High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19.