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Am Fam Physician. 2019;99(10):online

Clinical Question

Which oral anticoagulants have the highest risk of causing upper gastrointestinal (GI) tract bleeding, and does cotherapy with a proton pump inhibitor (PPI) lower that risk?

Bottom Line

Among patients using oral anticoagulants alone, the risk of hospitalization for upper GI tract bleeding is highest with rivaroxaban (Xarelto) and lowest with apixaban (Eliquis). Cotherapy with a PPI reduces the risk among patients using any oral anticoagulant. (Level of Evidence = 2b)


The risk of serious upper GI tract bleeding associated with individual anticoagulant drug choice (with or without PPI cotherapy) is uncertain. These investigators analyzed the U.S. Medicare beneficiary files of patients 30 years or older who initiated oral anticoagulation treatment with apixaban, dabigatran (Pradaxa), rivaroxaban, or warfarin (Coumadin). The primary outcome of interest was hospitalization for upper GI tract bleeding that is potentially preventable by PPI cotherapy, including esophagitis, peptic ulcer disease, and gastritis. Multiple analyses occurred to control for covariates, including cardiovascular disease, low-dose aspirin prophylaxis, frailty, alcohol abuse, liver disease, history of previous upper GI tract bleeding, current use of other medications that affect bleeding risk (e.g., nonsteroidal anti-inflammatory drugs), and age and other demographic factors.

A total of 1,643,123 patients had 1,713,183 new episodes of oral anticoagulant treatment from January 1, 2011, through September 30, 2015. The mean age of the patients was 76.4 years and the indication for anticoagulation was atrial fibrillation for 74.9% of them. In patients receiving anticoagulant treatment without PPI cotherapy, the adjusted incidence of hospitalization for upper GI tract bleeding was significantly higher in those who received rivaroxaban compared with those who received dabigatran, warfarin, or apixaban (144 per 10,000 person-years vs. 120, 113, and 73, respectively). For patients receiving anticoagulant treatment with PPI cotherapy, the adjusted incidence of severe upper GI tract bleeding was lower than for patients not receiving cotherapy for all anticoagulants (76 per 10,000 per year vs. 115 per 10,000 per year; number needed to treat = 256), although still significantly highest with rivaroxaban.

Study design: Cohort (retrospective)

Funding source: Government

Setting: Outpatient (any)

Reference: Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018;320(21):2221–2230.

POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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This series is coordinated by Natasha J. Pyzocha, DO, contributing editor.

A collection of POEMs published in AFP is available at

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