Proton pump inhibitor (PPI) medications are often prescribed prophylactically with initiation of clopidogrel, with the goal of reducing the risk of gastrointestinal tract bleeding while taking dual-antiplatelet therapy. Recent mechanistic studies, however, suggest that PPIs may reduce the inhibitory effect of clopidogrel on platelet aggregation. In addition, variations in platelet reactivity have been associated with adverse outcomes following stent implantation.
To date, there remains significant ongoing controversy regarding the clinical outcomes of patients taking clopidogrel and PPIs. The US Food and Drug Administration recently released an early communication about a safety review of the potential interaction between these 2 types of medications.
To address this gap in knowledge, authors evaluated the prevalence of use of clopidogrel plus PPI following hospital discharge for ACS in a national Veterans Affairs (VA) cohort and compared rates of all-cause mortality and rehospitalization for ACS, including myocardial infarction (MI) and unstable angina, between patients taking clopidogrel plus PPI vs clopidogrel without PPI.
Authors analyzed a 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.
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).
In conclusion, this study found that concomitant use of clopidogrel and PPI after rehospitalization for ACS is associated with a higher risk of adverse outcomes compared with clopidogrel use without PPI. These findings, coupled with prior mechanistic studies, suggest that concomitant PPI use may attenuate the benefits of clopidogrel use after ACS. Pending further studies to confirm these results and prospectively assess cardiovascular outcomes for patients taking clopidogrel
plus PPI vs clopidogrel without PPI, the results of this study may suggest that PPIs should be used for patients with a clear indication for the medication, rather than routine prophylactic prescription.
Cumulative Risk of All-Cause Mortality and Recurrent Acute Coronary Syndrome (ACS) Among Patients Taking Clopidogrel After Hospital Discharge for ACS and Prescribed a Proton Pump Inhibitor (PPI) at Hospital Discharge or During Follow-up (n=5244)