Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy
Authors: Kamel Hooman , Longstreth W. T. , Tirschwell David L. , Kronmal Richard A. , Marshall Randolph S. , Broderick Joseph P. , Aragón García Rebeca , Plummer Pamela , Sabagha Noor , Pauls Qi , Cassarly Christy , Dillon Catherine R. , Di Tullio Marco R. , Hod Eldad A. , Soliman Elsayed Z. , Gladstone David J. , Healey Jeff S. , Sharma Mukul , Chaturvedi Seemant , Janis L. Scott , Krishnaiah Balaji , Nahab Fadi , Kasner Scott E. , Stanton Robert J. , Kleindorfer Dawn O. , Starr Matthew , Winder Toni R. , Clark Wayne M. , Miller Benjamin R. , Elkind Mitchell S. V. ,   ARCADIA Investigators, Asaithambi Ganesh , Klaiman Maxwell , Malhotra Konark , Fetter Mary , Wanahita Anna , Merritt Stacie , Sajjad Rehan , McPolin Kate , Coull Bruce , Kavathia Shriya , Kolikonda Murali , Calhoun Sara , de los Rios la Rosa Felipe , Del Conde Ian , Elysée Josette , Aghaebrahim Amin , Stratoberdha Melissa , Ford Andria , Giles James , Wang Yan , Babka Jennifer , Damani Rahul , Gutierrez-Flores Barbara , Kumar Sandeep , Marchina Sarah , Swerdloff Marc , Scott Margaret , Sangha Amandeep , Patterson Kelly , Shulman Julie , Feske Steven , Rafael Romero Jose , Aparicio Hugo , Greer David , Stafford Rebecca , Tamayo Arturo , Anderson Leanne , Smirnakis Stelios , Rademaker Quinn , Hourihane Maurice , Sawyer Robert , Ching Marilou , Kandel Amit , Magun Rakesh , Crumlish Annemarie , Bosco Annaliese , Singh Sanjay , Singh Abhishek , Traynor Elizabeth , Sankaraneni Ram , Haddad. Toufik , Isder Carly , Rasmussen Lois , Rochestie Dustin , Brunetti Nancy , Pandya Dhruvil , Baligod Rosemarie , Capampangan Dan , Sahelian Allegra , Nomura Jason , Gannon Kimberly , Raser-Schramm Jonathan , Murphy Kathleen , Itrat Ahmed , Hudock Debra , Wisco Dolora , Sweeney Laura , Likosky William , Garcia Rebekah , Schumacher Hermann , Colman Lindsey , Lisle Benjamin , Atkinson Uriah , Aude Wady , Trevino Cassandra , Attenhoffer Kevin , Fortiche Claudia , Rajamani Kumar , Reyes Amanda , Arshad Hasnain , Weidman Julie , Adamczyk Peter , Galvez Leah , Nahab Fadi , Frankel Michael , Escobar Alicia , Schindler Kiva , Schultz Megan , Bhadsavle Lori , Craft Leah , Mackey Ariane , Verreault Steve , Camden Marie-Christine , Gosselin-Lefebvre Stéphanie , Lavoie Suzy , Patel Nirav , Bailey Richard , Lazzaro Marc , Cierny Marek , Helms Ann , Moore Caitlin , Book Diane , Attar Hatim , Morse Tiffany , Aboagye Sophia , Coleman Lakiesha , Alter-Troilo Katie , Short Rodney , Weakley Desyree , Wold 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Cummins Benjamin , McDaneld Logan , Bertrand Lisa , Matmati Kelly , Matmati Nabil , Vora Nirali , Garcia Madelleine , Spence David , Mabb Tisha , Benesch Curtis , Prentiss Emily , Hopyan Julia , Gladstone David , Fatakdawala Idris , Mittal Manoj , Donnel Tammy , Lenakakis Dawn , Gelinas Katharyn , Bennett Alicia , Burgin William , Hairston Marla , Katz Paul , Reimer Hannah , Salem Rony , Stern Tracy , Dharia Robin , Paglione Sasha , Goshgarian Christopher , Smith Stacy , Melkumova Emiliya , Melkumyan Nikolas , Onteddu Sanjeeva , Richardson Lisa , Shafie Mohammad , Yu Wengui , Fong Julia , Prado Josue , Rapp Karen , Smith Wade , Wilson Christina , May Neringa , Sundararajan Sophia , Andrews Mary , Goddeau Richard , Silver Brian , Manxhari Christina , Demers-Peel Meaghan , Kenmuir Cynthia , Kerfoot Kristen , Ireland Christy , Starr Matthew , Shang Ty , Johnson Mark , Jones Erica , Gebreyohannas Mehari , Clark Jessica , Southerlandc Andrew , Worrallc Bradford , Gusler Matthew , JohnsonN Keri , Roach Necrisha , Chapman Sherita , Solenski Nina , Bhole Rohini , Sohail Amna , Johnston Karen , Weko Andrew , Perch Miah , Batton Cheyenne , Ramsey Allison , Gunter Sonya , Monita Jane , Meyer Marie , Murwin Jennifer , Lundell Kaitlin , Essa Nimco , Lyerly Michael , Davis Tammy , Shuaib Ashfaq , Piquette Lori , Hill Michael , Coutts Shelagh , Save Supriya , Ryckborst Karla , Kenney Carol , Toussaint Lana , Brorson James , Coleman Elisheva , Hall Emma , Stanton Robert , Kleindorfer Dawn , Demel Stacie , Powers Jennifer , Testai Fernando , Hillmann Maureen , Leira Enrique , Olalde Heena , Kawano-Castillo Jorge , Pendurthi Aparna , Houghton Margaret , Moore Justin , Maruthanal Joel , Fugate Alissa , Das Saurav , Pettigrew Creed , Arnold Pattricia , Ander Tracy , Jerde Ann , Chaturvedi Seemant , Spadafora Christina , Carrera Joseph , Becker Christopher , Brown Devin , Burke James , Conyers Frank , Harrington Anthony , Hill Christopher , Roberts Jessica , Johnson Patty , Shekhar Shashank , Gangadhara Shreyas , Smith Margaret , Fayad Pierre , Obaro Helen , Girotra Tarun , Morales Jacqueline , Rael Erin , Saleemi Muhammad-Adeel , Sugg Rebecca , Grissett Tamekia , White Stefanie , Behrouz Reza , Richardson Jody , Chung Lee , Majersik Jennifer , DeWitt Dana , Lyden Stephanie , Reddy Vivek , Tekiela Peter , Hannon Peter , de Havenon Adam , Marcus Brian , Hoversten Knut , Meyer Chelsea , Ruff Jerdan , Rock Theodore , Dela Cruz Michael , Bradbury Edward , Bock Jenna , Call Kevin , McQuivey Ryan , Belanger Karen , Huffer Andrew , McRae Sharon , Hassan Ameer , Khan Raza , Sanchez Olive , Field Thalia , Wilson Laura , Gorman John , Van Gaal Stephen , Yip Samuel , Teal Philip , Benavente Oscar , Mann Sharanpal , King-Azote Princess , Maclean Genoveva , Ma Carson , Villaluna Karina , Froehler Michael , Rajpal Hemangi , Alvi Muhammad , Dobrzynski Sara , Sherman Jay , Bushnell Cheryl , Schmidt Krystal , Wallis Roi , Panizzon Kimberly , Narula Reshma , Kuohn Lindsey , Jasak Sara , Kampp Michael , Pish Melissa 
Published: February 2024

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