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

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Abstract

Aims

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.

Conclusion

Our results suggest that the three beta-blockers investigated have similar effects on mortality amongst patients with CHF.

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References

  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

    Article  PubMed  Google 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):9–13

  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):2001–2007

  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

    Article  CAS  PubMed  Google 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):2793–2799

    Article  CAS  PubMed  Google 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):1295–1302

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1184–1191

    Article  CAS  PubMed  Google Scholar 

  11. Brophy JM, Joseph L, Rouleau JL (2001) Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 134(7):550–560

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google 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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):1127–1134

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google 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

  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

    Article  CAS  PubMed  Google Scholar 

  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):461–470

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):31–37

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rosenbaum PR (2002) Observational studies, 2nd edn. Springer, Heidelberg

    Book  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google 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

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Angiology and Pulmology, University Hospital Heidelberg, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Hanna Fröhlich, Lorella Torres, Tobias Täger, Dieter Schellberg, Anna Corletto, Hugo A. Katus & Lutz Frankenstein

  2. Castle Hill Hospital, Hull York Medical School, Hull, UK

    Syed Kazmi & Andrew L. Clark

  3. Medical Department, Innlandet Hospital Trust Division Lillehammer, Lillehammer, Norway

    Morten Grundtvig

  4. Medical Faculty, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Torstein Hole

  5. Medical Clinic, Helse Møre and Romsdal HF, Ålesund, Norway

    Torstein Hole

  6. National Heart and Lung Institute, Royal Brompton, Harefield Hospitals, Imperial College, London, UK

    John G. F. Cleland

  7. Robertson Centre for Biostatistics & Clinical Trials, Glasgow, UK

    John G. F. Cleland

  8. Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway

    Dan Atar & Stefan Agewall

  9. Hull York Medical School, University of Hull, Hull, UK

    Kevin Goode

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  1. Hanna Fröhlich
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  2. Lorella Torres
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Correspondence to Lutz Frankenstein.

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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.

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Fröhlich, H., Torres, L., Täger, T. et al. Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure. Clin Res Cardiol 106, 711–721 (2017). https://doi.org/10.1007/s00392-017-1115-0

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