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

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Does antiplatelet therapy administered to critically ill patients with COVID-19 improve organ support–free days (a composite end point of in-hospital mortality and duration of intensive care unit–based respiratory or cardiovascular support) up to day 21?

Findings  In this bayesian randomized clinical trial that included 1557 patients, antiplatelet therapy with either aspirin or a P2Y12 inhibitor, compared with no antiplatelet therapy, resulted in a 95.7% posterior probability of futility with regard to the odds of improvement in organ support–free days within 21 days.

Meaning  Among critically ill patients with COVID-19, there was a low likelihood that treatment with an antiplatelet agent provided improvement in organ support–free days within 21 days.

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

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Article Information

Corresponding Author: Charlotte A. Bradbury, MD, PhD, Bristol Haematology and Oncology Centre, Horfield Road, Bristol BS2 8ED, England (c.bradbury@bristol.ac.uk).

Accepted for Publication: February 14, 2022.

Published Online: March 22, 2022. doi:10.1001/jama.2022.2910

Authors/Writing Committee: Charlotte A. Bradbury, MD, PhD; Patrick R. Lawler, MD, MPH; Simon J. Stanworth, MD; Bryan J. McVerry, MD; Zoe McQuilten, PhD; Alisa M. Higgins, PhD; Paul R. Mouncey, MSc; Farah Al-Beidh, PhD; Kathryn M. Rowan, PhD; Lindsay R. Berry, PhD; Elizabeth Lorenzi, PhD; Ryan Zarychanski, MD, MSc; Yaseen M. Arabi, MD; Djillali Annane, MD, PhD; Abi Beane, PhD; Wilma van Bentum-Puijk, MSc; Zahra Bhimani, MPH; Shailesh Bihari, PhD; Marc J. M. Bonten, MD, PhD; Frank M. Brunkhorst, MD, PhD; Adrian Buzgau, MSc; Meredith Buxton, PhD; Marc Carrier, MD, MSc; Allen C. Cheng, MBBS, PhD; Matthew Cove, MBBS; Michelle A. Detry, PhD; Lise J. Estcourt, MBBCh, PhD; Mark Fitzgerald, PhD; Timothy D. Girard, MD, MSCI; Ewan C. Goligher, MD, PhD; Herman Goossens, PhD; Rashan Haniffa, PhD; Thomas Hills, MBBS, PhD; David T. Huang, MD, MPH; Christopher M. Horvat, MD; Beverley J. Hunt, MD, PhD; Nao Ichihara, MD, MPH, PhD; Francois Lamontagne, MD; Helen L. Leavis, MD, PhD; Kelsey M. Linstrum, MS; Edward Litton, MD, PhD; John C. Marshall, MD; Daniel F. McAuley, MD; Anna McGlothlin, PhD; Shay P. McGuinness, MD; Saskia Middeldorp, MD, PhD; Stephanie K. Montgomery, MSc; Susan C. Morpeth, MD, PhD; Srinivas Murthy, MD; Matthew D. Neal, MD; Alistair D. Nichol, MD, PhD; Rachael L. Parke, PhD; Jane C. Parker, BN; Luis F. Reyes, MD, PhD; Hiroki Saito, MD, MPH; Marlene S. Santos, MD, MSHS; Christina T. Saunders, PhD; Ary Serpa-Neto, PhD, MSc, MD; Christopher W. Seymour, MD, MSc; Manu Shankar-Hari, MD, PhD; Vanessa Singh; Timo Tolppa, MBBS; Alexis F. Turgeon, MD, MSc; Anne M. Turner, MPH; Frank L. van de Veerdonk, MD, PhD; Cameron Green, MSc; Roger J. Lewis, MD, PhD; Derek C. Angus, MD, MPH; Colin J. McArthur, MD; Scott Berry, PhD; Lennie P. G. Derde, MD, PhD; Steve A. Webb, MD, PhD; Anthony C. Gordon, MBBS, MD.

Affiliations of Authors/Writing Committee: University of Bristol, Bristol, England (Bradbury); Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada (Lawler, Goligher); University of Toronto, Toronto, Ontario, Canada (Lawler, Goligher); University of Oxford, Oxford, England (Stanworth, Beane); NHS Blood and Transplant, Oxford, England (Stanworth, Estcourt); University of Pittsburgh, Pittsburgh, Pennsylvania (McVerry, Girard, Huang, Linstrum, Montgomery, Neal, Seymour, Angus); Monash University, Melbourne, Victoria, Australia (McQuilten, Higgins, Buzgau, Cheng, McGuinness, Nichol, Parker, Serpa-Neto, Singh, Green, Webb); Monash Health, Melbourne, Victoria, Australia (McQuilten); Intensive Care National Audit and Research Centre (ICNARC), London, England (Mouncey, Rowan); Imperial College London, London, England (Al-Beidh, Gordon); Berry Consultants, Austin, Texas (L. R. Berry, Lorenzi, Detry, Fitzgerald, McGlothlin, Saunders, Lewis, S. Berry); University of Manitoba, Winnipeg, Canada (Zarychanski); King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Arabi); Hospital Raymond Poincaré (Assistance Publique Hôpitaux de Paris), Garches, France (Annane); Université Versailles SQY–Université Paris Saclay, Montigny-le-Bretonneux, France (Annane); University Medical Center Utrecht, Utrecht, the Netherlands (van Bentum-Puijk, Bonten, Leavis, Derde); St Michael’s Hospital Unity Health, Toronto, Ontario, Canada (Bhimani, Marshall, Santos); Flinders University, Bedford Park, South Australia, Australia (Bihari); Jena University Hospital, Jena, Germany (Brunkhorst); Global Coalition for Adaptive Research, Los Angeles, California (Buxton); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (Carrier); Institut du Savoir Montfort, Ottawa, Ontario, Canada (Carrier); Alfred Health, Melbourne, Victoria, Australia (Cheng); Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Cove); University of Antwerp, Wilrijk, Belgium (Goossens); University of Oxford, Bangkok, Thailand (Haniffa); National Intensive Care Surveillance (NICST), Colombo, Sri Lanka (Haniffa, Tolppa); Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand (Hills, Turner); UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (Horvat); Kings Healthcare Partners, London, England (Hunt); The University of Tokyo, Tokyo, Japan (Ichihara); Université de Sherbrooke, Sherbrooke, Québec, Canada (Lamontagne); Fiona Stanley Hospital, Perth, Western Australia, Australia (Litton); University of Western Australia, Perth, Australia (Litton); Queen’s University Belfast, Belfast, Northern Ireland (McAuley); Royal Victoria Hospital, Belfast, Northern Ireland (McAuley); Auckland City Hospital, Auckland, New Zealand (McGuinness, Parke, McArthur); Radboud University Medical Center, Nijmegen, the Netherlands (Middeldorp, van de Veerdonk); Middlemore Hospital, Auckland, New Zealand (Morpeth); University of British Columbia, Vancouver, Canada (Murthy); University College Dublin, Dublin, Ireland (Nichol); University of Auckland, Auckland, New Zealand (Parke); Universidad de La Sabana, Chia, Colombia (Reyes); Clinica Universidad de La Sabana, Chia, Colombia (Reyes); St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan (Saito); Hospital Israelita Albert Einstein, Sao Paulo, Brazil (Serpa-Neto); King’s College London, London, England (Shankar-Hari); Guy’s and St Thomas’ NHS Foundation Trust, London, England (Shankar-Hari); Université Laval, Québec City, Québec, Canada (Turgeon); CHU de Québec–Université Laval Research Center, Québec City, Québec, Canada (Turgeon); Harbor-UCLA Medical Center, Torrance, California (Lewis); St John of God Hospital, Subiaco, Western Australia, Australia (Webb); Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, England (Gordon).

Author Contributions: Drs Bradbury and Lewis had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Webb and Gordon are joint last authors.

Concept and design: Bradbury, Lawler, McVerry, Rowan, Lorenzi, Zarychanski, Bhimani, Bihari, Bonten, Brunkhorst, Cheng, Fitzgerald, Goligher, Goossens, Hills, Huang, Hunt, Litton, Marshall, McAuley, McGuinness, Middeldorp, Murthy, Neal, Nichol, Parke, Parker, Saito, Seymour, Shankar-Hari, Singh, Turgeon, van de Veerdonk, Lewis, Angus, McArthur, S. Berry, Derde, Webb, Gordon.

Acquisition, analysis, or interpretation of data: Bradbury, Lawler, Stanworth, McVerry, McQuilten, Higgins, Mouncey, Al-Beidh, Rowan, L. Berry, Lorenzi, Zarychanski, Arabi, Annane, Beane, van Bentum-Puijk, Buzgau, Buxton, Carrier, Cove, Detry, Estcourt, Fitzgerald, Girard, Haniffa, Hills, Horvat, Hunt, Ichihara, Lamontagne, Leavis, Linstrum, Litton, Marshall, McAuley, McGlothlin, Middeldorp, Montgomery, Morpeth, Murthy, Nichol, Parker, Reyes, Santos, Saunders, Serpa-Neto, Shankar-Hari, Tolppa, Turgeon, Turner, Green, Lewis, McArthur, S. Berry, Derde, Webb, Gordon.

Drafting of the manuscript: Bradbury, Lawler, McVerry, McQuilten, Lorenzi, Buzgau, Linstrum, Santos, Serpa-Neto, S. Berry, Webb, Gordon.

Critical revision of the manuscript for important intellectual content: Bradbury, Stanworth, McVerry, McQuilten, Higgins, Mouncey, Al-Beidh, Rowan, L. Berry, Lorenzi, Zarychanski, Arabi, Annane, Beane, van Bentum-Puijk, Bhimani, Bihari, Bonten, Brunkhorst, Buxton, Carrier, Cheng, Cove, Detry, Estcourt, Fitzgerald, Girard, Goligher, Goossens, Haniffa, Hills, Huang, Horvat, Hunt, Ichihara, Lamontagne, Leavis, Litton, Marshall, McAuley, McGlothlin, McGuinness, Middeldorp, Montgomery, Morpeth, Murthy, Neal, Nichol, Parke, Parker, Reyes, Saito, Saunders, Serpa-Neto, Seymour, Shankar-Hari, Singh, Tolppa, Turgeon, Turner, van de Veerdonk, Green, Lewis, Angus, McArthur, S. Berry, Derde, Webb, Gordon.

Statistical analysis: Bradbury, McQuilten, Higgins, L. Berry, Lorenzi, Detry, Fitzgerald, Goligher, Ichihara, McGlothlin, Saunders, Serpa-Neto, Lewis, S. Berry.

Obtained funding: Higgins, Rowan, Beane, Buxton, Carrier, Cheng, Cove, Goligher, Goossens, Litton, Marshall, McGuinness, Murthy, Nichol, Reyes, Turgeon, McArthur, Derde, Webb, Gordon.

Administrative, technical, or material support: Bradbury, McQuilten, Mouncey, Al-Beidh, Rowan, Zarychanski, Arabi, Beane, van Bentum-Puijk, Bhimani, Bihari, Brunkhorst, Buzgau, Buxton, Cheng, Cove, Estcourt, Girard, Horvat, Ichihara, Linstrum, Litton, McAuley, McGuinness, Nichol, Parker, Reyes, Santos, Seymour, Shankar-Hari, Singh, Tolppa, Turgeon, Turner, Green, Lewis, McArthur, Derde, Webb, Gordon.

Supervision: Lawler, Stanworth, Rowan, Bonten, Buxton, Estcourt, Girard, Lamontagne, Neal, Nichol, Reyes, Saito, Shankar-Hari, Lewis, Derde, Webb, Gordon.

Conflict of Interest Disclosures: Dr Bradbury reported receipt of personal fees from Lilly, BMS-Pfizer, Bayer, Amgen, Novartis, Janssen, Portola, Ablynx, and Grifols. Dr Lawler reported receipt of personal fees from Novartis, CorEvitas, and Brigham and Women’s Hospital and royalties from McGraw-Hill Publishing. Dr McVerry reported receipt of grants from the National Heart, Lung, and Blood Institute and Bayer Pharmaceuticals and personal fees from Boehringer Ingelheim. Dr L. Berry reported being an employee of Berry Consultants; Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Lorenzi reported being an employee of Berry Consultants; Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Zarychanski reported receipt of grants from the Canadian Institutes of Health Research, LifeArc, Research Manitoba, the CancerCare Manitoba Foundation, Peter Munk Cardiac Centre, and the Thistledown Foundation and research operating support as the Lyonel G. Israels Research Chair in Hematology. Dr Bonten reported membership in international study steering committees, advisory boards, and independent data safety and monitoring committees funded by Janssen Vaccines, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Sanofi Pasteur (all reimbursements to UMC Utrecht). Dr Brunkhorst reported receipt of grants from Jena University Hospital. Dr Buxton reported receipt of a gift from the Breast Cancer Research Foundation and contracts with Amgen and Eisai. Dr Carrier reported receipt of grants from BMS-Pfizer and personal fees from Bayer, Sanofi, Servier, Leo Phama, and BMS-Pfizer to his institution. Dr Cove reported receipt of grants from the National Medical Research Council and personal fees from Baxter and Medtronic. Dr Estcourt reported receipt of grants from the UK National Institute for Health Research (NIHR) and the European Union Horizon 2020 Research and Innovation Programme. Dr Haniffa reported receipt of grants from the UK Research and Innovation/Medical Research Council African Critical Care Registry Network. Dr Horvat reported receipt of grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Dr Ichihara reported being affiliated with the Department of Healthcare Quality Assessment, University of Tokyo, which is a social collaboration supported by the National Clinical Database, Johnson & Johnson, and Nipro Corporation. Dr Marshall reported receipt of personal fees from AM Pharma and Critical Care Medicine. Dr McAuley reported receipt of personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Lilly, Vir Biotechnology, Faron Pharmaceutical, and SOBI and grants from the NIHR, the Wellcome Trust, Innovate UK, the UK Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division; in addition, Dr McAuley had a Queen’s University Belfast patent for novel treatment for inflammatory disease (US8962032), was co-director of research at the Intensive Care Society until June 2021, and was director of the Efficacy and Mechanisms Evaluation Program for the UK Medical Research Council/NIHR. Dr Middeldorp reported receipt of personal fees from Daiichi Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Portola/Alexion, AbbVie, BMS-Pfizer, Sanofi, and Viatris, all paid to his institution, and grants from Daiichi Sankyo, Bayer, Pfizer, and Boehringer Ingelheim. Dr Neal reported equity in Haima Therapeutics, receipt of personal fees from Janssen Pharma and Haemonetics, and receipt of grants from Instrumentation Laboratory, the National Institutes of Health, and the Department of Defense. Dr Nichol reported receipt of personal fees from AM Pharma, paid to his university, and grants from Baxter. Dr Parke reported receipt of grants from Fisher and Paykel Healthcare NZ. Dr Serpa-Neto reported receipt of personal fees from Drager and Endpoint Health. Dr Seymour reported receipt of grants from the Gordon and Betty Moore Foundation and the National Institutes of Health/National Institute of General Medical Sciences. Dr Lewis reported being senior medical scientist at Berry Consultants; Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr S. Berry reported being an employee with an ownership role at Berry Consultants; Berry Consultants receives payments for the statistical analysis and design of REMAP-CAP. Dr Derde reported being a coordinating committee member for the European Clinical Research Alliance on Infectious Diseases, a member of the Dutch Intensivists Task Force on Acute Infectious Threats, a member of the International Scientific Advisory Board for Sepsis Canada, and a member of the Dutch Academy of Sciences’ Pandemic Preparedness Plan committee. Dr Gordon reported receipt of personal fees from 30 Respiratory, paid to his institution. No other disclosures were reported.

Funding/Support: This study was funded by the following: the Platform for European Preparedness Against (Re-)Emerging Epidemics (PREPARE) consortium of the European Union, FP7-HEALTH-2013-INNOVATION-1 (grant 602525), the Rapid European COVID-19 Emergency Research Response (RECOVER) consortium of the European Union’s Horizon 2020 Research and Innovation Programme (grant 101003589), the Australian National Health and Medical Research Council (grant APP1101719), the Health Research Council of New Zealand (grant 16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program (grant 158584), the NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (grant CTN 2014-012), the University of Pittsburgh Medical Center (UPMC) Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (grant PHRC-20-0147), the Minderoo Foundation, and the Wellcome Trust Innovations Project (grant 215522). Dr Shankar-Hari is funded by an NIHR clinician scientist fellowship (grant CS-2016-16-011) and Dr Gordon is funded by an NIHR research professorship (grant RP-2015-06-18).

Role of the Funder/Sponsor: The study funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The platform trial has 4 regional nonprofit sponsors: Monash University, Melbourne, Victoria, Australia (Australasian sponsor); Utrecht Medical Center, Utrecht, the Netherlands (European sponsor); St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor); and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). Several authors are employees of these organizations. However, beyond the declared author contributions, the sponsors had no additional role.

Disclaimer: The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Dr Seymour is Associate Editor of JAMA, Dr Angus is Senior Editor of JAMA, and Dr Lewis is Statistical Editor of JAMA, but none were involved in any of the decisions regarding review of the manuscript or its acceptance.

Group Information: The REMAP-CAP Investigators are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

Meeting Presentation: This study was presented at the International Symposium on Intensive Care and Emergency Medicine (ISICEM); March 22, 2022; Brussels, Belgium.

Additional Contributions: We are grateful to the NIHR Clinical Research Network, the UPMC Health System Health Services Division, and the Direction de la Recherche Clinique et de l’Innovation de l’AP-HP for their support of participant recruitment. We are also very thankful to the patients who have participated in this trial.

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