New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding

A Systematic Review and Meta-analysis

I. Lisanne Holster; Vera E. Valkhoff; Ernst J. Kuipers; Eric T. T. L. Tjwa


Gastroenterology. 2013;145(1):105-112. 

In This Article

Abstract and Introduction


Background & Aims A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients' risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC.

Methods We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I2 test.

Results The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07–1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91–1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31–1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03–2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58–10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56–2.73), the OR for dabigatran was 1.58 (95% CI, 1.29–1.93), the OR for edoxaban was 0.31 (95% CI, 0.01–7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21–1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00–1.34), with similar trends among subgroups.

Conclusions Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.


Gastrointestinal bleeding (GIB) is a serious medical condition that causes considerable morbidity and mortality (5%–15%) and poses an enormous burden on global health care use.[1] The mean hospital costs are reported to range from $2500 to $7300 for upper GIB, $4800 for lower GIB, and around $40,000 for small-bowel bleeding.[2] The expanding indications and increasingly intensive treatment with antithrombotic agents have increased the burden of GIB related to these agents.[3] Antiplatelet agents (eg, aspirin and thienopyridine derivatives) can give rise to GIB by producing ulcers and erosions throughout the gastrointestinal tract. Anticoagulants (ie, vitamin K antagonists [VKA]) and heparins might precipitate bleeding from pre-existing lesions.[4] The relative risk of GIB varies from 1.5 for low-dose aspirin compared with nonuse[5] and more than 5 for the combination of aspirin and VKA.[3] In light of their efficacy, the increased risk of bleeding induced by the therapy is acceptable. Two important limitations of the traditional antithrombotic agents comprise the need for international normalized ratio monitoring with tailored VKA dosing, or subcutaneous administration of low-molecular-weight heparins (LMWH).

New oral anticoagulants (nOAC) (eg, factor IIa [thrombin] or factor Xa inhibitors) have been developed and theoretically lack these limitations.[6–8] These drugs are as effective as current therapy. Some randomized controlled trials (RCTs) reported an isolated higher GIB risk,[9,10] which is potentially fatal, costly, and avoidable. It is therefore important to carefully review the literature on GIB risk attributable to use of nOAC. This is particularly relevant because patients on nOAC often use concomitant low-dose aspirin and/or thienopyridines, which may add substantially to the as yet unknown GIB risk. Furthermore, in contrast with the traditional OAC, no clinically tested antidote is currently available for the novel agents, hampering therapeutic options in case of GIB.[11] For these reasons, we conducted a systematic review focusing on the risk of GIB of all nOAC. Because not all trials separately reported GIB risk, we also reviewed the evidence on risk of clinically relevant bleeding associated with nOAC use.