Key result
Amiodarone use links to ~47% higher stroke or systemic embolism risk without altering apixaban's benefit.
Why the study?
Amiodarone prevents AF but interferes with warfarin metabolism, prompting this evaluation of how baseline amiodarone use relates to major thrombotic events and bleeding among patients treated with apixaban or warfarin in the ARISTOTLE trial.
Does amiodarone use affect the risk of major thrombotic events and bleeding, and modify the treatment effect of apixaban versus warfarin in patients with atrial fibrillation?
RCT
Randomized
Does amiodarone use affect the risk of major thrombotic events and bleeding, and modify the treatment effect of apixaban versus warfarin in patients with atrial fibrillation?
Hazard Ratio: 1.47 (95% CI 1.03–2.1)
Absolute Event Rate: 1.58% vs 1.19%
p-value: p=0.0322
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We looked at the specific drug combination of apixaban and amiodarone. We found that if you had atrial fibrillation and were taking amiodarone to control your heart rhythm, your stroke risk would be higher if you took warfarin than if you took apixaban.”
“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.”
“the duration of amiodarone was not specified and neither was information about its efficacy in maintaining sinus rhythm”
In patients with atrial fibrillation, concomitant amiodarone use increases the risk of stroke and systemic embolism and lowers warfarin time in therapeutic range, whereas apixaban consistently reduces stroke, death, and major bleeding compared with warfarin regardless of amiodarone use.
Background Amiodarone is an effective medication in preventing atrial fibrillation (AF), but it interferes with the metabolism of warfarin. Objectives This study sought to examine the association of major thrombotic clinical events and bleeding with the use of amiodarone in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods Baseline characteristics of patients who received amiodarone at randomization were compared with those who did not receive amiodarone. The interaction between randomized treatment and amiodarone was tested using a Cox model, with main effects for randomized treatment and amiodarone and their interaction. Matching on the basis of a propensity score was used to compare patients who received and who did not receive amiodarone at the time of randomization. Results In ARISTOTLE, 2,051 (11.4%) patients received amiodarone at randomization. Patients on warfarin and amiodarone had time in the therapeutic range that was lower than patients not on amiodarone (56.5% vs. 63.0%; p < 0.0001). More amiodarone-treated patients had a stroke or a systemic embolism (1.58%/year vs. 1.19%/year; adjusted hazard ratio [HR]: 1.47, 95% confidence interval [CI]: 1.03 to 2.10; p = 0.0322). Overall mortality and major bleeding rates were elevated, but were not significantly different in amiodarone-treated patients and patients not on amiodarone. When comparing apixaban with warfarin, patients who received amiodarone had a stroke or a systemic embolism rate of 1.24%/year versus 1.85%/year (HR: 0.68, 95% CI: 0.40 to 1.15), death of 4.15%/year versus 5.65%/year (HR: 0.74, 95% CI: 0.55 to 0.98), and major bleeding of 1.86%/year versus 3.06%/year (HR: 0.61, 95% CI: 0.39 to 0.96). In patients who did not receive amiodarone, the stroke or systemic embolism rate was 1.29%/year versus 1.57%/year (HR: 0.82, 95% CI: 0.68 to 1.00), death was 3.43%/year versus 3.68%/year (HR: 0.93, 95% CI: 0.83 to 1.05), and major bleeding was 2.18%/year versus 3.03%/year (HR: 0.72, 95% CI: 0.62 to 0.84). The interaction p values for amiodarone use by apixaban treatment effects were not significant. Conclusions Amiodarone use was associated with significantly increased stroke and systemic embolism risk and a lower time in the therapeutic range when used with warfarin. Apixaban consistently reduced the rate of stroke and systemic embolism, death, and major bleeding compared with warfarin in amiodarone-treated patients and patients who were not on amiodarone.
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Flaker et al. (2014) conducted an RCT in Atrial fibrillation. Amiodarone use at randomization (in patients randomized to apixaban vs. warfarin) vs. No amiodarone use at randomization (and warfarin vs. apixaban) was evaluated on Stroke or systemic embolism (HR 1.47, 95% CI 1.03-2.10, p=0.0322). Amiodarone use increased stroke or systemic embolism (1.58%/yr vs 1.19%/yr; HR 1.47, 95% CI 1.03-2.10; p=0.0322), while apixaban consistently reduced events vs warfarin regardless of amiodarone.
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