Adding P2Y12 inhibitor to heparin offered no benefit in non-critically ill COVID-19 inpatients
An open-label randomized trial at 60 hospitals in four countries found no increase in organ support-free days in patients who received a therapeutic dose of heparin plus a P2Y12 inhibitor versus heparin alone.
Adding a P2Y12 inhibitor to a therapeutic dose of heparin did not appear to improve organ support-free days in non-critically ill patients hospitalized for COVID-19.
Researchers at 60 hospitals in the United States, Brazil, Italy, and Spain performed an open-label trial to examine the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy in patients who were hospitalized with COVID-19 and were not critically ill. Patients were randomly assigned to receive a therapeutic dose of heparin plus a P2Y12 inhibitor or a therapeutic dose of heparin only for 14 days or until hospital discharge, whichever occurred first. The study's composite primary outcome was organ support-free days, which were evaluated on an ordinal scale that combined in-hospital death and the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization for those who survived to hospital discharge (range, −1 to 21 days, with higher scores indicating less organ support and better outcomes). Major bleeding by 28 days, as defined by the International Society on Thrombosis and Hemostasis, was the primary safety outcome. The study results were published Jan. 18 by JAMA.
Patients were enrolled in the trial between February 2021 and June 2021; the date of final 90-day follow-up was Sept. 15, 2021. Enrollment was discontinued when the trial met the prespecified criterion for futility. Patients' mean age was 52.7 years, and 41.5% were women. All 562 enrolled patients completed the trial (293 assigned to the P2Y12 group, and 269 assigned to the usual care group), with 87% receiving a therapeutic dose of heparin by the end of study day 1. Among patients assigned to a P2Y12 inhibitor, 63% received ticagrelor and 37% received clopidogrel. The median number of organ support-free days was 21 days (interquartile range, 20 to 21 days) in the P2Y12 inhibitor group and 21 days (interquartile range, 21 to 21 days) in the usual care group (adjusted odds ratio, 0.83; 95% credible interval, 0.55 to 1.25). Six patients in the P2Y12 group and two patients in the usual care group experienced major bleeding (2.0% vs. 0.7%; adjusted odds ratio, 3.31 [95% CI, 0.64 to 17.2]; P=0.15).
The trial was limited by its open-label design and by the relatively short time that P2Y12 inhibitors were administered, among other factors, the authors noted. They concluded that in non-critically ill patients hospitalized for COVID-19, adding a P2Y12 inhibitor to a therapeutic dose of heparin did not improve organ support-free days in the short term. “It remains uncertain whether other platelet-mediated thromboinflammatory pathways may be better therapeutic targets in patients with COVID-19,” the authors wrote.
The authors of an accompanying editorial agreed that “platelets may still represent a promising therapeutic target in COVID-19” but said the results of the current trial indicate that additional P2Y12 inhibition did not improve outcomes in moderately ill hospitalized patients with COVID-19. While awaiting the results of ongoing trials, the editorialists wrote, “further studies should explore the role of other antiplatelet agents, which may potentially also target some of the pathogenic inflammatory pathways, and also may have a favorable risk-benefit ratio that provides protection without further compromising the individual patient's bleeding risk.”
