Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy
Authors: Hooman Kamel, W. T. Longstreth, David L. Tirschwell, Richard A. Kronmal, Randolph S. Marshall, Joseph P. Broderick, Rebeca Aragón García, Pamela Plummer, Noor Sabagha, Qi Pauls, Christy Cassarly, Catherine R. 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 O. Kleindorfer, Matthew Starr, Toni R. Winder, Wayne M. Clark, Benjamin R. Miller, Mitchell S. V. Elkind, Ganesh Asaithambi, Maxwell Klaiman, Konark Malhotra, Mary Fetter, Anna Wanahita, Stacie Merritt, Rehan Sajjad, Kate McPolin, Bruce Coull, Shriya Kavathia, Murali Kolikonda, Sara Calhoun, Felipe de los Rios la Rosa, Ian Del Conde, Josette Elysée, Amin Aghaebrahim, Melissa Stratoberdha, Andria 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 Feske, Jose Rafael Romero, Hugo Aparicio, David Greer, Rebecca Stafford, Arturo Tamayo, Leanne Anderson, Stelios Smirnakis, Quinn Rademaker, Maurice Hourihane, Robert Sawyer, Marilou Ching, Amit Kandel, Rakesh Magun, Annemarie Crumlish, Annaliese Bosco, Sanjay Singh, Abhishek Singh, Elizabeth Traynor, Ram Sankaraneni, Toufik Haddad., Carly Isder, Lois Rasmussen, Dustin Rochestie, Nancy Brunetti, Dhruvil Pandya, Rosemarie Baligod, Dan Capampangan, Allegra Sahelian, Jason Nomura, Kimberly Gannon, Jonathan Raser-Schramm, Kathleen Murphy, Ahmed Itrat, Debra Hudock, Dolora Wisco, Laura Sweeney, William Likosky, Rebekah Garcia, Hermann Schumacher, Lindsey Colman, Benjamin Lisle, Uriah Atkinson, Wady Aude, Cassandra Trevino, Kevin Attenhoffer, Claudia Fortiche, Kumar Rajamani, Amanda Reyes, Hasnain Arshad, Julie Weidman, Peter Adamczyk, Leah Galvez, Fadi Nahab, Michael Frankel, Alicia Escobar, Kiva Schindler, Megan Schultz, Lori Bhadsavle, Leah Craft, Ariane Mackey, Steve Verreault, Marie-Christine Camden, Stéphanie Gosselin-Lefebvre, Suzy Lavoie, Nirav Patel, Richard Bailey, Marc Lazzaro, Marek Cierny, Ann Helms, Caitlin Moore, Diane Book, Hatim Attar, Tiffany Morse, Sophia Aboagye, Lakiesha Coleman, Katie Alter-Troilo, Rodney Short, Desyree Weakley, Jana Wold, Kinga Aitken, Harmeet Sachdev, Audrey Paulson, Nicolas Bianchi, Kelvin Ng, Kanchana Ratnayake, David Tirschwell, Mary Asirot, Allison Kunze, Yan Hou, Reena Patel, Laura Greiner, Benjamin Miller, Julie Scherber, Angelos Katramados, Teresa Wiegand, Scott Kasner, Rebecca Burdett, Brett Cucchiara, Steven Messe, Qingyang Yuan, Donna Kurowski George, Jens Witsch, Laura Stein, Christopher Favilla, James Siegler, Jesse Thon, Michael Mullen, Aaron Rothstein, Ossama Khaazal, Daniel Cristancho, Emily Grodinsky, Farhan Khan, Christopher Renner, Jonah Zuflacht, Kelley Humbert, Arooshi Kumar, Judy Dawod, Gbambele Kone, Sahily Reyes-Esteves, Nino Kvantaliani, Mary Liz De Santo, Nichole Gallatti, Devin Keating, Mauricio Concha, Robynn Pannell, Nick Murray, Jacki Anderson, Lindsay Bosh, Erika Marulanda-Londono, Andrea Escobar, Zahra Ajani, Nathalie Gonzalez, William Neil, Michael Fechter, Nerses Sanossian, Jesus Pena, Clare Binley, Elsadig Elamin, Meghan GEREIN, Susan Law, Monique Tita, Shirin Jalini, Andrew Nguyen, Siddharth Sehgal, Collin Culbertson, Penhleakhena Ou, Kaitlyn Kirchhoffer, Danielle Cross, Louise Kruse, Martin Gizzi, Karla Kummer, Hussam Yacoub, Andrew Orzel, Salman Azhar, Ronnie Elsaadany, Luciano Sposato, Jennifer Mandzia, Lauren Mai, Alexander Khaw, Sebastian Fridman, Beth Beauchamp, Lindsay Lambourn, Nima Ramezan-Arab, Deysi Caballero, Omid Omidvar, Michael Thompson, Melanie Altamirano, Svetlana Pundik, Manda Double, Oladi Bentho, Christopher Streib, Muhammad Affan, Haitham Hussein, Margy McCullough-Hicks, Praveen Hariharan, Amelia Solei, Kate Bard, Amanda Weller, Kathleen Miller, Anna Brauch, Chloe Lawyer, Deb Quigley, Abbey Staugaitis, Qingliang Wang, Maryna Mootoo, Aneesh Singhal, Rhianna Carr, Alejandro Rabinstein, Eugene Scharf, Amy Headlee, Michelle Lin, Meredith McDonald, Taylor Reid, Aniel Majjhoo, Roberts Marci, Mahmoud Rayes, Emily Paschall, Karl Meisel, Colleen Shaw, Andrew Stemer, Emma Waldon, Amie Hsia, Chandni Kalaria, Shannon Burton, Yongwoo Kim, Sana Somani, Veronica Craft, Jamal Smith, Juby Matthews, Megan Grainger, Cassidy Anderson, Christine Holmstedt, Caitlan Lematty, Anjail Sharrief, Gabretta Cooksey, Yazan Alderazi, Chad Tremont, Lucian Maidan, Danielle Hornbuckle, Osama Zaidat, Cynthia Upham, Balaji Krishnaiah, Andrei Alexandrov, Cheran Elangovan, Mark Rubin, Quentin Thacker, Joseph Hanna, Dana Cook, Bradley Jacobs, Christina Weller, Kathryn Kirchoff-Torres, Mellanie Springer, Khadean Moncrieffe, Tanzina Islam, Pramod Sethi, Jamil Ahmed, Steven Rudolph, Holly Morhaim, Carolyn Brockington, Naresh Poondla, Calvin Hansen, Heather Banker, Imama Naqvi, Eliza Miller, Carmen Castillo, Rebeca Aragon Garcia, Kevin Slane, Neal Parikh, Babak Navi, Saad Mir, Alan Segal, Halina White, Ava Liberman, Dana Leifer, Hooman Kamel, Carla Sherman, Jed Kaiser, Vanessa Liao, Natalie LeMoss, Kelsey Lansdale, Aaron Lord, Maria Cotrina, Jose Torres, Danika Anganoo-Khan, Toni Winder, Jill Elliot, Yahya Atalay, Courtney Stathis, Jeffrey Katz, Erin Schwartz, Kayla Stanton, Sandra Anghel, Ahmad Ballout, Alicia Dee, Morteza Modaber, Neisha Patel, Rohan Arora, Ina Teron, Richard Libman, Kirendra Pasram, Fan Caprio, Rachel Vincent, Arun Talkad, Ashwath Ravisankar, Alicia Zha, Mohammad Hamed, Evgeny SIdorov, Danny Samkutty, David Gordon, Robert Hamilton, Faddi Velez, Jason King, Bappaditya Ray, April Vaughn, Blair Hill, Jason Sharps, Richard Zweifler, Jessica Henry, Wayne Clark, Hormozd Bozorgchami, Parker Miller, Rachel Laursen, Sonesh Amin, Megan Pattle, Jon Foley, Monica Dolan, Emilie Nagle, Paulo Zortea, Reilly Leonard, Souvik Sen, Nishanth Kodumuri, Justin Lowe, Makenzie Logue, Amanda Kabetso, Phil Fleming, Corey White, Damon Gates, Amytis Towfighi, Monica Ayala-Rivera, Raul Guisado, Karen De La Cuest, Maria Pyle, Tina Burton, Karen Furie, Shadi Yaghi, Narendra Kala, Ashley Schomer, Scott Moody, Deepica Chaudhry, Catrina Elizardo, Nirav Vora, Katy Groezinger, Deviyani Mehta, Michelle Moccio, Edward Stenroos, Jeffrey Saver, Daisy Mercado, Brett Graham, Gary Hunter, Lissa Peeling, Michael Kelly, Regan Cooley, Sanchea Wasyliw, Cassandra Tyson, Emily Junk, Kaitlyn Foster, Kala Bolt, Lilian Urroz, Ruth Whelan, Aaron Gardner, Shrijal Bhavsar, Laurel Cherian, James Conners, Sarah Song, Rima Dafer, Alejandro Vargas, Henna McCoy, Karin Olds, Debbie Summers, Rene Colorado, Terri Nielsen, Juan Morales, Claude Hemphill, Dominica Randazzo, Destini Spaeth, Jason Neal, Melissa Zdroik, Royya Modir, Theresa McQuaid, Yu Cheng, Cary Murphy, Henrik Manassarians, Fazeel Siddiqui, Laura Reiser, Muhib Khan, Heidi Taylor, Stephanie Mueller, Naim Khoury, Lauren Bainter, Supreet Kaur, Guadalupe Calzadillas, Randall Edgell, Benjamin Cummins, Logan McDaneld, Lisa Bertrand, Kelly Matmati, Nabil Matmati, Nirali Vora, Madelleine Garcia, David Spence, Tisha Mabb, Curtis Benesch, Emily Prentiss, Julia Hopyan, David Gladstone, Idris Fatakdawala, Manoj Mittal, Tammy Donnel, Dawn Lenakakis, Katharyn Gelinas, Alicia Bennett, William Burgin, Marla Hairston, Paul Katz, Hannah Reimer, Rony Salem, Tracy Stern, Robin Dharia, Sasha Paglione, Christopher Goshgarian, Stacy Smith, Emiliya Melkumova, Nikolas Melkumyan, Sanjeeva Onteddu, Lisa Richardson, Mohammad Shafie, Wengui Yu, Julia Fong, Josue Prado, Karen Rapp, Wade Smith, Christina Wilson, Neringa May, Sophia Sundararajan, Mary Andrews, Richard Goddeau, Brian Silver, Christina Manxhari, Meaghan Demers-Peel, Cynthia Kenmuir, Kristen Kerfoot, Christy Ireland, Matthew Starr, Ty Shang, Mark Johnson, Erica Jones, Mehari Gebreyohannas, Jessica Clark, Andrew Southerlandc, Bradford Worrallc, Matthew Gusler, Keri JohnsonN, Necrisha Roach, Sherita Chapman, Nina Solenski, Rohini Bhole, Amna Sohail, Karen Johnston, Andrew Weko, Miah Perch, Cheyenne Batton, Allison Ramsey, Sonya Gunter, Jane Monita, Marie Meyer, Jennifer Murwin, Kaitlin Lundell, Nimco Essa, Michael Lyerly, Tammy Davis, Ashfaq Shuaib, Lori Piquette, Michael Hill, Shelagh Coutts, Supriya Save, Karla Ryckborst, Carol Kenney, Lana Toussaint, James Brorson, Elisheva Coleman, Emma Hall, Robert Stanton, Dawn Kleindorfer, Stacie Demel, Jennifer Powers, Fernando Testai, Maureen Hillmann, Enrique Leira, Heena Olalde, Jorge Kawano-Castillo, Aparna Pendurthi, Margaret Houghton, Justin Moore, Joel Maruthanal, Alissa Fugate, Saurav Das, Creed Pettigrew, Pattricia Arnold, Tracy Ander, Ann Jerde, Seemant Chaturvedi, Christina Spadafora, Joseph Carrera, Christopher Becker, Devin Brown, James Burke, Frank Conyers, Anthony Harrington, Christopher Hill, Jessica Roberts, Patty Johnson, Shashank Shekhar, Shreyas Gangadhara, Margaret Smith, Pierre Fayad, Helen Obaro, Tarun Girotra, Jacqueline Morales, Erin Rael, Muhammad-Adeel Saleemi, Rebecca Sugg, Tamekia Grissett, Stefanie White, Reza Behrouz, Jody Richardson, Lee Chung, Jennifer Majersik, Dana DeWitt, Stephanie Lyden, Vivek Reddy, Peter Tekiela, Peter Hannon, Adam de Havenon, Brian Marcus, Knut Hoversten, Chelsea Meyer, Jerdan Ruff, Theodore Rock, Michael Dela Cruz, Edward Bradbury, Jenna Bock, Kevin Call, Ryan McQuivey, Karen Belanger, Andrew Huffer, Sharon McRae, Ameer Hassan, Raza Khan, Olive Sanchez, Thalia Field, Laura Wilson, John Gorman, Stephen Van Gaal, Samuel Yip, Philip Teal, Oscar Benavente, Sharanpal Mann, Princess King-Azote, Genoveva Maclean, Carson Ma, Karina Villaluna, Michael Froehler, Hemangi Rajpal, Muhammad Alvi, Sara Dobrzynski, Jay Sherman, Cheryl Bushnell, Krystal Schmidt, Roi Wallis, Kimberly Panizzon, Reshma Narula, Lindsey Kuohn, Sara Jasak, Michael Kampp, Melissa Pish
Journal: JAMA (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 V 1 , serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m 2 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