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

REMAP-CAP Writing Committee

doi:10.1001/jama.2022.2910

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

REMAP-CAP Writing Committee

Bristol Medical School (THS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

120 Citations (Scopus)

185 Downloads (Pure)

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 30th 2020 and June 23rd 2021 from 105 sites in 8 countries and followed for 90 days (final follow up date July 26, 2021).
INTERVENTIONS Patients were randomized to either open-label aspirin (n=565), P2Y12 inhibitor (n=455), or no antiplatelet therapy (control, n=529). Interventions were continued in hospital for 14 days maximum 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 ICU-based respiratory or cardiovascular organ support, OSFDs) 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)>1 represented improved survival, more OSFDs, or both. Efficacy was defined as >99% posterior probability of an OR>1. Futility was defined as a >95% posterior probability of an OR<1.2 compared with control. Intervention equivalence was defined as >90% probability the OR (compared with each other) was between 1/1.2 and 1.2 for two non-control interventions.
RESULTS The aspirin and P2Y12 inhibitor groups met the pre-defined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the pre-specified criterion for futility was met for 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). Median(IQR) OSFDs was 7(-1, 16) in both antiplatelet and control groups (median adjusted OR 1.02(95%Crl: 0.86, 1.23); 95.7% posterior probability of futility). The proportion of patients surviving to hospital discharge was 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups (median adjusted OR 1.27 (95%Crl: 0.99, 1.62); adjusted absolute difference 5% (95%CrI: -0.2, 9.5), 97% posterior probability of efficacy). Among survivors, median OSFDs 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 number:NCT02735707

Original language	English
Article number	13
Pages (from-to)	1247-1259
Number of pages	13
Journal	JAMA - Journal of the American Medical Association
Volume	327
Issue number	13
DOIs	https://doi.org/10.1001/jama.2022.2910
Publication status	Published - 22 Mar 2022

Bibliographical note

Funding Information:
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).

Funding Information:
The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists.

Funding Information:
REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands

Funding Information:
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.

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© 2022 American Medical Association. All rights reserved.

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@article{a9e86becafe2400da06b695688874bd0,

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

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 30th 2020 and June 23rd 2021 from 105 sites in 8 countries and followed for 90 days (final follow up date July 26, 2021). INTERVENTIONS Patients were randomized to either open-label aspirin (n=565), P2Y12 inhibitor (n=455), or no antiplatelet therapy (control, n=529). Interventions were continued in hospital for 14 days maximum 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 ICU-based respiratory or cardiovascular organ support, OSFDs) 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)>1 represented improved survival, more OSFDs, or both. Efficacy was defined as >99\% posterior probability of an OR>1. Futility was defined as a >95\% posterior probability of an OR<1.2 compared with control. Intervention equivalence was defined as >90\% probability the OR (compared with each other) was between 1/1.2 and 1.2 for two non-control interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the pre-defined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the pre-specified criterion for futility was met for 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). Median(IQR) OSFDs was 7(-1, 16) in both antiplatelet and control groups (median adjusted OR 1.02(95\%Crl: 0.86, 1.23); 95.7\% posterior probability of futility). The proportion of patients surviving to hospital discharge was 71.5\% (723/1011) and 67.9\% (354/521) in the antiplatelet and control groups (median adjusted OR 1.27 (95\%Crl: 0.99, 1.62); adjusted absolute difference 5\% (95\%CrI: -0.2, 9.5), 97\% posterior probability of efficacy). Among survivors, median OSFDs 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 number:NCT02735707 ",

author = "\{REMAP-CAP Writing Committee\} and Bradbury, \{Charlotte A\}",

note = "Funding Information: 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{\textquoteright}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). Funding Information: The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists. Funding Information: REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands Funding Information: 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{\textquoteright}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{\textquoteright}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{\textquoteright} Pandemic Preparedness Plan committee. Dr Gordon reported receipt of personal fees from 30 Respiratory, paid to his institution. No other disclosures were reported. Publisher Copyright: {\textcopyright} 2022 American Medical Association. All rights reserved.",

year = "2022",

month = mar,

day = "22",

doi = "10.1001/jama.2022.2910",

language = "English",

volume = "327",

pages = "1247--1259",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "13",

}

TY - JOUR

T1 - Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19

T2 - A Randomized Clinical Trial

AU - REMAP-CAP Writing Committee

AU - Bradbury, Charlotte A

N1 - Funding Information: 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). Funding Information: The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists. Funding Information: REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands Funding Information: 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. Publisher Copyright: © 2022 American Medical Association. All rights reserved.

PY - 2022/3/22

Y1 - 2022/3/22

N2 - 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 30th 2020 and June 23rd 2021 from 105 sites in 8 countries and followed for 90 days (final follow up date July 26, 2021). INTERVENTIONS Patients were randomized to either open-label aspirin (n=565), P2Y12 inhibitor (n=455), or no antiplatelet therapy (control, n=529). Interventions were continued in hospital for 14 days maximum 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 ICU-based respiratory or cardiovascular organ support, OSFDs) 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)>1 represented improved survival, more OSFDs, or both. Efficacy was defined as >99% posterior probability of an OR>1. Futility was defined as a >95% posterior probability of an OR<1.2 compared with control. Intervention equivalence was defined as >90% probability the OR (compared with each other) was between 1/1.2 and 1.2 for two non-control interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the pre-defined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the pre-specified criterion for futility was met for 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). Median(IQR) OSFDs was 7(-1, 16) in both antiplatelet and control groups (median adjusted OR 1.02(95%Crl: 0.86, 1.23); 95.7% posterior probability of futility). The proportion of patients surviving to hospital discharge was 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups (median adjusted OR 1.27 (95%Crl: 0.99, 1.62); adjusted absolute difference 5% (95%CrI: -0.2, 9.5), 97% posterior probability of efficacy). Among survivors, median OSFDs 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 number:NCT02735707

AB - 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 30th 2020 and June 23rd 2021 from 105 sites in 8 countries and followed for 90 days (final follow up date July 26, 2021). INTERVENTIONS Patients were randomized to either open-label aspirin (n=565), P2Y12 inhibitor (n=455), or no antiplatelet therapy (control, n=529). Interventions were continued in hospital for 14 days maximum 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 ICU-based respiratory or cardiovascular organ support, OSFDs) 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)>1 represented improved survival, more OSFDs, or both. Efficacy was defined as >99% posterior probability of an OR>1. Futility was defined as a >95% posterior probability of an OR<1.2 compared with control. Intervention equivalence was defined as >90% probability the OR (compared with each other) was between 1/1.2 and 1.2 for two non-control interventions. RESULTS The aspirin and P2Y12 inhibitor groups met the pre-defined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the pre-specified criterion for futility was met for 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). Median(IQR) OSFDs was 7(-1, 16) in both antiplatelet and control groups (median adjusted OR 1.02(95%Crl: 0.86, 1.23); 95.7% posterior probability of futility). The proportion of patients surviving to hospital discharge was 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups (median adjusted OR 1.27 (95%Crl: 0.99, 1.62); adjusted absolute difference 5% (95%CrI: -0.2, 9.5), 97% posterior probability of efficacy). Among survivors, median OSFDs 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 number:NCT02735707

U2 - 10.1001/jama.2022.2910

DO - 10.1001/jama.2022.2910

M3 - Article (Academic Journal)

C2 - 35315874

SN - 0098-7484

VL - 327

SP - 1247

EP - 1259

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 13

M1 - 13

ER -

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

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