Abstract
Individual randomized controlled trials (RCTs) enrolling patients with venous thromboembolism (VTE) have demonstrated that novel oral anticoagulants (NOACs) are comparable to vitamin K antagonists (VKAs) in reducing the risk of recurrent VTE but hold a safer bleeding profile. Nonetheless, pooled data from RCTs on the safety of NOACs versus VKAs in patients with VTE are still scarce.
We aimed to compare the effect of NOACs versus VKA on the risk of fatal bleeding, major bleeding, clinically relevant non-major bleeding (CRNMB) and any bleeding in patients with VTE through a meta-analysis of RCTs.
We performed a systematic review of the literature, from January 1970 to December 2021, using PubMed database with four independent reviewers (L.R.; G.M.; V.C.; F.G.). Discrepancies were solved by consensus with a senior researcher (D.M.). Phase 3 randomized controlled trials comparing NOACs versus VKAs, either as an acute treatment or as an extended therapy, in patients with pulmonary embolism or deep vein thrombosis were selected. We performed a meta-analysis using a random-effects model with the Mantel–Haenszel method for each safety endpoint. Study outcomes were expressed as odd ratios (OR) with 95% confidence interval (CI) and illustrated in a Forest plot diagram. A two-sided p-value <0.05 was considered statistically significant. Heterogeneity was tested using the I2-statistic.
Seven trials were included (n=29,879 patients), either investigating the direct thrombin inhibitor dabigatran (RE-COVER, RE-COVER II and RESONATE trials) or the factor Xa inhibitors rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE studies), apixaban (AMPLIFY study) and edoxaban (Hokusai-VTE study). Compared to VKAs, treatment with NOACs was associated with lower risk of fatal bleeding (OR 0.35; 95% CI 0.16-0.81), major bleeding (OR 0.60; 95% CI 0.45-0.80), and any bleeding (OR 0.62; 95% CI 0.54-0.72) - fig. 1. There was no significant difference between the two groups concerning the risk of CRNMB.
In patients with VTE, treatment with NOACs was associated with fewer bleeding complications compared with VKAs.
