efficacy of β blockers in patients with heart failure plus atrial fibrillation: an...

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www.thelancet.com Published online September 2, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61373-8 1

Effi cacy of β blockers in patients with heart failure plus atrial fi brillation: an individual-patient data meta-analysisDipak Kotecha, Jane Holmes, Henry Krum, Douglas G Altman, Luis Manzano, John G F Cleland, Gregory Y H Lip, Andrew J S Coats, Bert Andersson, Paulus Kirchhof, Thomas G von Lueder, Hans Wedel, Giuseppe Rosano, Marcelo C Shibata, Alan Rigby, Marcus D Flather, on behalf of the Beta-Blockers in Heart Failure Collaborative Group

SummaryBackground Atrial fi brillation 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 effi cacy of these drugs in patients with concomitant atrial fi brillation is uncertain. We therefore meta-analysed individual-patient data to assess the effi cacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fi brillation.

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 fi brillation 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 fi brillation 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 fi brillation. β-blocker therapy led to a signifi cant 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 fi brillation (0·97, 0·83–1·14; p=0·73), with a signifi cant p value for interaction of baseline rhythm (p=0·002). The lack of effi cacy for the primary outcome was noted in all subgroups of atrial fi brillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy.

Interpretation Based on our fi ndings, 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 fi brillation.

Funding Menarini Farmaceutica Internazionale (administrative support grant).

Introductionβ-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 signifi cant 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 effi cacy in some groups, notably patients with atrial fi brillation, 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 defi nitive 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 effi cacy and safety of treatment.4

Chronic heart failure and atrial fi brillation 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 fi brillation 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 fi brillation within 12 months.10 Despite improved medical therapy, heart failure remains an important driver of health-care cost.11 Patients with concomitant atrial fi brillation have even higher mortality and hospital admission rates, irrespective of which illness arises fi rst.12,13 Additionally, the prevalence of atrial fi brillation is determined by the severity of heart failure, as defi ned by the New York Heart Association (NYHA) functional class.14

We assessed the effi cacy and safety of β blockers in patients with heart failure and concomitant atrial fi brillation by meta-analysing individual-patient data.

Published OnlineSeptember 2, 2014http://dx.doi.org/10.1016/S0140-6736(14)61373-8

University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK (D Kotecha PhD, Prof G Y H Lip MD, Prof P Kirchhof MD); Clinical Trials and Evaluation Unit, Royal Brompton and Harefi eld NHS Trust, London, UK (D Kotecha); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (D Kotecha, Prof H Krum PhD, T G von Lueder PhD); Centre for Statistics in Medicine, University of Oxford, Oxford, UK (J Holmes PhD, Prof D G Altman DSc); Internal Medicine Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain (Prof L Manzano MD); National Heart and Lung Institute, Royal Brompton and Harefi eld Hospitals, Imperial College, London, UK (Prof J G F Cleland MD); Hull York Medical School, University of Hull, Kingston upon Hull, UK (Prof J G F Cleland); City Hospital, Sandwell and West Birmingham NHS Trust, Birmingham, UK (Prof G Y H Lip, Prof P Kirchhof); Monash University, Melbourne, VIC, Australia (Prof A J S Coats DSc); Warwick University, Warwick, UK (Prof A J S Coats); Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden (Prof B Andersson PhD); Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany (Prof P Kirchhof); Department of Cardiology, Oslo University Hospital, Oslo, Norway (T G von Lueder); Nordic School of Public Health, Gothenburg, Sweden (Prof H Wedel PhD); Department of Medical Sciences, Instituto di Ricovero e Cura a Carattere Scientifi co

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2 www.thelancet.com Published online September 2, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61373-8

Patients with atrial fi brillation are often prescribed β blockers for both prognostic benefi t in heart failure and heart-rate control, although there is little and underpowered evidence for effi cacy 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 benefi ts of β-blocker therapy in patients with heart failure and atrial fi brillation compared with those in sinus rhythm.

MethodsSearch strategy and data gatheringThe detailed rationale and design have been reported previously.4 Briefl y, the Beta-Blockers in Heart Failure Collaborative Group is a multinational eff ort 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, ethics

committee approval was judged to be unnecessary by the National Research Ethics Service, London, UK.

We identifi ed published and unpublished randomised controlled trials through computer-aided searches of Medline and Current Contents using MeSH terms relating to heart failure with free text search for β blockers since the inception of Medline (about 1960), reference lists of trials, trials registries, meeting abstracts, review articles, and discussion with group members and pharmaceutical manufacturers. There were no language restrictions. Randomised controlled trials in which mortality was a primary or composite outcome of the comparison of β blockers versus placebo in patients with heart failure were included in the meta-analysis. Only unconfounded head-to-head trials with recruitment of more than 300 patients and a planned follow-up of more than 6 months were eligible to make the project technically feasible and clinically relevant. The search results, individual study demographics, and a standardised data request form to obtain individual-patient data from each trial have been reported previously.4

Eleven studies accounted for 95·7% of the eligible recruited participants.18–28 All included studies had low risk of bias as assessed with the Cochrane Collaborations Risk of Bias Tool.29 The CHRISTMAS trial21 had atrial fi brillation as an exclusion criterion, so although the data could not be used in this meta-analysis they were extracted for future analysis in other subgroups. Data were extracted from original source fi les and additional follow-up outcomes were available in seven studies.18–20,24,25,27,28 The primary outcome was all-cause mortality, including an analysis of total mortality where deaths occurred after early study termination or following a fi xed censor point. The mean follow-up until death or censoring was 1·5 years (SD 1·1) for all studies; range 0·9–5·3 years in the individual trials. Major secondary outcomes were cardiovascular death, the composite of all-cause mortality and cardiovascular hospitalisation, and non-fatal stroke. Hospital admission outcomes included the time to hospital admission (any cause), cardiovascular hospital admission and heart-failure-related hospital admission, and the number and duration of cardiovascular or heart-failure hospital admissions. An additional post-hoc defi ned outcome was the composite of cardiovascular death and heart-failure-related hospital admission. Drug safety outcomes were focused on discontinuation of study drug therapy due to hypotension, bradycardia, renal impairment, heart failure exacerbation, or any adverse event.

The diagnosis of sinus rhythm and atrial fi brillation or atrial fl utter was based on the baseline electrocardiograph (ECG). The two atrial arrhythmias could only be distinguished in two trials.19,27 Consistent with clinical expectation, fl utter accounted for only 4% of the combined group. For the purposes of this report, reference to atrial fi brillation therefore includes atrial fl utter. Incident atrial fi brillation was defi ned as atrial fi brillation during follow-up in patients with sinus

Sinus rhythm (n=13 946)

Atrial fi brillation (n=3066)

Age (years) 64 (54–71) 69 (60–74)

Women 3498 (25%) 594 (19%)

Diabetes mellitus 3221 (25%) 674 (23%)

Years with heart failure diagnosis 3·0 (1·0–6·0) 3·0 (1·0–7·0)

LVEF 0·27 (0·21–0·33) 0·27 (0·22–0·33)

NYHA class III or IV 7782 (63%) 1901 (72%)

Systolic blood pressure (mm Hg) 123 (110–140) 127 (113–140)

Diastolic blood pressure (mm Hg) 78 (70–82) 80 (70–85)

Heart rate (bpm) 80 (72–88) 81 (72–92)

Body-mass index (kg/m²) 27 (24–31) 27 (25–31)

Estimated glomerular fi ltration rate (mL/min) 64 (52–78) 61 (49–74)

Any diuretic therapy 11 888 (85%) 2866 (93%)

Angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker

13 213 (95%) 2898 (95%)

Aldosterone antagonists 1093 (8%) 500 (17%)

Digoxin 7380 (53%) 2560 (83%)

Amiodarone 797 (6%) 319 (10%)

Oral anticoagulation 3652 (26%) 1772 (58%)

Data are median (IQR) or percentage, unless otherwise indicated. Within-group characteristics according to treatment allocation are presented in the appendix. Data were missing for diabetes mellitus (844 patients in the sinus rhythm group and 149 in the atrial fi brillation group), years with heart failure (2464 and 320), LVEF (60 and 16), NYHA class (1506 and 431), systolic blood pressure (ten and none), diastolic blood pressure (15 and two), heart rate (seven and one), body-mass index (128 and 22), and glomerular fi ltration rate (634 and 101). LVEF=left-ventricular ejection fraction. NYHA=New York Heart Association functional class.

Table 1: Baseline characteristics of pooled patients with heart failure and sinus rhythm or atrial fi brillation

San Raff aele Pisana, Rome, Italy (Prof G Rosano PhD);

Division of Cardiology, University of Alberta,

Edmonton, Canada (M C Shibata MD); Academic

Cardiology, Castle Hill Hospital, Kingston upon Hull, UK

(A Rigby MSc); and Norwich Medical School, University of

East Anglia, Norwich, UK (Prof M D Flather MBBS)

Correspondence to:Dr Dipak Kotecha, University of

Birmingham Centre for Cardiovascular Sciences, Medical

School, Vincent Drive, Edgbaston, Birmingham

B15 2TT, [email protected]

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rhythm at baseline. Follow-up ECGs or adverse event data refl ecting new-onset or recurrence of atrial fi brillation were available in all studies, with data missing for 862 (6%) of 13 946 individual patients.

Statistical analysisData are presented as median and IQR, or percentages. Estimated glomerular fi ltration rate was calculated with the Modifi cation of Diet in Renal Disease formula, normalised to a body surface area of 1·73 m². Three patients (two with atrial fi brillation and one with sinus rhythm) had missing event dates and were excluded from outcome analyses. Hospital admission was not recorded for the MDC trial and NYHA class was not explicitly obtained in the COPERNICUS study.24,25 Because the amount of missing data for other major variables was low, there was no need to impute missing values.

All analyses were by intention to treat. The primary and major secondary outcomes were analysed with a stratifi ed Cox proportional hazards regression model.30 This is a one-stage fi xed-eff ects approach and the assumption is that all trials are estimating a common treatment eff ect with baseline hazards that vary across studies. HRs and 95% CIs are presented with corresponding p values, with adjustment for age, sex, and baseline left-ventricular ejection fraction (LVEF), heart rate, and use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. Kaplan-Meier plots are used to present the data (pooled from all trials). Because the follow-up in individual studies varied, data were censored at 1200 days (3·3 years). Heterogeneity for pooled outcomes was assessed with the χ² test and I² statistic, with the estimate of heterogeneity taken from the inverse-variance fi xed-eff ects two-stage model.31

Sensitivity analyses included alternative censor points, separate exclusion of the BEST19 and CAPRICORN20 studies, additional baseline adjustment, and random-eff ects modelling.32 Exploratory analyses included a per-protocol analysis of patients who remained on study therapy throughout the trial and factors associated with incident atrial fi brillation (with an adjusted logistic regression model because time to diagnosis of atrial fi brillation was not available).

A two-tailed p value of 0·05 was judged to be signifi cant. Analyses were done with Stata (version 11.2) and R (version 3.0.2).

This study is registered with Clinicaltrials.gov, number NCT0083244, and with PROSPERO, number CRD42014010012.33

Role of the funding sourceMenarini Farmaceutica Internazionale provided an unrestricted research grant for administrative costs and GlaxoSmithKline provided data extraction support. None of the pharmaceutical groups had any role in data analysis or manuscript preparation. The steering committee lead (DK) and the Centre for Statistics in

Medicine, Oxford, UK, had full access to all the data and had joint responsibility for the decision to submit for publication after discussion with all the named authors.

ResultsOf 18 254 patients with heart failure, 13 946 (76%) had sinus rhythm at baseline, 3066 (17%) had atrial fi brillation, 1124 (6%) had other rhythms (predominantly paced rhythm or heart block), and 118 (<1%) had a missing or uninterpretable baseline ECG. Minimal diff erences 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 atrial fi brillation. The median duration of heart failure before enrolment in the

Deaths in sinus rhythm (n=2237)

Deaths in atrial fi brillation (n=633)

Acute myocardial infarction

126 (6%) 13 (2%)

Sudden death 927 (41%) 231 (36%)

Heart failure 539 (24%) 184 (29%)

Cardiac (not heart failure) 59 (3%) 11 (2%)

Stroke 43 (2%) 27 (4%)

Vascular (not stroke) 99 (4%) 38 (6%)

Non-cardiovascular 180 (8%) 45 (7%)

Unknown 264 (12%) 84 (13%)

Data are number (%), unless otherwise indicated. *Including deaths reported after the closure or early termination of the study.

Table 2: Causes of deaths* in patients with heart failure and sinus rhythm or atrial fi brillation

Pooled data for sinus rhythm (n=13 645)

Pooled data for atrial fi brillation (n=3002)

All-cause hospital admissions

Patients with one or more admissions 5150 (38%) 1205 (40%)

Per patient (mean; range) 0·78 (0–26) 0·79 (0–26)

Per patient per year 0·86 0·94

Cardiovascular hospital admissions

Patients with one or more admissions 3508 (26%) 866/3002 (29%)



Length of stay (mean, median; range)* 9·7 days, 6 days (1–368) 11·9 days, 8 days (1–179)

Heart-failure hospital admissions

Patients with one or more admission 2241 (16%) 631/3002 (21%)



Length of stay (mean, median; range)* 9·8 days, 6·5 days (1–148) 12·0 days, 8·0 days (1–179)

Data are number (%), unless otherwise indicated. Hospital admission data were not available for the Metoprolol in Dilated Cardiomyopathy Trial.25 Data do not account for diff erences in baseline demographics between groups. *Average of fi rst fi ve hospital admissions for a cardiovascular or heart-failure cause in patients with at least one hospital admission.

Table 3: Hospital admissions for patients with heart failure and sinus rhythm or atrial fi brillation

See Online for appendix

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studies was 3 years (table 1). Compared with patients in sinus rhythm, those with atrial fi brillation were 5 years older, with a higher percentage being men (table 1). Small diff erences were noted in systolic blood pressure and glomerular fi ltration rate, but LVEF and heart rate were similar (table 1). Patients with atrial fi brillation were more symptomatic (NYHA class III or IV) than were those with sinus rhythm (table 1). More patients with atrial fi brillation used diuretics, aldosterone antagonists, digoxin, or oral anticoagulants; however, 95% in both groups were taking an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker at baseline (table 1).

Inclusion of deaths reported after early study termination or study closure resulted in a crude mortality of 21% in patients with atrial fi brillation (633 of 3064) and 16% in those with sinus rhythm (2237 of 13 945). Based on the number of deaths during the individual study periods only, crude mortality was 18% in patients with atrial fi brillation (556 of 3064) and 14% in those with sinus rhythm (2021 of 13 945). The most common causes of death in both groups were sudden death and heart failure (table 2). Fatal stroke was uncommon, but as expected more frequent in patients with atrial fi brillation than in those with sinus rhythm (table 2).

Table 3 shows the pooled data for all-cause, cardiovascular disease, and heart-failure-related hospital admissions. The total number of hospital admissions and the yearly rate per patient were higher and the mean length of stay was longer in patients with atrial fi brillation than in those with sinus rhythm (table 3).

A consistent benefi t of β blockers versus placebo was noted for all death or hospital admission outcomes in patients with sinus rhythm, but the diff erences were not signifi cant in patients with atrial fi brillation (table 4). The pinteraction values for treatment effi cacy and baseline heart rhythm were signifi cant for each of these outcomes (table 4). Including all reported deaths, the adjusted HR was 0·73 for all-cause mortality in patients with sinus rhythm and 0·97 in patients with atrial fi brillation (pinteraction=0·002; table 4; fi gure 1). These results were similar to those for cardiovascular deaths or when the analysis was restricted to deaths during the study (table 4).

For time-to-fi rst cardiovascular hospital admission, the adjusted HR for patients with sinus rhythm was 0·78 and for those with atrial fi brillation was 0·91 (pinteraction=0·05; table 4; fi gure 2). Results were similar for heart-failure-related hospital admission and the composite clinical outcomes (death or cardiovascular-hospital admission and cardiovascular-death or heart-failure-related hospital admission). β-blocker therapy had no eff ect on incident non-fatal stroke in either sinus rhythm or atrial fi brillation (table 4).

Sensitivity analyses for the primary outcome are presented in the appendix. There were no eff ects with additional baseline adjustment, exclusion of specifi c trials, or use of diff erent censor points (appendix). The HRs in the two-stage meta-analysis for all-cause mortality (fi gure 3) were almost identical to those obtained with the one-stage approach, using both fi xed and random eff ects modelling (data not shown). Importantly, we identifi ed no hetero-geneity between the individual studies for all-cause mortality in patients with atrial fi brillation (fi gure 3). Heterogeneity was signifi cant for sinus rhythm (fi gure 3).

In an exploratory subgroup analysis of the atrial fi brillation cohort for all-cause mortality, no signifi cant interactions were noted at clinical cutoff s for variables including age, sex, LVEF, NYHA class, blood pressure or heart rate, and medical therapy (fi gure 4). We also did a per-protocol assessment of all reported deaths in the patients with atrial fi brillation. No diff erence was noted in the effi cacy of β-blocker therapy in patients with atrial fi brillation who remained on therapy (HR 0·84, 95% CI 0·68–1·04), with no signifi cant interaction for discontinuation of study treatment in the atrial fi brillation group (p=0·09).

Of 13 084 patients with sinus rhythm at baseline and data for follow-up heart rhythm, 610 (5%) developed atrial fi brillation. The factors independently associated with incident atrial fi brillation in an exploratory analysis were advanced age, male sex, BMI of at least 30 kg/m², and NYHA class III or IV at baseline (appendix).

Number of events/sample size

Sinus rhythm, β blockers versus placebo

Atrial fi brillation, β blockers versus placebo

pinteraction, atrial fi brillation versus sinus rhythm

Hazard ratio (95% CI)*

p value Hazard ratio (95% CI)*

p value

All-cause mortality (including all reported deaths)

2870/17 009 0·73(0·67–0·80)

<0·001 0·97(0·83–1·14)

0·73 0·002

All-cause mortality (deaths during study)

2577/17 009 0·73(0·67–0·80)

<0·001 0·93(0·79–1·10)

0·43 0·01

Cardiovascular deaths (including all reported deaths)

2297/17 009 0·72(0·65–0·79)

<0·001 0·92(0·77–1·10)

0·35 0·02

First cardiovascular hospital admission

4374/16 644 0·78(0·73–0·83)

<0·001 0·91(0·79–1·04)

0·15 0·05

Death or cardiovascular hospital admission

5670/16 644 0·76(0·72–0·81)

<0·001 0·89(0·80–1·01)

0·06 0·01

First heart-failure-related hospital admission

2872/16 644 0·71(0·65–0·77)

<0·001 0·91(0·78–1·07)

0·26 0·005

Cardiovascular death (during study) or heart-failure-related hospital admission†

4151/16 644 0·70(0·65–0·75)

<0·001 0·90(0·79–1·03)

0·13 0·001

Non-fatal stroke 296/16 644 1·02(0·78–1·32)

0·91 1·04(0·66–1·63)

0·87 0·94

Metoprolol in Dilated Cardiomyopathy Trial25 did not contribute to analyses of hospital admissions or incident stroke. *Hazard ratios derived from the one-stage Cox regression model were stratifi ed by study and adjusted for age, sex, baseline left ventricular ejection fraction (data missing for 76 patients), baseline heart rate (data missing for eight patients), and use of angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker. †Outcome was not prespecifi ed.

Table 4: Primary and secondary outcomes

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Allocation to β blockers was associated with a 33% reduction in the adjusted odds ratio of incident atrial fi brillation (253 [4%] of 6722 patients randomly assigned to β blockers developed atrial fi brillation vs 357 [6%] of 6362 allocated to placebo; appendix).

There were minimal diff erences in the dose of study drug achieved according to baseline heart rhythm, with overall 84% of patients achieving maximal study dose in the placebo group and 73% in the β-blocker group (appendix). The attained heart rate and change from baseline heart rate were similar in patients with sinus rhythm and those with atrial fi brillation, although the interpretation was confounded by lack of measurements in patients who died before the interim study visit (appendix). 15% of patients discontinued the study drug due to adverse eff ects in those randomised to β blockers

or placebo. No diff erences were noted in β-blocker discontinuation in the sinus rhythm and atrial fi brillation groups (14% vs 15%; appendix). The incidences of withdrawal of therapy due to specifi c adverse eff ects were low (eg, hypotension or bradycardia in 1–2%).

DiscussionOur principal fi ndings in this individual-patient data analysis are that patients with heart failure and atrial fi brillation given β blockers had no signifi cant reduction in all-cause mortality, cardiovascular hospital admission, or composite clinical outcomes compared with those receiving placebo. The atrial fi brillation group comprised 3066 participants with 633 deaths, and although we cannot exclude limited power, the results

Figure 1: Kaplan-Meier survival curve for patients with sinus rhythm (A) and atrial fi brillation (B) in the β-blocker and placebo groupsData are unadjusted survival curves for all reported deaths. HRs are derived from the adjusted one-stage Cox regression model and stratifi ed by study. HR=hazard ratio.

Number at riskβ-blocker group

Placebo group

0

71236819

1

50144604

2

17981530

3

722561

Time (years)

50

60

70

80

90

100

Surv

ivor

s (%

)

A

0

15211542

1

9971020

2

331346

3

113115

Time (years)

B

HR 0·73 (95% CI 0·67–0·80); p<0·001 HR 0·97 (95% CI 0·83–1·14); p=0·73

β-blocker groupPlacebo group

Figure 2: Kaplan-Meier event curve for cardiovascular hospital admission in patients with sinus rhythm (A) and atrial fi brillation (B) in the β-blocker and placebo groupsData are unadjusted event curves for cardiovascular hospital admission during the study. HRs are derived from the adjusted one-stage Cox regression model, stratifi ed by study. HR=hazard ratio.

Number at riskβ-blocker group

Placebo group

0

69696665

1

40893540

2

13351013

3

482305

Time (years)

50

60

70

80

90

100

Even

t-fre

e (%

)

A

0

14851512

1

791768

2

238230

3

7158

Time (years)

B

HR 0·78 (95% CI 0·73–0·83); p<0·001 HR 0·91 (95% CI 0·79–1·04); p=0·15

β-blocker groupPlacebo group

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of this analysis suggest that clinical benefi t from β blockers is unlikely in patients with combined heart failure and atrial fi brillation. Patients with atrial fi brillation had higher crude rates of death, more frequent hospital admission, and longer stay in hospital than did those with sinus rhythm.

Heart failure and atrial fi brillation are two common disorders that are increasing in prevalence. Although the incidence of heart failure has remained static over the past 25 years,34 the incidence of atrial fi brillation is increasing35 and not simply as a function of the ageing population.36 These two disorders often coexist, with observational data suggesting the presence of atrial

fi brillation in 14–50% of patients with symptomatic heart failure.14 Atrial remodelling often occurs in heart failure because of sustained increases in pressure, volume, and neurohormonal stress, making the development of atrial fi brillation more likely. Similarly, atrial fi brillation can lead to heart failure both as a direct cause (eg, in tachycardia-induced cardiomyopathy) and due to loss of atrioventricular synchrony and impairment in diastolic fi lling. Heart failure with preserved ejection fraction is as common as the syndrome with reduced LVEF;2 however, the eff ect of pharmacotherapy on diastolic function in patients with atrial fi brillation has not been investigated previously. Irrespective of the type of heart failure, the combination with atrial fi brillation is known to adversely aff ect prognosis37 and overall represents a massive burden on aff ected patients, health-care systems, and societies, including substantial health-care costs.38 Hospital admission in heart failure is the greatest cost contributor11 and the results of our analysis suggest that atrial fi brillation increases both the risk of hospital admission and the length of stay, reinforcing the importance of fi nding effi cacious therapies in this population.

A cause for concern is the previous lack of focus on optimal management of the combination of heart failure and atrial fi brillation. Indeed, all current guideline recommendations for treatment of heart failure with reduced LVEF stem from trials predominantly with patients who have sinus rhythm. Guidelines from the European Society of Cardiology1 and the American College of Cardiology Foundation and American Heart Association2 recommend β-blocker therapy in patients with heart failure and atrial fi brillation, based on the effi cacy shown in the trials assessed in this report. The results of our analysis suggest that the substantial benefi t identifi ed in patients with sinus rhythm should not be extrapolated to patients with atrial fi brillation. The reason for the lack of effi cacy of β blockers in patients with atrial fi brillation might be due to several physiological diff erences.15 Unlike sinus rhythm, slower heart rates are not associated with improved survival in atrial fi brillation,39 although this association remains to be adequately tested in prospective studies. The irregular rhythm in atrial fi brillation is also associated with a detrimental eff ect on systolic and diastolic cardiac function that is independent of heart rate.40,41 There are also structural42 and cellular43 consequences of atrial fi brillation that might aff ect treatment effi cacy. These observations, however, do not fully explain why the positive eff ects of β blockers, particularly on myocardial metabolism, do not correspond to prognostic benefi t in patients with atrial fi brillation, an anomaly that requires further investigation.

It is also important to consider the substantial reduction in the rates of hospital admission and death in patients with sinus rhythm. Rates of β-blocker uptake among patients with heart failure have been consistently

MDC25

CIBIS I22

US-HF28

ANZ18

CIBIS II23

MERIT-HF26

COPERNICUS24

CAPRICORN20

BEST19

SENIORS27

Overall (I2=56%, p=0·016)

0·67 (0·38–1·18)

0·70 (0·47–1·06)

0·74 (0·50–1·10)

0·91 (0·49–1·70)

0·60 (0·47–0·76)

0·58 (0·45–0·74)

0·53 (0·39–0·72)

0·83 (0·64–1·09)

0·91 (0·78–1·06)

0·78 (0·61–1·01)

0·74 (0·68–0·81)

2·3%

4·4%

4·9%

1·9%

12·3%

12·6%

8·0%

10·3%

31·8%

11·5%

HR (95% CI) WeightA

0·25 0·5 1·0 2·0 4·0

0·25 0·5 1·0 2·0 4·0

Favours β blocker Favours placebo

MDC25

CIBIS I22

US-HF28

ANZ18

CIBIS II23

MERIT-HF26

COPERNICUS24

CAPRICORN20

BEST19

SENIORS27

Overall (I2=0%, p=0·65)

1·00 (0·34–2·95)

1·14 (0·46–2·83)

1·14 (0·56–2·32)

0·28 (0·05–1·63)

0·98 (0·64–1·51)

1·03 (0·65–1·64)

0·91 (0·54–1·54)

0·90 (0·46–1·75)

0·76 (0·54–1·06)

1·14 (0·81–1·62)

0·95 (0·81–1·12)

2·3%

3·2%

5·3%

0·8%

14·4%

12·4%

9·8%

6·0%

23·4%

22·4%

HR (95% CI) WeightB


Figure 3: Two-stage adjusted meta-analysis for all-cause mortality in patients with sinus rhythm (A) and atrial fi brillation (B) in the studies included in the meta-analysisCox regression models, adjusted for age, sex, left ventricular ejection fraction, heart rate, and use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, were meta-analysed with a fi xed-eff ects approach. Analysis included all reported deaths, censored at 1200 days (3·3 years). HR=hazard ratio. ANZ=Australia/New Zealand Heart Failure Study. BEST=Beta-Blocker Evaluation Survival Trial. CAPRICORN=Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study. CIBIS I=Cardiac Insuffi ciency Bisoprolol Study. CIBIS II=Cardiac Insuffi ciency Bisoprolol Study II. COPERNICUS=Carvedilol Prospective Randomized Cumulative Survival Study. MDC=Metoprolol in Dilated Cardiomyopathy Trial. MERIT-HF=Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. SENIORS=Study of the Eff ects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure Study. US-HF=US Carvedilol Heart Failure Study.

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suboptimum44,45 and might suggest concern about symptom deterioration after initiation of treatment or the poor generalisability of data from randomised controlled trials to the real-world setting.46 One of the major aims of the Beta-Blockers in Heart Failure Collaboration was to improve rates of appropriate β-blocker use by identifying key patient groups that benefi t most from therapy. In this respect, use of β blockers in patients with sinus rhythm is strongly recommended and further subgroup analyses in relation to age, sex, and other patient characteristics are planned (to explain the remaining heterogeneity). We also noted a reduction in incident atrial fi brillation in patients with sinus rhythm treated with β blockers. This fi nding confi rms a previous tabular analysis of β-blocker trials in heart failure47 and might be an important component of the benefi t noted in patients with sinus rhythm.

Although we found no evidence that β-blocker therapy prevents adverse clinical events in patients with heart failure and atrial fi brillation, it did seem to be safe with no increase in mortality or hospital admission rates. This fi nding should reassure clinicians, particularly for patients with another indication for β blockers—eg, myocardial infarction or the need for rate control of rapid atrial fi brillation with ongoing symptoms. However, for the primary reason of preventing major adverse cardiovascular outcomes in patients with chronic heart failure and reduced LVEF, β blockers do not seem to be eff ective in patients with atrial fi brillation and should no longer be regarded as standard therapy to improve prognosis.

The strength of our analysis was the use of individual-patient data from large, high-quality randomised controlled trials, with nearly all available randomised data. Our careful and methodical data extraction from original datasets4 resulted in improved quality of baseline and outcome data across trials. Although the process of individual-patient data meta-analysis is arduous, there are substantial benefi ts including the ability to adjust for covariates and produce time-to-event analyses.16 We were also able to include post-publication data for mortality, explaining the small diff erences from previously published results in the component randomised controlled trials. We confi rmed that our conclusions apply across various subgroups of atrial fi brillation and irrespective of meta-analysis methods. To the best of our knowledge, the results of this study provide the most powerful analysis available of the effi cacy of β blockers in atrial fi brillation, thereby addressing a key clinical question about the management of this important group of patients with heart failure.

As with all meta-analytical techniques, we are limited by the data provided from the individual studies. Although there were missing data for some variables, their eff ect was minimised by extracting data from source datasets with a published data extraction plan.4 As already noted, we were unable to separate patients with atrial fi brillation and atrial fl utter; however, only a small percentage of

patients had atrial fl utter. The rate of incident atrial fi brillation was lower than expected from clinical practice and might refl ect under-reporting, particularly of paroxysmal atrial fi brillation. Our inability to characterise the type, persistence, and duration of atrial fi brillation is also a limitation. Although the validity and reproducibility of LVEF measurement has not been adequately shown in patients with atrial fi brillation, we did not see any diff erence in the variance of LVEF when comparing patients with sinus rhythm or atrial fi brillation. Heart

Figure 4: Subgroup analysis of all-cause mortality in patients with atrial fi brillation for the comparison of β-blocker therapy versus placeboDashed line is the overall eff ect of β blockers versus placebo in patients with atrial fi brillation. HRs and interaction p values were derived from the one-stage Cox regression model, stratifi ed by study and censored at 1200 days (3·3 years). HR=hazard ratio. NYHA=New York Heart Association. GFR=glomerular fi ltration rate. BMI=body-mass index. LVEF=left ventricular ejection fraction. bpm=beats per min.

Age

<70 years

≥70 years

Sex

Female

Male

Diabetes

No

Yes

NYHA class

I or II

III or IV

Blood pressure

<140/90 mm Hg

≥140/90 mm Hg

Estimated GFR

≥60 mL/min

<60 mL/min

BMI

≤30 kg/m2

>30 kg/m2

LVEF

>0·35

≤0·35

Heart rate

≤90 bpm

>90 bpm

Digoxin

No

Yes

Angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker

No

Yes

Oral anticoagulant

No

Yes

Overall, crude

Overall, adjusted

279/1617

337/1446

114/593

502/2470

413/2242

161/674

105/734

447/1898

566/2634

50/429

249/1517

342/1447

422/2077

186/964

83/510

528/2537

453/2231

163/831

102/505

514/2558

37/167

579/2896

488/2480

105/500

616/3063

611/3046

Deaths/number logHR (95% CI) pinteraction

0·643

0·402

0·305

0·513

0·867

0·940

0·828

0·403

0·444

0·165

0·580

0·835

1·00·50–0·5–1·0


0·92 (0·73–1·16)

0·98 (0·79–1·22)

0·82 (0·56–1·19)

0·99 (0·83–1·17)

0·88 (0·72–1·06)

1·09 (0·79–1·49)

0·87 (0·59–1·28)

0·98 (0·82–1·19)

0·94 (0·80–1·11)

1·04 (0·59–1·83)

0·97 (0·76–1·25)

0·94 (0·76–1·17)

0·95 (0·78–1·15)

0·93 (0·69–1·24)

1·17 (0·76–1·80)

0·92 (0·77–1·09)

1·00 (0·83–1·20)

0·88 (0·65–1·21)

1·11 (0·75–1·65)

0·91 (0·76–1·08)

0·85 (0·43–1·67)

0·97 (0·82–1·14)

0·93 (0·73–1·18)

0·96 (0·78–1·18)

0·97 (0·83–1·14)

0·97 (0·83–1·14)

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failure with preserved ejection fraction accounts for over half of patients with heart failure, but there are few data from randomised controlled trials comparing β blockers versus placebo in this group.48 Of the studies included in our analysis, only SENIORS27 recruited patients with LVEF of at least 0·50, which accounted for only 1·8% of the pooled dataset. Hence, we are unable to comment on the effi cacy of β blockers according to the rhythm status for patients with heart failure and preserved LVEF.

By contrast with the benefi cial eff ects noted for patients with sinus rhythm, β-blocker therapy has no or minimal eff ect on mortality or cardiovascular hospital admission in patients with heart failure with reduced ejection fraction and atrial fi brillation. Based on our results, we dispute the preferential use of β blockers compared with other rate-control medications and emphasise the need for further trials in this common and increasingly important group of patients.ContributorsDK participated in the design of the study, managed the collaborative group, and did the data management, statistical analysis, and manuscript preparation. HK, LM, and MDF participated in the design and coordination of the study. JH and DGA did the primary statistical analyses. All authors read, revised, and approved the fi nal manuscript.

Declaration of interestsDK has received grants from Menarini during the conduct of the study; and honoraria from Menarini (>36 months ago). HK has received honoraria from GlaxoSmithKline, Roche, and Merck (>36 months ago). JGFC has received grants and personal fees from Roche and GlaxoSmithKline outside of the submitted work. AJSC has received grants and personal fees from Menarini during the conduct of the study, and personal fees from Lone Star Heart outside of the submitted work. PK has received grants and personal fees from several research funders including European Union, British Heart Foundation, German Research Foundation, Leducq Foundation, German Ministry of Education and Research, and from medical device and pharmaceutical companies outside the submitted work; PK also has patents pending for atrial fi brillation therapy and markers. HW has received consulting fees from AstraZeneca as a member of the MDC and MERIT-HF steering committees. MDF has received grants from Menarini during the conduct of the study, and personal fees from AstraZeneca outside the submitted work. TGvL was supported by a grant from Southern and Eastern Norway Health Authority during the conduct of the study. GYHL has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi , Bristol-Myers Squibb–Pfi zer, Biotronik, Portola, and Boehringer Ingelheim, and has been on the speakers’ bureau for Bayer, Bristol-Myers Squibb–Pfi zer, Boehringer Ingelheim, and Sanofi -Aventis. MCS has received honoraria and speakers’ fees from Forest Laboratories. The other authors declare no competing interests.

AcknowledgmentsThe Beta-Blockers in Heart Failure Collaborative Group was investigator initiated. DK is funded by the National Institute for Health Research (NIHR) Clinical Lectureship scheme. The BEST trial was principally sponsored by the US National Heart, Lung and Blood Institute and the Department of Veterans Aff airs Cooperative Studies Program. All other trials were funded by pharmaceutical companies. We are indebted to the other members of the Beta-Blockers in Heart Failure Collaborative Group for database access and extraction support (full list available in Kotecha and colleagues4) and the late Philip Poole-Wilson (National Heart and Lung Institute, Imperial College, London, UK). This project was only possible with the support of the pharmaceutical companies that have marketed β blockers in heart failure, and the group wishes to extend their gratitude to AstraZeneca, GlaxoSmithKline, Menarini Farmaceutica, and Merck Serono. The views expressed in this publication are those of the authors and not those of the NIHR or the UK Department of Health.

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efficacy of β blockers in patients with heart failure plus atrial fibrillation: an...

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