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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2015 Jun;15(Suppl 1):e6168 doi: 10.5867/medwave.2015.6168
Is carvedilol better than other beta-blockers for heart failure?
Carmen Rain, Gabriel Rada
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Abstract

There is wide consensus about the benefits of beta-blockers in systolic heart failure. However, it is not clear if one specific beta-blocker is superior to the others. Some guidelines favor three “evidence-based” beta-blockers (carvedilol, bisoprolol and metoprolol) that have proved to decrease mortality. Carvedilol might have different physiological properties, commonly referred as pleiotropic effects, but the clinical meaning of them is not clear.


 
Problem

Beta-blockers constitute standard treatment in heart failure with systolic dysfunction given their proven effect in morbidity and mortality. Some guidelines have recommended three “evidence-based beta-blockers” (carvedilol, bisoprolol and metoprolol) that have proved to decrease mortality in large trials. It has been postulated that carvedilol, a non-selective beta-blocker, would exhibit pleiotropic effects, such as increasing insulin-sensitivity, and vasodilator, antioxidant and antiarrhytmic effects, which might confer it superiority against the other beta-blockers. In the last years, nebivolol, a new beta-blocker with alleged pleiotropic effects has also been suggested as an option.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • There is little or no difference between carvedilol and bisoprolol or metoprolol in hospitalization risk, but carvedilol might decrease mortality compared to metoprolol or bisoprolol in patients with heart failure.
  • It is uncertain whether nebivolol increases or decreases hospitalization risk or mortality in comparison to carvedilol because the certainty of the evidence is very low.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found four systematic reviews [1-4] including 14 primary studies, reported in 15 articles [5-19], from which eight (reported in nine articles) correspond to randomized controlled trials pertinent to the question [5],[7],[9],[11-13],[15],[16],[19].

This table and the summary in general are based on the latter.

What types of patients were included

Average age between the studies ranged from 57 to 73 years. All studies considered heart failure of any etiology, except one [15] that restricted inclusion to ischemic heart failure.

All studies except one [5] only included patients with low ejection fraction, defined as < 45% in one [7], < 40% in two [11],[12] and < 35% in four [9],[13],[15],[16],[19].

What types of interventions were included

All studies evaluated carvedilol, compared to metoprolol in four studies [9],[13],[15],[16],[19],  bisoprolol in two [5], [7] and nebivolol in two [11],[12]. 

What types of outcomes were measured

All-Cause mortality, cardiovascular or sudden death, All-cause hospitalization, cardiovascular- or heart failure-cause hospitalization, non-fatal cardiovascular events, vital signs, quality of life, exercise tolerance, echocardiographic parameters, NYHA classification.
Summary of findings

The information on the effects of carvedilol is based on eight randomized trials [5],[7],[9],[11],[12],[13],[15],[16],[19]. All of them reported total mortality, three reported All-cause hospitalization [7],[12],[16],[19] and only one reported heart failure-related hospitalization [11].

1)      Carvedilol versus other “evidence-based” beta-blockers (bisoprolol, metoprolol)

 Six studies evaluated this comparison, including 4333 patients [5],[7],[9],[13],[15],[16],[19].

  • There is little or no difference between carvedilol and bisoprolol or metoprolol in hospitalization risk. The certainty of the evidence is high.
  • Carvedilol might decrease mortality compared to metoprolol or bisoprolol in patients with heart failure.  The certainty of the evidence is low.

2) Carvedilol versus nebivolol

Two studies evaluated this comparison, including 191 patients [11],[12].

  •  It is uncertain whether nebivolol increases or decreases mortality in comparison to carvedilol. The certainty of the evidence is very low.

Other considerations for decision-making

To whom this evidence does and does not apply
  • The studies included almost only patients with low ejection fraction heart failure, so the evidence presented only applies to this group. There is representation of all etiologies and severities of heart failure, without important exclusions.
  • This evidence does not apply to patients with airway reactivity, since the recommendation for these patients is to use a beta-1 selective beta-blocker.
  • There is one study that was excluded in our summary comparing carvedilol against betaxolol (BETACAR [8]). Its inclusion in the analysis of evidence-based beta-blockers gives a similar result (risk ratio 0.86 for mortality; 95% CI: 0.78 to 0.94). 
About the outcomes included in this summary
  • The outcomes presented are those considered critical for decision-making from clinician and patient perspective. Additionally, they are the same as in the main guidelines [20],[21],[22],[23]. 
Balance between benefits and risks, and certainty of the evidence
  • The main difference identified is carvedilol might decrease mortality compared to bisoprolol or metoprolol. Considering analysed beta-blockers have a similar safety profile it is reasonable to think carvedilol might have a favorable risk/benefit ratio. However, it is important to emphasize this is based on low certainty evidence.
Resource considerations
  • Using carvedilol is not more expensive than the alternative beta-blockers analysed in this summary. It might have a favorable cost/benefit ratio, but again, it is important to highlight this is based on low certainty evidence.

Differences between this summary and other sources
  • Our summary is in partial agreement with the identified systematic reviews, which conclude there is no difference between the different beta-blockers [2], or there might be superiority of carvedilol [1],[3],[4].
  • Our conclusions partially differ from the main guidelines, which recommend bisoprolol, metoprolol or carvedilol indistinctly [22],[23], or recommend any beta-blocker [20],[21].  All guidelines incorporate only a small proportion of the evidence identified.
Could this evidence change in the future?
  • There is a high probability that future evidence change what we know about the effects of carvedilol compared with alternative beta-blockers in heart failure because the certainty of the evidence is low.
  • There are at least two ongoing randomized trials that may provide relevant information [24],[25].
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Matrix of evidence

Follow the link to access the interactive version Carvedilol versus cardioselective betablockers or nebivolol for heart failure

 

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Matrix of evidence
Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Es indiscutido el beneficio de los betabloqueadores para pacientes con insuficiencia cardiaca con disfunción sistólica, sin embargo, no existe claridad sobre cuál de ellos es superior. Algunas guías clínicas han favorecido a tres de ellos (carvedilol, bisoprolol y metoprolol) por su probado beneficio en disminución de mortalidad. Carvedilol podría tener diversos efectos fisiológicos, normalmente llamados efectos pleiotrópicos, pero el real significado clínico de estos no está claro.

Authors: Carmen Rain[1], Gabriel Rada[1,2,3,4,5]

Affiliation:
[1] Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile
[2] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile
[3] GRADE working group
[4] The Cochrane Collaboration
[5] Fundación Epistemonikos

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Rain C, Rada G. Is carvedilol better than other beta-blockers for heart failure?. Medwave 2015 Jun;15(Suppl 1):e6168 doi: 10.5867/medwave.2015.6168

Publication date: 26/6/2015

PubMed record

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  1. Briasoulis A, Palla M, Afonso L. Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. Am J Cardiol. 2015 Apr 15;115(8):1111-5. | CrossRef | PubMed |
  2. Chatterjee S, Biondi-Zoccai G, Abbate A, D'Ascenzo F, Castagno D, Van Tassell B, et al. Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ. 2013 Jan 16;346:f55. | CrossRef | PubMed |
  3. de Peuter OR, Lussana F, Peters RJ, Büller HR, Kamphuisen PW. A systematic review of selective and non-selective beta blockers for prevention of vascular events in patients with acute coronary syndrome or heart failure. Neth J Med. 2009 Oct;67(9):284-94. | PubMed |
  4. DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. Meta-analysis of carvedilol versus beta 1 selective beta-blockers (atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol. 2013 Mar 1;111(5):765-9. | CrossRef | PubMed |
  5. Aygul N, Ozdemir K, Duzenli MA, Aygul MU. The comparative effects of long-term carvedilol versus bisoprolol therapy on QT dispersion in patients with chronic heart failure. Cardiology. 2009;112(3):168-73. | CrossRef | PubMed |
  6. Delea TE, Stanford R, Hagiwara M, Edelsberg JS, Oster G. Death and hospitalization in heart failure patients receiving carvedilol vs. metoprolol tartrate. Int J Cardiol. 2005 Mar 10;99(1):117-24. | PubMed |
  7. Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, et al. Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011 Jun;13(6):670-80. | CrossRef | PubMed |
  8. Figulla HR, Krzeminska-Pakula M, Wrabec K, Chochola J, Kalmbach C, Fridl P. Betaxolol is equivalent to carvedilol in patients with heart failure NYHA II or III: result of a randomized multicenter trial (BETACAR Trial). Int J Cardiol.2006 Nov 10;113(2):153-60. | PubMed |
  9. Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C, Ocampo ON, Eng C. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation. 1999 May 25;99(20):2645-51. | PubMed |
  10. Lazarus DL, Jackevicius CA, Behlouli H, Johansen H, Pilote L. Population-based analysis of class effect of β blockers in heart failure. Am J Cardiol. 2011 Apr 15;107(8):1196-202. | CrossRef | PubMed |
  11. Lombardo RM, Reina C, Abrignani MG, Rizzo PA, Braschi A, De Castro S. Effects of nebivolol versus carvedilol on left ventricular function in patients with chronic heart failure and reduced left ventricular systolic function. Am J Cardiovasc Drugs. 2006;6(4):259-63. | PubMed |
  12. Marazzi G, Volterrani M, Caminiti G, Iaia L, Massaro R, Vitale C, et al. Comparative long term effects of nebivolol and carvedilol in hypertensive heart failure patients. J Card Fail. 2011 Sep;17(9):703-9. | CrossRef | PubMed |
  13. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation. 2000 Aug 1;102(5):546-51. | PubMed |
  14. Pasternak B, Svanström H, Melbye M, Hviid A. Association of treatment with carvedilol vs metoprolol succinate and mortality in patients with heart failure. JAMA Intern Med. 2014 Oct;174(10):1597-604. | CrossRef | PubMed |
  15. Piccirillo G, Quaglione R, Nocco M, Naso C, Moisè A, Lionetti M, et al. Effects of long-term beta-blocker (metoprolol or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol. 2002 Nov 15;90(10):1113-7. | PubMed |
  16. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. 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. 2003 Jul 5;362(9377):7-13. | PubMed |
  17. Rector TS, Anand IS, Nelson DB, Ensrud KE. Carvedilol versus controlled-release metoprolol for elderly veterans with heart failure. J Am Geriatr Soc. 2008 Jun;56(6):1021-7. | CrossRef | PubMed |
  18. Shore S, Aggarwal V, Zolty R. Carvedilol or sustained-release metoprolol for congestive heart failure: a comparative effectiveness analysis. J Card Fail. 2012 Dec;18(12):919-24. | CrossRef | PubMed |
  19. Torp-Pedersen C, Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, et al. Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET. Am Heart J. 2005 Feb;149(2):370-6. | PubMed |
  20. Arnold JM, Liu P, Demers C, Dorian P, Giannetti N, Haddad H, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol. 2006 Jan;22(1):23-45. | PubMed |
  21. Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010 Jun;16(6):e1-194. | CrossRef | PubMed |
  22. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012 Jul;33(14):1787-847. | CrossRef | PubMed |
  23. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):1810-52. | CrossRef | PubMed |
  24. The Cardiac Insufficiency BIsoprolol Study in Japanese Patients With Chronic Heart Failure (CIBIS-J) 2014. [on line]. | Link |
  25. A Phase Ⅲ Study of Extended-Release Carvedilol Sulfate for the Treatment of Heart Failure. 2013 [on line]. | Link |
Briasoulis A, Palla M, Afonso L. Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. Am J Cardiol. 2015 Apr 15;115(8):1111-5. | CrossRef | PubMed |

Chatterjee S, Biondi-Zoccai G, Abbate A, D'Ascenzo F, Castagno D, Van Tassell B, et al. Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ. 2013 Jan 16;346:f55. | CrossRef | PubMed |

de Peuter OR, Lussana F, Peters RJ, Büller HR, Kamphuisen PW. A systematic review of selective and non-selective beta blockers for prevention of vascular events in patients with acute coronary syndrome or heart failure. Neth J Med. 2009 Oct;67(9):284-94. | PubMed |

DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. Meta-analysis of carvedilol versus beta 1 selective beta-blockers (atenolol, bisoprolol, metoprolol, and nebivolol). Am J Cardiol. 2013 Mar 1;111(5):765-9. | CrossRef | PubMed |

Aygul N, Ozdemir K, Duzenli MA, Aygul MU. The comparative effects of long-term carvedilol versus bisoprolol therapy on QT dispersion in patients with chronic heart failure. Cardiology. 2009;112(3):168-73. | CrossRef | PubMed |

Delea TE, Stanford R, Hagiwara M, Edelsberg JS, Oster G. Death and hospitalization in heart failure patients receiving carvedilol vs. metoprolol tartrate. Int J Cardiol. 2005 Mar 10;99(1):117-24. | PubMed |

Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, et al. Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011 Jun;13(6):670-80. | CrossRef | PubMed |

Figulla HR, Krzeminska-Pakula M, Wrabec K, Chochola J, Kalmbach C, Fridl P. Betaxolol is equivalent to carvedilol in patients with heart failure NYHA II or III: result of a randomized multicenter trial (BETACAR Trial). Int J Cardiol.2006 Nov 10;113(2):153-60. | PubMed |

Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C, Ocampo ON, Eng C. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation. 1999 May 25;99(20):2645-51. | PubMed |

Lazarus DL, Jackevicius CA, Behlouli H, Johansen H, Pilote L. Population-based analysis of class effect of β blockers in heart failure. Am J Cardiol. 2011 Apr 15;107(8):1196-202. | CrossRef | PubMed |

Lombardo RM, Reina C, Abrignani MG, Rizzo PA, Braschi A, De Castro S. Effects of nebivolol versus carvedilol on left ventricular function in patients with chronic heart failure and reduced left ventricular systolic function. Am J Cardiovasc Drugs. 2006;6(4):259-63. | PubMed |

Marazzi G, Volterrani M, Caminiti G, Iaia L, Massaro R, Vitale C, et al. Comparative long term effects of nebivolol and carvedilol in hypertensive heart failure patients. J Card Fail. 2011 Sep;17(9):703-9. | CrossRef | PubMed |

Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation. 2000 Aug 1;102(5):546-51. | PubMed |

Pasternak B, Svanström H, Melbye M, Hviid A. Association of treatment with carvedilol vs metoprolol succinate and mortality in patients with heart failure. JAMA Intern Med. 2014 Oct;174(10):1597-604. | CrossRef | PubMed |

Piccirillo G, Quaglione R, Nocco M, Naso C, Moisè A, Lionetti M, et al. Effects of long-term beta-blocker (metoprolol or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol. 2002 Nov 15;90(10):1113-7. | PubMed |

Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. 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. 2003 Jul 5;362(9377):7-13. | PubMed |

Rector TS, Anand IS, Nelson DB, Ensrud KE. Carvedilol versus controlled-release metoprolol for elderly veterans with heart failure. J Am Geriatr Soc. 2008 Jun;56(6):1021-7. | CrossRef | PubMed |

Shore S, Aggarwal V, Zolty R. Carvedilol or sustained-release metoprolol for congestive heart failure: a comparative effectiveness analysis. J Card Fail. 2012 Dec;18(12):919-24. | CrossRef | PubMed |

Torp-Pedersen C, Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, et al. Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET. Am Heart J. 2005 Feb;149(2):370-6. | PubMed |

Arnold JM, Liu P, Demers C, Dorian P, Giannetti N, Haddad H, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol. 2006 Jan;22(1):23-45. | PubMed |

Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010 Jun;16(6):e1-194. | CrossRef | PubMed |

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012 Jul;33(14):1787-847. | CrossRef | PubMed |

Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):1810-52. | CrossRef | PubMed |

The Cardiac Insufficiency BIsoprolol Study in Japanese Patients With Chronic Heart Failure (CIBIS-J) 2014. [on line]. | Link |

A Phase Ⅲ Study of Extended-Release Carvedilol Sulfate for the Treatment of Heart Failure. 2013 [on line]. | Link |

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