Amiodarone use together with warfarin increases risk of stroke/SE and lowers TTR

Flaker G, Lopes RD, Hylek E, et al; ARISTOTLE Committees and Investigators.
J Am Coll Cardiol. 2014 Oct 14;64(15):1541-50. doi: 10.1016/j.jacc.2014.07.967

Background

Amiodarone is an effective anti-arrhythmic drug for the prevention of atrial fibrillation (AF), recommended for patients with frequent, symptomatic AF episodes [1]. Amiodarone interferes with warfarin metabolism through the CYP 2C9 pathways, and makes it more difficult to maintain INR values of 2 to 3 [2-5]. This limits the use of amiodarone in patients with AF who receive warfarin to prevent stroke.  
Amiodarone may also cause noncardiovascular side-effects, including occasionally possibly life-threatening pulmonary toxicity [6,7]. Amiodarone has furthermore been associated with an increased risk of cancer [8-10] and excess non-CV deaths [11].
This study evaluated the effects of amiodarone on outcomes in the ARISTOTLE trial. The effects of apixaban or warfarin treatment on CV outcomes (stroke and systemic embolism (SE), death and bleeding) in relation to amiodarone use at the time of randomisation were compared. 2051 patients enrolled in ARISTOTLE received amiodarone and 15856 patients did not. Mean follow-up time was 21.7 months for the amiodarone group and 21.8 months for patient who were not on amiodarone.

Main results

• Patients assigned to warfarin showed a mean TTR of 56.5% when they also received amiodarone and 63.0% if they did not (P<0.0001). Mean time below range (INR<2) was 28.5% for those on amiodarone and 24.2% for those not on amiodarone (P<0.0001). 15% and 12.8% of time was spent above range (INR>3) in those with or without amiodarone respectively.
• For patients assigned to amiodarone, stroke/SE rate was 1.24%/year for those on apixaban and 1.85%/year for those assigned to warfarin (HR: 0.68, 95%CI: 0.40-1.145). In patients not assigned to amiodarone, the respective stroke/SE rates were 1.29% and 1.57%/year (HR: 0.82, 95%CI: 0.68-1.00).
• In amiodarone-receiving patients, the rate of all-cause death was 4.15%/year when assigned to apixaban and 5.65%/year when on warfarin (HR: 0.74, 95%CI: 0.55-0.98). In patients not on amiodarone, the rates were 3.43%/year on apixaban and 3.68%/year on warfarin (HR: 0.93, 0.83-1.05).
• The rate of major bleeding in patients receiving amiodarone was 1.86%/year on apixaban and 3.06%/year on warfarin (HR: 0.61, 95%CI: 0.39-0.96). In patients not on amiodarone at baseline, the rate was 2.18%/year on apixaban or 3.03%/year on warfarin (HR: 0.72, 95%CI: 0.62-0.84).
• A propensity score-adjusted analysis revealed that patients on amiodarone (1.58%/year) had a higher rate of stroke/SE than those not on amiodarone (1.19%/year, adjusted HR: 1.47, 95%CI: 1.03-2.10, P=0.0322). Amiodarone-treated patients showed numerically, but not statistically significantly higher rates of all-cause death, C death and non-CV death.

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Conclusion

This analysis of the ARISTOTLE trial shows that amiodarone use in patients with AF was associated with a significantly increased risk of stroke and SE and a lower TTR when used simultaneously with warfarin. Apixaban consistently and similarly reduced the rate of stroke and SE, death and major bleeding when compared with warfarin, whether patients received amiodarone or not.

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