• Robert G Hart, Mukul Sharma, Hardi Mundl, Scott E Kasner, Shrikant I Bangdiwala, Scott D Berkowitz, Balakumar Swaminathan, Pablo Lavados, Yongjun Wang, Yilong Wang, Antonio Davalos, Nikolay Shamalov, Robert Mikulik, Luis Cunha, Arne Lindgren, Antonio Arauz, Wilfried Lang, Anna Czlonkowska, Jens Eckstein, Rubens J Gagliardi, Pierre Amarenco, Sebastian F Ameriso, Turgut Tatlisumak, Roland Veltkamp, Graeme J Hankey, Danilo Toni, Daniel Bereczki, Shinichiro Uchiyama, George Ntaios, Byung-Woo Yoon, Raf Brouns, Matthias Endres, Keith W Muir, Natan Bornstein, Serefnur Ozturk, Martin J O'Donnell, Matthys M De Vries Basson, Guillaume Pare, Calin Pater, Bodo Kirsch, Patrick Sheridan, Gary Peters, Jeffrey I Weitz, W Frank Peacock, Ashkan Shoamanesh, Oscar R Benavente, Campbell Joyner, Ellison Themeles, Stuart J Connolly, and NAVIGATE ESUS Investigators.
• From the Departments of Medicine-Neurology (R.G.H., M.S., A.S.), Health Research Methods, Evidence, and Impact (S.I.B.), Pathology and Molecular Medicine (G. Pare), and Medicine-Cardiology (S.J.C.), Population Health Research Institute (B.S., P.S., E.T.), and the Thrombosis and Atherosclerosis Research Institute and McMaster University (J.I.W.), Hamilton, ON, the Vancouver Stroke Program, University of British Columbia, Vancouver (O.R.B.), and Sunnybrook Health Sciences Centre, University of Toronto, Toronto (C.J.) - all in Canada; Bayer, Wuppertal (H.M.), Klinik für Neurologie, Charité-Universitätsmedizin Berlin (M.E.), and Bayer (B.K.), Berlin, and Bayer, Leverkusen (C.P.) - all in Germany; the Department of Neurology, University of Pennsylvania, Philadelphia (S.E.K.), and Janssen Research and Development, Spring House (G. Peters) - both in Pennsylvania; Bayer U.S., Pharmaceuticals Clinical Development Thrombosis, Whippany, NJ (S.D.B.); Clínica Alemana de Santiago, Santiago, Chile (P.L.); the Department of Neurology and Stroke Center, Beijing Tiantan Hospital, Beijing (Yongjun Wang, Yilong Wang); Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona (A.D.); Pirogov Russian National Research Medical University, Moscow (N.S.); International Clinical Research Center and Neurology Department, St. Anne's University Hospital, Brno, Czech Republic (R.M.); Centro Hospitalar e Universitário de Coimbra, Hospitais da Universidade de Coimbra, Coimbra, Portugal (L.C.); the Department of Clinical Sciences (Neurology), Lund University, and the Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund (A.L.), and the Department of Clinical Neuroscience-Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg (T.T.) - all in Sweden; Instituto Nacional de Neurología y Neurocirugía, Mexico City (A.A.); Hospital St. John of God, Sigmund Freud Private University, Medical Faculty, Vienna (W.L.); the 2nd Department of Neurology, Institute of Psychiatry and Neurology, and the Department of Pharmacology, Medical University of Warsaw, Warsaw, Poland (A.C.); the Department of Internal Medicine, University Hospital Basel, Basel, Switzerland (J.E.); Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo (R.J.G.); Assistance Publique-Hôpitaux de Paris, Bichat Hospital, Paris-Diderot, Sorbonne Paris Cité University, Paris (P.A.); Institute for Neurological Research-Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Buenos Aires (S.F.A.); the Department of Neurology, Helsinki University Central Hospital, Helsinki (T.T.); Imperial College London, London (R.V.); Medical School, University of Western Australia, and Sir Charles Gairdner Hospital, Perth, Australia (G.J.H.); the Department of Human Neurosciences, Sapienza University of Rome, Rome (D.T.); the Department of Neurology, Semmelweis University, Budapest, Hungary (D.B.); International University of Health and Welfare, Sanno Hospital and Sanno Medical Center, Tokyo (S.U.); the Department of Medicine, University of Thessaly, Larissa, Greece (G.N.); Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea (B.-W.Y.); the Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels (R.B.); the Department of Neurology, ZorgSaam Hospital, Terneuzen, the Netherlands (R.B.); Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, United Kingdom (K.W.M.); Shaare Zedek Medical Center, Jerusalem (N.B.); the Department of Neurology, Selcuk University, Konya, Turkey (S.O.); Health Research Board Clinical Research Facility, National University of Ireland, Galway (M.J.O.); Tiervlei Trial Centre and Head of Internal Medicine Karl Bremer Hospital, Bellville, South Africa (M.M.D.V.B.); and Baylor College of Medicine, Houston (W.F.P.).
• N. Engl. J. Med. 2018 Jun 7; 378 (23): 2191-2201.

BackgroundEmbolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.MethodsWe compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.ResultsA total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).ConclusionsRivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

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