Efficacy and Safety of Intensified Versus Standard Prophylactic Anticoagulation Therapy in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-Analysis

Background: Randomized controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in coronavirus disease 2019 (COVID-19). We performed an aggregate data meta-analysis from available trials to quantify effect on nonfatal and fatal outcomes and identify subgroups who may benefit. Methods: We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) vs prophylactic anticoagulation in adults with laboratory-confirmed COVID-19 through 19 January 2022. We used random-effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events (at end of follow-up or discharge) and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results: Eleven RCTs were included (N = 5873). Intensified vs prophylactic anticoagulation was not associated with a mortality reduction up to 45 days (risk ratio [RR], 0.93 [95% confidence interval {CI}, .79-1.10]). There was a possible signal of mortality reduction for non-intensive care unit (ICU) patients, although with low precision and high heterogeneity (5 studies; RR, 0.84 [95% CI, .49-1.44]; I ² = 75%). Risk of venous thromboembolism was reduced (RR, 0.53 [95% CI, .41-.69]; I ² = 0%), with effect driven by therapeutic rather than intermediate dosing (interaction P = .04). Major bleeding was increased with intensified anticoagulation (RR, 1.73 [95% CI, 1.17-2.56]) with no interaction for dosing and clinical setting. Conclusions: Intensified anticoagulation has no effect on mortality among hospitalized adults with COVID-19 and is associated with increased bleeding risk. The observed reduction in venous thromboembolism risk and trend toward reduced mortality in non-ICU settings requires exploration in additional RCTs. Clinical Trials Registration. CRD42021273449 (PROSPERO).