Digoxin treatment increases mortality risk in patients with newly diagnosed AF

Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation Findings From the TREAT-AF Study

Literature - Turakhia MP et al., J Am Coll Cardiol. 2014 - J Am Coll Cardiol. 2014;64(7):660-668

Turakhia MP, Santangeli P, Winkelmayer WC,  et al.,
J Am Coll Cardiol. 2014;64(7):660-668. doi:10.1016/j.jacc.2014.03.060


Digoxin is a commonly used rate control agent in atrial fibrillation/atrial flutter (AF, collectively). Although evidence from randomised trials is lacking, its use in AF is endorsed by clinical guidelines [1,2]. The effectiveness and safety of digoxin was shown to vary with serum digoxin concentrations in heart failure (HF) cohorts [3-5], which might mean that kidney function affects the effect of digoxin [6].
Because adequate safety data of digoxin use in AF is lacking, this study examined the association of digoxin therapy with mortality in a large cohort of patients with newly diagnosed AF, from the U.S. Department of Veterans Affairs (VA) healthcare system. 28.679 (23.4%) of the 122.465 patients in the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study cohort received digoxin during the first 90 days after initial AF diagnosis. Medication Possession Ratio (MPR) was calculated as a measure of digoxin exposure, reflecting the proportion of total outpatient days’ supply out of days after diagnosis. Mean MPR was 0.79+0.27 in patients receiving digoxin.

Main results

  • Digoxin recipients had higher unadjusted mortality as compared with nonrecipients. In a multivariate Cox regression model, digoxin was associated with higher risk of death (HR: 1.26, 95%CI: 1.23-1.29, P<0.001), as well as after propensity matching (HR: 1.21, 95%CI: 1.17-1.25, P<0.001).
  • When MPR was included as a time-varying covariate, the results were similar and statistically significant.
  • Both in multivariate adjusted and propensity matched analyses, digoxin was associated with a significant increase in risk of death in nearly all strata of eGFR, except in dialysis patients. There was, however, no evidence of effect modification across strata of kidney dysfunction (P=0.76).
  • Patients with prior MI were the only subgroup in whom there was evidence of possible effect modification in the full cohort (P(interaction)=0.002) and in the propensity matched cohort (P(interaction)=0.077).


This analysis of a large, retrospective cohort shows that digoxin treatment in patients with newly diagnosed AF is associated with increased mortality, irrespective of drug adherence, kidney dysfunction, HF or concomitant drug therapy. Patients with prior MI may be at higher risk. These findings are in contrast with current CV society guidelines.

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1. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935–44.
2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429.
3. Ahmed A, Pitt B, Rahimtoola SH, et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol 2008;123:138–46.
4. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525–33.
5. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289: 871–8.
6. Chan KE, Lazarus JM, Hakim RM. Digoxin associates with mortality in ESRD. J Am Soc Nephrol 2010;21:1550–9.

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