학술논문
Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.
Document Type
Academic Journal
Author
Higgins AM; Monash University, Melbourne, Victoria, Australia.; Berry LR; Berry Consultants, Austin, Texas.; Lorenzi E; Berry Consultants, Austin, Texas.; Murthy S; University of British Columbia, Vancouver, British Columbia, Canada.; McQuilten Z; Monash University, Melbourne, Victoria, Australia.; Monash Health, Melbourne, Victoria, Australia.; Mouncey PR; Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.; Al-Beidh F; Imperial College London, London, United Kingdom.; Annane D; Hospital Raymond Poincaré (Assistance Publique Hôpitaux de Paris), Garches, France.; Université Versailles SQY - Université Paris Saclay, Montigny-le-Bretonneux, France.; Arabi YM; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia.; Beane A; University of Oxford, Oxford, United Kingdom.; van Bentum-Puijk W; University Medical Center Utrecht, Utrecht, the Netherlands.; Bhimani Z; St Michael's Hospital Unity Health, Toronto, Ontario, Canada.; Bonten MJM; University Medical Center Utrecht, Utrecht, the Netherlands.; Bradbury CA; University of Bristol, Bristol, United Kingdom.; Brunkhorst FM; Jena University Hospital, Jena, Germany.; Burrell A; Monash University, Melbourne, Victoria, Australia.; Buzgau A; Monash University, Melbourne, Victoria, Australia.; Buxton M; Global Coalition for Adaptive Research.; Charles WN; Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.; Cove M; Yong Loo Lin Scholle of Medicine, National University Singapore, Singapore.; Detry MA; Berry Consultants, Austin, Texas.; Estcourt LJ; NHS Blood and Transplant, Oxford, United Kingdom.; Fagbodun EO; Imperial College London, London, United Kingdom.; Fitzgerald M; Berry Consultants, Austin, Texas.; Girard TD; University of Pittsburgh, Pittsburgh, Pennsylvania.; Goligher EC; Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada.; University of Toronto, Toronto, Ontario, Canada.; Goossens H; University of Antwerp, Antwerp, Belgium.; Haniffa R; University of Oxford, Bangkok, Thailand.; National Intensive Care Surveillance (NICST), Colombo, Sri Lanka.; Hills T; Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand.; Horvat CM; UPMC Children's Hospital of Pittsburg, Pittsburg, Pennsylvania.; Huang DT; University of Pittsburgh, Pittsburgh, Pennsylvania.; Ichihara N; University of Tokyo, Tokyo, Japan.; Lamontagne F; Université de Sherbrooke, Sherbrooke, Québec, Canada.; Marshall JC; St Michael's Hospital Unity Health, Toronto, Ontario, Canada.; McAuley DF; Queen's University Belfast, Belfast, Northern Ireland.; Royal Victoria Hospital, Belfast, Northern Ireland.; McGlothlin A; Berry Consultants, Austin, Texas.; McGuinness SP; Monash University, Melbourne, Victoria, Australia.; Auckland City Hospital, Auckland, New Zealand.; McVerry BJ; University of Pittsburgh, Pittsburgh, Pennsylvania.; Neal MD; University of Pittsburgh, Pittsburgh, Pennsylvania.; Nichol AD; Monash University, Melbourne, Victoria, Australia.; University College Dublin, Dublin, Ireland.; Parke RL; Auckland City Hospital, Auckland, New Zealand.; University of Auckland, Auckland, New Zealand.; Parker JC; Monash University, Melbourne, Victoria, Australia.; Parry-Billings K; Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.; Peters SEC; Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.; Reyes LF; Universidad de La Sabana, Chia, Colombia.; Clinica Universidad de La Sabana, Chia, Colombia.; Rowan KM; Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.; Saito H; St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan.; Santos MS; St Michael's Hospital Unity Health, Toronto, Ontario, Canada.; Saunders CT; Berry Consultants, Austin, Texas.; Serpa-Neto A; Monash University, Melbourne, Victoria, Australia.; Hospital Israelita Albert Einstein, Sao Paulo, Brazil.; Seymour CW; University of Pittsburgh, Pittsburgh, Pennsylvania.; Shankar-Hari M; King's College London, London, United Kingdom.; Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.; Stronach LM; Imperial College London, London, United Kingdom.; Turgeon AF; Université Laval, Québec City, Québec, Canada.; CHU de Québec-Université Laval Research Center, Québec City, Canada.; Turner AM; Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand.; van de Veerdonk FL; Radboud University Medical Center, Nijmegen, the Netherlands.; Zarychanski R; University of Manitoba, Winnipeg, Manitoba, Canada.; Green C; Monash University, Melbourne, Victoria, Australia.; Lewis RJ; Berry Consultants, Austin, Texas.; Harbor-UCLA Medical Center, Torrance, California.; Angus DC; University of Pittsburgh, Pittsburgh, Pennsylvania.; McArthur CJ; Auckland City Hospital, Auckland, New Zealand.; Berry S; Berry Consultants, Austin, Texas.; Derde LPG; University Medical Center Utrecht, Utrecht, the Netherlands.; Gordon AC; Imperial College London, London, United Kingdom.; Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom.; Webb SA; Monash University, Melbourne, Victoria, Australia.; St John of God Hospital, Subiaco, Australia.; Lawler PR; Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada.; University of Toronto, Toronto, Ontario, Canada.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 7501160 Publication Model: Print Cited Medium: Internet ISSN: 1538-3598 (Electronic) Linking ISSN: 00987484 NLM ISO Abbreviation: JAMA Subsets: MEDLINE
Subject
Language
English
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.
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.