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Original Investigation
April 8, 2019

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

Author Affiliations
  • 1Division of Cardiology, Hamilton Health Sciences, Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 2Division of Neurology and Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre and Sunnybrook Research Institute, Toronto, Ontario, Canada
  • 3Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 4Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
  • 5Department of Internal Medicine, University Hospital Basel, Basel, Switzerland
  • 6Bayer AG, Wuppertal, Germany
  • 7Electrophysiology Section, Cardiovascular Division University of Pennsylvania, Cardiology Section, Philadelphia VA Medical Center, Philadelphia
  • 8Department of Neurology, Universitätsklinikum Würzburg, Würzburg, Germany
  • 9International Clinical Research Center and Neurology Department, St. Anne’s University Hospital and Masaryk University, Brno, Czech Republic
  • 10Department of Neurology, University of Pennsylvania, Philadelphia
  • 11Department of Human Neurosciences, “Sapienza” University of Rome, Rome, Italy
  • 12Instituto Nacional de Neurologia y Neurocirugia, Mexico D.F., Mexico City, Mexico
  • 13Department of Medicine, University of Thesally, Larissa, Greece
  • 14UWA Medical School, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia
  • 15McMaster University/Population Health Research Institute, Department of Medicine (Neurology), Hamilton, Ontario, Canada
  • 16Unitat d’Ictus, Servei de Neurologia, Hospital Universitari Vall d’Hebrón, Barcelona, Spain
  • 17Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  • 18Department of Neurology, OHSU, VA Portland Health Care System, Portland, Oregon
  • 19Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  • 20International University of Health and Welfare, Sanno Hospital and Sanno Medical Center, Tokyo, Japan
  • 21Klinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 22Department of Clinical Neurosciences, Radiology, and Community Health Sciences, University of Calgary, Foothills Medical Centre, Calgary, Alberta, Canada
  • 23Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
  • 242nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
  • 25Department of Pharmacology, Medical University of Warsaw, Warsaw, Poland
  • 26Vall d’Hebron Stroke Unit. Hospital Universitari Vall d’Hebron, Barcelona, Spain
  • 27Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
  • 28Bayer US LLC, Pharmaceuticals Clinical Development Thrombosis, Whippany, New Jersey
JAMA Neurol. 2019;76(7):764-773. doi:10.1001/jamaneurol.2019.0617
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.


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.