Acknowledgment: The authors thank the State of Tennessee Bureau of TennCare and Department of Health, which provided study data.
Grant Support: By the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics cooperative agreement (HS1-16974) and the National Heart, Lung, and Blood Institute (HL081707).
Potential Conflicts of Interest: Drs. Ray and Griffin, Ms. Hall, Mr. Daugherty, and Ms. Kaltenbach have disclosed the following: Grants received (to institution): Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics, National Heart, Lung, and Blood Institute, National Institutes of Health. Dr. Ray has also disclosed that he has given expert testimony on rofecoxib (Attorney General, Texas Medicaid), hormone replacement therapy (insurance companies), and zoledronic acid (plaintiff attorneys). Ms. Kaltenbach has also disclosed receipt (to institution) of support for travel to meetings for the study or otherwise, fees for participation in review activities (such as data monitoring boards, statistical analysis, end point committees, and the like), and payment for writing or reviewing the manuscript from the Agency for Healthcare Research and Quality, as well as support in kind (such as writing, provision of medicines or equipment, or administrative support) from the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics and the National Heart, Lung, and Blood Institute. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-0566.
Reproducible Research Statement:Study protocol: Available from Dr. Ray (e-mail, Wayne.Ray@vanderbilt.edu). Statistical code and data set: Not available.
Requests for Single Reprints: Wayne A. Ray, PhD, Department of Preventive Medicine, 1500 21st Avenue South, Suite 2600, Nashville, TN 37212; e-mail, Wayne.Ray@vanderbilt.edu.
Current Author Addresses: Drs. Ray and Griffin, Ms. Hall, Mr. Daugherty, and Ms. Kaltenbach: Vanderbilt University School of Medicine, Department of Preventive Medicine, 1500 21st Avenue, 2600 Village at Vanderbilt, Nashville, TN 37212.
Dr. Murray: Vanderbilt University School of Medicine, Department of Clinical Pharmacology, 559 PRB, Nashville, TN 37232.
Dr. Chung: Department of Medicine, Johns Hopkins Bayview Medical Center, 10 J Aspinwood Way, Baltimore, MD 21237.
Dr. Smalley: Vanderbilt University School of Medicine, Division of Gastroenterology, 1030 Corridor MRB IV, Nashville, TN 37212.
Dr. Stein: Vanderbilt University School of Medicine, Division of Rheumatology, 542 RRB, 2222 Pierce Avenue, Nashville, TN 37232.
Author Contributions: Conception and design: W.A. Ray, K.T. Murray, M.R. Griffin, C.P. Chung, W.E. Smalley, C.M. Stein.
Analysis and interpretation of the data: W.A. Ray, K.T. Murray, M.R. Griffin, C.P. Chung, W.E. Smalley, L.A. Kaltenbach, C.M. Stein.
Drafting of the article: W.A. Ray, K.T. Murray, C.P. Chung, C.M. Stein.
Critical revision of the article for important intellectual content: W.A. Ray, K.T. Murray, M.R. Griffin, C.P. Chung, L.A. Kaltenbach, C.M. Stein.
Final approval of the article: W.A. Ray, K.T. Murray, M.R. Griffin, C.P. Chung, L.A. Kaltenbach, C.M. Stein.
Provision of study materials or patients: W.A. Ray, K. Hall.
Statistical expertise: W.A. Ray, L.A. Kaltenbach.
Obtaining of funding: W.A. Ray.
Administrative, technical, or logistic support: W.A. Ray, C.P. Chung, K. Hall, J.R. Daugherty.
Collection and assembly of data: W.A. Ray, K.T. Murray, C.P. Chung, K. Hall, J.R. Daugherty.
From Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear.
To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease.
Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease.
20Â 596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris.
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).
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.
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.
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.
Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.
Published: Ann Intern Med. 2010;152(6):337-345.