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 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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Participants in the COVID-19 Antiplatelet Domain of the REMAP-CAP Randomized Clinical Trial

NSAID indicates nonsteroidal anti-inflammatory drug; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. As a platform trial with a single master protocol (Supplement 1) and multiple treatments evaluated simultaneously, this trial applied eligibility criteria at the platform level and at the domain level. Patients had to be eligible for both platform and domain to be randomized. With an adaptive platform design, it allowed treatments to be stopped for futility, to declare 1 or more treatments to be superior, or to add new treatments or whole therapeutic areas during the course of the trial. A domain refers to a common therapeutic area (eg, antiviral therapy or immunoglobulin therapy) within which several interventions or intervention dosing strategies could be randomly assigned. aPatients could meet more than 1 ineligibility criterion. bContraindications to antiplatelet agents, including hypersensitivity to an antiplatelet agent specified as an intervention, excluded patients from receiving that antiplatelet intervention; known or suspected pregnancy excluded patients from the P2Y12 inhibitor intervention; administration or intention to administer lopinavir/ritonavir excluded patients from receiving a P2Y12 inhibitor at sites that were using clopidogrel and ticagrelor. cParticipants were randomized via a centralized computer program to each intervention starting with balanced assignment and then adapted with preferential assignment to interventions that appeared most favorable until predefined statistical triggers of superiority or futility were met. dCritically ill patients were required to have at least 1 of high-flow nasal cannula oxygenation, invasive or noninvasive mechanical ventilation, or vasopressor or inotropic infusion. eResults for non–critically ill patients were used for borrowing within the primary model, meaning that results for non–critically ill patients were partially pooled with critically ill patients in the primary analysis. This partial pooling provides a more precise estimate of the treatment effect of antiplatelet therapy in critically ill patients if the observed data in the 2 groups are similar. fThe primary analysis of alternative interventions within the antiplatelet domain is estimated from a model that adjusts for patient factors and for assignment to other interventions; all patients enrolled in the COVID-19 cohort for whom consent was obtained and follow-up data were available are included. The final estimate of an antiplatelet domain intervention’s effectiveness relative to any other within that domain is generated from patients who might have been randomized to either.

Figure 2.. Primary Outcome: Organ Support–Free Days Up to Day 21 in Critically Ill Patients

A, Distributions of organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21 in critically ill patients. The ordinal scale includes in-hospital death (the worst possible outcome) and the numbers of days alive without organ support. The curves represent the cumulative proportion (y-axis) for each group by day (x-axis), and the bars represent the proportion (y-axis) for each group by day (x-axis). Curves that increase more slowly are more favorable. The difference in the height of the 2 curves at any point represents the difference in the cumulative probability of having a value for days without organ support of less than or equal to that point on the x-axis. B, Organ support–free days as horizontally stacked proportions by intervention group. Red represents worse values and blue represents better values; the deepest red is death and deepest blue is 21 organ support–free days. The primary analysis compared organ support–free days in the control (no antiplatelet therapy) group with the pooled aspirin and P2Y12 inhibitor groups. Accordingly, the distribution of organ support–free days is shown for the pooled antiplatelet group, separate aspirin and P2Y12 inhibitor groups, and control (no antiplatelets) group.

Figure 3.. Survival Through 90 Days in Critically Ill Patients

Kaplan-Meier curve of 90-day all-cause mortality in critically ill patients. Patients who survived to 90 days were censored at day 90 with no event. The pooled antiplatelet group is the composite of patients in the aspirin and P2Y12 inhibitor groups. A hazard ratio greater than 1 represents improved survival. The hazard ratio for aspirin is 1.19 (95% credible interval [CrI], 1.00-1.42; 97.5% posterior probability of efficacy) and the hazard ratio for P2Y12 inhibitors is 1.23 (95% CrI, 1.02-1.49; 98.7% posterior probability of efficacy).