Greg Flaker1, Renato D Lopes2, Elaine Hylek3, Daniel M Wojdyla2, Laine Thomas2, Sana M Al-Khatib2, Renee M Sullivan4, Stefan H Hohnloser5, David Garcia6, Michael Hanna7, John Amerena8, Veli-Pekka Harjola9, Paul Dorian10, Alvaro Avezum11, Matyas Keltai12, Lars Wallentin13, Christopher B Granger2. 1. University of Missouri, Columbia, Missouri. Electronic address: flakerg@missouri.edu. 2. Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina. 3. Boston University Medical Center, Boston, Massachusetts. 4. University of Missouri, Columbia, Missouri. 5. J.W. Goethe-University, Frankfurt, Germany. 6. Division of Hematology, University of Washington, Seattle, Washington. 7. Bristol-Myers Squibb, Princeton, New Jersey. 8. Geelong Cardiology Research Center, Deakin University, Victoria, Australia. 9. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. 10. St. Michael's Hospital, Toronto, Ontario, Canada. 11. Danta Pazzanese Institute of Cardiology, São Paulo, Brazil. 12. Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary. 13. Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
Abstract
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.
RCT Entities:
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.
Authors: Sarah Hanigan; Jessica Das; Kristen Pogue; Geoffrey D Barnes; Michael P Dorsch Journal: J Thromb Thrombolysis Date: 2020-05 Impact factor: 2.300
Authors: Liang-Han Ling; Peter M Kistler; Jonathan M Kalman; Richard J Schilling; Ross J Hunter Journal: Nat Rev Cardiol Date: 2015-12-10 Impact factor: 32.419
Authors: Markus Gulilat; Denise Keller; Bradley Linton; A Demetri Pananos; Daniel Lizotte; George K Dresser; Jeffrey Alfonsi; Rommel G Tirona; Richard B Kim; Ute I Schwarz Journal: J Thromb Thrombolysis Date: 2020-02 Impact factor: 2.300
Authors: Todd A Miano; Wei Yang; Michael G S Shashaty; Athena Zuppa; Jeremiah R Brown; Sean Hennessy Journal: Clin Pharmacol Ther Date: 2020-03-26 Impact factor: 6.875