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McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045ZDocumentSummaryInformation8,Current UserG{Gilard M1, Arnaud B2, Cornily JC1, Le Gal G3, Lacut K3, Le Calvez G2, Mansourati J1, Mottier D2, Abgrall JF2, Boschat J1. .|          $ $ ((, ,004 4 88< <      Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-60. Z Introduction Platelet activation & aggregation play an important role in the pathogenesis of arterial thrombosis and can lead to acute coronary syndrome (ACS) associated with percutaneous coronary intervention (PCI). Clopidogrel (Plavix*) a thienopyridine, inhibits platelet activation induced by adenosine diphosphate (ADP). Clopidogrel metabolites form an inactive disulfide bond with the platelet P2Y12 ADP receptor, inhibiting platelet reactivity. Clopidogrel is a prodrug, needing hepatic metabolism to acquire platelet anti-aggregation properties.0!P f Introduction^Vasodilator-Stimulated Phosphoprotein Phosphorylation (VASP) provides an functional index of platelet reactivity to clopidogrel. The higher the platelet reactivity index (PRI) the more frequently thrombosis occurs with clopidogrel treatment. The hepatic CYP450 isoenzyme CYP2C19 is the dominant enymatic pathway of prodrug (clopidogrel) activation._Z_s IntroductionOmeprazole (OMP) is a racemic compound commonly used to suppress gastric acid production in the treatment of peptic ulcer disease and Gastroesophageal Reflux Disease (GERD). OMP is a prodrug, predominantly metabolized by hepatic CYP450 isoenzyme CYP2C19. Competitive inhibition of the CYP2C19 metabolic pathway by OMP may decrease Clopidogrel activation thereby decreasing PRI values and increasing risk for ACS., ;Hepatic CYP450 Activation of Prodrugs: PPIs and Clopidogrel<<\AimThe authors sought to test the hypothesis that OMP reduces the biological action of clopidogrel (platelet reactivity index or PRI) , probably due to competitive inhibition of the CYP2C19 pathway. In a prospective, randomized double-blind study, Gilard, et al, evaluated the impact of OMP 20mg/day vs. placebo on clopidogrel effect by measuring platelet phosphorylation-VASP as expressed as PRI.Z Study Design:Prospective, blinded, placebo controlled, randomized trial Consecutive patients undergoing elective coronary stent implantation were considered for inclusion All patients gave written informed consent Controlled Treatment (all patients received) Aspirin 75 mg/day Clopidogrel 300 mg loading, followed by 75 mg/day Randomization Treatment Omperazole 20 mg or Placebo Treatment daily for 7 daysn; D7;D  7z Study Design%Study Design: Study Population  ()Exclusion Criteria Previous treatment with Clopidogrel Previous treatment with PPI History of thrombocytopenia < 150K Bleeding disorder Liver disease Peptic ulcer disease Pregnancy* j Study Design: Study Evaluations  !() Conducted on Day 1 (pre-Clopidogrel) and 7 days after (clopidogrel + OMP vs. placebo) Platelet Reactivity Evaluation Vasodilator-Stimulated Phosphoprotein (VASP) Biodis-Stago, Asnieres, France. Platelet mean fluorescence intensity (MFI) Platelet Reactivity Index (PRI)B vvk Study Design: Study Evaluations  !(%Platelet Reactivity Index (PRI) calculation: % PRI = (MFI[PGE1] - MF1[PGE1+ADP] X 100 MFI (PGE1) Established Criteria for Clopidogrel response: Good % PRI < 50% Poor % PRI > 50%F 6  vStudy Results: DemographicslStudy Results: Demographics].Study Results: Platelet Reactivity Index (PRI)// mStudy Results: Variation of PRI $^Study Results: SummaryBaseline demographic characteristics between the Omp and placebo treated groups were statistically similar, Table 1. Day 1, mean PRI was similar in both groups (83.9% vs. 83.2%), but PRI on Day 7 was significantly higher in the Omp group (51.4% vs.. 39.8%), (p< 0.0001) Figure 1. Clopidogrel  poor responders (defined as PRI >50%) were more common in the Omp group 60.9% vs. 26.7% in the placebo group (p < 0.0001). The odds ratio of being a clopidogrel  poor responder when treated with Omp was 4.31 (95% CI 2.0 to 9.2). P{ Conclusions:   6Omp significantly decreased the effect of clopidogrel on platelet activation as tested by VASP phosphorylation. Clinical implications of this study suggest that 1/3 of patients on clopidogrel alone are unprotected against ACS (PRI > 50%) and that patients co-treated with Omp have double the risk of ACS (60.9% have PRI > 50%). The empiric prescription of Omp to prevent the potential of gastrointestinal bleeding caused by aspirin-clopidogrel antiplatelet therapy should be stopped. Risk stratification for GI complications should guide Omp use in these patients.7 " Z7yReviewer Comments*Gilard, et al, do not answer the following questions? Although all of the PPIs are prodrugs with some metabolism through the CYP450. Each PPI has unique CYP450 metabolic pathways. This study does not determine if all PPIs convey the same negative effect on clopidogrel (PRI > 50%) as shown with Omp. PPI Primary Pathway (Secondary pathway) Omperazole CYP2C19 (CYP3A4) Esomperazole CYP3A4 (CYP2C19) Lansoprazole CYP3A4 (CYP2C19,CYP1A) Dexlansoprazole CYP2C19 (CYP3A4) Rabeprazole CYP2C19 + CYP3A4 Pantoprazole CYP2C9 (CYP2C19sulfate conjugation) The investigators did not evaluate for CYP2C19 polymorphisms or other confounding variables that may have influenced clopidogrel hepatic metabolism and explained high PRI (>50%) seen in 30% of the placebo group.7P" P1P" P" P" P7    $$(( ,, 004493Reviewer Comments Dr. Gilard and colleagues are commended for using a readily available clinical assay (VASP phosphorylation) to demonstrate the effects of Omp on clopidogrel inhibition of the ACS marker, PRI. The study is well designed, the results striking and with important negative clinical implication for the coadministration of omp and clopidogrel among patients at risk for ACS. This study design should be applied in a similar fashion to evaluate the effect of other PPIs on clopidogrel and the ACS risk measured by PRI > 50%. For now, we should all use restraint in the prescription of PPI among patients on clopidogrel and follow the current recommendation of the FDA until further studies are available. B P " PBhttp://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm CC The identification of increased risk for Acute Coronary Syndrome when at risk cardiac patients receiving clopidogrel are concomitantly given PPIs has lead to the Food & Drug Administration to issue the following warning:  Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.  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