In a cohort of noncritically ill patients with COVID-19, the addition of a P2Y12 inhibitor to anticoagulation did not extend survival or lessen disease severity, according to results of the ACTIV-4a trial.

Thrombosis and inflammation contribute to the risk for death and complications in patients with COVID-19.

Jeffrey S. Berger

“Data from the [multiplatform randomized controlled trial] demonstrated that therapeutic-dose heparin increased days alive and free of organ support in noncritically ill (moderate) patients with COVID-19,” Jeffrey S. Berger, MD, MS, associate professor of medicine and surgery with appointments in cardiology, hematology and vascular surgery at NYU Grossman School of Medicine and director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health, said during a presentation at the American Heart Association Scientific Sessions. “Nonetheless, nearly one out of four patients receiving therapeutic-dose heparin still died or received intensive care level support, highlighting the need for additional therapies in this cohort.”

This led Berger and colleagues to conduct the open-label ACTIV-4a trial, in which they randomly assigned patients 1:1 to a P2Y12 inhibitor plus standard care anticoagulation of therapeutic-dose heparin or standard care anticoagulation and no P2Y12 inhibitor (usual care).

The preferred recommended P2Y12 inhibitor was ticagrelor (60 mg twice daily without a loading dose; Brilinta, AstraZeneca). Clopidogrel (300 mg loading dose followed by 75 mg daily) and prasugrel (30 mg loading dose and 10 mg daily; Effient, Daiichi Sankyo/Eli Lilly) were also allowed. Patients received P2Y12 inhibitor treatment for 14 days or until hospital discharge, whichever came first.

The researchers defined the primary endpoint as 21-day organ support-free days; key secondary endpoint as the composite of major thrombotic events or death; and primary safety endpoint as major bleeding according to the International Society on Thrombosis and Haemostasis definition.

The study continued until a conclusion of superiority (> 99% posterior probability proportional OR > 1) or futility (> 95% posterior probability proportional OR < 1.2) with P2Y12 inhibitor treatment was reached.

In all, researchers enrolled 562 noncritically ill patients with laboratory-confirmed SARS-CoV-2 infection at the time of enrollment discontinuation. Among them, 293 patients received a P2Y12 inhibitor and 269 received usual care.

Primary endpoint data indicated an adjusted OR of 0.83 (95% credible interval, 0.55-1.25), with a futility probability of 96.2%.

In addition, there was no benefit with P2Y12 inhibition on the composite of death or organ support (aHR = 1.19; 95% CI, 0.84-1.68; P = .34); the key secondary outcome (aOR = 1.42; 95% CI, 0.64-3.13); or the primary safety endpoint (aOR = 3.31; 95% CI, 0.64-17.2).

“In noncritically ill hospitalized patients with COVID-19, use of P2Y12 inhibitors did not result in a greater number of days alive and free of cardiovascular or respiratory organ support,” Berger concluded, noting the low rate of major bleeding with the therapy, which increased the absolute risk by approximately 1%. “Testing P2Y12 inhibitors in critically ill patients is ongoing.”