Non-vitamin K antagonist oral anticoagulants, proton pump inhibitors and gastrointestinal bleeds

Heart. 2022 Apr;108(8):613-618. doi: 10.1136/heartjnl-2021-319332. Epub 2021 Aug 2.


Objective: To evaluate if proton pump inhibitor (PPI) treatment reduces the risk of upper gastrointestinal bleeding (UGIB) in patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs).

Design: We used a common protocol, common data model approach to conduct a cohort study including patients with AF initiated on a NOAC in Stockholm, Denmark and the Netherlands from April 2011 until July 2018. The outcome of interest was a UGIB diagnosed in a secondary care inpatient setting. We used an inverse probability weighted (IPW) Poisson regression to calculate incidence rate ratios (IRRs), contrasting PPI use to no PPI use periods.

Results: In 164 290 NOAC users with AF, providing 272 570 years of follow-up and 39 938 years of PPI exposure, 806 patients suffered a UGIB. After IPW, PPI use was associated with lower UGIB rates (IRR: 0.75; 95% CI: 0.59 to 0.95). On an absolute scale, the protective effect was modest, and was found to be largest in high-risk patients, classified as age 75-84 years (number needed to treat for 1 year (NNTY): 787), age ≥85 years (NNTY: 667), HAS-BLED score ≥3 (NNTY: 378) or on concomitant antiplatelet therapy (NNTY: 373).

Conclusion: Concomitant treatment with a PPI in NOAC-treated patients with AF is associated with a reduced risk of severe UGIB. This indicates that PPI cotreatment can be considered, in particular among the elderly patients, patients with a HAS-BLED score ≥3, and/or in patients on concomitant antiplatelet therapy.

Keywords: atrial fibrillation; oral anticoagulants.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Anticoagulants / therapeutic use
  • Atrial Fibrillation* / complications
  • Atrial Fibrillation* / drug therapy
  • Atrial Fibrillation* / epidemiology
  • Cohort Studies
  • Gastrointestinal Hemorrhage / chemically induced
  • Gastrointestinal Hemorrhage / drug therapy
  • Gastrointestinal Hemorrhage / epidemiology
  • Humans
  • Platelet Aggregation Inhibitors / adverse effects
  • Proton Pump Inhibitors / adverse effects
  • Risk Factors
  • Stroke* / etiology


  • Anticoagulants
  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors