|Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure
|Kuenzli A, Bucher HC, Anand I, Arutiunov G, Kum LC, McKelvie R, Afzal R, White M, Nordmann LJ
This review concluded that angiotensin II receptor blockers added to angiotensin-converting enzyme inhibitor therapy did not reduce mortality in people with heart failure and were associated with a reduction in hospitalisation for heart failure, but not overall hospitalisation. There was an increase in adverse events. The review appeared well conducted and the authors’ conclusions are likely to be reliable.
To assess the effects of adding angiotensin II receptor blockers (ARBs) to angiotensin converting enzyme (ACE) inhibitors in people with heart failure.
MEDLINE, EMBASE, PASCAL and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to December 2009. Search terms were reported. No language restrictions were applied. Reference lists of identified articles, clinical trial registers and recently published editorials and reviews were checked.
Randomised controlled trials (RCTs) with at least six months follow-up that compared ARBs and ACE inhibitors to ACE inhibitors alone in people with left ventricular dysfunction or congestive heart failure were eligible for inclusion. Studies had to report on mortality and hospitalisation. At least 90% of participants had to be on ACE inhibitors. Outcomes of interest were total mortality, hospitalisations for heart failure, hospitalisations for any reason, nonfatal myocardial infarction, fatal myocardial infarction, revascularisation procedures, fatal and non-fatal strokes, quality of life and adverse effects (worsening renal function as defined in trials, symptomatic hypotension, hyperkalaemia, cough, rash, angioedema and permanent discontinuation of study medication). Hospitalisation was defined as the number of distinct participants hospitalised.
In the included studies, mean ages ranged from 54 to 69 years and between 48% and 94% were men. Some participants had diabetes, hypertension, prior myocardial infarction or were smokers; 82% had ischaemic heart disease. Mean left ventricular ejection fraction (LVEF) ranged from 25% to 35%. Most participants had New York Heart Association (NYHA) Class II or III heart failure and a few had Class IV. ARBs assessed included losartan, candesartan, valsartan and irbesartan; only four trials aimed to reach the maximum recommended dose of ARB. Where indicated, ACE inhibitors were captopril and enalapril. Between 6% and 95% of participants also took betablockers; other concomitant treatments varied. Follow-up ranged from 0.5 to 3.4 years.
Two authors independently assessed studies for inclusion.
Assessment of study quality
Two authors independently assessed the quality of studies according to concealment of treatment allocation, blinding of participants, caregivers or outcome assessors, description of losses to follow up and withdrawals, and proportion of participants with complete clinical follow-up.
Two authors independently extracted data. Risk ratios (RR) and 95% confidence intervals (CI) were calculated. Authors were contacted for additional data.
Methods of synthesis
Pooled risk ratios and 95% CI were calculated using a random-effects model. Heterogeneity was assessed using the Cochran Q test and I2. Sensitivity analyses were undertaken based on quality of trials (with or without allocation concealment, double blind, blinded outcome assessors), presence or absence of participants with acute myocardial infarction, specification of target dose and proportion reaching target (≥80% versus <80%), use of betablockers (≥50% of participants versus <50%), study size (over 100 participants) and trials with difference causes (ischaemic versus non-ischaemic) and severity (NYHA I and II versus NYHA III and IV) of heart failure
Publication bias was investigated using funnel plots.
Results of the review
Eight RCTs (18,061 participants) were included. Study size ranged from 33 to 9,794 participants.
Five trials reported concealment of treatment allocation, six were double blind and in three trials outcome assessors were blinded. Full details of losses to follow-up were reported in six trials; in all trials loss to follow up was <10%.
Use of ARBs with ACE inhibitors compared to ACE inhibitors alone had no effect on risk of total mortality, fatal myocardial infarction, nonfatal myocardial infarction and hospitalisation for any reason. Risk of heart failure related hospitalisation was reduced with combination therapy (RR 0.81, 95% CI 0.72 to 0.91, I2=57%).
There was insufficient data for the outcomes of stroke and revascularisation procedures. Five trials reported on quality of life; two trials found a significant difference in favour of combination therapy and three trials found no difference between the two groups.
Treatment with combination therapy increased the risk of worsening renal function (RR 1.91 95% CI 1.40 to 2.60, I2=46%; five trials), symptomatic hypotension (RR 1.57, 95% CI 1.44 to 1.71, I2=0%; five trials) and permanent discontinuation of study treatments (RR 1.21, 95% CI 1.07 to 1.37, I2=38%; seven trials). The risk of developing hypokalaemia was increased, but this did not reach statistical significance (RR 1.95, 95% CI 0.85 to 4.48, I2=75%; four trials). There were no differences between the two groups in incidence of cough, angioedema or rash.
In sensitivity analyses, analysis according to individual quality components and analysis that excluded those trials that only included people with acute myocardial infarction showed similar results to the main analyses. Removing trials on people with acute myocardial infarction removed the heterogeneity for heart failure-related hospital admissions (I2=23%), but for hospitalisation for any reason (I2=90%). Other sensitivity analyses showed similar results to the main analyses.
Funnel plots showed no evidence of publication bias.
Compared to ACE inhibitor therapy alone, combination therapy with ARBs and ACE inhibitors did not reduce mortality in people with heart failure. Although combination therapy reduced hospitalisation for heart failure it was associated with an increase in adverse events and had no effect on all-cause hospitalisation.
The aims of the review were clearly stated in terms of participants, intervention and study design. A number of relevant sources were searched and no language limits were applied, which was likely to have reduced any possible effect of publication and language biases. Tests showed no evidence of publication bias; however, the authors acknowledged that these were limited by small number of available trials. The methods of study selection, data extraction and quality assessment aimed at reduced reviewer error and bias. Study quality was assessed appropriately, the methods of synthesis were appropriate and heterogeneity was investigated.
Overall the review appeared well conducted and the authors' conclusions are likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that combination therapy with ARBs and ACE inhibitors may be reserved for people who remain symptomatic on ACE inhibitor treatment, under strict monitoring for signs of worsening renal function or symptomatic hypotension.
Research: The authors stated a need for RCTs to evaluate the effect of adding ARB therapy to people taking ACE inhibitors and betablockers for heart failure to assess any additional benefits. Individual patient data meta-analysis of completed trials may identify subgroups of patients who could potentially benefit from combination therapy.
Unrestricted grant from AstaZeneca. Some authors were supported by an unrestricted grant from santesuisse and the Gottfried and Julia Bangerter-Rhyner-Foundation.
Kuenzli A, Bucher HC, Anand I, Arutiunov G, Kum LC, McKelvie R, Afzal R, White M, Nordmann LJ. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS ONE 2010; 5(4):e9946
Subject indexing assigned by NLM
Angiotensin II Type 1 Receptor Blockers /adverse effects /therapeutic use; Angiotensin-Converting Enzyme Inhibitors /adverse effects /therapeutic use; Drug Therapy, Combination; Heart Failure /complications /drug therapy /mortality; Hospitalization; Humans; Hypotension /chemically induced; Randomized Controlled Trials as Topic; Renal Insufficiency /chemically induced; Risk Assessment; Survival Rate
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.