Systematic review with meta‐analysis: the risk of major gastrointestinal bleeding with non‐vitamin K antagonist oral anticoagulants

Abstract

Summary Background Gastrointestinal (GI) bleeding is a common complication among anticoagulated patients. Non‐vitamin K antagonist oral anticoagulants (NOACs) are associated with increased risk of GI (major and clinically relevant non‐major) bleeding. However, more information is needed regarding severe events. Aim To evaluate the risk of NOACs major GI bleeding. Methods We searched for phase III randomised clinical trials (RCT) evaluating NOACs (apixaban, dabigatran, edoxaban and rivaroxaban) and reporting major GI bleeding events, in MEDLINE, Cochrane Library, SciELO collection and Web of Science databases (July 2015). Meta‐analysis was performed to estimate risk ratio (RR) and 95% confidence intervals (95% CIs). Heterogeneity was assessed with the I2 test. Results A total of 23 studies were included. Among patients with atrial fibrillation, the risk of major GI bleeding was not different between NOACs and vitamin K antagonists (VKA) (RR 1.08, 95% CI 0.85–1.36, I2 = 78%; 5 RCTs) or acetylsalicylic acid (RR 0.78, 95% CI 0.36–1.72; 1 RCT). Similar results were found for patients undergoing orthopaedic surgery and those with venous thromboembolism. NOACs were not found to increase the risk compared to low‐molecular‐weight heparin (LWMH) alone (RR 1.42, 95% CI 0.55–3.71, I2 = 7%; 8 RCTs), the sequential treatment with LMWH‐VKA (RR 0.77, 95% CI 0.49–1.21, I2 = 43%; 7 RCTs) or placebo (RR 1.48, 95% CI 0.15–14.84, I2 = 21%; 2 RCTs). Conclusion Despite previous evidence supporting the association of non‐vitamin K antagonist oral anticoagulants and overall GI bleeding, non‐vitamin K antagonist oral anticoagulants are not associated with increased risk of major GI bleeding compared to other anticoagulant drugs (with known increased risk of these events).

The association between non‐vitamin K antagonist oral anticoagulants and gastrointestinal bleeding: a meta‐analysis of observational studies

“…Notably, among the included studies, the outcome was specifically defined as major GIB in Graham et al , while Chan et al stratified the outcomes and reported the results of minor and major GIB separately. It was reported in the meta‐analysis of RCTs that dabigatran and rivaroxaban were associated with an approximately 50% increase in overall GIB risk compared with warfarin ; however, they were not associated with the risk of major GIB . Thus, the lower risk of GIB observed in the present meta‐analysis may also be partially attributed to the effect of combining overall GIB and major GIB in the outcome.…”

“…By contrast, findings from four recent meta‐analyses did not support an association between NOACs and GIB, and did not report separate risks for specific NOACs. Additionally, a recent meta‐analysis by Caldeira et al , which included the most recent RCTs, reported that NOACs were not associated with a risk of major GIB.…”

Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management

“…The risk of GIB was also increased with high-dose edoxaban of 60 mg daily (HR 1.23), but was reduced with low-dose edoxaban of 30 mg daily (HR 0.89)[14]. However, subsequent systematic reviews and meta-analyses which included more trials with different inclusion and exclusion criteria yielded conflicting results, showing either no or only a marginal increase in the risk of GIB[23-29]. …”

Recent advances in the treatment of venous thromboembolism in the era of the direct oral anticoagulants

“…Thus, in a pooled analysis of the phase 3 VTE treatment trials, there was a non-significant trend for less bleeding with the DOACs than with VKAs (RR 0.77, 95% CI 0.49–1.21; p=0.11) 30 .…”