A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

Abstract

Background: Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown.

Methods: We conducted a population-based nested case-control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31-90 days) or remote (91-180 days).

Results: Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03-1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70-1.47).

Interpretation: Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.

Figure 1: Study design. The solid black line indicates the period following hospital discharge after treatment of acute myocardial infarction. We excluded patients who did not receive a prescription for clopidogrel within 3 days of the discharge date (upward arrow). Among the remaining patients, cases were those readmitted because of myocardial infarction within 90 days after discharge. We attempted to identify 3 matched controls, with no myocardial infarction before the same date (the index date, indicated by downward arrow) for each case. Use of proton pump inhibitors before the index date was categorized as current (within 30 days), previous (31–90 days) or remote (91–180 days).

Figure 2: Association between acid-reducing therapies and adverse outcomes. Current use of proton pump inhibitors (within 30 days before the index date) was associated with recurrent infarction within 90 days and 1 year following hospital discharge after treatment of acute myocardial infarction (MI) among patients who were receiving clopidogrel. No such association was apparent with earlier therapy or among patients who were not receiving clopidogrel following acute MI. Treatment with histamine H₂-receptor antagonists or pantoprazole, neither of which inhibits cytochrome P450 2C19, was not associated with recurrent infarction, whereas treatment with other proton pump inhibitors (omeprazole, lansoprazole and rabeprazole) was associated with reinfarction. Risk of death was not increased during therapy with proton pump inhibitors. *Data are for current proton pump inhibitor use unless stated otherwise.