Abstract 2128: Cardiovascular Risk Associated With Concurrent Proton Pump Inhibitor and Clopidogrel Therapy: Is It Explained by Interaction With CYP2C19 Genotype?
Background: Clopidogrel (CLOP) is a prodrug activated by hepatic CYP450, principally, CYP2C19. CLOP is widely used after acute coronary syndromes and coronary interventions (e.g., stenting) to prevent arterial thrombosis. Because CLOP increases bleeding risk, a proton pump inhibitor (PPI) often is given concurrently. PPIs inhibit CYP2C19 and have been reported to increase cardiovascular risk when given with CLOP. Whether PPI risk is conditioned on carriage of the common CYP2C19*2 reduced function variant is unknown.
Methods: Patients (pts; N=938) enrolled in the Intermountain Heart Collaborative Study, received a drug eluting stent (DES), and discharged on CLOP were studied. Pts were genotyped for CYP2C19*2 using Taqman© 3′ exonuclease technology. Results were analyzed for incident myocardial infarction (MI), death (D), and combined D/MI (primary) at 1 year by genotype and PPI use.
Results: CYP2C19*2 was carried by 27.1% of DES recipients. One-year D/MI rates were increased with PPI prescription: 14.4% for PPI use and 5.8% for no PPI among common allele homozygotes (n=684, log-rank p<0.001) and 17.6% for PPI use and 9.3% for no PPI use among CYP2C19*2 carriers (n=254, log-rank p=0.05). In Cox regression, PPI use was associated with a hazard ratio (HR) = 2.37 (95% CI=1.56, 3.61), p<0.001, for D/MI. CYP2C19*2 carriers had HR=1.35 (95% CI=0.90, 2.03), p=0.15. No statistical interaction between the effect of PPI and CYP2C19 genotype on D/MI was present (p-interaction=0.57).
Conclusions: Our results demonstrate an increase in risk at 1-year of D/MI in pts given a PPI after DES placement. The magnitude of risk exceeds that associated with CYP2C19*2 carriage. Further, risk is not limited to (or conditioned by) carriage of the reduced function variant. Thus, genotyping will not be useful to avoid the apparent hazard associated with PPIs given concurrently with CLOP. Our data do not resolve the question of the mechanism of PPI risk, which might include selection bias (uncorrected confounding) or a direct toxic effect of PPIs, as well as an interaction with CYP2C19. Hence, the issue of causation should be addressed by a randomized clinical trial. Meanwhile, routine use of PPIs with CLOP should be discouraged in pts receiving DES.