Comparative Risk of Ischemic Stroke Among Users of Clopidogrel Together With Individual Proton Pump Inhibitors

Abstract

Background and Purpose There is controversy and little information concerning whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We therefore aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. Methods We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999–2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole and pantoprazole—with pantoprazole serving as the referent. The endpoint was hospitalization for acute ischemic stroke, defined by International Classification of Diseases 9th Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Results Among 325,559 concomitant users of clopidogrel and a PPI, we identified 1,667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval: 2.3–2.5). Adjusted hazard ratios for ischemic stroke vs. pantoprazole were: 0.98 (0.82–1.17) for esomeprazole; 1.06 (0.92–1.21) for lansoprazole; 0.98 (0.85–1.15) for omeprazole; and 0.85 (0.63–1.13) for rabeprazole. Conclusions PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared to pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel.

Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011

“…Most of the interacting regimens we identified involved statins, antiplatelets (eg, clopidogrel and aspirin), NSAIDs, or omega-3 fish oils, which may not only lead to adverse drug events due to drug-drug interactions but also worsen cardiovascular risk. 20–24,42 For example, the use of clopidogrel in combination with omeprazole or NSAIDs is associated with an increased risk of myocardial infarction, hemorrhagic complications, or cardiovascular death. 20,22–24 However, according to our analyses, approximately 1.8% of older adults (or 1 million) regularly use clopidogrel in interacting combinations.…”

“…In addition to these forces, a growing number of safety concerns associated with commonly used medications, including statins, 14–16 NSAIDs, 17,18 proton pump inhibitors, 19 and medication combinations, 20–24 have emerged that may also have affected medication and supplement use among older adults. A recent study 25 using the National Health and Nutrition Examination Survey (NHANES) indicates that the use of prescription medications and polypharmacy has increased between 1999 and 2012 among adults 65 years and older.…”

Pharmacoepidemiologic Methods for Studying the Health Effects of Drug–Drug Interactions

“…Design 3 is just like Design 2 except that the association measure is the incidence rate ratio (or OR) of the precipitant of interest explicitly vs. the control precipitant, among persons taking the object. For example, Leonard et al . conducted a cohort study of persons taking clopidogrel, examining the rate of ischemic stroke among persons taking individual proton pump inhibitors, each vs. pantoprazole as the negative control precipitant.…”

Clopidogrel safety communication impact on histamine‐2 receptor antagonist and proton‐pump inhibitor use trends

“…identified a potential drug interaction with omeprazole use which may lead to diminished biological action of clopidogrel, possibly due to a competitive effect on CYP2C19. Subsequent trials testing the effects of this potential interaction have produced mixed results . This prompted concerns for negative outcomes, resulting in a safety communication from the Food and Drug Administration (FDA) and updated package labelling in 2009 regarding avoidance of clopidogrel with omeprazole and esomeprazole.…”