Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy
Hooman Kamel, W. T. Longstreth, David Tirschwell, Richard A. Kronmal, Randolph S. Marshall, Joseph P. Broderick, Rebeca Aragón García, Pamela Plummer, Noor Sabagha, Qi Pauls, Christy Cassarly, Catherine Dillon, Marco R. Di Tullio, Eldad A. Hod, Elsayed Z. Soliman, David J. Gladstone, Jeff S. Healey, Mukul Sharma, Seemant Chaturvedi, L. Scott Janis, Balaji Krishnaiah, Fadi Nahab, Scott E. Kasner, Robert J. Stanton, Dawn Kleindorfer, Matthew Starr, Toni R. Winder, Wayne M. Clark, Benjamin Miller, Mitchell S.V. Elkind, ARCADIA Investigators, Ganesh Asaithambi, Maxwell Klaiman, Konark Malhotra, Mary Fetter, Anna Wanahita, Stacie Merritt, Rehan Sajjad, Kate McPolin, Bruce M. Coull, Shriya Kavathia, Murali Kolikonda, S Calhoun, Felipe De Los Rios La Rosa, Ian Del Conde, Josette Elysée, Amin Aghaebrahim, Melissa Stratoberdha, Andria L. Ford, James Giles, Yan Wang, Jennifer Babka, Rahul Damani, Barbara Gutierrez-Flores, Sandeep Kumar, Sarah Marchina, Marc Swerdloff, Margaret Scott, Amandeep Sangha, Kelly Patterson, Julie Shulman, Steven K. Feske, José R. Romero, Hugo J. Aparicio, David M. Greer, Rebecca Stafford, Arturo Tamayo, Leanne Anderson, Stelios M. Smirnakis, Quinn Rademaker, Maurice Hourihane, Robert G. Sawyer, Marilou Ching, Amit Kandel, Rakesh Magun, Annemarie Crumlish, Annaliese Bosco, Sanjay Singh, Abhishek Singh, Elizabeth Traynor, Ram Mohan Sankaraneni, Toufik Mahfood Haddad, Carly C. Isder, L. Larsen Rasmussen, Dustin Rochestie, Nancy Brunetti, Dhruvil J. Pandya, Rosemarie R. Baligod, Dan J. Capampangan, Allegra Sahelian, Jason T. Nomura, Kimberly Gannon, Jonathan Raser-Schramm, Kathleen Murphy, Ahmed Itrat, Debra Hudock, Dolora Wisco, Laura Sweeney, William Likosky, Rebekah Garcia
Abstract
Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 μV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.