Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
Simin Florescu, Delia Stanciu, Mihaela Zaharia, Alma kosa, Daniel Codreanu, Aneela Kidwai, Sobia Masood, Callum Kaye, Amanda Coutts, Lynn Mackay, Charlotte Summers, Petra Polgarova, Neda Farahi, Eleonore Fox, Stephen Mcwilliam, Daniel Hawcutt, Laura Rad, Laura O’malley, Jennifer Whitbread, Dawn Jones, Rachael Dore, Paula Saunderson, Olivia Kelsall, Nicholas Cowley, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin, János Bélteczki, István Magyar, Ágnes Fazekas, Sándor Kovács, Viktória Szőke, Adrian Donnelly, Martin Kelly, Naoise Smyth, Sinéad O’kane, Declan Mcclintock, Majella Warnock, Ryan Campbell, Edmund Mccallion, Amine azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron, Paul Johnson, Shirley Mckenna, Joanne Hanley, Andrew Currie, Barbara Allen, Clare Mcgoldrick, Moyra Mcmaster, Ashwin Mani, Meghena Mathew, Revathi Kandeepan, C Vignesh, Bharath Tv, N Ramakrishnan, Augustian James, Evangeline Elvira, Devachandran Jayakumar, Ramachandran Pratheema, Suresh Babu, R Ebenezer, S Krishnaoorthy, Lakshmi Ranganathan, Manisha Ganesan, Madhu Shree, Eileen Guilder, Magdalena Butler, Keri-Anne Cowdrey, Melissa Robertson, Farisha Ali, Ellie Mcmahon, Eamon Duffy, Yan Chen, Catherine Simmonds, Rachael Mcconnochie, Caroline O’connor, Khaled El-Khawas, Angus Richardson, Dianne Hill, Robert Commons, Hussam Abdelkharim, Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Aibhilin O’connor, Saranya Thurairatnam, Dipak Mukherjee, Agilan Kaliappan, Mark Vertue, Anne Nicholson, Joanne Riches, Gracie Maloney, Lauren Kittridge, Amanda Solesbury, Angelo Ramos, Daniel Collins, Kathy Brickell, Liadain Reid, Michelle Smyth, Patrick Breen, Sandra Spain, Gerard Curley, Natalie Mcevoy, Pierce Geoghegan, Jennifer Clarke, Jon Silversides, Peter Mcguigan, Kathryn Ward, Aisling O’neill, Stephanie Finn, Chris Wright, Jackie Green, Érin Collins, Cameron Knott, Julie Smith, Catherine Boschert, Kitty Slieker, Esther Ewalds, Arnate Sanders, Wendy Wittenberg, Heidi Geurts, Brenda Reeve, William Dechert, Barbara Phillips, Laura Oritz-Ruiz De gordoa, Julia Affleck, Yogesh Apte, Umesh Subbanna, Roland Bartholdy, Thuy Frakking, Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood, Karuna Keat, Deepak Bhonagiri, Ritesh Sanghavi, Jodie Nema, Megan Ford, Harshel Parikh, Bronwyn Avard, Mary Nourse, Oscar Hoiting, Marco Peters, Els Rengers, Mirjam Evers, Anton Prinssen, Matt Morgan, Jade Cole, Helen Hill, Michelle Davies, Angharad Williams, Emma Thomas, Rhys Davies, Matt Wise, Patrick Grimm, Jens Soukup, Richard Wetzold, Madlen Löbel, Lisa Starke, Francois Lellouche, Patricia Lizotte, Pierre Declerq, Marchalot Antoine, Gelinotte Stephanie, Eraldi Jean-Pierre, Bourgerol François, Beuzelin Marion, Rigaud Philippe, Franck Pourcine, Mehran Monchi, David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Jack Richecoeu, Daniele Combaux, Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Delphine Lemaire-Brunel, Frédérick Carbonneau, Julie Leblond, Gaetan Plantefeve, Cécile Leparco, Damien Contou, Muriel Fartoukh, Laura Courtin, Vincent Labbe, Guillaume Voiriot, Sara Salhi, Michaël Chassé, François Carrier, Dounia Boumahni, Fatna Benettaib, Ali Ghamraoui, Arnaud Sement, Alexandre Gachet, Alexis Hanisch, Abdelmagid Haffiane, Anne-Hélène Boivin, Amelie Barreau, Elodie Guerineau, Séverine Poupblanc, Pierre Egreteau, Montaine Lefevre, Simon Bocher, Guillaume Le Loup, Lenaïg Le Guen, Vanessa Carn, Melanie Bertel, David Antcliffe, Maie Templeton, Roceld Rojo, Phoebe Coghlan, Joanna Smee, Gareth Barker, André Finn, Gabriele Kreß, Uwe Hoff, Carl Hinrichs, Jens Nee, Euan Mackay, Jon Cort, Amanda Whileman, Thomas Spencer, Nick Spittle, Sarah Beavis, Anand Padmakumar, Katie Dale, Joanne Hawes, Emma Moakes, Rachel Gascoyne, Kelly Pritchard, Lesley Stevenson, Justin Cooke, Karolina Nemeth-Roszpopa, Basanta Gauli, Sirjana Bastola, Grégoire Muller, Mai-Anh Nay, Toufik Kamel, Dalila Benzekri
JAMA, doi:10.1001/jama.2022.2910
IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis.
MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from −1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions.
RESULTS The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, −1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, −0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase,..
Role of the Funder/Sponsor: The study funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The platform trial has 4 regional nonprofit sponsors: Monash University, Melbourne, Victoria, Australia (Australasian sponsor); Utrecht Medical Center, Utrecht, the Netherlands (European sponsor); St Michael's Hospital, Toronto, Ontario, Canada (Canadian sponsor); and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). Several authors are employees of these organizations. However, beyond the declared author contributions, the sponsors had no additional role.
Disclaimer: The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Dr Seymour is Associate Editor of JAMA, Dr Angus is Senior Editor of JAMA, and Dr Lewis is Statistical Editor of JAMA, but none were involved in any of the decisions regarding review of the manuscript or its acceptance.
Group Information: The REMAP-CAP Investigators are listed in Supplement 3.
Data Sharing Statement: See Supplement 4. Meeting Presentation: This study was presented at the International Symposium on Intensive Care and Emergency Medicine (ISICEM); March 22, 2022; Brussels, Belgium.
Additional Contributions: We are..
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