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 Jana , Aitken Kinga , Sachdev Harmeet , Paulson Audrey , Bianchi Nicolas , Ng Kelvin , Ratnayake Kanchana , Tirschwell David , Asirot Mary , Kunze Allison , Hou Yan , Patel Reena , Greiner Laura , Miller Benjamin , Scherber Julie , Katramados Angelos , Wiegand Teresa , Kasner Scott , Burdett Rebecca , Cucchiara Brett , Messe Steven , Yuan Qingyang , Kurowski George Donna , Witsch Jens , Stein Laura , Favilla Christopher , Siegler James , Thon Jesse , Mullen Michael , Rothstein Aaron , Khaazal Ossama , Cristancho Daniel , Grodinsky Emily , Khan Farhan , Renner Christopher , Zuflacht Jonah , Humbert Kelley , Kumar Arooshi , Dawod Judy , Kone Gbambele , Reyes-Esteves Sahily , Kvantaliani Nino , De Santo Mary Liz , Gallatti Nichole , Keating Devin , Concha Mauricio , Pannell Robynn , Murray Nick , Anderson Jacki , Bosh Lindsay , Marulanda-Londono Erika , Escobar Andrea , Ajani Zahra , Gonzalez Nathalie , Neil William , Fechter Michael , Sanossian Nerses , Pena Jesus , Binley Clare , Elamin Elsadig , GEREIN Meghan , Law Susan , Tita Monique , Jalini Shirin , Nguyen Andrew , Sehgal Siddharth , Culbertson Collin , Ou Penhleakhena , Kirchhoffer Kaitlyn , Cross Danielle , Kruse Louise , Gizzi Martin , Kummer Karla , Yacoub Hussam , Orzel Andrew , Azhar Salman , Elsaadany Ronnie , Sposato Luciano , Mandzia Jennifer , Mai Lauren , Khaw Alexander , Fridman Sebastian , Beauchamp Beth , Lambourn Lindsay , Ramezan-Arab Nima , Caballero Deysi , Omidvar Omid , Thompson Michael , Altamirano Melanie , Pundik Svetlana , Double Manda , Bentho Oladi , Streib Christopher , Affan Muhammad , Hussein Haitham , McCullough-Hicks Margy , Hariharan Praveen , Solei Amelia , Bard Kate , Weller Amanda , Miller Kathleen , Brauch Anna , Lawyer Chloe , Quigley Deb , Staugaitis Abbey , Wang Qingliang , Mootoo Maryna , Singhal Aneesh , Carr Rhianna , Rabinstein Alejandro , Scharf Eugene , Headlee Amy , Lin Michelle , McDonald Meredith , Reid Taylor , Majjhoo Aniel , Marci Roberts , Rayes Mahmoud , Paschall Emily , Meisel Karl , Shaw Colleen , Stemer Andrew , Waldon Emma , Hsia Amie , Kalaria Chandni , Burton Shannon , Kim Yongwoo , Somani Sana , Craft Veronica , Smith Jamal , Matthews Juby , Grainger Megan , Anderson Cassidy , Holmstedt Christine , Lematty Caitlan , Sharrief Anjail , Cooksey Gabretta , Alderazi Yazan , Tremont Chad , Maidan Lucian , Hornbuckle Danielle , Zaidat Osama , Upham Cynthia , Krishnaiah Balaji , Alexandrov Andrei , Elangovan Cheran , Rubin Mark , Thacker Quentin , Hanna Joseph , Cook Dana , Jacobs Bradley , Weller Christina , Kirchoff-Torres Kathryn , Springer Mellanie , Moncrieffe Khadean , Islam Tanzina , Sethi Pramod , Ahmed Jamil , Rudolph Steven , Morhaim Holly , Brockington Carolyn , Poondla Naresh , Hansen Calvin , Banker Heather , Naqvi Imama , Miller Eliza , Castillo Carmen , Aragon Garcia Rebeca , Slane Kevin , Parikh Neal , Navi Babak , Mir Saad , Segal Alan , White Halina , Liberman Ava , Leifer Dana , Kamel Hooman , Sherman Carla , Kaiser Jed , Liao Vanessa , LeMoss Natalie , Lansdale Kelsey , Lord Aaron , Cotrina Maria , Torres Jose , Anganoo-Khan Danika , Winder Toni , Elliot Jill , Atalay Yahya , Stathis Courtney , Katz Jeffrey , Schwartz Erin , Stanton Kayla , Anghel Sandra , Ballout Ahmad , Dee Alicia , Modaber Morteza , Patel Neisha , Arora Rohan , Teron Ina , Libman Richard , Pasram Kirendra , Caprio Fan , Vincent Rachel , Talkad Arun , Ravisankar Ashwath , Zha Alicia , Hamed Mohammad , SIdorov Evgeny , Samkutty Danny , Gordon David , Hamilton Robert , Velez Faddi , King Jason , Ray Bappaditya , Vaughn April , Hill Blair , Sharps Jason , Zweifler Richard , Henry Jessica , Clark Wayne , Bozorgchami Hormozd , Miller Parker , Laursen Rachel , Amin Sonesh , Pattle Megan , Foley Jon , Dolan Monica , Nagle Emilie , Zortea Paulo , Leonard Reilly , Sen Souvik , Kodumuri Nishanth , Lowe Justin , Logue Makenzie , Kabetso Amanda , Fleming Phil , White Corey , Gates Damon , Towfighi Amytis , Ayala-Rivera Monica , Guisado Raul , De La Cuest Karen , Pyle Maria , Burton Tina , Furie Karen , Yaghi Shadi , Kala Narendra , Schomer Ashley , Moody Scott , Chaudhry Deepica , Elizardo Catrina , Vora Nirav , Groezinger Katy , Mehta Deviyani , Moccio Michelle , Stenroos Edward , Saver Jeffrey , Mercado Daisy , Graham Brett , Hunter Gary , Peeling Lissa , Kelly Michael , Cooley Regan , Wasyliw Sanchea , Tyson Cassandra , Junk Emily , Foster Kaitlyn , Bolt Kala , Urroz Lilian , Whelan Ruth , Gardner Aaron , Bhavsar Shrijal , Cherian Laurel , Conners James , Song Sarah , Dafer Rima , Vargas Alejandro , McCoy Henna , Olds Karin , Summers Debbie , Colorado Rene , Nielsen Terri , Morales Juan , Hemphill Claude , Randazzo Dominica , Spaeth Destini , Neal Jason , Zdroik Melissa , Modir Royya , McQuaid Theresa , Cheng Yu , Murphy Cary , Manassarians Henrik , Siddiqui Fazeel , Reiser Laura , Khan Muhib , Taylor Heidi , Mueller Stephanie , Khoury Naim , Bainter Lauren , Kaur Supreet , Calzadillas Guadalupe , Edgell Randall , 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

ImportanceAtrial 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.ObjectiveTo compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy.Design, Setting, and ParticipantsMulticenter, 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.InterventionsApixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508).Main Outcomes and MeasuresThe 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.ResultsWith 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 RelevanceIn patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin.Trial RegistrationClinicalTrials.gov Identifier: NCT03192215