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Systematic review

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When conventional heart failure therapy is not enough: angiotensin receptor blocker, direct renin inhibitor, or aldosterone antagonist?

Journal Congestive heart failure (Greenwich, Conn.)
Year 2013
Links Pubmed DOI

This article is included in 1 Broad synthesis 16 Broad syntheses (1 reference)

This article includes 16 Primary studies 16 Primary studies (16 references)

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In patients on conventional heart failure therapy including angiotensin-converting enzyme (ACE) inhibitors, the addition of angiotensin receptor blockers (ARBs), direct renin inhibitors (DRIs), or aldosterone antagonists are therapeutic options to further reduce the risk of cardiovascular events. However, whether one is preferable over the other is not known. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for randomized clinical trials (RCTs), until March 2011, of trials testing either an ARB, DRI, or an aldosterone antagonist in patients with heart failure who were on conventional heart failure therapy with follow-up of at least 3 months. Efficacy (death, cardiovascular death, nonfatal myocardial infarction, heart failure hospitalization and composite of cardiovascular death or heart failure hospitalization) and safety (hyperkalemia, hypotension, renal failure) outcomes were compared. The authors identified 16 RCTs involving 31,429 participants that satisfied the inclusion criteria. When compared with placebo (reference rate ratio [RR] of 1), aldosterone antagonists reduced the rate of death (RR, 0.79; 95% credibility interval [CrI], 0.66-0.98), cardiovascular death (RR, 0.78; 95% CrI, 0.65-0.93), heart failure hospitalization (RR, 0.74; 95% CrI, 0.55-0.94), and the composite of cardiovascular death or heart failure hospitalization (RR, 0.73; 95% CrI, 0.55-0.90) with no difference for other efficacy outcomes. However, ARBs and DRIs did not result in any significant reduction in the rate of any of the efficacy outcomes when compared with placebo. When compared with placebo (RR=1), ARBs increased the rate of hyperkalemia (138% increase), renal failure (126% increase), and hypotension (63% increase). Similarly, aldosterone antagonists resulted in a 110% increase in hyperkalemia and DRIs with a 98% increase in hypotension. In patients with heart failure and reduced systolic function on conventional heart failure medications, the risk benefit ratio favors the addition of aldosterone antagonists over ARBs or DRIs.

Systematic review

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Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis.

Authors Hu LJ , Chen YQ , Deng SB , Du JL , She Q
Journal British journal of clinical pharmacology
Year 2013
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis 8 Broad syntheses (1 reference)

This article includes 8 Primary studies 8 Primary studies (8 references)

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AIMS: Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients. METHODS: PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models. RESULTS: Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 μmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23). CONCLUSIONS: Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.

Systematic review

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Eplerenone is not superior to older and less expensive aldosterone antagonists.

Journal The American journal of medicine
Year 2012
Links Pubmed DOI

This article is included in 2 Structured summaries of systematic reviews 15 Structured summaries of systematic reviews (2 references) 1 Broad synthesis 15 Broad syntheses (1 reference)

This article includes 17 Primary studies 15 Primary studies (17 references)

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INTRODUCTION: Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data. METHODS AND RESULTS: The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P=.0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P <.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P=.0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P <.0001), without contributing significantly to an improved side-effect profile. CONCLUSION: Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists.

Systematic review

Unclassified

Aldosterone antagonists improve ejection fraction and functional capacity independently of functional class: A meta-analysis of randomised controlled trials

Journal Heart (British Cardiac Society)
Year 2012
Links Pubmed DOI

This article is included in 1 Broad synthesis 14 Broad syntheses (1 reference)

This article includes 14 Primary studies 14 Primary studies (14 references)

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Context: Current guidelines recommend the use of aldosterone antagonists (AA) in patients with moderately severe to severe symptoms [New York Heart Association (NYHA) class III to IV] and systolic heart failure. Objective: To determine the efficacy of AA in improving ejection fraction (EF) and functional capacity and to assess whether this effect was influenced by baseline NYHA classification. Study design: Meta-analysis of randomized controlled trials. Data extraction performed independently by two researchers. Data Sources: MEDLINE and the Cochrane Library. Study Selection: Prospective randomized controlled trials using AA were included if there was a clear description of the baseline NYHA classification and change in EF in patients from study initiation to completion. Results: Data from 1,575 patients enrolled in fourteen studies were included. Overall, there was a weighted mean improvement in EF of 3.2% and in NYHA classification of 0.13 in subjects treated with AA when compared to controls (p<0.001). A mixed effects meta-regression analysis revealed that baseline NYHA was not predictive of improvement in EF (p=0.67) nor NYHA status (p=0.18). Conclusions: The results of this meta-analysis suggest that AA is associated with significant improvements in EF and functional class independent of baseline functional capacity. This supports and expands on the recently published EMPHASIS-HF trial and suggests that the current restriction of AA use to patients with NYHA class III-IV symptoms should be reconsidered.

Systematic review

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Aldosterone blockade and left ventricular dysfunction: A systematic review of randomized clinical trials

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Authors Ezekowitz JA , McAlister FA
Journal European heart journal
Year 2009
Links Pubmed DOI

This article is included in 2 Structured summaries of systematic reviews 18 Structured summaries of systematic reviews (2 references) 1 Broad synthesis 18 Broad syntheses (1 reference)

This article includes 19 Primary studies 18 Primary studies (19 references)

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Context: Aldosterone blockade has been used to treat acute myocardial infarction (MI) and chronic heart failure. Objective: The aim of this study is to summarize the evidence on the efficacy of spironolactone (SP), eplerenone (EP), or canrenoate (CAN) in patients with left ventricular dysfunction. Data sources: A search of multiple electronic databases until June 2008 was supplemented by hand searches of reference lists of included studies and review articles, meeting abstracts, FDA reports, and contact with study authors and drug manufacturers. Study selection and data extraction: Studies were eligible for inclusion if they included patients with left ventricular systolic or diastolic dysfunction, treatment with SP, EP, or CAN vs. control, and reported clinical outcomes. Nineteen randomized controlled trials (four in acute MI and 15 in heart failure, n = 10 807 patients) were included - 14 of SP, three of EP, and three of CAN. Analysis was performed using relative risks (RRs) with 95% confidence intervals (CIs) and a random effects model with statistical heterogeneity assessed by I2. Data synthesis: Aldosterone blockade reduced all-cause mortality by 20% (RR 0.80, 95% CI 0.74-0.87). All-cause mortality was reduced in both heart failure (RR = 0.75, 95% CI 0.67-0.84) and post-MI (RR 0.85, 95% CI 0.76-0.95) patients. Only nine trials reported hospitalizations, and the RR reduction was 23% (RR 0.77, 95% CI 0.68-0.87), although 98% of the outcomes came from two trials. Ejection fraction (EF) improved in the seven heart failure trials, which assessed this outcome (weighted mean difference 3.1%, 95% CI 1.6-4.5). Conclusion: We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI. In addition, we found a 3.1% improvement in EF. Further study in those with less severe symptoms or preserved systolic function is warranted. © The Author 2008.