Clinical Research in Cardiology

, Volume 106, Issue 9, pp 711–721 | Cite as

Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure

  • Hanna Fröhlich
  • Lorella Torres
  • Tobias Täger
  • Dieter Schellberg
  • Anna Corletto
  • Syed Kazmi
  • Kevin Goode
  • Morten Grundtvig
  • Torstein Hole
  • Hugo A. Katus
  • John G. F. Cleland
  • Dan Atar
  • Andrew L. Clark
  • Stefan Agewall
  • Lutz FrankensteinEmail author
Original Paper



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.


Beta-blocker Heart failure with reduced ejection fraction Survival Effectiveness 


Compliance with ethical standards

Funding sources

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.

Informed consent

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. 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. 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. 3.
    The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial (1999). Lancet 353 (9146):9–13Google Scholar
  4. 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. 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. 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. 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. 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
  9. 9.
    Baker JG (2010) The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol 160(5):1048–1061. doi: 10.1111/j.1476-5381.2010.00754.x CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP (1998) Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 98(12):1184–1191CrossRefPubMedGoogle Scholar
  11. 11.
    Brophy JM, Joseph L, Rouleau JL (2001) Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 134(7):550–560CrossRefPubMedGoogle Scholar
  12. 12.
    Chatterjee S, Biondi-Zoccai G, Abbate A, D’Ascenzo F, Castagno D, Van Tassell B, Mukherjee D, Lichstein E (2013) Benefits of beta blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ 346:f55. doi: 10.1136/bmj.f55 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O’Keefe JH (2013) Meta-analysis of carvedilol versus beta 1 selective beta-blockers (atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol 111(5):765–769. doi: 10.1016/j.amjcard.2012.11.031 CrossRefPubMedGoogle Scholar
  14. 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. 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
  16. 16.
    Lazarus DL, Jackevicius CA, Behlouli H, Johansen H, Pilote L (2011) Population-based analysis of class effect of beta blockers in heart failure. Am J Cardiol 107(8):1196–1202. doi: 10.1016/j.amjcard.2010.12.017 CrossRefPubMedGoogle Scholar
  17. 17.
    Pasternak B, Svanstrom H, Melbye M, Hviid A (2014) Association of treatment with carvedilol vs metoprolol succinate and mortality in patients with heart failure. JAMA Intern Med 174(10):1597–1604. doi: 10.1001/jamainternmed.2014.3258 CrossRefPubMedGoogle Scholar
  18. 18.
    Konishi M, Haraguchi G, Kimura S, Inagaki H, Kawabata M, Hachiya H, Hirao K, Isobe M (2010) Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure. Circ J 74(6):1127–1134CrossRefPubMedGoogle Scholar
  19. 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
  20. 20.
    Shore S, Aggarwal V, Zolty R (2012) Carvedilol or sustained-release metoprolol for congestive heart failure: a comparative effectiveness analysis. J Cardiac Fail 18(12):919–924. doi: 10.1016/j.cardfail.2012.10.016 CrossRefGoogle Scholar
  21. 21.
    Pasternak B, Mattsson A, Svanstrom H, Hviid A (2015) Comparative effectiveness of bisoprolol and metoprolol succinate in patients with heart failure. Int J Cardiol 190:4–6. doi: 10.1016/j.ijcard.2015.03.441 CrossRefPubMedGoogle Scholar
  22. 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
  23. 23.
    Briasoulis A, Palla M, Afonso L (2015) Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. Am J Cardiol 115(8):1111–1115. doi: 10.1016/j.amjcard.2015.01.545 CrossRefPubMedGoogle Scholar
  24. 24.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470CrossRefPubMedGoogle Scholar
  25. 25.
    Austin PC (2009) Some methods of propensity-score matching had superior performance to others: results of an empirical investigation and Monte Carlo simulations. Biom J 51(1):171–184. doi: 10.1002/bimj.200810488 CrossRefPubMedGoogle Scholar
  26. 26.
    Kveiborg B, Major-Petersen A, Christiansen B, Torp-Pedersen C (2007) Carvedilol in the treatment of chronic heart failure: lessons from the Carvedilol Or Metoprolol European Trial. Vasc Health Risk Manag 3(1):31–37PubMedPubMedCentralGoogle Scholar
  27. 27.
    Rosenbaum PR (2002) Observational studies, 2nd edn. Springer, HeidelbergCrossRefGoogle Scholar
  28. 28.
    Love TE (2008) Spreadsheet-based sensitivity analysis calculations for matched samples. Center for Health Care Research & Policy.
  29. 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
  30. 30.
    Rienstra M, Damman K, Mulder BA, Van Gelder IC, McMurray JJ, Van Veldhuisen DJ (2013) Beta-blockers and outcome in heart failure and atrial fibrillation: a meta-analysis. JACC Heart Fail 1(1):21–28. doi: 10.1016/j.jchf.2012.09.002 CrossRefPubMedGoogle Scholar
  31. 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
  32. 32.
    Galatius S, Gustafsson F, Atar D, Hildebrandt PR (2004) Tolerability of beta-blocker initiation and titration with bisoprolol and carvedilol in congestive heart failure—a randomized comparison. Cardiology 102(3):160–165. doi: 10.1159/000080485 CrossRefPubMedGoogle Scholar
  33. 33.
    Maack C, Cremers B, Flesch M, Hoper A, Sudkamp M, Bohm M (2000) Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium. Br J Pharmacol 130(5):1131–1139. doi: 10.1038/sj.bjp.0703400 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Hanna Fröhlich
    • 1
  • Lorella Torres
    • 1
  • Tobias Täger
    • 1
  • Dieter Schellberg
    • 1
  • Anna Corletto
    • 1
  • Syed Kazmi
    • 2
  • Kevin Goode
    • 9
  • Morten Grundtvig
    • 3
  • Torstein Hole
    • 4
    • 5
  • Hugo A. Katus
    • 1
  • John G. F. Cleland
    • 6
    • 7
  • Dan Atar
    • 8
  • Andrew L. Clark
    • 2
  • Stefan Agewall
    • 8
  • Lutz Frankenstein
    • 1
    Email author
  1. 1.Department of Cardiology, Angiology and Pulmology, University Hospital HeidelbergUniversity of HeidelbergHeidelbergGermany
  2. 2.Castle Hill HospitalHull York Medical SchoolHullUK
  3. 3.Medical DepartmentInnlandet Hospital Trust Division LillehammerLillehammerNorway
  4. 4.Medical FacultyNorwegian University of Science and Technology (NTNU)TrondheimNorway
  5. 5.Medical ClinicHelse Møre and Romsdal HFÅlesundNorway
  6. 6.National Heart and Lung Institute, Royal BromptonHarefield Hospitals, Imperial CollegeLondonUK
  7. 7.Robertson Centre for Biostatistics & Clinical TrialsGlasgowUK
  8. 8.Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical SciencesUniversity of OsloOsloNorway
  9. 9.Hull York Medical SchoolUniversity of HullHullUK

Personalised recommendations