Abstract 997: Cardiovascular Risk Associated With Concurrent Proton Pump Inhibitor and Clopidogrel Therapy: How Much? How Specific?
Background: Clopidogrel (CLOP) is a prodrug activated by hepatic CYP450 enzymes, principally CYP2C19. CLOP is widely used after acute coronary interventions to prevent thrombosis. Because CLOP increases the bleeding risk, a proton pump inhibitor (PPI) often is given concurrently. Omeprazole (O), and to a lesser extent other PPIs, inhibits CYP2C19, and ex vivo studies indicate that concurrent O reduces the generation of CLOP active metabolite. However, evidence for a clinical interaction is inconclusive.
Methods: We prospectively analyzed patient data from the Intermountain Heart Collaborative Study Registry to assess 1-y risk for death/myocardial infarction (D/MI) of CLOP + PPI vs. CLOP alone (N=10,703; age 60±15, 62% male). Subanalyses assessed trends by PPI type, with prospective risk hypothesized to be O (n=3912) > lansoprazole (L; n=5020) > pantoprazole (P; n=1733), based on ex vivo pharmacodynamics (PD). Hazard ratios (HR) were adjusted (adj) for multiple potential confounders.
Results: Results are shown in the Table⇓. D/MI was higher for CLOP + PPI than CLOP. Risk was substantially but not completely reduced by adjustment, with an adj HR of 1.64, 95% confidence interval 1.41–1.90, p<0.001. The result was driven primarily by MI (HR for MI=1.50, p<0.001; HR for D=1.09, p=0.13). By specific agent, risk was unexpectedly lowest with O, intermediate with L, and highest with P, arguing against an exclusive PD explanation based on extent of CYP2C19 interaction.
Conclusions: PPIs are associated with an increase in risk of D/MI in cardiovascular patients receiving CLOP. None of the PPIs are free of apparent risk. However, failure to show increased risk in an order consistent with ex vivo data raises the question of selection bias (uncorrected confounding) or a direct toxic effect of PPIs, as well as an interaction with CYP2C19. The issue of causation should be addressed by a randomized clinical trial. Meanwhile, routine use of PPIs with CLOP should be discouraged.