|Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis
|Huang G, Xu JB, Liu JX, He Y, Nie XL, Li Q, Hu YM, Zhao SQ, Wang M, Zhang WY, Liu XR, Wu T, Arkin A, Zhang TJ
The authors concluded that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decreased incidence of atrial fibrillation in patients with hypertension, chronic heart failure and atrial fibrillation and were effective for primary and secondary prevention of atrial fibrillation. The reliability of the authors' conclusions is limited by likely language bias, unclear study quality and uncertainties about combining variable studies.
To assess the antiarrhythmic effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the incidence of atrial fibrillation.
MEDLINE, EMBASE and The Cochrane Library were searched for papers published between 1950 and May 2009. Search terms were reported. Only papers published in English were considered. Reference lists of identified trials and review articles were handsearched.
Randomised controlled trials (RCTs) that compared ACEIs or ARBs (all types, doses and regimens) to active treatment or placebo in patients with cardiovascular diseases (hypertension, chronic heart failure, coronary artery disease, atrial fibrillation, myocardial infarction) were eligible for inclusion. The outcome measure was incidence of atrial fibrillation (new-onset atrial fibrillation, recurrent atrial fibrillation or atrial fibrillation reported as an adverse event) recorded by electrocardiogram (ECG) or 24-hour Holter monitoring at follow-up visits.
Study settings were varied: multinational (nine), Europe (10) and Asia (two). Mean patient ages (where reported) ranged from 52.6 to 76 years. Studies enrolled patients with different diagnoses (such as hypertension, chronic heart failure, post-myocardial infarction, atrial fibrillation, coronary heart disease and coronary artery, peripheral vascular or cerebrovascular disease). Some studies excluded patients with atrial fibrillation. Types and doses of ACEIs and ARBs varied (enalapril and lisinopril, valsartan, Irbesartan, telmisartan, perindopril, trandolapril, captopril, candesartan, losartan, ramipril). Comparators included placebo, amlodipine, amiodarone, atenolol and conventional therapy with or without calcium antagonists. Some patients also received beta-blockers and antiarrhythmic drugs. Follow-up ranged from 42 days to 6.1 years.
Two reviewers independently assessed studies for inclusion; disagreements were resolved with a third reviewer.
Assessment of study quality
Two reviewers independently assessed study quality (Delphi list and Jadad scores) by considering the adequacy of concealment of treatment allocation, eligibility criteria, blinding of outcome assessors, follow-up and use of intention-to-treat analysis. Disagreements were resolved by a third reviewer.
Two reviewers independently extracted data (using a predefined data extraction sheet) to enable calculation of relative risks (RRs) and their 95% confidence intervals (CIs). Disagreements were resolved by involvement of a third reviewer. Authors of primary studies were contacted for original data (events, treatment and control group information).
Methods of synthesis
Pooled relative risks and 95% CIs were calculated using random-effects meta-analysis. Heterogeneity was assessed with Χ² and Ι². Subgroup analyses were performed according to patient groups, primary and secondary prevention, onset of atrial fibrillation and agent class (ACEIs, ARBs). Sensitivity analysis assessed the effects of dimensions of study outcome measures and quality on effect estimates. Publication bias was assessed using Egger’s test.
Results of the review
Twenty-two RCTs (91,381 patients) were included. Seventeen trials had Jadad scores of at least 3 (maximum score 5); criteria used to compute the overall Jadad scores were unclear. Six RCTs were open label.
ACEIs and ARBs combined were associated with a 25% reduction in the incidence of atrial fibrillation (RR 0.75, 95% CI 0.66 to 0.85, Ι²=80%; 91,381 patients, 21 RCTs) compared to control.
Subgroup analyses (compared to control):
ACEIs and ARBs combined for primary prevention were associated with a 24% reduction in incidence of atrial fibrillation (RR 0.76, 95% CI 0.65 to 0.88, Ι²=78%; 66,937 patients, nine RCTs).
ACEIs and ARBs combined for secondary prevention were associated with a 27% reduction in the incidence of atrial fibrillation (RR 0.73, 95% CI 0.59 to 0.89, Ι²=81%; 24,444 patients, 12 RCTs).
ACEIs/ARBs combined were associated with a 20% reduction in incidence of new-onset atrial fibrillation (RR 0.80, 95% CI 0.70 to 0.92, Ι²=79%; 84,536 patients, 11 RCTs) and a 36% reduction in incidence of recurrent atrial fibrillation (RR 0.64, 95% CI 0.48 to 0.84, Ι²=83%; 6,845 patients, 10 RCTs).
ACEIs were associated with a 31% reduction in incidence of atrial fibrillation (RR 0.69, 95% CI 0.56 to 0.85, Ι²=77%; 46,186 patients, 11 RCTs). ARBs were associated with a 25% reduction in the incidence of atrial fibrillation (RR 0.75, 95% CI 0.63 to 0.88, Ι²=83%; 45,377 patients, 12 RCTs).
Further results of subgroup analyses (chronic and persistent atrial fibrillation, congestive heart failure, paroxysmal atrial fibrillation and others) were reported in the paper.
Egger’s test suggested presence of publication bias (p=0.002). Overall results did not change significantly in sensitivity analyses.
ACEIs and ARBs decreased the incidence of atrial fibrillation in patients with hypertension, chronic heart failure and atrial fibrillation and were effective for primary prevention and secondary prevention of atrial fibrillation.
The review addressed a clearly stated question. Three major databases were searched for publications in English, which raised the possibility of language bias. Study selection, data extraction and validity assessment were done in duplicate, which minimised likely biases and errors. Study quality was assessed with appropriate criteria, but criteria for individual trial scores was unclear.
The decision to combine study results may have been inappropriate given significant study differences. Statistical heterogeneity was explored, but no moderator variables were identified. The review included several studies with a large overall sample size.
The reliability of the authors' conclusions is limited by weaknesses (likely language bias, uncertainty regarding study quality and considerable variation among studies) that mean that meta-analysis may not have been appropriate.
Implications of the review for practice and research
Practice: The authors stated that the conclusions should be interpreted cautiously "although ACEIs showed larger magnitude of effect than ARBs it is not reasonable to conclude that ACEIs have a greater effect than ARBs in reducing the incidence of atrial fibrillation".
Research: The authors noted that there ongoing RCTs were investigating the effects of ACEIs or ARBs on atrial fibrillation in patients with hypertension, post-catheter ablation, postcardiac surgery, sick sinus syndrome and hypertension and permanent pacemakers (further details were reported). They also stated that large double-blinded RCTs and head-to-head comparative studies of ACEIs and ARBs on patients with atrial fibrillation accompanied by coronary heart disease or post-myocardial infarction were needed.
Huang G, Xu JB, Liu JX, He Y, Nie XL, Li Q, Hu YM, Zhao SQ, Wang M, Zhang WY, Liu XR, Wu T, Arkin A, Zhang TJ. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis. European Journal of Clinical Investigation 2011; 41(7): 719-733
Subject indexing assigned by NLM
Aged; Angiotensin II Type 1 Receptor Blockers /therapeutic use; Angiotensin-Converting Enzyme Inhibitors /therapeutic use; Anti-Arrhythmia Agents /therapeutic use; Atrial Fibrillation /drug therapy /prevention & control; Humans; Middle Aged; Randomized Controlled Trials as Topic /methods /standards; Treatment Outcome
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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.