aliskiren and Heart-Failure

Aliskiren is a newly developed drug. Its role in lowering BP has been recognized. However, the role of aliskiren in treating heart and renal diseases are still controversial.. To evaluate the existing evidence about clinical efficacy, safety and tolerability of aliskiren monotherapy (AM).. An umbrella review of systematic reviews of interventional studies. We searched Pubmed, Embase and Cochrane Library up to June 2019. Two reviewers applied inclusion criteria to the select potential articles independently. The extract and analyze of accessible data were did by two reviewers independently too. Discrepancies were resolved with discussion or the arbitration of the third author.. Eventually, our review identified 14 eligible studies. Results showed that for essential hypertension patients, aliskiren showed a great superiority over placebo in BP reduction, BP response rate and BP control rate. Aliskiren and placebo, ARBs or ACEIs showed no difference in the number or extent of adverse events. For heart failure patients, AM did not reduce BNP levels (SMD -0.08, - 0.31 to 0.15) or mortality rate (RR 0.76, 0.32 to 1.80), but it decreased NT-proBNP (SMD -0.12, - 0.21 to - 0.03) and PRA levels (SMD 0.52, 0.30 to 0.75), increased PRC levels (SMD -0.66, - 0.8 to - 0.44). For patients who are suffered from hypertension and diabetes and/or nephropathy or albuminuria at the same time, aliskiren produced no significant effects (RR 0.97, 0.81 to 1.16).. We found solid evidence to support the benefits of aliskiren in the treatment of essential hypertension, aliskiren can produce significant effects in lowering BP and reliable safety. However, the effects of aliskiren in cardiovascular and renal outcomes were insignificant.. Study has been registered in PROSPERO (CRD42019142141).

Topics: Albuminuria; Amides; Antihypertensive Agents; Blood Pressure; Diabetic Nephropathies; Essential Hypertension; Fumarates; Heart Failure; Humans; Renin; Systematic Reviews as Topic; Treatment Outcome

Aliskiren might be beneficial for heart failure. However, the results of various studies are controversial. We conducted a systematic review and meta-analysis to explore the efficacy of aliskiren supplementation for heart failure.. PubMed, Embase, Web of Science, EBSCO, and the Cochrane Library databases were systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of aliskiren for heart failure were included. Two investigators independently searched for articles, extracted data, and assessed the quality of included studies. The meta-analysis was performed using the random-effect model.. Five RCTs comprising 1973 patients were included in the meta-analysis. Compared with control interventions in heart failure, aliskiren supplementation was found to significantly reduce NT-proBNP levels (standardized mean difference [SMD] = -0.12; 95% CI = -0.21 to -0.03 pg/ml; p = 0.008) and plasma renin activity (SMD = -0.66; 95% CI = -0.89 to -0.44 ng/ml.h; p < 0.00001) while increasing plasma renin concentration (SMD = 0.52; 95% CI = 0.30-0.75 ng/l; p < 0.00001); however, it demonstrated no significant influence on BNP levels (SMD = -0.08; 95% CI = -0.31-0.15 pg/ml; p = 0.49), mortality (RR = 0.97; 95% CI = 0.79-1.20; p = 0.79), aldosterone levels (SMD = -0.09; 95% CI = -0.32-0.14 pmol/l; p = 0.44), adverse events (RR = 3.03; 95% CI = 0.18-49.51; p = 0.44), and serious adverse events (RR = 1.34; 95% CI = 0.54-3.33; p = 0.53).. Aliskiren supplementation was found to significantly decrease NT-proBNP levels and plasma renin activity and to improve plasma renin concentration in the setting of heart failure.

Topics: Amides; Antihypertensive Agents; Dietary Supplements; Female; Fumarates; Heart Failure; Humans; Male; Randomized Controlled Trials as Topic

There have been few major breakthroughs in heart failure (HF) drug therapies in recent years yet HF morbidity and mortality remain high, and there is a clear need for further research. Several newer agents that appear promising in Phase I and II trials do not progress to show clinical benefit in later trials. Part of the failure to find new therapies may lie in flawed trial design compounded by the need for ever-increasing patient numbers in order to prove outcome benefit. We summarize some of the most recent and promising medical therapies for HF.

Topics: Amides; Cardiotonic Agents; Chronic Disease; Diuretics; Forecasting; Fumarates; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Naphthyridines; Oligopeptides; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Vasodilator Agents

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Topics: Adrenergic beta-Antagonists; American Heart Association; Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Biphenyl Compounds; Calcium Channel Blockers; Cardiology; Cardiotonic Agents; Cardiovascular Agents; Digoxin; Diuretics; Drug Combinations; Erythropoietin; Evidence-Based Medicine; Fumarates; Heart Failure; Hematinics; Humans; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Isosorbide Dinitrate; Ivabradine; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Societies, Medical; Stroke Volume; Tetrazoles; United States; Valsartan; Vasodilator Agents

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

Topics: Amides; Aminobutyrates; Atrial Natriuretic Factor; Biphenyl Compounds; Digoxin; Drug Combinations; Fumarates; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Snake Venoms; Tetrazoles; Valsartan

The European Society of Cardiology held their annual congress in Amsterdam between the 31st of August and 4 September 2013 to discuss the latest developments in the field. The meeting included an update of the latest treatments currently under investigation for the treatment of heart failure. Updates were provided on the RELAX-AHF study that had, for the first time, demonstrated an improvement in post-discharge outcome in patients with acute heart failure treated with seralaxin. The meeting also gave the opportunity to highlight the latest goings on from the promising agent omecamtiv mecarbil as shown in the ATOMIC-AHF study. Indeed, its unique inotropic effect showed a potential to improve dyspnea without increasing myocardial oxygen consumption. Other presentations at the meeting included: a recent study evaluating ultrafiltration in the treatment of acute HF with renal impairment and the effects of the vasodilator cinaciguat. The unremarkable results from the recent ASTRONAUT study with aliskiren were also touched upon. It is important to note that while the data from seralaxin and omecamtiv mecarbil has been promising, the long term benefits of these therapies in heart failure still need to be evaluated. The authors also highlight the need for these promising agents to be further evaluated in women and other ethnic groups.

Topics: Amides; Benzoates; Cardiac Resynchronization Therapy; Cardiotonic Agents; Fumarates; Heart Failure; Humans; Recombinant Proteins; Relaxin; Ultrafiltration; Urea

Unlike the prolonged benefit produced by the treatment of chronic heart failure, newer drugs tested for the treatment of acute heart failure in the last decade have failed to provide evidence of clinical benefit beyond some improvement in symptom relief. In particular, no drug has shown the ability to reduce the higher medium- and long-term risk of morbidity and mortality in these patients after an episode of decompensation. Current understanding of the pathophysiology of acute heart failure and its consequences has led to the hypothesis that, beyond symptom control, effective therapies for this syndrome should target not only the hemodynamic changes of the initial phase of the syndrome but should also "protect" the organism from the activation of neurohumoral and inflammatory pathways triggered by the decompensation episode, which persist in time and confer a risk of deleterious effects in several organs and tissues. Serelaxin, a new drug related to the peptidic endogenous hormones of the relaxin family, has recently been shown to provide multiple beneficial effects in terms of "organ protection" - not only in the cardiovascular and renal systems - from these acute heart failure-related deleterious changes. This drug has already been tested in acute heart failure patients with encouraging results in terms of medium-term clinical benefit, rendering serelaxin as a serious candidate for first-line, prognosis-modifying therapy in this syndrome.

Topics: Acute Disease; Amides; Benzazepines; Cardio-Renal Syndrome; Dobutamine; Fumarates; Heart Failure; Humans; Hydrazones; Inflammation; Kaplan-Meier Estimate; Multicenter Studies as Topic; Natriuretic Peptide, Brain; Prognosis; Pyridazines; Randomized Controlled Trials as Topic; Recombinant Proteins; Relaxin; Simendan; Therapies, Investigational; Tolvaptan

The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure-associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1-7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.

Topics: Amides; Antihypertensive Agents; Cardio-Renal Syndrome; Fumarates; Heart Failure; Humans; Renin; Renin-Angiotensin System

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

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

Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and β-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright © 2010 Wiley Periodicals, Inc.The authors have no funding, financial relationships, or conflicts of interest to disclose.

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Disease Progression; Fumarates; Heart Failure; Humans; Natriuretic Peptide, Brain; Prognosis; Renin; Renin-Angiotensin System

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

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

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

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

Topics: Amides; Cardiovascular Agents; Etiocholanolone; Fumarates; Heart Failure; Humans; Neovascularization, Physiologic; Ventricular Remodeling

Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Thus, strategies for the treatment of heart failure have focused on agents that block the RAS. More recently, the role of angiotensin receptor blockers (ARBs) in heart failure therapy has been better defined. This article examines the rationale and role of ARBs in the treatment of patients with heart failure on the basis of evidence from clinical trials.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Heart Failure; Humans; Losartan; Randomized Controlled Trials as Topic; Renin; Tetrazoles; Treatment Outcome; Valine; Valsartan

Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years.. This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF.. The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro-B-type natriuretic peptide.. Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life-median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)-despite similar left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001).. Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.

Topics: Adult; Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Follow-Up Studies; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Quality of Life; Sex Factors; Stroke Volume

Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes.. ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups.. In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cause of Death; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Male; Middle Aged; Prospective Studies; Stroke Volume; Survival Rate

The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren.. This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13).. Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387.

Topics: Aged; Amides; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Inpatients; Male; Middle Aged; Prospective Studies; Renin; Renin-Angiotensin System; Stroke Volume; Treatment Outcome

Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.. After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.. After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).. In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Renin; Stroke Volume; Treatment Failure

We examined the effect of the renin inhibitor, aliskiren, on renal blood flow (RBF) in patients with heart failure with reduced ejection fraction (HFREF) and decreased glomerular filtration rate (GFR). Renal blood flow is the main determinant of GFR in HFREF patients. Both reduced GFR and RBF are associated with increased mortality. Aliskiren can provide additional renin-angiotensin-aldosterone system inhibition and increases RBF in healthy individuals.. Patients with left ventricular ejection fraction ≤45% and estimated GFR 30 to 75 mL/min per 1.73 m(2) on optimal medical therapy were randomized 2:1 to receive aliskiren 300 mg once daily or placebo. Renal blood flow and GFR were measured using radioactive-labeled (125)I-iothalamate and (131)I-hippuran at baseline and 26 weeks. After 41 patients were included, the trial was halted based on an interim safety analysis showing futility. Mean age was 68 ± 9 years, 82% male, GFR (49 ± 16 mL/min per 1.73 m(2)), RBF (294 ± 77 mL/min per 1.73 m(2)), and NT-proBNP 999 (435-2040) pg/mL. There was a nonsignificant change in RBF after 26 weeks in the aliskiren group compared with placebo (-7.1 ± 30 vs +14 ± 54 mL/min per 1.73 m(2); P = .16). However, GFR decreased significantly in the aliskiren group compared with placebo (-2.8 ± 6.0 vs +4.4 ± 9.6 mL/min per 1.73 m(2); P = .01) as did filtration fraction (-2.2 ± 3.3 vs +1.1 ± 3.1%; P = .01). There were no significant differences in plasma aldosterone, NT-proBNP, urinary tubular markers, or adverse events. Plasma renin activity was markedly reduced in the aliskiren group versus placebo throughout the treatment phase (P = .007).. Adding aliskiren on top of optimal HFREF medical therapy did not improve RBF and was associated with a reduction of GFR and filtration fraction.

Topics: Aged; Amides; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Renal Circulation; Renin; Renin-Angiotensin System; Stroke Volume

To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.. A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.. ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diabetes Mellitus; Drug Therapy, Combination; Enalapril; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Renin; Stroke Volume; Ventricular Dysfunction, Left

Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality.. To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients.. International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012.. All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months.. In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo.. Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge.. clinicaltrials.gov Identifier: NCT00894387.

Topics: Aged; Amides; Antihypertensive Agents; Double-Blind Method; Female; Follow-Up Studies; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Patient Readmission; Renin; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).. ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction).. This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.

Topics: Administration, Oral; Amides; Cardiotonic Agents; Death, Sudden, Cardiac; Diabetic Cardiomyopathies; Double-Blind Method; Female; Fumarates; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prospective Studies; Renin; Treatment Outcome

The renin-angiotensin-aldosterone system (RAAS) has dual pathways to angiotensin II production; therefore, multiple blockages may be useful in heart failure. In this study, we evaluated the short-term haemodynamic effects of aliskiren, a direct renin inhibitor, in patients with decompensated severe heart failure who were also taking angiotensin-converting enzyme (ACE) inhibitors.. A total of 16 patients (14 men, two women, mean age: 60.3 years) were enrolled in the study. The inclusion criteria included hospitalisation due to decompensated heart failure, ACE inhibitor use, and an ejection fraction < 40% (mean: 21.9 ± 6.7%). The exclusion criteria were: creatinine > 2.0 mg/dl, cardiac pacemaker, serum K(+) > 5.5 mEq/l, and systolic blood pressure < 70 mmHg. Patients either received 150 mg/d aliskiren for 7 days (aliskiren group, n = 10) or did not receive aliskiren (control group, n = 6). Primary end points were systemic vascular resistance and cardiac index values. Repeated-measures analysis of variance (ANOVA) was used to assess variables before and after intervention. A two-sided p-value < 0.05 was considered statistically significant.. Compared to pre-intervention levels, systemic vascular resistance was reduced by 20.4% in aliskiren patients, but it increased by 2.9% in control patients (p = 0.038). The cardiac index was not significantly increased by 19.0% in aliskiren patients, but decreased by 8.4% in control patients (p = 0.127). No differences in the pulmonary capillary or systolic blood pressure values were observed between the groups.. Aliskiren use reduced systemic vascular resistance in patients with decompensated heart failure taking ACE inhibitors.

Topics: Amides; Antihypertensive Agents; Female; Fumarates; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Vascular Resistance

Hospitalizations for acute heart failure syndromes (AHFS) are associated with high post-discharge mortality and readmission rates in spite of available therapies. Renin-angiotensin-aldosterone system (RAAS) antagonists improve outcomes in outpatients with heart failure (HF) and reduced ejection fraction, however these therapies have not been tested in AHFS. Aliskiren is a direct renin inhibitor (DRI) that is known to enhance RAAS inhibition, which may result in improved clinical outcomes in AHFS. The aim of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) study is to evaluate the effect of aliskiren on cardiovascular death and HF in AHFS patients.. ASTRONAUT will be an event-driven trial with an estimated enrolment of 1782 patients hospitalized with worsening chronic HF, a left ventricular ejection fraction ≤40%, and an estimated glomerular filtration rate ≥40 mL/min/1.73 m(2). Patients will be randomized 1:1 in a double-blind fashion to receive aliskiren or placebo, in addition to standard HF therapy. The primary endpoint will be a composite of time to either cardiovascular death or first occurrence of HF re-hospitalization.. Aliskiren is a DRI with a favourable neurohormonal and haemodynamic profile that may benefit patients hospitalized with worsening HF. Given the neurohormonal abnormalities that are present during and after hospitalization for AHFS, it is hypothesized that adding aliskiren to standard therapy will reduce post-discharge mortality and re-hospitalization. NCT00894387.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Europe; Fumarates; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Hospitalization; Humans; Multivariate Analysis; Outpatients; Placebos; Proportional Hazards Models; Renin; Renin-Angiotensin System; Research Design; Stroke Volume; Syndrome; Time Factors; United States; Ventricular Function, Left

To examine the relationships between baseline characteristics and urinary albumin excretion in the extensively phenotyped patients in the ALiskiren Observation of heart Failure Treatment (ALOFT) study.. Urinary albumin creatinine ratio (UACR) was available in 190 of 302 (63%) patients randomized in ALOFT. Of these, 107 (56%) had normal albumin excretion, 63 (33%) microalbuminuria, and 20 (11%) macroalbuminuria. Compared with patients with normoalbuminuria, those with microalbuminuria had a greater prevalence of diabetes (48 vs. 26%, P = 0.005) and a lower estimated glomerular filtration rate (eGFR) (60.7 vs. 68.3 mL/min/1.73 m(2), P = 0.01). Patients with macroalbuminuria had additional differences from those with a normal UACR, including younger age (63 vs. 69 years, P = 0.02), higher glycated haemoglobin (HbA1c; 7.9 vs. 6.2%, P < 0.001), and different echocardiographic findings. Of the non-diabetic patients, 28% had microalbuminuria and 7% had macroalbuminuria. Independent predictors of UACR in these patients included N-terminal pro B-type natriuretic peptide (NT-proBNP), HbA1c, and left ventricular diastolic dimension. Increased UACR was not associated with markers of inflammation or of renin angiotensin aldosterone system activation and was not reduced by aliskiren.. Increased UACR is common in patients with heart failure, including non-diabetics. Urinary albumin creatinine ratio is independently associated with HbA1c and NT-proBNP, even in non-diabetic patients.

Topics: Aged; Albumins; Albuminuria; Amides; Antihypertensive Agents; Confidence Intervals; Creatinine; Female; Fumarates; Glycated Hemoglobin; Heart Failure; Humans; Linear Models; Male; Middle Aged; Phenotype; Prognosis; Statistics as Topic; Stroke Volume; Surveys and Questionnaires; Ventricular Function, Left

We evaluated the influence of concomitant mineralocorticoid receptor antagonists (MRAs) on the safety and neurohumoral effects of a direct renin inhibitor in the ALiskiren Observation of Heart Failure Treatment (ALOFT) study.. Patients with stable New York Heart Association class II-IV heart failure (HF), plasma B-type natriuretic peptide (BNP) concentration >100 pg/mL, and treated with an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and β-blocker were randomized to once-daily, double-blind treatment with aliskiren 150 mg or placebo, added to optimal HF therapy, for 12 weeks. Safety, tolerability, and effects of aliskiren on neurohumoral biomarkers were assessed in patients who received (MRA+) and did not receive (MRA-) MRA treatment at baseline. Of the 302 randomized patients, 101 were receiving MRA treatment (aliskiren, n = 52; placebo, n = 49). Mineralocorticoid receptor antagonist status did not affect the ability of aliskiren 150 mg, added to standard HF therapy, to lower BNP, N-terminal proBNP, plasma renin activity, and urinary aldosterone. For example, the end-of-study to baseline ratio of geometric mean for BNP was: MRA+ group: aliskiren 0.68 [95% confidence interval (CI) 0.47, 0.98], placebo 0.85 (0.58, 1.24); MRA- group: aliskiren 0.62 (0.45, 0.84), placebo 0.85 (0.63, 1.15), interaction P= 0.720. The incidence of pre-specified adverse events (renal dysfunction, symptomatic hypotension, and hyperkalaemia) was low, and there were no significant differences between aliskiren and placebo in either MRA subgroup.. Aliskiren 150 mg added to standard HF therapy was well tolerated over 12 weeks and provided beneficial changes in neurohumoral biomarkers regardless of concomitant MRA treatment.

Topics: Adrenergic beta-Antagonists; Aged; Amides; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Confidence Intervals; Female; Fumarates; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Statistics as Topic; Stroke Volume; Ventricular Function, Left

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

Suppression of the renin-angiotensin-aldosterone system (RAAS) is therapeutically valuable in chronic heart failure (CHF). RAAS inhibition can be achieved in a number of ways though an orally active renin inhibitor (RI) has never been studied before. We describe the neurohumoral effects of an RI.. 27 patients with NYHA class II or III CHF and an ejection fraction

Topics: Aged; Aldosterone; Amides; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Ramipril; Renin; Statistics, Nonparametric; Treatment Outcome

The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure.. Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks.. Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate.. Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.

Topics: Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensins; Animals; Biomarkers; Biphenyl Compounds; Blood Pressure; Creatine Kinase, MB Form; Drug Combinations; Female; Fumarates; Heart Failure; Heart Rate; Kidney; Matrix Metalloproteinase 9; Natriuretic Peptide, Brain; Neprilysin; Peptide Fragments; Ramipril; Rats, Wistar; Renin; Tetrazoles; Troponin I; Valsartan

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Exercise Tolerance; Female; Fumarates; Heart Failure; Humans; Male; Randomized Controlled Trials as Topic; Stroke Volume

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

Topics: Amides; Animals; Benzimidazoles; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fumarates; Heart; Heart Failure; Hypertrophy; Lung Diseases; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines; Piperidines; Protective Agents; Random Allocation; Renin

Topics: Acute Disease; Amides; Fumarates; Heart Failure; Hospitalization; Humans; Inpatients; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction caused by Chagas' disease, with other etiologies, in the era of modern HF therapies.. This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94;. Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies.. PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chagas Cardiomyopathy; Female; Fumarates; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Latin America; Male; Middle Aged; Multicenter Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Risk Factors; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left

Change in NT-proBNP level is a common surrogate endpoint in early phase heart failure (HF) trials, but whether this endpoint is influenced by atrial fibrillation/flutter (AFF) is unclear.. This analysis included 1358 patients from the ASTRONAUT trial, which randomized patients hospitalized for HF with EF ≤40% to aliskiren or placebo in addition to standard care. Patients were stratified by presence of AFF on baseline ECG. NT-proBNP was measured longitudinally by a core laboratory at baseline, 1 month, 6 months, and 12 months. Compared with non-AFF patients, AFF patients experienced greater reduction from baseline in log-transformed NT-proBNP (interaction P < 0.001), but this difference was not significant after adjustment (interaction P = 0.726). The ability of aliskiren to lower NT-proBNP during follow-up differed by AFF status (interaction P = 0.001), with aliskiren lowering NT-proBNP more than placebo among non-AFF patients only. After adjustment, baseline AFF was not associated with mortality or HF hospitalization at 12 months (all P ≥ 0.152).. In this hospitalized HF cohort, AFF status did not influence post-discharge NT-proBNP trajectory or clinical outcomes after adjustment for patient characteristics. Aliskiren lowered follow-up NT-proBNP levels in patients without AFF, but had no influence among patients with AFF. This study generates the hypothesis that the ability of a HF trial to meet an NT-proBNP defined endpoint may be influenced by the prevalence of AFF in the population. Because aliskiren did not improve outcomes in patients without AFF, this analysis suggests changes in NT-proBNP induced by investigational therapies may be dissociated from clinical effects.

Topics: Aged; Amides; Antihypertensive Agents; Atrial Fibrillation; Atrial Flutter; Disease Progression; Female; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Randomized Controlled Trials as Topic

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

Topics: Amides; Animals; Fumarates; Heart; Heart Failure; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Myocardial Infarction; Oxidative Stress; Prorenin Receptor; Protease Inhibitors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Signal Transduction

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials Data Monitoring Committees; Diabetes Mellitus, Type 2; Fumarates; Government Regulation; Heart Failure; Humans; Randomized Controlled Trials as Topic; Renin

The purpose of this study was to determine the prognostic significance and associated clinical profile of early post-discharge N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory among patients hospitalized for worsening chronic heart failure (HHF).. This post-hoc analysis of the Aliskiren Trial in Acute Heart Failure Outcomes (ASTRONAUT) included 1351 HHF patients with ejection fraction (EF) ≤40%, elevated B-type natriuretic peptide ≥400 pg/mL or NT-proBNP ≥1600 pg/mL at admission, and available NT-proBNP measurements (from a central core laboratory) at baseline (median 5 days after admission) and 1-month follow-up. The co-primary endpoints were all-cause mortality and cardiovascular mortality or HHF within 12 months. Median follow-up was 11.3 months. Patients with decreasing post-discharge NT-proBNP trajectory tended to be younger and have non-ischaemic HF aetiology. The presence of baseline atrial fibrillation was associated with high NT-proBNP at 1 month (i.e. above the median), regardless of the baseline value. After adjustment for patient characteristics and 1-month NT-proBNP level, every twofold increase in continuous NT-proBNP change from baseline to 1 month was predictive of increased cardiovascular mortality or HHF (hazard ratio 1.14; 95% confidence interval 1.02-1.26), but not all-cause mortality (hazard ratio 0.95; 95% confidence interval 0.81-1.11).. In this cohort of HHF patients with reduced EF, early post-discharge NT-proBNP trajectory was associated with a distinct clinical profile and carried independent prognostic value after adjustment for patient characteristics and absolute NT-proBNP level. Future prospective study of serial NT-proBNP measurement during the hospital and early post-discharge periods is warranted to validate these findings and evaluate post-discharge NT-proBNP trajectory as a therapeutic target.

Topics: Aged; Amides; Chronic Disease; Cohort Studies; Disease Progression; Female; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Renin

Regulatory guidelines for drug development suggest a strong control of the familywise error rate, when multiple hypotheses are simultaneously tested in confirmatory clinical trials. Accordingly, a variety of multiple test procedures exist for pharmaceutical trial applications, which are typically defined on a single structured family of null hypotheses. For some confirmatory clinical trials with multiple objectives, however, it is advantageous to address the arising multiplicity problems via grouped families of hypotheses. Graphical test procedures have been developed to construct, visualize, and perform multiple test procedures that are tailored to either a single or multiple families of structured hypotheses of interest. This note complements the existing literature by introducing a general algorithm to calculate adjusted p-values for any sequentially rejective graphical test procedure where the test procedures within the individual families of hypotheses are not necessarily graphical.

Topics: Algorithms; Amides; Antihypertensive Agents; Clinical Trials as Topic; Computer Graphics; Data Interpretation, Statistical; Drug Combinations; Enalapril; Endpoint Determination; Fumarates; Heart Failure; Humans

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Fumarates; Heart Failure; Humans; Renin; Stroke Volume; Ventricular Dysfunction, Left

Topics: Amides; Cardiotonic Agents; Diabetic Cardiomyopathies; Female; Fumarates; Heart Failure; Humans; Male

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

In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats.. Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks.. showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations.. Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

Topics: Amides; Animals; Blotting, Western; Diabetes Mellitus, Experimental; Echocardiography; Electrophoresis, Polyacrylamide Gel; Fumarates; Heart Failure; Male; Mitochondria, Heart; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction

Heart failure with preserved systolic function (HFPSF) has attained epidemic proportions; however evidence-based therapeutic interventions have not advanced despite continued research over the past three decades. We propose the combined use of direct renin inhibitor and carvedilol for this condition.. The Renin Angiotensin Aldosterone System (RAAS) plays a central role in myocyte hypertrophy, fibrosis and ventricular remodeling which is responsible for the diastolic dysfunction in HFPSF. Rising serum aldosterone levels with age have been implicated as a cause of myocardial fibrosis in the elderly. The sole use of Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers is associated with angiotensin-II and aldosterone escape and increased plasma renin activity. Carvedilol is a novel third generation non-selective β-blocker. The use of combination therapy will facilitate in better blood pressure control, reduce afterload, improve ventricular relaxation, cause regression of ventricular remodeling/fibrosis, maintain atrioventricular synchrony and enhance cardio-metabolic profile. The individual benefits of direct renin inhibitor and carvedilol could plausibly have a supra-additive effect when used in combination. Besides this, carvedilol can further reduce generation of free radicals, decrease LDL oxidation, improve Doppler echo diastolic parameters and decrease cardiac norepinephrine and density of cardiac β-receptors.. Evidence suggests that patients with HFPSF are treated less aggressively as compared to patients with heart failure with systolic dysfunction. Aggressive therapy with concurrent use of direct renin inhibitor and carvedilol will help in improving outcomes in this vulnerable patient sub-population. No prior trial has evaluated the combined use of these drugs for the treatment of HFPSF.

Topics: Adrenergic beta-Antagonists; Amides; Carbazoles; Carvedilol; Fumarates; Heart Failure; Humans; Propanolamines; Protease Inhibitors; Renin; Renin-Angiotensin System; Systole

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Clinical Trials Data Monitoring Committees; Congresses as Topic; Diabetes Mellitus, Type 2; Endpoint Determination; Fumarates; Heart Failure; Humans; Randomized Controlled Trials as Topic; Rats; Renin; Renin-Angiotensin System

Despite significant advances in pharmacological and non-pharmacological therapy, epidemiological data from European and US hospitals show that the prevalence of heart failure (HF) hospitalization, especially for patients >65 years, continues to rise. Hospitalization for worsening HF is one of the most important predictors of short- and long-term outcomes in patients with chronic HF. There is therefore a clear need for new therapies that can work synergistically with standard medications to reverse the progression of the disease and improve myocardial efficiency. In the last years, researches in chronic HF focused on drugs that can exert a greater attenuation of neurohormonal activation and that can improve cardiac energy and substrate utilization.

Topics: Algorithms; Amides; Benzazepines; Chronic Disease; Fumarates; Heart Failure; Heart Rate; Humans; Ivabradine

To compare the effect of the direct renin inhibitor aliskiren on neurohumoral activity in heart failure patients treated with low-dose and high-dose ACE inhibitor.. A retrospective analysis of the ALOFT trial. Comparison of the effects of 6 months treatment with aliskiren (versus placebo) in patients receiving

Topics: Aged; Aldosterone; Amides; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Randomized Controlled Trials as Topic; Renin; Retrospective Studies; Single-Blind Method

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

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; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Fumarates; Heart Failure; Humans; Renin; Renin-Angiotensin System

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the European Society of Cardiology Congress 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. In the 3CPO study, non-invasive ventilation produced a more rapid resolution of symptoms in patients hospitalised with acute cardiogenic pulmonary oedema; but had no effect on survival, compared to standard oxygen therapy. The ALOFT study showed that the selective oral renin inhibitor aliskiren reduces plasma BNP levels and is well tolerated in patients with heart failure receiving ACE inhibitors or ARBs, although the study was not powered to show clinical benefit. In the PROSPECT study, no echocardiographic measure of mechanical dyssynchrony was identified that was useful for identifying patients more or less likely to respond to CRT. Low dose atorvastatin reduced the incidence of sudden cardiac death in a small placebo controlled study of patients with advanced chronic heart failure.

Topics: Acute Disease; Amides; Atorvastatin; Cardiac Pacing, Artificial; Clinical Trials as Topic; Fumarates; Heart Failure; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pulmonary Edema; Pyrroles; Renin; Respiration, Artificial

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V(2) antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered >6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.

Topics: Abciximab; Acute Coronary Syndrome; Amides; Antibodies, Monoclonal; Benzazepines; Clinical Trials as Topic; Clopidogrel; Electrocardiography; Europe; Fumarates; Heart Diseases; Heart Failure; Hirudins; Humans; Immunoglobulin Fab Fragments; Myocardial Infarction; Peptide Fragments; Probucol; Recombinant Proteins; Ticlopidine; Tolvaptan