Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation

Insights from the ARISTOTLE trial

Greg Flaker, Renato D. Lopes, Elaine Hylek, Daniel M. Wojdyla, Laine Thomas, Sana M. Al-Khatib, Renee M. Sullivan, Stefan H. Hohnloser, David Garcia, Michael Hanna, John Amerena, Veli Pekka Harjola, Paul Dorian, Alvaro Avezum, M. Keltai, Lars Wallentin, Christopher B. Granger

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1541-1550
Number of pages10
JournalJournal of the American College of Cardiology
Volume64
Issue number15
DOIs
Publication statusPublished - Oct 14 2014

Fingerprint

Amiodarone
Atrial Fibrillation
Stroke
Warfarin
Embolism
Confidence Intervals
Hemorrhage
Random Allocation
apixaban
Therapeutics
Propensity Score

Keywords

  • antiarrhythmia agents
  • anticoagulants
  • antithrombotic agents
  • factor Xa
  • stroke
  • thromboembolism
  • warfarin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation : Insights from the ARISTOTLE trial. / Flaker, Greg; Lopes, Renato D.; Hylek, Elaine; Wojdyla, Daniel M.; Thomas, Laine; Al-Khatib, Sana M.; Sullivan, Renee M.; Hohnloser, Stefan H.; Garcia, David; Hanna, Michael; Amerena, John; Harjola, Veli Pekka; Dorian, Paul; Avezum, Alvaro; Keltai, M.; Wallentin, Lars; Granger, Christopher B.

In: Journal of the American College of Cardiology, Vol. 64, No. 15, 14.10.2014, p. 1541-1550.

Research output: Contribution to journalArticle

Flaker, G, Lopes, RD, Hylek, E, Wojdyla, DM, Thomas, L, Al-Khatib, SM, Sullivan, RM, Hohnloser, SH, Garcia, D, Hanna, M, Amerena, J, Harjola, VP, Dorian, P, Avezum, A, Keltai, M, Wallentin, L & Granger, CB 2014, 'Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: Insights from the ARISTOTLE trial', Journal of the American College of Cardiology, vol. 64, no. 15, pp. 1541-1550. https://doi.org/10.1016/j.jacc.2014.07.967
Flaker, Greg ; Lopes, Renato D. ; Hylek, Elaine ; Wojdyla, Daniel M. ; Thomas, Laine ; Al-Khatib, Sana M. ; Sullivan, Renee M. ; Hohnloser, Stefan H. ; Garcia, David ; Hanna, Michael ; Amerena, John ; Harjola, Veli Pekka ; Dorian, Paul ; Avezum, Alvaro ; Keltai, M. ; Wallentin, Lars ; Granger, Christopher B. / Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation : Insights from the ARISTOTLE trial. In: Journal of the American College of Cardiology. 2014 ; Vol. 64, No. 15. pp. 1541-1550.
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title = "Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: Insights from the ARISTOTLE trial",
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.",
keywords = "antiarrhythmia agents, anticoagulants, antithrombotic agents, factor Xa, stroke, thromboembolism, warfarin",
author = "Greg Flaker and Lopes, {Renato D.} and Elaine Hylek and Wojdyla, {Daniel M.} and Laine Thomas and Al-Khatib, {Sana M.} and Sullivan, {Renee M.} and Hohnloser, {Stefan H.} and David Garcia and Michael Hanna and John Amerena and Harjola, {Veli Pekka} and Paul Dorian and Alvaro Avezum and M. Keltai and Lars Wallentin and Granger, {Christopher B.}",
year = "2014",
month = "10",
day = "14",
doi = "10.1016/j.jacc.2014.07.967",
language = "English",
volume = "64",
pages = "1541--1550",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
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TY - JOUR

T1 - Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation

T2 - Insights from the ARISTOTLE trial

AU - Flaker, Greg

AU - Lopes, Renato D.

AU - Hylek, Elaine

AU - Wojdyla, Daniel M.

AU - Thomas, Laine

AU - Al-Khatib, Sana M.

AU - Sullivan, Renee M.

AU - Hohnloser, Stefan H.

AU - Garcia, David

AU - Hanna, Michael

AU - Amerena, John

AU - Harjola, Veli Pekka

AU - Dorian, Paul

AU - Avezum, Alvaro

AU - Keltai, M.

AU - Wallentin, Lars

AU - Granger, Christopher B.

PY - 2014/10/14

Y1 - 2014/10/14

N2 - 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.

AB - 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.

KW - antiarrhythmia agents

KW - anticoagulants

KW - antithrombotic agents

KW - factor Xa

KW - stroke

KW - thromboembolism

KW - warfarin

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DO - 10.1016/j.jacc.2014.07.967

M3 - Article

VL - 64

SP - 1541

EP - 1550

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 15

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