Resúmenes Epistemonikos
Medwave 2015 Abr;15(3):e6129 doi: 10.5867/medwave.2015.03.6129
¿Tienen un rol los digitálicos en la insuficiencia cardíaca crónica?
Is there a role for digitalis in chronic heart failure?
Carmen Rain, Gabriel Rada
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Abstract

The main clinical guidelines recommend the use of digitalis for chronic heart failure when moderate to severe symptoms persist after standard therapy, even though there is controversy about its efficacy and security. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including 13 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of digitalis for chronic heart failure probably leads to little or no decrease in mortality, but might reduce hospitalizations and clinical deterioration. However, the certainty of the evidence is low.


 
Problem

Digitalis have been in use for treatment of heart failure for more than two centuries. However, their effects on heart failure are controversial. On one hand, they would improve symptoms and exercise tolerance. On the other hand, they might increase mortality, especially when there is underlying ischemic heart disease. Furthermore, they carry a high risk of adverse effects.

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

  • Use of digitalis in chronic heart failure might lead to little o no decrease in mortality. Nonetheless, they might lead to a reduction in hospitalizations and clinical deterioration.
  • The conclusions of this summary are in agreement with the systematic reviews identified and with the main guidelines.

About the body of evidence for this question

What is the evidence
(See evidence matrix  in Epistemonikos later)

We found three systematic reviews [1],[2],[3] including 13 randomized controlled trials that are reported in 15 articles [4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18].

What types of patients were included

All studies considered heart failure of any etiology, being the most frequent ischemic.

All studies included patients in sinus rhythm.

Only five studies included patients with reduced ejection fraction: < 45% [7],[18], < 40% [14] and < 35% [11],[16].

The average age was between 58 to 69 years in the different studies.

What types of interventions were included

All studies evaluated digoxin, eight using dose adjustments to reach a specific serum level [8],[9],[10],[11],[13],[14],[16],[17].

All studies compared against placebo.

What types of outcomes were measured

Total mortality or heart failure mortality; hospitalization for any cause or for heart failure, emergency room visits, clinical deterioration, quality of life, walking test, neurohumoral markers and echocardiographic parameters.

Summary of findings

The following information is based on 13 randomized trials that included 8,304 patients. Only eight studies reported total mortality. One study reported hospitalization by any cause, four reported hospitalization from heart failure and 12 reported clinical deterioration.

  • Use of digitalis in chronic heart failure might lead to little o no decrease in mortality. The certainty of the evidence is low.
  • Digitalis might lead to a reduction in hospitalization and clinical deterioration, but the certainty of the evidence is low.

Digitalis for chronic heart failure

Other considerations for decision-making

To whom this evidence does and does not apply

  • All studies included patients with heart failure in sinus rhythm with no restriction on etiology or ejection fraction, so the evidence can be applied to the totality of patients with this condition. 
 About the outcomes included in this summary
  • The outcomes presented in this summary are those considered critical for decision-making by the authors of this summary, and they agree with those used by the main clinical guidelines. 
 Balance between benefits and risks, and certainty of the evidence
  • With a low level of certainty, we can say it is an intervention that offers some benefits on hospitalization and clinical deterioration, but not on mortality. In some patients the benefit/risk balance might be in favor of the benefit, but it will not be favorable in others, like the elderly or other populations vulnerable to adverse effects, such as digitalis intoxication. 
  • Given that the balance will vary in different patients, and that the certainty of the evidence is low, it is particularly relevant to inform the patient and to promote share decision-making. 
 Resource considerations
  • Digitalis are inexpensive, and there is some benefit, so the cost/benefit ratio is probably favorable in most patients.
  • In patients at risk of adverse effects, the cost derived from complications can surpass the potential benefits. 

Differences between this summary and other sources

  • The conclusion of this summary agrees with the systematic reviews identified and with the main guidelines [19],[20],[21],[22].
Could this evidence change in the future?
  • It is highly likely that this evidence will change in the future, because the certainty of the evidence is low.
  • We did not identify ongoing studies, and the last one was conducted in 1997 [7], so it is unlikely that new evidence relevant for this question would appear in the future. 
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 Digitalis for chronic 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.

 

The main clinical guidelines recommend the use of digitalis for chronic heart failure when moderate to severe symptoms persist after standard therapy, even though there is controversy about its efficacy and security. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified three systematic reviews including 13 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of digitalis for chronic heart failure probably leads to little or no decrease in mortality, but might reduce hospitalizations and clinical deterioration. However, the certainty of the evidence is low.

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

Filiación:
[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

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63,
Santiago Centro
Chile

Citación: Rain C, Rada G. Is there a role for digitalis in chronic heart failure?. Medwave 2015 Abr;15(3):e6129 doi: 10.5867/medwave.2015.03.6129

Fecha de publicación: 27/4/2015

Ficha PubMed

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  1. Hood WB, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis. J Card Fail. 2004;10(2):155-64. | CrossRef | PubMed |
  2. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of heart failure in patients in sinus rhythm. Cochrane Database Syst Rev. 2014 Apr 28;4:CD002901. | CrossRef | PubMed |
  3. Jaeschke R, Oxman AD, Guyatt GH. To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis. Am J Med. 1990 Mar;88(3):279-86. | CrossRef | PubMed |
  4. Blackwood R, Mayou RA, Garnham JC, Armstrong C, Bryant B. Exercise capacity and quality of life in the treatment of heart failure. Clin Pharmacol Ther. 1990 Sep;48(3):325-32. | CrossRef | PubMed |
  5. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med. 1989 Mar 16;320(11):677-83. | CrossRef | PubMed |
  6. Double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. The German and Austrian Xamoterol Study Group. Lancet. 1988 Mar 5;1(8584):489-93. | PubMed |
  7. Digitalis Investigation G. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. The New England journal of medicine. N Engl J Med. 1997 Feb 20;336(8):525-33. | CrossRef | PubMed |
  8. Fleg JL, Gottlieb SH, Lakatta EG. Is digoxin really important in treatment of compensated heart failure? A placebo-controlled crossover study in patients with sinus rhythm. Am J Med. 1982 Aug;73(2):244-50. | PubMed |
  9. Guyatt GH, Sullivan MJ, Fallen EL, Tihal H, Rideout E, Halcrow S, et al. A controlled trial of digoxin in congestive heart failure. A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988 Feb 1;61(4):371-5. | CrossRef | PubMed |
  10. Lee DC, Johnson RA, Bingham JB, Leahy M, Dinsmore RE, Goroll AH, et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med. 1982 Mar 25;306(12):699-705. | CrossRef | PubMed |
  11. Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1-7. | CrossRef | PubMed |
  12. Pugh SE, White NJ, Aronson JK, Grahame-Smith DG, Bloomfield JG. Clinical, haemodynamic, and pharmacological effects of withdrawal and reintroduction of digoxin in patients with heart failure in sinus rhythm after long term treatment. Br Heart J. 1989 Jun;61(6):529-39. | PubMed | Link |
  13. Taggart AJ, Johnston GD, McDevitt DG. Digoxin withdrawal after cardiac failure in patients with sinus rhythm. J Cardiovasc Pharmacol. 1983 Mar-Apr;5(2):229-34. | PubMed |
  14. The Captopril - Digoxin Multicenter Research G. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group. JAMA. 1988 Jan 22-29;259(4):539-44. | CrossRef | PubMed |
  15. Trial DIG. Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials. 1996 Feb;17(1):77-97. | CrossRef | PubMed |
  16. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993 Oct;22(4):955-62. | PubMed |
  17. van Veldhuisen DJ, Man in 't Veld AJ, Dunselman PH, Lok DJ, Dohmen HJ, Poortermans JC, et al. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol. 1993 Nov 15;22(6):1564-73. | PubMed |
  18. Yusuf S, Garg R, Held P, Gorlin R. Need for a large randomized trial to evaluate the effects of digitalis on morbidity and mortality in congestive heart failure. Am J Cardiol. 1992 Jun 4;69(18):64G-70G. | PubMed |
  19. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm 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 |
  20. 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 |
  21. 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. | CrossRef | PubMed |
  22. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010 Jun;16(6):e1-194. | CrossRef | PubMed |
Hood WB, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis. J Card Fail. 2004;10(2):155-64. | CrossRef | PubMed |

Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of heart failure in patients in sinus rhythm. Cochrane Database Syst Rev. 2014 Apr 28;4:CD002901. | CrossRef | PubMed |

Jaeschke R, Oxman AD, Guyatt GH. To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis. Am J Med. 1990 Mar;88(3):279-86. | CrossRef | PubMed |

Blackwood R, Mayou RA, Garnham JC, Armstrong C, Bryant B. Exercise capacity and quality of life in the treatment of heart failure. Clin Pharmacol Ther. 1990 Sep;48(3):325-32. | CrossRef | PubMed |

DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med. 1989 Mar 16;320(11):677-83. | CrossRef | PubMed |

Double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. The German and Austrian Xamoterol Study Group. Lancet. 1988 Mar 5;1(8584):489-93. | PubMed |

Digitalis Investigation G. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. The New England journal of medicine. N Engl J Med. 1997 Feb 20;336(8):525-33. | CrossRef | PubMed |

Fleg JL, Gottlieb SH, Lakatta EG. Is digoxin really important in treatment of compensated heart failure? A placebo-controlled crossover study in patients with sinus rhythm. Am J Med. 1982 Aug;73(2):244-50. | PubMed |

Guyatt GH, Sullivan MJ, Fallen EL, Tihal H, Rideout E, Halcrow S, et al. A controlled trial of digoxin in congestive heart failure. A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988 Feb 1;61(4):371-5. | CrossRef | PubMed |

Lee DC, Johnson RA, Bingham JB, Leahy M, Dinsmore RE, Goroll AH, et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med. 1982 Mar 25;306(12):699-705. | CrossRef | PubMed |

Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams KF, Cody RJ, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993 Jul 1;329(1):1-7. | CrossRef | PubMed |

Pugh SE, White NJ, Aronson JK, Grahame-Smith DG, Bloomfield JG. Clinical, haemodynamic, and pharmacological effects of withdrawal and reintroduction of digoxin in patients with heart failure in sinus rhythm after long term treatment. Br Heart J. 1989 Jun;61(6):529-39. | PubMed | Link |

Taggart AJ, Johnston GD, McDevitt DG. Digoxin withdrawal after cardiac failure in patients with sinus rhythm. J Cardiovasc Pharmacol. 1983 Mar-Apr;5(2):229-34. | PubMed |

The Captopril - Digoxin Multicenter Research G. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group. JAMA. 1988 Jan 22-29;259(4):539-44. | CrossRef | PubMed |

Trial DIG. Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials. 1996 Feb;17(1):77-97. | CrossRef | PubMed |

Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993 Oct;22(4):955-62. | PubMed |

van Veldhuisen DJ, Man in 't Veld AJ, Dunselman PH, Lok DJ, Dohmen HJ, Poortermans JC, et al. Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT). J Am Coll Cardiol. 1993 Nov 15;22(6):1564-73. | PubMed |

Yusuf S, Garg R, Held P, Gorlin R. Need for a large randomized trial to evaluate the effects of digitalis on morbidity and mortality in congestive heart failure. Am J Cardiol. 1992 Jun 4;69(18):64G-70G. | PubMed |

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm 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 |

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. | CrossRef | PubMed |

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