0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Articles |

Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors: A Cohort Study

Wayne A. Ray, PhD; Katherine T. Murray, MD; Marie R. Griffin, MD, MPH; Cecilia P. Chung, MD, MPH; Walter E. Smalley, MD, MPH; Kathi Hall, BS; James R. Daugherty, MS; Lisa A. Kaltenbach, MS; and C. Michael Stein, MB, ChB
[+] Article and Author Information

From Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.


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.


Ann Intern Med. 2010;152(6):337-345. doi:10.7326/0003-4819-152-6-201003160-00003
Text Size: A A A

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.

Figures

Grahic Jump Location
Appendix Figure 1.
Study flow diagram.

* Prescription days of supply recently ended, so the person was neither a current user nor a nonuser.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Distribution of person-years of follow-up, according to baseline propensity score (probability of baseline PPI use), for PPI users and nonusers.

Vertical lines indicate deciles for the propensity score. PPI = proton-pump inhibitor.

Grahic Jump Location
Grahic Jump Location
Figure 1.
HRs for gastroduodenal and other bleeding, according to PPI use.

GI = gastrointestinal; HR = hazard ratio; PPI = proton-pump inhibitor.

* Rate is per 1000 person-years. Analysis by PPI dose and individual drug excludes person-time with concurrent use of multiple PPIs.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Risk for hospitalizations for gastroduodenal bleeding in current users of clopidogrel, according to concurrent use of PPIs.

“Rate Difference” is for nonusers of PPIs versus current users and is adjusted for potential confounders. The individual risk factors are age 65 years or older, history of hospitalization for upper gastrointestinal disease or bleeding, recent use of anticoagulants, current use of other medications that increase bleeding risk (systemic corticosteroids, nonsteroidal anti-inflammatory drugs, or cyclooxygenase-2 inhibitors), and any hospital discharge in the past year. PPI = proton-pump inhibitor.

Grahic Jump Location
Grahic Jump Location
Figure 2.
HRs for serious CVD, according to PPI use.

AMI = acute myocardial infarction; CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio; PPI = proton-pump inhibitor; SCD = sudden cardiac death.

* Rate is per 1000 person-years. Analysis by PPI dose and individual drug excludes person-time with concurrent use of multiple PPIs.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 4.
End point of risk for serious cardiovascular disease in current clopidogrel users who had percutaneous coronary intervention with stenting during the qualifying hospitalization, according to concurrent PPI use.

Unadjusted cumulative proportions with serious cardiovascular disease (nonfatal or fatal myocardial infarction, stroke, or other cardiovascular death) are shown. The dashed lines indicate the 95% CI for the PPI nonuser group. Both clopidogrel and PPI use status could change on each day of follow-up; thus, the cumulative proportions were calculated by using the method of Simon and Makuch (43). PPI = proton-pump inhibitor.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)