Abstract
IMPORTANCE The longer-term effects of therapies for the management 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 Pre-specified 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 9 March 2020 and 22 June 2021 from 197 sites in 14 countries. The final day-180 follow up was completed on 2 March 2022.
INTERVENTIONS Patients were randomized to one or more interventions within six 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)1 represented worsened survival (harm); futility was represented by a < 20% relative improvement in outcome shown by a HR>0.83 (1/1.2).
RESULTS Among 4869 patients who were randomized (mean age, 59.3 years; 1537 (32.1%) females), 4107 (84.3%) had known day 180 vital status and 2590 (63.1%) were alive. Interleukin-6 receptor antagonists and antiplatelet agents had a >99.9% and 95.0% probability of improving 6-month survival compared with control (adjusted hazard ratios [HR] 0.74 [95% CrI 0.61-0.90] and 0.85 [0.71-1.03]), 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 probability of harm from hydroxychloroquine and the combination of lopinavir-ritonavir and hydroxychloroquine was high (96.9% and 96.8%, HR 1.51 [95% CrI 0.98-2.29] and 1.61 [95% CrI 0.97-2.67]). 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 one or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a >99.9% probability of improved 180-day mortality compared with patients randomized to control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to 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 Pre-specified 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 9 March 2020 and 22 June 2021 from 197 sites in 14 countries. The final day-180 follow up was completed on 2 March 2022.
INTERVENTIONS Patients were randomized to one or more interventions within six 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)1 represented worsened survival (harm); futility was represented by a < 20% relative improvement in outcome shown by a HR>0.83 (1/1.2).
RESULTS Among 4869 patients who were randomized (mean age, 59.3 years; 1537 (32.1%) females), 4107 (84.3%) had known day 180 vital status and 2590 (63.1%) were alive. Interleukin-6 receptor antagonists and antiplatelet agents had a >99.9% and 95.0% probability of improving 6-month survival compared with control (adjusted hazard ratios [HR] 0.74 [95% CrI 0.61-0.90] and 0.85 [0.71-1.03]), 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 probability of harm from hydroxychloroquine and the combination of lopinavir-ritonavir and hydroxychloroquine was high (96.9% and 96.8%, HR 1.51 [95% CrI 0.98-2.29] and 1.61 [95% CrI 0.97-2.67]). 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 one or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a >99.9% probability of improved 180-day mortality compared with patients randomized to control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to 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.
| Original language | English |
|---|---|
| Pages (from-to) | 39-51 |
| Number of pages | 13 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 329 |
| Issue number | 1 |
| Early online date | 16 Dec 2022 |
| DOIs | |
| Publication status | Published - 5 Jan 2023 |
Bibliographical note
Funding Information:Funding/Support : The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union’s Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Australian Medical Research Future Fund (#APP2002132), the Health Research Council of New Zealand (#16/631), the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584) and the Canadian Institute of Health Research COVID-19 Rapid Research Funding (#447335), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Wellcome Trust Innovations Project (215522), the Minderoo Foundation, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the Translational Breast Cancer Research Consortium, the NSW Office of Health and Medical Research, Amgen, Eisai, and the Pittsburgh Foundation. Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). Dr McQuilten is funded by an NHMRC Emerging Leadership Fellowship (APP194811). Dr Gordon is funded by an NIHR Research Professorship (RP-2015-06-18) and Dr Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011). Dr Turgeon is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Dr Lawler is supported by a career award from the Heart and Stroke Foundation of Canada.
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