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PPIs May Help Reduce Hospitalizations for Gastroduodenal Bleeding in Patients Treated With Clopidogrel
Laurie Barclay, MD


Explore a hypothetical case in insomnia March 20, 2010 — Concurrent use of proton pump inhibitors (PPIs) in patients with serious coronary heart disease treated with clopidogrel is associated with fewer hospitalizations for gastroduodenal bleeding, according to the results of a retrospective cohort study reported in the March 16 issue of the Annals of Internal Medicine.

"We need to make sure that the medicines we give patients help and don't harm," said the Agency for Healthcare Research and Quality (AHRQ) director Carolyn M. Clancy, MD, in a news release. "This evidence on benefits and risks helps inform the combined use of these two drugs."

"Although...PPIs are commonly prescribed with clopidogrel to reduce the risk for serious gastroduodenal bleeding, concern is growing that this practice decreases the efficacy of clopidogrel," write Wayne A. Ray, PhD, from Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System in Nashville, Tennessee, and colleagues.

Using automated data from the Tennessee Medicaid program, the investigators identified 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) who received clopidogrel between 1999 and 2005 after hospitalization for coronary heart disease, which was defined as myocardial infarction, coronary artery revascularization, or unstable angina pectoris.

Automated records of dispensed prescriptions allowed determination of baseline and follow-up drug use. The main study endpoints were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease, defined as fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death.

Concurrent PPI use included pantoprazole in 62% and omeprazole in 9% of patients. Compared with nonusers of PPIs, concurrent PPI users had a 50% lower adjusted incidence of hospitalization for gastroduodenal bleeding (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.39 - 0.65). PPI use was associated with an absolute reduction of 28.5 (95% CI, 11.7 - 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years, for those patients at highest risk of bleeding.

For the entire cohort, the HR associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (95% CI, 0.82 - 1.19). For the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization, HR was 1.01 (95% CI, 0.76 - 1.34).

Limitations of this study include possible unmeasured confounding, misclassification of exposure and endpoints, and difficulties comparing PPI users from one hospital vs nonusers from a different hospital.

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

Editorial: Study a Counterpoint to Previous Studies

In an accompanying editorial, Michael E. Griswold, PhD, from University of Mississippi Medical Center in Jackson and colleagues discuss applications of propensity score adjustment with multilevel data to this study and others.

"Consistency in the overall results for Ray and colleagues' analyses is comforting and offers a counterpoint to previous studies. Given multiple other studies with conflicting or uncertain results, we believe that the safety of coprescription of PPIs and clopidogrel remains an unanswered question," the editorialists write.

The AHRQ and the National Heart, Lung, and Blood Institute at the National Institutes of Health supported this study.

Ann Intern Med. 2010;152:337-345, 393-395. Abstract