Risk of Lower Gastrointestinal Bleeding in Nonsteroidal Anti-inflammatory Drug (NSAID) and Proton Pump Inhibitor Users Compared with NSAID-Only Users: A Common Data Model Analysis

Abstract

Background/aims: Recent studies have shown an increased risk of lower gastrointestinal bleeding in patients who use both nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs). We analyzed the risk of lower gastrointestinal bleeding and compared this risk between NSAID+PPI users and NSAID-only users.

Methods: In this retrospective, observational study, data from five hospitals were analyzed using a common data model to determine the risk of lower gastrointestinal bleeding and compare this risk between NSAID+PPI users (target cohort) and NSAID-only users (comparative cohort). Cox proportional hazard models and the Kaplan-Meier estimations were employed after extensive propensity score matching.

Results: Among 24,530 individuals in the target cohort and 57,264 in the comparative cohort, 8,728 propensity score-matched pairs were analyzed. The risk of lower gastrointestinal bleeding was significantly higher in NSAID+PPI users than in NSAID-only users (hazard ratio [HR], 2.843; 95% confidence interval [CI], 1.998 to 4.044; p<0.001). Similar findings were also noted in elderly patients >65 years (HR, 2.737), males (HR, 2.963), and females (HR, 3.221). However, the risk of lower gastrointestinal bleeding was comparable between NSAID+mucoprotective agent users and NSAID-only users (HR, 2.057; 95% CI, 0.714 to 5.924; p=0.172).

Conclusions: The risk of lower gastrointestinal bleeding was higher in NSAID+PPI users than in NSAID-only users. However, the risk of lower gastrointestinal bleeding was comparable between NSAID+mucoprotective agent users and NSAID-only users.

Keywords: Hemorrhage; Nonsteroidal anti-inflammatory drug; Proton pump inhibitors.

Fig. 1

Study flowchart of cohort data from the five hospitals. Patients in both cohorts with a history of lower gastrointestinal bleeding who did not have ≥1 day at risk and were not matched in terms of propensity score were excluded. Finally, 8,728 propensity-matched pairs between nonsteroidal anti-inflammatory drug (NSAID)+protein pump inhibitor users (target cohort) and NSAID-only users (comparative cohort) were included in the analyses.

Fig. 2

Kaplan-Meier plots for lower gastrointestinal bleeding between nonsteroidal anti-inflammatory drug (NSAID)+protein pump inhibitor (PPI) users (target cohort) and NSAID-only users (comparative cohort). The risk of lower gastrointestinal bleeding was significantly higher in NSAID+PPI users than in NSAID-only users (hazard ratio, 2.843; 95% confidence interval, 1.998 to 4.044; p<0.001).

Fig. 3

Kaplan-Meier plots for lower gastrointestinal bleeding between nonsteroidal anti-inflammatory drug (NSAID)+protein pump inhibitor (PPI) users and NSAID-only users in older patients (age >65 years). The risk of lower gastrointestinal bleeding was significantly higher in NSAID+PPI users than in NSAID-only users (hazard ratio, 2.737; 95% confidence interval, 1.178 to 4.202; p<0.001).

Fig. 4

Kaplan-Meier plots for lower gastrointestinal bleeding between nonsteroidal anti-inflammatory drug (NSAID)+protein pump inhibitor (PPI) users and NSAID-only users according to sex (A: male cohort; B: female cohort). The risk of lower gastrointestinal bleeding was significantly higher in NSAID+PPI users than in NSAID-only users in both males (hazard ratio [HR], 2.963; 95% confidence interval [CI], 1.952 to 4.499; p<0.001) and females (HR, 3.221; 95% CI, 1.909 to 5.434; p<0.001).

Fig. 5

Kaplan-Meier plots for lower gastrointestinal bleeding between nonsteroidal anti-inflammatory drug (NSAID)+mucoprotective agent (MPA) users and NSAID-only users. The risk of lower gastrointestinal bleeding was comparable between NSAID+MPA users and NSAID-only users (hazard ratio, 2.057; 95% confidence interval, 0.714 to 5.924; p=0.172).