Efficacy and safety of increased doses of anticoagulants in COVID-19 patients: a systematic review and meta-analysis

Abstract

The aim of the study was to evaluate the efficacy and safety of increased doses of anticoagulants in comparison with standard doses in inpatients with COVID-19. Material and methods. A systematic review was carried out in October 2021 using the Pubmed database. The analysis included only randomized clinical trials with ≥200 participants that reported the death rate as the total number of cases or the percentage of patients. The primary outcome was all-cause mortality within the observation period. Additionally, the risk of arterial and venous thrombotic events, major and clinically relevant non-major bleeding was assessed. Results. Searching of Pubmed identified 8,903 references, of which the results of 6 randomized clinical trials (INSPIRATION, 3 platforms study in REMAP-CAP, ACTIV-4a, and ATTACC including stable and unstable patients, RAPID, ACTION and HEP-COVID) with the total of 5,228 patients were included in the final qualitative analysis and quantitative synthesis. Among all the patients, 2,660 received increased doses and 2,568 — standard doses of anticoagulants. The follow-up period varied from 21 to 30 days. The administration of increased doses did not affect the risk of death (OR, 0.95; 95 % CI, 0.73–1.24; I² = 59.14 %), but was associated with a reduced risk of thrombotic events (OR, 0.56; 95 % CI, 0.43–0.73; I² = 24.90 %), and an increased risk of major bleeding (OR, 1.86; 95 % CI, 1.23–2.80; I² = 0.00 %) or clinically relevant non-major bleeding (OR, 3.66; 95 % CI, 1.65–8.10; I² = 0.00 %). Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill or stable patients and individuals with increased D-dimer. The maximal reduction in the risk of thrombotic events was found for the subgroup of patients with increased D-dimer (OR, 0.48; 95 % CI, 0.34–0.70; I² = 36.38 %). Conclusions. The use of increased doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death. Still, it is associated with a decrease in the risk of arterial and venous thrombosis and an increased risk of major bleeding.