Elsevier

The Lancet

Volume 384, Issue 9961, 20 December 2014–2 January 2015, Pages 2235-2243
The Lancet

Articles
Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis

https://doi.org/10.1016/S0140-6736(14)61373-8Get rights and content

Summary

Background

Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation.

Methods

We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012.

Findings

18 254 patients were assessed, and of these 13 946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13 945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67–0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83–1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy.

Interpretation

Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation.

Funding

Menarini Farmaceutica Internazionale (administrative support grant).

Introduction

β-blocker therapy for patients with chronic heart failure with reduced ejection fraction was instituted after a series of mechanistic studies and large randomised controlled trials showed a significant reduction in the rates of morbidity and mortality. According to both European and American guidelines, the use of β blockers in symptomatic patients with heart failure has a class 1A recommendation.1, 2 Nonetheless, uptake of therapy in clinical practice remains suboptimum, with patients at greatest risk of death least likely to receive evidence-based therapy.3 There have also been concerns about treatment efficacy in some groups, notably patients with atrial fibrillation, women, and elderly people. Previous analyses in these patient subsets have lacked statistical power but further large randomised studies are now unlikely because these β blockers are no longer patented. The Beta-Blockers in Heart Failure Collaborative Group was formed to provide definitive answers to open questions about heart failure and β-blocker therapy, with the aim of optimising the use of these drugs and providing clear guidance about efficacy and safety of treatment.4

Chronic heart failure and atrial fibrillation are two common illnesses that are associated with substantial morbidity and risk of death.1, 5 Importantly, both are predicted to continue increasing in prevalence,6, 7 with the incidence of atrial fibrillation expected to double in the next 20 years.8 More than 50% of patients with heart failure are readmitted to hospital within 6 months9 and nearly 40% of patients with atrial fibrillation within 12 months.10 Despite improved medical therapy, heart failure remains an important driver of health-care cost.11 Patients with concomitant atrial fibrillation have even higher mortality and hospital admission rates, irrespective of which illness arises first.12, 13 Additionally, the prevalence of atrial fibrillation is determined by the severity of heart failure, as defined by the New York Heart Association (NYHA) functional class.14

We assessed the efficacy and safety of β blockers in patients with heart failure and concomitant atrial fibrillation by meta-analysing individual-patient data. Patients with atrial fibrillation are often prescribed β blockers for both prognostic benefit in heart failure and heart-rate control, although there is little and underpowered evidence for efficacy in terms of clinical outcomes.15 Regarded as the gold-standard of meta-analysis, individual-patient data enable assessment of subgroups, accurate combination of original data (thereby improving data quality), full time-to-event analyses, and generation of hazard ratios (HRs) adjusted for baseline covariates.16 Analysis of data from more than 18 000 patients randomly assigned to β blockers or placebo allows a robust and adequately powered analysis of the clinical benefits of β-blocker therapy in patients with heart failure and atrial fibrillation compared with those in sinus rhythm.

Section snippets

Search strategy and data gathering

The detailed rationale and design have been reported previously.4 Briefly, the Beta-Blockers in Heart Failure Collaborative Group is a multinational effort to combine individual-patient data from the major randomised controlled trials of β blockers in patients with heart failure. This report was prepared according to the PRISMA guidelines.17

All the original trials were done under the supervision of an appropriate human ethics committee. The current analysis involves anonymised data only; hence,

Results

Of 18 254 patients with heart failure, 13 946 (76%) had sinus rhythm at baseline, 3066 (17%) had atrial fibrillation, 1124 (6%) had other rhythms (predominantly paced rhythm or heart block), and 118 (<1%) had a missing or uninterpretable baseline ECG. Minimal differences were noted in baseline characteristics between patients who were randomly assigned to β blockers or placebo in any group (appendix). Table 1 shows the baseline characteristics of patients with heart failure and sinus rhythm or

Discussion

Our principal findings in this individual-patient data analysis are that patients with heart failure and atrial fibrillation given β blockers had no significant reduction in all-cause mortality, cardiovascular hospital admission, or composite clinical outcomes compared with those receiving placebo. The atrial fibrillation group comprised 3066 participants with 633 deaths, and although we cannot exclude limited power, the results of this analysis suggest that clinical benefit from β blockers is

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