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

Jeff S. Healey, David J. Gladstone, Balakumar Swaminathan, Jens Eckstein, Hardi Mundl, Andrew E. Epstein, Karl Georg Haeusler, Robert Mikulik, Scott E. Kasner, Danilo Toni, Antonio Arauz, George Ntaios, Graeme J. Hankey, Kanjana Perera, Jorge Pagola, Ashfaq Shuaib, Helmi Lutsep, Xiaomeng Yang, Shinichiro Uchiyama, Matthias EndresShelagh B. Coutts, Michal Karliński, Anna Czlonkowska, Carlos A. Molina, Gustavo Santo, Scott D. Berkowitz, Robert G. Hart, Stuart J. Connolly

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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..

Original languageEnglish (US)
Pages (from-to)764-773
Number of pages10
JournalJAMA Neurology
Issue number7
StatePublished - Jul 2019

ASJC Scopus subject areas

  • Clinical Neurology


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