New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis

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.

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 I(2) test.

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.

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.