Association Between Oral Anticoagulant PPI Cotherapy and UGl Bleeding | Gastroenterology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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.


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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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 (

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.

Ruff  CT, Giugliano  RP, Braunwald  E,  et al.  Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.  Lancet. 2014;383(9921):955-962. doi:10.1016/S0140-6736(13)62343-0PubMedGoogle ScholarCrossref
Connolly  SJ, Ezekowitz  MD, Yusuf  S,  et al.  Dabigatran versus warfarin in patients with atrial fibrillation.  N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561PubMedGoogle ScholarCrossref
Mazurek  M, Lip  GYH.  Gastrointestinal bleeding and direct oral anticoagulants amongst patients with atrial fibrillation in the “real world”.  Gastroenterology. 2017;152(5):932-934. doi:10.1053/j.gastro.2017.02.027PubMedGoogle ScholarCrossref
Ray  WA, Chung  CP, Murray  KT,  et al.  Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding.  Gastroenterology. 2016;151(6):1105-1112. doi:10.1053/j.gastro.2016.08.054PubMedGoogle ScholarCrossref
Graham  DJ, Reichman  ME, Wernecke  M,  et al.  Stroke, Bleeding, and mortality risks in elderly medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation.  JAMA Intern Med. 2016;176(11):1662-1671. doi:10.1001/jamainternmed.2016.5954PubMedGoogle ScholarCrossref
Abraham  NS, Noseworthy  PA, Yao  X, Sangaralingham  LR, Shah  ND.  Gastrointestinal safety of direct oral anticoagulants: a large population-based study.  Gastroenterology. 2017;152(5):1014-1022. doi:10.1053/j.gastro.2016.12.018PubMedGoogle ScholarCrossref
Li  XS, Deitelzweig  S, Keshishian  A,  et al.  Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in “real-world” clinical practice. a propensity-matched analysis of 76,940 patients.  Thromb Haemost. 2017;117(6):1072-1082. doi:10.1160/TH17-01-0068PubMedGoogle ScholarCrossref
Proietti  M, Romanazzi  I, Romiti  GF, Farcomeni  A, Lip  GYH.  Real-world use of apixaban for stroke prevention in atrial fibrillation: a systematic review and meta-analysis.  Stroke. 2018;49(1):98-106. doi:10.1161/STROKEAHA.117.018395PubMedGoogle ScholarCrossref
Brunner  G, Creutfeldt  W.  Omeprazole in the long-term treatment of patients with acid-related disease resistant to ranitidine.  Scand J Gastroenterol. 1989;24(suppl 166):101-105. doi:10.3109/00365528909091254Google ScholarCrossref
Chan  EW, Lau  WC, Leung  WK,  et al.  Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study.  Gastroenterology. 2015;149(3):586-95.e3. doi:10.1053/j.gastro.2015.05.002PubMedGoogle ScholarCrossref
Ray  WA.  Population-based studies of adverse drug effects.  N Engl J Med. 2003;349(17):1592-1594. doi:10.1056/NEJMp038145PubMedGoogle ScholarCrossref
Ray  WA.  Evaluating medication effects outside of clinical trials: new-user designs.  Am J Epidemiol. 2003;158(9):915-920. doi:10.1093/aje/kwg231PubMedGoogle ScholarCrossref
Uddin  MJ, Groenwold  RH, Ali  MS,  et al.  Methods to control for unmeasured confounding in pharmacoepidemiology: an overview.  Int J Clin Pharm. 2016;38(3):714-723.PubMedGoogle Scholar
Cunningham  A, Stein  CM, Chung  CP, Daugherty  JR, Smalley  WE, Ray  WA.  An automated database case definition for serious bleeding related to oral anticoagulant use.  Pharmacoepidemiol Drug Saf. 2011;20(6):560-566. doi:10.1002/pds.2109PubMedGoogle ScholarCrossref
Arbogast  PG, Kaltenbach  L, Ding  H, Ray  WA.  Adjustment for multiple cardiovascular risk factors using a summary risk score.  Epidemiology. 2008;19(1):30-37. doi:10.1097/EDE.0b013e31815be000PubMedGoogle ScholarCrossref
Arbogast  PG, Ray  WA.  Use of disease risk scores in pharmacoepidemiologic studies.  Stat Methods Med Res. 2009;18(1):67-80. doi:10.1177/0962280208092347PubMedGoogle ScholarCrossref
Arbogast  PG, Ray  WA.  Performance of disease risk scores, propensity scores, and traditional multivariable outcome regression in the presence of multiple confounders.  Am J Epidemiol. 2011;174(5):613-620. doi:10.1093/aje/kwr143PubMedGoogle ScholarCrossref
Glynn  RJ, Gagne  JJ, Schneeweiss  S.  Role of disease risk scores in comparative effectiveness research with emerging therapies.  Pharmacoepidemiol Drug Saf. 2012;21(suppl 2):138-147. doi:10.1002/pds.3231PubMedGoogle ScholarCrossref
Tadrous  M, Gagne  JJ, Stürmer  T, Cadarette  SM.  Disease risk score as a confounder summary method: systematic review and recommendations.  Pharmacoepidemiol Drug Saf. 2013;22(2):122-129. doi:10.1002/pds.3377PubMedGoogle ScholarCrossref
Vinogradova  Y, Coupland  C, Hill  T, Hippisley-Cox  J.  Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care.  BMJ. 2018;362:k2505. doi:10.1136/bmj.k2505PubMedGoogle ScholarCrossref
Gong  IY, Kim  RB.  Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.  Can J Cardiol. 2013;29(suppl 7):S24-S33. doi:10.1016/j.cjca.2013.04.002PubMedGoogle ScholarCrossref
Reilly  PA, Lehr  T, Haertter  S,  et al.  The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).  J Am Coll Cardiol. 2014;63(4):321-328. doi:10.1016/j.jacc.2013.07.104PubMedGoogle ScholarCrossref
[REMOVED IF= FIELD]Singh  S, Savage  L, Klein  M, Thomas  C.  Severe necrotic oesophageal and gastric ulceration associated with dabigatran  [published online April 2, 2013].  BMJ Case Rep. doi:10.1136/bcr-2013-009139PubMedGoogle Scholar
Zhang  N, Liu  XS, Li  G, Liu  T.  Dabigatran-induced esophagitis: A frequently overlooked adverse effect.  Int J Cardiol. 2016;212:358-359. doi:10.1016/j.ijcard.2016.03.178PubMedGoogle ScholarCrossref
Bolek  T, Samoš  M, Stančiaková  L,  et al.  The impact of proton pump inhibition on dabigatran levels in patients with atrial fibrillation  [published online April 25, 2017].  Am J Ther. doi:10.1097/MJT.0000000000000599PubMedGoogle Scholar
Liesenfeld  KH, Lehr  T, Dansirikul  C,  et al.  Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.  J Thromb Haemost. 2011;9(11):2168-2175. doi:10.1111/j.1538-7836.2011.04498.xPubMedGoogle ScholarCrossref
Bosch  J, Eikelboom  JW, Connolly  SJ,  et al.  Rationale, design and baseline characteristics of participants in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial.  Can J Cardiol. 2017;33(8):1027-1035. doi:10.1016/j.cjca.2017.06.001PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity



My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right