FAQ
Is there a drug-drug interaction between clopidogrel and omeprazole?
Background
Clopidogrel (Plavix) is a thienopyridine that inhibits adenosine diphosphate (ADP)-induced platelet activation through the formation of an inactivating disulfide bond within the platelet P2Y12 ADP receptor’s active site. The blockade of ADP-induced platelet activation leads to a reduction in platelet aggregation and arterial thrombus formation. Clopidogrel, as monotherapy or when used concomitantly with aspirin, has proven to be effective in treatment of acute coronary syndromes and in the reduction of stent thrombosis. Clopidogrel is a prodrug activated in the liver to an active metabolite via cytochrome P450 isoenzymes. Variations in polymorphic expression of CYP2C19 specifically seem to be associated with differences in pharmacodynamic response to clopidogrel.
Omeprazole (Prilosec) is a proton-pump inhibitor (PPI), available over-the-counter. It is often used to prevent gastrointestinal bleeding in patients on chronic aspirin-clopidogrel antiplatelet dual therapy. Omeprazole is hepatically metabolized by and is a substrate of CYP2C19. PPIs may compete for CYP2C19 binding with clopidogrel, thus reducing the amount of active clopidogrel metabolite produced.
Identification of a possible drug-drug interaction between clopidogrel and omeprazole is concerning because it may mimic cases of clopidogrel resistance. In clopidogrel resistance, polymorphisms of CYP2C19 reduce metabolism of the prodrug to the active antiplatelet metabolite. Consequentially, this is associated with an increased risk of recurrent arterial thrombosis in patients with a history of acute coronary syndrome or stent thrombosis after placement.
Literature Review
The inhibitory effect of clopidogrel on ADP leads to dephosphorylation of intraplatelet vasodilator-stimulated phosphoprotein (VASP). The degree of VASP phosphorylation can be measured through flow cytometry and reported as a platelet reactivity index (PRI). PRI is directly proportional to rate of thrombosis and indirectly proportional to clopidogrel treatment efficacy. A PRI of less than 50% is thought to be indicative of a “good response” to clopidogrel and a PRI of greater than 50% is thought to be associated with “poor response,” or resistance to clopidogrel.
The Omeprazole CLopidogrel Aspirin (OCLA) Study was a prospective, double-blind, placebo-controlled, randomized trial of patients undergoing elective coronary stent implantation and receiving standardized, dual antiplatelet therapy with aspirin and clopidogrel. Patients were randomized to receive either the intervention of omeprazole 20 mg daily for 7 days or placebo. The purpose of the OCLA study was to prove the authors’ hypothesis that concomitant omeprazole reduces pharmacological action of clopidogrel. The primary outcome parameter was the mean PRI on day 7. Secondary endpoints included the change from baseline of PRI and the proportion of patients with a PRI less than 50% on day 7. The statistical power was met with data from 124 patients analyzed. Although the difference in mean PRI values between the omeprazole and placebo groups was not statistically significant at baseline, the values were statistically significantly different at day 7 (omeprazole: 51.4% ± 16.4; placebo: 39.8% ± 15.4; p<0.0001). The secondary outcome parameters were also statistically significant for mean PRI variation from baseline (omeprazole: -32.6% ± 16.4; placebo: -43.4% ± 15.9; p<0.0001) and proportion of patients with PRI less than 50% (omeprazole: 60.9% poor responders; placebo: 26.7% poor responders; p<0.0001). The odds ratio of being a poor responder in the omeprazole group was 4.31 (95% confidence interval 2 to 9.2). It was hypothesized that CYP2C19 was responsible for the reduction in pharmacologic effect; however, the genetic polymorphism status of each subject was unknown. The authors of the OCLA study concluded that omeprazole significantly reduced clopidogrel’s antiplatelet effect. As a consequence of their results, the authors also recommend against adding a PPI to dual antiplatelet therapy with aspirin and clopidogrel for gastrointestinal prophylaxis.
Conclusion
Clopidogrel and a PPI, such as omeprazole, are often used concomitantly in patients with a history of acute coronary syndrome or cardiac stenting to decrease the risk of gastrointestinal bleeding. The recent OCLA study showed a statistically significant difference in platelet reactivity index for patients taking both clopidogrel and omeprazole. The study postulated that this interaction occurred via inhibition of CYP2C19 by omeprazole, decreasing the activation of clopidogrel, a prodrug. Even though the underlying mechanism of the interaction cannot be assumed from the study, practitioners should be cautious of using these agents simultaneously in patients with no previous risk factors for gastrointestinal bleeding.
References
Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin (OCLA). J Am Coll Cardiol. 2008;51(3):256-260.
Yusuf S, Fox KAA, Tognoni G, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized control trial. JAMA. 2002;288(19):2411-2420.
Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-2247.
Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109(25):3171-3175.
Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Cathet Cardiovasc Intervent. 2003;59(3):295-302.
By: Deanna McMahon, PharmD