P2Y12 Inhibitors in Non–Critically Ill Hospitalized COVID-19 Patients

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  • In this study of 562 non–critically ill patients hospitalized with COVID-19, the addition of P2Y12 inhibitors to usual care with systemic anticoagulation did not reduce the need for organ support. Study enrollment was stopped for futility.

Study Questions:

Among non–critically ill patients hospitalized with coronavirus disease 2019 (COVID-19), what are the effects of adding P2Y12 inhibitors to anticoagulant therapy?


ACTIV-4a (Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute) is an international, adaptive, randomized clinical trial, designed to evaluate whether P2Y12 inhibition increases organ support-free days among patients hospitalized with COVID-19. This report includes results from the non–critically ill study cohort (enrollment of critically ill patients is still ongoing). Patients at 60 sites in the United States, Brazil, Italy, and Spain were enrolled from February–June 2021. To qualify, patients were required to meet any one of the following criteria: 1) D-dimer level ≥2-fold upper limit of normal, 2) 60-84 years of age, 3) <60 years of age with oxygen requirement >2 L/min, diabetes, hypertension, chronic kidney disease, cardiovascular disease, or body mass index ≥35 kg/m2. A notable exclusion criterion was a clinical requirement for dual antiplatelet therapy. Participants were randomized to P2Y12 inhibitor + therapeutic anticoagulation with heparin, versus therapeutic anticoagulation only (standard of care). The preferred P2Y12 inhibitor was ticagrelor. P2Y12 inhibitor treatment was continued for 14 days or until hospital discharge, whichever occurred first. The composite primary outcome was organ support-free days (up to 21 days, with in-hospital death receiving a value of -1). The primary safety outcome was major bleeding by 28 days, as defined by the International Society of Thrombosis and Hemostasis.


A total of 562 patients (mean age 52.7 years, 41.5% women, 38.1% non-White) were enrolled before the study was stopped for futility. In the intervention group, 98.3% of patients received ≥1 dose of P2Y12 inhibitor (63% ticagrelor, 37% clopidogrel) by the end of study day 1, and median duration of study drug treatment was 6 days. No patients in the usual care group received a P2Y12 inhibitor.

The median number of organ support-free days was 21 in both the P2Y12 inhibitor and usual care groups. The adjusted odds ratio (OR) for the effect of P2Y12 inhibition on organ support-free days was 0.83 (95% credible interval, 0.55-1.25; posterior probability of futility, 96%). In the P2Y12 inhibitor group, 75 patients (26%) died or required respiratory or cardiovascular organ support during the first 28 days, as compared with 58 patients (22%) in the usual care group (adjusted hazard ratio, 1.19; 95% confidence interval [CI], 0.84-1.68; p = 0.34). Major bleeding events occurred in six patients (2.0%) in the P2Y12 inhibitor group and two patients (0.7%) in the usual care group (adjusted OR, 3.31; 95% CI, 0.64-17.2; p = 0.15).


In non–critically ill patients hospitalized with COVID-19, addition of a P2Y12 inhibitor to therapeutic anticoagulation does not decrease the need for organ support during the first 21 days of hospitalization. Major bleeding complications were not significantly increased by P2Y12 inhibitor treatment.


In the RECOVERY trial (Lancet 2022;399:143-51), aspirin was found to have no significant impact on 28-day mortality among patients hospitalized with COVID-19. Similarly, the findings of the present study suggest that P2Y12 inhibition does not have an additive benefit among COVID-19 patients who are also receiving systemic anticoagulation. Mean duration of P2Y12 inhibitor therapy in the trial was relatively short (<1 week), and it is possible that longer-term therapy could be beneficial in selected, higher-risk patients. The ongoing arm of ACTIV-4a will provide insights into the utility of antiplatelet therapy among critically ill COVID-19 patients.

Keywords: Anticoagulants, Aspirin, Body Mass Index, COVID-19, Critical Illness, Diabetes Mellitus, Hemorrhage, Heparin, Hospital Mortality, Hypertension, Metabolic Syndrome, Patient Discharge, Platelet Aggregation Inhibitors, Primary Prevention, Renal Insufficiency, Chronic, Standard of Care

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