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Randomized Controlled Trial
. 2019 Jul 1;76(7):764-773.
doi: 10.1001/jamaneurol.2019.0617.

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  1 , David J Gladstone  2   3 , Balakumar Swaminathan  4 , Jens Eckstein  5 , Hardi Mundl  6 , Andrew E Epstein  7 , Karl Georg Haeusler  8 , Robert Mikulik  9 , Scott E Kasner  10 , Danilo Toni  11 , Antonio Arauz  12 , George Ntaios  13 , Graeme J Hankey  14 , Kanjana Perera  15 , Jorge Pagola  16 , Ashfaq Shuaib  17 , Helmi Lutsep  18 , Xiaomeng Yang  19 , Shinichiro Uchiyama  20 , Matthias Endres  21 , Shelagh B Coutts  22 , Michal Karlinski  23 , Anna Czlonkowska  24   25 , Carlos A Molina  25   26 , Gustavo Santo  27 , Scott D Berkowitz  28 , Robert G Hart  4 , Stuart J Connolly  1
Affiliations
Randomized Controlled Trial

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 et al. JAMA Neurol. .

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Distribution of HAVOC Scores Within the Study Population
Figure 2.
Figure 2.. Kaplan-Meier Curves for Time to First Ischemic Stroke
Patients with left ventricular diameter more than 4.6 cm (A) and 4.6 cm or less (B).
See this image and copyright information in PMC

Comment in

References

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