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, Kanjana Perera, Graeme J Hankey, Jorge Pagola, Ashfaq Shuaib, Helmi Lutsep, Xiaomeng Yang, Shinichiro Uchiyama, Matthias EndresShelagh B Coutts, Michal Karlinski, Anna Czlonkowska, Carlos A Molina, Gustavo Santo, Scott D Berkowitz, Robert G Hart, Stuart J Connolly

Research output: Contribution to journalArticlepeer-review

79 Citations (Scopus)


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
Pages (from-to)764-773
Number of pages10
JournalJAMA Neurology
Issue number7
Early online date8 Apr 2019
Publication statusPublished - Jul 2019


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