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Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial FibrillationSecondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial

Educational Objective
To determine whether patients with embolic stroke of undetermined source are more likely to benefit from rivaroxaban compared with aspirin if they are at greater risk of having atrial fibrillation?
1 Credit CME
Key Points

Question  Are patients with embolic stroke of undetermined source more likely to benefit from rivaroxaban compared with aspirin if they are at a greater risk of having atrial fibrillation?

Findings  This secondary analysis of a randomized clinical trial examined 7112 patients who were stratified by clinical predictors of atrial fibrillation, left atrial diameter, and frequency of premature atrial contractions. In the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm, there was a significant reduction in recurrent stroke among patients who had been treated with rivaroxaban.

Meaning  Rivaroxaban appears to modestly reduce recurrent stroke in a small subgroup of patients with embolic stroke of undetermined source and moderate to severe left atrial enlargement.

Abstract

Importance  The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).

Objective  To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF.

Design, Setting, and Participants  Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018.

Intervention  Rivaroxaban treatment vs aspirin.

Main Outcomes and Measures  Risk of ischemic stroke.

Results  Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02).

Conclusions and Relevance  The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

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Article Information

Corresponding Author: Jeff S. Healey, MD, 30 Birge St, Room C3-121, Hamilton, ON L8L 0A6, Canada (jeff.healey@phri.ca).

Accepted for Publication: February 15, 2019.

Published Online: April 8, 2019. doi:10.1001/jamaneurol.2019.0617

Author Contributions: Dr Healey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Healey, Gladstone, Mundl, Hankey, Pagola, Shuaib, Berkowitz, Hart, Connolly.

Acquisition, analysis, or interpretation of data: Healey, Gladstone, Swaminathan, Eckstein, Mundl, Epstein, Haeusler, Mikulik, Kasner, Toni, Arauz, Ntaios, Hankey, Perera, Pagola, Lutsep, Yang, Uchiyama, Endres, Coutts, Karlinski, Czlonkowska, Molina, Santo, Berkowitz, Hart.

Drafting of the manuscript: Healey, Gladstone, Swaminathan, Pagola, Hart.

Critical revision of the manuscript for important intellectual content: Gladstone, Eckstein, Mundl, Epstein, Haeusler, Mikulik, Kasner, Toni, Arauz, Ntaios, Hankey, Perera, Pagola, Shuaib, Lutsep, Yang, Uchiyama, Endres, Coutts, Karlinski, Czlonkowska, Molina, Santo, Berkowitz, Hart, Connolly.

Statistical analysis: Swaminathan, Ntaios.

Obtained funding: Berkowitz, Hart, Connolly.

Administrative, technical, or material support: Healey, Eckstein, Yang, Uchiyama, Berkowitz, Hart.

Supervision: Healey, Haeusler, Pagola, Uchiyama, Molina, Hart, Connolly.

Conflict of Interest Disclosures: Dr Healey reports grants from Bayer during the conduct of the study; grants and personal fees from Bristol-Meyers Squibb/Pfizer outside the submitted work; personal fees from Servier outside the submitted work; and is the Population Health Research Institute Chair in Cardiology Research. Dr Gladstone reports personal fees from Bayer, Bristol-Meyers Squibb/Pfizer, and Boehringer Ingelheim outside the submitted work and serves as a Medical Monitor for the ARCADIA trial. Dr Eckstein reports personal fees and other support from the University Hospital Basel during the conduct of the study. Dr Mundl reports grants from Bayer during the conduct of the study and personal fees from Bayer outside the submitted work and is an employee of Bayer but did not suggest any changes to this article. Dr Epstein reports grants from University of Pennsylvania during the conduct of the study. Dr Haeusler reports grants from Bayer during the conduct of the study; personal fees from Bayer, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Boehringer Ingelheim, and Metronic during the conduct of the study; nonfinancial support from Getemed AG during the conduct of the study; and personal fees from Edwards Lifesciences and Sanofi-Aventis outside the submitted work. Dr Mikulik reports grants from Project no.LQ1605 from the National Program of Sustainability II of the Ministry of Education of Czech Republic during the conduct of the study. Dr Kasner reports grants and personal fees from Bayer and Janssen Pharmaceutical during the conduct of the study; personal fees from Boehringer Ingelheim outside the submitted work; and grants and personal fees from Medtronic and WL Gore outside the submitted work. Dr Toni reports grants and personal fees from Boehringer Ingelheim and personal fees from Bayer, Pfizer, Medtronic, and Abbott Laboratories outside the submitted work. Dr Arauz reports other support from Bayer during the conduct of the study and personal fees from Bayer outside the submitted work. Dr Ntaios reports grants, personal fees, and nonfinancial support from Bayer during the conduct of the study and grants and nonfinancial support from Bayer, Boehringer Ingelheim, and Pfizer outside the submitted work. Dr Hankey reports personal fees from Bayer during the conduct of the study and outside the submitted work. Dr Perera reports grants from Bayer AG during the conduct of the study and outside the submitted work. Dr Shuaib reports other support from University of Alberta during the conduct of the study. Dr Lutsep reports personal fees from National Institute of Neurological Disorders and Stroke (via Mayo Clinic), Abbott Laboratories, Coherex Medical, and Medscape outside the submitted work. Dr Uchiyama reports grants and personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Otsuka Pharmaceutical, Takeda, AstraZeneca, Sumitomo Dainippon Pharma, MitsubishiTanabe Pharma, Shionogi, Amgen Astellas, Bristol-Myers Squibb, and Japan Cardiovascular Research Foundation outside the submitted work. Dr Endres reports grants and nonfinancial support from Bayer during the conduct of the study; grants and other support from Bayer outside the submitted work; and other support from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, Sanofi, Covidien, GlaxoSmithKline, EVER Pharma, and Novartis outside the submitted work. Dr Karlinski reports personal fees and nonfinancial support from Boehringer Ingelheim and EVER Pharma and personal fees from Medtronic outside the submitted work. Dr Czlonkowska reports other support from Population Health Research Institute of McMaster University in Canada and personal fees from Bayer during the conduct of the study. Dr Berkowitz reports personal fees from Bayer during the conduct of the study and outside the submitted work. Dr Hart reports personal fees from Bayer AG during the conduct of the study. Dr Connolly reports grants and personal fees from Bayer during the conduct of the study; grants and personal fees from Bristol-Myers Squibb, Pfizer, Portola Pharmaceuticals, and Medtronic outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by Bayer AG and Janssen Research LLC. Dr Gladstone’s research is supported by a midcareer award from the Heart and Stroke Foundation of Canada; Eaton Scholar Award from the Department of Medicine at the University of Toronto; the Bastable-Potts Chair; the Tory family; and the Department of Medicine at Sunnybrook Research Institute.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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