therapeutic alternatives on target-organ protection still need to be confirmed.

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II; Antihypertensive Agents; Baroreflex; Carotid Sinus; Electric Stimulation Therapy; Electrodes, Implanted; Fumarates; Humans; Hypertension; Immunotherapy, Active; Oligopeptides; Randomized Controlled Trials as Topic; Renin; Vaccines, Synthetic

Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs) was recently approved for the treatment of hypertension. In this review, we discuss the history of the development of DRIs and available data regarding the effects of DRIs in the treatment of hypertension and related target organ damage.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Angiotensins; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Fifty years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its antihypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an angiotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Molecular Structure; Renin; Renin-Angiotensin System

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Dose-Response Relationship, Drug; Fumarates; Humans; Hypertension; Renin

Hypertension is a major risk factor for cardiovascular morbidity and mortality and currently has been estimated at 30% of the US population. Of these, only 36.8% have their blood pressure reduced to recommended levels of lower than 140/90 mmHg for uncomplicated hypertension, or less than 130/80 mmHg for patients with diabetes mellitus or renal disease. Since monotherapy controls blood pressure in less than 50% of treated hypertensive patients, combination therapy is often required to bring blood pressure to the recommended levels of the 7th Joint National Committee report. One of the most effective and widely used combinations is the combination of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with hydrochlorothiazide (HCTZ). Aliskiren, a new blocker of the renin-angiotensin system has been developed and approved by the US FDA on 18th January 2008 for the treatment of hypertension. Aliskiren is a direct inhibitor of renin, the rate-limiting enzyme for the production of angiotensin II, a powerful vasoconstrictive peptide. Several randomized clinical trials have demonstrated that aliskiren administered in single daily doses of 150, 300 or 600 mg alone and in combination with HCTZ 12.5 and 25 mg is effective in lowering blood pressure, and is safe and well tolerated. In this article, the pharmacokinetic and pharmacodynamic profile and the clinical application of aliskiren alone and in combination with HCTZ will be discussed.

Topics: Amides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Interactions; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Randomized Controlled Trials as Topic; Renin; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome; United States; United States Food and Drug Administration

The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Aliskiren is the first of a new class of antihypertensive agents known as renin inhibitors.. The goal of this article was to discuss the clinical pharmacology of aliskiren and its use in the management of hypertension, as well as potential uses in other cardiovascular disorders.. Peer-reviewed articles and abstracts were identified from the MEDLINE and Current Contents databases (both 1966-October 1, 2007) using the search terms aliskiren, drug interaction, pharmacokinetics, and pharmacology. Citations from available articles were reviewed for additional references. Abstracts presented at recent professional meetings were also examined.. Nine published clinical studies have evaluated the effect of aliskiren in lowering blood pressure in hypertensive patients, either alone or in combination with other antihypertensive agents. This review summarizes those studies. Patients treated with aliskiren had significantly lower blood pressure compared with patients with mild to moderate hypertension (systolic blood pressure [SBP] 140-180 mm Hg and diastolic blood pressure [DBP] 95-110 mm Hg) who received placebo. Aliskiren in doses of 75 to 300 mg daily produced reductions of SBP (-5.3 to -15.8 mm Hg) and DBP (-5.8 to -12.3 mm Hg); placebo produced reductions of SBP that ranged from -2.85 to -10.0 mm Hg and DBP reductions from -3.26 to -8.6 mm Hg (P < 0.05 in all studies between aliskiren and placebo). Aliskiren's blood pressure-lowering effect at doses of 75 to 300 mg daily was comparable to irbesartan 150 mg daily and valsartan 80 to 360 mg daily alone. When aliskiren was added to ramipril, hydrochlorothiazide, amlodipine, irbesartan, or valsartan, significant additive blood pressure-lowering effects were reported (P < 0.05 in all clinical trials). The total incidence of adverse events was similar to placebo and other comparative agents, including irbesartan, valsartan, losartan, ramipril, and hydrochlorothiazide. The overall adverse-event rates were 22%, 35% to 52%, 25% to 52%, 34% to 55%, and 33% to 52% for aliskiren 37.5, 75, 150, 300, and 600 mg, respectively. The most commonly reported adverse events included headache, dizziness, and fatigue. Studies with cardiovascular outcomes as end points have not been performed with aliskiren.. Aliskiren is an effective alternative agent for blood pressure management. Before aliskiren can be recommended as a routine first-line agent, however, clinical studies must explore if the blood pressure-lowering effect will translate into improvement in cardiovascular outcomes.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren, the first renin inhibitor with sufficient bioavailability for oral use, is now available to clinicians treating hypertension.. The novel mechanism by which aliskiren works was used to provide understanding of its therapeutic and adverse effects.. After reviewing physiology and preclinical studies, human studies of aliskiren in hypertension were reviewed. Effects of aliskiren on serum levels and enzymatic activity of renin were explored.. Aliskiren has antihypertensive efficacy similar to existing medications such as thiazide diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and can be used in drug combinations. Preclinical studies indicate possible cardioprotective and renoprotective effects, similar to other inhibitors of the renin-angiotensin cascade, but future studies are needed in humans.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Biological Availability; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

The first oral direct renin inhibitor, aliskiren, recently received approval for the treatment of hypertension. This article addresses the premise, promise, and potential limitations of this new class of renin-angiotensin system inhibitor. Although aliskiren adds to a list of more than 100 drugs approved for the treatment of hypertension, its introduction into clinical medicine is of particular interest because of the novel mechanism of action: inhibition of renin's catalytic activity, the most proximal and rate-limiting step in renin-angiotensin system activation. By producing more complete renin-angiotensin system inhibition than with existing agents, direct renin inhibitors may afford greater protection from hypertensive complications. Other potential advantages include additional blood pressure reduction when used in combination therapy, a placebo-like side-effect profile, avid renal concentration, and long duration of action. Potential limitations include modest levels of blood pressure reduction that are equivalent to but not greater than angiotensin receptor blockers, reduced gastrointestinal absorption with a high-fat meal, and large reactive increases in renin secretion--the functional importance of which is under intense investigation. The results of outcomes trials are eagerly awaited.

Topics: Administration, Oral; Amides; Blood Pressure Determination; Drug Approval; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Severity of Illness Index; Treatment Outcome; United States; United States Food and Drug Administration

Aliskiren, a renin inhibitor, is the first in a new class of drugs interfering with the renin angiotensin system. Aliskiren was approved by the US Food and Drug Administration (FDA) in March 2007, and in Europe in August 2007 for the treatment of hypertension (marketed as Tekturna and Rasilez, respectively). Several clinical trials demonstrated effective blood pressure reduction due to aliskiren treatment. Whether aliskiren exhibits morbidity and mortality benefits for patients beyond its blood pressure reduction capability, can only be judged after realization of comparative long-term clinical trials. Furthermore, it remains to be seen, whether the use of aliskiren will be indicated for treatment of additional diseases, as it was the case for other inhibitors of the renin angiotensin system. In fact, recent and ongoing clinical trials regarding heart failure and diabetic nephropathy demonstrated first beneficial effects of aliskiren in these conditions (reduction of urinary albumin/creatinine-ratio and NTproBNP, respectively).

Topics: Amides; Animals; Antihypertensive Agents; Cardiovascular Diseases; Contraindications; Fumarates; Gastrointestinal Diseases; Humans; Hypertension; Kidney Diseases; Renin

To review the safety, efficacy, pharmacology, pharmacokinetics, and drug interactions of aliskiren for the treatment of mild-to-moderate hypertension.. A literature search was conducted using MEDLINE (1966-January 2007), International Pharmaceutical Abstracts (1970-January 2007), and Cochrane database (2006) for the key words aliskiren or SPP100. References of selected articles were also reviewed. Abstract data were included only in the absence of significant published data.. Available English-language data from reviews, abstracts, and clinical trials were selected. For review of efficacy, randomized controlled trials were preferred.. Aliskiren is a renin inhibitor, the first in a new class of antihypertensives. As renin catalyzes the rate-limiting step of the renin-angiotensin system (RAS), renin inhibition may offer a theoretical advantage over other RAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In short-term clinical trials (< or =8 wk) of subjects with mild-to-moderate hypertension, single daily doses of aliskiren 150-300 mg produced significant systolic and diastolic blood pressure reduction similar to that achieved with ACE inhibitors and ARBs, with placebo-like tolerability, without an elevation in heart rate or evidence of tolerance.. Aliskiren appears to be a safe and effective treatment option in mild-to-moderate hypertension. Although long-term outcome data have not been published, aliskiren is a promising option for RAS inhibition.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Interactions; Fumarates; Humans; Hypertension; Renin

This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

Topics: Administration, Oral; Aldosterone; Amides; Angiotensin II; Animals; Antihypertensive Agents; Enzyme Activation; Enzyme Reactivators; Fumarates; Heart Failure; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Vasoconstrictor Agents

The previous dogma that the renin-angiotensin system exerts its effects entirely through angiotensin II is now under challenge as scientists explore the properties of the prorenin/renin receptor and start to study local vascular actions of renin independent of its production of angiotensin in the plasma. The demonstrated blood pressure effects of the first clinically developed renin inhibitor, aliskiren, have confirmed the validity of this new class of drugs. Future research, exploring effects on the renin-angiotensin system that perhaps cannot be provided by the currently used blockers of this system, will test whether enhanced clinical benefits might result from this new pharmacologic strategy in patients at risk of cardiovascular events.

Topics: Amides; Fumarates; Heart Failure; Humans; Hypertension; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is a potent, highly specific renin inhibitor with better oral bioavailability than earlier renin inhibitors and a long plasma half-life that makes it suitable for once-daily dosing. The efficacy and safety of aliskiren in treating hypertension has been studied in clinical trials both as monotherapy, comparing it with existing antihypertensive therapies, and in combination with other antihypertensive agents, including the diuretic hydrochlorothiazide, the angiotensin-converting enzyme inhibitor ramipril, and the calcium channel blocker amlodipine. From the extensive database acquired to date, it is clear that aliskiren is an effective antihypertensive agent, with once-daily administration resulting in dose-dependent systolic and diastolic blood pressure reductions. Combinations with existing antihypertensives are producing promising additional blood pressure-lowering effects.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Topics: Adult; Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

A review of six clinical trials of aliskiren involving >5,000 patients with mild to moderate hypertension indicated that this first of a new class of orally active antihypertensive drugs is no more effective than angiotensin-converting enzyme inhibitors (CEIs), angiotensin receptor blockers (ARBs), or diuretics for lowering blood pressure. The starting dose is 150 mg; 300 mg is usually more effective, but 600 mg is no better than 300 mg. Aliskiren in combination with a diuretic appeared to lower blood pressure more than an aliskiren-ARB combination, but still failed to control blood pressure (<140/90) in 50% of the patients. Although aliskiren suppresses plasma renin activity, it causes much greater reactive rises in plasma renin concentration than does any other antihypertensive class tested. Because aliskiren, like CEIs and ARBs, only blocks 90% to 95% of plasma renin, the pressor consequences of its greater reactive increases in plasma renin concentration appear to offset its net ability to lower blood pressure, especially with higher doses. Patients with hyperreactive renin systems (renovascular, advanced, and malignant hypertension) were excluded from all of the trials. Until the possibility is eliminated of inducing increases in blood pressure with aliskiren in patients with highly reactive renin levels, it seems safe and simple to stick to the less expensive, equally effective and widely available generic CEI drugs for treating the renin factor in hypertension.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Renin

The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable

Topics: Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Aliskiren (Tekturna) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5-25 mg/day, ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated. The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The first renin inhibitor, aliskiren, will soon enter the clinical arena. This review summarizes the potential differences between renin inhibitors and the currently existing blockers of the renin-angiotensin system (RAS) [ie, the ACE inhibitors and the angiotensin II type 1 (AT(1)) receptor antagonists], taking also into consideration the recently discovered (pro)renin receptor. This receptor not only activates the inactive precursor of renin, prorenin, but it also exerts direct renin/prorenin-induced effects, independently of angiotensin. The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Drug Delivery Systems; Fumarates; Humans; Hypertension; Prorenin Receptor; Receptors, Cell Surface; Renin; Renin-Angiotensin System

As an important cascade involved in the regulation of blood pressure and volume homeostasis, the renin-angiotensin system (RAS) has been targeted for blood pressure control. In the last decades, the most successful strategy to control the RAS has been the inhibition of the angiotensin-converting enzyme (ACE) and the angiotensin type 1 (AT(1)) receptor. Small-molecule inhibitors targeting these steps have been widely used clinically. However, complete inhibition of the RAS is not achievable by blocking the ACE or the AT(1) because of the compensatory rise in plasma renin activity, which limits the efficacy of many RAS drugs. Direct inhibition of renin, the first and rate-limiting step in the RAS cascade, is the preferred strategy for controlling the RAS, and much progress has been made in the research and development of renin inhibitors. This review covers the evolution of renin inhibitors and discusses the advantages of renin inhibition at the enzymatic and biosynthetic levels for blood pressure control.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies; Antihypertensive Agents; Blood Pressure; Drug Design; Enzyme Inhibitors; Fumarates; Humans; Hypertension; Molecular Structure; Peptides; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases; Vitamin D

The suppression of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been proven in many studies to treat hypertension and reduce cardiovascular events; however, reducing angiotensin I receptor stimulation results in the loss of the negative-feedback signal, leading to increased plasma renin activity. Numerous direct renin inhibitors were synthesized, but abandoned owing to low potency, poor bioavailability and short half-life. Aliskiren, a direct renin inhibitor of a novel structural class, inhibits the activity of the renin produced and, thus, its capacity to form angiotensin I, as measured by plasma renin activity. Aliskiren has been recently shown to be efficacious in hypertensive patients at once-daily oral dosing with favorable pharmacokinetics and the potential to improve end-organ protection.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Drug Interactions; Fumarates; Humans; Hypertension; Kidney; Renin; Renin-Angiotensin System

Despite the availability of many effective, well-tolerated drugs, a significant proportion of treated hypertensive patients still have uncontrolled high blood pressure (BP) and thus face serious morbidity and mortality. The renin-angiotensin aldosterone system (RAAS) is a key target for BP control and for cardiovascular and renal protection. Renin controls the rate-limiting step in the RAAS cascade and hence is the optimal target for RAAS suppression. Aliskiren is the first direct renin inhibitor (DRI) to be approved by the U.S. Food and Drug Administration and the European Medicines Agency for treating hypertension.. To provide an overview of the pharmacology, pharmacokinetics, preclinical, and clinical efficacy and safety data on the DRI aliskiren.. Approximately 70% of essential hypertension is associated with elevated renin levels. Aliskiren is a potent and highly specific inhibitor of renin, with oral bioavailability of 2.6% and an elimination half-life of 40 hours, making it suitable for once-daily oral administration. Aliskiren dose-dependently reduced BP, inhibited plasma renin activity (PRA), attenuated renal damage in animal models, and showed efficient and longer- lasting blockade of the RAAS in normotensive human subjects compared with other RAAS inhibitors. The clinical efficacy and safety of aliskiren have been evaluated both as monotherapy and in combination with other antihypertensive agents in phase II and phase III trials of patients with mild to severe hypertension. When used as monotherapy, aliskiren led to significant dose-dependent reductions in BP from baseline that were greater than those obtained with placebo and comparable with those achieved with an angiotensin II receptor blocker (ARB). The combination of aliskiren with a diuretic, a calcium channel blocker (CCB), an angiotensin-converting enzyme inhibitor (ACEI), or an ARB generally had greater and longer-lasting BP-lowering efficacy than did single agents alone. Aliskiren also countered the reactive increase in PRA caused by diuretic, CC B, ACEI, and ARB therapy. Once-daily treatment with aliskiren was well tolerated.. As a DRI, aliskiren blocks the RAAS more completely than do other current downstream RAAS inhibitors. When used once daily, aliskiren is a safe and effective antihypertensive agent that can be used as monotherapy or in combination with other agents to provide additional options to improve BP control.

Topics: Amides; Animals; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin inhibitor was halted due to insufficient pharmacokinetics. This indicated that the peptidomimetic approach to the development of antihypertensive agents was improper. Real non-peptide drug candidates were then expected to provide the necessary framework for obtaining the desired properties. For this purpose a homology model of the enzyme was used to characterize the binding mode of CGP38560 in complex with the renin model and served as a basis for the four chemistry laboratories that were assigned to this project. The renin team worked in a full structure-based perspective with this model, and four chemically-unrelated non-peptide series were discovered acting as renin inhibitors at the 1-3 nanomolar level. One of these leads was selected for further development and led to Aliskiren, which has been just approved by the FDA. Here is presented the successful structure-based strategy that enabled the discovery of several non-peptide inhibitors and the recent launch of a new drug that will be commercialized in the United States under the name Tekturna (for the treatment of high blood pressure as monotherapy or in combination with other high blood pressure medications).

Topics: Amides; Animals; Biomimetic Materials; Drug Approval; Drug Design; Enzyme Inhibitors; Fumarates; Humans; Hypertension; Models, Molecular; Renin; Structure-Activity Relationship; United States; United States Food and Drug Administration

Aliskiren is the first member of a novel class of antihypertensive agents, the renin inhibitors, that has been approved by the US Food and Drug Administration for the treatment of hypertension. This review discusses its potential differences compared with existing renin-angiotensin-aldosterone system blockers, focusing also on the inactive precursor of renin, prorenin, and the recently discovered (pro)renin receptor. The review summarizes the findings from all clinical trials with aliskiren published so far, and provides an overview of the safety and tolerability of the new drug.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Aliskiren (CGP-60536 or SPP100) is the first oral direct renin inhibitor and the first new class of antihypertensive agents to be introduced in more than a decade. Aliskiren taken once a day, alone or in combination with other antihypertensive agents, has been shown to be effective in reducing blood pressure and is generally well tolerated. Based on an extensive clinical trials program, aliskiren was approved for the treatment of hypertension in March 2007 (as Tekturna; Novartis Pharmaceuticals, East Hanover, NJ, USA) by the U.S. Food and Drug Administration and in August 2007 (as Rasilez, Enviage, Sprimeo, Tekturna and Riprazo, all from Novartis) for the treatment of essential hypertension by the European Commission. Although the indication for aliskiren is treatment of essential hypertension, benefits similar to those demonstrated with certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are anticipated for aliskiren. Some of the 44 trials with aliskiren are listed in Table II. Inhibition of renin, which is the first and rate-limiting step in the renin-angiotensin pathway has theoretical advantages over either ACE inhibitors or ARBs.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.

Topics: Amides; Antihypertensive Agents; Drug Interactions; Fumarates; Humans; Hypertension; Renin

With the development of aliskiren, blockade of the renin-angiotensin-aldosterone system (RAAS) at the level of the interaction of renin with a substrate has become a clinical reality. This review covers the specific features of the first agent likely to achieve widespread clinical exposure, aliskiren. The potential of renin inhibition must be viewed in the context of the remarkable efficacy of both angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockers (ARBs). The implications of blockade of the renin system at its rate-limiting step are reviewed, with the therapeutic implications for both the renin inhibitor employed alone or the renin inhibitor combined with an ACE inhibitor or ARB. The relevant and necessary studies are ongoing.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases

In the Hungarian population, there is also a growing number of patients with hypertension. In order to prevent the target organ's damage or in order to slow down the process, it is indispensable to reach the therapeutic target blood pressure. An opportunity for reducing the cardiovascular morbidity and mortality is the inhibition of the renin-angiotensin-aldosterone system. So far, we have had three large families, the angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists, to our disposal. The above are the key molecules for the hypertension treatment, but their application is accompanied by plasma renin level elevations, and thus, increase of plasma renin activation. The protection against increased plasma renin activation is helped by the renin inhibitors. Several decades were needed for their clinical introduction, till a non-peptide, safety medicament was successfully produced, which can be administered orally in small once-per-day doses. Their most promising representative is aliskiren. Still an open question is the mapping of the advantage of the angiotensin-converting enzyme inhibitor and angiotensin receptor blockers combination with aliskiren. The morbidity and mortality investigations are still missing and we curiously await them.

Topics: Amides; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Adipocytes; Amides; Angiotensin-Converting Enzyme 2; Antihypertensive Agents; Biphenyl Compounds; Fumarates; Hypertension; Insulin Resistance; Irbesartan; Metabolic Syndrome; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptors, Angiotensin; Receptors, Cell Surface; Renin-Angiotensin System; Tetrazoles; Vacuolar Proton-Translocating ATPases

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Aspartic Acid Endopeptidases; Benzimidazoles; Biphenyl Compounds; Drug Combinations; Drug Design; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Fumarates; Humans; Hypertension; Immunotherapy, Active; Metalloendopeptidases; Mineralocorticoid Receptor Antagonists; Phenylpropionates; Pyrimidines; Randomized Controlled Trials as Topic; Renin; Tetrazoles

Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.

Topics: Abnormalities, Drug-Induced; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Clinical Trials as Topic; Fumarates; Humans; Hyperkalemia; Hypertension; Hypotension; Inappropriate ADH Syndrome; Male; Mice; Renin

The renin-angiotensin system (RAS) plays a pivotal role in the progression of some forms of hypertension and cardiovascular disease. The development of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has provided physicians with effective and well-tolerated inhibitors of the RAS. However, it remains open to question whether ACE inhibitors and ARBs have fully delivered the reductions in cardiovascular risk that we might have expected. There is little doubt that in conditions such as chronic and acute heart failure or diabetic nephropathy these drugs have provided significant protection. But, in patients with high-risk hypertension, for instance, the anticipated benefits of RAS blockade have been less obvious. This article provides a critical assessment of the results of clinical trials of ACE inhibitors and ARBs across a variety of clinical conditions and assesses the potential need for new methods for blocking the renin system, including the use of renin inhibitors.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Meta-Analysis as Topic; Renin; Renin-Angiotensin System; Terminology as Topic

A new drug might make a positive contribution to existing therapies for hypertension by: 1) reducing blood pressure (BP) via a novel pharmacologic mechanism; 2) possessing pharmacologic or pharmacokinetic properties that make it superior to other members of its class; or 3) facilitating BP control in refractory patients. In this paper, we review four experimental agents that promise to advance therapeutics by one of these mechanisms. Aliskiren is the first in a new class of potent, orally effective renin inhibitors. Aliskiren produces dose-dependent BP reduction with few side effects and constitutes a novel pharmacologic approach to renin-angiotensin-aldosterone inhibition. Nebivolol is a third-generation, cardioselective beta-blocker that produces vasodilation and improves endothelial function via the l-arginine/nitric oxide pathway. Clevidipine is an ultra-short-acting, vascular-selective, dihydropyridine calcium antagonist that is being developed for intravenous use in acute hospitalized patients. Darusentan is an endothelin(A) selective endothelin receptor antagonist that is effective in achieving BP control in a significant percentage of patients who remain uncontrolled despite treatment with three or more antihypertensive drugs.

Topics: Adrenergic beta-Antagonists; Amides; Antihypertensive Agents; Benzopyrans; Blood Pressure; Calcium Channel Blockers; Drugs, Investigational; Endothelin A Receptor Antagonists; Ethanolamines; Fumarates; Humans; Hypertension; Nebivolol; Phenylpropionates; Pyridines; Pyrimidines; Renin; Treatment Outcome

In recent years, the renin-angiotensin-aldosterone system has been shown to be crucial not only in blood pressure haemostasis but also in the evolution of atherosclerosis, which ultimately determines morbidity and mortality. The angiotensin-converting enzyme inhibitors and, recently, the angiotensin receptor blockers (with their low adverse-effect profile) have added a new dimension to the drug treatment of hypertension. Just a decade after the introduction of angiotensin receptor blockers, physicians treating hypertension are now offered another exciting approach to achieving blockade of the renin-angiotensin-aldosterone system through the inhibition of renin. This review outlines the background evidence for aliskiren, the first orally active renin inhibitor.

Topics: Amides; Animals; Antihypertensive Agents; Drugs, Investigational; Fumarates; Humans; Hypertension; Renin

Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development. This Review summarises the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren.

Topics: Administration, Oral; Adult; Aged; Amides; Animals; Biological Availability; Blood Pressure; Female; Fumarates; Half-Life; Humans; Hypertension; Kidney; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Structure-Activity Relationship

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage. However, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion present limitations for existing renin-angiotensin-aldosterone system inhibitors. A once-daily, orally effective, small-molecule renin inhibitor, aliskiren, is now available to address angiotensin production directly at its rate-limiting step. Studies in humans attest to an effective BP-lowering effect, a side effect profile no different from AT1 receptor blockers, and the option of combination therapies. A novel animal model of high human renin hypertension in the rat attest to target organ protection. Because angiotensin receptor blockade, angiotensin-converting enzyme inhibition, calcium channel blockade, and diuretic therapy all lead to sharp increases in plasma renin activity, aliskiren offers a novel circumvention.

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The renin-angiotensin aldosterone system (RAAS) plays a key role in the regulation of blood pressure, acting via the effects of the hormone angiotensin (Ang) II. Ang II increases blood pressure and can exert growth-promoting effects leading to end-organ damage. Excess RAAS activity has been shown to be a major underlying cause of hypertension, heart failure, and related cardiovascular disorders. Inhibitors of renin block the RAAS at its first and rate-limiting step and thus appear to offer an excellent opportunity for blood pressure control. In the past two decades various potential renin inhibitors have been developed but have not been clinically useful. This review discusses a recent patent in the development of a novel class of non-peptide renin inhibitors: an alkanecarboxamide, aliskiren (SPP-100; Novartis). Aliskiren is effective in animal models, while recent results from studies in humans indicate that aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System

We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients.. Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ± N omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation.. A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress.. Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

Topics: Amides; Blood Pressure; Diabetes Mellitus; Endothelium, Vascular; Fumarates; Humans; Hypertension; Nitric Oxide; Renin; Vasodilation

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Topics: Aged; Aldosterone; Amides; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Middle Aged; Receptors, Cell Surface; Renal Insufficiency, Chronic; Renin-Angiotensin System; Vacuolar Proton-Translocating ATPases; Vascular Stiffness

Aliskiren penetrates adipose and skeletal muscle in hypertensive patients with abdominal obesity and reduces renin-angiotensin-aldosterone system activity. After discontinuation, blood pressure-lowering effects are observed possibly through drug-tissue binding. We performed microdialysis evaluation of adipose tissue and skeletal muscle before and during an insulin-modified frequently sampled intravenous glucose tolerance test (IM-FSIGT). Aliskiren 300 mg (n = 8) or amlodipine 5 mg (n = 8) once daily were administered during a 12-week randomized treatment period. Aliskiren elicited variable changes in median interstitial angiotensin II (Ang II) in adipose (2.60-1.30 fmol/mL) and skeletal muscle (2.23-0.68 fmol/mL); amlodipine tended to increase adipose and skeletal muscle Ang II (P = .066 for skeletal muscle treatment difference). Glucose/insulin increased median plasma Ang II 1 hour after glucose injection (1.04-2.50 fmol/mL; P = .001), which was markedly attenuated by aliskiren but not amlodipine. Aliskiren increased glucose disposition index (P = .012) and tended to increase acute insulin response to glucose (P = .067). Fasting adipose glycerol (-17%; P = .064) and fasting muscle glucose dialysate (-17%; P = .025) were decreased by aliskiren but not amlodipine. In summary, aliskiren decreased Ang II production in response to glucose/insulin stimulus and elicited metabolic effects in adipose and skeletal muscle suggestive of increased whole-body glucose utilization.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Angiotensin II; Antihypertensive Agents; Blood Glucose; Double-Blind Method; Female; Fumarates; Glucose; Humans; Hypertension; Insulin; Lipolysis; Male; Microdialysis; Middle Aged; Muscle, Skeletal; Obesity; Renin; Renin-Angiotensin System

Topics: Aged; Amides; Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Prescriptions; Female; Fumarates; Humans; Hypertension; Male; Ontario; Retrospective Studies

The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension.. A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15).. Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9-42] mg/d) was reduced by DRI only (12 [5-28] mg/d, P = 0.030).. In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension.. Dutch trial register, registration number: 2532 www.trialregister.nl.

Topics: Albuminuria; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Double-Blind Method; Fumarates; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Overweight; Ramipril; Renal Circulation; Renin; Renin-Angiotensin System

The aim of this study was to compare an aliskiren/amlodipine combination with high-dose amlodipine monotherapy on ambulatory blood pressure monitoring (ABPM) and organ protection. The study was a prospective, randomized, multicenter, open-label trial in elderly essential hypertensive patients. A total of 105 patients with clinic BP (CBP) ≥140/90 mm Hg with amlodipine 5 mg were randomly allocated to aliskiren (150-300 mg)/amlodipine (5 mg) (ALI/AML group, n=53) or high-dose amlodipine (10 mg) (h-dAML group, n=52) and treated for 16 weeks. Each patient's CBP, ABPM, urine albumin-to-creatinine ratio (UACR), and brachial-ankle pulse wave velocity (baPWV) were measured at baseline and at the end of the study. The ALI/AML and h-dAML groups showed similarly reduced mean 24-hour SBP, daytime SBP, nighttime SBP, and baPWV. However, UACR reduction was significantly greater in the ALI/AML group (P=.02). ALI/AML was significantly less effective in reducing early-morning BP (P=.002) and morning BP surge (P=.001) compared with h-dAML.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Creatinine; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Japan; Male; Organ Sparing Treatments; Prospective Studies; Renin; Serum Albumin

To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit.. In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression.. The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints).. The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Topics: Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Middle Aged; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Renin; Risk Factors

The authors investigated the long-term effectiveness and safety of aliskiren (ALIS) with particular attention on its association with dual blockade of the renin-angiotensin system (RAS). The open, prospective 3A Registry (N=8723) in Germany assigned patients in a 4:1:1 ratio to ALIS, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or non-RAS drugs. Patients taking ALIS compared with those taking ACE inhibitors/ARBs or non-RAS had more comorbidities and risk factors, were taking more antihypertensive agents, and had higher blood pressure (BP) values at entry. At 2 years, BP reduction from baseline was similar in all groups (mean, -20.5/-9.9 mm Hg). A total of 2.3% of patients died, 0.5% had myocardial infarction, 0.6% had stroke, 2.9% were hospitalized, and 5.5% had any event (not significant between groups). ALIS alone or combined with another RAS inhibitor was well tolerated and effective in lowering BP in typical unselected patients with hypertension. Given the methodical limitations of the design, the study cannot be used to confirm or refute safety concerns for dual RAS blockade as suggested by the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Treatment Outcome

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.. We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria.. Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients.. DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen.

Topics: Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Outcome

The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy.. In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively.. After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (-11.37% and -8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (-10.67% and -9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (-67.62% and -49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001).. The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril.

Topics: Aged; Albuminuria; Amides; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diastole; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Potassium; Ramipril; Systole

In hypertension, changes in small arterial structure are characterized by an increased wall-to-lumen ratio (WLR). These adaptive processes are modulated by the rennin-angiotensin system. It is unclear whether direct renin inhibitors exert protective effects on small arteries in hypertensive patients.. In this double-blind, randomized, placebo-controlled study (http://www.clinicaltrials.gov: NCT01318395), 114 patients with primary hypertension were randomized to additional therapy with either placebo or aliskiren 300 mg for 8 weeks after 4 weeks of standardized open-label treatment with valsartan 320 mg (run-in phase). Parameter of arteriolar remodelling was WLR of retinal arterioles (80 - 140 μm) assessed noninvasively and in vivo by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). In addition, pulse wave analysis (SphygmoCor, AtCor Medical, Australia) and pulse pressure (PP) amplification were determined.. In the whole study population, no clear effect of additional therapy with aliskiren on vascular parameters was documented. When analyses were restricted to patients with vascular remodelling, defined by a median of WLR more than 0.3326 (n = 57), WLR was reduced after 8 weeks by the treatment with aliskiren compared with placebo (-0.044 ± 0.07 versus 0.0043 ± 0.07, P = 0.015). Consistently, after 8 weeks of on-top treatment with aliskiren, there was an improvement of PP amplification compared with placebo (0.025 ± 0.07 versus -0.034 ± 0.08, P = 0.013), indicative of less stiff arteries in the peripheral circulation.. Thus, our data indicate that treatment with aliskiren, given on top of valsartan therapy, improves altered vascular remodelling in hypertensive patients.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Arterioles; Blood Pressure; Double-Blind Method; Essential Hypertension; Female; Fumarates; Humans; Hypertension; Laser-Doppler Flowmetry; Male; Middle Aged; Pulse Wave Analysis; Retinal Vessels; Valsartan; Vascular Remodeling

The purpose of the present study was to compare the direct renin inhibitor aliskiren to the diuretic hydrochlorothiazide (HCTZ) in their ability to modulate renal tissue oxygenation in hypertensive patients.. 24 patients were enrolled in this randomized prospective study and 20 completed the protocol. Patients were randomly assigned to receive either aliskiren 150-300 mg/d or HCTZ 12.5 - 25 mg/d for 8 weeks. Renal oxygenation was measured by BOLD-MRI at weeks 0 and 8. BOLD-MRI was also performed before and after an i.v. injection of 20 mg furosemide at week 0 and at week 8. BOLD-MRI data were analyzed by measuring the oxygenation in 12 computed layers of the kidney enabling to asses renal oxygenation according to the depth within the kidney and by the classical method of regions of interest (ROI).. The classical ROI analysis of the data showed no difference between the groups at week 8. The analysis of renal oxygenation according to the 12 layers method shows no significant difference between aliskiren and HCTZ at week 8 before administration of furosemide. However, within group analyses show that aliskiren slightly but not significantly increased oxygenation in the cortex and decreased medullary oxygenation whereas HCTZ induced a significant overall decrease in renal tissue oxygenation. With the same method of analysis we observed that the response to furosemide was unchanged in the HCTZ group at week 8 but was characterized by an increase in both cortical and medullary oxygenation in aliskiren-treated patients. Patients responding to aliskiren and HCTZ by a fall in systolic blood pressure of >10 mmHg improved their renal tissue oxygenation when compared to non-responders.. With the classical method of evaluation using regions no difference were found between aliskiren and HCTZ on renal tissue oxygenation after 8 weeks. In contrast, with our new method that takes into account the entire kidney, within group analyses show that aliskiren slightly increases cortical and medullary renal tissue oxygenation in hypertensive patients whereas HCTZ decreases significantly renal oxygenation at trough.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Kidney; Male; Middle Aged; Oxygen Consumption; Prospective Studies; Renin; Single-Blind Method

The aim of this study was to compare the effects of direct renin inhibitor, aliskiren, and amlodipine combination therapy with those of high-dose amlodipine monotherapy on endothelial function in elderly hypertensive patients.. Participants included 105 patients (mean age 77 years) who had receive 5mg amlodipine for 4 weeks. Patients were allocated to the aliskiren/amlodipine group (AL/AM) or the high-dose amlodipine (AM) group. The AL/AM group received 150mg aliskiren in addition to 5mg amlodipine for 8 weeks; then the dose of aliskiren was doubled to 300mg for another 8 weeks. The AM group received 10mg amlodipine for 16 weeks. Of the 105 patients, 87 who underwent measurements of brachial flow-mediated vasodilation (FMD) and nitroglycerin-mediated vasodilation (NMD) before and after the study were included in the analysis.. Blood pressure-lowering effects were similar in the 2 groups. Plasma renin activity significantly decreased in the AL/AM group (P < 0.001) but increased in the AM group (P < 0.001). Improvement of FMD was found in the AL/AM group (2.6% to 3.7%, P = 0.001) but not in the AM group, while NMD did not change in either group. The changes in 24-hour systolic blood pressure (r = -0.60, P < 0.001) and diastolic blood pressure (r = -0.46, P = 0.004) were significantly correlated with improvement of FMD in the AL/AM group but not in the AM group.. Addition of aliskiren improved endothelial function in elderly hypertensive patients treated with amlodipine.. UMIN000010163.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Humans; Hypertension; Japan; Male; Renin; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Antihypertensive agents may, even within the same class, exert variable effects on arterial stiffness variables. Nebivolol could have a better impact than atenolol on arterial stiffness, by increasing the bioavailability of endothelium-derived nitric oxide. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase plasma renin activity (enhancing the production of angiotensin II via non-ACE-related pathways) whereas aliskiren does not, potentially affecting central hemodynamics differently. We compared the effects of two renin-angiotensin-aldosterone system (RAAS) inhibitors (quinapril and aliskiren) and 2 beta-blockers (atenolol and nebivolol) on arterial stiffness variables. Treatment-naïve patients (n = 72; 68.1% males; age, 47.6 ± 10.6 years) with uncomplicated stage I-II essential hypertension were randomly assigned to quinapril, aliskiren, atenolol, or nebivolol for 10 weeks. Central systolic and diastolic blood pressure (BP), central pulse pressure (PP), augmentation index (AIx), and pulse wave velocity (PWV) were measured at baseline, 2, and 10 weeks. The same measurements were performed in 20 normotensive subjects (65.0% males; age, 40.0 ± 8.9 years). Peripheral and central systolic and diastolic BP, peripheral PP, and PWV were significantly and similarly reduced by all agents. However, PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol. Central PP and AIx decreased in patients on quinapril, aliskiren, and nebivolol but did not change in those taking atenolol. The decrease in central PP and AIx did not differ between patients on quinapril, aliskiren, and nebivolol. Despite similar reductions in peripheral BP, atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics. Aliskiren exerts similar effects on markers of arterial stiffness as quinapril. The clinical relevance of these differences remains to be established.

Topics: Adrenergic beta-Antagonists; Adult; Amides; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Monitoring; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Pulse Wave Analysis; Quinapril; Renin-Angiotensin System; Tetrahydroisoquinolines; Treatment Outcome; Vascular Stiffness

Recent trials with inhibition of the renin-angiotensin-aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62±3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19-36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis.

Topics: Amides; Antihypertensive Agents; Disease Progression; Double-Blind Method; Down-Regulation; Female; Fumarates; Humans; Hypertension; Magnetic Resonance Imaging; Male; MicroRNAs; Middle Aged; Plaque, Atherosclerotic; Prospective Studies; Renin; Signal Transduction

Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD).. The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy.. A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group.. Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

A direct renin inhibitor (DRI), aliskiren, may be effective for blood pressure (BP) control in hemodialysis patients. However, it is unclear whether aliskiren has a greater beneficial effect on BP and humoral factors than angiotensin II receptor antagonists (ARBs) in hypertensive patients on hemodialysis.. Eighteen hemodialysis patients (58 ± 14 years) on the recommended dose of an ARB were prospectively randomized into two groups: ARB and DRI groups. Patients in the ARB group continued taking their previous ARB, whereas those in the DRI group switched to aliskiren (150 mg/day) for 12 weeks. Baseline measurements of BP and humoral factors such as plasma renin activity (PRA), plasma aldosterone concentration (PAC) and brain natriuretic peptide (BNP) were performed. Measurements were repeated every 4 weeks.. At baseline, no differences were observed in age, gender or BP between the two groups. Systolic BP was unaffected by treatment in either groups (group effect, p = 0.26; time effect, p = 0.38; group × time effect, p = 0.24). PRA decreased in DRI (p ≤ 0.02, group effect, p = 0.65; time effect, p = 0.13; group × time effect, p = 0.048), but not in ARB (p ≥ 0.94). PAC increased only in DRI (p ≤ 0.03), whereas BNP was unaffected in either group.. Aliskiren at a dose of 150 mg/day had a similar effect on BP compared with ARBs, but significantly lowered PRA.

Topics: Adult; Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis; Renin

Aim of the present study was to compare the effectiveness of two renin-angiotensin-aldosterone system inhibitors in arterial stiffness reduction in previously untreated hypertensive patients.. In this open label study, 154 naïve, or not treated in the last six months hypertensive patients were randomly assigned to receive aliskiren 300 mg or ramipril 5 mg daily. Six weeks after the initiation of treatment, patients were evaluated for blood pressure (BP) control. Patients with SBP ≥140 and/or DBP ≥90 mmHg were assigned to an adjunct of 25 mg hydrochlorothiazide as combination treatment. A re-evaluation of BP control was done after another 6 weeks. Individuals with BP ≥140/90 mmHg were further administered amlodipine 5 mg. The final evaluation was performed six months after the start of the study. Twenty four-hour ambulatory blood pressure monitoring was carried out and the ambulatory arterial stiffness index (AASI) was calculated at baseline and after 6 months of treatment.. Aliskiren-based therapy, as compared with ramipril-based therapy reduced BP to a similar degree: 13±11 vs. 12±11 mmHg reduction in systolic (P=0.34) and 8±7 vs. 7±7 mmHg reduction in diastolic BP (P=0.44). AASI was reduced by 0.04±0.1 in the aliskiren group and by 0.02±0.2 in the ramipril group. AASI reduction did not differ significantly in the two groups (P=0.13).. In hypertensive patients, aliskiren-based treatment as well as ramipril-based treatment appears to have a beneficial effect on arterial stiffness. As arterial stiffness is an important modifiable risk factor, our findings highlight the value of aliskiren beyond BP lowering properties.

Topics: Adult; Aged; Amides; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Greece; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Predictive Value of Tests; Ramipril; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilator Agents

We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg.. We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P < 0.001) by aliskiren, 6.8/3.3 mm Hg (P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37-1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19-1.04) for 6.8 mm Hg; and HR 0.25 (0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure.. Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension.. NCT01259297.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Medication Adherence; Potassium; Treatment Outcome

Arterial stiffness and endothelial dysfunction are important determinants of cardiovascular events in patients with arterial hypertension. There are few data regarding the role of aliskiren on the central hemodynamics and endothelial function in patients with uncontrolled arterial hypertension. The aim of this study was to assess the addition of aliskiren to other antihypertensive drug treatment for arterial stiffness and endothelial function. Thirty uncontrolled hypertensive patients (mean age, 60.4±12.2 years), without any other cardiovascular risk factors, were enrolled. Augmentation index (AIx) and carotid-femoral pulse wave velocity (cfPWV) by applanation tonometry and reactive hyperemia peripheral arterial tonometry (RH PAT) index using peripheral arterious tonometry at baseline and after 6 months of aliskiren titrated to 300 mg once a day was evaluated. The addition of aliskiren had no effect on values of central AIx (33.26±10.74% vs 28.86±10.74%; P=.36) but did significantly improve values of cfPWV (9.36±2.65 m/s vs 8.72±2.48 m/s; P=.04) and RH PAT index (1.64±0.57 vs 1.75±0.45; P=.05). In addition to improving systolic and diastolic blood pressure, the addition of aliskiren to concomitant antihypertensive drugs in uncontrolled hypertensive patients may be effective in improving aortic stiffness and endothelial function. These results encourage further studies to evaluate the use of aliskiren for cardiovascular prevention.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Body Mass Index; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Hemodynamics; Humans; Hypertension; Male; Manometry; Middle Aged; Pulse Wave Analysis; Renin; Treatment Outcome; Vascular Stiffness

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteries; Blood Pressure; Diabetes Mellitus, Type 2; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril; Skin; Time Factors; Treatment Outcome; Vascular Resistance

The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Autonomic Nervous System; Comorbidity; Drug Therapy, Combination; Endothelium, Vascular; Female; Fumarates; Heart Rate; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Renin; Tetrazoles; Treatment Outcome; Valine; Valsartan; Vasodilation

Systolic hypertension is the most common form of hypertension in elderly patients. There is increasing evidence that measurement of central aortic pressure (CAP) better accounts for cardiovascular risk than brachial blood pressure (BP). The Aliskiren for GEriatric LowEring of SyStolic hypertension (AGELESS) study in elderly patients with systolic hypertension showed that aliskiren-based therapy provided greater reductions in peripheral BP than ramipril-based therapy over 12 and 36 weeks of treatment. Here, we present CAP results in a substudy of elderly patients from the AGELESS study.. This was a post hoc analysis of a 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study in patients ≥65 years of age with systolic BP ≥140 mmHg. Changes in both central and peripheral BP and pulse pressure (PP) and changes in systolic and PP amplification ratios from baseline to the week 36 end point with aliskiren-based versus ramipril-based therapy were analyzed.. Of the 901 patients randomized in the overall study, 154 patients (aliskiren, n=78; ramipril, n=76) had CAP data. Numerically comparable reductions were seen for central aortic systolic pressure (CASP) in aliskiren-based therapy (baseline: 143.7±15.0; week 36: -20.3±16.2) compared with ramipril-based therapy (baseline: 147.9±11.9; week 36: -20.7±14.6). However, for the change in central aortic diastolic pressure, the least squares mean between-treatment difference (-3.6 mmHg [95% confidence interval, -6.76, -0.43; P=0.0263]) was in favor of aliskiren, while the other changes were comparable between the two groups with a trend in favor of aliskiren for CASP as well (-2.6 mmHg [95% confidence interval, -7.38, 2.19; P=0.2855)]. Correlation coefficients for change from baseline between CASP and systolic BP and between central aortic pulse pressure and PP (r=0.8, P<0.0001) were highly significant.. Aliskiren-based therapy provides comparable reductions in CASP to ramipril-based therapy. Although the results did not reach statistical significance, these findings, when coupled with those of the main study, suggest that aliskiren may offer effective control of central BP in elderly patients with systolic hypertension and may be a good alternative to ramipril.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aorta; Arterial Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Ramipril; Systole; Time Factors; Treatment Outcome

It has been suggested that aliskiren has a long half-life and maintains a blood pressure (BP)-lowering effect following a missed dose. We tested the hypothesis that every other day (eod) administration of aliskiren has the same effects as the once daily (od) dosing in albuminuric hypertensive patients.. Fifteen hypertensive patients, after a 4-week wash-out period on clonidine, received 300 mg aliskiren od as the sole treatment. In patients who remained out of target, other nonrenin-angiotensin system blockers were added. Patients who completed a 24-week (w24) treatment period were switched to eod administration of aliskiren for an additional period of 24 weeks (w48).. Thirteen patients completed the full study protocol. The mean office BP was reduced at the end of w24 (-9/3 mmHg), a reduction that continued to be observed at w48 (-11/1 mmHg). At the end of the study, the 48 h ambulatory BP monitoring was divided into two 24 h periods. The mean 24 h systolic BP, and the mean daytime systolic and diastolic BP were significantly lower (P<0.05) in the first 24 h (when aliskiren was taken) compared with the second period. Central hemodynamics showed no significant differences at any time during monitoring. Administration of aliskiren resulted in a median reduction of urine albumin/creatinine ratio of 103 mg/g (od) and 102 mg/g (eod). Differences in plasma renin activity, plasma renin concentration, and aldosterone-level measurements were not significant.. The BP-lowering effect of eod aliskiren administration, although adequate, is less efficient compared with od administration, despite the fact that in terms of reducing albuminuria, it appears to be effective.

Topics: Adult; Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Prospective Studies; Renin; Time Factors

We attempted to test the hypothesis that the direct renin inhibitor aliskiren can improve diastolic dysfunction, glucose, and insulin metabolism (GIM) in overweight and obese hypertensive patients.. Seventy-eight hypertensive patients were divided into two groups: 38 treated with aliskiren for six months, and 40 treated without aliskiren but with only traditional anti-hypertensive therapy, as controls. Doppler mitral flow velocity patterns were assessed before and after aliskiren during a six-month period. GIM (three-hour intravenous glucose tolerance test) was measured after four to six weeks of washout and six months of treatment. The mitral E/A ratio increased from 0.65 ± 0.11 to 0.75 ± 0.19. None of the indexes changed in the control group. In the control group, GIM parameters, fasting glucose levels (5.3 ± 0.9 to 6.0 ± 1.5 mmol/l; p = 0.003), fasting insulin levels (121 ± 121 to 189 ± 228 pmol/l; p = 0.03), and most other relevant metabolic measures (p < 0.05 for all) significantly worsened. Aliskiren did not affect GIM. In the control group LVM/height was not affected (119 ± 12 to 120 ± 17 g/m; p = 0.8), whereas aliskiren significantly reduced LVM/height (120 ± 13 to 111 ± 19 g/m; p = 0.04).. Optimal target BP was achieved in the group as a whole and in both obese patient groups, while benefits to cardiac structure were of a smaller magnitude. In high-risk, overweight/obese patients with hypertension, traditional therapy provides significantly greater BP- versus aliskiren-lowering throughout the 24-hour dosing interval. Therefore in obese, hypertensive individuals, adequate and similar blood pressure control was achieved with aliskiren; however, the aliskiren group and not the control group was associated with a more favorable GIM profile and led to a significant regression of LVM; overall aliskiren-based treatment offers sustained control of PRA.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Blood Glucose; Female; Fumarates; Humans; Hypertension; Insulin; Male; Middle Aged; Obesity; Overweight; Renin; Renin-Angiotensin System; Ultrasonography; Ventricular Function, Left

The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.. A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.. Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.. Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (-42 vs -15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.. Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin-angiotensin-aldosterone system blockade.

Topics: Adult; Aged; Albumins; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Arterial Pressure; Biomarkers; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril; Renin; Single-Blind Method; Treatment Outcome

Central blood pressure (CBP) is superior to brachial blood pressure as a predictor of cardiovascular risk in patients with hypertension. There is currently no consensus regarding whether a direct renin inhibitor (DRI) selectively acts on CBP.. Thirty subjects with essential hypertension who showed a CBP of 140 mm Hg or higher after 12 weeks of treatment with a standard dose of a DRI (150 mg) were analyzed. The patients were randomly divided into 2 groups: the high-dose DRI group (n=15) received 300 mg of DRI per day, and the combination group (n=15) received both the standard dose of the DRI and a diuretic (12.5 mg of hydrochlorothiazide). The systolic blood pressure (SBP), CBP, and the augmentation index (AI) were determined before treatment and after 12 and 24 weeks of treatment.. The SBP, CBP and AI were significantly decreased after 12 weeks of treatment with standard dose of the DRI (p<0.05). From 12 to 24 weeks after assignment the SBP and CBP were also significantly decreased in both the high-dose DRI group and the combination group. The high-dose DRI group showed a greater decrease in the CBP, but not in the SBP, than did the combination group (p<0.05). The AI decreased significantly from 12 to 24 weeks in the high-dose DRI group (p<0.05) but not in the combination group (p=0.14).. Treatment with a DRI contributes to a decrease in the CBP and AI, and high-dose DRI therapy leads to a further decrease in the CBP and AI.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Prospective Studies; Renin; Time Factors; Treatment Outcome

Aliskiren is a novel blood pressure-lowering agent acting as an oral direct renin inhibitor. The aim of this study was to assess the effect of aliskiren on arterial stiffness, compared with that of ramipril in mild to moderate essential hypertensive patients.. Following a two week placebo run-in period, patients with a mean sitting diastolic blood pressure (ms-DBP) ≥ 95 and < 110 mmHg (1 mmHg = 0.133 kPa), and a mean sitting systolic blood pressure (ms-SBP) < 180 mmHg were randomly allocated to treatment with aliskiren (150 mg/d, n = 20) or ramipril (5 mg/d, n = 20) for eight weeks. Blood pressure, plasma renin activity, and the brachial-ankle pulse wave velocity (ba-PWV) were measured before and after eight weeks of treatment.. Eight weeks of treatment significantly decreased systolic blood pressure and diastolic blood pressure in both the aliskiren group and ramipril group. The hypotensive effect did not differ between the two groups. Plasma renin activity decreased after aliskiren treatment and increased after ramipril treatment. There was no significant difference in baseline ba-PWV between the aliskiren and ramipril groups (P = 0.892). The ba-PWV was significantly reduced in both the aliskiren group (1535 (1405 - 1666) vs. 1464 (1360 - 1506) cm/s) (P < 0.01) and the ramipril group (1544 (1433 - 1673) vs. 1447 (1327 - 1549) cm/s) (P < 0.01). No statistically significant difference was found in the decline of ba-PWV between the two groups (P = 0.766).. The current study revealed that aliskiren (150 mg/d) could ameliorate arterial stiffness and its effect was similar to ramipril (5 mg/d) in mild to moderate hypertensive patients, indicating that in addition to lowering blood pressure, aliskiren had beneficial effect on vascular protection.

Topics: Adult; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Vascular Stiffness

To assess the pharmacokinetics (PK) and safety profile of aliskiren in pediatric patients (6-17 years old) with hypertension.. Patients were randomized to a single weight-based dose of either 2 mg/kg (n = 19) or 6 mg/kg (n = 20) of aliskiren daily for 8 days. The PK, pharmacodynamics, safety profile, and efficacy of aliskiren were assessed.. Of the 39 randomized patients, 37 (94.9%) completed the study. Aliskiren plasma concentration (maximum plasma concentration and area under the plasma concentration-time curve) increased dose dependently, achieving peak concentrations in 1 to 2 hours, and t(max) was comparable across the dose and age groups. Treatment-emergent adverse events (AEs) were reported in 18 (46.2%) patients, with headache, abdominal pain, and nausea being the most frequent.. Aliskiren 2 mg/kg and 6 mg/kg daily showed dose-dependent increases in the plasma concentration. The drug was well tolerated in hypertensive children aged 6 to 17 years. AEs were generally mild and not related to either the drug or the dose.

Topics: Administration, Oral; Adolescent; Age Factors; Amides; Analysis of Variance; Antihypertensive Agents; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Male; Regression Analysis; Tablets; Treatment Outcome

Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four-hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Aorta, Thoracic; Benzimidazoles; Benzoates; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Brachial Artery; Circadian Rhythm; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Middle Aged; Prognosis; Prospective Studies; Renin; Reproducibility of Results; Telmisartan

Currently there is no consensus regarding which add-on therapy to use in resistant hypertension. We have conducted an open observational study of the use of aliskiren in resistant hypertensive patients. Forty-three patients with resistant hypertension were included in the study. The inclusion criteria were as follows: 1) office blood pressure (BP) > 140/90 mmHg despite treatment with at least three or more antihypertensive drugs; 2) no prior therapy with aliskiren; and 3) no renal insufficiency. Follow-up BP was determined at 1 and 3 months. Baseline BP was 153 ± 12/79 ± 12 mmHg. After 3 months, systolic BP (SBP) and diastolic BP (DBP) dropped significantly: 140 ± 19/73 ± 13 mmHg (P < 0.0001). Twenty-one patients (49%) had an office BP < 140/90 mmHg, and these patients were assigned to the good BP control group. Another 22 were placed into the poor BP control group. BP reductions from baseline in the good BP control group (SBP/ DBP: 19 ± 11/8 ± 7 mmHg) were larger than those in the poor BP control group (5 ± 15/3 ± 9 mmHg, P < 0.05). Mean BP (MBP) values at baseline, 1, and 3 months were higher in the poor BP control group. There was no significant difference in pulse pressure at baseline between the 2 groups. In multivariate analysis, only MBP at baseline correlated with lack of BP control. Aliskiren administration to resistant hypertensive patients was effective in reducing BP. The present findings suggest aliskiren may be useful as a fourth-line or fifth-line treatment added to other drugs in the treatment of resistant hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Renin; Salvage Therapy; Treatment Outcome

Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment.. One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes.. A significant reduction (all P<0.0001) of clinic systolic (-28.6 mmHg) and diastolic (-12.8 mmHg) BP values, mean 24h-systolic (-12.3 mmHg) and 24h-diastolic (-6.5 mmHg), day-time systolic (-11.5 mmHg) and diastolic (-6.4 mmHg), night-time systolic (-11.9 mmHg) and diastolic (-7 mmHg) ABPM values and in the use of antihypertensive drugs was observed (3.0±0.9 vs. 2.0±0.7, p=0.01). LVMI was significantly reduced (130.2±36.1 vs. 115.9±33.4 g/m2, P<0.0001); eGFR was steady (75.3±17.3 vs. 73.1±21.5 ml/min/1.73m2, P>0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia).. Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed.

Topics: Aged; Alopecia; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diarrhea; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Prospective Studies; Renin; Renin-Angiotensin System; Risk; Ventricular Remodeling

We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

Topics: Aged; Albuminuria; Aldosterone; Amides; Blood Pressure; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Incidence; Longitudinal Studies; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin; Renin-Angiotensin System; Spironolactone; Time Factors

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for reducing pain and other symptoms in osteoarthritis (OA). NSAIDs have been associated with an increase in blood pressure (BP) in both normotensive and hypertensive individuals and a blunting effect on various anti-hypertensive medications. Acetaminophen effects on anti-hypertensive treatment, instead, are still a matter of debate.. To assess the effect of naproxen versus acetaminophen on ramipril, valsartan and aliskiren therapy in hypertensive patients with OA in a double-blind, cross-over study, by measuring clinic, ambulatory BP and heart rate (HR).. One hundred seventy four patients were randomly treated with ramipril, valsartan or aliskiren for 8 weeks and 135 patients with normalized BP were randomized to receive naproxen or acetaminophen for 2 weeks. Naproxen significantly increased clinic and ambulatory systolic/diastolic BP (SBP/DBP) values in patients treated with ramipril (p < 0.01) or valsartan (p < 0.05), but did not affect aliskiren effects. Also acetaminophen slightly but significantly affected clinic and ambulatory SBP/DBP in all three groups and, surprisingly, it also produced a slight increase in HR (+3.1, +3.3 and +3.4 b/min day-time HR values, for ramipril, valsartan and aliskiren, respectively; p < 0.05).. Both naproxen and acetaminophen can affect anti-hypertensive therapy with ramipril, valsartan or aliskiren with a different extent. When acetaminophen is chosen for OA management in subjects with hypertension, patients should be evaluated as carefully as when traditional NSAIDs are given.

Topics: Acetaminophen; Adult; Aged; Amides; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Naproxen; Ramipril; Tetrazoles; Valine; Valsartan

Cardiovascular risk remains high in patients with hypertension even with adequate blood pressure (BP) control. One possible mechanism may be sympathetic activation via the baroreflex. We tested the hypothesis that chronic inhibition of renin reduces BP without sympathetic activation, but diuresis augments sympathetic activity in elderly hypertensives. Fourteen patients with stage-I hypertension (66 ± 5 (SD) years) were treated with a direct renin inhibitor, aliskiren (n = 7), or a diuretic, hydrochlorothiazide (n = 7), for 6 months. Muscle sympathetic nerve activity (MSNA), BP, direct renin and aldosterone were measured during supine and a graded head-up tilt (HUT; 5 min 30° and 20 min 60°), before and after treatment. Sympathetic baroreflex sensitivity (BRS) was assessed. Both groups had similar BP reductions after treatment (all P < 0.01), while MSNA responses were different between hydrochlorothiazide and aliskiren (P = 0.006 pre/post × drug). Both supine and upright MSNA became greater after hydrochlorothiazide treatment (supine, 72 ± 18 post vs. 64 ± 15 bursts (100 beats)(-1) pre; 60° HUT, 83 ± 10 vs. 78 ± 13 bursts (100 beats)(-1); P = 0.002). After aliskiren treatment, supine MSNA remained unchanged (69 ± 13 vs. 64 ± 8 bursts (100 beats)(-1)), but upright MSNA was lower (74 ± 15 vs. 85 ± 10 bursts (100 beats)(-1); P = 0.012 for pre/post × posture). Direct renin was greater after both treatments (both P < 0.05), while upright aldosterone was greater after hydrochlorothiazide only (P = 0.002). The change in upright MSNA by the treatment was correlated with the change of aldosterone (r = 0.74, P = 0.002). Upright sympathetic BRS remained unchanged after either treatment. Thus, chronic renin inhibition may reduce upright MSNA through suppressed renin activity, while diuresis may evoke sympathetic activation via the upregulated renin-angiotensin-aldosterone system, without changing intrinsic sympathetic baroreflex function in elderly hypertensive patients.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Muscles; Peroneal Nerve; Posture; Renin; Sodium Chloride Symporter Inhibitors; Sympathetic Nervous System

The renin-angiotensin-aldosterone system is not necessarily suppressed in end-stage renal disease patients undergoing dialysis. Of all the inhibitors of this system, the clinical efficacy of the renin inhibitor, aliskiren, has not been well demonstrated in dialysis patients. We evaluated the antihypertensive effect of aliskiren, administered as a single daily dose of 150 mg for 24 weeks, in 23 chronic hemodialysis patients (age 65 ± 12 years, 15 men and eight women) with blood pressure ≥140/90 mm Hg, and assessed the factors relating to blood pressure reduction. At 4 weeks, the average systolic blood pressure before the dialysis session was insignificantly reduced from 163 ± 10 mm Hg to 160 ± 15 mm Hg, while it was significantly lowered at 12 (154 ± 13 mm Hg) and 24 weeks (155 ± 10 mm Hg), although the pulse rate was not significantly altered. Serum K increased at 24 weeks from 4.9 ± 0.6 mEq/L to 5.2 ± 0.8 mEq/L. Only 10 out of 23 patients showed systolic blood pressure reduction by ≥10 mm Hg. Naturally, plasma renin immunoreactivity increased, while plasma renin activity, along with angiotensin II and aldosterone levels decreased. Basal levels of the components of the renin-angiotensin-aldosterone system were not significantly different in patients showing systolic blood pressure reduction by ≥10 mm Hg (n = 10) vs. those with <10 mm Hg changes (n = 13). The reduction in systolic blood pressure in all 23 patients taken as a whole correlated with changes in plasma renin activity (r = -0.432, P < 0.05) and angiotensin II (r = 0.467, P < 0.05). In chronic hemodialysis patients, aliskiren modestly lowers blood pressure over the long term, although the antihypertensive effect seems dependent on the changes, but not on the basal levels of plasma renin activity and angiotensin II.

Topics: Aged; Amides; Angiotensin II; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary β2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Topics: Aged; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetic Nephropathies; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome

Most patients with hypertension need more than one drug to achieve blood pressure (BP) control. This randomized, double-blind, multifactorial study evaluated whether combinations of aliskiren and amlodipine provided superior BP reductions to component monotherapies in patients with hypertension (mean sitting diastolic BP (msDBP) 95-<110 mm Hg). Overall, 1688 patients were randomized to once-daily monotherapy with aliskiren 150 or 300 mg or amlodipine 5 or 10 mg, combination therapy with one of four corresponding aliskiren/amlodipine doses, or placebo for 8 weeks. At week 8 end point, aliskiren/amlodipine combinations provided significant msDBP reductions from baseline of 14.0-16.5 mm Hg, compared with reductions of 8.0 and 10.2 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 11.0 and 13.8 mm Hg for amlodipine 5 and 10 mg, respectively (P<0.05). Aliskiren/amlodipine combinations provided reductions in mean sitting systolic BP 20.6-23.9 mm Hg, compared with decreases of 10.7 and 15.4 mm Hg for aliskiren 150 and 300 mg, respectively (P<0.001), and 15.8 and 21.0 mm Hg for amlodipine 5 (P< or =0.001) and 10 mg (P=NS), respectively. Aliskiren/amlodipine combination therapy provides greater BP lowering than either agent alone, hence offering an effective treatment option for patients with hypertension.

Topics: Adult; Aged; Amides; Amlodipine; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin

Blockade of the renin-angiotensin system (RAS) is a critical approach to the management of hypertension, especially in proteinuric patients. It is well proven that the direct renin inhibitor aliskiren shows comparable clinical efficacy to the angiotensin II receptor blocker valsartan on blood pressure control and albuminuria. However, there is only limited data on the hand-to-hand effectiveness of these two RAS blockers in improving arterial stiffness. We tested whether aliskiren or valsartan would improve arterial stiffness in hypertensive patients with albuminuria who are already on antihypertensive therapy.. Thirty-four patients with hypertension and albuminuria < 1 g, after a wash-out period of three weeks, were randomized to aliskiren or valsartan in a 24-week randomized parallel-group study.. A nonsignificant difference in blood pressure was seen between the two treatment groups. Albuminuria was significantly reduced in both groups (56% for the aliskiren group, p < 0.05, and 38% for the valsartan group, p < 0.05). Only valsartan but not aliskiren significantly reduced carotid-femoral pulse wave velocity (-1.1 ± 0.8 m/s (p = 0.02) for valsartan and +0.1 ± 0.7 m/s (ns) for aliskiren).. The results of our study showed that valsartan improves arterial stiffness to a significantly greater extent than aliskiren, despite a similar antihypertensive and antiproteinuric effect.

Topics: Albuminuria; Amides; Antihypertensive Agents; Demography; Female; Fumarates; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pulse Wave Analysis; Tetrazoles; Treatment Outcome; Valine; Valsartan

The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria.. We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90 mmHg, an estimated glomerular filtration rate of 90-30 mL/min/1.73 m(2), and albuminuria >30 mg/g, despite treatment with a 160 mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160 mg/day valsartan to 150 mg/day aliskiren, which was later increased to 300 mg/day (n = 20); and the valsartan group, who continued with 160 mg/day valsartan (n = 20).. After 12 weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r = 0.564, P = 0.0084).. We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Topics: Adult; Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Female; Fumarates; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Nephritis; Nephrosclerosis; Tetrazoles; Valine; Valsartan

Poor adherence to antihypertensive drug treatment is common and is often associated with marked prolongations of the dosing interval. Hence, selecting a treatment that has the potential to provide a sustained blood pressure (BP)-lowering effect is important. The objective of this analysis is to compare the sustained efficacy of aliskiren with telmisartan after a single missed dose. This is part of a 12-week double-blind study conducted in patients with mild to moderate hypertension randomized to once-daily aliskiren 150 mg or telmisartan 40 mg for 2 weeks, force-titrated to double the doses for 10 weeks, followed by placebo for 1 week. The changes in BP from the end of active treatment (EOA) to 48 hours after treatment withdrawal (day 2) were analyzed. Demographic and baseline characteristics were comparable between the treatment groups. Aliskiren continued to show significantly greater reductions in mean sitting systolic BP (-0.7 vs +1.3 mm Hg; P<.05), 24-hour mean ambulatory systolic BP (-3.6 vs +2.6 mm Hg; P<.01), and 24-hour mean ambulatory diastolic BP (-3.7 vs +0.4 mm Hg; P<.01) compared with telmisartan from EOA to day 2, despite the similar BP reductions from randomization to EOA. In conclusion, aliskiren sustained the BP-lowering efficacy better than telmisartan after a single missed dose.

Topics: Adult; Amides; Antihypertensive Agents; Benzimidazoles; Benzoates; Double-Blind Method; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Least-Squares Analysis; Male; Patient Compliance; Telmisartan; Treatment Outcome

In this double-blind study, 1143 hypertensive participants with type 2 diabetes and stage 1 or 2 chronic kidney disease (CKD) were randomized to receive combination aliskiren/valsartan 150/160 mg or valsartan 160 mg monotherapy for 2 weeks, with force-titration to 300/320 mg and 320 mg, respectively, for another 6 weeks. Ambulatory blood pressure (ABP), the primary outcome, was available for 665 participants. Reductions from baseline to week 8 in 24-hour ABP were -14.1/-8.7 mm Hg with aliskiren/valsartan vs -10.2/-6.3 mm Hg with valsartan (P<.001). Adverse events were reported in 202 participants (35.2%) taking aliskiren/valsartan and 182 participants (32.2%) taking valsartan. No participant had blood urea nitrogen values>40 mg/dL or serum creatinine values>2.0 mg/dL. There were no confirmed cases of serum potassium values≥6.0 mEq/L. Combination aliskiren/valsartan has additive effects on blood pressure reduction and tolerability similar to valsartan in hypertensive/diabetic participants with early-stage (stages 1 and 2) CKD.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Comorbidity; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Severity of Illness Index; Tetrazoles; Treatment Outcome; Valine; Valsartan

Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin-angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.

Topics: Administration, Oral; Adolescent; Adult; Amides; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diuretics; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Least-Squares Analysis; Male; Middle Aged; Models, Biological; Renin; Tablets; Therapeutic Equivalency; Treatment Outcome; Young Adult

This 8-week, randomized, double-blind, parallel-group study compared the efficacy and safety of aliskiren with ramipril in Asian patients with mild to moderate hypertension. Following a 2- to 3-week placebo run-in period, patients with mean sitting diastolic blood pressure (msDBP) ≥95 and <110 mm Hg were randomized to receive once daily dose of either aliskiren 75, 150, 300 mg or ramipril 5 mg for 8 weeks. Efficacy variables were the changes in msDBP and mean sitting systolic BP (msSBP) and BP control rates (<140/90 mm Hg). Safety was assessed by recording adverse events (AEs) and serious AEs (SAEs). Of 1316 randomized patients, 1160 (88.1%) completed the study. At the study endpoint, patients on aliskiren had greater mean BP reductions (14.39/11.63 mm Hg for 300 mg; 12.16/10.04 mm Hg for 150 mg; 12.24/10.66 mm Hg for 75 mg) than those on 5 mg ramipril (11.46/9.19 mm Hg). All aliskiren doses were statistically non-inferior (P<0.0001) to ramipril in reducing msDBP. The reduction in BP for aliskiren 300 mg was statistically superior vs. ramipril (P<0.002). Blood pressure control rates were higher for aliskiren (300 mg, 52.29%; 150 mg, 48.11%; 75 mg, 45.68%) than for ramipril (5 mg, 43.7%); the difference for aliskiren 300 mg vs. ramipril 5 mg was statistically significant (P<0.05). Aliskiren was well tolerated with a fourfold lower incidence of cough (0.6-1.2%) compared with ramipril (5.2%). SAEs were rare in this study (0.5%). Aliskiren produced greater BP reductions with a lower incidence of cough than ramipril in Asian patients with mild to moderate hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Severity of Illness Index; Treatment Outcome

To evaluate the effect of aliskiren compared to amlodipine on QT duration and dispersion in hypertensive patients with type 2 diabetes.. A total of 170 outpatients aged 50-75 years with mild to moderate hypertension (SBP >130 and <180 mmHg and DBP >80 and <100 mmHg) and type 2 diabetes were randomly treated with aliskiren 300 mg or amlodipine 10 mg, both given once daily for 24 weeks, according to a prospective, open label, blinded-end point, parallel group design. At the end of the placebo run-in, and after 12, and 24 weeks of treatment blood pressure (BP) measurements (by mercury sphygmomanometer, Korotkoff I and V), plasma biochemistry and a standard 12-lead surface ECG were evaluated.. Both aliskiren and amlodipine significantly reduced systolic blood pressure (SBP)/diastolic blood pressure (DBP) values (-27.2/-14.3 mmHg, p < 0.001 vs. placebo and -27.8/-14.2 mmHg, p < 0.001 vs. placebo, respectively), with no statistical difference between the two drugs. Aliskiren, but not amlodipine, significantly reduced maximum QT interval (QTmax) (-14 ms at 12 weeks and -17 ms at 24 weeks, both p < 0.05 vs. placebo) and corrected QT max (QTc max) (-26 ms and -31 ms, p < 0.01) as well as the dispersion of both QT (-11 ms and -13 ms, p < 0.01) and QTc (-18 ms and -19 ms, p < 0.01).. Despite similar BP lowering effect, aliskiren, but not amlodipine, reduced QT duration and dispersion, which might be related to the ability of aliskiren to interfere with mechanisms underlying myocardial electrical instability in the heart of diabetic hypertensive patients.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Electrocardiography; Female; Fumarates; Heart Conduction System; Humans; Hypertension; Long QT Syndrome; Male; Middle Aged; Prospective Studies

We aimed to investigate whether the single pill combination (SPC) of aliskiren 300 mg and amlodipine 10 mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40 mg and amlodipine 10 mg (OLM 40/AMLO 10).. Open-label, non-randomized single-arm study. Patients with stage 2 hypertension were titrated to the SPC OLM 40/AMLO 10 (4-week Phase 1). If hypertension was not controlled they were switched to the SPC ALIS 300/AMLO 10 (4-week Phase 2). In the optional 4-week study extension hydrochlorothiazide (HCT) 12.5 mg was added. EudraCT 2009-016693-33.. In the 342 patients treated, OLM 40/AMLO 10 reduced systolic BP (SBP)/diastolic BP (DBP) by 24.5/14.5 mmHg by end of Phase 1. Those 187 patients with uncontrolled hypertension at the end of Phase 1 switched to ALIS 300/AMLO 10 experienced a further SBP reduction of 5.1 mmHg (95% confidence interval [CI] 3.7 to 6.5, p < 0.0001) and a DBP reduction of 4.8 mmHg (95% CI 3.8 to 5.8; p < 0.0001) in Phase 2. DBP or SBP responder rates were achieved by 51.3% or 44.4%, respectively, SBP and DBP normalization by 36.4%. In 65 patients whose BP was not controlled in Phase 2, SPC ALIS 300/AMLO 10/HCT 12.5 mg decreased SBP/DBP by further 8.1/6.7 mmHg (p < 0.0001 each). No deaths or serious adverse events were noted. Significant adverse events leading to study discontinuation were reported in 2.6% (Phase 1), 2.7% (Phase 2), and 0% (extension). Limitations included the open-label, single-arm non-randomized design, and the relatively short duration.. In this switch study reflecting clinical practice, patients with moderate hypertension not controlled by the SPC OLM 40/AMLO 10 achieved a clinically and statistically significant reduction of blood pressure from the SPC ALIS 300/AMLO 10 and the optional addition of HCT. All drug combinations were well tolerated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Drug Combinations; Drug Resistance; Drug Substitution; Female; Fumarates; Humans; Hypertension; Imidazoles; Male; Middle Aged; Tablets; Tetrazoles; Treatment Failure; Treatment Outcome; Young Adult

This randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of aliskiren 75, 150, and 300 mg to clarify the dose-response relationship and characterize the optimum aliskiren dose when given with a light meal to elderly hypertensive patients. After washout, 754 patients aged ≥65 years with hypertension (mean sitting systolic blood pressure [msSBP] ≥150 and <180 mm Hg; mean sitting diastolic blood pressure [msDBP] <110 mm Hg) were randomized to aliskiren 75, 150, or 300 mg or placebo for 8 weeks; medication was taken each morning with a light meal. The primary efficacy variable was change in msSBP from baseline to week 8 end point. Change from baseline in msDBP and dose-response curves for aliskiren 75, 150, and 300 mg were also assessed. At week 8 end point, all 3 aliskiren doses provided significantly greater least squares mean reductions in msSBP/msDBP (75 mg, 13/5 mm Hg; 150 mg, 15/6 mm Hg; 300 mg, 14/7 mm Hg) compared with placebo (8/4 mm Hg; P < .05). Aliskiren was generally well tolerated at all doses. There was a significant dose-response relationship for aliskiren, with an estimated minimum effective dose of 81.9 mg. In conclusion, aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Meals; Treatment Outcome

In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients.. We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle.. We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine.. In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Extracellular Fluid; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Muscle, Skeletal; Obesity; Pilot Projects; Renin-Angiotensin System

Many patients with hypertension will require multiple antihypertensive drugs to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combinations (SPCs) in patients with mild-to-moderate hypertension who were non-responsive to aliskiren monotherapy. After a 4-week run-in with aliskiren 300 mg, patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg were randomized to oncedaily aliskiren/ amlodipine 300/10 mg or 300/5 mg, or aliskiren 300 mg for 8 weeks. Aliskiren/amlodipine SPCs provided significantly greater mean reductions in mean sitting systolic BP/msDBP (300/10 mg, 18.0/13.1 mmHg; 300/5 mg, 14.4/10.5 mmHg) than aliskiren 300 mg (6.4/5.8 mmHg) at week 8 endpoint. This represents additional mean reductions of 11.6/7.2 mmHg (300/10 mg) and 8.0/4.7 mmHg (300/5 mg) over aliskiren alone (both p < 0.0001). Significantly more patients achieved BP control ( < 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (65.5%) and 300/5 mg (56.6%) than with aliskiren (31.5% both p < 0.0001). Aliskiren, alone and in combination with amlodipine, was well tolerated, with a slightly higher incidence of adverse events with SPCs (29.0-30.1%) than with monotherapy (22.7%). In conclusion, aliskiren/amlodipine SPCs offer an effective next step for patients who have an inadequate BP response to aliskiren alone.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Resistance; Europe; Female; Fumarates; Humans; Hypertension; India; Least-Squares Analysis; Logistic Models; Male; Middle Aged; Republic of Korea; Tablets; Time Factors; Treatment Outcome; Vasodilator Agents; Venezuela

Most patients with hypertension will require treatment with at least two antihypertensive agents to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combination (SPC) therapy in patients with mild-to-moderate hypertension who are inadequately responsive to amlodipine monotherapy. Patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg 110 mmHg after 4 weeks' treatment with amlodipine 10 mg were randomized to once-daily aliskiren/amlodipine 300/10 mg (n = 279) or 150/10 mg (n = 285) or amlodipine 10 mg monotherapy (n = 283) for 8 weeks. Aliskiren/amlodipine 300/10 and 150/10 mg SPCs provided significantly greater reductions in mean sitting systolic BP/msDBP (14.4/11.0 and 11.0/9.0 mmHg, respectively) than amlodipine 10 mg (8.2/7.2 mmHg) at week 8 endpoint. This represents additional mean reductions of 6.2/3.8 mmHg (300/10 mg) and 2.8/1.7 mmHg (150/10 mg) over amlodipine alone (all P < 0.01). Significantly more patients achieved BP control (< 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (58.8%) than amlodipine 10 mg (38.4%; P < 0.0001). Aliskiren/amlodipine SPCs were generally well tolerated. In conclusion, aliskiren/amlodipine SPCs offers an effective option for management of patients who have an inadequate BP response to amlodipine alone.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Argentina; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Resistance; Europe; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Tablets; Time Factors; Treatment Outcome; Turkey; Vasodilator Agents

The renin-angiotensin system (RAS) is a key target for blood pressure control and for cardiovascular and renal protection. Aliskiren is the first-in-class direct oral inhibitor of renin that controls the rate-limiting step in the RAS cascade. So far little is known about the use and efficacy of aliskiren in the treatment of essential hypertension under clinical practice conditions.. The 3A registry was an open, prospective cohort study (observational registry) of 14,988 patients in 899 offices throughout Germany. Consecutive patients were eligible for inclusion if their physician had decided to modify their antihypertensive therapy. This included treatment with aliskiren or an angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB) or agents not blocking the RAS, alone or on top of an existing drug regimen.. Mean age of patients was 65 years, their mean body mass index was 28.2 kg/m(2) 53.5% were men, 36% working, 90% in statutory health insurance and 26% in any disease management programme. Patients in the aliskiren and the RAS groups compared with the non-RAS group were older, more often men, had a longer history of hypertension, and had a higher prevalence of comorbidities (diabetes, chronic heart failure, ischaemic heart disease, renal disease). Mean systolic, but not diastolic blood pressure was substantially higher in the aliskiren group (158/91 mmHg vs. 154/89 mmHg in ACE-I/ARB vs. 152/89 mmHg in non-RAS). Mean number of antihypertensive drugs was higher in the aliskiren group compared with the other groups (3.0 drugs vs. 2.5 in ACE-I/ARB vs. 1.6 in non-RAS; p < 0.0001).. In this large cohort of outpatients with hypertension, aliskiren was used mainly in patients with more severe stages of hypertension and those with concomitant diseases such as diabetes mellitus and impaired renal function. The 3A registry will provide important information about the use and efficacy of aliskiren in a real-life setting.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Substitution; Drug Utilization Review; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Registries; Risk Factors

The AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients (ASSERTIVE) study was designed to assess the sustained blood pressure (BP)-lowering effect of aliskiren vs. telmisartan after a 7-day treatment withdrawal in patients with hypertension.. Patients were randomized to once-daily aliskiren 150  mg (N = 414) or telmisartan 40  mg (N = 408). After 2 weeks, all patients were uptitrated to double the initial dose for 10 weeks; subsequently, all patients were treated with placebo to simulate a 7-day treatment withdrawal.. At the end of active treatment (EoA), similar decreases in mean ambulatory BP were observed with aliskiren and telmisartan. From EoA to day 7 of treatment withdrawal (end of withdrawal, EoW), the least squares mean increase in 24-h mean ambulatory SBP was smaller for aliskiren (2.7 mmHg) vs. telmisartan (6.5  mmHg). Between-treatment difference was significant in favour of aliskiren (-3.8  mmHg; P < 0.0001). Similar effects were observed for the increase in 24-h mean ambulatory DBP after EoW (-2.1 mmHg; P < 0.0001). Mean sitting SBP and DBP were also significantly lower with aliskiren than telmisartan after EoW with SBP (2.0  mmHg) and DBP (1.1  mmHg) differences in favour of aliskiren, already evident on day 2 after a single 'missed dose'.. Aliskiren showed a greater and more sustained BP-lowering effect than telmisartan during a 7-day treatment withdrawal. Aliskiren may provide sustained BP lowering during 1 day or more missed dose.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Benzimidazoles; Benzoates; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Complications; Double-Blind Method; Female; Fumarates; Humans; Hypertension; International Cooperation; Male; Medication Adherence; Middle Aged; Placebos; Telmisartan; Time Factors; Treatment Outcome

Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin-converting enzyme-inhibitor ramipril.. Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 μmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril.. Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection.

Topics: Adult; Amides; Antihypertensive Agents; Arterioles; Blood Flow Velocity; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Fumarates; Humans; Hypertension; Male; Middle Aged; omega-N-Methylarginine; Ramipril; Vascular Resistance; Vascular Stiffness; Vasodilator Agents

To evaluate the clinic and ambulatory blood pressure (BP)-lowering efficacy and safety of an aliskiren/amlodipine/hydrochlorothiazide (HCT) triple combination compared with the component dual combinations, in patients with moderate-to-severe hypertension.. This 8-week, double-blind, randomized, active-controlled study, after 1-4 weeks single-blind placebo run-in period, randomized 1191 patients to receive once-daily aliskiren/amlodipine 150/5 mg (n = 287), aliskiren/HCT 150/12.5 mg (n = 298), amlodipine/HCT 5/12.5 mg (n = 296), or aliskiren/amlodipine/HCT 150/5/12.5 mg (up-titrated from aliskiren/HCT 150/12.5 mg after initial 3 days) (n = 310) for 4 weeks, followed by forced titration to double the initial dose for the next 4 weeks.. Baseline mean sitting SBP and DBP (msSBP/msDBP) was comparable among treatment groups. The aliskiren/amlodipine/HCT combination resulted in significant least squares mean reduction in msSBP/msDBP from baseline to endpoints (week 4, -30.7/-15.9  mmHg; week 8, -37.9/-20.6  mmHg), superior (P < 0.001) to each of the dual combinations. The triple combination was associated with -27.8  mmHg reduction in msSBP at week 2, significantly better than the dual combinations (P < 0.05). Significantly greater mean SBP/DBP-lowering effect for triple vs. dual combinations was also demonstrated through 24-h, daytime, and night-time ambulatory BP measurements. Significantly greater (P < 0.001) BP control (msSBP/msDBP < 140/90  mmHg) was achieved with triple combination in patients with moderate-to-severe (62.3%) and severe (57.5%) hypertension.. Aliskiren/amlodipine/HCT at 150/5/12.5 mg (week 4) and 300/10/25 mg (week 8) provided statistically superior reductions in msSBP/msDBP and greater BP control rates vs. the dual combinations, and was well tolerated. The improved efficacy of BP reduction was evident within 2 weeks of initiating triple therapy even at low dose.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Placebos; Severity of Illness Index; Single-Blind Method

In a prespecified subgroup analysis of a 12-week multinational, randomized, double-blind, parallel-group trial, self-identified Hispanic/Latino adult men and women with systolic blood pressure 160 mm Hg to 179 mm Hg received combination aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg (force-titrated to 300/25 mg and 300 mg, respectively, at week 1). At week 12, combination aliskiren/HCT provided greater reduction in mean sitting systolic blood pressure from baseline, the primary efficacy variable, compared with aliskiren monotherapy (-32.6 mm Hg vs -19.6 mm Hg; P<.0001). Differences in mean sitting diastolic blood pressure reductions followed a similar pattern (-13.5 mm Hg vs -7.1 mm Hg; P<.0001). Notable blood pressure reductions were evident at week 1 in both treatment groups, with near-maximal effects reached by week 8. Results were consistent regardless of country of residence. Both treatments were well tolerated. Aliskiren alone or in combination with HCT is safe and effective in Hispanic/Latino patients with stage 2 hypertension. Combination aliskiren/HCT produced greater blood pressure reductions than aliskiren monotherapy.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diastole; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Hispanic or Latino; Humans; Hydrochlorothiazide; Hypertension; International Cooperation; Male; Middle Aged; Severity of Illness Index; Systole; Treatment Outcome

Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151 ± 11 mm Hg vs 132 ± 11 mm Hg; clinic diastolic BP, 91 ± 13 mm Hg vs 82 ± 9 mm Hg; 24-hour systolic BP, 144 ± 12 mm Hg vs 133 ± 11 mm Hg; 24-hour diastolic BP, 88 ± 8 mm Hg vs 81 ± 9 mm Hg; central BP, 162 ± 16 mm Hg vs 148 ± 14 mm Hg; baPWV, 1625 ± 245 cm/s vs 1495 ± 199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Female; Fumarates; Hemodynamics; Humans; Hypertension; Japan; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Vascular Stiffness

To assess the extent of reduction in blood pressure (BP) of aliskiren/amlodipine combination therapy compared with amlodipine monotherapy in moderate-to-severe hypertensive patients.. This was an 8-week multicentre, randomised, double-blind study. After a 1-to 4-week washout period, eligible patients [mean sitting systolic blood pressure (msSBP) ≥ 160 to < 200 mmHg] were randomised to receive a once-daily dose of aliskiren/amlodipine 150/5mg (n = 244) or amlodipine 5 mg (n = 241) for 1 week, followed by up-titration to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. Efficacy outcome measures included change from baseline to week 8 endpoint in msSBP (primary endpoint), mean sitting diastolic blood pressure (msDBP), and BP control rate (< 140/90 mmHg). Safety was assessed by monitoring and recording all adverse events (AEs) and laboratory abnormalities.. Patients' demographic characteristics were balanced between the two groups, mean baseline BP being 171.0/94.3 mmHg for aliskiren/amlodipine and 171.8/95.6 mmHg for amlodipine. Of 485 randomised patients, 433 (89.3%) completed the study. At week 8 endpoint, combination therapy resulted in significantly greater msSBP/msDBP reductions and BP control rate, compared with monotherapy (all: p ≤ 0.0001). The overall incidence of AEs was similar between the two groups. The most commonly reported AE was peripheral oedema with the incidence lower for combination therapy (14.4%) than for monotherapy (18.3%).. In this population with considerably elevated BP, use of aliskiren/amlodipine combination showed significantly greater BP reductions and allowed more patients to achieve BP control compared with amlodipine monotherapy, with no additional safety concerns.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Double-Blind Method; Drug Combinations; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis.. Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations.. Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration-time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred.. The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.

Topics: Administration, Oral; Adult; Amides; Blood Pressure; Drug Administration Schedule; Fumarates; Humans; Hypertension; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Renin

Combination antihypertensive therapies are recommended to attain blood pressure (BP) targets especially in high-risk patients in whom rapid and pronounced BP control is essential. This 28- to 54-week, open-label, multicenter study evaluated the safety and efficacy of a triple combination, aliskiren with amlodipine and hydrochlorothiazide (HCTZ), in patients with moderate to severe hypertension. Following a washout period of up to 4 weeks, patients received aliskiren/HCTZ 300/12.5 mg for 1 week, followed by add-on amlodipine 5 mg for 1 week. Thereafter, the doses of amlodipine and HCTZ were doubled. The first 206 of 564 patients who completed 28 weeks of study continued for an additional 26 weeks. Safety was assessed by recording all adverse events. Efficacy variables included changes in BP from baseline to endpoint and BP control rate. Of 564 patients, 493 completed the study. Peripheral edema (9.4%), headache (5.7%), nasopharyngitis (4.1%), and bronchitis (3.7%) were reported frequently. Clinically significant reductions in mean sitting systolic BP/mean sitting diastolic BP from baseline (-34.2/-20.3 mm Hg and -37.3/-21.8 mm Hg at weeks 28 and 54, respectively) were observed. Corresponding BP control rates were 69.1% and 77.1%. The aliskiren/amlodipine/HCTZ combination in patients with moderate to severe hypertension was well tolerated and provided clinically significant BP reductions and effective BP control.

Topics: Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Monitoring; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Middle Aged; Pharmacovigilance; Severity of Illness Index; Treatment Outcome

Pharmacological inhibition of renin-angiotensin-aldosteron system (RAAS) may reduce proteinuria and the rate of chronic kidney disease progression. The aim was to compare the effects on albuminuria of the therapy with either: (i) telmisartan 80 mg and aliskiren 300 mg, (ii) telmisartan 80 mg and eplerenone 50 mg, (iii) telmisartan 160 mg as monotherapy.. Randomized, double-center, double-blind, cross-over, three treatments-three periods of 8 weeks each study. 18 patients with non-diabetic proteinuric CKD stage 1-3 completed the protocol.. There was significant difference in albuminuria between studied therapies (ANOVA; p<0.01). The combination therapy with telmisartan plus aliskiren decreased albuminuria more effectively than the treatment with telmisartan plus eplerenone and monotherapy with telmisartan 160 mg OD [376 mg/g creatinine (286-686) vs. 707 (502-1204) vs. 525 (318-763); post-hoc p<0.01 and p<0.05, respectively].. The study demonstrated that the combination therapy with angiotensin receptor blocker (ARB) and renin inhibitor was more effective in albuminuria lowering than the concomitant usage of ARB and mineralocorticoid receptor antagonist as well as than ARB in doses two-fold higher than usually used in treatment of hypertension in patients with non-diabetic CKD and that this higher antiproteinuric efficacy was independent on changes in blood pressure.

Topics: Adult; Albuminuria; Amides; Angiotensin Receptor Antagonists; Benzimidazoles; Benzoates; Comorbidity; Cross-Over Studies; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Severity of Illness Index; Spironolactone; Telmisartan; Treatment Outcome

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Glucose; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Inflammation; Irbesartan; Lipids; Male; Metabolic Syndrome; Middle Aged; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

The majority of patients with essential hypertension of moderate severity (WHO grade 2) require combination therapy. We aimed to investigate whether the single-pill combination of aliskiren 300  mg and hydrochlorothiazide (HCT) 25  mg (ALIS 300/HCT 25) improves the BP reduction in hypertensive patients not adequately controlled by the free combination of candesartan 32  mg and HCT 25  mg (CAN 32 + HCT 25).. In an open-label, single-arm study, patients with mean sitting diastolic blood pressure (DBP) between 100-109  mmHg at baseline received 4-week treatment with CAN 32 + HCT 25 (Phase 1), followed - in patients whose BP was not controlled - by 4-week treatment with ALIS 300/HCT 25 (Phase 2). The DBP change between weeks 4 and 8 was the primary endpoint. The ClinicalTrials.gov Identifier is NCT00867490.. In the 186 patients treated, CAN 32 + HCT 25 reduced systolic BP (SBP)/DBP by 18.9/12.2 mmHg. Those 123 patients with uncontrolled hypertension switched to ALIS 300/HCT 25 experienced a further SBP/DBP reduction of 2.8/3.1  mmHg between week 4 and week 8 (p = 0.0064 and p < 0.0001), and 33.3% achieved DBP normalisation. In 61 patients not controlled after week 8 (SBP ≥ 140  mmHg or DBP  ≥  90  mmHg), who participated in an optional study extension, amlodipine 5  mg was added. Triple therapy over 4 weeks decreased SBP/DBP by further 9.2/5.9  mmHg (p < 0.0001 each). Adverse events with suspected drug relationship were noted in 4.3% (Phase 1), 3.3% (Phase 2), and 1.6% (extension) of the patients. Limitations of the study include the open-label, non-randomised approach and short treatment duration across the individual phases.. In this open-label, single-arm switch study reflecting clinical practice, patients with moderate hypertension not controlled by the free combination of CAN 32 + HCT 25 achieved a clinically and statistically significant reduction of blood pressure from the single pill combination of ALIS 300/HCT 25, and the optional addition of amlodipine.

Topics: Adult; Aged; Algorithms; Amides; Amlodipine; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Tetrazoles; Treatment Failure; Treatment Outcome

The 'DRIVER' study was designed to investigate the 'real-world' effectiveness of aliskiren-based treatment of hypertension. This article reports the 180-day blood pressure (BP) outcomes, and the multilevel (physician- and patient-level) determinants thereof.. DRIVER was a prospective, observational, open-label, multi-centre, pharmaco-epidemiologic study of hypertensive patients treated with aliskiren in whom prior treatment failed or was not tolerated. 2070 patients (enrolled by 426 physicians) were enrolled; 1695 patients (81.9%) completed the 180-day aliskiren treatment period. Mean patient age was 64.2 ± 12.1 years; 53.7% were men, 25.3% diabetic and 40.7% had a high or very high cardiovascular (CV) risk. At 180 days, the mean ± SD reductions in systolic and diastolic BP were -22.9 ± 16.7 mmHg and -10.5 ± 10.9 mmHg respectively (both p < .001). 2007 and 2009 guideline-defined BP control was achieved in 36.4% and 56.3% of patients, respectively (both p < .001). 64.2% of eligible patients had a reduction in CV risk (p < .001). A physician-level class effect was responsible for 22.8% and 28.1% of variability in systolic and diastolic BP, respectively, for 20.1% of variability in BP control, and for 16.1% of variability in the reduction of CV risk. Both patient- (e.g. adherence) and physician-related factors (e.g. age and knowledge) were significant in profiling best response to treatment with aliskiren. Adverse events reported in this article were consistent with the aliskiren scientific leaflet.. Aliskiren is safe and effective in reducing BP, improving BP control and reducing global CV risk in a 'real-world' setting and for patients in whom prior treatment failed or was not tolerated. Optimising treatment adherence and strategic medical education may be ways of improving BP outcomes in patients with hypertension.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Risk Factors; Treatment Outcome

Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses.. To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk.. For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%).. Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients).. To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Topics: Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Medication Adherence; Ramipril; Risk Factors; Tetrazoles; Treatment Outcome

Short-term studies have suggested that the use of initial combination therapy for the control of blood pressure improves early effectiveness. We tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy.. We did a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862.. 318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001). At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI -0·05 to 2·9; p=0·059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension.. We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended.. Novartis Pharma AG.

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Diastole; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Systole

Patients with stage 2 systolic hypertension require sizable blood pressure (BP) reductions to achieve recommended targets. This randomized double-blind study compared a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (aliskiren/HCTZ) with HCTZ monotherapy in older patients (older than 55 years) with systolic BP ≥160 mm Hg and <200 mm Hg. After a 1- to 4-week washout, 451 patients were randomized to once-daily aliskiren/HCTZ 150/12.5 mg or HCTZ 12.5 mg for 1 week, and then double the doses for 7 weeks. Overall baseline BP was 168.8/91.4 mm Hg. At week 4 (primary) end point, aliskiren/HCTZ provided significantly greater BP reductions from baseline than HCTZ monotherapy (29.6/9.3 mm Hg vs 22.3/6.8 mm Hg) and resulted in a greater proportion of patients achieving BP goal of <140/90 mm Hg (51.1% vs 33.3%). Aliskiren/HCTZ therapy provides substantial BP reductions and may thus be a useful treatment option for older patients with stage 2 hypertension.

Topics: Age Factors; Aged; Amides; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Body Mass Index; Disease Progression; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Health Status Indicators; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Systole; Treatment Outcome; United States

Recent guidelines for the management of hypertension recommend an individualised stepped-care treatment approach in mild-to-moderate hypertensive patients, to achieve blood pressure (BP) goals. This study evaluated the probability of patients achieving BP targets with an aliskiren-based stepped-care treatment regimen.. This was a 24-week, open-label, non-comparator study design that included six sequential 4-week treatment periods in patients with mild-to-moderate hypertension. Over the potential 24 weeks of active treatment, incremental therapy included the following add-on therapies at 4-week intervals: aliskiren 150-300 mg once daily, hydrochlorothiazide (HCTZ) 12.5-25 mg once daily, and finally amlodipine 5-10 mg once daily, as needed to achieve target BP. Subjects achieving BP targets following any given 4 weeks of therapy were considered study completers, while subjects not achieving their clinical BP target entered into the next step of incremental therapy. The primary efficacy end-point was the estimated cumulative probability of patients achieving BP target.. Of 256 patients treated, 232 (90.6%) completed the study. Baseline mean sitting BP was 155.7/91.7 mmHg. At study end-point, the estimated cumulative probability of reaching BP target was 86.12%. The stepped-care treatment regimen was well tolerated at the maximal recommended doses of all the individual complimentary therapies.. An aliskiren-based stepped-care treatment regimen that subsequently included both HCTZ and amlodipine is effective in achieving BP goals in approximately 90% of patients with mild-to-moderate hypertension.

Topics: Adult; Aged; Algorithms; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Blood Pressure Determination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP).. After 4-week placebo, 120 outpatients with grade 1 - 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed.. Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01).. Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.

Topics: Amides; Amlodipine; Ankle; Ankle Joint; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Drug Synergism; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Prospective Studies; Renin; Renin-Angiotensin System

Efficacy of antihypertensive agents on central blood pressure (BP) in African Americans is not well studied. The authors report on an 8-week double-blind, randomized study of African American patients with stage 2 hypertension that compared brachial and central BP responses (substudy of 53 patients) to combination aliskiren/hydrochlorthiazide (HCTZ) and amlodipine monotherapy. Following a 1- to 4-week washout, initial therapy was aliskiren/HCTZ 150/12.5 mg (n=166) or amlodipine 5 mg (n=166) for 1 week, forced-titrated to aliskiren/HCTZ 300/25 mg or amlodipine 10 mg for 7 weeks. Mean seated systolic BP reductions from baseline was similar with both treatments (-28.6 mm Hg with aliskiren/HCTZ vs -28.2 mm Hg with amlodipine). In the substudy, significantly greater reductions in central systolic BP was observed with aliskiren/HCTZ vs amlodipine (-30.1 mm Hg vs -21.2; P=.031), although 24-hour mean ambulatory BP reductions between the two groups were similar. Central pressure is considered an important risk factor in African Americans, and these findings may suggest a new treatment option for these patients.

Topics: Adult; Amides; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Brachial Artery; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Headache; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome

High circulating aldosterone levels stimulate myocardial fibrosis and left ventricular hypertrophy (LVH). However, it is not clear whether suppression of aldosterone directly contributes to LVH regression in hypertensive patients.. The Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial randomised 465 hypertensive overweight subjects with LVH to the direct renin inhibitor aliskiren 300 mg, losartan 100 mg or the combination and followed patients for 9 months. All patients were treated to standard blood pressure targets. Left ventricular (LV) mass index (LVMI) and LV wall thickness (LVWT) were assessed by cardiac magnetic resonance. A subset of 136 patients who had plasma aldosterone concentration (ALDO) measured at baseline and study end was analysed.. At baseline, plasma ALDO was modestly related to systolic blood pressure, LVMI, and wall thickness (all, p < 0.05). Aliskiren, either alone or in combination, was associated with a significantly greater reduction from baseline to 9 months in plasma aldosterone than losartan alone (p < 0.02). Reduction in ALDO was related to reduction in LVMI even after adjustment for baseline ALDO, BP reduction and treatment group (p for trend = 0.042).. In hypertensive patients with increased LVWT, aliskiren alone or in combination with the angiotensin receptor blocker losartan provides greater reduction in aldosterone compared to losartan alone. Moreover, suppression of aldosterone was associated with reduction of LVH, independently of the change in SBP, suggesting that suppression of aldosterone, a known mediator of LVH, may be particularly important for LVH regression and as a target for therapy.

Topics: Aldosterone; Amides; Antihypertensive Agents; Blood Pressure; Demography; Female; Fumarates; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Organ Size; Systole

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

Topics: Adult; Amides; Amlodipine; Black or African American; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Drug Therapy, Combination; Edema; Fatigue; Female; Fumarates; Headache; Humans; Hypertension; Incidence; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome

Hypertension frequently coexists with diabetes mellitus, resulting in increased cardiovascular risk. Thus, BP control is crucial in decreasing morbidity and mortality in this difficult-to-treat patient population.. The objective of this study was to evaluate the efficacy and safety of aliskiren in hypertensive patients with diabetes not adequately responsive to the combination of valsartan and hydrochlorothiazide (HCT).. After a 1- to 4-week washout period, patients with a mean sitting diastolic BP (msDBP) ≥95 mmHg were treated with valsartan 160 mg for 2 weeks followed by valsartan/HCT 160 mg/25 mg for an additional 4 weeks (single-blind active run-in period). Patients whose msDBP remained ≥85 mmHg after the active run-in period were randomized (1 : 1) to receive aliskiren 150 mg (n = 184) or placebo (n = 179) as add-on therapy for 6 weeks. Aliskiren was then force-titrated to 300 mg once daily for another 6 weeks. Efficacy variables were: the change in msDBP and mean sitting systolic BP (msSBP) from baseline to week 12 endpoint, diastolic response (msDBP <80 mmHg or reduction of at least 10 mmHg), and BP control rate (<130/80 mmHg).. Of the 363 patients randomized, 328 (90.4%) completed the study (aliskiren and placebo groups: 89.7% and 91.1%, respectively). At week 12 endpoint, the least squares mean (LSM) changes in msDBP (aliskiren vs placebo: -5.8 vs -4.8 mmHg; p = 0.2767) and msSBP (aliskiren vs placebo: -7.3 vs -4.8 mmHg; p = 0.0725) were numerically greater in patients treated with aliskiren compared with those treated with placebo; however, this difference was not statistically significant. The proportion of diastolic responders (aliskiren and placebo: 68.5% and 72.9%, respectively; p = 0.8482) and patients achieving BP control (aliskiren and placebo: 16.0% and 16.4%, respectively; p = 0.7511) were similar for both groups. Overall, 63 (34%) and 59 (33%) patients in the aliskiren and placebo groups, respectively, experienced adverse events (AEs). The most commonly reported AEs were headache (placebo group: 6.1%) and dizziness (aliskiren group: 4.4%). Aliskiren was well tolerated.. The reductions in BP with aliskiren added to valsartan/HCT in this study were numerically greater compared with placebo added to valsartan/HCT, although not statistically significant.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Patient Dropouts; Potassium; Single-Blind Method

Most patients with hypertension will require combination therapy with at least two agents from different antihypertensive classes to achieve blood pressure (BP) control. Thiazide diuretics, such as hydrochlorothiazide (HCTZ), are widely used in combination therapy. The volume reduction with these agents stimulates the renin-angiotensin system (RAS), making RAS inhibitors such as the direct renin inhibitor aliskiren a logical choice for combination therapy with HCTZ.. The aim of this study was to investigate the long-term safety, tolerability and efficacy of the direct renin inhibitor aliskiren, with or without addition of the diuretic HCTZ.. In the 12-month core study, patients with hypertension (mean sitting diastolic BP ≥90 mmHg and <110 mmHg) were randomized in a 3 : 2 ratio to once-daily aliskiren 150 mg or 300 mg. At months 2, 3, 4, 6 and 9, treatment was adjusted in patients not achieving a BP goal of <140/90 mmHg. Patients not at goal on aliskiren 150 mg once daily were up-titrated to aliskiren 300 mg once daily. Patients not at goal with aliskiren 300 mg once daily received add-on HCTZ 12.5 mg once daily, which was up-titrated to 25 mg once daily if BP remained inadequately controlled. At month 12, patients who received aliskiren/HCTZ 300 mg/25 mg once daily for at least 8 months in the core study were eligible to enter a 4-month extension study.. Overall, 1625/1955 patients completed the core study, and 870/1955 patients received add-on HCTZ; 189/198 patients completed the 4-month extension. Aliskiren, with or without add-on HCTZ, was generally well tolerated; the incidence of adverse events (AEs) during the core study was similar among the four final treatment groups. The most frequently reported AEs in the core and extension studies were mild and transient cases of nasopharyngitis, headache and dizziness. Few patients exhibited laboratory abnormalities. Overall, aliskiren, with or without add-on HCTZ, reduced mean BP by 18.0/12.7 mmHg at core study endpoint, and 61.2% of patients achieved BP control. BP reductions with aliskiren/HCTZ 300 mg/25 mg combination therapy at the core study endpoint were maintained during the extension study.. In patients with hypertension, long-term treatment with aliskiren, with or without add-on HCTZ, is well tolerated and provides effective BP lowering that is sustained over 12 months.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Time Factors; Young Adult

Patients with stage 2 hypertension and diabetes are at high cardiovascular risk and require large blood pressure (BP) reductions to reach treatment goals. This randomized double-blind study compared aliskiren/hydrochlorothiazide (HCTZ) combination therapy with amlodipine monotherapy in 860 patients with mean sitting systolic BP (msSBP) ≥160 mm Hg to <200 mm Hg and type 2 diabetes. Patients received either once-daily aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg for 1 week then force-titrated to double the doses for 7 weeks. Baseline BP was 167.7/91.4 mm Hg. At week 8 end point, aliskiren/HCTZ provided significantly greater reductions in msSBP than amlodipine (28.8 mm Hg vs 26.2 mm Hg; P<.05). Mean sitting diastolic BP reductions were similar with aliskiren/HCTZ (9.9 mm Hg) and amlodipine (9.0 mm Hg). Achievement of BP control (<130/80 mm Hg) was significantly greater with aliskiren/HCTZ (23.2%) than amlodipine (13.8%; P<.0001). Aliskiren/HCTZ provides substantial msSBP reductions and greater BP control rates than amlodipine, and offers an attractive treatment option for patients with hypertension and diabetes mellitus.

Topics: Amides; Amlodipine; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin; Systole

Most patients inadvertently miss an occasional dose of antihypertensive therapy, and hence drugs that provide sustained blood-pressure (BP) reduction beyond the 24-h dosing interval are desirable. The primary objective of this study was to compare the 24-h mean ambulatory BP reductions from baseline after a simulated missed dose of the direct renin inhibitor aliskiren, irbesartan or ramipril. In this double-blind study, 654 hypertensive patients (24-h mean ambulatory diastolic BP (MADBP) >or=85 mm Hg) were randomized 1:1:1 to once-daily aliskiren 150 mg, irbesartan 150 mg or ramipril 5 mg. Doses were doubled after 2 weeks. At day 42, patients were again randomized equally within each group to receive 1 day of placebo ('missed dose') on either day 42 or day 49. Patients with a successful 24-h ambulatory BP measurement at baseline and on day 42/49 were included in the analyses. The 24-h mean ambulatory systolic BP (MASBP)/MADBP reductions from baseline after a missed dose of aliskiren 300 mg (9.3/7.0 mm Hg) were similar to irbesartan 300 mg (9.5/7.3 mm Hg) and significantly larger than ramipril 10 mg (7.1/5.0 mm Hg, P

Topics: Adult; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Brazil; Canada; Double-Blind Method; Drug Administration Schedule; Europe; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Medication Adherence; Middle Aged; Ramipril; Tetrazoles; Time Factors; Treatment Outcome

This 12-week, multicenter, open-label study assessed the efficacy, pharmacokinetics and safety of a once-daily aliskiren in Japanese hypertensive patients with renal dysfunction. Patients (n=40, aged 20-80 years) with mean sitting diastolic blood pressure (msDBP) >or=95 and <110 mm Hg and serum creatinine between >or=1.3 and <3.0 mg per 100 ml in males or between >or=1.2 and <3.0 mg per 100 ml in females were eligible. Patients began therapy with a once-daily morning oral dose of 75 mg of aliskiren. In patients with inadequate blood pressure control (msDBP >or=90 or mean sitting systolic blood pressure [msSBP] >or=140 mm Hg) and without safety concerns (serum potassium >5.5 mEq l(-1) or an increase in serum creatinine >or=20%), the aliskiren dose was increased to 150 mg and then to 300 mg in sequential steps starting from Week 2. Efficacy was assessed as change in msSBP/msDBP from baseline to the Week 8 endpoint (with the last observation carried forward). The mean reduction from baseline to Week 8 endpoint was 13.9+/-16.6 and 11.6+/-9.7 mm Hg for msSBP and msDBP, respectively. At the Week 8 endpoint, 65% patients had achieved blood pressure response (msDBP <90 or a 10 mm Hg decrease or msSBP <140 or a 20 mm Hg decrease) and 30% had achieved blood pressure control (msSBP <140 mm Hg and msDBP <90 mm Hg). Aliskiren was well tolerated with no new safety concerns in Japanese hypertensive patients with renal dysfunction.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Chemical Analysis; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Japan; Kidney Diseases; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Assessment; Young Adult

Efficacy and safety of the direct renin inhibitor aliskiren was compared with ramipril for treatment of essential systolic hypertension in elderly patients. A 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study was performed in 901 patients (aliskiren, n=457; ramipril, n=444) > or =65 years of age with systolic blood pressure (SBP) > or =140 mm Hg. Aliskiren 150-300 mg per day or ramipril 5-10 mg per day for was administered for 12 weeks with optional add-on therapy of hydrochlorothiazide (12.5-25 mg per day) at week 12 and amlodipine (5-10 mg per day) at week 22. The primary end point was non-inferiority of aliskiren vs ramipril monotherapy for change from baseline in mean sitting SBP (msSBP) at week 12. Decreases from baseline msSBP and mean sitting diastolic BP with aliskiren monotherapy (-14.0 and -5.1 mm Hg, respectively) were non-inferior (P<0.001 for both values) and superior to ramipril monotherapy (-11.6, -3.6 mm Hg; P=0.02, P<0.01, respectively). More patients achieved BP control with aliskiren (42%) than ramipril (33%; P<0.01). At week 36, fewer patients receiving aliskiren-based therapy required add-on treatment with hydrochlorothiazide or amlodipine (P=0.01 and 0.048, respectively). Tolerability was similar, but more patients receiving ramipril reported cough (P<0.001). In elderly patients with systolic hypertension, aliskiren proved to be more effective and better overall anti-hypertensive therapy compared to ramipril.

Topics: Aged; Amides; Antihypertensive Agents; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Ramipril; Renin; Treatment Outcome

Aliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP]≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (<140/90 mmHg) after 12 weeks of monotherapy was larger with aliskiren (34/88, 38.6%) than with ramipril (22/87, 25.3%; P = 0.038). In this post hoc analysis, 12 weeks of monotherapy with aliskiren 150-300 mg provided effective mean BP reductions (22/13 mmHg) and was superior to ramipril 5-10 mg in controlling BP in patients with stage 2 systolic hypertension.

Topics: Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Time Factors; Treatment Outcome

The optimal antiproteinuric dose of aliskiren is unknown. This study compared the effect of placebo and increasing doses of aliskiren on urinary albumin excretion rate (UAER).. The trial was a double-blind crossover design. Twenty-six patients with type 2 diabetes mellitus, hypertension and albuminuria were randomised to 2-month treatments with placebo or aliskiren 150 mg, 300 mg or 600 mg once daily, in random order. Primary endpoint was change in UAER; secondary endpoints included changes in 24-h BP, GFR, biomarkers and components of the renin-angiotensin-aldosterone system.. Placebo geometric mean UAER was 350 mg/day, mean 24-h BP was 137/81 (SD 12/9) mmHg, GFR was 85 (SD 26) ml min(-1) 1.73 m(-2). Aliskiren 150, 300 and 600 mg daily reduced UAER significantly by 36% (95% CI 17-51), 48% (33-60) and 52% (38-63) respectively (p < 0.001) compared with placebo. UAER reduction during the 600 mg dose was not significantly different from the 300 mg dose. Twenty-four-hour systolic BP was reduced by 4.5, 8.0 and 9.2 mmHg versus placebo, significant for 300 and 600 mg (p < or = 0.001). Twenty-four-hour diastolic BP was reduced by 3.0, 4.1 and 4.4 mmHg, significant versus placebo (p = 0.019, p = 0.001 and p < 0.001). GFR was reduced by 3.0, 5.1 and 6.5 ml min(-1) 1.73 m(-2). hsPRA was reduced by 63%, 70%, and 82% (p < 0.001 for all). Adverse events, most frequently dizziness and fatigue, occurred during all doses.. In patients with type 2 diabetes mellitus, hypertension and albuminuria there is no improved antiproteinuric effect when using 600 mg aliskiren daily compared with the maximal recommended antihypertensive dose of 300 mg.. Clinicaltrials.gov NCT00464776. Novartis Pharma AG.

Topics: Adult; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fumarates; Humans; Hypertension; Renin

The aim of this study was to compare the effect of aliskiren and losartan on fibrinolysis and insulin sensitivity (IS) in hypertensive patients with metabolic syndrome. After 2-week placebo period, 76 outpatients with mild to moderate hypertension and metabolic syndrome were randomized to aliskiren 300 mg od or losartan 100 mg od for 12 weeks. Clinic blood pressure (BP), plasma PAI-1 antigen, and tPA activity were evaluated after 2, 4, 8, and 12 weeks of treatment. At the end of each treatment period patients performed an euglycemic hyperinsulinemic clamp and IS was assessed by glucose infusion rate (GIR). Both aliskiren and losartan induced a significant and similar SBP/DBP reduction (-15.6/10.7 mmHg and -15.5/10.5 mmHg, p<0.001 vs. baseline, respectively). Both drugs decreased PAI-1 antigen and activity after 2 weeks of treatment; subsequently, only the decreasing effect of aliskiren was sustained throughout the 12 weeks [-7.5 ng/ml (-31%) p<0.05 vs. baseline], while with losartan PAI-1 increased at week 12 [+3.6 ng/ml (+15%), p<0.05 vs. baseline and p<0.01 vs. aliskiren)]. The tPA activity showed no significant change with aliskiren and a decrease with losartan [-0.04 IU/ml (-8%), p<0.05 vs. baseline and p<0.01 vs. aliskiren]. Aliskiren significantly increased GIR [+1.4 mg/min/kg (+28%), p<0.01 vs. baseline] while losartan did not change it [+0.2 mg/min/kg (+4%), NS vs. baseline, p<0.05 vs. aliskiren)]. These results indicated that in this type of patients, despite similar BP reduction, aliskiren improved the fibrinolytic balance as well as IS, while losartan worsened the fibrinolytic balance and did not affect IS. The clinical relevance of these different effects remains to be clarified.

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Female; Fibrinolysis; Fumarates; Humans; Hypertension; Insulin; Losartan; Male; Metabolic Syndrome; Middle Aged; Young Adult

Dietary sodium reduction and, as necessary, pharmacologic treatment are recommended for hypertension management. This prospective, randomized, open-label, blinded-end point, multicenter, crossover study investigated the effect of dietary sodium intake on mean ambulatory systolic blood pressure (maSBP) in patients with hypertension receiving aliskiren 300 mg once daily. Following a 2- to 4-week washout period, patients were randomized to a high- (≥ 200 mmol/d) or low- (≤ 100 mmol/d) sodium diet and were started on aliskiren, 300 mg/d. After 4 weeks, patients were crossed over to the alternate diet for an additional 4 weeks. The primary efficacy variable was change in maSBP between diets. During treatment with aliskiren, maSBP was significantly lower with the low-sodium diet compared with the high-sodium diet (least squares mean difference, 9.4 mm Hg; 95% CI, 7.5-11.4; P < .0001). The percentage of patients achieving a maSBP response to aliskiren (<130 mm Hg or a ≥ 20-mm Hg reduction from baseline) was greater with the low- (76.5%) versus the high-sodium diet (42.6%; P < .0001). Overall, 40.9% patients had ≥ 1 adverse event and the rates were similar between groups. In this study, aliskiren was well tolerated and a low-sodium diet accentuated its antihypertensive effect.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Systole; Young Adult

To assess the long-term safety and antihypertensive efficacy of aliskiren/valsartan 300/320 mg combination.. This was a 54-week, multicenter, open-label study (core phase), followed by a 26-week extension phase. Efficacy variables were change in msDBP and msSBP from baseline to endpoint (54-week and 80-week). Safety was assessed by monitoring and recording adverse events (AEs). ClinicalTrials.gov Identifier: NCT00386607 RESULTS: A total of 601 patients (msDBP ≥ 90 and <110 mmHg) entered the 54-week core study. Optional add-on HCT was allowed at week 10 onwards if BP was ≥ 140/90 mmHg at two consecutive visits. Of the 486 patients completed the core study, 180 patients entered the extension phase and received aliskiren/valsartan and add-on HCT (12.5 or 25 mg). Overall the combination of aliskiren/valsartan was well-tolerated and the majority of AEs were mild-to-moderate in severity. The incidence of SAEs was low (core phase: n = 22 [3.7%]; extension phase: n = 4 [2.2%]). Elevated serum potassium (>5.5 mmol/L at any time during the study) was observed in 21 (3.6%) patients. The majority of these elevations were transient and returned to normal in subsequent visits, and the discontinuation rate due to elevated serum potassium was low (0.3% [n = 2]). Decreased serum potassium levels (<3.5 mmol/L at any time during the study) was observed in 26 (4.4%) patients, mainly in patients receiving aliskiren/valsartan/HCT (n = 22; 7.1%). At the 54-week endpoint, a mean BP reduction of 20.5/13.4 mmHg from baseline (baseline BP: 152.9/97.0 mmHg) was observed and 66.9% (n = 398/595) of patients achieved BP control with aliskiren/valsartan with or without HCT. At the end of the extension phase (80-week endpoint), additional reduction in BP was obtained (overall, 28.8/18.3 mmHg) and 86.6% (n = 155/179) of patients achieved BP control with aliskiren/valsartan/HCT. A limitation is the absence of an active comparator group.. Long-term treatment with the combination of aliskiren/valsartan with or without HCT provided clinically meaningful BP reductions and high rates of BP control and was well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Amides; Antihypertensive Agents; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Middle Aged; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan; Young Adult

Patients with stage 2 hypertension (systolic blood pressure [SBP] ≥160mm Hg and/or diastolic blood pressure [DBP] ≥100mm Hg) are at high cardiovascular risk and require intensive blood pressure (BP)-lowering therapy. This randomized double-blind study is the first prospective trial specifically designed to evaluate the direct renin inhibitor aliskiren in patients with a mean sitting SBP ≥160 mm Hg and <180mm Hg (the lower ranges of stage 2 systolic hypertension). After a 2- to 4-week washout period, 688 patients were randomized to once-daily aliskiren/hydrochlorothiazide (HCT) 150/12.5mg or aliskiren 150mg for 1 week and then double the doses for 11 weeks. Baseline BP was 167.1/95.0mm Hg. At week 12, both aliskiren/HCT and aliskiren provided substantial BP reductions from baseline (30.0/12.6 mm Hg and 20.3/8.2 mm Hg, respectively). Aliskiren/HCT lowered BP significantly more than aliskiren (least-squares mean between-treatment differences [95% confidence interval] were -9.7 [-12.0 to -7.4] for SBP and -4.5 [-5.8 to -3.2] for DBP; both P<.0001). Similar BP reductions were seen in the subgroups of patients with isolated systolic hypertension and obesity. Aliskiren, with or without HCT, provides clinically significant BP reductions and may therefore be an effective treatment option in patients with stage 2 hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension.. After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (-20.3/-14.2 versus -18.6/-13.0 mm Hg; P<0.05) and were also greater at week 52 (-22.1/-16.0 versus -21.2/-15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (-17.4/-12.2 versus -14.7/-10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001).. Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.

Topics: Administration, Oral; Adult; Aged; Amides; Antihypertensive Agents; Double-Blind Method; Dyspepsia; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin; Single-Blind Method; Time

Left ventricular (LV) hypertrophy, a marker of cardiac end-organ damage, is associated with an increased risk of cardiovascular morbidity and mortality. Inhibitors of the renin-angiotensin-aldosterone system may reduce LV mass to a greater extent than other antihypertensive agents. We compared the effect of aliskiren, the first orally active direct renin inhibitor, the angiotensin-receptor blocker losartan, and their combination on the reduction of LV mass in hypertensive patients.. We randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m(2) to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the renin-angiotensin-aldosterone system and beta-blockers. Patients underwent cardiovascular magnetic resonance imaging for assessment of LV mass at baseline and at study completion. The primary objective was to compare change in LV mass index from baseline to follow-up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow-up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups (6.5+/-14.9/3.8+/-10.1 mm Hg in the aliskiren group; 5.5+/-15.6/3.7+/-10.7 mm Hg in the losartan group; 6.6+/-16.6/4.6+/-10.5 mm Hg in the combination arm; P<0.0001 within groups, P=0.81 between groups). LV mass index was reduced significantly from baseline in all treatment groups (4.9-, 4.8-, and 5.8 g/m(2) reductions in the aliskiren, losartan, and combination arms, respectively; P<0.0001 for all treatment groups). The reduction in LV mass index in the combination group was not significantly different from that with losartan alone (P=0.52). Aliskiren was as effective as losartan in reducing LV mass index (P<0.0001 for noninferiority). Safety and tolerability were similar across all treatment groups.. Aliskiren was as effective as losartan in promoting LV mass regression. Reduction in LV mass with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of blood pressure lowering. These findings suggest that aliskiren was as effective as an angiotensin receptor blocker in attenuating this measure of myocardial end-organ damage in hypertensive patients with LV hypertrophy.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome

Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25 mg therapy.. In this study, 722 patients with hypertension and an inadequate response to 4 weeks of HCT 25 mg (mean sitting diastolic BP > or =90 and <110 mmHg) were randomized to once-daily, double-blind treatment for 8 weeks with an SPC of aliskiren/HCT 300/25 mg or 150/25 mg, or continued HCT 25 mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week 8 endpoint.. Aliskiren/HCT 300/25 mg and 150/25 mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5 mmHg, respectively, both significantly greater reductions than HCT 25 mg alone (7.1/4.8 mmHg; both p < 0.001). Rates of BP control (<140/90 mmHg) were also significantly higher with aliskiren/HCT 300/25 mg (58%) and 150/25 mg (49%) than with HCT (26%; both p < 0.001). Aliskiren/HCT 300/25 mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25 mg SPC dose (all p < 0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5 mmol/L; aliskiren/HCT, 1.3-2.2%: HCT alone, 3.4%).. Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25 mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Young Adult

Inhibition of renin, the first rate-limiting enzyme in the renin-angiotensin system, has long been a therapeutic goal for treatment of hypertension. Aliskiren, the first in a new class of oral direct renin inhibitors, has been shown to reduce blood pressure (BP) in several short-term studies. In this 52-week, open-label, multicenter, parallel-group study, the long-term safety, tolerability, and efficacy of aliskiren-based therapy were assessed in Japanese patients (N=345) with mild-to-moderate essential hypertension. The study had two periods: (i) an 8-week, dose-titration period and (ii) a 44-week, fixed-dose period with an optional addition of a diuretic or a calcium channel blocker (CCB). Safety was assessed by monitoring all adverse events (AEs), serious AEs (SAEs), vital signs, laboratory parameters, ECGs, and physical examinations. Efficacy was assessed by trough mean sitting BP and responder rate. Aliskiren alone or in combination with a diuretic or a CCB was well tolerated. No deaths were reported during this study. Nine SAEs were reported, and for three of these, a possible relation to the study drug could not be excluded. The overall incidence of AEs was 85.2%, and most of these were mild-to-moderate events such as nasopharyngitis. The incidence of suspected study drug-related AEs was 25.3%. A clinically meaningful reduction of 17.6/12.8 mm Hg from baseline was achieved in the mean sitting BP at the end point with aliskiren, irrespective of the dose and additional treatments. The overall responder rate was 73.3% at the end point. In conclusion, this first long-term study in Japanese patients showed the safety and efficacy of aliskiren-based therapy in mild-to-moderate essential hypertension.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Female; Fumarates; Heart Rate; Humans; Hypertension; Japan; Long-Term Care; Male; Middle Aged; Renin; Young Adult

To compare the long-term efficacy, safety and tolerability of the direct renin inhibitor aliskiren against the diuretic hydrochlorothiazide (HCTZ) in obese patients with hypertension.. A post hoc analysis of 396 obese patients (body mass index > or = 30 kg/m2) in a 52-week study in 1124 patients with hypertension was performed. Patients were randomized to receive aliskiren 150 mg or HCTZ 12.5 mg for 3 weeks, or placebo for 6 weeks. At week 3, active treatment doses were doubled. Patients receiving placebo were randomized to aliskiren 300 mg or HCTZ 25 mg at week 6. Add-on amlodipine 5-10 mg was permitted from week 12 to achieve blood pressure (BP) control (<140/90 mmHg).. In the subgroup of obese patients, aliskiren monotherapy provided significantly greater BP reductions than HCTZ at week 12 endpoint (-16.7/-12.3 vs. -12.2/-9.1 mmHg, P < or = 0.001). Reductions were also greater with aliskiren-based therapy than HCTZ-based therapy at week 52 endpoint (-19.9/-15.5 vs. -17.5/-13.3 mmHg; P = 0.138 for systolic BP and P = 0.007 for diastolic BP). Mean BP reductions from baseline with aliskiren-based therapy were similar in obese and nonobese patients. By contrast, HCTZ-based therapy provided significantly smaller mean reductions in BP from baseline in obese patients vs. nonobese patients (P < 0.05). Aliskiren-based therapy was generally well tolerated in obese patients, and was associated with a significantly lower incidence of hypokalemia (1.0 vs. 14.0%, P < 0.0001) than HCTZ-based therapy.. Aliskiren-based therapy provided superior BP reductions to HCTZ-based therapy with good tolerability in obese patients with hypertension.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Obesity; Placebos

This study investigated the efficacy and safety of several different multi-drug regimens including aliskiren, valsartan, and hydrochlorothiazide (HCTZ) in patients not adequately responsive to HCTZ as monotherapy. After 4 weeks of HCTZ treatment, patients (N=641) whose diastolic blood pressure (DBP) was > or =95 mm Hg were treated for 8 weeks with either aliskiren/valsartan/HCTZ, aliskiren/HCTZ, valsartan/HCTZ, or HCTZ alone. The primary efficacy variable was change in DBP from baseline to week 8 end point. The aliskiren/valsartan/HCTZ combination produced statistically significant additional reductions in systolic blood pressure (SBP)/DBP when compared with other groups. At week 8 end point, reductions in SBP/DBP in the respective treatment groups were 22/16, 15/11, 18/14, or 6/6 mm Hg. Aliskiren/valsartan/HCTZ produced significantly better blood pressure control (SBP/DBP <140/90 mm Hg; 66.7%) compared with other treatment groups (20.5%-48.7%). The safety profile of aliskiren/valsartan/HCTZ was similar to the 2-drug combinations, with a greater blood pressure-lowering effect in patients who had not responded to HCTZ monotherapy.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Hypertensive patients with low-baseline plasma renin activity (PRA) are known to respond best to natriuretic drugs, and those with high PRA respond best to renin-angiotensin system (RAS) blockade. However, there has been recent speculation that blood pressure (BP)-lowering responses to the renin inhibitor, aliskiren, might also be blunted in some patients with medium-to-high baseline PRA. It has been suggested that treatment resistance in these patients may result from excessive reactive increases in renin secretion, such that aliskiren's blockade of PRA is overwhelmed. In order to test for evidence in support of this hypothesis, we conducted a reanalysis of original data from three published clinical trials of aliskiren. When aliskiren was administered as a monotherapy, or in combination with other blockers of the RAS, changes in PRA were closely correlated with baseline PRA. Patients with low-baseline PRA demonstrated small reductions or rises in PRA, rather than patients with medium-to-high baseline PRA. We confirmed that ambulatory BP-lowering responses to full dose aliskiren monotherapy were greatest and least among patients with high- and low-baseline PRA, respectively. However no such association was demonstrated during aliskiren combination therapy. With either monotherapy or combination therapy, no patient with a baseline PRA >0.65 ng/ml/h was observed to have a rise in both PRA and BP. We conclude, therefore, that there is only evidence for one type of resistance to aliskiren--as with all blockers of the RAS, lesser BP-lowering responses to aliskiren occur in those with the least renin to block.

Topics: Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Irbesartan; Ramipril; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination.. This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR).. Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination.. The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Irbesartan; Kidney; Male; Middle Aged; Tetrazoles; Treatment Outcome

This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed.. After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95-109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase.. BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren- than ramipril-based therapy at Week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, p<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, p<0.05; n=103), while ramipril-based therapy increased PRA (+143%, p<0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both p<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy.. Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug.

Topics: Albuminuria; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Demography; Diastole; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Renin-Angiotensin System; Systole; Time Factors

Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission. It is generally well tolerated and provides 24-hour, dose-dependent blood pressure (BP) reduction; however, the effect of the 75-mg dose has been inconsistent in previous trials.. This study was designed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren (75, 150, and 300 mg).. In this 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, patients aged > or =18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week, single-blind, placebo run-in period. Eligible patients were randomized (1:1:1:1) to receive oral, once-daily doses of aliskiren 75, 150, or 300 mg or placebo. The primary efficacy variable was the change from baseline in mean sitting diastolic BP (msDBP) at the week-8 end point. Tolerability was assessed by monitoring and recording all adverse events (AEs).. A total of 642 patients (mean [SD] age, 52.0 [10.73] years; 60.0% male; 80.8% white; mean body weight, 89.2 [18.4] kg [range, 50-160 kg]) were included in the study. Overall, 576 patients (89.7%) completed the double-blind treatment period. The most frequent reasons for discontinuation were unsatisfactory therapeutic effect (27/642 randomized patients [4.2%]) and AEs (17/642 [2.6%]). At end point, aliskiren 150 and 300 mg significantly reduced msDBP (both, P < 0.001) and mean sitting systolic. This study found a positive linear dose-response relationship in BP reduction with aliskiren 75, 150, and 300 mg dosed once daily, but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo. All 3 doses of aliskiren were generally well tolerated.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Fumarates; Humans; Hypertension; Logistic Models; Male; Middle Aged; Placebo Effect; Renin; Severity of Illness Index; Time Factors; Treatment Outcome; United States

Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Middle Aged; Multivariate Analysis; Proteinuria; Renin

Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension.. In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] > or = 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma renin activity (PRA) was measured in a subset of patients.. At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, and diastolic BP reductions were greater than with aliskiren alone (p<0.001). Diastolic BP changes were larger with atenolol than with aliskiren (p=0.003, correlating with the large reductions in pulse rate (> 10 bpm) observed with atenolol. Aliskiren, atenolol and aliskiren/atenolol reduced geometric mean PRA from baseline by 65%, 52% and 61%, respectively. In patients with moderate or high baseline PRA (> or = 0.65 ng/ml/hour), PRA was reduced to low levels (< 0.65 ng/ml/hour) at Week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events compared with atenolol or combination treatment, and unlike atenolol was not associated with bradycardia.. Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone.

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Atenolol; Blood Pressure; Demography; Diastole; Drug Therapy, Combination; Endpoint Determination; Female; Fumarates; Heart Rate; Humans; Hypertension; Male; Renin; Renin-Angiotensin System; Systole

Patients with stage 2 hypertension require large absolute reductions in blood pressure (BP) to achieve recommended BP goals. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker, valsartan, has been shown to produce greater BP reductions than either agent alone in a double-blind study in 1797 hypertensive patients.. This post-hoc analysis evaluated the BP-lowering efficacy of aliskiren in combination with valsartan in a subset of patients (n=581) with stage 2 hypertension (baseline mean sitting systolic BP [msSBP] > or =160 mmHg). Patients were randomized to receive aliskiren/valsartan 150/160 mg, aliskiren 150 mg, valsartan 160 mg, or placebo once daily for 4 weeks followed by 4 weeks at double the initial dose. Mean changes from baseline in msSBP and mean sitting diastolic BP were assessed at week-8 endpoint (intent-to-treat population).. Aliskiren/valsartan 300/320 mg reduced BP from baseline by 22.5/11.4 mmHg at week-8 endpoint. BP reductions with combination therapy were significantly greater than with aliskiren 300 mg (17.3/8.9 mmHg, P<0.05), valsartan 320 mg (15.5/8.3 mmHg, P<0.01), or with placebo (7.9/3.7 mmHg, P<0.0001). BP control rates (<140/90 mmHg) were also significantly higher (P<0.05) with aliskiren/valsartan 300/320 mg (29.8%) compared with either aliskiren 300 mg (19.0%) or valsartan 320 mg (13.8%) monotherapy, or placebo (8.9%). All treatments were generally well tolerated.. Combination therapy with aliskiren and valsartan provided significantly greater BP reductions over aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

To evaluate the efficacy, safety and tolerability of a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT) in patients with hypertension and an inadequate BP response to aliskiren monotherapy (mean sitting diastolic BP [msDBP] > 90 and < or = 110 mmHg following 4 weeks of aliskiren 300 mg).. In this study, 880 patients with hypertension and an inadequate BP response to aliskiren monotherapy were randomized to once-daily, double-blind treatment with a single-pill combination of aliskiren/HCT 300/25 mg or 300/12.5 mg, or aliskiren 300 mg monotherapy. At the week 8 endpoint, least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from baseline were analyzed for the intent-to-treat population.. Aliskiren/HCT 300/25 mg and 300/12.5 mg provided significantly greater msSBP/DBP reductions from baseline (15.9/11.0 mmHg and 13.5/10.5 mmHg, respectively) than aliskiren 300 mg alone (8.0/7.4 mmHg; both p<0.001). Rates of BP control (<140/90 mmHg) were significantly higher with aliskiren/HCT 300/25 mg (60.2%) and 300/12.5 mg (57.9%) than with aliskiren 300 mg alone (40.9%; both p<0.001). Aliskiren/HCT single-pill combination treatment showed similar tolerability to aliskiren monotherapy.. Aliskiren/HCT single-pill combinations provide clinically significant additional BP reductions and improved BP control rates over aliskiren alone in patients who are non-responsive to aliskiren 300 mg monotherapy.

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Diuretics; Double-Blind Method; Drug Combinations; Drug Resistance; Endpoint Determination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Treatment Outcome; Young Adult

Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct renin inhibitor. We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure.. Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients' mean age was 68 years, mean ejection fraction was 31%, and mean+/-SD systolic blood pressure was 129+/-17.4 mm Hg. Sixty-two percent of the patients were in New York Heart Association functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762+/-6123 pg/mL with placebo and fell by 244+/-2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo.. Addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Female; Fumarates; Heart Failure; Humans; Hypertension; Male; Natriuretic Peptide, Brain; Severity of Illness Index; Treatment Outcome

Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters).. Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS.. Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]).. In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.

Topics: Adolescent; Adult; Allopurinol; Amides; Antihypertensive Agents; Celecoxib; Cimetidine; Cyclooxygenase Inhibitors; Drug Interactions; Female; Fumarates; Gout Suppressants; Histamine H2 Antagonists; Humans; Hypertension; Male; Middle Aged; Pyrazoles; Reference Values; Renin; Sulfonamides

This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension.. After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase.. Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%).. Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Ramipril; Renin; Time Factors; Treatment Outcome

Inhibition of renin with an active site inhibitor, aliskiren, lowers blood pressure (BP) in diabetic patients. Here, we studied the time course of the antihypertensive and antiproteinuric effect of renin inhibition in 15 patients with type 2 diabetes and elevated urinary albumin/creatinine ratios (UACRs) to check whether aliskiren can decrease proteinuria. After a 4-week washout of previous medications, patients received aliskiren and furosemide daily for 28 days followed by a 4-week withdrawal period. Twenty-four-hour BPs were measured at baseline throughout treatment and withdrawal periods. The UACR was significantly reduced after 2-4 days of treatment with another significant reduction after 28 days. Systolic blood pressure (SBP) was significantly lower after 7 days with no further reduction after 28 days. The BP returned toward baseline 3 days after withdrawal, whereas the UACR was still significantly reduced compared with baseline 12 days after withdrawal. Our study shows that aliskiren reduced 24 h SBP, and this was associated with a reduction in albuminuria in type 2 diabetic patients.

Topics: Aged; Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Female; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Renin; Treatment Outcome

Aliskiren is a novel, orally active renin inhibitor. Its antihypertensive efficacy and safety, alone and in combination with hydrochlorothiazide (HCTZ), were investigated in an 8-week, double-blind, placebo-controlled trial in hypertensive patients. The effects of these treatments on plasma renin activity (PRA) were also assessed.. A total of 2776 patients aged >or=18 years with mean sitting diastolic blood pressure (MSDBP) 95-109 mmHg were randomized to receive once-daily treatment with aliskiren (75, 150 or 300 mg), HCTZ (6.25, 12.5 or 25 mg), the combination of aliskiren and HCTZ, or placebo, in a factorial design. The primary endpoint was the change in MSDBP from baseline to week 8. PRA was assessed at these timepoints at selected study centers.. Aliskiren monotherapy was superior to placebo (P < 0.001; overall Dunnett's test) in reducing MSDBP and mean sitting systolic blood pressure (MSSBP). Combination treatment was superior to both component monotherapies in reducing BP (maximum MSSBP/MSDBP reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg), and resulted in more responders (patients with MSDBP < 90 mmHg and/or >or=10 mmHg reduction) and better control rates (patients achieving MSSBP/MSDBP < 140/90 mmHg) than either monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline. Although HCTZ monotherapy increased PRA by up to 72%, PRA decreased in all of the combination therapy groups. All active treatments were well tolerated.. Aliskiren monotherapy demonstrated significant BP lowering, and its effect was considerably greater when combined with HCTZ. Renin inhibition with aliskiren neutralized the compensatory rise in PRA induced by HCTZ.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Least-Squares Analysis; Male; Middle Aged; Renin; Time Factors; Treatment Outcome

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: -18.4 [2.1]/ -10.6 [1.7] versus -10.4 [1.8]/-5.8 [1.4]; nighttime: -15.6 [2.7]/-8.1 [1.8] versus -8.8 [2.9]/-5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: -10.5 [2.9]/-8.1 [2.1] and -14 [3.7]/-8.7 [2.3] versus -6.1 [2.4]/-5.9 [1.5]; nighttime: -8.1 [2.6]/-5.3 [2.4] and -9.6 [3.4]/-5.3 [2.4] versus -2 [2.3]/-0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: -14.8 [2]/-8.2 [1.3] and -13.3 [1.6]/-6.8 [0.9] versus -11.4 [1.6]/-6.5 [1.1]; nighttime: -16.1 [2.4]/-8.6 [1.7] and -13.2 [2.7]/-7.2 [1.9] versus -9.0 [2.5]/-4.7 [1.9]). Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angi

Topics: Adult; Aged; Aged, 80 and over; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Middle Aged; Patient Compliance; Ramipril; Renin; Sodium Chloride Symporter Inhibitors; Tetrazoles

By blocking the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step, renin inhibition may provide improved RAAS suppression. We investigated the blood pressure (BP)-lowering effects of the oral direct renin inhibitor aliskiren, alone or in combination with the angiotensin receptor blocker valsartan.. In this multicenter, randomized, placebo-controlled, 8-week trial, 1123 patients with mild-to-moderate hypertension underwent a 3 to 4 week single-blind placebo run-in and were then randomized in a modified factorial study design to receive once-daily, double-blind oral treatment with placebo, aliskiren monotherapy (75, 150, or 300 mg), valsartan monotherapy (80, 160, or 320 mg), aliskiren and valsartan in combination, or valsartan/hydrochlorothiazide (160/12.5 mg). The primary efficacy variable was the change from baseline in mean sitting diastolic BP (DBP) at endpoint.. Once-daily oral treatment with aliskiren 300 mg significantly (P < .0001) lowered mean sitting DBP and systolic BP (SBP) compared with placebo; aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo. Changes in DBP and SBP were fitted to a first-order dose-response surface (lack-of-fit test, P = .65), which showed that aliskiren and valsartan alone and in combination produced dose-related reductions in DBP and SBP. Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone, comparable in magnitude to the effect of valsartan/hydrochlorothiazide, with similar tolerability to the component monotherapies and to placebo.. Aliskiren monotherapy provides antihypertensive efficacy and placebo-like tolerability in patients with hypertension. Aliskiren and valsartan in combination may provide additive BP-lowering effects with maintained tolerability.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Tetrazoles; Valine; Valsartan

Current guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients. The renin system is activated in obesity-associated arterial hypertension. Therefore, we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension (body mass index >or=30 kg/m(2); mean sitting diastolic blood pressure: 95 to 109 mm Hg) who had not responded to 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg. After a 2- to 4-week washout, 560 patients received single-blind HCTZ (25 mg) for 4 weeks; 489 nonresponders were randomly assigned to double-blind aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg), or placebo for 4 weeks added to HCTZ (25 mg), followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment (4 weeks on the higher dose), aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mm Hg, significantly more (P<0.0001) than placebo/HCTZ (8.6/7.9 mm Hg). Aliskiren/HCTZ provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively), with similar tolerability to placebo/HCTZ. Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema (11.1% versus 0.8% to 1.6% in other groups). In conclusion, combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diastole; Double-Blind Method; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Middle Aged; Obesity; Renin; Systole; Tetrazoles; Treatment Outcome

This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension.. Low blood pressure (BP) control rates among patients with hypertension indicate a need for improved treatment options. This study investigates aliskiren, the first in a new antihypertensive class called renin inhibitors.. Patients with mean sitting diastolic BP 95 to 109 mm Hg were randomized to aliskiren 150, 300, or 600 mg or placebo once daily for 8 weeks. Patients completing this treatment phase entered a 2-week treatment-free withdrawal period. Office BP was recorded at baseline, weeks 2, 4, 6, and 8 of treatment, and 4 days and 2 weeks after cessation of treatment. A subgroup of patients underwent ambulatory BP monitoring.. In total, 672 patients were randomized to treatment. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean sitting BP (systolic/diastolic) by 13.0/10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (all p < 0.0001 for systolic and diastolic BP). The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren significantly reduced mean 24-h ambulatory BP (p < 0.0001 vs. placebo with all doses) exhibiting smooth, sustained effects and high trough-to-peak ratios. Aliskiren was well tolerated; overall adverse event rates were 40.1%, 46.7%, and 52.4% with aliskiren 150, 300, and 600 mg, respectively, and 43.0% with placebo. Few patients discontinued treatment due to adverse events.. Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on blood pressure after treatment withdrawal.

Topics: Administration, Oral; Aged; Amides; Blood Pressure Determination; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Male; Maximum Tolerated Dose; Middle Aged; Multivariate Analysis; Probability; Reference Values; Renin; Risk Assessment; Severity of Illness Index; Treatment Outcome

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Lisinopril; Male; Middle Aged; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension.. In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo.. Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg.. Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

Topics: Administration, Oral; Adult; Amides; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin

The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan, compared with each drug alone in patients with hypertension.. In this double-blind study, 1797 patients with hypertension (mean sitting diastolic blood pressure 95-109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or =90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg (n=437), valsartan 160 mg (455), a combination of aliskiren 150 mg and valsartan 160 mg (446), or placebo (459) for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov with the number NCT00219180.. 196 (11%) patients discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren/valsartan group), mainly due to lack of therapeutic effect. At week 8 endpoint, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg, significantly more than either monotherapy (aliskiren 300 mg 9.0 mm Hg decrease, p<0.0001; valsartan 320 mg, 9.7 mm Hg decrease, p<0.0001), or with placebo (4.1 mm Hg decrease, p<0.0001). Rates of adverse events and laboratory abnormalities were similar in all groups.. The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that with aliskiren and valsartan alone.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin; Tetrazoles; Valine; Valsartan

To evaluate the efficacy, safety and tolerability of aliskiren in elderly patients (> or =65 years old) with essential hypertension.. In this double-blind, multicenter study, 355 elderly patients with hypertension [office mean sitting systolic blood pressure (msSBP) > or =145-<180 mmHg and mean 24-h ambulatory systolic BP (ASBP) > or =135 mmHg] were randomized to once-daily treatment for 8 weeks with aliskiren 75 mg (n = 91), 150 mg (n = 84), 300 mg (n = 94) or the comparator lisinopril 10 mg (n = 86). The primary efficacy variable was change in mean 24-h ASBP.. At endpoint, aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg lowered mean 24-h ASBP (least-squares mean+/-SEM) by 8.4+/-0.8, 7.1+/-0.8, 8.7+/-0.8 and 10.2+/-0.9 mmHg, and mean 24-h ambulatory diastolic BP by 4.5+/-0.5, 3.6+/-0.5, 3.9+/-0.5 and 6.3+/-0.5 mmHg, respectively, with no significant difference between aliskiren doses. The trough-to-peak ratio for ASBP reduction with aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg was 0.77, 0.64, 0.79 and 0.87, respectively. All treatments lowered office msSBP and mean sitting diastolic BP (msDBP) compared with baseline. A significantly greater proportion of patients receiving aliskiren 300 mg achieved BP control (msSBP/msDBP <140/90 mmHg) compared with those receiving aliskiren 75 mg (36.2% vs 24.2%, p = 0.033). There was no evidence of dose-related increases in the rate of adverse events with aliskiren treatment.. Aliskiren, a novel direct renin inhibitor, provides effective 24-h BP lowering with no evidence of dose-related increases in the incidence of adverse events in elderly patients with hypertension.

Topics: Administration, Oral; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Humans; Hypertension; Lisinopril; Male; Renin

To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension.. In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed.. At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean+/-SEM) by 11.3+/-0.5, 10.7+/-0.5 and 12.8+/-0.5 mmHg, and msSBP by 14.7+/-0.9, 12.0+/-0.9 and 16.6+/-0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0.043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021). All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril.. Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

Topics: Amides; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Complications; Diastole; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Systole; Treatment Outcome

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects.. In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4-10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma renin concentration (PRC) and plasma renin activity (PRA).. Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: C(max) 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC(0-72 h) 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: C(max) 1.30 (90% CI 1.00, 1.70); AUC(0-tau) 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 +/- 10.2 h and 32.0 +/- 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration-time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups.. The oral renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.

Topics: Adult; Amides; Antihypertensive Agents; Asian People; Blood Pressure; Fumarates; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; White People

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Asian People; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Placebos; Renin; Treatment Outcome

Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator.. The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups.. Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diastole; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Middle Aged; Placebos; Renin; Substance Withdrawal Syndrome; Systole; Tetrazoles; Treatment Outcome

Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities.. Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18-45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data.. Mean AUC and t1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean Cmax was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, Cmax and t1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib.. Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Amides; Atenolol; Celecoxib; Cimetidine; Cross-Over Studies; Cyclooxygenase 2 Inhibitors; Drug Interactions; Enzyme Inhibitors; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Lovastatin; Male; Middle Aged; Pyrazoles; Renin; Sulfonamides

Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Two hundred twenty-six patients, 21 to 70 years of age, with mild to moderate hypertension, were randomly assigned to receive 37.5 mg, 75 mg, 150 mg, or 300 mg aliskiren or 100 mg losartan daily for 4 weeks. Dose-dependent reductions in daytime ambulatory systolic pressure (mean change, mm Hg [SD of change]; -0.4 [11.7], -5.3 [11.3], -8.0 [11.0], and -11.0 [11.0], P=0.0002) and in plasma renin activity (median change % [interquartile range]; -55 [-64, -11], -60 [-82, -46], -77 [-86, -72], and -83 [-92, -71], P=0.0008) were observed with 37.5, 75, 150, and 300 mg aliskiren. The change in daytime systolic pressure with 100 mg losartan (-10.9 [13.8]) was not significantly different from the changes seen with 75, 150, and 300 mg aliskiren. Aliskiren was well tolerated at all doses studied. This study demonstrates that aliskiren, through inhibition of renin, is an effective and safe orally active BP-lowering agent. Whether renin inhibition results in protection from heart attack, stroke, and nephropathy, similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade, needs to be researched.

Topics: Administration, Oral; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Losartan; Male; Middle Aged; Patient Compliance; Renin

Pre-exposure prophylaxis (PrEP) is an important tool for preventing HIV infection. However, PrEP's impact on cardiometabolic health is understudied.. To examine the risk of incident hypertension and statin initiation among adult (age ≥18 years) health plan members starting PrEP with tenofovir alafenamide fumarate (TAF) compared with propensity score-matched adults taking tenofovir disoproxil fumarate (TDF).. This retrospective cohort study used electronic health records (EHRs) from Kaiser Permanente Southern California. Adult members starting PrEP in Kaiser Permanente Southern California between October 2019 and May 2022 were included. Propensity score matching with multiple imputation (50 matched data sets) was conducted to generate 1 TAF:4 TDF matched data sets with balanced baseline covariates.. PrEP initiation with either TAF or TDF during the study period.. Incident hypertension and statin initiation within 2 years of PrEP initiation were ascertained through blood pressure and outpatient pharmacy records, respectively. Risk differences and odds ratios (ORs) were estimated using logistic regression and g-computation.. A total of 6824 eligible individuals were identified (mean [SD] age, 33.9 [10.3] years; 6618 [97%] male). This pool was used to generate 2 cohorts without baseline hypertension or statin use for matching (hypertension: n = 5523; statin: n = 6149) In both cohorts, those starting PrEP with TAF were older and were more likely to be non-Hispanic White compared with those starting with TDF. In matched analysis adjusting for baseline covariates, TAF use was associated with elevated risk of incident hypertension (TAF: n = 371; risk difference, 0.81 [95% CI, 0.12-1.50]; OR, 1.64 [95% CI, 1.05-2.56]). TAF use was also associated with elevated risk of statin initiation (TAF: n = 382; risk difference, 0.85 [95% CI, 0.37-1.33]; OR, 2.33 [95% CI, 1.41-3.85]). Subgroup analyses restricted to individuals 40 years and older at PrEP initiation showed similar results with larger risk difference in statin initiation (risk difference, 4.24 [95% CI, 1.82-6.26]; OR, 3.05 [95% CI, 1.64-5.67]).. In this study of people taking PrEP, TAF use was found to be associated with higher incident hypertension and statin initiation compared with TDF use, especially in those 40 years or older. Continued monitoring of blood pressure and lipids for TAF users is warranted.

Topics: Adenine; Adolescent; Adult; Female; Fumarates; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Male; Pre-Exposure Prophylaxis; Retrospective Studies; Tenofovir

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Morpholines; Renin; Renin-Angiotensin System

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE

Topics: Amides; Amlodipine; Angiotensin II; Animals; Antihypertensive Agents; Apolipoproteins E; Blood Pressure; Cysteine-Rich Protein 61; Fumarates; Gene Expression Regulation; Humans; Hypertension; Irbesartan; Mice; Mice, Knockout; Renal Artery; Renal Artery Obstruction

Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes.. All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162).. More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports.. The reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes.

Topics: Aged; Amides; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Databases, Factual; Drug Prescriptions; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Odds Ratio; Renin-Angiotensin System; Smoking

Fumaric acid esters (FAE) represent the most widely-used oral systemic treatment for moderate-to-severe psoriasis in Germany. Not licensed outside Germany, little is known about the demographics of patients receiving FAE. PsoBest is a large national patient registry documenting long-term treatment of psoriasis in Germany.. To evaluate FAE relative to methotrexate (MTX) in patients from the PsoBest registry.. Patient demographics, disease severity at baseline and dosing regimen were reported for patients who initiated treatment with either FAE or MTX between 2007 and 2015.. Overall, 1,409 patients treated with FAE and 877 with MTX were analysed. At baseline, compared with the MTX cohort, patients receiving FAE were younger (45.4 vs. 50.2 years; p≤0.001) and had a lower BMI (28.0 vs. 28.3 kg/m. This study contributes to a better understanding of the usual practices of long-term FAE use, which may also lead to improved treatment strategies not only in Germany, but in other countries where FAE may become available in the near future.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Comorbidity; Dermatologic Agents; Female; Fumarates; Germany; Humans; Hypertension; Male; Methotrexate; Middle Aged; Prevalence; Psoriasis; Quality of Life; Registries; Severity of Illness Index; Time Factors; Young Adult

Topics: Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; COVID-19; Female; Fumarates; Humans; Hypertension; Male; Renin; Retrospective Studies

It has been suggested that aldosterone breakthrough during treatment with a type 1 angiotensin II receptor (AT1R) blocker (ARB) may be an important risk factor for the progression of renal and cardiovascular disease. We examined whether the direct renin inhibitor, aliskiren caused aldosterone breakthrough in angiotensin II (Ang II)-dependent hypertensive mice. The effect of combination therapy with aliskiren and eplerenone was compared with that of therapy using renin-angiotensin system (RAS) blockade. Tsukuba hypertensive mice were treated for 12 weeks with aliskiren (30 mg/kg/day, i.p), candesartan (5 mg/kg/day, p.o), eplerenone (100 mg/kg/day, p.o) aliskiren and candesartan, aliskiren and eplerenone or candesartan and eplerenone. Blood pressure, urinary aldosterone and angiotensinogen (AGTN) excretion; plasma endothelin-1 concentration; kidney weight; urinary albumin excretion (UAE); glomerular injury; and renal messenger RNA (mRNA) levels for transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, angiotensin-converting enzyme (ACE) and AT1R were measured. Combination therapy with aliskiren and candesartan caused a further decrease in blood pressure (p < 0.05) compared with either agent alone. Urinary aldosterone excretion was decreased significantly by 4 weeks of treatment with aliskiren or candesartan (p < 0.05). However, it was increased again by treatment with candesartan or aliskiren for 12 weeks. Combination therapy with aliskiren and eplerenone significantly decreased UAE, the glomerulosclerosis index, and PAI-1 and TGF-β1 mRNA levels compared with all other therapies (p < 0.05). Treatment with aliskiren decreased urinary aldosterone excretion at 4 weeks and increased it at 12 weeks. Combination therapy with a direct renin inhibitor and a mineralocorticoid receptor blocker may be effective for the prevention of renal injury in Ang II-dependent hypertension.

Topics: Aldosterone; Amides; Animals; Antihypertensive Agents; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eplerenone; Fumarates; Hypertension; Male; Mice; Mineralocorticoid Receptor Antagonists

Topics: Amides; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Hyponatremia; Middle Aged; Nifedipine; Renal Artery Obstruction; Renin; Syndrome; Thirst

Topics: Amides; Complement Activation; Fumarates; Humans; Hypertension; Kidney Diseases; Renin

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

Topics: Amides; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Fumarates; Heart; Hypertension; Nanoparticles; Nitric Oxide; Polyesters; Rats; Rats, Inbred SHR

Neither ACEI nor ARBs completely repress the RAAS. Aliskiren is a newer agent that inhibits renin. However, it increases the biosynthesis and secretion of renin and prorenin, that might induce renal tissue damage. This study was conducted to investigate the renoprotective effects of aliskiren and valsartan the ARB, either alone or in combination, on hypertensive nephropathy induced by L-NAME. Aliskiren (50 mg/kg/daily i.p.), valsartan (10 mg/kg daily i.p.) alone or in half dose combination were administered with L-NAME (30-40 mg daily in drinking water) for 8 weeks. Aliskiren and valsartan significantly reduced systolic blood pressure, proteinuria, serum creatinine, blood urea nitrogen, oxidative stress, and structural renal injury although not to the same extent. Valsartan reduced systolic blood pressure and proteinuria in L-NAME treated rats more significantly than aliskiren. However, glomerular collapse index and the expansion of interstitial tissue were significantly attenuated by aliskiren than by valsartan. Cotreatment with aliskiren and valsartan markedly reduced the oxidative stress and further reduced the glomerular collapse and the expansion of interstitial tissue compared with aliskiren monotherapy.. These results suggest that therapies aimed at different targets within the RAAS may have additional effects in attenuating structural injury in experimental hypertensive nephropathy.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Fumarates; Hypertension; Kidney; Kidney Diseases; Male; NG-Nitroarginine Methyl Ester; Oxidative Stress; Proteinuria; Rats; Rats, Wistar; Valsartan

Because of the presence of the blood-brain barrier, brain renin-angiotensin system activity should depend on local (pro)renin synthesis. Indeed, an intracellular form of renin has been described in the brain, but whether it displays angiotensin (Ang) I-generating activity (AGA) is unknown. Here, we quantified brain (pro)renin, before and after buffer perfusion of the brain, in wild-type mice, renin knockout mice, deoxycorticosterone acetate salt-treated mice, and Ang II-infused mice. Brain regions were homogenized and incubated with excess angiotensinogen to detect AGA, before and after prorenin activation, using a renin inhibitor to correct for nonrenin-mediated AGA. Renin-dependent AGA was readily detectable in brain regions, the highest AGA being present in brain stem (>thalamus=cerebellum=striatum=midbrain>hippocampus=cortex). Brain AGA increased marginally after prorenin activation, suggesting that brain prorenin is low. Buffer perfusion reduced AGA in all brain areas by >60%. Plasma renin (per mL) was 40× to 800× higher than brain renin (per gram). Renin was undetectable in plasma and brain of renin knockout mice. Deoxycorticosterone acetate salt and Ang II suppressed plasma renin and brain renin in parallel, without upregulating brain prorenin. Finally, Ang I was undetectable in brains of spontaneously hypertensive rats, while their brain/plasma Ang II concentration ratio decreased by 80% after Ang II type 1 receptor blockade. In conclusion, brain renin levels (per gram) correspond with the amount of renin present in 1 to 20 μL of plasma. Brain renin disappears after buffer perfusion and varies in association with plasma renin. This indicates that brain renin represents trapped plasma renin. Brain Ang II represents Ang II taken up from blood rather than locally synthesized Ang II.

Topics: Amides; Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Blood-Brain Barrier; Brain; Desoxycorticosterone Acetate; Disease Models, Animal; Fumarates; Hypertension; Mice; Mice, Knockout; Random Allocation; Rats; Rats, Inbred SHR; Reference Values; Renin-Angiotensin System

The renoprotective effects of the direct renin inhibitor, aliskiren, in renal transplant recipients have been supposed, but not finally proven. We performed an exploratory double-blind, losartan controlled, cross-over study to evaluate the influence of aliskiren, direct renin inhibitor, on albuminuria and other surrogate markers of kidney injury in patients after renal transplantation. The safety of this therapy was also evaluated.. 16 of 18 patients (12 M, 4 F), 48.3 ± 9.0 years, 57.7 ± 9.1 months after kidney transplantation, with hypertension and stable serum creatinine 1.4 ± 0.08 mg/dl without proteinuria, completed the protocol. Each patient underwent two 8-week treatment periods (one with 150 mg of aliskiren, and one with 50 mg of losartan) in random order, allowing an 8-week placebo washout between them.. There were no differences in albuminuria, transforming growth factor β-1 and 15-F2t-isoprostanes urine excretion between aliskiren and losartan. Creatinine serum level, eGFR, 24 h systolic and 24 h diastolic blood pressure were stable through the study. There were no differences in haemoglobin and potassium serum concentration between studied drugs.. Aliskiren decreases albuminuria in renal transplant recipients with clinically minimal side effects. The effect does not differ from that of losartan.

Topics: Adult; Aged; Albuminuria; Amides; Blood Pressure; Creatinine; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Kidney Transplantation; Losartan; Male; Middle Aged

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Topics: Amides; Animals; Antihypertensive Agents; Cell-Derived Microparticles; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Imidazoles; Male; Nebivolol; Neovascularization, Pathologic; Random Allocation; Rats; Rats, Sprague-Dawley; Tetrazoles

A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs).. The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs).. A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case-control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs.. A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24-2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08-3.17), aliskiren monotherapy 1.71 (0.74-3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41-2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31-3.66). The case-control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45-2.20) and 1.06 (0.40-2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42-4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10-12.05)].. The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Amides; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Case-Control Studies; Cohort Studies; Databases, Factual; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; United States; Young Adult

This study determined whether angiotensinogen (AGT) has angiotensin II-independent effects using multiple genetic and pharmacological manipulations.. All study mice were in low-density lipoprotein receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor -/- mice. In mice with established adiposity, administration of AGT antisense oligonucleotide versus aliskiren led to equivalent reductions of systolic blood pressure and atherosclerosis. AGT antisense oligonucleotide administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat, and human revealed 4 highly conserved sequences within the des(angiotensin I)AGT domain. des(angiotensin I)AGT, through adeno-associated viral infection in hepatocyte-specific AGT-deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis.. AGT contributes to body weight gain and liver steatosis through functions of the des(angiotensin I)AGT domain, which are independent of angiotensin II production.

Topics: Amides; Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Atherosclerosis; Blood Pressure; Conserved Sequence; Dependovirus; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fumarates; Genetic Vectors; Genotype; Hepatocytes; Hypertension; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Oligonucleotides, Antisense; Phenotype; Protein Binding; Protein Interaction Domains and Motifs; Receptors, LDL; Renin; Signal Transduction; Time Factors; Transduction, Genetic; Weight Gain

A direct renin inhibitor, aliskiren, has a longer stable antihypertensive effect compared with other renin-angiotensin-aldosterone system (RAAS) inhibitors.. This study was a 6-month, single-center, open trial conducted between December 2010 and November 2011 to assess the antihypertensive effect of adding aliskiren (300 mg) to the treatment of essential hypertension patients whose target blood pressure (BP) had not been achieved and to assess whether it was possible to reduce the amount of antihypertensive drugs used.. The results showed an overall improvement in the target BP achievement rate of 60% for clinic BP and 52% for home BP measurements (75 cases total). The mean number of drugs before treatment with aliskiren was 3.28±1.52, whereas at the end of the six months the mean number of drugs prescribed other than aliskiren was 2.85±1.72 (p<0.0001). Moreover, no worsening of the renal function was observed in patients with diabetes or chronic kidney disease (CKD) who were being treated with other RAAS inhibitors in combination to aliskiren.. These results showed that when aliskiren was added to the treatment of poorly controlled hypertension, the BP achievement rate increased, and it was possible to reduce the amount of antihypertensive drugs used in combination with aliskiren. Moreover, as a result of careful monitoring of the renal function or decreasing the amounts of drugs used in combination, no worsening of the renal function was observed even in the cases complicated by diabetes or CKD being treated with other RAAS inhibitors.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Japan; Male; Renin; Renin-Angiotensin System; Treatment Outcome

The authors sought to retrospectively analyze the real-world evidence on aliskiren in diabetic patients with or without concomitant renin-angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non-RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS-blocking therapy alone.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Registries; Retrospective Studies; Treatment Outcome

Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription-event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59-76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as "effective" by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on-treatment events), malaise/lassitude (3.0%), and nausea/vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End-Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Amides; Child; Child, Preschool; Cohort Studies; England; Essential Hypertension; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Young Adult

The influence of intracellular renin on the inward calcium current in isolated smooth muscle cells from SHR mesenteric arteries was investigated. Measurements of calcium current were performed using the whole cell configuration of pCLAMP. The results indicated that: 1) renin (100nM) dialyzed into smooth muscle cells, increased the inward calcium current; 2) verapamil (10-9M) administered to the bath inhibited the effect of renin on the inward calcium current; 3) concurrently with the increase of calcium current a depolarization of 6.8+/-2.1mV (n=16)(P<0.05) was found in cells dialyzed with renin; 4) intracellular dialysis of renin (100nM) into smooth muscle cells isolated from mesenteric arteries of normal Wystar Kyoto rats showed no significant change on calcium current; 5) aliskiren (10-9M) dialyzed into the cell together with renin (100nM) abolished the effect of the enzyme on the calcium current in SHR; 6) Ang II (100nM) dialyzed into the smooth muscle cell from mesenteric artery of SHR in absence of renin, decreased the calcium current-an effect greatly reduced by valsartan (10-9M) added to the cytosol; 7) administration of renin (100nM) plus angiotensinogen (100nM) into the cytosol of muscles cells from SHR rats reduced the inward calcium current; 8) extracellular administration of Ang II (100nM) increased the inward calcium current in mesenteric arteries of SHR.. intracellular renin in vascular resistance vessels from SHR due to internalization or expression, contributes to the regulation of vascular tone and control of peripheral resistance-an effect independently of Ang II. Implications for hypertension and vascular remodeling are discussed.

Topics: Amides; Angiotensin II; Animals; Calcium; Calcium Signaling; Disease Models, Animal; Fumarates; Humans; Hypertension; Mesenteric Arteries; Myocytes, Smooth Muscle; Rats; Renin; Vascular Remodeling; Verapamil

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Brazil; Calcium Channel Blockers; Diuretics; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Renin; Vasodilator Agents

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR).. Four groups of 12-week-old male offspring were sacrificed: control, CR, CR+aliskiren, and CR+losartan group. The CR group included offspring from 50% food-restricted maternal rats. The CR+aliskiren and CR+losartan groups were produced by treating CR offspring with oral aliskiren 10 mg/kg/day or losartan 20 mg/kg/day between 2-4 weeks of age, respectively.. Blood pressure increased in CR rats, which was prevented by aliskiren or losartan. CR increased plasma ADMA levels, which aliskiren prevented. Renal renin and prorenin receptor (PRR) expression increased in CR rats treated with aliskiren, whereas both were reduced by losartan. Both aliskiren and losartan decreased renal mRNA expression of angiotensinogen, angiotensin II type 2 receptor, and Mas in CR rats. However, aliskiren increased angiotensin II type 2 receptor and Mas protein levels in CR kidneys.. Early aliskiren therapy prevents CR-induced hypertension via ADMA reduction, decreases angiotensinogen expression, and increases renal angiotensin II type 2 receptor and Mas protein.

Topics: Amides; Angiotensin-Converting Enzyme 2; Animals; Animals, Newborn; Arginine; Blood Pressure; Blotting, Western; Body Weight; Caloric Restriction; Female; Fumarates; Gene Expression Regulation; Histone Deacetylases; Hypertension; Losartan; Male; Peptidyl-Dipeptidase A; Rats, Sprague-Dawley

The aim of this study was to investigate the effects of aliskiren on vascular function and endothelial progenitor cells (EPCs) in patients with type 2 diabetes and essential hypertension.. The study enrolled type 2 diabetic patients aged >50 years under stable glycemic control and first diagnosed mild essential hypertension. In phase A (n = 20), patients received aliskiren 150-300 mg daily for 3 months. In phase B (n = 12), hydrochlorothiazide (HCTZ) 12.5-25mg daily substituted for aliskiren for 3 more months. At baseline and at the end of each phase, we assessed (i) brachial blood pressure (BBP); (ii) central aortic systolic pressure (CSP), aortic augmentation index (Aix), and pulse wave velocity (PWV) as markers of arterial stiffness; (iii) brachial artery flow-mediated dilatation (FMD) as a marker of endothelial function; (iv) left ventricular (LV) twisting and untwisting as markers of LV function and (v) EPC numbers in culture of peripheral blood mononuclear cells.. Aliskiren similarly reduced BBP and CSP, increased FMD (P < 0.001) and EPC numbers (P < 0.001), decreased PWV and Aix (P < 0.05), and improved LV twisting and untwisting (P < 0.05). Although substitution of HCTZ sustained BBP at similar levels, CSP and echocardiographic indices nearly returned at baseline levels, and the improvement of FMD, PWV, Aix, and EPC numbers was abolished.. Aliskiren had a favorable effect on endothelial function and EPCs, reduced arterial stiffness, and improved LV twisting and untwisting. These effects were independent of BBP lowering, as they were not observed after the achievement of similar values of BBP with HCTZ.

Topics: Aged; Amides; Antihypertensive Agents; Arterial Pressure; Biomarkers; Cells, Cultured; Diabetes Mellitus, Type 2; Diuretics; Drug Substitution; Endothelial Progenitor Cells; Endothelium, Vascular; Female; Fumarates; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Pilot Projects; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilation; Ventricular Function, Left

We aimed to analyze benefits and risks of aliskiren treatment in older adults (⩾ 65 years) in clinical practice. Patients (n = 14,986) were assigned to either aliskiren (ALIS), an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB), or an agent not blocking the renin-angiotensin system (non-RAS). Older adults (n = 7396) had a longer history of hypertension (8.7 vs 4.7 years; P < 0.0001), lower mean diastolic blood pressure (DBP; 87.7 ± 11.0 vs 92.1 ± 11.0 mm Hg) and more renal (12.0 vs 5.6%; P < 0.0001) or cardiovascular disease (44.0 vs 18.9%; P < 0.0001); 4548 received aliskiren (68.8%), 1215 ACEi/ARBs (18.4%) and 850 non-RAS treatments (12.9%). Office BP at 1 year was reduced by 18.4 ± 21.5/7.2 ± 12.0 mm Hg. BP reductions were greater (19.5 ± 21.7/7.6 ± 12.1 mm Hg) in the aliskiren group than in the ACEi/ARB (15.6 ± 20.9/6.4 ± 11.9) and non-RAS groups (16.1 ± 20.7/6.5 ± 11.7 mm Hg), respectively (P<0.0001 for systolic BP (SBP) and <0.01 for DBP). After multivariable adjustment, differences in SBP reductions were clinically irrelevant and no differences were noted for DBP. Adverse effects were higher in older adults with no differences between treatment groups. In conclusion, the present analysis of a large, unselected cohort of patients in clinical practice from the 3A study, offers real-life evidence of the effectiveness and safety of aliskiren for the treatment of hypertension in older adults.

Topics: Age Factors; Aged; Amides; Antihypertensive Agents; Blood Pressure; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Assessment; Treatment Outcome

This study aimed to analyze the hemodynamic and cardiac effects of direct renin inhibitor (DRI) treatment and swimming training in hypertensive rats.. Seventy-seven rats were divide into eight groups: sedentary normotensive (SN), trained normotensive (TN), sedentary normotensive treated with DRI (SN_DRI), trained normotensive treated with DRI (TN_DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH_DRI), trained hypertensive treated with DRI (TH_DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg ċ kg(-1) ċ day(-1) L-NAME for four weeks. Groups treated with DRI received 10 mg ċ kg(-1) ċ day(-1) of aliskiren for four weeks. After the treatment period, all the animals underwent femoral artery catheterization surgery for direct measurement of cardiovascular variables.. The SH group presented hypertension (136.4 ± 5.0 mmHg) compared to the SN (107.1 ± 1.7 mmHg). The TH group showed lower mean arterial pressure (MAP) than the SH (121.1 ± 1.3 mmHg), but the treatment with DRI did not attenuate hypertension (128.2 ± 4.9 mmHg). The analysis of collagen areas demonstrated that treatment with DRI may attenuate cardiac remodeling in situations of hypertension, in the condition of treatment alone or combined with physical training.. Both interventions in combination may be more effective at reducing cardiovascular risk in hypertensive subjects.

Topics: Amides; Animals; Blood Pressure; Disease Models, Animal; Enzyme Inhibitors; Fumarates; Heart; Hypertension; Male; NG-Nitroarginine Methyl Ester; Physical Conditioning, Animal; Rats; Rats, Wistar; Renin; Risk Factors; Swimming

Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. A number of studies show a link between aliskiren and intravascular thrombosis.. The goal of the present study was to investigate the impact of aliskiren on arterial thrombosis in normotensive and renovascular hypertensive rats. The contribution of each coagulation and fibrinolytic parameters in the mode of aliskiren action was determined. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Animals were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10 days. Arterial thrombosis was induced by electrical stimulation of the common carotid artery.. It was found that aliskiren in a dose-dependent manner decreased weight of the arterial thrombus in normotensive and hypertensive rats. It has been shown that this result was not associated with the effects on blood pressure, TF, PT, APTT, fibrinogen and hematological parameters. It was found that aliskiren caused increase of t-PA activity and decrease of its inhibitor activity.. The presented results indicate that aliskiren inhibits hemostasis in the arterial thrombosis in rats. The antithrombotic effect is related with improvement of the fibrinolytic balance, and also depends on antiplatelet action.

Topics: Amides; Animals; Antihypertensive Agents; Blood Coagulation; Blood Coagulation Factors; Blood Pressure; Disease Models, Animal; Fumarates; Hemostasis; Hypertension; Male; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Rats; Thrombosis; Tissue Plasminogen Activator

This observational study evaluated the efficacy and tolerability of 3-month aliskiren/amlodipine therapy under outpatient conditions.. This Austria-wide observational study included 579 hypertensive patients (566 [98 %] who could be analyzed biometrically) under the care of 140 physicians. The average age of the patient collective was 64 ± 11 years and the mean duration of hypertension was 10 ± 7 years. Regarding 92 % of the study participants, an antihypertensive therapy already existed. Efficacy was assessed in accordance with the Austrian hypertension guidelines while tolerability was evaluated on the basis of adverse events. A descriptive physician judgment based on efficacy, tolerability, and compliance was available for 539 patients (95 %). Office blood pressure values were used for the evaluation.. On average, the systolic and diastolic blood pressures were reduced from 161 ± 14 to 135 ± 10 mmHg and 93 ± 9 to 81 ± 6 mmHg, respectively. Blood pressure values of < 140/90 mmHg and < 130/80 mmHg were achieved in 56 and 7 % patients, respectively. A subgroup analysis of 242 patients (43 %) with diabetes mellitus and/or renal disease, as well as those with a high cardiovascular risk, demonstrated nearly identical results compared to the total population. Overall, 44 adverse events were documented in 41 patients, and physicians reported that 94 % of patients were compliant in a final survey on evaluation of therapy.. The fixed-dose combination of aliskiren/amlodipine provided clinically relevant blood pressure reductions along with good tolerance and compliance. During the 3-month duration of observation under outpatient conditions, it was seen that aliskiren and amlodipine reduced the systolic and diastolic blood pressures on average by 26 and 13 mmHg, respectively.

Topics: Aged; Aged, 80 and over; Amides; Amlodipine; Antihypertensive Agents; Austria; Drug Combinations; Female; Fumarates; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Arterioles; Female; Fumarates; Humans; Hypertension; Male; Retinal Vessels; Vascular Remodeling

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

Topics: Albuminuria; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cytoprotection; Disease Models, Animal; Disease Progression; Down-Regulation; Fumarates; Humans; Hydralazine; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Ramipril; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Time Factors

To report a case of difficult-to-treat hypertension ultimately managed with triple antirenin (anti-R) therapy using plasma renin activity (PRA) to guide medication selection.. A 66-year-old white man was referred to the cardiology pharmacotherapy clinic for difficult-to-treat hypertension. His initial office blood pressure (BP) was 152/71 mm Hg on diltiazem and chlorthalidone. After a series of medication adjustments based on serial PRA measurements, the patient achieved his target BP with a regimen that included 3 anti-R angiotensin system medications: carvedilol, valsartan, and aliskiren.. Despite continued progress in the understanding and advances in pharmacological therapy for hypertension, uncontrolled hypertension remains a major problem. The most common strategy to control hypertension is the stepped-care approach with progressive addition of medications to eventually reach BP goal. An alternative approach includes the use of PRA measurements to guide both the addition and removal of drugs in an attempt to effectively control BP. At times, this has the potential to result in a drug regimen that is incongruous with current guidelines and practice recommendations. However, if this results in more effective BP control with the same, or fewer, number of medications, it may represent a reasonable alternative.. This case report illustrates a real-world application of PRA-guided therapeutics in a patient with difficult-to-treat hypertension. It highlights how a personalized approach can lead to BP control with a more streamlined regimen than would likely result if a stepped-care approach was used.

Topics: Aged; Amides; Antihypertensive Agents; Carbazoles; Carvedilol; Fumarates; Humans; Hypertension; Male; Propanolamines; Renin; Tetrazoles; Valine; Valsartan

This case represents an individual with accelerating hypertension and declining kidney function associated with atherosclerotic renal artery stenosis. Key features include loss of GFR (reaching stage V CKD) during intensified antihypertensive drug therapy including agents that block the renin-angiotensin system and failure to appreciate the extent to which moderate renal artery stenosis was affecting his better kidney. Interpretation of duplex ultrasound studies was complicated by a discrepancy between near-normal peak systolic velocities and markedly abnormal segmental arterial waveforms. It was essential to recognize that both kidneys were abnormal and focus on recovery of perfusion to the better of these kidneys. Successful revascularization of one kidney allowed major improvement in GFR and BP control.

Topics: Aged; Amides; Antihypertensive Agents; Atherosclerosis; Atrophy; Blood Pressure; Carbazoles; Carvedilol; Disease Progression; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Propanolamines; Renal Artery Obstruction; Stents; Teaching Rounds

We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), and examined the mechanism by which this occurs.. Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg(-1) day(-1)) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure-lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3-kinase (PI3K), phospho-Akt and phospho-endothelial nitric oxide synthase (phospho-eNOS), but increased expression of inducible nitric oxide synthase (iNOS); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine-3',5'-monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 (TIMP-1) following I/R. In a Langendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function.. Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fumarates; Hypertension; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Renin; Signal Transduction; Stroke Volume; Superoxides; Tissue Inhibitor of Metalloproteinase-1; Ventricular Function, Left

Aliskiren is a direct renin inhibitor developed to treat hypertension. Several clinical studies have suggested that aliskiren has beneficial effects on cardiovascular diseases beyond its antihypertensive effect. In the present study, we examined whether aliskiren limits the progression of AAA (abdominal aortic aneurysm), VH (ventricular hypertrophy) and atherosclerosis in an AngII (angiotensin II)-infused mouse model. ApoE-/- (apolipoprotein-E-deficient) mice were infused subcutaneously with AngII (1000 ng/kg of body weight per day; 4 weeks) to induce AAA and VH. At the completion of the AngII infusion, mice were randomly allocated to three groups to receive vehicle control, low-dose aliskiren (10 mg/kg of body weight per day) or high-dose aliskiren (50 mg/kg of body weight per day) for 4 weeks. Suprarenal aortic diameter assessed by ultrasound was significantly smaller in mice administered aliskiren at days 42 and 56. Aliskiren also significantly reduced the normalized heart weight, ventricular myocyte cell width and aortic arch atherosclerosis. Aliskiren lowered PRR (pro-renin receptor) expression and MAPK (mitogen-activated protein kinase) activity in the suprarenal aorta and heart. Aortic infiltration of T-lymphocytes and macrophages was reduced by aliskiren. In conclusion, aliskiren limits the progression of AAA, VH and atherosclerosis in an AngII-infused mouse model.

Topics: Amides; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Fumarates; Hypertension; Hypertrophy; Mice; Mice, Inbred C57BL; Mice, Knockout

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population.. In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In-life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In-life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed.. With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64.. All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Female; Fumarates; Hypertension; Kidney; Lymphocyte Count; Male; Maternal Exposure; Postpartum Period; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Toxicokinetics

Imaging of the kidney using blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) presents a major opportunity to examine differences in tissue oxygenation within the cortex and medulla applicable to human disease. The aim of this study was to evaluate BOLD signals before and after treatment with RAS inhibitors in hypertensive chronic kidney disease (CKD) patients. Ten patients with stable CKD and 5 healthy volunteers were included. Five CKD patients were subjected to BOLD MRI scan before and after chronic treatment with 300 mg/day aliskiren for at least 6 weeks. Five other CKD patients received BOLD MRI before and 1 hour after acute treatment with 50 mg captopril. A group of healthy volunteers (n=5) was scanned before and 1 hour after acute treatment with 50 mg captopril. The 10 patients had a mean age of 61±17 years; eGFR of 30±11 mL/min per 1.73 m(2) . Office systolic and diastolic blood pressures when on a RAS inhibito, were 130±10 and 86±5 mmHg in CKD patients. Control subjects had normal kidney function and were not on any medication. In untreated condition, systolic and diastolic arterial blood pressure elevated, 145±6 and 95±4 mmHg, respectively. After chronic treatment with aliskiren, arterial blood pressure decreased in all patients in this group, 127±3 mmHg and 77±3 mmHg. After acute treatment with captopril arterial blood pressure reduced to 125±4 and 71±8 mmHg. Tissue intensity signal (T2*) was increased in medulla after chronic treatment from 29±6 to 34±6 and after acute treatment with captopril from 34±9 to 38±11 in CKD patients. In addition, T2* ratio between cortex and medulla decreased in CKD patients after chronic treatment and acute treatment. This ratio remained stable in healthy volunteers before and after treatment with captopril 1.62±0.1 and 1.65±0.1, respectively. This study shows for the first time that RAS inhibitors change BOLD signal in CKD patients. Importantly, in healthy volunteers, a RAS inhibitor had no such effect. Further investigation is required.

Topics: Adult; Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Case-Control Studies; Comorbidity; Feasibility Studies; Female; Fumarates; Humans; Hypertension; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen; Pilot Projects; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Treatment Outcome

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Coronary Artery Disease; Female; Fumarates; Humans; Hypertension; Male

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cohort Studies; Disease-Free Survival; Drug Substitution; Enalapril; Female; Fumarates; Humans; Hypertension; Ovarian Neoplasms; Perindopril; Protein Kinase Inhibitors; Recurrence; Vascular Endothelial Growth Factor A

Topics: Amides; Antihypertensive Agents; Endothelium, Vascular; Female; Fumarates; Humans; Hypertension; Male; Vascular Stiffness

Glomerular filtration rate (GFR) is commonly calculated using the modification of diet in renal disease (MDRD) and Cockroft-Gault (CG) formulas and recently by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm and not directly measured, so that the real impact of antihypertensive therapy on GFR could not be well defined. In this study, the effect of Aliskiren on the GFR measured by radionuclide clearance of 99mTc-diethylene triamine penta-acetic acid (DTPA) was investigated.. In 106 hypertensive subjects (53% men) aged 61.9±12.7 years with uncontrolled blood pressure (BP) receiving at least 2 antihypertensive medications, Aliskiren was added once-daily at a dose of 150-300 mg for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while 24-hours ambulatory BP and GFR (in mL/min/1.73 m2) were evaluated at baseline and at the end of the follow-up. Analysis of variance for repeated measures of BP, GFR and microalbuminuria was provided.. With the use of Aliskiren a significant reduction of BP and microalbuminuria was found (P<0.0001). Only in male population, a significant reduction in GFR calculated with CKD-EPI (82.4±15 vs. 78.6±18.2, P<0.01) and CG (81.6±29.5 vs. 74.2±28.4, P<0.0001) formulas was observed. This impairment of GFR was not found either with MDRD formula (70.5±19.6 vs. 68.3±23.4) or by radionuclide clearance (62.4±18.6 vs. 61.4±20.5).. This study seems to demonstrate that the efficacy on BP control of Aliskiren is not accompanied by an impairment of GFR. In order to evaluate the effect of Aliskiren on GFR scintigraphy technique or MDRD formula resulted to be the most accurate methods.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Radiopharmaceuticals; Sex Factors; Technetium Tc 99m Pentetate; Time Factors

Topics: Amides; Antihypertensive Agents; Endothelium, Vascular; Female; Fumarates; Humans; Hypertension; Male; Vascular Stiffness

Current data on characteristics and outcomes of patients with high blood pressure (BP) managed under clinical practice conditions are limited.. The 3A registry is an open, prospective observational cohort study in German primary care offices, with a 4:1:1 inclusion ratio to either aliskiren (ALIS), an ACE inhibitor/angiotensin receptor blocker (ACEI/ARB), or to an antihypertensive agent not affecting the renin angiotensin system (non-RAS). A nonlinear mixed regression model was used to assess BP changes during follow-up regarding different BP values at inclusion in the various groups. ClinicalTrial.gov identifier is NCT01454583. In the total cohort of 13,433 patients with 1-year follow-up results, the mean age of patients was 64.7 years, 54% were men. Mean number of antihypertensive drugs was higher in the ALIS group compared to the other groups (3.0 drugs versus 2.5 in ACEI/ARB versus 1.6 in non-RAS; p<0.0001). Statistical regression analysis revealed baseline BP as the dominant covariate. After adjustment for baseline BP and 12 other confounders, no significant differences in BP reduction between the three groups were observed. The rate of major cardiac events (death, myocardial infarction, and stroke) was 1.3% in the total cohort, and did not differ across groups.. ALIS at beginning of the observation was mostly used by the physicians in patients with higher BP at entry and in higher risk populations. By study end, in all groups, stringent BP lowering measures, usually with combination therapy, led to significant improvements; more than half of these at-risk patients reached the BP targets.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Primary Health Care; Prospective Studies; Registries; Treatment Outcome

Aliskiren, a direct renin inhibitor, is a novel antihypertensive drug. To study whether aliskiren can reverse chronic kidney disease, we administered it to renin transgenic mice, a strain characterized by elevated blood pressure and a slow decline of renal function, mimicking well the progression of hypertensive chronic kidney disease. Ten-month-old transgenic mice were treated either with aliskiren or placebo for 28 days. Age-matched wild-type mice treated or not with aliskiren were considered as normotensive controls. Aliskiren reduced blood pressure to wild-type levels from as early as day 14. Proteinuria and cardiac hypertrophy and fibrosis were also normalized. Renal interstitial fibrosis and inflammation were significantly ameliorated in aliskiren-treated mice (shown by the decrease of proinflammatory and profibrotic markers), and the phenotypes of tubular epithelial cells and podocytes were restored as evidenced by the reappearance of cellular proteins characteristic of normal phenotype of these cells. Profibrotic p38 and Erk mitogen-activated protein kinases were highly activated in placebo-treated transgenic animals. Aliskiren treatment cancelled this activation. This nephroprotection was not attributed to the antihypertensive activity of aliskiren, because blood pressure normalization after treatment with hydralazine failed to induce the regression of renal fibrosis. Direct inhibition of renin can restore renal function and structure in aged hypertensive animals with existing proteinuria. This finding suggests that, in addition to antihypertensive action, aliskiren can be also used to treat chronic kidney disease.

Topics: Amides; Animals; Disease Models, Animal; Fibrosis; Fumarates; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Renin

Our previous study indicated that the exchange from an angiotensin receptor blocker (ARB) to aliskiren reduced morning blood pressure and albuminuria in hypertensive patients with diabetic nephropathy. We extended the above study and assessed the effects of exchanging from an ARB to aliskiren on home blood pressure in hypertensive patients with diabetic nephropathy on chronic hemodialysis. The patients who were persistently hypertensive despite antihypertensive therapy, including ARB, were considered as candidates for the exchange from the ARB to aliskiren. Patients' age and durations of diabetes and hemodialysis were averaged as 62 ± 9 years old, 15 ± 8 and 7 ± 3 years, respectively. Aliskiren decreased morning systolic blood pressure (149 ± 14 to 144 ± 13 mm Hg, n = 30, P < .01) and plasma renin activity (3.5 ± 1.1 to 1.2 ± 0.6 ng/mL/h, P < .01) without changes in serum potassium. Aliskiren also reduced interdialytic weight gain (2.7 ± 0.6 to 2.5 ± 0.5 kg/interval, P < .05) and attenuated the magnitude of intradialytic declines in systolic (-20 ± 11 to -17 ± 10 mm Hg, P < .05) and diastolic blood pressure (-9 ± 6 to -5 ± 5 mm Hg, P < .01). The exchange from an ARB to aliskiren is safe and useful to control home blood pressure in hypertensive hemodialysis patients with diabetic nephropathy. Aliskiren reduced both intradialytic blood pressure drops and interdialytic weight gain in patients with DN.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Diabetic Nephropathies; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renin; Retrospective Studies; Weight Gain

Topics: Amides; Aorta, Thoracic; Benzimidazoles; Benzoates; Blood Pressure; Brachial Artery; Circadian Rhythm; Female; Fumarates; Humans; Hypertension; Male; Telmisartan

Hypertension (HTN) is one of the major risk factors for cardiovascular disease in Western countries, and disease control is of major relevance in order to reduce cardiovascular morbidity and mortality. Different approaches have shown efficacy, and one of the proven therapies for HTN control is the blockade of the renin-angiotensin-aldosterone system, which may be accomplished by means of various drugs with different modes of action. Aliskiren is a novel direct renin inhibitor that reduces both angiotensin I and II blood levels. Different randomized clinical trials (phase II and III) have shown its safety and efficacy either alone or in combination with hydrochlorothiazide. However, although aliskiren has been on the market for some years, reports on the post-marketing experience with aliskiren in the real-world setting are lacking.. The Aliskiren in Latin America Study (ALAS) was designed with the aim of describing the effectiveness of aliskiren at reducing blood pressure (BP) values by prospectively assessing BP control in outpatient clinics in different countries in Latin America. A total of 435 sites in 5 Latin American countries (Mexico, Ecuador, Colombia, Argentina, and Venezuela) enrolled 4588 patients who had just been initiated on aliskiren (either alone or in combination with hydrochlorothiazide) based on their treating physicians' discretion, and they were followed for a 6-month period. Prior antihypertensive drugs could be continued if their doses were not modified along the study.. At the end of the follow-up period, a statistically significant reduction in BP values was observed, with a mean systolic BP reduction of 29.2 mmHg and a mean diastolic BP reduction of 13.78 mmHg from baseline at the 6-month visit.. The BP reduction levels and the low adverse event rate demonstrate the adequate efficacy and safety profile of aliskiren (alone or with hydrochlorothiazide).

Topics: Adult; Aged; Ambulatory Care; Amides; Antihypertensive Agents; Blood Pressure; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Latin America; Male; Middle Aged; Prospective Studies; Renin; Young Adult

Topics: Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Ramipril; Vascular Stiffness

We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.

Topics: Aldosterone; Amides; Angiotensin II; Animals; Antihypertensive Agents; Complement C3; Epithelial-Mesenchymal Transition; Fumarates; Hypertension; Kidney; Kruppel-Like Transcription Factors; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Nephrosclerosis; Orphan Nuclear Receptors; Renin; Renin-Angiotensin System; Transforming Growth Factor beta1; Ureteral Obstruction

The aim of this French observational study was to evaluate how the direct renin inhibitor aliskiren is being prescribed to treat hypertension by primary care providers (PCPs) and office-based cardiologists.. Each participating physician included the first three consecutive hypertensive patients who had been prescribed aliskiren at least 4 weeks beforehand and noted whether aliskiren was prescribed: alone or as part of a combination; as first-line therapy, to replace another drug or as an add-on therapy.. Five thousand, four hundred and eleven patients were analyzed [mean age, 63; 58% men; 24% diabetic; mean blood pressure (BP) 148/85 mmHg]. A total of 23.6% of patients had a controlled BP. Aliskiren was prescribed alone in 49.4% patients and as part of a combination in 50.6% (bitherapy 28.3%, tritherapy 14.7%, and quadri+therapy 7.6%), at the higher recommended dosage (300 mg daily) to two-thirds of cases. Aliskiren replaced another drug in 71.9% [mainly an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi)] and was added to an existing regimen in 22.5%. For bitherapy, aliskiren was combined with a diuretic (D; 39%) or a calcium channel blocker (CCB; 32%). For tritherapy, it was prescribed with CCB and D in 28% and β-blocker and D in 26%. In 8.9% of patients, aliskiren was prescribed with an ACEi or an ARB.. French physicians are generally following the current prescribing recommendations for aliskiren, but the place of this new class of antihypertensive in the management of essential hypertension will become clearer with longer experience, especially concerning effective doses and combinations.

Topics: Aged; Amides; Antihypertensive Agents; Cross-Sectional Studies; Female; France; Fumarates; Humans; Hypertension; Male; Middle Aged; Practice Patterns, Physicians'; Renin

To report a case of difficult-to-treat hypertension ultimately managed with triple antirenin (anti-R) therapy using plasma renin activity (PRA) to guide medication selection.. A 66-year-old white man was referred to the cardiology pharmacotherapy clinic for difficult-to-treat hypertension. His initial office blood pressure (BP) was 152/71 mm Hg on diltiazem and chlorthalidone. After a series of medication adjustments based on serial PRA measurements, the patient achieved his target BP with a regimen that included 3 anti-R angiotensin system medications: carvedilol, valsartan, and aliskiren.. Despite continued progress in the understanding and pharmacological therapy for hypertension, uncontrolled hypertension remains a major problem. The most common strategy to control hypertension is the stepped-care approach, with progressive addition of medications to eventually reach the BP goal. An alternative approach includes the use of PRA measurements to guide both the addition and removal of drugs in an attempt to effectively control BP. At times, this has the potential to result in a drug regimen that is incongruous with current guidelines and practice recommendations. However, if this results in more effective BP control with the same, or fewer, number of medications, it may represent a reasonable alternative.. This case report illustrates a real-world application of PRA-guided therapeutics in a patient with difficult-to-treat hypertension. It highlights how a personalized approach can lead to BP control with a more streamlined regimen than would likely result if a stepped-care approach was used.

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Carbazoles; Carvedilol; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Male; Practice Guidelines as Topic; Precision Medicine; Predictive Value of Tests; Propanolamines; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome; Valine; Valsartan

Topics: Amides; Antihypertensive Agents; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Sodium Chloride Symporter Inhibitors

Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease.. Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone.. In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Catheterization; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Female; Fumarates; Heart Failure; Hypertension; Lisinopril; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Transgenic; Recovery of Function; Renin; Renin-Angiotensin System; Stroke Volume; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Hyperactivation of the renin-angiotensin system contributes to hypertension-induced upregulation of vascular matrix metalloproteinases (MMPs) and remodeling, especially in the two kidney, one clip (2K1C) hypertension model. We hypothesized that the AT1R antagonist losartan or the renin inhibitor aliskiren, given at doses allowing similar antihypertensive effects, could prevent in vivo vascular MMPs upregulation and remodeling, and collagen/elastin deposition found in 2K1C hypertension by preventing the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and transforming growth factor-β1 (TGF-β1). We also hypothesized that aliskiren could enhance the effects of losartan.. 2K1C rats were treated with aliskiren (50mg.kg(-1).day(-1)), or losartan (10mg.kg(-1).day(-1)), or both by gavage during 4 weeks.. Aliskiren, losartan, or both drugs exerted similar antihypertensive effects when compared with 2K-1C rats treated with water. Aliskiren reduced plasma renin activity in both sham and 2K-1C rats. Losartan alone or combined with aliskiren, but not aliskiren alone, abolished 2K1C-induced aortic hypertrophy and hyperplasia, and prevented the increases in aortic collagen/elastin content, MMP-2 levels, gelatinolytic activity, and expression of phospho-ERK 1/2 and TGF-β1. No significant differences were found in the aortic expression of the (pro)renin receptor.. These findings show that although losartan and aliskiren exerted similar antihypertensive effects, only losartan prevented the activation of vascular profibrotic mechanisms and MMP upregulation associated with vascular remodeling in 2K1C hypertension. Our findings also suggest that aliskiren does not enhance the protective effects exerted by losartan.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Fumarates; Hypertension; Losartan; Male; Random Allocation; Rats; Rats, Wistar; Treatment Outcome; Ventricular Remodeling

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers can improve insulin resistance and vascular dysfunction in insulin-resistant rats; however, there are few reports on the effects of direct renin inhibitors on these conditions. We investigated the effects of a direct renin inhibitor, aliskiren, on insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats. Male Wistar-Kyoto rats were divided into four groups (n=6 per group) and studied for 8 weeks: Group Con: standard chow diet; group Fru: high-fructose diet (60% fructose); Group FruA: high-fructose diet with concurrent aliskiren treatment (100 mg kg(-1) per day); and Group FruB: high-fructose diet with subsequent aliskiren treatment 4 weeks later. Blood was collected for biochemical assays, and isolated rings of the thoracic aorta were obtained for analysis of vascular reactivity, vascular structure and lipid peroxide. Rats fed with high-fructose diets developed significant systolic hypertension, decreased plasma nitrite (NO(2); nitric oxide metabolite) levels and increased plasma glucose, insulin, triglyceride, total cholesterol and aortic lipid peroxide levels, and aortic wall thickness compared with control rats. Aliskiren treatment, either concurrent or subsequent, elevated plasma NO(2) levels and reduced systolic hypertension, insulin resistance, dyslipidemia, aortic lipid peroxide levels and aortic wall hypertrophy in FHR. The peak endothelium-dependent aortic relaxations were significantly higher in rats that received aliskiren treatment than in those that did not. In conclusion, our findings suggest that aliskiren prevents and ameliorates insulin resistance, aortic endothelial dysfunction and oxidative vascular remodeling in fructose-fed hypertensive rats.

Topics: Amides; Animals; Aorta, Thoracic; Dietary Carbohydrates; Disease Models, Animal; Endothelium, Vascular; Fructose; Fumarates; Hypertension; Insulin Resistance; Lipid Peroxides; Male; Nitrites; Oxidative Stress; Rats; Rats, Inbred WKY; Renin; Vasodilation

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II-AT1-receptor and survival Ang(1-7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Fumarates; Hypertension; Imidazoles; Male; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renin

We examined the antihypertensive effects of valsartan, aliskiren, or both drugs combined on circulating, cardiac, and renal components of the renin-angiotensin system in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg per day; n=10), aliskiren (SC by osmotic mini-pumps, 50 mg/kg per day; n=10), or valsartan (30 mg/kg per day) combined with aliskiren (50 mg/kg per day; n=10). Arterial pressure and heart rate were measured by telemetry before and during 2 weeks of treatment; trunk blood, heart, urine, and kidneys were collected for measures of renin-angiotensin system components. Arterial pressure and left-ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren, and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma angiotensin (Ang) II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1-7) induced by aliskiren recovered in the combination group. Kidney Ang-(1-12) was increased by the combination therapy whereas the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate end points of blood pressure, ventricular mass, and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response attributable to loss of tubuloglomerular feedback by Ang II.

Topics: Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Heart Rate; Hemodynamics; Hypertension; Kidney; Male; Rats; Renin; Renin-Angiotensin System; Telemetry; Tetrazoles; Valine; Valsartan

Numerous randomized clinical trials have demonstrated the efficacy and tolerability of aliskiren and aliskiren hydrochlorothiazide (aliskiren HCT) single-pill combination therapy in patients with hypertension. The objective of the present study was to evaluate the effectiveness and safety of aliskiren-based therapy under daily life conditions in a multiethnic population.. This observational, multicenter, noninterventional study, conducted at 420 centers in Asia and the Middle East, included adult patients with hypertension who received treatment with aliskiren or aliskiren HCT as single or add-on therapy for a planned treatment period of at least 26 weeks. The main effectiveness assessments included the proportion of patients achieving therapeutic blood pressure (BP) goal (defined as systolic BP [SBP]/diastolic BP [DBP]<140/90 mmHg, or <130/80 mmHg in patients with diabetes) and BP response, and change in mean sitting BP from baseline to study end.. Of 4,826 patients (mean age 51.4 years, 65.9% male, 64.5% Asian, 41.5% diabetic) included in the study, 3,473 received aliskiren and 1,353 received aliskiren HCT. Almost half the study population (48.1%) received aliskiren or aliskiren HCT as add-on therapy. The therapeutic BP goal was achieved in 49.5% of patients treated with aliskiren and 48.3% of patients receiving aliskiren HCT; attainment of BP goal increased to more than 70% when a classic BP target of <140/90 mmHg was applied for all patients. Reductions in mean sitting SBP/DBP were significantly lower versus baseline for both aliskiren (24.1/12.2 mmHg) and aliskiren HCT (27.6/14.1 mmHg) and BP response rates were consistently achieved in more than 80% of all patients during the study. Aliskiren treatment was well tolerated with only a small proportion of patients experiencing adverse events (AEs; 2.1%) and serious AEs (0.3%).. In this real-world, naturalistic setting, antihypertensive treatment with an aliskiren-based regimen was effective and well-tolerated in this multiethnic population with arterial hypertension.

Topics: Adult; Amides; Antihypertensive Agents; Asian People; Drug Combinations; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Prospective Studies; Treatment Outcome

Topics: Amides; Animals; Aorta, Thoracic; Endothelium, Vascular; Fructose; Fumarates; Hypertension; Insulin Resistance; Male; Renin

Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Humans; Hypertension; Male; Ramipril

Hypokalemic hypertension is a common condition leading to the diagnosis of secondary hypertension. We report the case of a 60-year-old woman for whom the diagnosis of autosomal dominant polycystic kidney disease arose during the investigation of possible hyperaldosteronism. Activation of the renin system, as supported by recent studies, can explain the mechanism of hypokalemia and hypertension in this inherited cystic kidney disorder. Clinicians should be aware of this relatively uncommon clinical phenomenon of secondary hypertension in polycystic kidney disease. Increased understanding of the disorder's underlying mechanism should lay the foundation for better appreciation of potentially effective blood pressure treatments. The availability of a direct renin inhibitor may redirect research toward finding a remedy for this troublesome disease.

Topics: Amides; Female; Fumarates; Humans; Hypertension; Hypokalemia; Middle Aged; Polycystic Kidney, Autosomal Dominant; Potassium Chloride; Renin; Treatment Outcome

Renal hemodynamic effects of inhibitors of the renin-angiotensin system can increase the risk of acute kidney injury under certain conditions. The BP-lowering effects of the renin inhibitor aliskiren are sustained 3-4 weeks after withdrawal. In this study, the reversibility of the renal hemodynamic effects of aliskiren was tested.. In this open-label study, renal perfusion was measured by 1.5-T magnetic resonance imaging-arterial spin labeling in 34 subjects with arterial hypertension before aliskiren (pre-aliskiren), after 4 weeks of aliskiren treatment (300 mg), and 4-5 days (∼2.5-3.0× plasma half-life) after withdrawal (post-aliskiren).. Aliskiren reduced systolic BP from 152 ± 14 to 139 ± 16 mmHg (P<0.0001), which was sustained post-aliskiren (136 ± 13 mmHg, P=1.00 versus aliskiren). Aliskiren significantly altered renal perfusion (P=0.005), increasing from 272 ± 25 pre-aliskiren to 287 ± 29 ml/min per 100 g during aliskiren (P=0.03). This increase in renal perfusion was completely reversed post-aliskiren (272 ± 26 ml/min per 100 g, P=0.03 versus aliskiren, P=0.63 versus pre-aliskiren). No changes were noted in urinary angiotensinogen levels. Plasma renin activity was reduced by aliskiren, which was sustained post-aliskiren. Angiotensin II and aldosterone were reduced by aliskiren but recovered post-aliskiren to pre-aliskiren levels.. After withdrawal of aliskiren, the effects on BP were sustained, whereas increase in renal perfusion was reversed, which was associated with recovery of angiotensin II and aldosterone to pretreatment levels. Renal hemodynamic effects are more readily reversible than systemic effects of aliskiren.

Topics: Adult; Aged; Aldosterone; Amides; Analysis of Variance; Angiotensin II; Antihypertensive Agents; Blood Pressure; Female; Fumarates; Germany; Half-Life; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Perfusion Imaging; Renal Circulation; Renin; Renin-Angiotensin System; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

Aliskiren, a novel direct renin inhibitor, is hypothesized to inhibit the renin-angiotensin- system. This study attempted to provide insight into this mechanism by examining the antihypertensive and renoprotective effects of aliskiren in hypertensive chronic kidney disease (CKD) patients.. After recruitment, 43 hypertensive CKD patients (mean age, 53.7 years) began treatment of aliskiren. The patients were classified into high (over 30 mL/min/1.73 m(2)) estimated glomerular filtration rate (eGFR) group or low (under 30 mL/min/1.73 m(2)) eGFR group for comparison of measurements of various parameters over the 6-month observation period.. Systolic blood pressure/diastolic blood pressure of 150 mg/day group decreased to an average of 126.8 ± 21.6 mmHg/69.3 ± 15.1 mmHg (average decrease: -7.4/-8.3 mmHg) over the 6-month observation period, while that of 300 mg/day group significantly decreased to an average of 133.5 ± 14.0 mmHg/71.5 ± 11.7 mmHg (average decrease: -21.1/-14.6 mmHg). Urinary protein of all patients decreased slightly and insignificantly to 1.1 ± 1.7 g/gCr from 1.4 ± 2.5 g/gCr. The serum creatinine (Cr) level of all patients decreased from 1.81 ± 1.10 mg/dL to 1.78 ± 0.82 mg/dL. Although the serum Cr level of the high eGFR group decreased from 1.28 ± 0.45 mg/dL to 1.27 ± 0.57 mg/dL, that of the low eGFR group slightly but insignificantly increased from 2.49 ± 0.64 mg/dL to 2.69 ± 1.11 mg/dL.. Administration of aliskiren exerts an antihypertensive effect on hypertensive CKD patients that may lead to a decrease in urinary protein and an improvement in renal functioning.

Topics: Aged; Amides; Blood Pressure; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Renin; Renin-Angiotensin System; Treatment Outcome

This study was performed to determine whether chronic direct renin inhibition can prevent the development of slowly progressive angiotensin (ANG) II-dependent hypertension and the associated derangements in renal function in Cyplal-Ren2 transgenic rats with inducible expression of the Ren2 gene.. Male Cyplal-Ren2 rats (n = 6) were fed a normal diet containing 0.15% indole-3-carbinol (I3C) for 16 days to induce slowly progressive ANG II-dependent hypertension. Conscious systolic blood pressure was measured daily using tail-cuff plethysmography. The rats were then anesthetized with pentobarbital sodium and surgically prepared for the measurement of mean arterial pressure (MAP) and renal hemodynamics and excretory function.. In rats induced with I3C, systolic blood pressure increased by day 3 (130 ± 7-160 ± 5 mm Hg, P < 0.01) and continued to increase to 191 ± 6 mm Hg (P < 0.001) by day 16. In a separate group of rats (n = 6), chronic administration of the direct renin inhibitor, aliskiren (30 mg/kg/d, sc), prevented the development of hypertension (113 ± 5 versus 114 ± 5 mm Hg, not significant). Rats treated with aliskiren exhibited significantly lower mean arterial pressure (138 ± 4 versus 201 ± 6 mm Hg, P < 0.001), renal vascular resistance (23 ± 4 versus 38 ± 3 mm Hg/mL/min · g, P < 0.01), urine flow (17.6 ± 1.4 versus 25.1 ± 2.9 μL/min, P < 0.05) and urinary sodium excretion (1.11 ± 0.32 versus 2.35 ± 0.28 μEq/min, P < 0.05) and higher renal plasma flow (4.22 ± 0.23 versus 2.56 ± 0.21 mL/min · g, P < 0.01) and glomerular filtration rate (1.19 ± 0.07 versus 0.78 ± 0.08 mL/min · g, P< 0.01), compared with induced rats not treated chronically with aliskiren.. The present findings demonstrate that chronic direct renin inhibition with aliskiren prevents the development of ANG II-dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyplal-Ren2 transgenic rats.

Topics: Amides; Angiotensin II; Animals; Arterial Pressure; Cytochrome P-450 CYP1A1; Fumarates; Hypertension; Kidney; Male; Rats; Rats, Transgenic; Renin

Central infusion of an angiotensin type 1 (AT(1)) receptor blocker prevents sympathetic hyperactivity and hypertension in Dahl salt-sensitive (S) rats on high salt. In the present study, we examined whether central infusion of a direct renin inhibitor exerts similar effects. Intracerebroventricular infusion of aliskiren at the rate of 0.05 mg/day markedly inhibited the increase in ANG II levels in the cerebrospinal fluid and in blood pressure (BP) caused by intracerebroventricular infusion of rat renin. In Dahl S rats on high salt, intracerebroventricular infusion of aliskiren at 0.05 and 0.25 mg/day for 2 wk similarly decreased resting BP in Dahl S rats on high salt. In other groups of Dahl S rats, high salt intake for 2 wk increased resting BP by ∼25 mmHg, enhanced pressor and sympathoexcitatory responses to air-stress, and desensitized arterial baroreflex function. All of these effects were largely prevented by intracerebroventricular infusion of aliskiren at 0.05 mg/day. Aliskiren had no effects in rats on regular salt. Neither high salt nor aliskiren affected hypothalamic ANG II content. These results indicate that intracerebroventricular infusions of aliskiren and an AT(1) receptor blocker are similarly effective in preventing salt-induced sympathetic hyperactivity and hypertension in Dahl S rats, suggesting that renin in the brain plays an essential role in the salt-induced hypertension. The absence of an obvious increase in hypothalamic ANG II by high salt, or decrease in ANG II by aliskiren, suggests that tissue levels do not reflect renin-dependent ANG II production in sympathoexcitatory angiotensinergic neurons.

Topics: Amides; Angiotensin II; Animals; Baroreflex; Blood Pressure; Fumarates; Heart Rate; Hyperkinesis; Hypertension; Infusions, Intraventricular; Male; Rats; Rats, Inbred Dahl; Rats, Wistar; Renin; Sodium Chloride, Dietary; Sympathetic Nervous System

Topics: Adipose Tissue; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Muscle, Skeletal; Renin-Angiotensin System

Drugs acting on the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and sartans, have been used for hypertension treatment in the HIV-negative population. These drugs reduce hypertension related cardiovascular diseases such as renal impairment in the general population. Limited data show similar findings also in the HIV-positive population. A new drug called aliskiren has recently become available on the market: it is able to block the RAS by a different mechanism acting as direct renin inhibitor. No data are available about the use of aliskiren in HIV-positive patients.. A 61-year-old HIV-infected Caucasian male (CDC C3) patient with hypertension for ten years and cardiovascular complications took carvedilol 25 mg twice a day, plus daily administration of irbesartan 300 mg, hydroclorotiazide 25 mg, doxazosin 4 mg, lacidipine 6 mg, and simvastatin 40 mg. He took AZT+ 3TC + RAL with a good profile on HIV replication and immunological parameters. We found a non-optimal blood pressure value and decided to start aliskiren 150 mg a day to improve blood pressure control. After one month blood pressure control and proteinuria improved. In our case the use of low doses of aliskiren appeared to improve the level of blood pressure, although five antihypertensive agents had already been used on the patient. Finally, although aliskiren would appear to have no direct effect on viro-immunological parameters and does not seem to interfere with cART, further studies are warranted in this context.

Topics: Amides; Antihypertensive Agents; Fumarates; HIV Seropositivity; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Treatment Outcome

This pooled analysis of ambulatory blood pressure (BP) monitoring data from two 8-week randomized controlled trials compared the antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan alone in hypertensive patients (nocturnal dippers or nondippers). At study end, patients were taking aliskiren/valsartan 300/320 mg or valsartan 320 mg. In dippers (n=138) and nondippers (n=132), aliskiren/valsartan provided significantly (P<.05) greater reductions from baseline to week 8 than valsartan in 24-hour, daytime, and last-4-hour mean ambulatory systolic BP (maSBP). Treatment differences were more pronounced in nondippers. Nighttime maSBP reductions with aliskiren/valsartan were significantly greater vs valsartan in nondippers (-17.0 mm Hg vs -8.9 mm Hg; P<.05) but not dippers (-7.6 mm Hg vs -4.5 mm Hg; P=.16). In all time periods, combination therapy was generally associated with BP reductions that were greater in nondippers than dippers. Conversion from nondipper to dipper status was 32% vs 22% for aliskiren/valsartan vs valsartan (P=.48). Both treatments were similarly well tolerated. Although the addition of aliskiren to valsartan did not significantly alter dipper status, our data suggest an increased contribution of the renin-angiotensin-aldosterone system to the nondipper status of hypertensive patients.

Topics: Adult; Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Tetrazoles; Treatment Outcome; Valine; Valsartan

Failure to intensify therapy when indicated is a serious problem in the management of hypertension. Patients having an antihypertensive prescription rejected because of utilization management tools may be at a high risk of failing to intensify their therapy when it is warranted.. The goal of this study was to investigate the patterns of therapy change after rejected aliskiren claims because of utilization management tools such as prior authorization, step therapy, and restrictive formulary.. A retrospective study was conducted using data from a large national pharmacy benefits manager. Patients with a rejected aliskiren claim because of utilization management and who were naive to aliskiren treatment before having a rejected aliskiren claim were included. Patients were followed up for 6 months after the initial rejected aliskiren claim to see whether there was a therapy change. Therapy change was defined as titration of old regimens, fulfillment of aliskiren, or fulfillment of a new antihypertensive medication not used previously.. A total of 1955 patients were identified (mean age, 64.5 years; 54.4% female). Six months after having rejected aliskiren claims, 36.8% overcame the utilization management and filled aliskiren; 45.1% filled a new antihypertensive medication not used previously; and 10.8% patients titrated old antihypertensive medications. More than one quarter of patients (28.4%) had no change in their antihypertensive treatment. Logistic regression analysis revealed that patients rejected because of prior authorization (odds ratio = 4.00 [95% CI, 1.89-8.44]) or step therapy (odds ratio = 2.59 [95% CI, 1.26-5.32]) were more likely to have a therapy change compared with patients rejected because of a restrictive formulary.. A significant number of patients had no therapy change 6 months after having rejected aliskiren claims because of utilization management tools, indicating potential clinical inertia or lack of therapy intensification in hypertension management. Patients with restrictive formularies were least likely to have a therapy change. More aggressive follow-up with patients with a rejected claim may be warranted to reduce treatment gaps.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Female; Follow-Up Studies; Formularies as Topic; Fumarates; Humans; Hypertension; Insurance, Pharmaceutical Services; Logistic Models; Male; Middle Aged; Practice Patterns, Physicians'; Retrospective Studies; Young Adult

Most hypertensive dialysis patients are currently treated with angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Aliskiren, the direct renin inhibitor, has not been specifically studied in peritoneal dialysis patients. The aim of the study was to compare hypotensive effects of aliskiren and ramipril and their influence on serum potassium and inflammatory parameters in hypertensive peritoneal dialysis patients. Eighteen hypertensive patients on chronic peritoneal dialysis were enrolled in an open-label comparative fixed-order study. The patients had been off RAAS blocking drugs for ≥4 weeks prior to an inclusion. At each of 3 study visits (baseline and after each of the treatment periods) blood pressure, serum lipids, potassium, renin, aldosterone, C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP-1) were measured. After the baseline visit aliskiren was started (150 mg/d) and after 12 weeks replaced with ramipril (5 mg/d) for the next 12 weeks. Blood pressure was 142/88±15/11 mmHg at baseline, 137/84±10/8 mmHg after aliskiren (ns) and 126/81±11/7 mmHg after ramipril (p<0.05 vs baseline and aliskiren). No incidents of hyperkalemia were observed. Plasma renin concentration increased significantly during aliskiren treatment compared to ramipril (227,6±844 vs. 58,3±765 pg/mL). CRP was similar after both therapies (8,8±34 vs. 8,4±32 µg/mL) but MCP-1 concentration was significantly lower after aliskiren than after ramipril (294,0±172,6 vs. 358,9±183,3 pg/mL). Aliskiren 150 mg/day decreases blood pressure less effectively than ramipril 5 mg/day in peritoneal dialysis patients. It does not influence serum potassium. The decrease of MCP-1 concentration after aliskiren treatment may provide an indirect evidence for its blood pressure independent cardioprotective and anti-inflammatory effects.

Topics: Adult; Aged; Amides; Anti-Inflammatory Agents; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Chemokine CCL2; Combined Modality Therapy; Comorbidity; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Peritoneal Dialysis; Pilot Projects; Potassium; Ramipril; Renal Insufficiency, Chronic; Renin; Treatment Outcome

Topics: Amides; Amlodipine; Drug Combinations; Fumarates; Humans; Hypertension

The addition of the direct renin inhibitor aliskiren is demonstrated to improve blood pressure (BP) control rate and reduce progression of organ damage in treated hypertensive patients in clinical trials with a relatively short follow-up period.. The objective of this study was to assess the effectiveness, safety and tolerability of aliskiren as an add-on antihypertensive therapy in high-risk, treated, hypertensive patients, who were not controlled with concomitant treatment with at least two antihypertensive drugs under 'real-life' conditions, during a planned observation and treatment period of at least 12 months in Italy.. Clinical data were derived from medical databases of treated, uncontrolled, hypertensive patients followed by specialized physicians operating in different clinical settings (hospital divisions or outpatient clinics) in Italy. Aliskiren was added to stable antihypertensive treatment, including at least two drug classes (independently of class or dosage) and unable to achieve BP control. Follow-up visits for measuring clinic BP levels and collecting data on drug safety and tolerability were planned at time intervals of 1, 6 and 12 months. At each predefined follow-up visit, aliskiren could be up-titrated from 150 to 300 mg daily if BP control was not achieved.. From May 2009 to June 2011, a total of 1186 treated, uncontrolled, hypertensive patients (46.3% female, aged 65.2 ± 11.7 years, mean duration of hypertension 13.2 ± 9.3 years, mean clinic BP levels 156.5 ± 15.9/90.3 ± 9.5 mmHg) were enrolled. Systolic and diastolic BP levels were 141.1/82.4, 134.9/79.8 and 133.6/78.9 mmHg at 1-, 6- and 12-month follow-up visits, respectively (p < 0.0001 vs baseline for all comparisons). These effects were consistent in all predefined subgroups, including those with left ventricular hypertrophy, renal disease, diabetes mellitus, coronary artery disease or cerebrovascular disease. Reduced levels of microalbuminuria were also reported, without affecting other renal and electrolyte parameters. Overall, compliance to study medication was high (93.0%), with a very low proportion of patients experiencing adverse events leading to drug discontinuation (3.6%).. In this observational, prospective, open-label, multicentre study, we reported the 12-month clinical effectiveness, safety and tolerability of adding aliskiren to treated, uncontrolled, hypertensive patients in a 'real-life' setting in Italy. This strategy leads to a significantly improved BP control rate and low incidence of drug-related side effects or discontinuations.

Topics: Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Albuminuria; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diastole; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hypertension; Italy; Male; Medication Adherence; Middle Aged; Prospective Studies; Renin; Systole

The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.

Topics: Amides; Analysis of Variance; Animals; Atrial Natriuretic Factor; Chemokine CCL2; Disease Models, Animal; Fumarates; Humans; Hypertension; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocardium; Nephrectomy; Oxidative Stress; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Ventricular Remodeling

In this issue of Curr Vasc Pharmacol, Pfeiffer et al. [1] and Glorioso et al. [2] report the efficacy and tolerability of aliskiren/amlodipine single-pill combinations (SPCs) in patients with inadequate blood pressure (BP) response to amlodipine or aliskiren monotherapy, respectively.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Male; Vasodilator Agents

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Coronary Vasospasm; Drug Therapy, Combination; Early Termination of Clinical Trials; Fumarates; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Telmisartan

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Consumer Advocacy; Drug Labeling; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Hypotension; Kidney; Randomized Controlled Trials as Topic; Renin; United States; United States Food and Drug Administration

Spontaneously hypertensive rats (SHRs) are characterized by capillary rarefaction, which may contribute to blood pressure elevation. We hypothesized that capillary rarefaction involves a suppressed angiogenesis; renin inhibition influences anti-angiogenesis homeostasis by acting on angiopoietins; transient renin blockade reduces anti-angiogenesis thereby ameliorating long-lasting blood pressure and cardiac hypertrophy in SHRs.. First, serum angiopoietin-1 and angiopoietin-2 were measured in 2-month old normotensive Wistar-Kyoto rats (WKYs) and SHRs after renin inhibition (aliskiren: 1 and 10 mg/kg per day) or placebo. Second, 4-week old SHRs were prehypertensively treated with aliskiren (1 and 10 mg/kg per day) or placebo for 4 weeks. After 4 weeks of 'drug holiday' 12-week old SHRs were given L-nitro-arginine methyl ester (L-NAME) (25 mg/kg per day) for a 4-week interval to promote capillary rarefaction. Thereafter, mean arterial pressure (MAP), cardiac remodeling, capillary density, pAkt/Akt as marker for cellular survival, pro-angiogenic genes and systemic angiopoietins were investigated.. Baseline angiopoietin levels were similar between WKYs and SHRs. Renin inhibition increased angiopoietin-1 in SHR and reduced angiopoietin-2 in both WKY and SHR blood pressure independently. Prehypertensive renin inhibition reduced MAP and cardiac hypertrophy in adult SHRs. This was associated with higher cardiac capillary density, pAkt/Akt, pro-angiogenic expression pattern and serum angiopoietin-1, whereas angiopoietin-2 was lower as compared to vehicle-pretreated SHRs. These results were independent of prehypertensive blood pressure lowering by aliskiren.. We conclude that renin inhibition modulates anti-angiogenesis signaling independently of blood pressure by increasing angiopoietin-1/angiopoietin-2 ratio. This promotes in SHR stabilization of endothelial cells, favors pro-angiogenic action and consequently results in higher capillary density.

Topics: Amides; Angiopoietin-1; Angiopoietin-2; Animals; Antihypertensive Agents; Blood Pressure; Capillaries; Fumarates; Hypertension; Male; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Signal Transduction; Ventricular Remodeling

Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin-aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB.. To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension.. Patients (aged ≥18 years) initiated on either combination therapy were identified in the MarketScan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period.. Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95% CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242).[2008 values].. In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARB versus ACEI plus ARB, despite the increased prescription costs associated with aliskiren plus ARB therapy.

Topics: Adult; Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Female; Fumarates; Health Care Costs; Health Resources; Humans; Hypertension; Male; Medication Adherence; Middle Aged

Topics: Adolescent; Age Factors; Amides; Antihypertensive Agents; Child; Child, Preschool; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Off-Label Use; Patient Selection; Proteinuria; Renin; Renin-Angiotensin System; Risk Assessment; Risk Factors

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner.

Topics: Amides; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Drug Interactions; Endothelium, Vascular; Fumarates; Heart Rate; Hypertension; Infusion Pumps, Implantable; Male; Oligopeptides; Rats; Rats, Inbred SHR; Renin; Reverse Transcriptase Polymerase Chain Reaction; Telemetry

The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension.. The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR.. Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats.. Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.

Topics: Amides; Angiotensinogen; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Female; Fumarates; Gene Expression Regulation; Heart Rate; Humans; Hypertension; Macaca mulatta; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; RNA, Messenger; Tissue Distribution

Hypertensive chronic kidney disease (CKD) patients often have sympathetic hyperactivity. In this pilot study, we evaluated the effect of 6 weeks treatment with aliskiren on sympathetic activity in hypertensive Stages 2-4 CKD patients.. In 10 CKD patients (8 males, aged 44 ± 11 years, estimated glomerular filtration rate ( 57 ± 22 mL/min/1.73 m(2)), blood pressure and sympathetic activity [quantified by assessment of muscle sympathetic nerve activity (MSNA)] were assessed, while taken off renin-angiotensin blocker, and during the 6 weeks of treatment with aliskiren 300 mg/day. Ten other CKD patients served as control and were studied twice with an interval of 6 weeks without any change in medication, to quantify within subject reproducibility.. In the aliskiren study group, MSNA was reduced from 36 ± 8 to 26 ± 8 bursts/min (P = 0.01). Aliskiren lowered supine systolic and diastolic blood pressure from 147 ± 10 to 120 ± 8 and from 96 ± 7 to 83 ± 7 mmHg, respectively (both P < 0.05). MSNA changed in patients treated with aliskiren [-9.6 bursts/min with 95% confidence interval (CI) -4.0 to -15.0; P-value = 0.003] but not in controls (-0.7 bursts/min with 95% CI -2.2 to 4.0; P-value = 0.6). The mean difference in change between aliskiren group and the control group was -8.9 with 95% CI of -15 to -3; P = 0.005.. In hypertensive CKD patients, 6 weeks aliskiren treatment lowers blood pressure and MSNA (Clinical trial government identifier number: NCT00719316).

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Case-Control Studies; Female; Follow-Up Studies; Fumarates; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Prognosis; Survival Rate; Sympathetic Nervous System

Topics: Amides; Amlodipine; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Neoplasms; Renin

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Topics: Amides; Amlodipine; Antihypertensive Agents; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Fumarates; Humans; Hypertension; Overweight

Topics: Amides; Antihypertensive Agents; Benzopyrans; Chlorthalidone; Ethanolamines; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Impotence, Vasculogenic; Losartan; Male; Middle Aged; Nebivolol; Risk Factors

The hyperactivation of renin-angiotensin-aldosterone system (RAAS) underlies the development and the progression of arterial hypertension and chronic kidney diseases. Aldosterone is the main unit of RAAS and self-sufficient predictor of the development of cardiovascular events. In this study, the angiotensin receptor blocker valsartan, ACE inhibitor enalapril, and direct renin inhibitor aliskiren were used for the correction of blood pressure and aldosterone levels in patients with hypertension and chronic kidney diseases. The data obtained suggest that the proposed complex therapy provides the most complete blood pressure reduction and aldosterone level correction (as evidence of RAAS activity recovery), greatly improves the prognoses, and ensures maximum nephroprotection in the patients with arterial hypertension and chronic kidney diseases.

Topics: Aged; Aldosterone; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Drug Therapy, Combination; Enalapril; Female; Fumarates; Humans; Hypertension; Indapamide; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

The challenge of managing hypertension is exemplified by the limited success of monotherapy and necessity for multiple drug regimens targeting complimentary pathways. Recent evidence suggests that combination therapy including angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) provides blood pressure control while reducing cardiovascular mortality and morbidity over ACE inhibitor/diuretic therapy. However, CCBs, ACE inhibitors and angiotensin receptor blockers all increase plasma renin activity (PRA), promoting angiotensin I accumulation and angiotensin II production through alternative pathways. While the clinical ramifications of this and other compensatory pathways activating the renin-angiotensin-aldosterone system are unclear, the recently approved aliskiren/amlodipine antihypertensive combination pill has been shown to decrease PRA via aliskiren's direct inhibition of renin. The purpose of this monograph is to review the mechanisms of action, pharmacodynamics, and safety and efficacy profile of the aliskiren/amlodipine combination pill.

Topics: Amides; Amlodipine; Antihypertensive Agents; Clinical Trials as Topic; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Renin

The role of the renin-angiotensin system in cognitive impairment is unclear. This work was undertaken to test our hypothesis that renin-angiotensin system may contribute to cognitive decline and brain damage caused by chronic cerebral ischemia. C57BL/6J mice were subjected to bilateral common carotid artery stenosis with microcoil to prepare mice with chronic cerebral hypoperfusion, a model of subcortical vascular dementia. The effects of aliskiren, a direct renin inhibitor, or Tempol, a superoxide scavenger, on brain damage and working memory in these mice were examined. Chronic cerebral hypoperfusion significantly increased brain renin activity and angiotensinogen expression in C57BL/6J mice, which was attributed to the increased renin in activated astrocytes and microvessels and the increased angiotensinogen in activated astrocytes in white matter. Aliskiren pretreatment significantly inhibited brain renin activity and ameliorated brain p67(phox)-related NADPH oxidase activity, oxidative stress, glial activation, white matter lesion, and spatial working memory deficits in C57BL/6J mice with bilateral common carotid artery stenosis. To elucidate the role of oxidative stress in brain protective effects of aliskiren, we also examined the effect of Tempol in the same mice with bilateral common carotid artery stenosis. Tempol pretreatment mimicked the brain protective effects of aliskiren in this mouse model. Posttreatment of mice with aliskiren or Tempol after bilateral common carotid artery stenosis also prevented cognitive decline. In conclusion, chronic cerebral hypoperfusion induced the activation of the brain renin-angiotensin system. Aliskiren ameliorated brain damage and working memory deficits in the model of chronic cerebral ischemia through the attenuation of oxidative stress. Thus, direct renin inhibition seems to be a promising therapeutic strategy for subcortical vascular dementia.

Topics: Amides; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Brain Ischemia; Cognition Disorders; Cyclic N-Oxides; Dementia, Vascular; Disease Models, Animal; Fumarates; Hypertension; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Renin; Renin-Angiotensin System; Risk Factors; Spin Labels

Topics: Adult; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Prospective Studies; Renin

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, decreases NO synthesis. Plasma ADMA concentrations increase markedly in hypertension. We tested whether the development of hypertension and the increases in ADMA in spontaneously hypertensive rats (SHR) are prevented by aliskiren, a renin inhibitor. Male SHRs and normotensive Wistar Kyoto (WKY) control rats, aged 4 weeks (pre-hypertensive stage), were assigned to 4 groups: untreated SHRs and WKY rats, and SHRs that received oral aliskiren 10 and 30 mg/kg/day for 6 weeks. All rats were sacrificed at age 10 weeks. Blood pressure decreased at age 6, 8, and 10 weeks in SHRs that received high-dose aliskiren. Aliskiren mitigated the increases in plasma ADMA in SHRs. Renal ADMA levels were lower in SHRs that received high-dose aliskiren versus SHRs. SHRs experienced decreased plasma and kidney l-Arg-to-ADMA ratios versus control rats, which were reverted by 30 mg/kg aliskiren. Renal cortical neuronal NOS-α and -β levels increased in SHRs fed with high-dose aliskiren. Early aliskiren treatment mitigates increases in ADMA, restores l-Arg-to-ADMA ratios, enhances neuronal NOS-α, prevents decreased nNOS-β levels in the kidney-which might restore NO bioavailability and contribute to the decrease of blood pressure in young SHRs. Our findings suggest that aliskiren is a therapeutic agent for prehypertension that regulates the ADMA/NO pathway.

Topics: Amides; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Dose-Response Relationship, Drug; Fumarates; Gene Expression Regulation, Enzymologic; Hypertension; Kidney Cortex; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Renin

Renin-angiotensin system (RAS) activation contributes to kidney injury through oxidative stress. Renin is the rate-limiting step in angiotensin (ANG II) generation. Recent work suggests renin inhibition improves proteinuria comparable to ANG type 1 receptor (AT1R) blockade (ARB). Thereby, we investigated the relative impact of treatment with a renin inhibitor vs. an ARB on renal oxidative stress and associated glomerular structural and functional changes in the transgenic Ren2 rat, which manifests hypertension, albuminuria, and increased tissue RAS activity. Young Ren2 and age-matched Sprague-Dawley (SD) controls (age 6-9 wk) were treated with a renin inhibitor (aliskiren), an ARB (irbesartan), or vehicle for 21 days. Ren2 rats exhibited increases in systolic pressure (SBP), albuminuria, and renal 3-nitrotyrosine content as well as ultrastructural podocyte foot-process effacement and diminution of the podocyte-specific protein nephrin. Structural and functional alterations were accompanied by increased renal cortical ANG II, AT1R, as well as NADPH oxidase subunit (Nox2) expression compared with SD controls. Abnormalities were attenuated to a similar extent with both aliskiren and irbesartan treatment. Despite the fact the dose of irbesartan used caused a greater reduction in SBP than aliskerin treatment (P < 0.05), the effects on proteinuria, nephrin, and oxidative stress were similar between the two treatments. Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Fumarates; Glomerular Filtration Rate; Hypertension; Irbesartan; Kidney; Membrane Glycoproteins; Membrane Proteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Podocytes; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles; Tyrosine

Topics: Ambulatory Care; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Obesity, Abdominal; Perindopril; Ramipril; Renin; Time Factors

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Clinical Trials as Topic; Female; Fumarates; Humans; Hypertension; Male; Renin; Sex Characteristics

The renin-angiotensin-aldosterone system plays a key role in the development of hypertension-related target organ damage. Nonetheless, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion limit the potential benefits of both angiotensin converting enzyme inhibitors and angiotensin receptor blockers. On the other hand, the ONTARGET trial reported that the combination of two renin-angiotensin system inhibitors was associated with more adverse events without an increase in benefit. Aliskiren is a novel direct renin inhibitor with promising results. In this manuscript the current evidence about aliskiren, alone or in combination, is analyzed.

Topics: Amides; Antihypertensive Agents; Cardiovascular System; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.

Topics: Amides; Antihypertensive Agents; Fumarates; Hypertension; Protease Inhibitors; Renin; Stereoisomerism; Substrate Specificity

The present drug utilization research project was conducted in order to evaluate the current status of antihypertensive drug treatment at launch of aliskiren - a drug targeting a completely new pharmacological mode of action - and to investigate the potential therapeutic value of this new therapeutic principle.. In 1,431 primary care practices in Germany, general practitioners and internal specialists were requested to determine the therapeutic value of different antihypertensive drugs (3rd and 4th quarter of 2007). Physicians were also requested to expose potential advantages of the new therapeutic principle of direct renin inhibition. Additional epidemiologic data such as age, gender and comorbidities were collected for each antihypertensive patient considered an optimal candidate to receive aliskiren in the respective medical practice due to an unfavorable response to the current antihypertensive treatment by using a second questionnaire.. On a scale between 1 (very important) and 6 (unimportant), the therapeutic value of antihypertensive drugs was judged as follows: angiotensin-inhibiting enzyme (ACE) inhibitors (98.8%), angiotensin (AT)(1) receptor blockers (87.4%), beta-receptor blockers (71.2%), calcium channel blockers (58.9%), thiazide diuretics (56,3%), and loop diuretics (32.3%) were judged with the mark 1 (very important) and 2 (important). From a total of 14,358 patients included in the present survey, age, gender, severity and duration of arterial hypertension, complications and comorbidities, and a detailed drug history were collected. 50.3% of the patients received an ACE inhibitor, 27.9% an AT(1) receptor blocker, 45.7% a beta-receptor blocker, 37.5% a calcium channel blocker, and 53.2% a diuretic. Dominating comorbidities up to the time of data collection were diabetes mellitus (43.8%), coronary heart disease (37.3%), and chronic heart failure (20.7%). 89.4% of patients with diabetes received either an ACE inhibitor or an AT(1) receptor blocker compared to 69.6% of patients not suffering from diabetes.. According to the evaluation of primary care physicians participating in this study, aliskiren might be useful for antihypertensive treatment in patients with severe arterial hypertension, in patients with an already long-lasting course of disease, and in the presence of comorbidities such as diabetes mellitus. The high percentage of patients in this study cohort already treated with an ACE inhibitor or an AT(1) receptor blocker represents good adherence of primary care physicians to current treatment guidelines. The evaluation of loop diuretics as important antihypertensive drugs by 32.3% of attending physicians in this study requires critical discussion.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Comorbidity; Drug Approval; Drug Therapy, Combination; Drug Utilization; Female; Fumarates; Germany; Humans; Hypertension; Male; Middle Aged; Practice Patterns, Physicians'; Primary Health Care; Renin; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension

The blood pressure-lowering effect of the renin inhibitor aliskiren equals that of angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II type 1 (AT1) receptor blockers. Whether aliskiren offers end-organ protection remains to be investigated. Here, we compared the cardiac effects of aliskiren, the AT1 receptor blocker irbesartan and the ACE inhibitor captopril in spontaneously hypertensive rats (SHR) at equi-hypotensive doses.. SHR were treated for 1-3 weeks with vehicle, aliskiren, captopril or irbesartan (100, 3 and 15 mg/kg per day, respectively) using an osmotic minipump, and compared to vehicle-treated Wistar-Kyoto (WKY) controls. All drugs lowered (but not normalized) mean arterial pressure in SHR equi-effectively, as monitored by radiotelemetry, without altering heart rate. All drugs also reduced the increased cardiomyocyte area in SHR, and tended to normalize the elevated brain natriuretic peptide plasma levels. In the Langendorff set-up, all drugs normalized the diminished endothelium-dependent vasodilator response to bradykinin in SHR. Moreover, aliskiren and irbesartan, but not captopril, decreased the enhanced coronary Ang II response in SHR. Aliskiren reduced plasma renin activity and the plasma and tissue angiotensin levels at 1 week of treatment; yet, after 3 weeks of aliskiren treatment only the cardiac angiotensin levels remained suppressed, whereas no tissue angiotensin reductions were seen with captopril or irbesartan.. For a given decrease in blood pressure, aliskiren improves coronary endothelial function and decreases cardiac hypertrophy in SHR to at least the same degree as ACE inhibition and AT1 receptor blockade. In addition, aliskiren diminishes the enhanced Ang II response in the coronary circulation of SHR and offers superior long-term cardiac angiotensin suppression.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Biphenyl Compounds; Blood Pressure; Captopril; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Heart; Heart Ventricles; Hypertension; Hypertrophy; Irbesartan; Male; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Tetrazoles

The relationship between angiotensin II (ANG II) and endothelin-1 (ET-1) is known to be complex; both peptides can initiate and potentiate the gene expression of each other. This pilot study investigated the effects of the AT(1) receptor blocker losartan or the direct renin inhibitor aliskiren on mean arterial pressure (MAP) and albuminuria and the renal ANG II and ET-1 levels. 3-month-old male Ren-2 transgenic rats (TGR) were treated either with losartan (5 mg kg(-1) day(-1)) or aliskiren (10 mg kg(-1) day(-1)) for 10 weeks. At the end of the experiment, rats were decapitated and cortical and papillary parts of kidneys were separated. Plasma and tissue ANG II levels were measured by RIA and tissue ET-1 concentrations by ELISA. In all four groups of animals ET-1 levels were lowest in renal cortex and more than 100-fold higher in the papilla. Cortical and papillary ET-1 concentrations in untreated TGR significantly exceeded those of control HanSD rats and were significantly depressed by both drugs. In both strains, papillary ANG II concentrations were moderately but significantly higher than cortical ANG II, TGR exhibited higher ANG II levels both in cortex and papilla as compared to control HanSD rats. Aliskiren and losartan at the doses used depressed similarly the levels of ANG II in cortex and papilla and reduced ET-1 significantly in the renal cortex and papilla below control levels in HanSD rats. Albuminuria, which was more than twice as high in TGR as in HanSD rats, was normalized with aliskiren and reduced by 28% with losartan, although MAP was reduced to a similar degree by both drugs. Despite similar reductions of MAP and renal ET-1 and ANG II levels aliskiren appears to be more effective than losartan, at the doses used, in reducing albuminuria in heterozygous hypertensive Ren-2 rats.

Topics: Albuminuria; Amides; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fumarates; Hypertension; Kidney; Losartan; Male; Mice; Pilot Projects; Radioimmunoassay; Rats; Rats, Transgenic; Renin; Time Factors

The effects of the human renin inhibitor aliskiren on blood pressure (BP), end-organ damage, proteinuria, and tissue and plasma angiotensin (ANG) II levels in young and adult heterozygous Ren-2 transgenic rats (TGR) were evaluated and compared with the effect of the ANG type 1 (AT(1)) receptor blocker losartan during treatment and after 12 days after the withdrawal of drug treatments. BP was monitored by telemetry from the age of 32 days on (young rats) and at 100 days (adult rats). Aliskiren (10 mg·kg(-1)·day(-1) in osmotic minipumps) or losartan (5 mg·kg(-1)·day(-1) in drinking water) treatment was applied for 28 days in young rats and for 70 days in adult rats. In young untreated TGR, severe hypertension rapidly evolved. Adult untreated TGR exhibited stable established hypertension. Both aliskiren and losartan fully prevented the development of hypertension and cardiac hypertrophy in young TGR and normalized BP and cardiac hypertrophy in adult TGR. After cessation of aliskiren treatment in both young and adult TGR BP and cardiac hypertrophy were persistently reduced, while after losartan withdrawal BP and cardiac hypertrophy rapidly increased. In adult aliskiren-treated rats proteinuria was significantly reduced compared with losartan (the effect persisting after withdrawal of treatment), and this decrease strongly correlated with normalization of glomerular size in these animals. In conclusion, aliskiren and losartan had similar antihypertensive effects during chronic treatment, but the antihypertensive and organoprotective effects of aliskiren were persistent even after the 12-day washout period. The durable effect on proteinuria can possibly be attributed to the normalization of glomerular morphology.

Topics: Amides; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Disease Models, Animal; Fumarates; Heart Rate; Hypertension; Kidney Glomerulus; Losartan; Male; Proteinuria; Rats; Rats, Transgenic; Renin; Time Factors

While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers is well known, less is known about the new direct renin inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short-term (≤2 months) placebo-controlled or long-term (>2 months) active-controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short-term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long-term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE inhibitors.

Topics: Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk

Topics: Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Drug Combinations; Drug Interactions; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin

Aliskiren is the first direct oral renin inhibitor approved for the treatment of hypertension. It acts by binding to the active site of renin and blocking its catalytic function, as a result preventing the formation of the angiotensin I and II. Used in monotherapy or in combination, this molecule proved its antihypertensive efficacy without showing, however, a clear superiority on the other antihypertensive drugs. Its benefit on cardiovascular morbidity and mortality and on target organ damage should be proved before aliskiren may be recommended as a first line therapy in essential hypertension. Data on cardiac insufficiency and diabetic nephropathy are preliminary.

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Antihypertensive Agents; Benchmarking; Fumarates; Humans; Hydrochlorothiazide; Hypertension

Most patients with hypertension require antihypertensive combination therapy to achieve BP control. This study investigated the safety and efficacy of the direct renin inhibitor aliskiren combined with the calcium channel blocker amlodipine.. Overall, 556 patients with hypertension (msDBP > or =95-<110 mmHg) received open-label aliskiren/amlodipine 150/5 mg for 2 weeks, followed by forced titration to aliskiren/amlodipine 300/10 mg for 52 weeks. Add-on hydrochlorothiazide (HCT) was permitted from week 10 to achieve BP control (<140/90 mmHg). The primary objective of the study was to evaluate the long-term safety and tolerability of aliskiren/amlodipine combination therapy; the BP-lowering efficacy of the combination was also assessed (week 54 endpoint; last observation carried forward).. ClinicalTrials.gov identifier NCT00402103.. In total, 452 patients completed 54 weeks' treatment with aliskiren/amlodipine 300/10 mg, with or without add-on HCT. The most frequently reported adverse events (AEs) were peripheral edema, upper respiratory tract infection, headache and bronchitis. Peripheral edema (the most common AE), occurred in 22.7% of treated patients, and was generally mild or moderate in intensity and transient in nature. Few patients exhibited laboratory abnormalities. Aliskiren/amlodipine combination therapy provided a mean BP reduction from baseline to week 54 of 24.2/15.5 mmHg; 74.3% of patients achieved BP control. In the subgroup of patients with stage 2 hypertension (baseline msSBP > or =160 mmHg and/or msDBP > or =100 mmHg), the mean BP reduction at week 54 was 29.1/17.1 mmHg, and 67.0% of patients achieved BP control.. In this open-label study, aliskiren/amlodipine 300/10 mg combination therapy, with or without add-on HCT, effectively reduced BP, particularly in patients with stage 2 hypertension. The most common AE was peripheral edema, consistent with the known AE profile of high-dose (10 mg) amlodipine. Further studies comparing the aliskiren/amlodipine combination with the component monotherapies and other antihypertensive combinations are warranted.

Topics: Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diastole; Drug Therapy, Combination; Drug Tolerance; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Patient Selection; Safety; Systole

We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

Topics: Acute Kidney Injury; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hyperkalemia; Hypertension; Renal Dialysis

Aliskiren is the first in a new class of orally effective direct renin inhibitors. Initial results of clinical efficacy studies have demonstrated at least equivalent or superior blood pressure-lowering efficacy when compared with existing drugs, and a favorable side-effect profile either as monotherapy or as a component of combination therapy. This report aims to introduce and provide a critical appraisal of the initial results of the ASPIRE HIGHER program, evaluating the potential cardio-renal protective effects of aliskiren.

Topics: Administration, Oral; Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Aliskiren/hydrochlorothiazide is a single-pill combination of the first in the new class of non-peptide direct renin inhibitors (aliskiren) and a thiazide diuretic (hydrochlorothiazide [HCTZ]) that achieves blood pressure (BP) reductions greater than those seen with either component alone. In double-blind, 8-week clinical trials, aliskiren and HCTZ (as a combination of the individual components or as single-pill combinations) reduced mean sitting systolic and diastolic BP from baseline to a significantly greater extent than placebo, aliskiren monotherapy and HCTZ monotherapy. Aliskiren/HCTZ produced additional BP reductions in patients inadequately responsive to 4 weeks' prior treatment with aliskiren or HCTZ alone. Responder rates and BP control rates further demonstrated the benefits of aliskiren/HCTZ combination therapy over monotherapy with individual components in patients with mild to moderate hypertension. Aliskiren plus HCTZ appeared to be effective as long-term (up to 1 year) combination treatment in an open-label trial. In a 12-week placebo-controlled trial in obese patients with hypertension, BP reductions and responder and control rates were significantly greater with aliskiren/HCTZ than with HCTZ alone. Aliskiren/HCTZ was generally well tolerated in clinical trials, with most adverse events being mild and transient in nature.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension

Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.

Topics: Albuminuria; Amides; Biphenyl Compounds; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fumarates; Health Care Costs; Humans; Hypertension; Irbesartan; Losartan; Quality-Adjusted Life Years; Tetrazoles

Renin is a basic component of renin-angiotensin-aldosteron system which contributes much to the activity of this system. Renin and its precursor prorenin can interact with prorenin receptors thus inducing hypertrophy and fibrogenesis in target tissues. Many variants of arterial hypertension are associated with plasmic renin activation suggesting high efficacy of direct renin inhibitors. Large controlled clinical trials demonstrated that one of such inhibitors, aliskiren, reduces high blood pressure and damage to target organs.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The purposes of this study are to investigate the cost-effectiveness of an implantable carotid body stimulator (Rheos; CVRx, Inc, Minneapolis, MN) for treating resistant hypertension and determine the range of starting systolic blood pressure (SBP) values where the device remains cost-effective. A Markov model compared a 20-mm Hg drop in SBP from an initial level of 180 mm Hg with Rheos to failed medical management in a hypothetical 50-year-old cohort. Direct costs (2007$), utilities, and event rates for future myocardial infarction, stroke, heart failure, and end-stage renal disease were modeled. Sensitivity analyses tested the assumptions in the model. The incremental cost-effectiveness ratio (ICER) for Rheos was $64,400 per quality-adjusted life-years (QALYs) using Framingham-derived event probabilities. The ICER was <$100,000 per QALYs for SBPs > or =142 mm Hg. A probability of device removal of <1% per year or SBP reductions of > or =24 mm Hg were variables that decreased the ICER below $50,000 per QALY. For cohort characteristics similar to Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm (ASCOT-BPLA) participants, the ICER became $26,700 per QALY. Two-way sensitivity analyses demonstrated that lowering SBP 12 mm Hg from 220 mm Hg or 21 mm Hg from 140 mm Hg were required. Rheos may be cost-effective, with an ICER between $50,000 and $100,000 per QALYs. Cohort characteristics and efficacy are key to the cost-effectiveness of new therapies for resistant hypertension .

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Carotid Body; Cohort Studies; Cost-Benefit Analysis; Drug Resistance; Electric Stimulation Therapy; Electrodes, Implanted; Fumarates; Humans; Hypertension; Markov Chains; Middle Aged; Quality-Adjusted Life Years; Sensitivity and Specificity; Treatment Outcome

Topics: Aged; Aged, 80 and over; Amides; Antihypertensive Agents; Blood Pressure; Catheter Ablation; Clinical Trials as Topic; Diastole; Dissection; Female; Fumarates; Humans; Hypertension; Kidney Transplantation; Life Expectancy; Male; Primary Prevention; Renal Artery; Renin; Risk Factors; Secondary Prevention; Smoking; Sympathectomy; Sympathetic Nervous System; Systole

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Fumarates; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Patient Readmission; Renin; Renin-Angiotensin System; Treatment Outcome

Aliskiren is a novel molecule which blocks the renin-angiotensin-aldosterone system in its rate limiting step by renin inhibition. Aliskiren is validated as an antihypertensive drug in many countries based on its efficacy data. Although some surrogate endpoint trials suggest that its potential advantages based on its mechanism of action provide clinical benefit beyond its blood pressure-lowering effect, hard endpoint clinical trials to reveal its long-term effects are yet to be completed.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

The inhibition of renin-angiotensin system (RAS) has an effect beyond reducing blood pressure in the treatment of cardiovascular diseases; it also reduces mortality and morbidity. Although the classic RAS blockage is effective, due to blockage of negative feedback inhibition, it increases plasma renin activity and as a result generates a residual cardiovascular risk. Different from ACE-i and ARB treatments, aliskiren, a direct renin inhibitor, is the only pharmacologic agent that noticeably reduces the plasma renin activity, an independent cardiovascular risk factor. This creates a new option in RAS blockage. The efficacy and safety of aliskiren in the treatment of hypertension has been well established. The effect of aliskiren on cardiovascular mortality and morbidity is being researched. At this point there are many experimental and clinical studies to answer questions on this subject.

Topics: Amides; Antihypertensive Agents; Atherosclerosis; Cardiovascular Diseases; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Although antihypertensive drugs currently used provide significant decreases in blood pressure and improve clinical results, cardiovascular morbidity and mortality are not sufficiently decreased; therefore, there is still a need for new approaches to the treatment of hypertension and related cardiovascular diseases. However, when a new blood-pressure lowering therapy is introduced, the question of whether this will be superior over other drug classes in terms of its advantages in hypertensive patients is frequently asked. In 1898, Tigerstedt and Bergman discovered "renin" as a consequence of an observation of blood-pressure elevation following the injection of rabbit renal extracts to rabbits; however, the first member of the renin system pharmacology, ACE inhibitors, could be developed in 1970's. This was followed by the development of angiotensin-receptor blockers (ARB) and, during the last 30 years, it has been shown that the pharmacologic blockage of renin-angiotensin system (RAS) improves the prognosis in hypertensive patients. It has been shown that renin system is the key system in the treatment of hypertension and related comorbidities and that the drugs which target renin system, such as ACE inhibitors and ARB, reduce the cardiovascular events to a large extent. In contrast, as the inhibition of angiotensin II (Ang II) production and effect prevents the negative feedback which helps Ang II to inhibit the renin release from the kidney, elevated Ang II levels suggest that renin enzyme, which can be considered to be the center of renin system, can be the optimal tool in the treatment. Aliskiren, which is the first oral direct renin inhibitor developed based on these ideas, was approved by the FDA in March 2007. During all this period, clinical studies have shown that aliskiren is as efficient as other antihypertensive drugs, and preclinical studies have shown that, in genetically modified rats, aliskiren is efficient in healing the cardiovascular damage associated with Ang II. The fact that the plasma renin activity (PRA), which increases with other antihypertensive therapies and is associated with increased cardiovascular complications, decreases with the use of direct renin inhibitors raises the question as to whether aliskiren may provide additional benefit in reducing cardiovascular morbidity and mortality. The ASPIRE HIGHER program designed to find an answer to this question includes several studies which investigate how aliskiren impacts the c

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Rabbits; Rats; Renin; Renin-Angiotensin System

(1) Pharmacological management of arterial hypertension is based on antihypertensive drugs with proven efficacy on morbidity and/or mortality endpoints. (2) Aliskiren is the first renin inhibitor to reach the market. (3) There are no published trials of aliskiren with clinical endpoints. Five double-blind short-term (8 weeks) placebo-controlled trials showed a moderate effect on blood pressure. This effect was not superior to that of other antihypertensive drugs with which aliskiren was compared: hydrochlorothiazide, amlodipine, irbesartan, losartan, valsartan, lisinopril and rampiril. (4) When added to another antihypertensive drug, aliskiren had little or no additional effect on blood pressure. In particular, there is no firm evidence that adding aliskiren to amlodipine 5 mg/day is any more effective than doubling the dose of amlodipine. (5) Aliskiren has not been tested in patients with renovascular hypertension or severe hypertension, but pharmacological data suggest that aliskiren might be less effective in these individuals. (6) Overall, the adverse effect profile of aliskiren does not seem to be any better than that of other antihypertensive drugs. Aliskiren contributes to the onset of angioedema, cough, diarrhea and abdominal pain, hyperuricaemia, gout attacks, kidney stones and skin rash. Pharmacovigilance should focus specifically on certain adverse effects that are known to occur with other drugs acting on renin-angiotensin axis, such as angioedema, muscle disorders and anaemia, even though few such cases were observed with aliskiren during clinical trials. (7) Aliskiren is contraindicated during pregnancy, as are other antihypertensive drugs acting on the renin-angiotensin axis. (8) In practice, it is better not to use aliskiren to treat hypertensive patients because better-assessed antihypertensive drugs with longer follow-up are available.

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Contraindications; Europe; Female; Fumarates; Humans; Hypertension; Male; Pregnancy; Renin; United States

The blockade of the renin-angiotensin-aldosterone system (RAAS) has been shown to be useful, or even mandatory, in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and nephropathy with albuminuria, due to diabetes or not. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors and/or recently a direct inhibitor of renin such as aliskiren. Various studies have demonstrated the advantage of optimising RAAS blockade in order to benefit of the best cardiorenal protection. The present article describes the various modalities to optimize the RAAS blockade, either by using a maximal dosage of a monotherapy, or by choosing a double inhibition of RAAS. New prospects for the RAAS blockade will be also briefly considered.

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Fumarates; Heart Failure; Humans; Hypertension; Kidney Diseases; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Treatment Outcome

Topics: Amides; Fumarates; Humans; Hypertension; Inhibitory Concentration 50; Renin

Topics: Amides; Animals; Antihypertensive Agents; Atherosclerosis; Fumarates; Humans; Hypertension; Nitric Oxide

Professor Hans Rudolf Brunner Born in 1937, Professor Brunner is a Swiss citizen. He is a Professor Emeritus of Medicine at the University of Lausanne, Switzerland. He has been at the forefront of research on the role of renin and the renin-angiotensin system in blood pressure regulation. He has been involved in the development of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. He was among the first medical practitioners to introduce the use of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Professor Brunner has been a medical advisor to Speedel since 1999.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Patient Selection; Renin

Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg, there are dose-related falls in blood pressure comparable to those seen with other major classes of antihypertensive drugs and that these falls are associated with a placebo level of side effects. Aliskiren was found to be effective either as monotherapy or in combination with drugs from the other major classes. As expected, there was a greater benefit from adding aliskiren to natriuretic drugs than to other blockers of the renin system. However, there was also some consistent benefit from dual renin blockade. Aliskiren is likely to be of most value in patients uncontrolled by, or intolerant of, other classes. Rational understanding of the renin system will maximize its value, for instance, by encouraging greater use of natriuretic agents in patients with resistant hypertension to render their hypertension renin dependent. Whether there are cardiovascular benefits other than blood pressure control in blocking the renin system remains to be demonstrated. It is hoped that long-term outcome studies with aliskiren will finally allow this question to be answered.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin

Topics: Adult; Amides; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Randomized Controlled Trials as Topic; Renin

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Kidney Failure, Chronic; Renin-Angiotensin System

High blood pressure is a major risk factor for cardiovascular disease worldwide. Drug treatments include those that target the renin-angiotensin system, a key hormone cascade in the regulation of blood pressure. One of these is aliskiren (Rasilez - Novartis), which belongs to a new class of drugs, direct renin inhibitors. Here we assess its place in managing adults with hypertension.

Topics: Adult; Amides; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Combinations; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Treatment Outcome

Topics: Amides; Cough; Fumarates; Humans; Hypertension; Incidence; Ramipril; Randomized Controlled Trials as Topic

Aliskiren (Rasilez) is the first oral renin inhibitor. Its present indication is essential hypertension, as monotherapy or in combination with other antihypertensive agents (diuretic, calcium antagonist, ...). It may also be associated with an angiotensin converting enzyme inhibitor (or an AT1 angiotensin receptor antagonist) in order to benefit of a dual blockade of the renin-angiotensin-aldosterone system. The usual daily dose is 150 mg, to be increased up to 300 mg if necessary. New clinical trials are ongoing to validate this novel therapeutic approach in other indications such as congestive heart failure and diabetic nephropathy.

Topics: Amides; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Antihypertensive Agents; Biological Availability; Blood Pressure; Drug Interactions; Fumarates; Humans; Hypertension; Renal Insufficiency; Renin; Renin-Angiotensin System

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cardiomegaly; Connexin 43; Dietary Fats; Disease Models, Animal; Electrocardiography; Electrophysiology; Fatty Acids, Omega-3; Fumarates; Humans; Hypertension; Magnetocardiography; Male; Rats; Rats, Sprague-Dawley; Renin; Up-Regulation

The prorenin/renin receptor is a recently discovered component of the renin-angiotensin system. The effects of aliskiren, a direct inhibitor of human renin, were compared with the handle region decoy peptide (HRP), which blocks the prorenin/renin receptor, in double-transgenic rats overexpressing the human renin and angiotensinogen genes. After 7 wk, all aliskiren-treated rats were alive, whereas mortality was 40% in vehicle-treated and 58% in HRP-treated rats. Aliskiren but not the HRP reduced BP and normalized albuminuria, cystatin C, and neutrophil gelatinase-associated lipocalin, a marker of renal tubular damage, to the levels of nontransgenic controls. In vitro, human renin and prorenin induced extracellular signal-regulated kinase 1/2 phosphorylation, independent of angiotensin II (AngII), in vascular smooth muscle cells. Preincubation with the HRP or aliskiren did not prevent renin- and prorenin-induced extracellular signal-regulated kinase 1/2 phosphorylation, whereas the MAP kinase kinase (MEK1/2) inhibitor PD98059 prevented both. In conclusion, renin inhibition but not treatment with the HRP protects against AngII-induced renal damage in double-transgenic rats. In addition, the in vitro data do not support the use of the HRP to block AngII-independent prorenin- or renin-mediated effects.

Topics: Amides; Angiotensin II; Animals; Blood Pressure; Fumarates; Humans; Hypertension; Muscle, Smooth, Vascular; Oligopeptides; Rats; Renin

Aliskiren, an octanamide, is nonpeptide, low molecular weight, orally active renin inhibitor effectively preventing angiotensin and aldosterone release. This drug has been recently approved for the treatment of hypertension. Considering potential links between hypertension, platelets, the coagulation cascade and fibrinolysis we sought to evaluate the effect of aliskiren on human biomarkers of hemostasis. In vitro effects of whole blood preincubation with escalating concentrations of aliskiren (500, 1,000 and 2,000 ng ml(-1)) were assessed in 20 aspirin-naive volunteers with multiple risk factors for vascular disease. A total of 33 biomarkers were measured, of which 18 are related to platelet function, 12 to coagulation and 3 to fibrinolysis. Pretreatment of blood samples with aliskiren 500 ng ml(-1) resulted in a significant increase of antithrombin-III (AT-III) activity (P=0.003). All other tested biomarkers were not significantly affected. Spiking whole blood with the higher aliskiren doses was associated with various trends in biomarker activity, where 1000 ng ml(-1) concentration mostly decreased (7/33), and 2,000 ng ml(-1) mostly increased (6/33) some biomarkers. In the therapeutic concentration of 500 ng ml(-1) aliskiren does not affect hemostatic biomarkers, except for a moderate but highly significant (P=0.003) increase of AT-III activity. Higher aliskiren doses were associated with more profound biomarker changes, but they are likely not to be clinically relevant since they show diverging (that is, both mild antiplatelet and platelet-activating) trends, and considering the 2- to 4-fold safety margin. It is suggested that antithrombotic properties of aliskiren be explored further in an ex vivo clinical setting.

Topics: Adult; Amides; Analysis of Variance; Antihypertensive Agents; Biomarkers; Blood Coagulation; Blood Platelets; Cardiovascular Diseases; Female; Fibrinolysis; Flow Cytometry; Fumarates; Humans; Hypertension; Male; Renin; Renin-Angiotensin System; Risk Factors; Statistics, Nonparametric

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Topics: Adult; Amides; Angioedema; Antihypertensive Agents; Female; Fumarates; Humans; Hypertension; Renin

1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study.

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fumarates; Humans; Hypertension

Renin-angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hypertension.. A total of 601 patients with hypertension (msDBP > or = 90 and < 110 mmHg) received a combination of aliskiren/valsartan 150/160 mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320 mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (> or = 140/90 mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a predefined safety outcome. BP was measured at regular intervals during the study.. At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations > 5.5 mmol/L. Only one patient (0.2%) exhibited potassium levels > or = 6.0 mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4 mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (< 140/90 mmHg; LOCF).. Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combination provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hypertension.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hyperkalemia; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; Valine; Valsartan

Hypertension is one of the major risk factors for cardiovascular morbidity and mortality. Lowering blood pressure (BP) may reduce the risk of stroke by 40% and the risk of ischemic heart disease by 20%. Despite the varied drugs available to lower BP, more than 50% of the hypertensive patients are not well-controlled. The major reason for the failure to control BP is noncompliance which is related to the side effects and inconvenience of drug administration. Aliskiren, a new oral direct renin inhibitor is very effective in BP reduction. It is given once daily and has very few side effects, almost like a placebo. It is well combined with diuretics, angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers. Unlike ACE inhibitors and angiotensin receptor blockers that block the renin angiotensin axis in its last part and thereby raise the rein-levels, the direct renin inhibitor block the renin-angiotensin axis in its beginning and keep the renin levels suppressed. Aliskiren is a promising agent but further prospective studies with morbidity and mortality data as endpoints are required, before the drug can be recommended as a first choice agent.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fumarates; Hypertension; Rats; Renin

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Forecasting; Fumarates; Humans; Hypertension; Male; Needs Assessment; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Risk Factors; Sensitivity and Specificity

Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Kidney; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Lisinopril; Renin; Renin-Angiotensin System; Treatment Outcome

Renin catalyzes the rate-limiting step of the renin-angiotensin system. A T allele variant at position -5312 within a distal enhancer region has been reported to increase in vitro renin gene transcription. Among 387 White bank employees, ambulatory blood pressures were higher in 133 -5312T allele carriers than in 254 CC homozygotes-mean differences [99% confidence interval] between carriers and homozygotes for daytime and night-time systolic/diastolic pressure were 2.5[0.4,4.6]/1.7[0.2,3.2] and 2.4[0.5,4.4]/1.5[0.1,2.9] respectively. Ambulatory pressure estimates for the only common renin haplotype including the -5312T variant (-5312T, 5090C, 5912A, 9479A, 10194G), were statistically significantly higher than estimates for all other haplotypes. Among 259 White hypertensive participants in a randomized double-blind clinical trial comparing a renin antagonist, aliskiren, with an angiotensin receptor blocker, losartan, plasma renin activity did not differ with renin -5312C/T genotype. Nocturnal blood pressure reductions with losartan 100 mg daily were significantly greater in -5312T allele carriers than in CC homozygotes (mean[standard error]; -12.9[3.7]/-7.9[2.4] versus -7.1[2.5]/-4.2[1.6]) whereas with aliskiren 150 and 300 mg daily, lesser reductions were observed in -5312T allele carriers than in CC homozygotes (-5.4[2.0]/-4.1[1.3] versus -10.1[1.4]/-6.5[1.1]; P<0.03 for treatmentxgenotype interaction for night-time systolic and diastolic pressures). Hence, the -5312 renin C/T enhancer polymorphism does contribute to blood pressure variation in Whites and also appears to predict responses to inhibition of the renin-angiotensin system. These findings suggest that genotyping at this locus may aid in the identification of susceptibility to hypertension and in the selection of optimal therapy for individual hypertensive patients.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chi-Square Distribution; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linear Models; Losartan; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Renin; Renin-Angiotensin System; Severity of Illness Index; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin

We studied the effects of extremely low-dose human renin inhibition (aliskiren) with low angiotensin II receptor blockade (losartan) in a novel double-transgenic rat model harbouring both human renin and angiotensinogen genes. We found that low-dose aliskiren and low-dose losartan effectively reduced mortality and target-organ damage with minimal, non-significant, effects on blood pressure (BP). Our data suggest that renin-angiotensin system (RAS) inhibition ameliorates target-organ damage in an Ang II-driven model of hypertension. Direct renin inhibition is equally efficacious in this regard. Our study does not fully answer the question of BP-lowering versus RAS inhibition. This question is important and was at least partially addressed with our low-dose model.

Topics: Amides; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Fumarates; Humans; Hypertension; Rats; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Blood Pressure; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diuretics; Drug Design; Drug Industry; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Renin; Tetrazoles; Valine; Valsartan

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hyperkalemia; Hypertension; Renin; Tetrazoles; Valine; Valsartan

Aliskiren, the direct renin inhibitor, is the first new class of drug available in 13 years for the treatment of hypertension. Renin has long been recognized as a preferred site for blockade of the renin-angiotensin-aldosterone system because it prevents conversion of angiotensinogen to angiotensin I. Aliskiren binds to the active site of the renin molecule, blocking angiotensinogen cleavage, thus, preventing the formation of angiotensin I. Clinical studies have demonstrated at least equivalent or superior blood pressure lowering efficacy compared with existing drugs with a favorable side effect profile. Aliskiren possesses possible synergistic potential when combined with a thiazide diuretic, ACE inhibitor, angiotensin receptor blocker and calcium channel blocker both in terms of efficacy and tolerability. This review aims to define the role of aliskiren in the therapeutic management of hypertension.

Topics: Amides; Animals; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

Topics: Amides; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Fumarates; Humans; Hypertension; Renin

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Topics: Adolescent; Adult; Amides; Amlodipine; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Ramipril; Renin; Renin-Angiotensin System; Tetrazoles; Valine; Valsartan

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Fumarates; Humans; Hypertension; Renin; Renin-Angiotensin System

Topics: Amides; Drug Industry; Fumarates; Humans; Hypertension; Renin

Topics: Amides; Animals; Fumarates; Humans; Hypertension; Kidney; Myocardium; Renin

We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202+/-4 mm Hg), serum creatinine, and albuminuria (34+/-5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115+/-6 and 139+/-5 mm Hg) and albuminuria (0.4+/-0.1 and 1.6+/-0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148+/-4 mm Hg) and albuminuria (2.1+/-0.7 mg per day), low-dose Val reduced BP (182+/-3 mm Hg) and albuminuria (24+/-3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4+/-0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Echocardiography; Fumarates; Humans; Hypertension; Kidney; Rats; Rats, Sprague-Dawley; Renin; Tetrazoles; Valine; Valsartan

Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.

Topics: Administration, Oral; Adolescent; Adult; Aged; Amides; Animals; Blood Pressure; Crystallography, X-Ray; Drug Design; Fumarates; Humans; Hydrogen-Ion Concentration; Hypertension; Inhibitory Concentration 50; Middle Aged; Models, Chemical; Models, Molecular; Peptides; Renin; Renin-Angiotensin System; Sodium; Species Specificity; Time Factors

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Benzyl Compounds; Child; Chlorothiazide; Clonidine; Cycloheptanes; Drug Combinations; Drug Evaluation; Drug Synergism; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Propylamines

Topics: Animals; Blood Pressure; Cycloheptanes; Diet; Fumarates; Hypertension; Kidney Diseases; Parasympatholytics; Propylamines; Rats; Water-Electrolyte Balance

Topics: Adult; Aged; Brain Neoplasms; Cerebral Angiography; Cycloheptanes; Diagnosis, Differential; Female; Fumarates; Glioma; Humans; Hypertension; Intracranial Aneurysm; Intracranial Arteriosclerosis; Male; Middle Aged; Papaverine; Parasympatholytics; Propylamines; Thrombosis; Vasodilator Agents