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 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 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. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 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). Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 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. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 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. References 1. Kannel WB, Wolf PA, Benjamin EJ, Levy D. 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