Individual NOACs have distinct major GI bleeding risk profiles

The risk of gastrointestinal hemorrhage with non-vitamin K antagonist oral anticoagulants: A network meta-analysis

Literature - Oh HJ, Ryu KH, Park BJ, Yoon BH - Medicine. 2021;100(11):e25216. doi: 10.1097/MD.0000000000025216.

Introduction and methods

NOACs have been used widely in the clinic for stroke prevention in AF and for the treatment and prevention of venous thromboembolism (VTE) [1]. These include apixaban, dabigatran, edoxaban, and rivaroxaban. However, various RCTs have reported increased GI bleeding risk in patients treated with a NOAC compared to those with warfarin [2-7]. Traditional pair-wise meta-analyses can assess safety of pairs of drugs, it cannot determine the safety of individual NOACs among multiple other anticoagulation drugs. A network meta-analysis on the other hand, is a useful method to compare the GI bleeding risk of multiple drugs.

This study evaluated the risk of major GI bleeding associated with the use of a NOAC using a network meta-analysis of RCTs and observational studies to combine indirect and direct comparisons among 6 anti-coagulation treatments.

A total of 29 double-blinded RCTs (n=121,246) and 4 observational studies (n=265,948) with propensity matching controls or nested case controls were included. All these studies had carried out a risk assessment for major GI bleeding by NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) and/or conventional anticoagulation therapy (warfarin and enoxaparin). Eligible studies had patients enrolled who were treated with anticoagulation for approved indications, such as prevention and treatment of venous thromboembolism (VTE)/pulmonary embolism, for the prevention of stroke or systemic embolism in AF, or as postsurgical prophylaxis. The primary outcome was incidence of major GI bleeding. The subgroup analysis was done according to indication. Bleedings in patients with AF (n=352,058) were assessed with a network meta-analysis. Bleeding events in VTE or pulmonary embolism (PE) [n=26,739], and post-surgical prophylaxis (n=28,766) were analyzed with an indirect comparison, because a closed network could not be formed with this dataset.

Main results

  • Patients treated with apixaban had a decreased risk of major GI bleeding compared to patients treated with warfarin (RR 0.54, 95% CI: 0.25-0.76, P<0.001).
  • Patients receiving rivaroxaban had an increased major GI bleeding risk compared to those treated with warfarin (RR 1.40, 95% CI: 1.06-1.85, P=0.017).
  • There was no significant increase in major GI bleeding risk in those on dabigatran (RR 1.25, 95% CI 0.98-1.60), edoxaban (RR 1.07, 95% CI: 0.69-1.65), and enoxaparin (RR 1.24, 95% CI:0.63-2.43) compared to warfarin.
  • Subgroup analyses according to indications showed that treatment with apixaban reduced the risk of major GI bleeding compared to warfarin in patients with AF(RR 0.50, 95% CI: 0.34-0.74 , P=0.001). Dabigatran, edoxaban, or rivaroxaban treatment had similar major GI bleeding rates compared to warfarin therapy in patients with AF.
  • Dabigatran and rivaroxaban treatment were both associated with increased major GI bleedings in patients with AF compared to apixaban (dabigatran RR 2.36, 95% CI: 1.55-3.60, P=0.037; rivaroxaban RR 1.75, 95% CI: 1.10-6.41, P=0.014). There was no significant increase in major GI bleeding with edoxaban compared to apixaban treatment (RR 1.79, 95% CI: 0.87-3.69).
  • Indirect comparison of patients with VTE or PE demonstrated no increased risk of major GI bleeding with dabigatran, rivaroxaban, apixaban, and edoxaban, and enoxaparin compared to warfarin. No significant difference in major GI bleeding among individual NOACs and enoxaparin was observed in patients with post-surgical prophylaxis of VTE.


This network meta-analysis of patients using NOACs or conventional showed that apixaban reduced the risk for major GI bleeding compared to warfarin. In contrast, rivaroxaban increased the risk for major GI bleeding compared to warfarin. No association with increased GI bleeding was found with dabigatran, edoxaban, or enoxaparin compared to warfarin.

In the subgroup analysis of patients with AF, apixaban significantly decreased the risk of major GI bleeding compared to warfarin. Similar GI bleeding rates were observed among the other individual NOACs.

The authors further state that high-quality head-to-head comparison studies are needed to confirm the clinical relevance and to establish practical guidelines for tailored therapy.


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7. Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013;145:105–12. e115.

Find this article online at Medicine.

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