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Visual Abstract. Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
Figure 1.  Flow of Participants in the COVID-19 Antiplatelet Domain of the REMAP-CAP Randomized Clinical Trial
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
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
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).

Table 1.  Baseline Characteristics of Critically Ill Participantsa
Baseline Characteristics of Critically Ill Participantsa
Table 2.  Primary and Selected Secondary Outcomes of Critically Ill Participants
Primary and Selected Secondary Outcomes of Critically Ill Participants
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Original Investigation
Caring for the Critically Ill Patient
March 22, 2022

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 for the REMAP-CAP Investigators
JAMA. 2022;327(13):1247-1259. doi:10.1001/jama.2022.2910
Visual Abstract. Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19
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

Introduction

Thrombotic events are common in patients hospitalized with COVID-19 and occur in spite of standard thromboprophylaxis, with critically ill patients being at highest risk.1-7 Thrombotic events have been reported in the venous, arterial, and microvascular circulations and are independently associated with poor outcomes.4 Vascular endothelial injury and inflammation activate intravascular coagulation through diverse mediators such as elevated fibrinogen, factor VIII, von Willebrand factor, platelet activation, impaired fibrinolysis, and reduced antithrombin.8

In a collaborative multiplatform trial that included the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), therapeutic-dose heparin was found to improve organ support–free days in non–critically ill patients,9 but not in critically ill patients,10 hospitalized for COVID-19. Accordingly, despite a high occurrence of thrombosis, optimal antithrombotic strategies in critically ill patients remain unknown. Platelet activation has been implicated in the COVID-19 inflammatory response,11,12 and autopsies have shown microvascular thrombi with megakaryocyte and platelet-fibrin deposition in the setting of organ failure.13-15 In this trial, the effect of antiplatelet therapy (aspirin or P2Y12 inhibitor) on the composite of hospital survival and organ support provision for up to 21 days was evaluated in patients hospitalized with COVID-19.

Methods
Trial Design and Oversight

REMAP-CAP is an international, adaptive platform trial designed to iteratively determine best treatment strategies for patients with severe pneumonia in both pandemic and nonpandemic settings, and has reported on corticosteroids, anticoagulants, antivirals, interleukin 6 receptor antagonists, and convalescent plasma in patients with COVID-19.9,10,16-19 Patients eligible for the platform are assessed for eligibility and potentially randomized to 1 or more interventions across multiple domains. Domains encompass therapeutic areas and contain 2 or more interventions (including control). Details of the trial design have been reported previously20 and are available in the trial protocol and statistical analysis plan (Supplement 1). The trial was approved by relevant regional ethics committees and conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.21 Written or oral informed consent, in accordance with regional legislation, was obtained from all patients or their surrogates. To account for the observed racial and ethnic differences in outcomes during the pandemic, this trial collected self-reported race and ethnicity data from either the participants or their surrogates via fixed categories appropriate to their region.

Participants

Patients admitted to the hospital, aged 18 years or older, with clinically suspected or microbiologically confirmed COVID-19 were eligible for enrollment. Patients admitted to an intensive care unit (ICU) and receiving respiratory or cardiovascular organ support were classified as critically ill and all others as non–critically ill. Respiratory organ support was defined as invasive or noninvasive mechanical ventilation including via high-flow nasal cannula if the flow rate was at least 30 L/min and the fraction of inspired oxygen was at least 0.4. Cardiovascular organ support was defined as receipt of vasopressors or inotropes. Exclusion criteria included presumption that death was imminent with lack of commitment to full support, clinical or laboratory-based bleeding risk sufficient to contraindicate antiplatelet therapy, creatinine clearance less than 30 mL/min or receipt of kidney replacement therapy, enrollment in an external trial of anticoagulation or antiplatelet therapy, or enrollment in the anticoagulation domain of the trial platform for participants older than 75 years. Patients were also excluded if they were already receiving antiplatelet therapy or nonsteroidal anti-inflammatory drugs (NSAIDs), if a clinical decision had been made to commence antiplatelet or NSAID therapy, or if a treating clinician believed that participation in the domain would not be in the best interests of a patient. Critically ill patients had to be enrolled within 48 hours of admission to an ICU. Patients were enrolled from 105 sites in 8 countries (Canada, France, Germany, India, Italy, Nepal, the Netherlands, and the United Kingdom). Additional platform and antiplatelet domain–specific exclusion criteria are listed in eAppendix 1 in Supplement 2.

Treatment Allocation

The antiplatelet domain included 3 groups to which patients could be assigned: aspirin, P2Y12 inhibitor, and no antiplatelet therapy (control). Each site’s clinical investigator team chose a priori at least 2 intervention groups, one of which had to be control, to which patients could be randomized. Sites that chose the P2Y12 inhibitor intervention further selected which P2Y12 inhibitor would be administered at their site (clopidogrel, prasugrel, or ticagrelor) according to availability and local preference. Patients were randomized via centralized computer program with allocation ratios dependent on the number of interventions at each site. Patients were initially randomized equally across the interventions available at each site. The domain also permitted variation in allocation ratios based on regular adaptive analysis. Randomization started on October 30, 2020. Response-adaptive randomization was applied on April 21, 2021 (see eFigure 1 in Supplement 2 for recruitment rates over time). Patients could be randomized to additional interventions within other domains, depending on domains active at the site, patient eligibility, and consent (see http://www.remapcap.org). Other aspects of care were provided per each site’s standard care.

Interventions

All antiplatelet interventions were administered enterally until study day 14 or hospital discharge, whichever occurred first. After 14 days, decisions regarding antiplatelet therapy were at the discretion of treating clinicians. Antiplatelet dosing was as follows: aspirin, 75 to 100 mg once daily; clopidogrel, 75 mg once daily without a loading dose; ticagrelor, 60 mg twice daily without a loading dose; prasugrel, a 60-mg loading dose followed by 10 mg daily (if aged <75 years and weight ≥60 kg) or 5 mg daily (if aged ≥75 years or weight <60 kg). Gastric acid suppression was recommended for patients receiving antiplatelet therapy through co-administration of either proton pump inhibitor or H2 receptor antagonist. Antiplatelet therapy could be discontinued if there was an adverse event or commenced in the control group if clinically warranted for a standard indication other than COVID-19. Patients received concurrent anticoagulation thromboprophylaxis according to standard care if not randomized in the anticoagulation domain of the trial.

Outcome Measures

The primary outcome was respiratory and cardiovascular organ support–free days to day 21. In this composite ordinal outcome, all deaths occurring during the index hospitalization were assigned the worst possible outcome (–1). Among survivors, respiratory and cardiovascular organ support–free days were calculated up to day 21 (survivors with no organ support were assigned a score of 22). Secondary outcomes were survival to day 90, progression to invasive mechanical ventilation, extracorporeal membrane oxygenation or death among those not receiving that support at baseline, vasopressor-/inotrope-free days, respiratory support–free days, duration of ICU stay, duration of hospital stay, serious adverse events, World Health Organization ordinal score for clinical improvement (ranging from 0 [no evidence of infection] to 8 [death]), major bleeding up to day 14 defined according to International Society of Hemostasis and Thrombosis criteria (see eAppendix 1 in Supplement 2 for details) including fatal and intracranial bleeding, venous thromboembolism (deep vein thrombosis, pulmonary embolism, and other venous thromboembolism), arterial thrombosis (cerebrovascular event, myocardial infarction, and other arterial thrombotic event), as well as a composite of thrombosis or death. Individual components of the above mentioned composite outcomes were also prespecified as secondary outcomes but are not analyzed individually in this report. Thrombotic outcomes and major bleeding events were centrally adjudicated in a blinded manner.

Sample Size Calculation

The trial was designed with no maximum sample size given the uncertainty of the pandemic. Sample size calculations for the primary outcome were performed using trial simulations of the adaptive design rules (see eFigure 2 in Supplement 2). The domain had at least 90% power to demonstrate superiority of an antiplatelet therapy to no antiplatelet therapy with 900 patients enrolled assuming an odds ratio effect size of 1.5. The cumulative type I error rate up to 3000 patients was less than 5%.

Statistical Analysis

The primary analysis was a bayesian cumulative logistic model, which calculated posterior probability distributions of organ support–free days (primary outcome) based on evidence accumulated in the trial and prior information. Prior distributions for treatment effects in critically and non–critically ill patients were nested in a hierarchical prior distribution centered on an overall intervention effect estimated with a neutral prior assuming no treatment effect (standard normal prior on the log odds ratio; see eFigure 2 in Supplement 2). The primary model estimated treatment effects for each intervention within each domain and prespecified treatment-by-treatment interactions. The primary model also adjusted for location (site nested within country), age (categorized into 6 groups), sex, and time period (2-week epochs). The model was fit using a Markov chain Monte Carlo algorithm that calculated the posterior distribution of the proportional odds ratios, including medians and 95% credible intervals (CrIs). The predefined statistical triggers for trial conclusions were (1) a superiority conclusion if there was greater than 99% posterior probability that an intervention was optimal compared with all other interventions; (2) an inferiority conclusion if there was less than 1% posterior probability that an intervention was optimal; (3) intervention efficacy if there was greater than 99% posterior probability that the odds ratio was greater than 1 compared with control; (4) intervention futility if there was greater than 95% posterior probability that the odds ratio was less than 1.2 compared with control; or (5) intervention equivalence if there was greater than 90% probability that the odds ratio (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions.

On March 22, 2021, the equivalence trigger was reached for the primary outcome in critically ill patients for the aspirin and P2Y12 inhibitor groups. Randomization continued for these 2 antiplatelet groups, but for critically ill patients, the groups were statistically pooled and a single treatment effect relative to control was estimated for subsequent primary analysis. The 2 antiplatelet groups were not pooled for non–critically ill patients as no equivalence threshold had been reached. A prespecified interaction was modeled between antiplatelet therapy and therapeutic-dose heparin in the anticoagulation domain of the trial.

The primary analysis was conducted by an independent statistical analysis committee including all patients with COVID-19 randomized to any domain up to June 23, 2021 (and with complete follow-up for the primary outcome). Patients were analyzed in the groups to which they were originally randomized. There was no imputation of missing data for primary or secondary outcomes. Recruitment of non–critically ill patients was stopped due to slow recruitment and external evidence even though no statistical threshold for the primary outcome had been reached. The analysis of the results for non–critically ill patients is presented in eTables 2-4 in Supplement 2 for completeness.

Not all patients enrolled in the platform were eligible for all domains or interventions (dependent on active domains/interventions at the site, eligibility criteria, and patient/surrogate consent). Therefore, the analytical model included covariate terms reflecting randomization to each domain and the site, so that treatment effects were estimated only from patients who were concurrently randomized within the domain and directly comparing specific interventions available at each site. Patients enrolled outside the antiplatelet domain did not contribute to estimates of antiplatelet treatment effect but did contribute to the estimates of the covariate effects, providing the most robust estimation of covariate effects.16,20

Sensitivity and secondary analyses were performed by investigators blinded to ongoing interventions, so these analyses were restricted to data from patients enrolled in domains that were unblinded at the time of analysis with no adjustment for assignment in the ongoing domains. Treatment effects were also analyzed for aspirin and P2Y12 inhibitors compared with control separately. Prespecified sensitivity analyses included removing time and site effects from the model, as well as independent priors for the 2 antiplatelet treatments and alternative priors for interactions with other interventions. Secondary dichotomous outcomes were analyzed with bayesian logistic regression models. The secondary time-to-event outcomes (mortality and length of stay) were analyzed using a piecewise exponential bayesian model to estimate hazard ratio effects. No formal hypothesis tests were performed on secondary outcomes, and summaries of the posterior distributions and probabilities are provided for descriptive purposes only. Prespecified subgroup analyses included baseline mechanical ventilation status, age category (<50, 50-70, or ≥70 years), and baseline anticoagulation dose (defined in eTable 1 in Supplement 2). In a post hoc analysis, the baseline anticoagulation categories were collapsed into 2 categories, therapeutic dose and less than therapeutic dose. If the dose was not recorded, it was included in an unknown-dose category. Further details of all analyses are provided in eAppendix 1 in Supplement 2 and in the statistical analysis plan (Supplement 1). Data management and summaries were created using R version 3.6.0; the primary analysis was computed in R version 4.0.0 using the rstan package version 2.21.1. Additional data management and analyses were performed in SQL 2016, SPSS version 26, and Stata version 14.2.

Results
Enrollment and Participant Characteristics

The first patient was enrolled into the antiplatelet domain on October 30, 2020. On March 22, 2021, the prespecified equivalence trigger for the aspirin and P2Y12 inhibitor groups (compared with each other) was reached in critically ill patients with 1016 patients enrolled with complete data (P2Y12 inhibitor to aspirin odds ratio, 1.00 [95% CrI, 0.80-1.23]; 90.1% posterior probability of equivalence). These groups continued to enroll separately but were subsequently statistically pooled into a combined antiplatelet group for all further adaptive analyses. On June 24, 2021, enrollment was discontinued after an adaptive analysis demonstrated that the prespecified stopping criterion for futility had been reached in critically ill patients, and patient follow-up continued until July 26, 2021. At that time, 1557 critically ill and 267 non–critically ill patients had been enrolled and randomized (Figure 1). Of these, 8 critically ill patients and 1 non–critically ill patient withdrew consent, and outcome data were not available for 17 critically ill and 3 non–critically ill patients. For non–critically ill patients, based on slow enrollment rates and external data,22 the international trial steering committee decided to simultaneously stop enrollment. Results for non–critically ill patients are shown in eAppendix 2 and eTables 2-4 in Supplement 2.

Baseline characteristics were comparable between the intervention groups (Table 1; eTable 2 in Supplement 2).

The median duration of antiplatelet therapy for critically ill patients randomized to receive aspirin was 12 (IQR, 7-14) days (data available for 560/565), and for those receiving a P2Y12 inhibitor the median duration was 11 (IQR, 6-14) days (data available for 433/455). Among 455 participants allocated to receive a P2Y12 inhibitor, 403 (88.5%) received clopidogrel, 6 (1.3%) received ticagrelor, 6 (1.3%) received prasugrel, and in 40 (8.8%) the P2Y12 inhibitor administered was unknown (for these remaining patients, site choice was clopidogrel for 13, ticagrelor for 17, prasugrel for 4, and unknown for 6). All patients with data available (n = 1419) received concurrent thromboprophylaxis according to usual care at the site or were concomitantly enrolled in the platform anticoagulation study. The most frequent concurrent anticoagulant at baseline was low-molecular-weight heparin (97.7%), and the most frequent dose was an intermediate dose (59%) (see eTable 1 in Supplement 2 for anticoagulation dose classification).

Primary Outcome

Among critically ill participants, the median number of organ support–free days was 7 (IQR, –1 to 16) in both the pooled antiplatelet and control groups. The median adjusted odds ratio for the effect of antiplatelet therapy compared with control was 1.02 (95% CrI, 0.86-1.23), yielding a posterior probability of futility of 95.7% (Table 2 and Figure 2). 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, yielding a median adjusted odds ratio for hospital survival of 1.27 (95% CrI, 0.99-1.62), with an adjusted absolute difference of 5% (95% CrI, −0.2% to 9.5%) and a posterior probability of efficacy of 97.0% for antiplatelet therapy compared with control. The median number of organ support–free days in survivors was 14 days in both groups (IQRs, 4-17 days in the antiplatelet group and 6.25-18 days in the control group). Patients with missing data for organ support–free days were excluded from the primary analysis (8/529 [1.5%] in the control group and 9/1020 [0.9%] in the pooled antiplatelet group). The secondary analysis of separate treatment effects of aspirin and P2Y12 inhibitors on the primary outcome are shown in Table 2.

Secondary Outcomes

Select secondary outcomes are shown in Table 2 and others are shown in eAppendix 2 and eTable 5 in Supplement 2. The effect of antiplatelet therapy on survival over 90 days is shown in Figure 3, with a median adjusted hazard ratio of 1.22 (95% CrI, 1.06-1.40) and 99.7% posterior probability of improved survival of the pooled antiplatelet group compared with control. Five patients were censored before 90 days (1 in the control group, 1 in the aspirin group, and 3 in the P2Y12 inhibitor group). The estimated mortality rate at 90 days for the control group was 32.7% (95% CI, 28.5%-36.6%) and for the pooled antiplatelet group was 29.5% (95% CI, 26.6%-32.2%) (Figure 3). Thrombotic event frequencies alongside mortality and major bleeding data are provided in Table 2, and other secondary outcomes are shown in eTable 5 in Supplement 2. Major bleeding occurred in 21 of 1002 participants (2.1%) in the pooled antiplatelet group and in 2 of 517 participants (0.4%) in the control group. An analysis of major bleeding comparing the pooled antiplatelet group with control showed an adjusted odds ratio of 2.97 (95% CrI, 1.23-8.28) and an adjusted absolute risk difference of 0.8% (95% CrI, 0.1%-2.7%), with a posterior probability of harm of 99.4%. The separate treatment effects of aspirin and P2Y12 inhibitors on thrombotic and bleeding rates are presented in Table 2.

Adverse Events

Serious adverse events were reported in 5 of 565 (0.9%), 4 of 455 (0.9%), and 3 of 529 (0.6%) participants in the aspirin, P2Y12 inhibitor, and control groups, respectively (eTable 6 in Supplement 2).

Subgroup Analyses and Interactions

The prespecified subgroup analyses for critically ill patients by age, baseline use of mechanical ventilation, and anticoagulant dose are presented in eTable 7 in Supplement 2. In the prespecified interaction analysis of patients co-enrolled in the antiplatelet domain and the therapeutic anticoagulant domain (n = 122 critically ill patients), the odds ratio for the combination of antiplatelet therapy and therapeutic-dose heparin anticoagulation, compared with no antiplatelet therapy and standard thromboprophylaxis, was 0.73 (95% CrI, 0.44-1.21) for organ support–free days and 0.72 (95% CrI, 0.41-1.28) for hospital survival. The odds ratio for the interaction of antiplatelet therapy and therapeutic-dose heparin anticoagulation was 0.79 (95% CrI, 0.50-1.30) for organ support–free days and 0.64 (95% CrI, 0.39-1.05) for hospital survival (eTable 8 in Supplement 2).

Post Hoc Analysis

A post hoc subgroup analysis of hospital mortality according to baseline concomitant anticoagulation dose (randomized and usual care; n = 1360 with a known dose of anticoagulation therapy) demonstrated that for patients receiving therapeutic-dose anticoagulation (n = 179), the adjusted odds ratio for hospital survival of antiplatelet therapy compared with control was 0.63 (95% CrI, 0.31-1.28; 89.9% probability that antiplatelet therapy led to harm in this context). In contrast, for patients receiving anticoagulation doses lower than therapeutic (n = 1181), the adjusted odds ratio for hospital survival was 1.33 (95% CrI, 0.99-1.79; 97.1% probability that pooled antiplatelet therapy improved hospital survival in this context) (eTable 9 and eFigure 3 in Supplement 2). For patients missing data on a baseline concomitant anticoagulation dose (n = 162), the adjusted odds ratio of hospital survival for antiplatelet therapy compared with control was 1.09 (95% CrI, 0.53-2.17).

Discussion

Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet treatment, had a low likelihood of providing improvement in the number of organ support–free days within 21 days.

Thrombotic complications are common in patients admitted to the hospital with COVID-19 in spite of conventional thromboprophylaxis among critically ill patients at highest risk. Macrovascular thrombosis occurs within venous and arterial circulations and microvascular thrombi contribute to organ dysfunction, including acute respiratory distress syndrome. The pathogenesis of thrombosis in COVID-19 is intimately linked with the inflammatory response to the virus, endothelial infection, activation, and injury, as well as hypercoagulability.6,23-33 Recognition that thrombosis is a key contributor to clinical deterioration and death in COVID-19 has led to global interest in whether enhanced antithrombotic treatments or extended duration improves patient outcomes.34 It was recently reported that therapeutic-dose heparin improves organ support–free days in hospitalized non–critically ill patients.9 Results from 2 subsequent randomized clinical trials have also supported the role of therapeutic-dose heparin in this cohort.35,36 In contrast, in critically ill patients, therapeutic-dose heparin did not improve outcomes, with a high probability of harm.10 The INSPIRATION trial also failed to demonstrate benefit of intermediate-dose heparin compared with a conventional low dose in this critically ill patient group.37 The factor Xa inhibitor rivaroxaban at a therapeutic dose for an extended duration, including postdischarge (30 days postrandomization), was not beneficial in a mixed population of patients with mild, moderate, and severe COVID-19.38 Therefore, efficacy of antithrombotic agents may vary by mechanism of action, illness severity, dose, and duration.

Platelets are activated and hyperaggregable in patients with COVID-19.11,12 Activated platelets reciprocally upregulate systemic inflammation, and therefore, platelet inhibition may have antithrombotic and anti-inflammatory benefits.19,39 Observational data support an association between antiplatelet therapy and reduced lung injury, ICU requirement, and mortality, without increased bleeding.39,40 Accordingly, this trial evaluated antiplatelet treatments in patients hospitalized for COVID-19, stratified by baseline illness severity.

In this trial, antiplatelet therapy met the prespecified criterion for futility in critically ill patients based on very similar outcomes for organ support–free days compared with control. However, in critically ill patients, there was a 97% probability that antiplatelet therapy improved survival to hospital discharge, with an adjusted absolute reduction in mortality of 5% and a 99.7% probability that it improved survival over 90 days. As recruitment occurred in 8 countries and antiplatelet therapy is inexpensive, widely available, and easy to administer and dose, these results are expected to have global applicability. The reduction in mortality was counterbalanced by an increase in the number of patients receiving short durations of organ support (<6 days), resulting in an overall net neutral effect on the outcome of organ support–free days. It is possible that antiplatelet therapy may reduce fatal complications of COVID-19 in critically ill patients while potentially increasing the need for organ support, possibly through bleeding that may or may not be clinically evident, such as alveolar hemorrhage.41 Major bleeding occurred more frequently in patients randomized to antiplatelet therapy. It is also possible that the net neutral effect of antiplatelet therapy on organ support–free days may have been influenced by a harmful interaction between antiplatelet therapy and therapeutic-dose anticoagulation, whereby patients receiving the combination appeared to have worse outcomes. No substantive effects of antiplatelet therapy on organ support–free days were observed in non–critically ill patients.

In the RECOVERY trial, 28-day mortality was not different in patients allocated to receive aspirin compared with control (17% in both groups), although a slightly higher proportion of patients were discharged from the hospital alive within 28 days (75% vs 74%; rate ratio, 1.06; 95% CI, 1.02-1.10; P = .006).22 Compared with the current trial, the majority of patients recruited to the RECOVERY trial were non–critically ill, and among those receiving noninvasive or invasive ventilation, the relative risk for 28-day mortality was 0.95 (95% CI, 0.87-1.03) with aspirin treatment (mortality in the usual-care group, 29.9% [750/2505]; mortality in the aspirin group, 28.4% [685/2415]). Compared with RECOVERY, other differences in this trial included the recommendation for gastric protection, exclusion of patients at elevated risk of bleeding (including those with severe kidney failure), and lower aspirin dose.

The recently published ACTIV-4a trial of P2Y12 inhibition in non–critically ill patients with COVID-19 (n = 562) demonstrated that addition of P2Y12 inhibition to therapeutic-dose heparin did not increase the odds of improvement in days alive and free of cardiovascular or respiratory organ support within 21 days (adjusted odds ratio, 0.83; 96% posterior probability of futility) compared with usual-care therapeutic anticoagulation.42,43 That trial differed from the REMAP-CAP antiplatelet intervention trial in that the cohort was non–critically ill, P2Y12 inhibition was provided in combination with therapeutic-dose anticoagulation, and the predominant P2Y12 inhibitor was ticagrelor, a more potent agent than clopidogrel. The ACTIV-4a trial testing P2Y12 inhibitors alongside prophylactic-dose heparin for critically ill patients is ongoing (NCT04505774).

In critically ill patients, although major bleeding was more common in patients allocated to antiplatelet therapy (aspirin [2.0%] or P2Y12 inhibitor [2.1%]) compared with control (0.4%), these absolute frequencies appear lower than those reported in observational studies5,6 but are consistent with recently reported anticoagulation study results (in critically ill patients, major bleeding occurred in 2.3% allocated to standard-of-care thromboprophylaxis and 3.8% in those allocated to therapeutic-dose heparin).10 The relatively low major bleeding rates may reflect exclusion of patients at higher bleeding risk, underascertainment, or collection of data only for major bleeding events that met the International Society of Hemostasis and Thrombosis criteria.

Limitations

The trial has several limitations. First, it used an open-label design, although the primary outcome of survival and need for organ support was selected to minimize bias. Second, the use of a composite outcome has the potential to identify different effects of treatment on each component. Although each component is reported separately, there is limited power to give definitive answers about the effect of treatment on each component. Third, although there was an estimated effect of the combination of antiplatelet therapy with therapeutic-dose anticoagulation, the limited numbers of patients randomized simultaneously to both treatment domains and the wide 95% CrIs limit definitive conclusions. Fourth, results from 4 antiplatelet agents were pooled in the analyses (although very few patients received ticagrelor or prasugrel), and there was also substantial underlying heterogeneity in anticoagulation regimens used, limiting ability to draw firm conclusions for any given combination.

Conclusions

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.

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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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