Initiation digoxin therapy associated with increased mortality in AF patients

Digoxin and Mortality in Patients With Atrial Fibrillation With and Without Heart Failure: Does Serum Digoxin Concentration Matter?

News - Mar. 23, 2017


Although randomised clinical data regarding the efficacy and safety of digoxin in atrial fibrillation (AF) patients are lacking, current guidelines recommend digoxin for rate control in these patients. In clinical practice worldwide, digoxin is used in approximately 30% of AF patients with or without HF. Moreover, there are no specific recommendations about serum digoxin concentration monitoring in the AF guidelines.

In the ARISTOTLE study, AF patients with at least one additional risk factor (DM, Hypertension. HF, age, or prior thromboembolic event), were randomised to receive either apixaban (5 mg twice daily) or warfarin (INR 2-3). The primary endpoint was stroke or systemic embolism.

In this secondary analysis of the ARISTOTLE study, the association between digoxin therapy and mortality was evaluated in 17,897 AF patients. Moreover, it was assessed whether the outcomes were modified by concomitant HF or baseline serum digoxin concentrations.

Main results

  • In the ARISTOTLE study, 32% of patients were on digoxin at baseline, and the digoxin levels were measured in 76% of them. 37% of patients had also HF at baseline.
  • In the baseline analysis, no significant difference in risk of all-cause death was seen between digoxin users and non-users (adjHR: 1.09, 95%CI: 0.96-1.23, P=0.191).
  • The risk of death was independently related to digoxin serum concentrations and was highest in patients with concentrations ≥1.2 ng/mL (adjHR: 1.56; 95% CI: 1.20-2.04; P=0.001).
  • New digoxin users showed a higher probability of death, as compared with matched controls (adjHR: 1.78, 95%CI: 1.37-2.31, P<0.001).
  • In patients without HF adjHR for all-cause death was 2.07 (95% CI: 1.39-3.08; P=0.0003) and in those with HF adjHR 1.58 (95% CI: 1.12-2.24; P=0.01).
  • There was a marked and early increase in sudden death among new digoxin users compared with matched controls, with most of the deaths occurring in the first 6 months after digoxin initiation (adjHR: 4.01; 95% CI: 1.90-8,47; P<0.001).
  • In a continuous analysis, a 19% increase of mortality risk was seen for each 0.5 ng/mL increase in baseline digoxin concentration (adjHR: 1.19, 95%CI: 1.07-1.32, P=0.001).
  • The benefits of apixaban over warfarin were consistent in digoxin users and non-users.


In a secondary analysis of the ARISTOTLE study, initiating digoxin in AF patients was associated with increased mortality, irrespective of the coexistence of HF. Increasing digoxin levels were associated with increased risk of death. These findings suggest that digoxin should not be initiated in AF patients. However, if patients are already taking digoxin, monitoring the serum concentrations may be important, with a target of <1.2 ng/mL.

During the press conference, it was emphasised that, although this was a secondary analysis rather than a randomised study, various efforts were made to make the data as informative as possible. For instance, in addition to a prevalence analysis, a propensity matched incidence analysis of new digoxin users was performed, to overcome the intrinsic survival bias in the analysis of digoxin use at baseline. Moreover, the data were stratified for three reasons that might have indicated digoxin use, but no differences were found.

The panel agreed that these data suggest that measuring digoxin levels may be measured more closely than ever before, and monthly rather than every six months may be appropriate. Although digoxin is not an agent of first choice, in certain clinical scenarios it is used. Also, use varies across geographical regions. These data show that extra care should be taken when managing AF patients who need it.


Our coverage of ACC.17 is based on the information provided during the congress.

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