Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study

Abstract

Background: Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear.

Objective: To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease.

Design: Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after 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 follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death).

Results: Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization.

Limitations: Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital.

Conclusion: In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk.

Primary funding source: Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.

Figure 1

Relative risk of bleeding endpoints for current clopidogrel users according to use of individual PPIs and PPI dose. Reference category is nonusers of any PPI. PY is person-years are person years of PPI use, events is number of cases of serious cardiovascular disease. The sum for individual drugs and doses does not equal total use because the former exclude persons with use of more than one PPI. HR is the adjusted hazard ratio, CI, confidence interval. The high dose cutpoints were: esomeprazole >40mg, omeprazole >20mg, pantoprazole >40mg, rabeprazole >20mg, and lanzoprazole >30mg.

Figure 2

Relative risk of serious cardiovascular disease endpoint (nonfatal or fatal myocardial infarction, stroke, or other cardiovascular death) for current clopidogrel users according to use of individual PPIs and PPI dose. Reference category is nonusers of any PPI. PY is person-years are person years of PPI use, events is number of cases of serious cardiovascular disease. The sum for individual drugs and doses does not equal total use because the former exclude persons with use of more than one PPI. HR is the adjusted hazard ratio, CI, confidence interval. The high dose cutpoints were: esomeprazole >40mg, omeprazole >20mg, pantoprazole >40mg, rabeprazole >20mg, and lanzoprazole >30mg.