Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors

Abstract

Background Proton-pump inhibitors (PPIs) and clopidogrel are frequently co-prescribed though the benefits and harms of their concurrent use are unclear. Objective To examine the association between concurrent PPI and clopidogrel use and the risks for gastroduodenal bleeding hospitalizations and serious cardiovascular disease. Design Retrospective cohort study that used automated data to identify patients who received clopidogrel between 1999 through 2005 following hospitalization for coronary heart disease. Setting Tennessee Medicaid Program Patients 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. Measurements Baseline and followup drug use assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction/sudden cardiac death, stroke, or other cardiovascular death). Results Pantoprazole and omeprazole accounted for 62% and 9% of the concurrent PPI use. Adjusted gastroduodenal bleeding hospitalization incidence in concurrent PPI users was 50% lower than that in nonusers (HR, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk of bleeding, PPI use was associated with an absolute reduction of 28 (12 to 37) gastroduodenal bleeding hospitalizations per 1000 person years. The hazard ratio associated with concurrent PPI use for risk of serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) and was 1.01 (CI, 0.77 to 1.30) among patients who had percutaneous coronary interventions with stenting. Limitations There was possible unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and endpoints (not confirmed by medical record review). Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjusting for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. Conclusion Among patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of gastroduodenal bleeding hospitalizations. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% confidence interval included a clinically important increased risk. Funding Agency for Healthcare Quality and Research, National Heart Lung and Blood Institute.

Changing Prescription Pattern of Omeprazole Among Patients Receiving Clopidogrel

“…2,3) Some of the studies confirmed an interaction between clopidogrel and PPI. 4,5,[8][9][10] Kyeong, et al found that the P2Y12 reaction unit (PRU) of omeprazole treated subjects was signifi cantly higher than that of the omeprazole untreated subjects and the percentage inhibition decreased in the omeprazole treatment versus no omeprazole treatment. 4) Moreover, it has been found that patients taking clopidogrel plus a PPI had a higher risk of hospitalization for recurrent acute coronary syndrome compared with patients taking clopidogrel without a PPI.…”

“…8) Loss-of-function polymorphisms in the CYP450 genes may also reduce clopidogrel metabolism and are therefore likely to intensify interactions between drugs metabolized by the CYP450 system. 9,10) Thus, The United States Food and Drug Administration (FDA) and the European Medicines Agency have recommended that physicians avoid the use of omeprazole in all patients taking clopidogrel. 12,13) Various studies have examined the impact of the FDA warnings on the prescription pattern of some drugs such as droperidol cisapride, antipsychotics and antidepressants, and glucose lowering drugs.…”

“…1,7) Different observational studies showed significant cardiovascular adverse events arising from a potential drug interaction due to concomitant use of clopidogrel and PPIs. 1,4,5,[8][9][10] The inhibitory effect of omeprazole on the antiaggregation effects of clopidogrel is most pronounced among the various PPIs studied.…”

Prescription behavior for gastroprotective drugs in new users as a result of communications regarding clopidogrel – proton pump inhibitor interaction

“…In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding (Ray et al. 2010). …”

PPIs and Clopidogrel: The Band Plays On…………

“…Furthermore, where particular outcomes are infrequent, observational studies may be FUNCTIONAL GI DISORDERS ucm191169.htm ), van Boxel et al found no diff erence in apparent cardiovascular risk among the PPIs they examined -including those discouraged by the FDA. Others have similarly found no apparent diff erence among the various PPIs with respect to rates of cardiovascular events in clopidogrel users ( 3,7 ). Th erefore, a patient who requires PPI co-therapy should be prescribed the agent that he or she fi nds most accessible and aff ordable.…”