Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

ABSTRACT

BackgroundRandomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. MethodsWe searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. ResultsEleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 - 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 - 1.44; I2 = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 - 0.69; I2 = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 - 2.56) with no interaction for dosing and clinical setting. ConclusionIntensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. SummaryIn this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding.