1 Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2 Gilard M 1, Arnaud B 2, Cornily JC 1, Le Gal G 3, Lacut K 3, Le Calvez G 2, Mansourati J 1, Mottier D 2, Abgrall JF 2, Boschat J 1. 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: Dept Hematology, INSERM 0502, 3 Center for Clinical Investigation EA3878 and Dept Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France 1 Dept Cardiology, 2 Dept Hematology, INSERM 0502, 3 Center for Clinical Investigation EA3878 and Dept Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France

3Introduction 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). 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 (Plavix*) a thienopyridine, inhibits platelet activation induced by adenosine diphosphate (ADP). Clopidogrel metabolites form an inactive disulfide bond with the platelet P2Y 12 ADP receptor, inhibiting platelet reactivity. Clopidogrel metabolites form an inactive disulfide bond with the platelet P2Y 12 ADP receptor, inhibiting platelet reactivity. Clopidogrel is a prodrug, needing hepatic metabolism to acquire platelet anti-aggregation properties. Clopidogrel is a prodrug, needing hepatic metabolism to acquire platelet anti-aggregation properties. Small DS, et al. Effects of PPI Lansoprazole on pharmacodynamics of Prasugrel and Clopidogrel. J Clin Pharm. 2008;48:

4Introduction Vasodilator-Stimulated Phosphoprotein Phosphorylation (VASP) provides an functional index of platelet reactivity to clopidogrel. 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 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. The hepatic CYP450 isoenzyme CYP2C19 is the dominant enymatic pathway of prodrug (clopidogrel) activation. Gilard M, et al. J Thromb Hemost 2006;4:2508-9

5Introduction Omeprazole (OMP) is a racemic compound commonly used to suppress gastric acid production in the treatment of peptic ulcer disease and Gastroesophageal Reflux Disease (GERD). Omeprazole (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. 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. Competitive inhibition of the CYP2C19 metabolic pathway by OMP may decrease Clopidogrel activation thereby decreasing PRI values and increasing risk for ACS. Gilard M, et al. J Thromb Hemost 2006;4:2508-9

Hepatic CYP450 Activation of Prodrugs: PPIs and Clopidogrel CYP-2C19 CYP-3A4 Pro Drugs Clopidogrel PPI’s Ishizaki T, et al. Aliment Pharmacol Ther. 1999;13:Suppl 3: Small DS, et al. J Clin Pharmacol. 2008;48: Competitive Inhibition ↓ Active Metabolites Active Metabolites R Sulfenamide Benzimidazole

7 Aim The 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. The 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. 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. Gilard M, et al. J Am Coll Cardiol 2008;51:

8 Study Design: Prospective, blinded, placebo controlled, randomized trial Consecutive patients undergoing elective coronary stent implantation were considered for inclusion Consecutive patients undergoing elective coronary stent implantation were considered for inclusion All patients gave written informed consent All patients gave written informed consent Controlled Treatment (all patients received) Controlled Treatment (all patients received) – Aspirin 75 mg/day – Clopidogrel 300 mg loading, followed by 75 mg/day Randomization Treatment Randomization Treatment – Omperazole 20 mg or Placebo – Treatment daily for 7 days Gilard M, et al. J Am Coll Cardiol 2008;51:

9 Study Design Gilard M, et al. J Am Coll Cardiol 2008;51: Total Assessed for Eligibility, N=354 Randomized N = 140 N=70 Omeprazole Evaluable n=64 (drop outs, 6) N=70 Placebo Evaluable n=60 (drop outs, 9)

10 Study Design: Study Population Exclusion Criteria Exclusion Criteria – Previous treatment with Clopidogrel – Previous treatment with PPI – History of thrombocytopenia < 150K – Bleeding disorder – Liver disease – Peptic ulcer disease – Pregnancy Gilard M, et al. J Am Coll Cardiol 2008;51:

11 Study Design: Study Evaluations Conducted on Day 1 (pre-Clopidogrel) and 7 days after (clopidogrel + OMP vs. placebo) Conducted on Day 1 (pre-Clopidogrel) and 7 days after (clopidogrel + OMP vs. placebo) Platelet Reactivity Evaluation Platelet Reactivity Evaluation – Vasodilator-Stimulated Phosphoprotein (VASP) Biodis-Stago, Asnieres, France. – Platelet mean fluorescence intensity (MFI) – Platelet Reactivity Index (PRI) Gilard M, et al. J Am Coll Cardiol 2008;51:

12 Study Design: Study Evaluations Platelet Reactivity Index (PRI) calculation: % PRI = (MFI[PGE1] - MF1[PGE1+ADP] X 100 MFI (PGE1) MFI (PGE1) Established Criteria for Clopidogrel response: Good% PRI < 50% Poor% PRI > 50% Gilard M, et al. J Am Coll Cardiol 2008;51: Barragan P et al. Catheter Cardiovasc Interv. 2003;107:32-7

13 Study Results: Demographics Gilard M, et al. J Am Coll Cardiol 2008;51: PlaceboN=60OmeprazoleN=64P-value Age6362ns ♂ gender 75%81%ns Smoker71%64%ns HTN47%53%ns FHx CAD 43%34%ns DM18%9%ns BMI2727ns Dyslipidemia71%66%ns

14 Study Results: Demographics Gilard M, et al. J Am Coll Cardiol 2008;51: PlaceboN=60OmeprazoleN=64P-value Previous MI 8%11%ns Beta-blocker91%83%ns ACE inhibitor 50%48%ns Atorvastatin68%67%ns Other statin 28%23%ns Table 1.

15 Study Results: Platelet Reactivity Index (PRI) Gilard M, et al. J Am Coll Cardiol 2008;51: P = NS P < Figure 1.

16 Study Results: Variation of PRI Gilard M, et al. J Am Coll Cardiol 2008;51: P < Figure 2.

17 Study Results: Summary Baseline demographic characteristics between the Omp and placebo treated groups were statistically similar, Table 1. Baseline 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 %), (p< ) Figure 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 %), (p< ) 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 50%) were more common in the Omp group 60.9% vs. 26.7% in the placebo group (p < ). The odds ratio of being a clopidogrel “poor” responder when treated with Omp was 4.31 (95% CI 2.0 to 9.2). The odds ratio of being a clopidogrel “poor” responder when treated with Omp was 4.31 (95% CI 2.0 to 9.2). Gilard M, et al. J Am Coll Cardiol 2008;51:

18 Conclusions: 1. Omp significantly decreased the effect of clopidogrel on platelet activation as tested by VASP phosphorylation. 2. 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%). 3. 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. Gilard M, et al. J Am Coll Cardiol 2008;51:

Reviewer Comments Gilard, et al, do not answer the following questions? 1.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. PPIPrimary Pathway (Secondary pathway ) a.Omperazole CYP2C19(CYP3A4) b.Esomperazole CYP3A4(CYP2C19) c.LansoprazoleCYP3A4(CYP2C19,CYP1A) d.DexlansoprazoleCYP2C19(CYP3A4) e.RabeprazoleCYP2C19 + CYP3A4 f.PantoprazoleCYP2C9(CYP2C19  sulfate conjugation) 2.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. Gilard M, et al. J Am Coll Cardiol 2008;51:

20 Reviewer Comments 1. 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. 2. 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. 3. 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%. 4. 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. Gilard M, et al. J Am Coll Cardiol 2008;51:

21 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.” “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.” “Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.” “Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.” “Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking PPI, including Prilosec OTC.” “Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking PPI, including Prilosec OTC.”