CRD summary

The authors concluded that treatment of left ventricular dysfunction or heart failure with angiotensin-converting enzyme inhibitors (ACEI) plus angiotensin receptor blockers significantly increases the risk of adverse events leading to discontinuation of therapy, compared to ACEI alone. Unexplained discrepancies in the sample numbers and the poor reporting of adverse events in the primary studies necessitate some caution in interpretation of the findings.

Authors' objectives

To evaluate the safety and tolerability of angiotensin-converting enzyme inhibitors (ACEIs) combined with angiotensin receptor blockers (ARBs) versus ACEIs alone, in the treatment of left ventricular (LV) dysfunction, with or without heart failure (HF).

Searching

The following databases were searched from inception to 2006: MEDLINE, the Cochrane Central Register of Controlled Trials, DARE, the Cochrane Database of Systematic Reviews, EMBASE and BIOSIS Previews. Search terms were reported. The proceedings of the American Heart Association, the American College of Cardiology, the European Congress of Cardiology and the Heart Failure Society of America were hand searched from 2001 to 2006. The reference lists of articles identified were also checked. The search was not restricted by language.

Study selection

Randomised controlled trials (RCTs) comparing ACEI plus ARB versus ACEI alone were eligible for inclusion. Eligible trials were also required to include participants that had either New York Heart Association functional class II to IV HF and an ejection fraction of less than 45%, or acute LV dysfunction following myocardial infarction (MI). The primary review outcome was safety/tolerability, defined as the rate of discontinuation of study treatment due to typical adverse effects such as hyperkalaemia, angioedema, cough, renal failure or hypertension. Discontinuation was at the discretion of the study investigator.

The trials in the review included participants whose LVEF was equal to or less than 35% to 45%. Most participants were white, and their mean age was 62 to 66 years. The mean proportion of females varied (range 0% to 69%). Only one trial enrolled participants immediately after MI; participants in the other trials had chronic HF. The prevalence of diabetes ranged from 23% to 33% and diuretic use varied from 44% to 100% (where stated). Some trials did not report renal dysfunction, diabetes, initial blood pressure and/or race. About half the trials used a placebo or active therapy run-in. ARBs used were losartan, candesartan, valsartan, irbesartan, eprosartan and telmisartan. In one trial a small proportion of patients (7%) did not receive an ACEI. Adverse events were not a primary outcome in any of the included studies; the definition of adverse events and method of ascertainment were often ill-defined. Most of the studies were multicentred; their mean duration of follow up was 1.08 years (range one to 41 months).

The authors did not state how the papers were selected for the review or how many reviewers performed the selection.

Assessment of study quality

Study validity was assessed using the following criteria: random sequence generation, allocation concealment, blinding (participants, caregivers, outcomes assessment, data analyst), use of intention to treat (ITT) analysis and rates of loss to follow up. Published scoring tools (Kahn 1996, Jadad 1996) were also used. The Jadad scale measures adequacy of randomisation, blinding, and management of withdrawals and drop-outs. Each trial is awarded a score out of a maximum of five points.

The authors did not state how the assessment was performed.

Data extraction

Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated from the numbers of events in the control and intervention groups of each trial, using ITT analysis. Only data deriving from the trial follow-up period were included.

Data were extracted by two reviewers working independently, with disagreements resolved by consensus or by a third reviewer.

Methods of synthesis

Data were combined using a random effects model to calculate a pooled RR and 95% CI. The number of patients needing to be treated to cause one additional harm was also calculated (number needed to harm, NNH). Heterogeneity was assessed using the χ² test and the I² statistic. Subgroup analyses were carried out to investigate heterogeneity and to assess the impact on outcomes of the following variables: diabetes, diuretic use, gender, duration of follow-up and diagnosis (chronic HF or acute MI with LV dysfunction). Statistical tests of interaction were conducted for these analyses. Publication bias was assessed by means of a funnel plot.

Results of the review

Nine parallel group RCTs were included (n=23,396, of whom 18,160 were included in analysis). Sample size varied from 33 to 14,703. All RCTs used appropriate methods of randomisation and allocation concealment and it was reported that all were analysed by ITT. Eight were double blinded, but it was not always clear whether the outcomes assessor and data analyst were blinded. Two RCTS achieved a Jadad score of five points, one scored four, three scored three and three scored two.

ACEI plus ARB versus ACEI alone:

The overall adverse event rate was low. Combined therapy was associated with a higher risk of any adverse event (i.e. hyperkalaemia, angioedema, cough, worsening renal function or hypotension) leading to discontinuation of therapy: RR 1.27 (95% CI: 1.15, 1.40, p<0.00001, NNH=42, 5 RCTs). The following specific adverse events were significantly more common in the intervention group: worsening renal function (RR 2.12, 95% CI: 1.30, 3.46, p=0.003; NNH=100, 6 RCTs), hypotension (RR 1.91, 95% CI: 1.37, 2.66, p=0.0002, NNH=89, 9 RCTs), hyperkalaemia (RR 4.17, 95% CI: 2.31, 7.53, p<0.00001, NNH=149, 6 RCTs).There was no statistically significant difference between the groups in risk of angioedema (3 RCTs) or cough (4 RCTs). The analysis for worsening renal function was associated with heterogeneity of borderline statistical significance (p=0.05, I² 67%); however the direction of effect for this outcome consistently favoured the control groups.

Sensitivity and subgroup analyses found no clinically significant association between outcomes and any of the variables evaluated, and there was no evidence of publication bias on visual inspection of the funnel plot.

Authors' conclusions

Treatment of LV dysfunction or HF with ACEI plus ARB significantly increases the risk of adverse events leading to discontinuation of therapy, compared to ACEI alone. The overall adverse event rate is low.

CRD commentary

The review objectives and inclusion criteria were clear in most respects, but it was unclear whether controls needed to be receiving placebo as well as ACEI. Relevant sources were searched, efforts were made to retrieve unpublished studies and there was no language restriction. Steps were taken to minimise bias and error in the process of data extraction by having more than one reviewer make decisions independently, but it was unclear whether this also applied to study selection and validity assessment. Relevant criteria were used to assess study validity. However there were large unexplained discrepancies between reported sample sizes in the primary studies and numbers included in the analysis in the review. Appropriate statistical techniques were used to combine the studies, assess for publication bias and heterogeneity and to explore potential sources of heterogeneity. The authors discussed potential limitations in the evidence, such as the exclusion of 37 studies that did not report whether specific adverse events were assessed, the small number of events and poor reporting of confounders in the included studies, and clinical heterogeneity between the studies. Unexplained discrepancies in the sample numbers and the poor reporting of adverse events in the primary studies necessitate some caution in interpretation of the findings.

Implications of the review for practice and research

Practice: the authors stated that ARB should not be added routinely to ACEI therapy in patients with HF or post MI LV dysfunction, in view of the increased risk of treatment discontinuation due to adverse effects, the lack of consistent evidence of mortality benefit and the availability of alternative treatment. Patients treated with combined therapy should be monitored closely for adverse effects. The current review addressed only adverse effects, not the effectiveness of combined treatment or alternative treatments.

Research: the authors did not state any implications for research.

Funding

Not stated.

Bibliographic details

Lakhdar R, Al-Mallah M H, Lanfear D E. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. Journal of Cardiac Failure 2008; 14(3): 181-188. [PubMed: 18381180]

Other publications of related interest

Lee VC, Rhew DC, Dylan M, et al. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004;141:693e704.

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers /administration & dosage; Angiotensin-Converting Enzyme Inhibitors /administration & dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography, Doppler; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left /diagnosis /drug therapy /mortality

AccessionNumber

12008103324

Database entry date

31/03/2009

Record Status

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.