Meta-Analysis of Versus Beta 1 Selective Beta-Blockers (, , , and )

James J. DiNicolantonio, PharmDa,*, Carl J. Lavie, MDb,c, Hassan Fares, MDb, Arthur R. Menezes, MDb, and James H. O’Keefe, MDd

Because carvedilol is a unique vasodilating b blocker (BB) exerting antioxidant activity and pleiotropic effects, it was theorized that it may confer more potent beneficial effects on cardiovascular mortality and morbidity in acute (AMI) and (HF) settings. A systematic review and meta-analysis was performed of randomized, controlled, direct-comparison trials that included adults receiving atenolol, bisoprolol, metoprolol, nebivolol, or carvedilol to evaluate the effects of carvedilol compared to other BBs on mortality, cardiovascular events, and hospital readmissions in the setting of AMI or systolic HF. Compared to b1-selective BBs used in HF (8 trials, n [ 4,563), carvedilol significantly reduced all-cause mortality (risk ratio 0.85, 95% confidence interval 0.78 to 0.93, p [ 0.0006). In 3 trials of patients with AMI (n [ 644), carvedilol significantly reduced all-cause mortality by 45% (fixed-effects model: risk ratio 0.55, 95% confidence interval 0.32 to 0.94, p [ 0.03, random-effects model: risk ratio 0.56, 95% confidence interval 0.26 to 1.12, p = 0.10), with no reduction in non-fatal MI (risk ratio 0.61, 95% confidence interval 0.31 to 1.22, p [ 0.16). In conclusion, carvedilol, as compared against atenolol, bisoprolol, metoprolol and nebivolol in randomized direct comparison trials, significantly reduced all-cause mortality in systolic HF patients. Additionally, carvedilol significantly reduced all-cause mortality compared with b1-selective BBs in AMI patients using the fixed-effects model but not using the random-effects model. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111:765e769)

Although guidelines for the treatment of patients with systematic reviews of intervention studies was performed.4 acute coronary syndromes, acute myocardial infarctions Studies were identified through searches of the following (AMIs), and heart failure (HF) recommend the use of sources: Ovid MEDLINE (1977 to 2012), PubMed (1978 to b blockers (BBs) as first-line therapy, they do not specifi- 2011), and Embase (1977 to 2012). To identify further cally recommend 1 BB over another.1,2 However, carvedilol potentially relevant studies missed by the electronic data- has been shown to significantly reduce all-cause mortality base search, reference lists from identified trials and review and cardiovascular (CV) events (nonfatal and fatal reports were manually screened. Searches were restricted to and myocardial infarction [MI]) compared to metoprolol in patients with HF (in the Carvedilol or Metoprolol European Trial [COMET]).3 Thus, we sought to compare carvedilol against the most frequently prescribed b1-selective BBs (atenolol, metoprolol, and bisoprolol) and the most recently approved b1-selective BB (nebivolol) in patients with AMI or systolic HF.

Methods A systematic review of the available published research according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the conduct of

aWegmans Pharmacy, Ithaca, New York; bJohn Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, Louisiana; cPennington Biomedical Research Center, Baton Rouge, Louisiana; and dMid America Heart Insti- tute at Saint Luke’s Hospital, University of MissourieKansas City, Kansas City, Missouri. Manuscript received November 2, 2012; revised manuscript received and accepted November 12, 2012. See page 768 for disclosure information. *Corresponding author: Tel: 607-277-5750; fax: 607-277-5890. E-mail address: [email protected] (J.J. DiNicolantonio). Figure 1. Process for selecting included trials.

0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. www.ajconline.org http://dx.doi.org/10.1016/j.amjcard.2012.11.031 766 The American Journal of Cardiology (www.ajconline.org)

Figure 2. Forest plot of relative risk for all-cause mortality in patients with HF. the English language and were updated using automated heterogeneity, and I2 >50% denotes substantial heteroge- weekly e-mail alerts until August 2012. Full details of the neity.7 Two-tailed p values <0.05 were considered statisti- search strategies and excluded trials are available as cally significant for all analyses. Cochrane Review Manager appendices by request. version 5 software was used for all analyses. A sensitivity Studies were selected for inclusion on the basis of the analysis was conducted to account for different BBs in the following criteria: (1) study design: randomized controlled direct-comparison trials against carvedilol. trials, (2) type of participants: adults (aged 18 years), (3) intervention: carvedilol, (4) comparator: atenolol, bisopro- Results lol, metoprolol, or nebivolol, and (5) outcomes: all-cause mortality, CV events (fatal and nonfatal , fatal and The search of the published research yielded 1,105 titles, of nonfatal MI), and HF or CV-related hospital readmissions. which 40 were reviewed in full text on the basis of the We excluded studies that did not report mortality or inclusion criteria (Figure 1). Of these, 11 studies were deemed morbidity outcomes. The titles and abstracts of studies eligible for inclusion (Figure 1).3,8e17 Tables containing the identified by the search strategy were independently characteristics of the included studies are available by request. screened by 2 reviewers (J.J.D. and H.F.), and clearly All trials were randomized direct comparison trials irrelevant studies were discarded. against carvedilol in patients with either HF or AMI. All The following data elements were extracted from each background medications and baseline characteristics were study: the number of patients per arm, the nature of the statistically similar between the comparison groups in each intervention, patient inclusion criteria, cause of HF, type of trial, except for 3 trials: Mrdovic et al8 had significantly AMI index event (i.e. percentage noneST-segment eleva- more patients with hyperlipidemia at baseline in the carve- tion MI, percentage ST-segment elevation MI, percentage dilol group and older, more Killip class IV HF patients in unstable ), and baseline and follow-up blood pres- the metoprolol group; Jonsson et al9 had significantly more sure, ejection fraction, and heart rate (supplemental tables atenolol patients being female and receiving intravenous are available by request). The following outcomes were also during treatment; and Marazzi et al10 had signifi- extracted from each trial: all-cause mortality, CV events cantly more baseline coronary artery disease or idiopathic (nonfatal and fatal stroke, nonfatal and fatal MI), and HF or dilated cardiomyopathy patients and higher baseline heart CV-related hospital readmissions. Quality assessment was rates in the carvedilol group but higher baseline systolic judged according to the following criteria: concealment of blood pressures and lower ejection fractions in the nebivolol treatment allocation; similarity of the 2 groups at baseline group. Trials enrolled a median of 150 patients (interquartile regarding prognostic factors and medication use; blinding of range 67 to 3.029) with a median follow-up period of outcome assessors, care providers, and patients; complete- 12 months (interquartile range 0.5 to 58). ness of follow-up; and intention-to-treat analysis (supple- Four studies scored well on the methodologic quality mental tables are available by request). Overall study quality indicators (supplemental tables with details are available by was quantified using the Jadad score.5 The data extraction request). Concealed allocation and blinding of 1 outcome and quality assessment was undertaken using a standardized assessment were stated in 3 and 5 of 11 trials, respectively. pro forma by 2 reviewers (H.F. and A.R.M.). Eight trials (n ¼ 4,563) reported on all-cause mortality in We express outcome results for each study as risk ratios patients with systolic HF. There was a significant decrease (RRs) with 95% confidence intervals (CIs). Summary esti- in mortality for carvedilol compared to b1-selective BBs mates were computed using a DerSimonian and Laird fixed (RR 0.85, 95% CI 0.78 to 0.93, p ¼ 0.0006, I2 ¼ 0%; and random-effects and fixed-effects meta-analysis model. Figure 2). The number needed to treat over the course of the We report pooled results as RRs and numbers needed to trials was 22 (95% CI 14 to 52). treat. Statistical heterogeneity across trials was estimated Three trials (n ¼ 644) reported on all-cause mortality in using the I2 statistic,6 where I2 <30% denotes low hetero- patients with AMI. There was a significant 45% reduction in 2 geneity, I ¼ 30% to 50% represents moderate all-cause mortality in patients on carvedilol vs. b1-selective Review/Carvedilol Versus b1 b Blockers 767

Figure 3. Forest plot of relative risk for all-cause mortality in patients with AMIs.

Figure 4. Forest plot of relative risk for nonfatal MI in patients with AMIs.

Figure 5. Forest plot of relative risk for HF readmissions in patients with HF.

BBs by using a fixed-effects model (RR 0.55, 95% CI 0.32 to Four HF trials compared metoprolol tartrate to carvedilol 0.94, p ¼ 0.03, Figure 3) but not by random-effects model (RR (n ¼ 3,376). Compared to metoprolol, carvedilol caused 0.56, 95% CI 0.26 to 1.12, p ¼ 0.10), I2 ¼ 10%. The number a significant reduction in all-cause mortality (RR 0.86, 95% CI needed to treat over the course of the trials was 21 (95% CI 11 0.78 to 0.94, p ¼ 0.001, I2 ¼ 0%). In the AMI setting, 2 direct- to 227). comparison trials (n ¼ 390) indicated no significant reduction Three trials (n ¼ 644) reported on nonfatal MI. For in all-cause mortality with carvedilol compared to metoprolol 2 patients taking carvedilol compared to b1-selective BBs, tartrate (RR 0.95, 95% CI 0.13 to 7.13, I ¼ 53%). However, there was no reduction in nonfatal MI (RR 0.61, 95% CI the study by Mrdovic et al,8 carrying approximately 86% of 0.31 to 1.22, p ¼ 0.16, I2 ¼ 0%; Figure 4). the weight for AMI mortality end points, indicated that car- Two trials (n ¼ 3,099) reported on HF readmissions. vedilol was associated with a significant 47% reduction in Compared to b1-selective BBs, there was no significant all-cause mortality (RR 0.53, 95% CI 0.29 to 0.94, p ¼ 0.02). benefit on reducing HF readmissions with carvedilol Two HF trials compared nebivolol to carvedilol (n ¼ (RR 0.98, 95% CI 0.93 to 1.03, p ¼ 0.45) I2 ¼ 0%; (Figure 5). 230). Compared to nebivolol, carvedilol was not associated Only 1 trial (n ¼ 232) compared atenolol to carvedilol in with a reduction in all-cause mortality (RR 0.80, 95% CI patients with AMI.9 Compared to atenolol, carvedilol did 0.22 to 2.91, p ¼ 0.73, I2 ¼ 0%).10,17 not reduce all-cause mortality, although the small sample fi size may have rendered this nonsigni cant (RR 0.39, 95% Discussion CI 0.08 to 1.95, p ¼ 0.25). Two trials in patients with HF (n ¼ 957) were performed In this systematic review of 11 randomized controlled with bisoprolol versus carvedilol. Compared to bisoprolol, trials in 5,207 patients, we found that carvedilol significantly carvedilol did not reduce all-cause mortality (RR 0.54, 95% reduced all-cause mortality in patients with HF. Addition- CI 0.22 to 1.34, p ¼ 0.19, I2 ¼ 0%).11,12 ally, in patients with AMI, carvedilol significantly reduced 768 The American Journal of Cardiology (www.ajconline.org)

all-cause mortality by fixed-effects model (but not by Furthermore, b1-selective BBs upregulate b1 receptor random-effects model) but did not reduce nonfatal MI density and increase b1 receptor sensitivity to compared to other commonly prescribed BBs, although stimulation; this has not been seen with carvedilol.22 carvedilol did demonstrate trends for reducing this end Missing doses of b1-selective BBs has been associated with point. The preferential reduction in mortality with carvedilol a significant increase in death (due to sudden cardiac death in HF, however, was not associated with a significant and HF), which may be caused by rebound tachycardia, reduction in HF hospital readmission compared to the other leading to deterioration in patients with HF.27 BBs, suggesting a discordant relative effect of these agents In summary, improvements in ejection fraction, symp- on mortality versus overall cardiac compensation. tomatic functional class, stroke volume, stroke work, cardiac The potential mechanisms responsible for the observed output, insulin sensitivity, and adrenergic activity with car- beneficial impact of carvedilol compared to other BBs may in vedilol, along with a potential increase in the risk for death part be established through carvedilol’s pleiotropic effects with b1-selective BBs if strict compliance is not followed, (antioxidant and vasodilating), which are not shared by the all may contribute to the overall morbidity and mortality commonly prescribed b1-selective BBs (i.e., atenolol, meto- benefits noted with carvedilol compared to b1-selective BBs. prolol, and bisoprolol). Compared to metoprolol, carvedilol has These findings suggest that carvedilol reduces all-cause been shown in 2 randomized, direct-comparison trials to mortality compared to b1-selective BBs in systolic HF patients significantly reduce atrial fibrillation after coronary artery and in patients with AMIs. Although current guidelines for the bypass graft surgery.18,19 Moreover, in the Carvedilol Post treatment of patients with HF and acute coronary syndromes Infarction Survival Control in Left Ventricular Dysfunction or AMIs do not recommend 1 BB over another,1,2 substantial (CAPRICORN) trial, carvedilol caused a 76% reduction in evidence, discussed previously, appears to favor carvedilol in (, fibrillation, or flutter; the settings of ischemic heart disease, particularly systolic HF. p <0.0001), a 52% reduction in supraventricular arrhythmias Although a large, randomized, multicenter trial is required to (p ¼ 0.0015), and a 26% reduction in sudden cardiac death (p ¼ confirm the results of this meta-analysis in patients with AMI, 0.098) compared to placebo.20 Thus, carvedilol appears to have COMET has confirmed carvedilol’sefficacy over metoprolol significant antiarrhythmic effects, which may not be as prom- in patients with systolic HF.3 Thus, clearly for patients with inent in b1-selective BBs. This would potentially lead to better systolic HF, carvedilol should be considered the BB of first reductions in sudden cardiac death and all-cause mortality in choice. Atenolol has not been shown to improve long-term patients with AMIs and those with HF. In fact, sudden cardiac CV prognosis after AMI, nor has it been shown to be effective death was significantly reduced with carvedilol compared to for improving outcomes in patients with HF.28 Additionally, metoprolol in the COMET trial (218 vs 262, hazard ratio 0.81, when used for , atenolol does not protect against 95% CI 0.68 to 0.97, p ¼ 0.02).21 Moreover, in a meta-analysis heart disease or reduce mortality despite lowering elevated of >2,000 patients with HF (encompassing 19 randomized blood pressure.29 The fact that atenolol continues to be 1 of trials), carvedilol significantly increased left ventricular most widely prescribed BBs (presumably because of habit) is systolic function more so than metoprolol.22 In the setting of indefensible from a scientific perspective. 23 HF, the b2 receptors in the heart are upregulated, and thus the Several important potential study limitations should use of a b1-selective BB may not adequately protect the be considered. First, not all of the trials included in our myocardium from excessive adrenergic tone. Carvedilol is meta-analysis were double blind (n ¼ 3), with 4 of the 11 a potent BB that blocks b1, b2,anda receptors in the heart and included trials being rated as moderate or good in quality thereby confers comprehensive adrenergic blockade, which (i.e., Jadad score 3 of 5). Second, most trials included may be especially advantageous for patients with HF or AMI. relatively small numbers of patients, with the exception Carvedilol lowers blood pressure mainly through vasodi- of COMET (n ¼ 3,029), which contributed approximately lation, whereas b1-selective BBs do so by a reduction in 94% of mortality events in the HF trials. In particular, cardiac output (an untoward effect in patients with HF).24 our meta-analysis may have been underpowered in patients Improved versus reduced cardiac output may allow carvedilol with AMIs to differentiate the relative benefits of carvedilol to improve insulin sensitivity, whereas atenolol and meto- compared to the other b1-selective BBs. Nevertheless, prolol worsen insulin sensitivity.24 In the COMET study, even in the patients with AMIs (n ¼ 644), significance in carvedilol, compared to metoprolol, reduced the risk for favor of carvedilol therapy was present. Moreover, all “hard new diabetes development over the 5-year study by 22% outcomes” showed minimal heterogeneity among trials, (p ¼ 0.048)3. In contrast to metoprolol and atenolol, carvedilol mortality in HF (I2 ¼ 0%), mortality in AMI (I2 ¼ 10%) has a neutral or favorable effect on levels of triglycerides and and nonfatal MI (I2 ¼ 0%). Finally, as in most such meta- high-density lipoprotein cholesterol.25 Additionally, in the analyses, comparing several therapeutic agents, various Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol dosages of the individual agents were used, which is also Comparison in Hypertensives (GEMINI) randomized trial, typically present in clinical situations, and generally, these 40% fewer patients progressed to microalbuminuria in the different BBs provided similar reductions in rest heart rate, carvedilol arm than in the metoprolol arm.25 which generally indicates potential clinical efficacy. Moreover, carvedilol has been shown to reduce cardiac adrenergic activity, improve New York Heart Association Disclosures functional class, improve stroke work, and improve stroke volume compared to atenolol and metoprolol.22,24 Addi- Dr. Lavie has served as a consultant and speaker for tionally carvedilol exerts favorable effects on cardiac output GlaxoSmithKline, London, United Kingdom (but not compared to the other standard nonvasodilating BBs.26 regarding b blockers). Dr. O’Keefe is a speaker for Review/Carvedilol Versus b1 b Blockers 769

GlaxoSmithKline and Forest Pharmaceuticals, St. Louis, 13. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L. Missouri. Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term e Supplementary Data effects of metoprolol versus carvedilol. Circulation 2000;102:546 551. 14. Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C, Ocampo ON, Eng C. Prospective, randomized comparison of effect of Supplementary data related with this article can be found, in long-term treatment with metoprolol or carvedilol on symptoms, the on-line version, at http://dx.doi.org/10.1016/j.amjcard. exercise, ejection fraction, and oxidative stress in heart failure. 2012.11.031 Circulation 1999;99:2645e2651. 15. Piccirillo G, Quaglione R, Nocco M, Naso C, Moise A, Lionetti M, Di 1. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Carlo S, Marigliano V. Effects of long-term beta-blocker (metoprolol Alonso-Coello P, Akl EA, Lansberg MG, Guyatt GH, Spencer FA. or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol 2002;90: Primary and secondary prevention of cardiovascular disease: antith- e rombotic therapy and prevention of thrombosis, 9th ed: American 1113 1117. College of Chest Physicians Evidence-Based Clinical Practice Guide- 16. Tolg R, Witt M, Schwarz B, Kurz T, Kurowski V, Hartmann F, Geist lines. Chest 2012;141:e637See668S. V, Richardt G. Comparison of carvedilol and metoprolol in patients with acute myocardial infarction undergoing primary coronary inter- 2. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats — e TG, Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson vention the PASSAT study. Clin Res Cardiol 2006;95:31 41. LW, Yancy CW. 2009 focused update: ACCF/AHA guidelines for the 17. Lombardo RM, Reina C, Abrignani MG, Rizzo PA, Braschi A, De diagnosis and management of heart failure in adults: a report of the Castro S. Effects of nebivolol versus carvedilol on left ventricular function in patients with chronic heart failure and reduced left ventric- American College of Cardiology Foundation/American Heart Associ- e ation Task Force on Practice Guidelines: developed in collaboration ular systolic function. Am J Cardiovasc Drugs 2006;6:259 263. 18. Acikel S, Bozbas H, Gultekin B, Aydinalp A, Saritas B, Bal U, Yildirir with the International Society for Heart and Lung Transplantation. fi Circulation 2009;119:1977e2016. A, Muderrisoglu H, Sezgin A, Ozin B. Comparison of the ef cacy of metoprolol and carvedilol for preventing atrial fibrillation after coro- 3. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, e Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Ped- nary bypass surgery. Int J Cardiol 2008;126:108 113. ersen C, Scherhag A, Skene A. Comparison of carvedilol and meto- 19. Haghjoo M, Saravi M, Hashemi MJ, Hosseini S, Givtaj N, Ghafar- inejad MH, Khamoushi AJ, Emkanjoo Z, Fazelifar AF, Alizadeh A, prolol on clinical outcomes in patients with chronic heart failure in the fi Carvedilol or Metoprolol European Trial (COMET): randomised Sadr-Ameli MA. Optimal beta-blocker for prevention of atrial bril- e lation after on-pump coronary artery bypass graft surgery: carvedilol controlled trial. Lancet 2003;362:7 13. e 4. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis versus metoprolol. Heart Rhythm 2007;4:1170 1174. JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA 20. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN rando- statement for reporting systematic reviews and meta-analyses of studies e that evaluate healthcare interventions: explanation and elaboration. mised trial. Lancet 2001;357:1385 1390. BMJ 2009;339:b2700. 21. Torp-Pedersen C, Poole-Wilson PA, Swedberg K, Cleland JG, Di 5. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan Lenarda A, Hanrath P, Komajda M, Lutiger B, Metra M, Remme WJ, DJ, McQuay HJ. Assessing the quality of reports of randomized clinical Scherhag A, Skene A. Effects of metoprolol and carvedilol on cause- e specific mortality and morbidity in patients with chronic heart failure— trials: is blinding necessary? Control Clin Trials 1996;17:1 12. e 6. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta- COMET. Am Heart J 2005;149:370 376. analysis. Stat Med 2002;21:1539e1558. 22. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, 7. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Interventions Version 5.0.0. Hoboken, New Jersey: John Wiley, 2008; e 633. Am Heart J 2001;141:899 907. 8. Mrdovic IB, Savic LZ, Perunicic JP, Asanin MR, Lasica RM, Jelena 23. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, MM, Matic MD, Vasiljevic ZM, Ostojic MC. Randomized active- Lohse MJ, Korchev YE, Harding SE, Gorelik J. Beta2- redistribution in heart failure changes cAMP compartmenta- controlled study comparing effects of treatment with carvedilol versus e metoprolol in patients with left ventricular dysfunction after acute tion. Science 2010;327:1653 1657. myocardial infarction. Am Heart J 2007;154:116e122. 24. Martsevich SY, Kutishenko NP, Deev AD, Oganov RG, Shalnova SA. 9. Jonsson G, Abdelnoor M, Muller C, Kjeldsen SE, Os I, Westheim A. Comparison of antihypertensive and metabolic effects of carvedilol and A comparison of the two beta-blockers carvedilol and atenolol on left metaprolol in hypertensive patients with overweight and obesity. ventricular ejection fraction and clinical endpoints after myocardial Camellia Trial. J Hyper 2010;28:e560. infarction. a single-centre, randomized study of 232 patients. Cardi- 25. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips ology 2005;103:148e155. RA, Raskin P, Wright JT Jr, Oakes R, Lukas MA, Anderson KM, Bell 10. Marazzi G, Volterrani M, Caminiti G, Iaia L, Massaro R, Vitale C, DS. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. Sposato B, Mercuro G, Rosano G. Comparative long term effects of e nebivolol and carvedilol in hypertensive heart failure patients. J Card JAMA 2004;292:2227 2236. Fail 2011;17:703e709. 26. Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, Lar- 11. Aygul N, Ozdemir K, Duzenli MA, Aygul MU. The comparative rabee P, Bristow MR. Comparative hemodynamic, left ventricular func- tional, and antiadrenergic effects of chronic treatment with metoprolol effects of long-term carvedilol versus bisoprolol therapy on QT e dispersion in patients with chronic heart failure. Cardiology 2009;112: versus carvedilol in the failing heart. Circulation 1996;94:2817 2825. 168e173. 27. Morimoto S, Shimizu K, Yamada K, Hiramitsu S, Hishida H. Can beta-blocker therapy be withdrawn from patients with dilated cardio- 12. Dungen HD, Apostolovic S, Inkrot S, Tahirovic E, Topper A, Mehrhof F, e Prettin C, Putnikovic B, Neskovic AN, Krotin M, Sakac D, Lainscak M, myopathy? Am Heart J 1999;138:456 459. Edelmann F, Wachter R, Rau T, Eschenhagen T, Doehner W, Anker SD, 28. Aursnes I, Osnes JB, Tvete IF, Gasemyr J, Natvig B. Does atenolol differ Waagstein F, Herrmann-Lingen C, Gelbrich G, Dietz R. Titration to from other beta-adrenergic blockers? BMC Clin Pharmacol 2007;7:4. 29. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is target dose of bisoprolol vs. carvedilol in elderly patients with heart e failure: the CIBIS-ELD trial. Eur J Heart Fail 2011;13:670e680. it a wise choice? Lancet 2004;364:1684 1689.