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


CONCLUSIONS
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.
Juurlink
David N
DN
Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, 2075 Bayview Ave., Toronto, Ontario. dnj@ices.on.ca
Gomes
Tara
T
Ko
Dennis T
DT
Szmitko
Paul E
PE
Austin
Peter C
PC
Tu
Jack V
JV
Henry
David A
DA
Kopp
Alex
A
Mamdani
Muhammad M
MM
D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D016022:Case-Control Studies; D000077144:Clopidogrel; D015331:Cohort Studies; D016001:Confidence Intervals; D003266:Continuity of Patient Care; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000628:therapy; D016017:Odds Ratio; D010351:Patient Discharge; D010359:Patient Readmission / Q000706:statistics & numerical data*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D012008:Recurrence; D018570:Risk Assessment; D017678:Sex Distribution; D015996:Survival Rate; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine