Standard Prophylactic Versus Intermediate Dose Enoxaparin in Adults with Severe COVID-19: A Multi-Center, Open-Label, Randomised Controlled Trial

Abstract

Background: Coronavirus disease 2019 (COVID-19) is associated with coagulopathy but the optimal prophylactic anticoagulation therapy remains uncertain and may depend on COVID-19 severity.Methods: We conducted a multi-center, open-label, randomised controlled trial comparing standard prophylactic dose versus intermediate dose enoxaparin in adults who were hospitalized with COVID-19 and admitted to an intensive care unit (ICU) and/or had laboratory evidence of coagulopathy. Patients were randomly assigned in a 1:1 ratio to receive standard prophylactic dose enoxaparin or intermediate weight-adjusted dose enoxaparin. The primary outcome was all-cause mortality at 30 days. Secondary outcomes included arterial or venous thromboembolism and major bleeding.Findings: A total of 176 patients (99 males and 77 females) underwent randomisation. In the intention-to-treat population, all-cause mortality at 30 days was 15% for intermediate dose enoxaparin and 21% for standard prophylactic dose enoxaparin (P=0.31 by chi-square test). Unadjusted Cox proportional hazards modeling demonstrated similar mortality with intermediate and standard dose enoxaparin (hazard ratio, 0.67; 95% confidence interval, 0.33 to 1.37; P=0.28. Arterial or venous thrombosis occurred in 13% of patients assigned to intermediate dose enoxaparin and 9% of patients assigned to standard dose enoxaparin. Major bleeding occurred in only 2% of patients in each arm.Interpretation: In hospitalized adults with severe COVID-19, standard prophylactic dose and intermediate dose enoxaparin did not differ significantly in preventing death or thrombosis at 30 days.Trial Registration: The trial was registered with ClinicalTrials.gov (NCT04360824).Funding Statement: National Institutes of Health Clinical and Translational Science Award.Declaration of Interests: SRL has served as a paid consultant for Novo Nordisk, UniQure, and Argenx, all outside the scope of the submitted work. All other authors declare no competing interests. SRB has served as an editor or committee member for Wiley, Abbott, and Boston Scientific Corporation. All other authors declare no competing interests.Ethics Approval Statement: The trial protocol was approved by the local institutional review boards of the participating sites. Written informed consent was obtained from all patients or their legally authorized representatives.