Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Background The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with COVID-19 remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. Methods and results We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) versus a standard-dose prophylactic anticoagulation regimen in critically and non-critically-ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5,154 patients followed on average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death (17.8% vs. 18.6%; Risk Ratio [RR] 0.96, 95% Confidence Interval [CI] 0.78-1.18) but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15-2.60). Compared to prophylactic anticoagulation used at a standard-dose, an escalated-dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41-0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47-1.36), stroke (RR 0.94, 95%CI 0.43-2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29-4.95). There were no significant interactions in the subgroup analysis for critically and non-critically-ill patients. Conclusions Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity. Study registration This study is registered in PROSPERO (CRD42021257203).