Amiodarone-warfarin Interaction Ups Risk in ARISTOTLE Patients

Payal Kohli, MD

In analysis of this randomized controlled trial of apixaban vs warfarin for nonvalvular atrial fibrillation, there was an increased risk of stroke and systemic embolism among patients taking amiodarone and warfarin.

Because of its high efficacy for prevention and rate and rhytym control in patients with atrial fibrillation (AF), amiodarone is considered a “first-line” advanced anti-arrhythmic drug for the treatment of AF and is commonly used in clinical practice. As a result of its interactions with the cytochrome 2C9 pathway, however, amiodarone can affect the bioavailability and metabolism of warfarin which, in turn, may lead to changes in the time in therapeutic range (TTR) for warfarin.  In addition, one of the metabolites of amiodarone can have an anticoagulant event.

In a post-randomization analysis of the ARISTOTLE study (RCT of apixaban vs warfarin for nonvalvular AF), Flaker et al reported that the 11.4% (n=2051) of patients on amiodarone had a lower TTR (56.5% vs 63%) and a higher adjusted incidence of stroke and systemic embolism (1.58% vs 1.19%, HR 1.47). There was no statistical difference between mortality and major bleeding, although bleeding events were numerically higher. Apixaban therapy consistently reduced rates of stroke/systemic embolism, death and major bleeding compared to warfarin, in both amiodarone-treated and untreated patients, with no significant interaction found between amidarone and apixaban. The mean follow-up was 21 months.

Although this study is limited by the usual challenges of a post-randomization analysis (residual confounding), it does illustrate that apixaban may be the preferred choice over warfarin, especially in patients who are receiving amiodarone and so are at higher risk of stroke/systemic embolism. Note, however, that although statistically significant, the overall rate of the primary endpoint is quite low in both arms so a randomized trial is needed to definitively draw conclusions from these results.


Flaker G, Lopes RD, Hylek E, et al; ARISTOTLE Committee and Investigators.   Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation. Insights rrom the ARISTOTLE trial.  J Am Coll Cardiol. 2014;64(15):1541-1550. doi:10.1016/j.jacc.2014.07.967