The optimal anticoagulation strategy for COVID-19, prophylactic or therapeutic?: a meta-analysis, trial sequential analysis, and meta-regression of more than 27,000 participants

BACKGROUND: Anticoagulants are promising regimens for treating coronavirus disease 2019 (COVID-19). However, whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion. METHODS: We comprehensively searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, ClinicalTrials, and MedRxiv databases on April 26, 2022. Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria. Notably, this is the first meta-analysis on COVID-19, taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation (PA) and intermediate-to-therapeutic anticoagulation (I-TA). RESULTS: We included 11 randomized controlled trials (RCTs) and 36 cohort studies with 27,051 COVID-19 patients. By analyzing all the RCTs, there was no significant difference in mortality between the PA and I-TA groups, which was further confirmed by trial sequential analysis (TSA) (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.71–1.22; P = 0.61; TSA adjusted CI: 0.71–1.26). The rate of major bleeding was remarkably higher in the I-TA group than in the PA group, despite adjusting for TSA (OR: 1.73; 95% CI: 1.15–2.60; P = 0.009; TSA adjusted CI: 1.09–2.58). RCTs have supported the beneficial effect of I-TA in reducing thrombotic events. After including all studies, mortality in the I-TA group was significantly higher than in the PA group (OR: 1.38; 95% CI: 1.15–1.66; P = 0.0005). The rate of major bleeding was similar to the analysis from RCTs (OR: 2.24; 95% CI: 1.86–2.69; P < 0.00001). There was no distinct difference in the rate of thrombotic events between the 2 regimen groups. In addition, in both critical and noncritical subgroups, I-TA failed to reduce mortality but increased major bleeding rate compared with PA, as shown in meta-analysis of all studies, as well as RCTs only. Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding (P = 0.14, P = 0.09, respectively). CONCLUSION: I-TA is not superior to PA for treating COVID-19 because it fails to lower the mortality rate but increases the major bleeding rate in both critical and noncritical patients.