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      Effect of aliskiren on cardiovascular outcomes in patients with prehypertension: a meta-analysis of randomized controlled trials

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          Abstract

          Background

          Aliskiren is a widely used therapy for patients with hypertension, however, the effect of aliskiren on major cardiovascular outcomes is a matter of debate. The aim of this study is to evaluate the effects of aliskiren therapy on major cardiovascular outcomes by this meta-analysis of randomized controlled trials.

          Methods

          We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials for relevant literature. All eligible studies were randomized controlled trials assessing the effect of aliskiren therapy compared with patients without aliskiren therapy. Relative risks (RRs) with 95% confidence intervals (CIs) were used to measure the effect of aliskiren therapy on major cardiovascular outcomes with a random-effect model.

          Results

          We included six trials reporting data on 12,465 patients. These studies reported 1,886 occurrences of major cardiovascular events, 1,074 events of total mortality, 739 events of cardiac death, 366 events of myocardial infarction, and 319 events of stroke. Aliskiren therapy had no effect on major cardiovascular events (RR, 0.93; 95% CI: 0.77–1.13; P=0.47), total mortality (RR, 1.00; 95% CI: 0.77–1.29; P=1.00), cardiac death (RR, 1.01; 95% CI: 0.79–1.29; P=0.95), myocardial infarction (RR, 0.71; 95% CI: 0.36–1.38; P=0.31), or stroke (RR, 0.87; 95% CI: 0.48–1.58; P=0.64).

          Conclusion

          Aliskiren therapy does not have an effect on the incidence of major cardiovascular events, total mortality, cardiac death, myocardial infarction, or stroke.

          Most cited references19

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          The interpretation of random-effects meta-analysis in decision models.

          This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors' analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.
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            Aliskiren combined with losartan in type 2 diabetes and nephropathy.

            Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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              Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial.

              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.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                02 April 2015
                : 9
                : 1963-1971
                Affiliations
                Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
                Author notes
                Correspondence: Ke-Ping Chen, Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing 100037, People’s Republic of China, Tel +86 10 8839 8866, Email chenkepingbj@ 123456yeah.net
                Article
                dddt-9-1963
                10.2147/DDDT.S75111
                4396461
                31b3efe7-5ba5-440d-a52c-6076f922676e
                © 2015 Zhang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                aliskiren,cardiovascular disease,stroke,systematic review,meta-analysis

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