aliskiren and Diarrhea

Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II.. To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema).. The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work.. We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension.. This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs.. 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue.. Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

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

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

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

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