Intermediate-to-therapeutic versus prophylactic anticoagulation for coagulopathy in hospitalized COVID-19 patients: a systemic review and meta-analysis

Background Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal anticoagulant strategy has not yet been defined. The objective of this meta-analysis was to investigate the effect of intermediate-to-therapeutic versus prophylactic anticoagulation for thromboprophylaxis on the primary outcome of in-hospital mortality and other patient-centered secondary outcomes in COVID-19 patients. Methods MEDLINE, EMBASE, and Cochrane databases were searched from inception to August 10th 2021. Cohort studies and randomized clinical trials that assessed the efficacy and safety of intermediate-to-therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients were included. Baseline characteristics and relevant data of each study were extracted in a pre-designed standardized data-collection form. The primary outcome was all-cause in-hospital mortality and the secondary outcomes were incidence of thrombotic events and incidence of any bleeding and major bleeding. Pooled analysis with random effects models yielded relative risk with 95 % CIs. Results This meta-analysis included 42 studies with 28,055 in-hospital COVID-19 patients totally. Our pooled analysis demonstrated that intermediate-to-therapeutic anticoagulation was not associated with lower in-hospital mortality (RR=1.12, 95 %CI 0.99-1.25, p=0.06, I 2 =77 %) and lower incidence of thrombotic events (RR=1.30, 95 %CI 0.79-2.15, p=0.30, I 2 =88 %), but increased the risk of any bleeding events (RR=2.16, 95 %CI 1.79-2.60, p<0.01, I 2 =31 %) and major bleeding events significantly (RR=2.10, 95 %CI 1.77-2.51, p<0.01, I 2 =11 %) versus prophylactic anticoagulation. Moreover, intermediate-to-therapeutic anticoagulation decreased the incidence of thrombotic events (RR=0.71, 95 %CI 0.56-0.89, p=0.003, I 2 =0 %) among critically ill COVID-19 patients admitted to intensive care units (ICU), with increased bleeding risk (RR=1.66, 95 %CI 1.37-2.00, p<0.01, I 2 =0 %) and unchanged in-hospital mortality (RR=0.94, 95 %CI 0.79-1.10, p=0.42, I 2 =30 %) in such patients. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from very low to moderate. Conclusions We recommend the use of prophylactic anticoagulation against intermediate-to-therapeutic anticoagulation among unselected hospitalized COVID-19 patients considering insignificant survival benefits but higher risk of bleeding in the escalated thromboprophylaxis strategy. For critically ill COVID-19 patients, the benefits of intermediate-to-therapeutic anticoagulation in reducing thrombotic events should be weighed cautiously because of its association with higher risk of bleeding. Trial registration The protocol was registered at PROSPERO on August 17th 2021 ( CRD42021273780 ). Graphical abstract