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Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

University of Bristol, Bristol, England. Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada. University of Toronto, Toronto, Ontario, Canada. University of Oxford, Oxford, England. NHS Blood and Transplant, Oxford, England. University of Pittsburgh, Pittsburgh, Pennsylvania. Monash University, Melbourne, Victoria, Australia. Monash Health, Melbourne, Victoria, Australia. Intensive Care National Audit and Research Centre (ICNARC), London, England. Imperial College London, London, England. Berry Consultants, Austin, Texas. University of Manitoba, Winnipeg, Canada. King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Hospital Raymond Poincaré (Assistance Publique Hôpitaux de Paris), Garches, France. Université Versailles SQY-Université Paris Saclay, Montigny-le-Bretonneux, France. University Medical Center Utrecht, Utrecht, the Netherlands. St Michael's Hospital Unity Health, Toronto, Ontario, Canada. Flinders University, Bedford Park, South Australia, Australia. Jena University Hospital, Jena, Germany. Global Coalition for Adaptive Research, Los Angeles, California. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Institut du Savoir Montfort, Ottawa, Ontario, Canada. Alfred Health, Melbourne, Victoria, Australia. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. University of Antwerp, Wilrijk, Belgium. University of Oxford, Bangkok, Thailand. National Intensive Care Surveillance (NICST), Colombo, Sri Lanka. Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand. UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Kings Healthcare Partners, London, England. The University of Tokyo, Tokyo, Japan. Université de Sherbrooke, Sherbrooke, Québec, Canada. Fiona Stanley Hospital, Perth, Western Australia, Australia. University of Western Australia, Perth, Australia. Queen's University Belfast, Belfast, Northern Ireland. Royal Victoria Hospital, Belfast, Northern Ireland. Auckland City Hospital, Auckland, New Zealand. Radboud University Medical Center, Nijmegen, the Netherlands. Middlemore Hospital, Auckland, New Zealand. University of British Columbia, Vancouver, Canada. University College Dublin, Dublin, Ireland. University of Auckland, Auckland, New Zealand. Universidad de La Sabana, Chia, Colombia. Clinica Universidad de La Sabana, Chia, Colombia. St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan. Hospital Israelita Albert Einstein, Sao Paulo, Brazil. King's College London, London, England. Guy's and St Thomas' NHS Foundation Trust, London, England. Université Laval, Québec City, Québec, Canada. CHU de Québec-Université Laval Research Center, Québec City, Québec, Canada. Harbor-UCLA Medical Center, Torrance, California. St John of God Hospital, Subiaco, Western Australia, Australia. Imperial College Healthcare NHS Trust, St Mary's Hospital, London, England.

Jama. 2022
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PICO Summary

Population

Critically ill patients with COVID-19 enrolled in the REMAP-CAP trial in 105 sites in 8 countries (n= 1,557).

Intervention

Antiplatelet therapy: open-label aspirin (n= 565), P2Y12 inhibitor (n = 455).

Comparison

No anti-platelet therapy (n= 529).

Outcome

The median for organ support-free days was 7 in both the antiplatelet and control groups. The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively. Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups.
Abstract
IMPORTANCE The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. OBJECTIVE To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). INTERVENTIONS Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02735707.
Study details
Language : eng
Additional Material : Commentary in: ‘Annals of Internal Medicine’, (2022), PMID: 35785539, DOI: <a href="http://dx.doi.org/10.7326/J22-0046">http://dx.doi.org/10.7326/J22-0046</a>
Credits : Bibliographic data from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine