Document Type : Original Article(s)

Authors

1 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

2 Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

3 Nursing and Midwifery Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

4 Cardiac Rehabilitation Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isahan, Iran

5 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

6 Heart Failure Research Center, Cardiovascular Research Institute, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran AND University of Central Lancashire, Preston, UK

Abstract

BACKGROUND: Numerous clinical trials have reported conflicting results regarding the benefit of digoxin in treating heart failure (HF) patients. This study was conducted with the aim to demonstrate the impact of added digoxin to beta-blocker and beta-blocker alone on all-cause mortality and rehospitalization among these patients.
METHODS: We investigated the data of 1998 patients admitted with a primary diagnosis of decompensated HF in the prospective Persian Heart Failure Patients Registry in Iran. The outcomes of interest were time until death and time until first rehospitalization. Multivariate cox regression was used to compare the impact of beta-blocker plus digoxin and beta-blocker alone on 2.5-year survival and 90-day rehospitalization.
RESULTS: The mean age of the participants was 69.18 ± 13.26 years, and 38.1% of patients were women. The incidence rate of all-cause mortality in the total sample was 0.18 and 0.22 in patients on beta-blocker plus digoxin and beta-blocker alone, respectively [incidence rate ratio (IRR) = 1.25; 95% CI: 0.92-1.7]. The adjusted risk of all-cause mortality was significantly higher in women discharged with beta-blocker plus digoxin than beta-blocker groups [hazard ratio (HR) = 2.31; 95% CI: 1.27-4.19]. Rates of 90-day first rehospitalization were 0.10 and 0.12 in the beta-blocker plus digoxin and beta-blocker alone groups, respectively (IRR = 0.85; 95% CI: 0.53-1.35). After adjustment for covariates, beta-blocker plus digoxin therapy had no significant effect on increasing the risk of 90-day first rehospitalization in the total cohort (HR = 0.77; 95% CI: 0.48-1.23), in men (HR = 0.73; 95% CI: 0.40-1.35), and women (HR = 0.76; 95% CI: 0.36-1.65).
CONCLUSION: In patients hospitalized with decompensated HF, digoxin administration at discharge was associated with increased 30-month mortality risk in women.

Keywords

  1. Malik A, Masson R, Singh S, Wu WC, Packer M, Pitt B, et al. Digoxin discontinuation and outcomes in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol 2019; 74(5): 617-27.
  2. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336(8): 525-33.
  3. Leor J, Goldbourt U, Rabinowitz B, Reicher-Reiss H, Boyko V, Kaplinsky E, et al. Digoxin and increased mortality among patients recovering from acute myocardial infarction: Importance of digoxin dose. The SPRINT Study Group. Cardiovasc Drugs Ther 1995; 9(5): 723-9.
  4. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347(18): 1403-11.
  5. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: A systematic review and meta-analysis of the literature. Eur Heart J 2015; 36(28): 1831-8.
  6. Whitbeck MG, Charnigo RJ, Khairy P, Ziada K, Bailey AL, Zegarra MM, et al. Increased mortality among patients taking digoxin--analysis from the AFFIRM study. Eur Heart J 2013; 34(20): 1481-8.
  7. Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ 2015; 351: h4451.
  8. Turakhia MP, Santangeli P, Winkelmayer WC, Xu X, Ullal AJ, Than CT, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: Findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64(7): 660-8.
  9. Wang ZQ, Zhang R, Chen MT, Wang QS, Zhang Y, Huang XH, et al. Digoxin Is associated with increased all-cause mortality in patients with atrial fibrillation regardless of concomitant heart failure: A meta-analysis. J Cardiovasc Pharmacol 2015; 66(3): 270-5.
  10. Givi M, Sarrafzadegan N, Garakyaraghi M, Yadegarfar G, Sadeghi M, Khosravi A, et al. Persian Registry of cardioVascular diseasE (PROVE): Design and methodology. ARYA Atheroscler 2017; 13(5): 236-44.
  11. Givi M, Shafie D, Garakyaraghi M, Yadegarfar G, Roohafza HR, Ahmadi SA, et al. patients characteristics and preliminary outcomes of heart failure registry in a middle-income country: Persian Registry of Cardiovascular Disease/Heart Failure (PROVE/HF). Galen Med J 2018; 7: e1026.
  12. Jonsson A, Edner M, Alehagen U, Dahlstrom U. Heart failure registry: A valuable tool for improving the management of patients with heart failure. Eur J Heart Fail 2010; 12(1): 25-31.
  13. Laothavorn P, Hengrussamee K, Kanjanavanit R, Moleerergpoom W, Laorakpongse D, Pachirat O, et al. Thai Acute Decompensated Heart Failure Registry (Thai ADHERE). CVD Prev Control 2010; 5(3): 89-95.
  14. Givi M, Heshmat-Ghahdarijani K, Garakyaraghi M, Yadegarfar G, Vakhshoori M, Heidarpour M, et al. Design and methodology of heart failure registry: Results of the Persian registry of cardiovascular disease. ARYA Atheroscler 2019; 15(5): 228-32.
  15. Cole SR, Hernan MA. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed 2004; 75(1): 45-9.
  16. Anstrom KJ, Tsiatis AA. Utilizing propensity scores to estimate causal treatment effects with censored time-lagged data. Biometrics 2001; 57(4): 1207-18.
  17. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11): 993-1004.
  18. Ambrosy AP, Butler J, Ahmed A, Vaduganathan M, van Veldhuisen DJ, Colucci WS, et al. The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol 2014; 63(18): 1823-32.
  19. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 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 2016; 37(27): 2129-200.
  20. Joglar JA, Acusta AP, Shusterman NH, Ramaswamy K, Kowal RC, Barbera SJ, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: Retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am Heart J 2001; 142(3): 498-501.
  21. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344(22): 1651-8.
  22. Andrey JL, Romero S, Garcia-Egido A, Escobar MA, Corzo R, Garcia-Dominguez G, et al. Mortality and morbidity of heart failure treated with digoxin. A propensity-matched study. Int J Clin Pract 2011; 65(12): 1250-8.
  23. Dhaliwal AS, Bredikis A, Habib G, Carabello BA, Ramasubbu K, Bozkurt B. Digoxin and clinical outcomes in systolic heart failure patients on contemporary background heart failure therapy. Am J Cardiol 2008; 102(10): 1356-60.
  24. Katz A, Maor E, Leor J, Klempfner R. Addition of beta-blockers to digoxin is associated with improved 1- and 10-year survival of patients hospitalized due to decompensated heart failure. Int J Cardiol 2016; 221: 198-204.
  25. Flory JH, Ky B, Haynes K, Brunelli M, Munson J, Rowan C, et al. Observational cohort study of the safety of digoxin use in women with heart failure. BMJ Open 2012; 2(2): e000888.
  26. Aebi S, Schnider TW, Los G, Heath DD, Darrah D, Kirmani S, et al. A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel. Cancer Chemother Pharmacol 1999; 44(3): 259-65.
  27. Furberg CD, Vittinghoff E, Davidson M, Herrington DM, Simon JA, Wenger NK, et al. Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: Lessons learned. Circulation 2002; 105(8): 917-22.
  28. Ahmed A, Bourge RC, Fonarow GC, Patel K, Morgan CJ, Fleg JL, et al. Digoxin use and lower 30-day all-cause readmission for Medicare beneficiaries hospitalized for heart failure. Am J Med 2014; 127(1): 61-70.
  29. Masson R, Malik A, Lam P, Moore H, Deedwania P, Allman R, et al. Poor outcomes associated with digoxin discontinuation in patients with heart failure with reduced ejection fraction (HFREF) may differ by beta-blocker use. J Am Coll Cardiol 2020; 75: 971.