Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

• Published in: JAMA : the journal of the American Medical Association Vol. 329; no. 1; pp. 39 - 51
• Main Authors: Higgins, Alisa M, Berry, Lindsay R, Lorenzi, Elizabeth, Murthy, Srinivas, McQuilten, Zoe, Mouncey, Paul R, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Beane, Abi, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc J. M, Bradbury, Charlotte A, Brunkhorst, Frank M, Burrell, Aiden, Buzgau, Adrian, Buxton, Meredith, Charles, Walton N, Cove, Matthew, Detry, Michelle A, Estcourt, Lise J, Fagbodun, Elizabeth O, Fitzgerald, Mark, Girard, Timothy D, Goligher, Ewan C, Goossens, Herman, Haniffa, Rashan, Hills, Thomas, Horvat, Christopher M, Huang, David T, Ichihara, Nao, Lamontagne, Francois, Marshall, John C, McAuley, Daniel F, McGlothlin, Anna, McGuinness, Shay P, McVerry, Bryan J, Neal, Matthew D, Nichol, Alistair D, Parke, Rachael L, Parker, Jane C, Parry-Billings, Karen, Peters, Sam E. C, Reyes, Luis F, Rowan, Kathryn M, Saito, Hiroki, Santos, Marlene S, Saunders, Christina T, Serpa-Neto, Ary, Seymour, Christopher W, Shankar-Hari, Manu, Stronach, Lucy M, Turgeon, Alexis F, Turner, Anne M, van de Veerdonk, Frank L, Zarychanski, Ryan, Green, Cameron, Lewis, Roger J, Angus, Derek C, McArthur, Colin J, Berry, Scott, Derde, Lennie P. G, Gordon, Anthony C, Webb, Steve A, Lawler, Patrick R
• Format: Journal Article
• Language: English
• Published: United States American Medical Association 03-01-2023; American Medical Association (AMA)
• Subjects: Adrenal Cortex Hormones - therapeutic use; Adult; Anticoagulants; Anticoagulants - adverse effects; Antiviral agents; Bayes Theorem; Bayesian analysis; Caring for the Critically Ill Patient; Clinical trials; Comments; Coronaviruses; Corticoids; Corticosteroids; COVID-19; COVID-19 Serotherapy; Critical Illness - therapy; Domains; Female; Follow-Up Studies; Humans; Hydrocortisone; Hydroxychloroquine; Hydroxychloroquine - therapeutic use; Immunomodulation; Interleukin 6; Interleukin 6 receptors; Life Sciences; Lopinavir; Lopinavir - therapeutic use; Male; Middle Aged; Modulators; Mortality; Online First; Original Investigation; Patients; Probability; Receptors; Receptors, Interleukin-6; Ritonavir; Ritonavir - therapeutic use; SARS-CoV-2; Secondary analysis; Statistical analysis; Statistics; Survival; Therapeutic applications; COVID-19; Adaptive platform trial randomized controlled trial intensive care, pneumonia COVID-19 antiplatelet immunoglobulin antiviral corticosteroid immune modulation anticoagulation; immunoglobulin; Adaptive platform trial; antiviral; anticoagulation; intensive care, pneumonia; corticosteroid; immune modulation; antiplatelet; randomized controlled trial
• ISSN: 0098-7484; 1538-3598; 1538-3598
• DOI: 10.1001/jama.2022.23257

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.