Risk of upper gastrointestinal bleeding in patients on oral anticoagulant and proton pump inhibitor co-therapy

Abstract

Background: Proton pump inhibitors (PPIs) are known to reduce the risk of upper gastrointestinal bleeding in patients on oral anticoagulants, and patients are increasingly on oral anticoagulants and PPI co-therapy. However, evidence is lacking on the safety and effectiveness of oral anticoagulants when co-administered with PPIs.

Methods: Among patients initiating oral anticoagulants (warfarin and non-vitamin K antagonist oral anticoagulants [NOACs], i.e. rivaroxaban, dabigatran, apixaban, and edoxaban) during 2013-2017, those concomitantly prescribed PPIs were identified (n = 19,851). The primary endpoint was hospitalization for major upper gastrointestinal bleeding, and secondary endpoints were death and ischemic stroke.

Results: During a mean 1.4 years of follow-up, the primary endpoint occurred in 512 (2.58%) patients. Overall, NOACs were associated with lower upper gastrointestinal bleeding risk after adjustment for age, sex, comorbidities and concomitant medications (adjusted hazard ratio 0.78, 95% confidence interval 0.65-0.94), compared to warfarin. There was no significant difference in upper gastrointestinal bleeding risk among the individual NOACs. This trend of reduced risk for upper gastrointestinal bleeding in NOACs compared to warfarin was consistent for both regular and reduced doses, throughout bleeding risk groups, and other subgroup analyses. NOACs were also associated with lower risk of death compared to warfarin. The risk for ischemic stroke was not significantly different among the oral anticoagulants in patients with atrial fibrillation.

Conclusion: In patients on oral anticoagulant and PPI co-therapy, NOACs were associated with lower risk of upper gastrointestinal bleeding and mortality compared to warfarin, while there was no difference among the oral anticoagulants for stroke prevention. In patients on PPI therapy, NOACs may preferred over warfarin for decreasing risk of upper gastrointestinal bleeding and mortality.

Fig 1. Study inclusion flow.

OAC, oral anticoagulant; AF, atrial fibrillation; VTE, venous thromboembolism; GI, gastrointestinal; PPI, proton pump inhibitor.

Fig 2. Weighted Kaplan-Meier curves for upper gastrointestinal bleeding events according to oral anticoagulants.

NOAC, non-vitamin K antagonist oral anticoagulant.

Fig 3. Differential risk of upper gastrointestinal bleeding, death, and ischemic stroke in users of warfarin and 4 NOACs.

In patients on combined proton pump inhibitor and oral anticoagulant therapy, NOACs were associated with lower risk of upper gastrointestinal bleeding and mortality compared to warfarin, while there was no significant difference among the OACs in risk of stroke. *Adjusted for age, sex, atrial fibrillation, venous thromboembolism, comorbidities (hypertension, diabetes mellitus, chronic kidney disease, ischemic heart disease, heart failure, peptic ulcer disease), and concomitant use of aspirin, P2Y₁₂ inhibitor, and nonsteroidal anti-inflammatory drug. ^†Additionally adjusted for the CHA₂DS₂-VASc score. NOAC, non-vitamin K antagonist oral anticoagulant; AF, atrial fibrillation.

Fig 4. Comparison of upper gastrointestinal bleeding risk in users of warfarin and 4 NOACs with consideration of dose regimens.

*IR: incidence rate per 1000 person-years. ^†Adjusted for age, sex, atrial fibrillation, venous thromboembolism, comorbidities (hypertension, diabetes mellitus, chronic kidney disease, ischemic heart disease, heart failure, peptic ulcer disease), and concomitant use of aspirin, P2Y₁₂ inhibitor, and nonsteroidal anti-inflammatory drug. NOAC, non-vitamin K antagonist oral anticoagulant; UGIB, upper gastrointestinal bleeding.

Fig 5. Upper gastrointestinal bleeding risk of NOACs with reference to warfarin in various subgroups.

*IR: incidence rate per 1000 person-years. ^†Adjusted for age, sex, atrial fibrillation, venous thromboembolism, comorbidities (hypertension, diabetes mellitus, chronic kidney disease, ischemic heart disease, heart failure, peptic ulcer disease), and concomitant use of aspirin, P2Y₁₂ inhibitor, and nonsteroidal anti-inflammatory drug. NOAC, non-vitamin K antagonist oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; NVAF, non-valvular atrial fibrillation; UGIB, upper gastrointestinal bleeding; VTE, venous thromboembolism.