Prevention of atrial fibrillation onset by beta-blocker Clinical research

Clinical research
European Heart Journal (2007) 28, 457–462
doi:10.1093/eurheartj/ehl484
Heart failure/cardiomyopathy
Prevention of atrial fibrillation onset by beta-blocker
treatment in heart failure: a meta-analysis
Imad Abi Nasr1*, Anissa Bouzamondo1, Jean-Sébastien Hulot1, Olivier Dubourg3,
Jean-Yves Le Heuzey2, and Philippe Lechat1
1
Clinical Pharmacology Department, La Pitié Salpetrière Hospital, Assistance Publique-Hôpitaux de Paris, 47 Boulevard de
l’Hôpital, 75013 Paris, France; 2Cardiology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux
de Paris, Paris, France; and 3Cardiology Department, Hôpital Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de
Paris, Boulogne, France
Received 2 May 2006; revised 22 November 2006; accepted 4 January 2007; online publish-ahead-of-print 8 February 2007
Beta-blocker;
Atrial fibrillation;
Heart failure;
Primary prevention;
Meta-analysis
Aims Atrial fibrillation (AF) is an important morbidity–mortality risk factor, especially in patients with
heart failure (HF). Beta-blockers reduce morbidity and mortality in HF. The study was designed to estimate the preventive efficacy of beta-blocker treatment on AF occurrence in patients with HF.
Methods and results A systematic review of the literature was performed to identify all clinical trials
evaluating beta-blockers’ efficacy in HF. Eligible studies had to be randomized, placebo-controlled and
providing information on the incidence of AF during follow-up among those with sinus rhythm at baseline. A total of seven studies which included 11 952 patients receiving a background treatment with
angiotensin-converting enzyme-inhibitors could be found. Overall, beta-blockers significantly reduced
incidence of onset of AF from 39 to 28 per 1000 patient-years: relative risk reduction ¼ 27% (95% confidence interval 14–38, P , 0.001); heterogeneity test: P ¼ 0.096. A same trend of efficacy was
observed in all trials except the SENIORS study. In this trial which included aged patients (.70 years)
with systolic or diastolic HF, a higher prevalence of AF at baseline (35%) was observed compared with
the mean baseline prevalence (13%).
Conclusion Beta-blockers appear to effectively prevent occurrence of AF in patients with systolic HF.
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac
arrhythmia found in clinical practice. Its prevalence dramatically increases with age.1 Chronic heart failure (HF)
predisposes to AF, and data from the Framingham study indicated that chronic HF was associated with a 4.5 to 6-fold risk
of AF for men and women.1
In congestive HF (CHF) patients, the presence of AF leads
to increased morbidity and mortality.2,3 In addition, AF
causes a significant economic burden which has grown in
the past decades and is expected to grow even further in
the upcoming period.4,5 The treatment of AF relies traditionally on two different strategies: rhythm or rate
control. Many studies have shown no difference between
the two strategies.6 Interestingly, there was a trend favouring rhythm control in patients with pre-existing HF.7
Preventing primary onset of AF could be an important goal
to decrease its burden on CHF patients and to eliminate the
need for potentially harmful agents (both antiarrhythmics
and anticoagulations). Thus, there is some evidence to
suggest that both ACE-inhibitors and angiotensin receptor
* Corresponding author. Tel: þ331 49095626; fax: þ331 49095344.
E-mail address: imad.abi-nasr@apr.aphp.fr
blockers prevent or delay onset of AF, with a greatest
benefit on patients with HF.8
Beta-blockers reduce morbidity and mortality in patients
with HF.9–11 The mechanisms of these benefits are still disputed but may involve prevention of AF. Only one randomized trial suggests such an effect; recent post hoc analyses
from the CAPRICORN trial indicated that an early treatment
with carvedilol reduced the incidence of atrial arrhythmias
following myocardial infarction in patients with LV systolic
dysfunction.12 It is not known whether beta-blockers,
added to ACE-inhibitor treatment, will further reduce AF
occurrence in chronic HF patients.
A systematic review of published and unpublished data is
timely and could allow estimating the effectiveness of betablockers to prevent chronic HF-related AF.
Methods
Literature search
The search was performed in accordance with the recommendations
of the Cochrane collaboration using Cochrane CENTRAL database
and PubMed. The initial search terms were ‘beta-blocker’, the individual name of all drugs used for CHF in this class, and ‘AF’. The
search was limited to randomized, controlled clinical trials and
English-language publications. Additional publications were sought
& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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KEYWORDS
458
I. Abi Nasr et al.
using the reference lists of identified papers, the published reviews
on the topic, and a manual search of abstracts from the scientific
sessions of the American College of Cardiology, the American
Heart Association, and the European Society of Cardiology. The
result sections and tables of these studies were then examined to
see whether data on AF at baseline and during follow-up were
reported. Attempts were made to contact authors of beta-blocker
trials that did not report AF incidence.
Two reviewers (I.A. and A.B.) then independently evaluated
identified titles, and manuscripts were retrieved for any publication
that either reviewer felt was potentially relevant.
Two blinded reviewers re-evaluated all of the abstracts and manuscripts identified as potentially relevant, and publications were
selected for this review. Relevant study data were independently
abstracted, in duplicate, using a standardized form. Discrepancies
during data abstraction were resolved by consensus.
Inclusion criteria for studies
Primary outcome
Primary outcome for comparison was the number of patients with
occurrence of AF during follow-up among those with sinus rhythm
at baseline.
Cardiac atrial arrhythmias were not a pre-specified endpoint in
the different trials included. Arrhythmias were identified and
characterized according to the adverse event reports. Indeed, AF
onset was notified in each trial as an adverse event notified by investigators and blindly assessed by independent committee of critical
event in these large-scale trials (except for the Waagstein trial).
The meta-analysis was performed using the relative risk (RR) as parameter of efficacy with a fixed effect model. Different techniques
were used: the combined logarithm of the RR, Mantel–Haenszel,
Greenland–Robins, and Peto. The results obtained from the different methods were very similar, and therefore only the results
from the combined logarithm of the RR with the corresponding
95% confidence interval (CI) are presented in this article. A x 2
association and x 2 heterogeneity tests were performed. P-value
for significance of association and heterogeneity tests was set,
respectively, at 0.05 and 0.10. Graphic representation of RR and
their 95% CI were performed with use of linear scale.
For robustness, the analysis was realized by adding studies for
which no effect is obtained (RR ¼ 1) and whose size and risk in
the control group are equal to the average of the values obtained
in the included trials.
The statistical analysis for the meta-analysis was performed using
EASYMA software.
Results
Identified studies
Our database search identified a total of 26 randomized,
controlled, double-blind human trials since 1985 comparing
beta-blockers with placebo in the field of HF, representing a
total of 19 170 patients. Ten of them were performed with
carvedilol,12–21 seven with metoprolol,11,22–27 four
with bucindolol,28–31 three with nebivolol,32–34 and two
with bisoprolol.9,35 Among these trials, seven studies
provided information on the number of patients with occurrence of AF during follow-up and were included in the
meta-analysis. The characteristics of studies included are
summarized in Tables 1 and 2. There were 13 715 patients
in the identified studies. After exclusion of patients on AF
Table 1 Characteristics of studies included, with drugs
Author/study, year
Drug
Number of patients
Mean age (years)
Follow-up (years)
Aetiology of HF
Mean LVEF(%)
CIBIS I,35 1994
MERIT HF,11 1999
BEST,31 2001
COPERNICUS,47 2002
Waagstein,26 2003
SENIORS,34 2004
CAPRICORN,12 2005
Bisoprolol
Metoprolol
Bucindolol
Carvedilol
Metoprolol
Nebivolol
Carvedilol
641
3991
2708
2289
169
2128
1789
60
64
60
63
57
76
63
2
1
2
0.9
0.5
1.8
1.3
CAD/DCM
CAD/DCM
CAD/DCM
CAD/DCM
CAD/DCM
CAD/DCM
CAD
25
28
23
20
28
36
33
a
CAD, coronary artery disease; DCM, idiopathic dilated cardiomyopathy.
Table 2 Characteristics of studies included, for the placebo and beta-blockers groups
Author/study, date
Rate of AF at
baseline (%)
NYHA class
ACE-I or ARB,
placebo group (%)
ACE-I or ARB, betablockers group (%)
CIBIS I,35 1994
MERIT HF,11 1999
BEST,31 2001
COPERNICUS,47 2002
Waagstein,26 2003
SENIORS,34 2004
CAPRICORN,12 2005
13
16
11
NA
0
35
9
III–IV
II–IV
III–IV
IV
II–III
I–IV
NA
91
90
91
97
75
88
97
89
89
91
97
76
90
98
ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor antagonists; NA, not applicable.
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Studies were included only if they met all of the following criteria:
(i) randomized, controlled trials with parallel design; (ii) comparing
beta-blockers with placebo; (iii) including patients with CHF; and
(iv) providing adequate data on AF incidence during follow-up. For
each trial analysis, patients with AF at baseline were excluded.
The results of all studies included in this meta-analysis for were
post hoc analyses and not specifically intended for AF evaluation.
Statistical methods
Prevention of AF onset by beta-blocker treatment
459
Table 3 Incidence of onset of AF in each trial in HF
Data source
Beta-blockers (events/
number of patients)
Placebo (events/
number of patients)
Weight (%)
RR (95% CI)
CIBIS I35(bisoprolol)a
MERIT HF (metoprolol)48
BEST (bucindolol)31
COPERNICUS (carvedilol)47
Waagstein (metoprolol)26
SENIORS (nebivolol)34
CAPRICORN (carvedilol)12
Total
9/280
33/1677
78/1208
12/1156
1/86
78/706
16/894
227/6007 (3.8%)
13/276
54/1681
111/1197
22/1133
8/79
74/684
31/895
313/5944 (5.3%)
4
15
36
5.7
0.7
30.8
7.8
100
0.68 (0.29–1.57)
0.61 (0.39–0.94)
0.69 (0.52–0.92)
0.53 (0.26–1.07)
0.11 (0.01–0.89)
1.02 (0.75–1.37)
0.51 (0.28–0.93)
0.73 (0.61–0.86)
a
Complementary data from the investigators.
at baseline, data from 11 952 patients were used for the
analysis.
During an average follow-up of 1.35 years, the incidence of
AF was 28 per 1000 patient-years in the beta-blockers arm
and 39 per 1000 patient-years in the placebo arm, with,
respectively, 227 and 313 events.
Beta-blockers significantly reduced incidence of onset of
AF (Table 3, Figure 1) with an RR reduction of 27% (95% CI
14–38, P , 0.001). There were differences in treatment
effect between individual trials, as indicated by the statistical test of heterogeneity (P ¼ 0.096). These beneficial
effects are added to those of ACE-inhibitors and angiotensin
receptor blockers, since 90% of the patients received this
background treatment as well in the placebo group and in
the beta-blockers group (Table 2).
The robustness analysis showed that more than 18 trials
(including more than 800 patients by trial) had to be
added to obtain a non-significant result of the meta-analysis
for the primary endpoint.
Statistical test of heterogeneity shows significant difference in the treatment effect (P ¼ 0.096). A same trend of
efficacy was observed in all trials except the SENIORS
study. Absence of nebivolol effect in the SENIORS trial is
responsible for this finding, since the withdrawal of the
study suppresses such heterogeneity (P ¼ 0.58). This trial
included older patients (.70 years) and was the only one
to include diastolic HF. In addition, we observe in the
SENIORS trial a higher prevalence of AF at baseline (35%)
compared with the mean baseline prevalence of 13% in the
others (11–15%).
Furthermore, we performed an effect model analysis
comparing annual incidence on AF onset between the two
groups (with or without beta-blockers) and excluding the
SENIORS study. It shows, with trials having studied similar
patients, a multiplicative model which means that the beneficial effect of beta-blockers is constant whatever baseline
risk evaluated with the annual incidence of AF in the
placebo groups (Figure 2). The weight of the Waagstein
et al. 26 trial is relatively small, which explains the position
of the regression line close to the largest trials.
Subgroup analysis according to the pharmacological
profile of drugs (Figure 3) showed an RR reduction of 17%
(95% CI 4–35) of the AF occurrence with selective compounds (metoprolol, nebivolol, and bisoprolol); however,
Figure 1 Prevention of AF with beta-blockers in HF.
Figure 2 Analysis of the effect model.
this reduction was not significant (P ¼ 0.11). When SENIORS
is withdrawn from this subgroup, the reduction becomes significant (RR reduction ¼ 41%; P ¼ 0.006; Figure 4) and similar
to that obtained with non-selective beta-blockers. Nonselective beta-blockers (bucindolol, carvedilol) showed a
significant RR reduction of 36% (95% CI 18–49, P , 0.001).
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Primary prevention of AF
460
I. Abi Nasr et al.
While considering pharmacological profile, the benefit of
beta-blocker therapy seems to be similar with selective
and non-selective beta-blockers when the SENIORS study is
excluded from the analysis. The old age of included
patients, the higher prevalence of AF at baseline, and the
high proportion (one-third) of patients with diastolic HF
may partly explain the absence of effect of nebivolol in
SENIORS.
In the other trials, beta-blocker therapy provides an
additional benefit to that already induced with ACEinhibitors and ARB since meta-analysis of Healey et al. 8
demonstrated that they both reduce the risk of occurrence
of AF by 28%.
Figure 4 Results on AF onset according to beta-blocker cardioselectivity
after exclusion of SENIORS trial from selective subgroup.
The study of the heterogeneity between the two groups did
not find any significant difference (P ¼ 0.15).
Discussion
This meta-analysis based on seven randomized, placebocontrolled trials and including .70% of the total patients’
population having taken part in HF studies with betablockers indicates that this therapy is effective in preventing the development of AF in HF whatever baseline risk.
These results are highly significant, and the robustness
analysis makes unlikely the possibility of publication bias,
owing to unpublished neutral trials.
Among the large-scale trials realized in the field of HF,
CIBIS II9(not included in this meta-analysis) provided
additional data on hospitalizations related to supraventricular arrhythmias (most often AF) showing a trend (although
non-significant) towards the reduction of such hospitalizations from 2.5% in the placebo group to 1.7% in the betablocker group.
Clinical implications
Beta-blockers generally have not been considered to be
atrial-stabilizing agents except in few well-defined situations. First, a small population of patients with adrenergically mediated AF associated with stress or anxiety37; these
patients may well respond to beta-blockade. Secondly, and
more common, is the use of beta-blockers in prevention of
AF for patients following cardiothoracic surgery, in which
AF occurs in 30% of patients.44 Kuhlkamp et al. 45 demonstrated in a third situation, a significant although small
effect in reducing relapse rates of AF following cardioversion, although the majority of patients did not suffer from
HF. But these results suggest especially that the preventive
effect cannot be solely attributed to a better control of
the underlying cardiac disease.
Quinidine, disopyramide, flecaı̈nide, propafenone, D,Lsotalol, and amiodarone have all shown efficacy in reducing AF
recurrence in patients with paroxysmal and/or persistent AF.
Unfortunately, these agents are associated with serious side
effects, and class I agents are classically contraindicated
among patients with LV dysfunction.
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Figure 3 Results on AF onset according to beta-blocker cardioselectivity.
Heterogeneity between subgroups not significant (P ¼ 0.15).
Mechanism of action
Although conventional beta-blockers do not possess atrial
stabilizing properties, there are several possible biological,
direct or indirect mechanisms by which they might reduce
the development of AF. They may prevent or improve
adverse ventricular remodelling with a consequent decrease
in LV and atrial end-diastolic pressure.36 Their antiarrhythmic effects could also be due to attenuation of the
actions of the sympathetic nervous system on automaticity
and conduction in the heart. Indeed, an increased sympathetic drive has been shown to induce atrial tachyarrhythmias.37 In addition, beta-adrenergic stimulation shortens
the action potential duration by increasing the magnitude
of Ik.38 In pacing-induced AF, shortening of the atrial refractoriness is thought to be an important mechanism by which
AF perpetuates itself.39 Furthermore, it has been shown
recently that the ultrarapid delayed rectifier K1 current
(IKUR) plays an important role in human atrial repolarization.40 An increase in IKUR decreases action potential duration, and it was shown that this current effect is reversed
by the addition of propranolol.41 Hence, there is evidence
from experimental observations that stimulation of adrenoceptors might facilitate the induction and perpetuation of
AF. Beta-blockers may also protect against AF by the prevention of atrial ischaemia42,43 and fibrosis in those with underlying ischaemic heart disease.
Prevention of AF onset by beta-blocker treatment
Our meta-analysis suggests that beta-blockers should be
used as the first-line agents on preventing occurrence or
recurrence of HF-related AF, with a similar and additional
benefit in comparison with ACE-inhibitors and Angiotensin II
receptor antagonists. It will be interesting to see the place
of beta-blocker therapy in the AF-CHF trial which is
ongoing.46 This trial compares rhythm and rate control strategies in patients with HF.
In addition to the different potential mechanisms of
beta-blockers-induced benefit in HF, our results show that
prevention of onset of AF could play an important role in
the overall reduction in mortality and morbidity in HF.
Limitations
Conclusion
Beta-blockers appear to effectively prevent occurrence of
AF in patients with systolic HF.
Conflict of interest: none declared.
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The trials included in this analysis were post hoc reports
of randomized trials designed to assess outcomes other
than AF.
In this meta-analysis, the presence of arrhythmia was
identified and characterized on the basis of adverse event
reports. It is possible that frequency of asymptomatic AF
may be underestimated, especially in the group taking betablocker, compared with the placebo group because of lower
ventricular rates.
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