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: [email protected] 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: [email protected] 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. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N–9N. 2. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91: 2D–8D. 3. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, D’Agostino RB, Murabito JM, Kannel WB, Benjamin EJ. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107:2920–2925. 4. Le Heuzey JY, Paziaud O, Piot O, Said MA, Copie X, Lavergne T, Guize L. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147:121–126. 5. Stewart S, Murphy N, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286–292. 6. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833. 7. Blackshear JL, Safford RE. AFFIRM RACE trials: implications for the management of atrial fibrillation. Card Electrophysiol Rev 2003;7:366–369. 8. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ. Prevention of atrial fibrillation with angiotensin-converting enzyme and angiotensin receptor blockers. J Am Coll Cardiol 2005;45: 1832–1839. 9. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. 10. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH, for the US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349–1355. 11. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007. 12. McMurray J, Kober L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, Remme W, Sharpe DN, Ford I. Antiarrhythmic effect of carvedilol after acute myocardial infarction. Results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) Trial. J Am Coll Cardiol 2005;45:525–530. 13. Australia–New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator–beta-blocker, in patients with congestive heart failure due to ischaemic heart disease. Circulation 1995;92: 212–218. 14. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD. Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995;92:1499–1506. 15. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996;94:2807–2816. 16. Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996;94:2793–2799. 17. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation 1996;94:2800–2806. 18. Cohn JN, Fowler MB, Bristow MR, Colucci WS, Gilbert EM, Kinhal V, Krueger SK, Lejemtel T, Narahara KA, Packer M, Young ST, Holcslaw TL, Lukas MA. Safety and efficacy of carvedilol in severe heart failure. The US Carvedilol Heart Failure Study Group. J Card Fail 1997;3:173–179. 19. Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;24:1678–1687. 20. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol 1995; 25:1225–1231. 21. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure (COPERNICUS). N Engl J Med 2001;344:1651–1658. 22. Engelmeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation 1985;72:536–546. 23. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441–1446. 24. Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol 1994; 23:943–950. 25. The RESOLVD Investigators. Effects of metoprolol CR in patients with ischaemic and dilated cardiomyopathy: the randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation 2000; 101:378–384. 26. Waagstein F, Stromblad O, Andersson B, Bohm M, Darius M, Delius W, Goss F, Osterziel KJ, Sigmund M, Trenkwalder SP, Wahlqvist I. Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischaemic or idiopathic dilated cardiomyopathy. Eur J Heart Fail 2003;5:679–691. 27. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, Hatfield BA, Marcoux LG, Malloy CR. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 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. 461 462 28. 29. 30. 31. 32. 33. 35. 36. 37. 38. cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1994;24:1310–1320. Bristow MR, O’Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P. Dose-response of chronic b-blocker treatment in heart failure from either idiopathic dilated or ischaemic cardiomyopathy. Bucindolol Investigators. Circulation 1994;89:1632–1642. Pollock SG, Lystash J, Tedesco C, Craddock G, Smucker ML. Usefulness of bucindolol in congestive heart failure. Am J Cardiol 1990;66:603–607. Woodley SL, Gilbert EM, Anderson JL, O’Connell JB, Deitchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R. Betablockade with bucindolol in heart failure caused by ischaemic versus idiopathic dilated cardiomyopathy. Circulation 1991;84:2426–2441. The BEST Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure (BEST). N Engl J Med 2001;344: 1659–1667. Lechat PB, Komajda M. Pilot study of cardiovascular effect of nebivolol in congestive heart failure. Drug Invest 1991;3:69–81. Wisenbaugh T, Katz I, Davis J, Essop R, Skoularigis J, Middlemost S, Rothlisberger C, Skudicky D, Sareli P. Long-term (3-month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol 1993;21:1094–1100. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, SolerSoler J, Tavazzi L, Spinarova L, Toman J, Bohm M, Anker SD, Thompson SG, Poole-Wilson PA, SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure. Eur Heart J 2005;26: 215–225. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765–1773. Kalifa J, Jalife J, Zaitsev AV, Bagwe S, Warren M, Moreno J, Berenfeld O, Nattel S. Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation 2003;108:668–671. Coumel P. Neural aspects of paroxysmal atrial fibrillation. In: Falk RH, Podrid PJ (eds). Atrial Fibrillation: Mechanisms and Management. New York: Raven Press; 1992. p109–125. Campbell DL, Rasmusson RL, Comer MB, Strauss HC. The cardiac calciumindependent outward potassium current: kinetics, molecular properties, and role in ventricular repolarization. In: Zipes DP, Jalife J (eds). Cardiac 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia: Saunders; 1995. p83–96. Daoud EG, Bogun F, Harvey M, Man C, Strickberger SA, Morady F. Effect of atrial fibrillation on atrial refractoriness in humans. Circulation 1996;94: 1600–1606. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward current in human atrial myocytes: evidence for a novel delayed rectifier K1 current similar to Kv1. 5 cloned channel currents. Circ Res 1993;73: 1061–1076. Li G-R, Feng J, Wang Z, Fermini B, Nattel S. Adrenergic modulation of ultrarapid delayed rectifier K1 current in human atrial myocytes. Circ Res 1996;78:903–915. Sinno H, Derakhchan K, Libersan D, Merhi Y, Leung TK, Nattel S. Atrial ischemia promotes atrial fibrillation in dogs. Circulation 2003;107: 1930–1936. Tjandrawidjaja MC, Fu Y, Kim DH, Burton JR, Lindholm L, Armstrong PW. CAPTORS II Investigators. Compromised atrial coronary anatomy is associated with atrial arrhythmias and atriventricular block complicating acute myocardial infarction. J Electrocardiol 2005;38:271–278. Prystowsky EN, Benson DW Jr, Fuster V, Hart RG, Kay GN, Myerburg RJ, Naccarelli GV, Wyse DG. AHA Medical/Scientific Statement Special Report: management of patients with atrial fibrillation: a statement for healthcare professionals from the Subcommittee on electrocardiography and electrophysiology, American Heart Association. Circulation 1996;93: 1262–1277. Kuhlkamp V, Schirdewan A, Stangl K, Homberg M, Matthias P, Beck OA. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized double blind placebo controlled study. J Am Coll Cardiol 2000;36:139–146. The AF-CHF investigators. Rationale and design of a study assessing treatment strategies of atrial fibrillation in patients with heart failure: the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial. Am Heart J 2002;144:197–607. Packer M, Fowler MB, DeMets DL. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002;106:2194–2199. Prakash C, Giles TD, Wikstrand J, on behalf of the MERIT-HF Study Group. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF. Am Heart J 2005;149:159–167. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 29, 2014 34. I. Abi Nasr et al.
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