Anticoagulant therapy in adult with COVID-19: a systematic review and meta-analysis of randomized controlled trial.

Background: Blood coagulation dysfunction is a risk factor for adverse outcomes in patients with coronavirus disease 2019 (COVID-19), especially in severe cases. The evidence for the effects of anticoagulation therapy on prognosis of COVID-19 patients and its risk of causing bleeding events is accumulating. Here we conducted a meta-analysis to assess the efficacy and safety of anticoagulants in COVID-19 patients of different severity. Methods: We searched PubMed, Embase databases, Cochrane Trials, OVID MEDLINE from December 2019 to April 2023. We included randomized controlled trials (RCTs) involving COVID-19 patients over 18 years of age, which explored the effect of anticoagulant and its dose on outcomes including all-cause mortality, bleeding events or thrombotic events. We calculated the risk ratio (RR) and its 95% confidence interval (CI) for each outcome. We also performed subgroup analyses to assess the impact of disease severity, using a fixed-effect model to test for heterogeneity. The risk of bias, publication bias, and the quality of evidence were also evaluated. Results: A total of 20 RCTs were included for final analysis. When compared with standard care, anticoagulation treatment reduced all-cause mortality (RR 0.47, 95% CI: 0.29-0.76) and thrombotic events (RR 0.35, 95% CI: 0.15-0.83) in the whole population with COVID-19 (n=2,365), without increase in bleeding events (total: RR 1.47, 95% CI: 0.54-4.00). Most of the studies only enrolled non-severe patients (n=2,329), while the number of severe patients (n=36) was scarce. In RCTs compared therapeutical and prophylactic doses of anticoagulants, no significant difference in on all-cause mortality was found in the whole population and non-severe and severe subgroups (total: RR 1.01, 95% CI: 0.92-1.10; non-severe: RR 1.03, 95% CI: 0.81-1.32; severe: RR 1.00, 95% CI: 0.91-1.11). Therapeutical dose reduced risk of thrombotic events (total: RR 0.59, 95% CI: 0.48-0.73; subtotal of non-severe: RR 0.57, 95% CI: 0.39-0.84; Subtotal of severe: RR 0.61, 95% CI: 0.47-0.78), while risk of bleeding was increased (total: RR 1.98, 95% CI: 1.47-2.66; non-severe: RR 2.38, 95% CI: 1.56-3.62; severe: RR 1.63, 95% CI: 1.07-2.47). Study heterogeneity was found only in the analysis of effects of anticoagulants on risk of thrombotic events. Conclusions: Anticoagulant therapy reduces all-cause mortality and risk of thrombosis in non-severe COVID-19 patients. Therapeutic dose of anticoagulant therapy can be considered in both non-severe and severe COVID-19 patients to reduce thrombosis, but may be associated with increased bleeding events.