Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure
- 1.3k Downloads
Beta-blockers are recommended for the treatment of chronic heart failure (CHF). However, it is disputed whether beta-blockers exert a class effect or whether there are differences in efficacy between agents.
Methods and results
6010 out-patients with stable CHF and a reduced left ventricular ejection fraction prescribed either bisoprolol, carvedilol or metoprolol succinate were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and the respective propensity scores for beta-blocker treatment. During a follow-up of 26,963 patient-years, 302 (29.5%), 637 (37.0%), and 1232 (37.7%) patients died amongst those prescribed bisoprolol, carvedilol, and metoprolol, respectively. In univariable analysis of the general sample, bisoprolol and carvedilol were both associated with lower mortality as compared with metoprolol succinate (HR 0.80, 95% CI 0.71–0.91, p < 0.01, and HR 0.86, 95% CI 0.78–0.94, p < 0.01, respectively). Patients prescribed bisoprolol or carvedilol had similar mortality (HR 0.94, 95% CI 0.82–1.08, p = 0.37). However, there was no significant association between beta-blocker choice and all-cause mortality in any of the matched samples (HR 0.90; 95% CI 0.76–1.06; p = 0.20; HR 1.10, 95% CI 0.93–1.31, p = 0.24; and HR 1.08, 95% CI 0.95–1.22, p = 0.26 for bisoprolol vs. carvedilol, bisoprolol vs. metoprolol succinate, and carvedilol vs. metoprolol succinate, respectively). Results were confirmed in a number of important subgroups.
Our results suggest that the three beta-blockers investigated have similar effects on mortality amongst patients with CHF.
KeywordsBeta-blocker Heart failure with reduced ejection fraction Survival Effectiveness
Compliance with ethical standards
This work was supported from the AOK Baden-Württemberg, Germany, within the scope of the junior researcher’s academy “health care research Baden-Württemberg, Germany”.
Conflict of interest
The authors declare that they have no conflict of interest.
All patients gave their written informed consent for data storage and evaluation. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the local ethics committees. Patients’ data were pseudonymised for analyses.
- 1.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37(27):2129–2200. doi: 10.1093/eurheartj/ehw128 CrossRefPubMedGoogle Scholar
- 2.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C (2016) 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. doi: 10.1016/j.jacc.2016.05.011 Google Scholar
- 3.The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial (1999). Lancet 353 (9146):9–13Google Scholar
- 4.MERIT-HF investigators: effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) (1999). Lancet 353 (9169):2001–2007Google Scholar
- 5.Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334(21):1349–1355. doi: 10.1056/NEJM199605233342101 CrossRefPubMedGoogle Scholar
- 6.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 (1996) 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 94(11):2793–2799CrossRefPubMedGoogle Scholar
- 7.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 G (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344(22):1651–1658. doi: 10.1056/NEJM200105313442201
- 8.Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vitovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Janosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P (2000) Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA J Am Med Assoc 283(10):1295–1302CrossRefGoogle Scholar
- 14.Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A, Carvedilol Or Metoprolol European Trial I (2003) Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 362(9377):7–13. doi: 10.1016/S0140-6736(03)13800-7 CrossRefPubMedGoogle Scholar
- 15.Hori M, Nagai R, Izumi T, Matsuzaki M (2014) Efficacy and safety of bisoprolol fumarate compared with carvedilol in Japanese patients with chronic heart failure: results of the randomized, controlled, double-blind, Multistep Administration of bisoprolol IN Chronic Heart Failure II (MAIN-CHF II) study. Heart Vessels 29(2):238–247. doi: 10.1007/s00380-013-0340-3 CrossRefPubMedGoogle Scholar
- 19.Wikstrand J, Wedel H, Castagno D, McMurray JJ (2014) The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. J Intern Med 275(2):134–143. doi: 10.1111/joim.12141 CrossRefPubMedGoogle Scholar
- 22.Fröhlich H, Zhao J, Täger T, Cebola R, Schellberg D, Katus H, Grundtvig M, Hole T, Atar D, Agewall S, Frankenstein L (2015) Carvedilol compared to metoprolol succinate in the treatment and prognosis of patients with stable chronic heart failure. The Carvedilol or Metoprolol Evaluation Study (COMES). Circ Heart Fail. doi: 10.1161/CIRCHEARTFAILURE.114.001701
- 28.Love TE (2008) Spreadsheet-based sensitivity analysis calculations for matched samples. Center for Health Care Research & Policy. http://www.chrp.org/propensity
- 29.Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, Beta-Blockers in Heart Failure Collaborative G (2014) Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 384(9961):2235–2243. doi: 10.1016/S0140-6736(14)61373-8 CrossRefPubMedGoogle Scholar
- 31.Dungen HD, Apostolovic S, Inkrot S, Tahirovic E, Topper A, Mehrhof F, Prettin C, Putnikovic B, Neskovic AN, Krotin M, Sakac D, Lainscak M, Edelmann F, Wachter R, Rau T, Eschenhagen T, Doehner W, Anker SD, Waagstein F, Herrmann-Lingen C, Gelbrich G, Dietz R; Investigators C-E; Project Multicentre Trials in the Competence Network Heart F (2011) Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail 13(6):670–680. doi: 10.1093/eurjhf/hfr020
- 34.Maack C, Tyroller S, Schnabel P, Cremers B, Dabew E, Sudkamp M, Bohm M (2001) Characterization of beta(1)-selectivity, adrenoceptor-G(s)-protein interaction and inverse agonism of nebivolol in human myocardium. Br J Pharmacol 132(8):1817–1826. doi: 10.1038/sj.bjp.0703992 CrossRefPubMedPubMedCentralGoogle Scholar