Author + information
- Received March 13, 2014
- Revision received June 17, 2014
- Accepted July 8, 2014
- Published online October 14, 2014.
- Greg Flaker, MD∗∗ (, )
- Renato D. Lopes, MD, PhD†,
- Elaine Hylek, MD, MPH‡,
- Daniel M. Wojdyla, MS†,
- Laine Thomas, PhD†,
- Sana M. Al-Khatib, MD, MHS†,
- Renee M. Sullivan, MD∗,
- Stefan H. Hohnloser, MD§,
- David Garcia, MD‖,
- Michael Hanna, MD¶,
- John Amerena, MBBS#,
- Veli-Pekka Harjola, MD, PhD∗∗,
- Paul Dorian, MD††,
- Alvaro Avezum, MD, PhD‡‡,
- Matyas Keltai, MD, DSc§§,
- Lars Wallentin, MD, PhD‖‖,
- Christopher B. Granger, MD†,
- ARISTOTLE Committees and Investigators
- ∗University of Missouri, Columbia, Missouri
- †Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- ‡Boston University Medical Center, Boston, Massachusetts
- §J.W. Goethe-University, Frankfurt, Germany
- ‖Division of Hematology, University of Washington, Seattle, Washington
- ¶Bristol-Myers Squibb, Princeton, New Jersey
- #Geelong Cardiology Research Center, Deakin University, Victoria, Australia
- ∗∗Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
- ††St. Michael’s Hospital, Toronto, Ontario, Canada
- ‡‡Danta Pazzanese Institute of Cardiology, São Paulo, Brazil
- §§Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary
- ‖‖Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
- ↵∗Reprint requests and correspondence:
Dr. Greg Flaker, University of Missouri, 1 Hospital Drive, CE306, Columbia, Missouri 65212.
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.
This study was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Flaker has received grants from Boehringer Ingelheim and Sanofi Aventis; and consulting fees from Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Daiichi Sankyo, and Sanofi-Aventis. Dr. Lopes has received grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo; and consulting fees from Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer. Dr. Hylek has received consulting fees and honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Boehringer Ingelheim, Johnson & Johnson, Pfizer, and Bayer; research grants from Bristol-Myers Squibb; and is a member of the advisory boards for Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, and Roche. Dr. Hohnloser has received grants from Sanofi Aventis and St. Jude Medical; consulting fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Boston Scientific, Cardiome, Gilead, Johnson & Johnson, Pfizer, Portola, Sanofi Aventis, Servier, St. Jude Medical, and Zoll; and lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi Aventis, St. Jude Medical, and Medtronic. Dr. Garcia has received consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Bayer Healthcare, and CSL Behring; and fees for the development of educational materials from Boehringer Ingelheim. Dr. Harjola has received consulting fees from Bristol-Myers Squibb/Pfizer. Dr. Dorian has received consulting fees and honoraria from Sanofi Aventis, Bayer Healthcare, Bristol-Myers Squibb, Pfizer, Servier, and Boehringer Ingelheim. Dr. Avezum has received research grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim; and consulting fees and honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer. Dr. Wallentin has received consulting fees and honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Regado Biosciences, Boehringer Ingelheim, Athera Biotechnologies, and AstraZeneca; and research grants from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Merck/Schering-Plough, and Bristol-Myers Squibb/Pfizer. Dr. Granger has received research grants and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Bayer Healthcare, Daiichi Sankyo, Sanofi Aventis, and Pfizer. All other authors have reported that they have no relationships relevant to this paper to disclose.
- Received March 13, 2014.
- Revision received June 17, 2014.
- Accepted July 8, 2014.
- American College of Cardiology Foundation