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

TY - JOUR

T1 - Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial

AU - Higgins, Alisa M

AU - Berry, Lindsay R

AU - Lorenzi, Elizabeth

AU - Murthy, Srinivas

AU - McQuilten, Zoe

AU - Mouncey, Paul R

AU - Al-Beidh, Farah

AU - Annane, Djillali

AU - Arabi, Yaseen M

AU - Beane, Abi

AU - van Bentum-Puijk, Wilma

AU - Bhimani, Zahra

AU - Bonten, Marc J M

AU - Bradbury, Charlotte A

AU - Brunkhorst, Frank M

AU - Burrell, Aiden

AU - Buzgau, Adrian

AU - Buxton, Meredith

AU - Charles, Walton N

AU - Cove, Matthew

AU - Detry, Michelle A

AU - Estcourt, Lise J

AU - Fagbodun, Elizabeth O

AU - Fitzgerald, Mark

AU - Girard, Timothy D

AU - Goligher, Ewan C

AU - Goossens, Herman

AU - Haniffa, Rashan

AU - Hills, Thomas

AU - Horvat, Christopher M

AU - Huang, David T

AU - Ichihara, Nao

AU - Lamontagne, Francois

AU - Marshall, John C

AU - McAuley, Daniel F

AU - McGlothlin, Anna

AU - McGuinness, Shay P

AU - McVerry, Bryan J

AU - Neal, Matthew D

AU - Nichol, Alistair D

AU - Parke, Rachael L

AU - Parker, Jane C

AU - Parry-Billings, Karen

AU - Peters, Sam E C

AU - Reyes, Luis F

AU - Rowan, Kathryn M

AU - Saito, Hiroki

AU - Santos, Marlene S

AU - Saunders, Christina T

AU - Serpa-Neto, Ary

AU - Seymour, Christopher W

AU - Shankar-Hari, Manu

AU - Stronach, Lucy M

AU - Turgeon, Alexis F

AU - Turner, Anne M

AU - van de Veerdonk, Frank L

AU - Zarychanski, Ryan

AU - Green, Cameron

AU - Lewis, Roger J

AU - Angus, Derek C

AU - McArthur, Colin J

AU - Berry, Scott

AU - Derde, Lennie P G

AU - Gordon, Anthony C

AU - Webb, Steve A

AU - Lawler, Patrick R

AU - Writing Committee for the REMAP-CAP Investigators

AU - Jarczak, Dominik

AU - Kluge, Stefan

AU - Nierhaus, Axel

AU - Roedl, Kevin

PY - 2023/1/3

Y1 - 2023/1/3

N2 - 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.

AB - 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.

KW - Adult

KW - Humans

KW - Female

KW - Middle Aged

KW - Male

KW - COVID-19

KW - Lopinavir/therapeutic use

KW - Ritonavir/therapeutic use

KW - Follow-Up Studies

KW - Hydroxychloroquine/therapeutic use

KW - SARS-CoV-2

KW - Critical Illness/therapy

KW - Bayes Theorem

KW - COVID-19 Serotherapy

KW - Adrenal Cortex Hormones/therapeutic use

KW - Anticoagulants/adverse effects

KW - Receptors, Interleukin-6

U2 - 10.1001/jama.2022.23257

DO - 10.1001/jama.2022.23257

M3 - SCORING: Journal article

C2 - 36525245

VL - 329

SP - 39

EP - 51

JO - JAMA-J AM MED ASSOC

JF - JAMA-J AM MED ASSOC

SN - 0098-7484

IS - 1

ER -