Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding

Abstract

Background & aims: Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding.

Methods: This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites.

Results: Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations.

Conclusions: In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the greatest reduction occurred in patients also taking antiplatelet drugs or NSAIDs.

Keywords: Antiplatelet Drugs; Proton-Pump Inhibitor; Warfarin.

Figure 1

Medication use patterns for 7 hypothetical warfarin patients: 1) Long-term warfarin use, no other study medications 2) Two 60 day warfarin courses separated by 60 days; 3)Warfarin with PPI; 4) Warfarin + PPI + P2Y₁₂; 5) Warfarin + P2Y₁₂, PPI starts after warfarin; 6) 90 day warfarin course, NSAID after warfarin start and subsequently PPI; 7) Intermittent warfarin and PPI therapy.

Figure 1

Incidence of warfarin-related upper gastrointestinal bleeding according to PPI co-therapy. Vertical bars indicate 95% confidence intervals. Stratified by concurrent use of antiplatelet drugs or nSAIDs. Incidence for patients with no PPI co-therapy (I₀) is unadjusted (confidence intervals calculated assuming Poisson distribution); that for patients with PPI co-therapy calculated as I₀*HR, where HR is the adjusted hazard ratio for PPI co-therapy (confidence intervals calculated analogously). HRs adjusted for the study population (Medicaid or Medicare), demographic characteristics, warfarin indication and treatment duration, gastrointestinal disease, risk factors for warfarin-related bleeding, medications thought to affect bleeding risk, cardiovascular comorbidity, alcohol abuse, liver disease, and recent medical care utilization (See Appendix Table 3 for detailed list of covariates). Numbers below the x-axis are the number of hospitalizations for upper gastrointestinal bleeding and the person-years of warfarin treatment.

Figure 2

Incidence of warfarin-related upper gastrointestinal bleeding according to PPI co-therapy. Vertical bars indicate 95% confidence intervals. Stratified by concurrent use of antiplatelet drugs or NSAIDs and history of risk factors for upper gastrointestinal bleeding (peptic ulcer, gastritis, abdominal pain, blood in stool/GI bleeding, anemia in past year). Incidence for patients with no PPI co-therapy (I₀) is unadjusted (confidence intervals calculated assuming Poisson distribution); that for patients with PPI co-therapy calculated as I₀*HR, where HR is the adjusted hazard ratio for PPI co-therapy (confidence intervals calculated analogously). HRs adjusted for the study population (Medicaid or Medicare), demographic characteristics, warfarin indication and treatment duration, gastrointestinal disease, risk factors for warfarin-related bleeding, medications thought to affect bleeding risk, cardiovascular comorbidity, alcohol abuse, liver disease, and recent medical care utilization (See Appendix Table 3 for detailed list of covariates). Numbers below the x-axis are the number of hospitalizations for upper gastrointestinal bleeding and the person-years of warfarin treatment.