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P. Michael Ho, MD, PhD; Thomas M. Maddox, MD, MSc; Li Wang, MS; Stephan D. Fihn, MD, MPH; Robert L. Jesse, MD, PhD; Eric D. Peterson, MD, MPH; John S. Rumsfeld, MD, PhD

JAMA. 2009;301(9):937-944.

Context  Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear.

Objective  To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS).

Design, Setting, and Patients  Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006.

Main Outcome Measures  All-cause mortality or rehospitalization for ACS.

Results  Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13).

Conclusion  Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.

Author Affiliations: Denver VA Medical Center, Denver, Colorado (Drs Ho, Maddox, and Rumsfeld); University of Colorado Health Sciences Center, Denver (Drs Ho, Maddox, and Rumsfeld); VA Puget Sound Health Care System, Seattle, Washington (Ms Wang and Dr Fihn); VA Central Office, Washington, DC (Drs Fihn and Jesse); Richmond VA Medical Center, Richmond, Virginia (Dr Jesse); and Duke Clinical Research Institute, Durham, North Carolina (Dr Peterson).

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