ticagrelor and Critical-Illness

Platelet activation is a potential therapeutic target in patients with COVID-19.. To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.. This 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.. Participants 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.. The 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.. At 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).. In 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.. ClinicalTrials.gov Identifier: NCT04505774.

Topics: COVID-19; Critical Illness; Hemorrhage; Hospital Mortality; Humans; Male; Middle Aged; Purinergic P2Y Receptor Agonists; Ticagrelor

Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation.. Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group.. The risk factors for major amputation in EUCLID patients are similar to previous large registries' reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the EUCLID trial compared with registry data. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Topics: Aged; Amputation, Surgical; Critical Illness; Female; Humans; Incidence; Ischemia; Limb Salvage; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome

Critical limb-threatening ischemia (CLTI) is associated with an increased risk of major adverse limb events and mortality. High on-treatment platelet reactivity (HPR) is associated with an increased risk of ischemic events, while low on-treatment platelet reactivity (LPR) is associated with an increased risk of bleeding. This study investigates the frequency with which patients with CLTI on clopidogrel or ticagrelor achieve a "therapeutic window" (TW) of platelet inhibition.. Data from the "Switch To Ticagrelor in Critical Limb Ischemia Anti-Platelet Study" were assessed retrospectively to determine the incidence of TW of on-treatment platelet reactivity in 50 consecutive patients with CLTI (mean age: 65.2 ± 10.5 years, 54% male). The data included 4 measurements of patients' platelet reactivity using the VerifyNow P2Y12 Assay: baseline and steady state platelet reactivity on clopidogrel 75 mg daily and on ticagrelor 90 mg twice daily.. At baseline, 46% of patients on clopidogrel were within TW of on-treatment platelet reactivity compared to 10% of patients on ticagrelor (. Although ticagrelor has been proposed as an alternative for patients with HPR on clopidogrel, the current study observes an excess of platelet inhibition with ticagrelor in most patients with CLTI at a dose of 90 mg twice daily.

Topics: Aged; Clopidogrel; Critical Illness; Drug Administration Schedule; Drug Monitoring; Female; Humans; Ischemia; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Ticagrelor; Time Factors; Treatment Outcome