Use of cholinesterase inhibitors and non-steroidal anti-inflammatory drugs and the risk of peptic ulcers: a population-based self-controlled case series study

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with caution in older adults, mainly due to gastrointestinal adverse events, including peptic ulcers. It is unknown whether patients on cholinesterase inhibitor (ChEI) treatment, which increases gastric acid secretion and internal propulsion, have exacerbated risk of a peptic ulcer when using NSAIDs concomitantly.

Objectives: To investigate the association between NSAIDs and ChEI use and the risk of peptic ulcers in older patients.

Methods: We conducted a self-controlled case series study including all older adults aged ≥65 years with a new prescription of ChEIs and NSAIDs, diagnosed with incident peptic ulcer in Sweden, 2007-2020. We identified cases from the Total Population Register individually linked to several nationwide registers. We fitted a conditional Poisson regression model, adjusted for age groups, to estimate the incidence rate ratio (IRR) of the first peptic ulcer diagnosis for mutually exclusive risk periods: use of ChEIs alone, NSAIDs alone, the combination of ChEIs and NSAIDs, compared with the non-treatment periods in the same individual. Thereby, intra-person time constant confounders were eliminated. We only considered the first occurrence of peptic ulcer because recurrent events were not independent. Risk periods were identified based on the prescribed daily dose, extracted via a text-parsing algorithm, and a 30-day grace period. We conducted several sensitivity analyses, including the addition of a pre-treatment period, different grace periods and risk periods calculated using defined daily doses. We used E-values for quantitative bias assessment.

Results: Out of 70,060 older patients initiating both ChEIs and NSAIDs, we identified 1500 cases (median age at peptic ulcer 80 years), of whom 58% were female. The most common comorbidities were hypertension (44%) and anaemia (23%). The most frequently co-prescribed drugs were antiplatelets (51%) and renin-angiotensin-aldosterone system inhibitors (42%).
Compared with the non-treatment periods, the risk of peptic ulcer was higher with the use of NSAIDs alone (adjusted IRR: 5.2, 95% confidence interval: 4.4-6.0, E-value: 9.8) and further increased with the combination of ChEIs and NSAIDs (9.0, 6.8-11.8, E-value: 17.5). No increased risk were found for the use ChEIs alone (1.0, 0.9-1.2, E-value: 1.2). The results were robust to variation in underlying study design choices.

Conclusions: We found that the risk of peptic ulcer was over and beyond the risk associated with NSAIDs alone when used with ChEIs. Our results underscore the importance of carefully considering the risk of peptic ulcers when prescribing NSAIDs to users of ChEIs.