Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non–Critically Ill Hospitalized Patients With COVID-19

Abstract

IMPORTANCEPlatelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.OBJECTIVE To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.INTERVENTIONS Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. MAIN OUTCOMES AND MEASURESThe composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, −1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis.RESULTS Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15).CONCLUSIONS AND RELEVANCE Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization.

Thrombotic and bleeding events, mortality, and anticoagulant use among 546,656 hospitalized patients with COVID-19 in the United States: a retrospective cohort study

“…Another area of debate is whether antiplatelet therapies should be used in combination with anticoagulants for the treatment of patients with COVID-19. Results of the ACTIVE-4a trial, which evaluated non-critically ill, hospitalized patients with COVID-19, found that the addition of a P2Y12 inhibitor to a therapeutic dose of heparin did not improve survival [ 20 ]. Other ongoing ACTIV-4 studies aim to provide more insights about the safety and efficacy of antithrombotic strategies for hospitalized patients with COVID-19 [ 21 ].…”

Clinical update on COVID-19 for the emergency and critical care clinician: Medical management

“…However, most patients were taking aspirin (83.9%), with less on clopidogrel (8.2%), dual antiplatelet therapy (7.4%), or ticagrelor or prasugrel, and the authors did not break down differences between therapies. The ACTIV-4a multicenter RCT compared heparin anticoagulation alone to added P2Y12 inhibitor administration (ticagrelor or clopidogrel) and found no significant benefit amongst 2219 non-critically ill patients, including no difference in days free of respiratory or cardiovascular support and major thrombotic events [ 98 ]. Similar trials with much smaller populations of less than 100 patients on antiplatelet therapy, most on aspirin, found no significant mortality benefit compared to controls [ 99 , 100 ].…”

To Anticoagulate or Not to Anticoagulate in COVID-19: Lessons after 2 Years

“…Use of anticoagulation with DOACs may be useful in patients for a month postdischarge, 69 hospitalization for COVID-19, antiplatelet and antithrombotic therapy has thus far shown no benefit. 54,55 When determining whether or not to initiate anticoagulation in COVID-19 positive patients, it is essential to consider their severity of illness as disease progresses, comorbidities, drug interactions, and any pertinent laboratory values that can help weigh the risks and benefits of whether or not to anticoagulate.…”