Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial
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, Manoj Saxena, Margaret Muteithia, Kelsey Dobell-Brown, 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, Latesh Poojara, Treena Sara, Kiran Nand, Brenda Reeve, William Dechert, Barbara Phillips, Laura Oritz-Ruiz De gordoa, Julia Affleck, Arif Shaikh, Andrew Murray, Mahesh Ramanan, Thuy Frakking, Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood, Ritesh Sanghavi, Deepak Bhonagiri, Megan Ford, Harshel G Parikh, Bronwyn Avard, Mary Nourse, Bree Mcdonald, Natasha Edmunds, 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 D'aragon, Elaine 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 Kreb, 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
JAMA, doi:10.1001/jama.2022.23257
Writing Committee for the REMAP-CAP Investigators IMPORTANCE The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. OBJECTIVE To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. DESIGN, SETTING, AND PARTICIPANTS Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. INTERVENTIONS Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).
MAIN OUTCOMES AND MEASURES The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. RESULTS Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the..
Author Contributions: Dr Higgins had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Webb, Lawler, and Gordon contributed equally as co-senior authors. Concept and design: Higgins, L. Berry, Lorenzi, Murthy, McQuilten, Bentum-Puijk, Bonten, Bradbury, Burrell, Girard, Goossens, Hills, McAuley, Neal, Parke, Parker, Rowan, Shankar-Hari, Turgeon, van
Additional Contributions: We are grateful to the NIHR Clinical Research Network (UK), UPMC Health System Health Services Division (US), and the Direction de la Recherche Clinique et de l'Innovation de l'AP-HP (France) for their support of participant recruitment. We are also very thankful to the patients who have participated in this trial.
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