Background: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with caution in adults aged 65 years and older. Their gastrointestinal adverse event risk might be further reinforced when using concomitant cholinesterase inhibitors (ChEIs). We aimed to investigate the association between NSAIDs and ChEI use and the risk of peptic ulcers in adults aged 65 years and older.

Methods: Register-based self-controlled case series study including adults ≥65 years with a new prescription of ChEIs and NSAIDs, diagnosed with incident peptic ulcer in Sweden, 2007–2020. We identified persons from the Total Population Register individually linked to several nationwide registers. We estimated the incidence rate ratio (IRR) of peptic ulcer with a conditional Poisson regression model for four mutually exclusive risk periods: use of ChEIs, NSAIDs, and the combination of ChEIs and NSAIDs, compared with the non-treatment in the same individual. Risk periods were identified based on the prescribed daily dose, extracted via a text-parsing algorithm, and a 30-day grace period.

Results: Of 70,060 individuals initiating both ChEIs and NSAIDs, we identified 1500 persons with peptic ulcer (median age at peptic ulcer 80 years), of whom 58% were females. Compared with the non-treatment periods, the risk of peptic ulcer substantially increased for the combination of ChEIs and NSAIDs (IRR: 9.0, [6.8–11.8]), more than for NSAIDs alone (5.2, [4.4–6.0]). No increased risks were found for the use of ChEIs alone (1.0, [0.9–1.2]).

Discussion: We found that the risk of peptic ulcer associated with the concomitant use of NSAIDs and ChEIs was over and beyond the risk associated with NSAIDs alone. Our results underscore the importance of carefully considering the risk of peptic ulcers when co-prescribing NSAIDs and ChEIs to adults aged 65 years and older.