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 B. 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 Géri, 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 J. 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
Abstract
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 findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.