Proton Pump Inhibitors and Myocardial Infarction: An Application of Active Comparators in a Self-controlled Case Series

Background: The association between proton pump inhibitors (PPIs) and short-term risk of myocardial infarction (MI) remains unclear in the current literature due to confounding and protopathic bias.

Objectives: To investigate this association using a conventional self-controlled case series (SCCS) and SCCS with an active comparator (H2 receptor antagonists, H2RA) to address confounding and protopathic bias.

Methods: We conducted a SCCS using data from the Clinical Data Analysis and Report System in Hong Kong. Adult with ≥1 outpatient oral PPI prescription or H2RA and first recorded MI as the principal diagnosis in either an inpatient setting or a visit to an A&E department from 2003-2014 were included. A random subset of H2RA user was included as an active comparator because H2RAs have no hypothesised causal association with MI. The rates of MI during risk periods were compared to the baseline to estimate the age adjusted incidence rate ratios (IRRs) using conditional Poisson regression. We used both simple ratio and effect modifier approaches to SCCS with an active comparator to obtain comparator adjusted estimates.

Results: A total of 2802 and 1889 people with MI who had exposure to PPIs and H2RA were included respectively. We observed a higher risk of MI during days 1—14 following the start of PPI prescription (IRR: 2.30, 95%CI: 1.76—3.00) but this did not persist during days 15—30 (IRR: 1.28, 95%CI: 0.90—1.81) and during days 31—60 (IRR: 1.25, 95%CI: 0.95—1.64) versus baseline. Similarly, we observed a higher risk of MI during days 1-14 following the start of H2RA prescription (IRR: 2.46, 95%CI: 1.92—3.16) but this also did not persist to days 15-30 (IRR: 1.04, 95%CI: 0.72—1.48) and days 31—60 (IRR: 1.33, 95%CI: 1.04—1.70) versus baseline. In the novel SCCS analyses, comparator adjusted estimates were 0.93 (95%CI: 0.57—1.30) and 0.83 (95%CI: 0.58—1.20) during days 1—14 in simple ratio and effect modifier approach respectively.

Conclusions: We observed no difference in risk of MI associated with PPIs compared with baseline using H2RA as the active comparator. The elevated risk of MI associated with PPIs is likely due to protopathic bias. More studies are required to explore the feasibility of using active comparators in SCCS to address protopathic bias in addition to confounding.