Reply to: Peptic ulcers with ChEIs, NSAIDs

Abstract

We sincerely thank Professor Montastruc for their letter.¹ We appreciate that our call for further research on the interaction between non-steroidal anti-inflammatory drugs (NSAIDs) and cholinesterase inhibitors (ChEIs) and their effects on peptic ulcer was noticed.² We value the use of established pharmacovigilance methods for detecting a signal for the drug–drug interaction we identified. Signal detection is an important first step in the process of establishing evidence, which we omitted in our research, where we directly moved to hypothesis testing with pharmacoepidemiologic methods.

Professor Montastruc investigated the drug–drug interaction using disproportionality analyses, which focuses on the differences in the proportion of adverse event reports in a global pharmacovigilance database. They found that the reporting odds ratios of peptic ulcer for the combination of ChEIs and NSAIDs were three times as high as for NSAIDs alone, an effect estimate that is in line with our findings. Furthermore, they highlighted that their study extends our research, as we compared treatment episodes with no treatment, whereas they compared the combination treatment with NSAIDs alone.

To quantify the comparison between combination of ChEIs and NSAIDs and NSAIDs alone, similarly to Montastruc, we performed a post hoc analysis on the results obtained from our self-controlled case series study. We found that the incidence rate ratio of peptic ulcer with concomitant use of ChEIs and NSAIDs is 1.74 (95% confidence interval: 1.27–2.38) compared to NSAIDs alone. This is a slightly smaller effect size than reported by Montastruc. This discrepancy could be due to the fact that Montastruc calculated reporting odds ratios, which might overestimate the true risk of adverse effects in pharmacovigilance databases, especially in the case of drug–drug interactions.³

We appreciate that our work has inspired further research on the topic, but there are necessary next steps. Following the detected signal from Montastruc and our pharmacoepidemiologic research, future studies should use big data, for example via federated networks of health data.⁴ Analyzing a large cohort would potentially allow for the examination of subgroups, such as different combinations of chemical substances in ChEIs (e.g., donepezil, rivastigmine, galantamine) and NSAIDs (e.g., diclofenac, naproxen, ibuprofen), and their effects on bleeding or non-bleeding peptic ulcers—analyses we could not perform. Increasing the size of the study population via federated networks would further enhance precision and enable wider generalizability of the results. Ultimately, when enough evidence is gathered, concomitant ChEIs and NSAIDs use should be carefully evaluated and potentially included in guidelines to prevent inappropriate medication use, ensuring better safety and outcomes for patients.^5-7

MS, GM, and JWW conceived and designed the study. MS performed the statistical analysis, interpreted the data, drafted and critically revised the manuscript. JWW, ACL, POB, GM, DPA, and KJ interpreted the data and critically revised the manuscript. KJ obtained funding and acquired the data. KJ, JWW, ACL, and DPA provided supervision. KJ and MS are the guarantors of the study and data integrity. All authors approved the final version of the manuscript.

The authors declare no actual conflict of interest regarding this article. Potential conflict of interest: MS received consulting fees from Pfizer, Macanda and Aurealis Therapeutics.

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

This work was supported by funding from the Swedish Research Council for Health, Working Life and Welfare (FORTE) and KID-funding.

The study was approved by the Regional Ethical Review Board in Stockholm (dnr: 2016/1001-31/4, 2020-03525, 2021-02004).