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Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding

Educational Objective
To understand that the risk of upper gastrointestinal tract bleeding in patients treated with an anticoagulant may be modified by cotherapy with a proton pump inhibitor.
1 Credit CME
Key Points

Question  Are anticoagulant drug choice and proton pump inhibitor (PPI) cotherapy associated with the risk of upper gastrointestinal tract bleeding in Medicare beneficiaries?

Findings  During 754 389 person-years of anticoagulation treatment with apixaban, dabigatran, rivaroxaban, and warfarin, the risk of hospitalization for upper gastrointestinal tract bleeding was highest for rivaroxaban. The use of PPI cotherapy (264 447 person-years) was associated with a significantly lower overall risk of gastrointestinal bleeding for all anticoagulants (incidence rate ratio, 0.66).

Meaning  Drug choice and PPI cotherapy may be important during oral anticoagulant treatment, particularly for patients with elevated risk of gastrointestinal bleeding.

Abstract

Importance  Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.

Objectives  To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.

Design, Setting, and Participants  Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.

Exposures  Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.

Main Outcomes and Measures  Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).

Results  There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, −47.5 [95% CI,−60.6 to −34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, −40.5 [95% CI, −50.0 to −31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, −24 [95% CI, −38 to −11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, −61.1 [95% CI, −74.8 to −47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, −35.5 [95% CI, −48.6 to −22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, −39.3 [95% CI, −44.5 to −34.2]).

Conclusions and Relevance  Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

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Article Information

Accepted for Publication: October 9, 2018.

Corresponding Author: Wayne A. Ray, PhD, Department of Health Policy, Vanderbilt University School of Medicine, Village at Vanderbilt, 1501 21st Ave S, Ste 2600, Nashville, TN 37212 (wayne.ray@vanderbilt.edu).

Author Contributions: Dr Ray had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ray, Chung, Murray, Smalley, Stein.

Acquisition, analysis, or interpretation of data: Ray, Chung, Daugherty, Dupont, Stein.

Drafting of the manuscript: Ray, Murray.

Critical revision of the manuscript for important intellectual content: Ray, Chung, Smalley, Daugherty, Dupont, Stein.

Statistical analysis: Ray, Dupont.

Obtained funding: Ray.

Administrative, technical, or material support: Chung, Daugherty.

Supervision: Ray, Murray.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by a grant from the National Heart, Lung, and Blood Institute (HL114518). Dr Chung was funded by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23AR064768) and the Rheumatology Research Foundation Career Development K Supplement.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Access to study data was provided by the Virtual Research Data Center of the US Centers for Medicare & Medicaid Services.

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