Does High-Dose Thromboprophylaxis Improve Outcomes in COVID-19 Patients? A Meta-analysis of Comparative Studies

Background  Thromboembolism remains a detrimental complication of novel coronavirus disease (COVID-19) despite the use of prophylactic doses of anticoagulation Objectives  This study aimed to compare different thromboprophylaxis strategies in COVID-19 patients Methods  We conducted a systematic database search until June 30, 2022. Eligible studies were randomized (RCTs) and nonrandomized studies that compared prophylactic to intermediate or therapeutic doses of anticoagulation in adult patients with COVID-19, admitted to general wards or intensive care unit (ICU). Primary outcomes were mortality, thromboembolism, and bleeding events. Data are analyzed separately in RCTs and non-RCTs and in ICU and non-ICU patients. Results.  We identified 682 studies and included 53 eligible studies. Therapeutic anticoagulation showed no mortality benefit over prophylactic anticoagulation in four RCTs (odds ratio [OR] = 0.67, 95% confidence interval [CI], 0.18-2.54). Therapeutic anticoagulation didn't improve mortality in ICU or non-ICU patients. Risk of thromboembolism was significantly lower among non-ICU patients who received enhanced (therapeutic/intermediate) anticoagulation (OR = 0.21, 95% CI, 0.06-0.74). Two additional RCTs (Multiplatform Trial and HEP-COVID), not included in quantitative meta-analysis, analyzed non-ICU patients, and reported a similar benefit with therapeutic-dose anticoagulation. Therapeutic anticoagulation was associated with a significantly higher risk of bleeding events among non-randomized studies (OR = 3.45, 95% CI, 2.32-5.13). Among RCTs, although patients who received therapeutic-dose anticoagulation had higher numbers of bleeding events, these differences were not statistically significant. Studies comparing prophylactic and intermediate-dose anticoagulation showed no differences in primary outcomes. Conclusion  There is a lack of mortality benefit with therapeutic-dose over prophylactic-dose anticoagulation in ICU and non-ICU COVID-19 patients. Therapeutic anticoagulation significantly decreased risk of thromboembolism risk in some of the available RCTs, especially among non-ICU patients. This potential benefit, however, may be counter balanced by higher risk of bleeding. Individualized assessment of patient's bleeding risk will ultimately impact the true clinical benefit of anticoagulation in each patient. Finally, we found no mortality or morbidity benefit with intermediate-dose anticoagulation.