Active and Non-Active Comparators Yield Different Estimates of the Association Between Proton Pump Inhibitor Use and...

Proton pump inhibitor (PPI) use has been associated with poorer outcomes in patients receiving immune checkpoint inhibitors (ICIs), but most previous studies have compared PPI users with non-users, which may differ in their underlying need for acid-suppressive therapy. We evaluated the association between PPI use and mortality using histamine-2 receptor antagonist (H2RA) users as an active comparator among patients with advanced non-small cell lung cancer (NSCLC) receiving ICIs.

We conducted a retrospective cohort study using a Japanese administrative claims database. Patients with advanced NSCLC who initiated first-line ICI-based therapy and received either a PPI or an H2RA within 30 days before or on the day of ICI initiation were included. The index date was defined as the initiation date of the first-line ICI-based regimen. The primary outcome was all-cause mortality within 3 years. Propensity score overlap weighting was used to balance baseline characteristics, and weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Among 6360 eligible patients, 5409 received conventional PPIs and 951 received H2RAs. After overlap weighting, mortality did not clearly differ between PPI and H2RA users (HR, 1.06; 95% CI, 0.93-1.20). In contrast, PPI users had higher mortality than patients receiving neither PPIs nor H2RAs (HR, 1.13; 95% CI, 1.05-1.20).

PPI use was not clearly associated with higher mortality when H2RA users were used as an active comparator, whereas a higher mortality estimate was observed when PPI users were compared with patients receiving neither PPI nor H2RA therapy. These findings highlight the importance of comparator selection in observational studies evaluating PPI use during ICI therapy.