Effect of therapeutic versus prophylactic anticoagulation therapy on clinical outcomes in COVID-19 patients: a systematic review with an updated meta-analysis
Authors: Duo Hong , Li Yahui , Sun Yujie , Wei Liang , Wang Ziqing , Fang Fang , Zhong Yuxin , Huang Jiao , Luo Linjie , Peng Zhiyong , Pan Huaqin 
Published: April 2022

Abstract
Background: Previous studies demonstrate a reduced risk of thrombosis and mortality with anticoagulant treatment in patients with COVID-19 than those without anticoagulation treatment. However, an open question regarding the efficacy and safety of therapeutic anticoagulation (T-AC) versus a lower dose, prophylaxis anticoagulation (P-AC) in COVID-19 patients is still controversial. Methods: We systematically reviewed currently available randomized clinical trials (RCTs) and observational studies (OBs) from January 8, 2019, to January 8, 2022, and compared prophylactic and therapeutic anticoagulant treatment in COVID-19 patients. The primary outcomes were risk of mortality, major bleeding, and the secondary outcomes included venous and arterial thromboembolism. Subgroup analysis was also performed between critically ill and non-critically ill patients with COVID-19 and between patients with higher and lower levels of D-dimer. Sensitive analysis was performed to decrease the bias and the impact of population heterogeneity.Results: We identified 11 RCTs and 17 OBs fulfilling our inclusion criteria. In the RCTs analyses, there was no statistically significant difference in the relative risk of mortality between COVID-19 patients with T-AC treatment and those treated with P-AC (RR 0.95, 95% CI, 0.78–1.16, P = 0.61). Similar results were also found in the OBs analyses (RR 1.21, 95% CI, 0.98-1.49, P = 0.08). The pooling meta-analysis using a random-effects model combined with effect sizes showed that in the RCTs and OBs analyses, patients with COVID-19 who received T-AC treatment had a significantly higher relative risk of the major bleeding event than those with P-AC treatment in COVID-19 patients (RCTs: RR 1.76, 95% CI, 1.19-2.62, P = 0.005; OBs: RR 2.39, 95% CI, 1.56-3.68, P < 0.0001). Compared with P-AC treatment in COVID-19 patients, patients with T-AC treatment significantly reduced the incidence of venous thromboembolism (RR 0.51, 95%, 0.39-0.67, P＜0.00001), but it is not associated with arterial thrombosis events (RR 0.97, 95%, 0.66-1.42, P = 0.88). The subgroup analysis of OBs shows that the mortality risk significantly reduces in critically ill COVID-19 patients treated with T-AC compared with those with P-AC treatment (RR 0.58, 95% CI, 0.39-0.86, P = 0.007), while the mortality risk significantly increases in non-critically ill COVID-19 patients treated with T-AC (RR 1.56, 95% CI, 1.34-1.80, P < 0.00001). In addition, T-AC treatment does not reduce the risk of mortality in COVID-19 patients with high d-dimer levels in RCTs. Finally, the overall sensitivity analysis after excluding two RCTs studies remains consistent with the previous results.Conclusions: A comprehensive meta-analysis of OBs demonstrated that T-AC treatment in critically ill patients with COVID-19 significantly increased survival compared with those treated with P-AC, which was not found in the RCTs analyses. Meanwhile, P-AC treatment showed survival superiority in non-critically ill patients with COVID-19. In both RCTs and OBs, T-AC treatment in COVID-19 patients significantly reduced the incidence of venous thromboembolism but showed a higher risk of bleeding than those with P-AC treatment. Protocol registration: PROSPERO (CRD42021293294). Registered ﻿24 November 2021.