Antiplatelet Therapy in Patients With COVID-19—More Is Less?

Because venous and arterial thromboembolism are common among patients hospitalized with COVID-19, 1,2 anticoagulant therapies were among the first to be evaluated in clinical trials to improve outcomes in moderately ill patients hospitalized with COVID-19.These studies have yielded thus far somewhat mixed results, varying from beneficial effects of therapeutic doses of low-molecularweight heparin in the ATTACC, ACTIV-4a, and REMAP-CAP trials 3 to no difference between therapeutic and prophylactic doses of low-molecular-weight heparin in the INSPIRATION, ACTION, and RAPID trials.[4][5][6] Therefore, it remains to be determined whether the addition of antiplatelet therapy will yield different results.Although platelets are thought to play a pivotal role in COVID-19-related hypercoagulability, 7 the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial showed no obvious benefit of aspirin added to standard thromboprophylaxis or anticoagulant therapy in hospitalized patients with COVID-19.8 Nevertheless, other antiplatelet drugs, such as P2Y12 inhibitors may have more potent platelet inhibiting properties and have been linked to certain anti-inflammatory effects.9 In this issue of JAMA, Berger and colleagues 10 report the results of the ACTIV-4a clinical trial.In this open-label, international, multicenter, randomized clinical trial, patients were randomly assigned in a 1:1 ratio to receive a therapeutic dose of heparin plus a P2Y12 inhibitor or a therapeutic dose of heparin only (usual care) and were stratified by hospital site and severity of illness.Ticagrelor was the preferred P2Y12 inhibitor, but clopidogrel and prasugrel were allowed.Duration of P2Y12 inhibitor therapy was 14 days or until hospital discharge.The current study described the analyses for the non-critically ill participants after the data safety and monitoring board stopped the trial early for this patient category based on futility.The enrollment of critically ill patients is still ongoing.Non-critically ill patients were enrolled if they were hospitalized for COVID-19 and met 1 of the following criteria: elevated D-dimer level (≥2-fold the upper limit of normal) or aged 60 to 84 years.Patients younger than 60 years could be enrolled if they met at least 1 of the following criteria: had a need for oxygen greater than 2 L per minute or had hypertension, diabetes, chronic kidney disease, cardiovascular disease, or a body mass index of 35 or greater.Altogether, 562 patients from 60 hospital sites (mean age, 52.7 years; 41.5% women; and 87% received a therapeutic dose of heparin) were randomized and they all completed the trial.The investigators found no significant differences in the primary outcome (a composite of organ support-free days evaluated on an ordinal scale combined with in-hospital death; for survivors,