Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs

Abstract

Objective: To measure the association between use of proton pump inhibitors and a range of harmful outcomes in patients using clopidogrel and aspirin.

Design: Observational cohort study and self controlled case series.

Setting: United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics (the cardiovascular disease research using linked bespoke studies and electronic records (CALIBER) collaboration)

Population: 24,471 patients receiving clopidogrel and aspirin.

Main outcome measures: The primary outcome was death or incident myocardial infarction. Secondary outcomes were death, incident myocardial infarction, vascular death, and non-vascular death. Comparisons were made between proton pump inhibitor use and non-use.

Results: Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1419 (11%) patients while they were receiving a proton pump inhibitor compared with 1341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors.

Conclusion: The lack of a specific association and the discrepancy between findings of the analyses between and within people suggests that the interaction between proton pump inhibitors and clopidogrel is clinically unimportant.

Trial registration: ClinicalTrials.gov NCT01231867.

Fig 1 Pictorial representation of study design; indicative single patient timeline

Fig 2 Association between proton pump inhibitors, ranitidine, paroxetine/fluoxetine, or citalopram and all outcomes in cohort analysis and self controlled case series. Relative risk expressed as hazard ratio for cohort analysis and incidence rate ratio for self controlled case series