Circulation. 2022 Aug 29. doi: 10.1161/CIRCULATIONAHA.122.061533. Online ahead of print.
ABSTRACT
Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically-ill COVID-19 patients remains uncertain. Methods: COVID-PACT was a multicenter, 2x2 factorial, open-label, randomized-controlled trial with blinded endpoint adjudication in ICU-level patients with COVID-19. Patients were randomized to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomized to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death due to venous or arterial thrombosis, pulmonary embolism, clinically-evident deep venous thrombosis (DVT), type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically-silent DVT, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win-ratio and time-to-first event analysis while patients were on-treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was GUSTO moderate/severe bleeding. Recruitment was stopped early in 03/2022 (∼50% planned recruitment) due to waning ICU-level COVID-19 rates. Results: At 34 centers in the United States, 390 patients were randomized between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio 1.95, 95%CI 1.08-3.55, p=0.028). Results were consistent in time-to-event analysis for the primary efficacy endpoint (full-dose versus standard-dose incidence 19/191 [9.9%] vs 29/191 [15.2%]; HR 0.56, 95%CI 0.32-0.99, p=0.046). The primary safety endpoint occurred in 4 (2.1%) on full-dose and in 1 (0.5%) on standard-dose (p=0.19); the secondary safety endpoint occurred in 15 (7.9%) versus 1 (0.5%; p=0.002). There was no difference in all-cause mortality (HR 0.91, 95%CI 0.56-1.48; p=0.70). There were no differences in the primary efficacy or safety endpoints with clopidogrel versus no antiplatelet therapy. Conclusions: In critically-ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality.
PMID:36036760 | DOI:10.1161/CIRCULATIONAHA.122.061533