Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation

Abstract

Background: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated.

Methods: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months.

Results: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54).

Conclusions: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke.

Clinical trial registration: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Conflict of interest statement

I have read the journal’s policy and have the following conflicts. Dr. Koge reports no disclosures. Dr. Yamagami reports research grants from Bristol-Myers Squibb, Terumo, JIMRO, and Striker; lecturer’s fees from Stryker, Terumo, Medtronic, Medico’s Hirata, Johnson and Johnson, Bayer, Daiichi-Sankyo, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, and Otsuka Pharmaceutical; and membership of the advisory boards for Daiichi-Sankyo and Biomedical Solutions. Dr. Toyoda reports lecturer’s fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb. Dr. Yasaka reports lecturer’s fees from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb and CSL Behring. Dr. Hirano reports lecturer’s fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, and Medtronic. Dr. Hamasaki reports no disclosures. Dr. Nagao reports lecturer’s fee from Bayer Yakuhin. Dr. Yoshimura reports lecture fees from Boehringer, Ingelheim, Bayer, Daiichi-Sankyo, Phizer, BMS, Takeda, Sanofi, Otsuka, Tanabe-Mitsubishi, Medtronic, Stryker, and Medico’s Hirata and research support from BMS and Takeda. Dr. Fujishige reports no disclosures. Dr. Tempaku reports no disclosures. Dr. Uchiyama reports honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, AstraZeneka, and Takeda. Dr. Mori reports lecture fees from Johnson & Johnson, Otsuka, Novartis, Daiichi-Sankyo, Sumitomo Dainippon Pharma, Sosei, Kyowahakko-Kirin, Toshiba, Medtronic, and Nihon Medi-Physics and research support from Eisai, Daiichi-Sankyo, Novartis, Fuji Film RI, General Electric, MHWL, MEXT, and JSPS. Dr. Koga reports honoraria from Bayer Yakuhin, Bristol-Myers-Squibb, Otsuka, Daiichi-Sankyo, Nippon Boehringer Ingelheim and Takeda, scientific advisory board from Ono, and research supports from Takeda, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Astellas, Pfizer and Shionogi, outside the submitted work. Dr. Minematsu reports honoraria from Bayer Yakuhin, Otsuka Pharmaceutical, Behringer Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma Corporation, Japan Stryker, Dai-ichi Sankyo, Astellas Pharma, Nippon Chemiphar, Fuji Film RI Pharma, MSD, Kyowa Hakko Kirin, Sanofi, advisory board from CSL Behring, Bayer Yakuhin, EPS, Corporation, HEALIOS K.K., T-PEC Corporation and BMS. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Timing of initiating rivaroxaban according to the infarct size and recanalization status.

(A) Days of initiating rivaroxaban after the index stroke. The median days of starting rivaroxaban were 2.3 days (IQR, 1.3–4.2 days) in patients with small-sized infarcts, 2.8 days (IQR, 1.8–6.4 days) in patients with medium-sized infarcts, and 4.8 days in patients with large-sized infarcts (IQR, 2.5–8.9 days). (B) The median days of starting rivaroxaban were 2.8 days (IQR, 1.5–6.0 days) in patients with successful recanalization, 4.0 days (IQR, 2.4–7.2 days) in patients with partial recanalization, and 4.7 days (IQR, 2.1–7.9 days) in patients with no recanalization. Boxes represent the interquartile range. Horizontal lines across the box indicate median values, and the top and bottom edges of each box indicate the interquartile range. The whiskers represent 1.5 times the interquartile range. The dots represent the days of starting rivaroxaban in patients with ischemic stroke or transient ischemic attack or systemic embolism. Abbreviations: SR, successful recanalization, PR, partial recanalization.

Fig 2. Kaplan-Meier curves for ischemic stroke or TIA or systemic embolism (A), major bleeding (B), recurrent ischemic stroke (C), intracranial hemorrhage (D), and death (E) according to the timing of starting rivaroxaban.

Abbreviations: TIA, transient ischemic attack.