Effect of P2Y12 Inhibitors on Organ Support–Free Survival in Critically Ill Patients Hospitalized for COVID-19

Abstract

ImportancePlatelet activation is a potential therapeutic target in patients with COVID-19.ObjectiveTo evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.Design, Setting, and ParticipantsThis international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care–level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.InterventionParticipants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.Main Outcomes and MeasuresThe primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.ResultsAt the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support–free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).Conclusions and RelevanceIn this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.Trial RegistrationClinicalTrials.gov Identifier: NCT04505774

Transforming research to improve therapies for trauma in the twenty-first century

“…Adaptive trial design has been successfully used in the critically ill to test COVID-19 therapies [ 78 – 83 ]. The MATIC-2 trauma trial (NCT06070350) makes use of an adaptive platform design to compare whole blood to component therapy, and TXA to placebo in children with traumatic bleeding.…”

Appropriate thromboprophylaxis strategy for COVID-19 patients on dosage, antiplatelet therapy, outpatient, and postdischarge prophylaxis: a meta-analysis of randomized controlled trials

“…A total of 25 studies 11 – 13 , 15 – 19 , 22 , 26 – 41 involving, 17 911 patients were included. There were 18 studies comparing different doses of anticoagulants on hospitalized patients.…”

“…However, recently, several randomized controlled trials (RCTs) have shown that intermediate and therapeutic doses are associated with lower thromboembolism risk 11 , 12 . Secondly, regarding the need for additional antiplatelet therapy in critically ill patients, many studies suggest that adding antiplatelet treatment on top of prophylactic anticoagulation does not provide additional benefits 11 , 13 . However, a meta-analysis incorporating retrospective studies suggests that antiplatelet therapy can improve clinical outcomes 14 .…”

Impact of P2Y12 inhibitors on clinical outcomes in sepsis-3 patients receiving aspirin: a propensity score matched analysis

“…P2Y12 inhibitors could reduce the incidence and in-hospital mortality of Staphylococcus aureus bacteremia [ 11 , 18 ]. Unlike bacterial infections, P2Y12 inhibitors appear to be ineffective against infections with viruses [ 19 ]. Under the sepsis-3 criterion, to the best of our knowledge, the present study is the first to assess the impact of P2Y12 inhibitors on clinical outcomes.…”