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Original Investigation
October 2017

Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation–Related Mild Ischemic StrokeA Randomized Clinical Trial

Keun-Sik Hong, MD1; Sun U. Kwon, MD2; Sang Hun Lee, MD3; et al Ji Sung Lee, PhD4; Yong-Jae Kim, MD5; Tae-Jin Song, MD5; Young Dae Kim, MD6; Man-Seok Park, MD7; Eung-Gyu Kim, MD8; Jae-Kwan Cha, MD9; Sang Min Sung, MD10; Byung-Woo Yoon, MD11; Oh Young Bang, MD12; Woo-Keun Seo, MD12; Yang-Ha Hwang, MD13; Seong Hwan Ahn, MD14; Dong-Wha Kang, MD2; Hyun Goo Kang, MD14; Kyung-Ho Yu, MD15; for the Phase 2 Exploratory Clinical Study to Assess the Effects of Xarelto (Rivaroxaban) Versus Warfarin on Ischemia, Bleeding, and Hospital Stay in Acute Cerebral Infarction Patients With Non-valvular Atrial Fibrillation (Triple AXEL) Study Group
Author Affiliations
  • 1Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, South Korea
  • 2Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
  • 3Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea
  • 4Clinical Research Center, Asan Medical Center, Seoul, South Korea
  • 5Department of Neurology, Ewha Women’s University School of Medicine, Seoul, South Korea
  • 6Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
  • 7Department of Neurology, Chonnam National University Medical School, Gwangju, South Korea
  • 8Department of Neurology, Busan Paik Hospital, Inje University, Busan, South Korea
  • 9Department of Neurology, Dong-A University Hospital, Busan, South Korea
  • 10Department of Neurology, Pusan National University Hospital, Busan, South Korea
  • 11Department of Neurology, Seoul National University Hospital, Seoul, South Korea
  • 12Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
  • 13Department of Neurology and Cerebrovascular Center, Kyungpook National University School of Medicine and Hospital, Daegu, South Korea
  • 14Department of Neurology, Chosun University School of Medicine, Gwangju, South Korea
  • 15Department of Neurology, Hallym University Sacred Heart Hospital, Anyang, South Korea
JAMA Neurol. 2017;74(10):1206-1215. doi:10.1001/jamaneurol.2017.2161
Key Points

Question  Is rivaroxaban safer and more effective compared with warfarin sodium for early anticoagulation in atrial fibrillation–related acute ischemic stroke?

Findings  In this randomized clinical trial of 195 patients with mild acute ischemic stroke and atrial fibrillation, new ischemic lesions or new intracranial hemorrhage on results of magnetic resonance imaging after 4 weeks occurred in 49.5% of patients receiving rivaroxaban and 54.5% receiving warfarin, a nonsignificant difference. Each group had 1 recurrence of clinical ischemic stroke, and no symptomatic intracranial hemorrhage occurred.

Meaning  Rivaroxaban and warfarin had comparable safety and efficacy for early anticoagulation in mild atrial fibrillation–related acute ischemic stroke.

Abstract

Importance  In atrial fibrillation (AF)–related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear.

Objective  To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke.

Design, Setting, and Participants  A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis.

Interventions  Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks.

Main Outcomes and Measures  The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length.

Results  Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001).

Conclusions and Relevance  In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy.

Trial Registration  clinicaltrials.gov Identifier: NCT02042534

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