PowerPoint Presentation - Literature Review

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Literature ReviewLiterature Review

Peter R. McNally, DO, FACP, FACGPeter R. McNally, DO, FACP, FACGUniversity Colorado Denver University Colorado Denver

School of MedicineSchool of MedicineCenter for Human SimulationCenter for Human Simulation

Aurora, Colorado 80045Aurora, Colorado 80045

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Gilard MGilard M11, Arnaud B, Arnaud B22, Cornily JC, Cornily JC11, Le Gal G, Le Gal G33, Lacut , Lacut KK33, Le Calvez G, Le Calvez G22, Mansourati J, Mansourati J11, Mottier D, Mottier D22, Abgrall , Abgrall

JFJF22, Boschat J, Boschat J11..

Influence of omeprazoleInfluence of omeprazoleon the antiplatelet action of clopidogrel associated withon the antiplatelet action of clopidogrel associated with

aspirin: the randomized, double-blind OCLA aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. (Omeprazole CLopidogrel Aspirin) study.

J Am Coll Cardiol 2008;51:256-60. J Am Coll Cardiol 2008;51:256-60.

1Dept Cardiology, 22Dept Hematology, INSERM 0502, Dept Hematology, INSERM 0502, 33Center for Clinical Investigation EA3878 and Dept Center for Clinical Investigation EA3878 and Dept

Internal Medicine and Chest Diseases, Brest Internal Medicine and Chest Diseases, Brest University Hospital, Brest, FranceUniversity Hospital, Brest, France

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IntroductionIntroduction• Platelet activation & aggregation play an important role Platelet activation & aggregation play an important role

in the pathogenesis of arterial thrombosis and can lead in the pathogenesis of arterial thrombosis and can lead to acute coronary syndrome (ACS) associated with to acute coronary syndrome (ACS) associated with percutaneous coronary intervention (PCI). percutaneous coronary intervention (PCI).

• Clopidogrel (Plavix*) a thienopyridine, inhibits platelet Clopidogrel (Plavix*) a thienopyridine, inhibits platelet activation induced by adenosine diphosphate (ADP).activation induced by adenosine diphosphate (ADP).

• Clopidogrel metabolites form an inactive disulfide bond Clopidogrel metabolites form an inactive disulfide bond with the platelet P2Ywith the platelet P2Y1212 ADP receptor, inhibiting platelet ADP receptor, inhibiting platelet reactivity.reactivity.

• Clopidogrel is a prodrug, needing hepatic metabolism Clopidogrel is a prodrug, needing hepatic metabolism to acquire platelet anti-aggregation properties.to acquire platelet anti-aggregation properties.

Small DS, et al. Effects of PPI Lansoprazole on pharmacodynamics of Small DS, et al. Effects of PPI Lansoprazole on pharmacodynamics of Prasugrel and Clopidogrel. J Clin Pharm. 2008;48:475-84.Prasugrel and Clopidogrel. J Clin Pharm. 2008;48:475-84.

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IntroductionIntroduction• Vasodilator-Stimulated Phosphoprotein Vasodilator-Stimulated Phosphoprotein

Phosphorylation (VASP) provides an functional Phosphorylation (VASP) provides an functional index of platelet reactivity to clopidogrel.index of platelet reactivity to clopidogrel.

• The higher the platelet reactivity index (PRI) the The higher the platelet reactivity index (PRI) the more frequently thrombosis occurs with more frequently thrombosis occurs with clopidogrel treatment.clopidogrel treatment.

• The hepatic CYP450 isoenzyme CYP2C19 is the The hepatic CYP450 isoenzyme CYP2C19 is the dominant enymatic pathway of prodrug dominant enymatic pathway of prodrug (clopidogrel) activation.(clopidogrel) activation.

Gilard M, et al. J Thromb Hemost 2006;4:2508-9Gilard M, et al. J Thromb Hemost 2006;4:2508-9

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IntroductionIntroduction• Omeprazole (OMP) is a racemic compound commonly Omeprazole (OMP) is a racemic compound commonly

used to suppress gastric acid production in the used to suppress gastric acid production in the treatment of peptic ulcer disease and treatment of peptic ulcer disease and Gastroesophageal Reflux Disease (GERD).Gastroesophageal Reflux Disease (GERD).

• OMP is a prodrug, predominantly metabolized by OMP is a prodrug, predominantly metabolized by hepatic CYP450 isoenzyme CYP2C19. hepatic CYP450 isoenzyme CYP2C19.

• Competitive Competitive inhibition of the CYP2C19 metabolic inhibition of the CYP2C19 metabolic pathway by OMP may decrease Clopidogrel activation pathway by OMP may decrease Clopidogrel activation thereby decreasing PRI values and increasing risk for thereby decreasing PRI values and increasing risk for ACS.ACS.

Gilard M, et al. J Thromb Hemost 2006;4:2508-9Gilard 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 3:27-36.

Small DS, et al. J Clin Pharmacol. 2008;48:475-484.

Competitive Inhibition

↓ Active Metabolites

Active Metabolites

R-130964

Sulfenamide

Benzimidazole

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AimAim• The authors sought to test the hypothesis that The authors sought to test the hypothesis that

OMP reduces the biological action of clopidogrel OMP reduces the biological action of clopidogrel (platelet reactivity index or PRI) , probably due to (platelet reactivity index or PRI) , probably due to competitive inhibition of the CYP2C19 pathway.competitive inhibition of the CYP2C19 pathway.

• In a prospective, randomized double-blind study, In a prospective, randomized double-blind study, Gilard, et al, evaluated the impact of OMP Gilard, et al, evaluated the impact of OMP 20mg/day vs. placebo on clopidogrel effect by 20mg/day vs. placebo on clopidogrel effect by measuring platelet phosphorylation-VASP as measuring platelet phosphorylation-VASP as expressed as PRI.expressed as PRI.

Gilard MGilard M, et al. J Am Coll Cardiol 2008;51:256-60., et al. J Am Coll Cardiol 2008;51:256-60.

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Study Design:Study Design:Prospective, blinded, placebo controlled, randomized trialProspective, blinded, placebo controlled, randomized trial• Consecutive patients undergoing elective coronary Consecutive patients undergoing elective coronary

stent implantation were considered for inclusionstent implantation were considered for inclusion• All patients gave written informed consentAll patients gave written informed consent• Controlled Treatment (all patients received)Controlled Treatment (all patients received)

– Aspirin 75 mg/dayAspirin 75 mg/day– Clopidogrel 300 mg loading, followed by 75 mg/dayClopidogrel 300 mg loading, followed by 75 mg/day

• Randomization TreatmentRandomization Treatment– Omperazole 20 mg or PlaceboOmperazole 20 mg or Placebo– Treatment daily for 7 daysTreatment daily for 7 days


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Study DesignStudy DesignGilard MGilard M, et al. J Am Coll Cardiol 2008;51:256-60., et al. J Am Coll Cardiol 2008;51:256-60.

Total Assessed for Eligibility, N=354

RandomizedN = 140

N=70Omeprazole

N=70Placebo

Evaluable n=64(drop outs, 6)

Evaluable n=60(drop outs, 9)

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Study Design: Study Design: Study PopulationStudy Population• Exclusion CriteriaExclusion Criteria

– Previous treatment with ClopidogrelPrevious treatment with Clopidogrel– Previous treatment with PPIPrevious treatment with PPI– History of thrombocytopenia < 150KHistory of thrombocytopenia < 150K– Bleeding disorderBleeding disorder– Liver diseaseLiver disease– Peptic ulcer diseasePeptic ulcer disease– PregnancyPregnancy


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Study Design: Study Design: Study EvaluationsStudy Evaluations

• Conducted on Day 1 (pre-Clopidogrel) and 7 Conducted on Day 1 (pre-Clopidogrel) and 7 days after (clopidogrel + OMP vs. placebo)days after (clopidogrel + OMP vs. placebo)

• Platelet Reactivity EvaluationPlatelet Reactivity Evaluation– Vasodilator-Stimulated Phosphoprotein Vasodilator-Stimulated Phosphoprotein

(VASP) Biodis-Stago, Asnieres, France.(VASP) Biodis-Stago, Asnieres, France.– Platelet mean fluorescence intensity (MFI)Platelet mean fluorescence intensity (MFI)– Platelet Reactivity Index (PRI)Platelet Reactivity Index (PRI)


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Study Design: Study Design: Study Evaluations Study Evaluations Platelet Reactivity Index (PRI) calculation:Platelet Reactivity Index (PRI) calculation:

% PRI = % PRI = (MFI[PGE1] - MF1[PGE1+ADP](MFI[PGE1] - MF1[PGE1+ADP] X 100 X 100 MFI (PGE1)MFI (PGE1)

Established Criteria for Clopidogrel response:Established Criteria for Clopidogrel response:GoodGood % PRI < 50%% PRI < 50%

PoorPoor % PRI > 50%% PRI > 50%


Barragan P et al. Catheter Cardiovasc Interv. 2003;107:32-7

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Study Results: DemographicsStudy Results: Demographics


PlaceboPlaceboN=60N=60

OmeprazoleOmeprazoleN=64N=64

P-valueP-value

AgeAge 6363 6262 nsns♂ ♂ gendergender 75%75% 81%81% nsnsSmokerSmoker 71%71% 64%64% nsnsHTNHTN 47%47% 53%53% nsnsFHx CADFHx CAD 43%43% 34%34% nsnsDMDM 18%18% 9%9% nsnsBMIBMI 2727 2727 nsnsDyslipidemiaDyslipidemia 71%71% 66%66% nsns

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Study Results: DemographicsStudy Results: Demographics


PlaceboPlaceboN=60N=60

OmeprazoleOmeprazoleN=64N=64

P-valueP-value

Previous MIPrevious MI 8%8% 11%11% nsnsBeta-blockerBeta-blocker 91%91% 83%83% nsnsACE ACE inhibitorinhibitor

50%50% 48%48% nsns

AtorvastatinAtorvastatin 68%68% 67%67% nsnsOther statinOther statin 28%28% 23%23% nsns

Table 1.Table 1.

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Study Results: Platelet Reactivity Index (PRI)Study Results: Platelet Reactivity Index (PRI)

83.9 83.2

51.439.8

0102030405060708090

100

PRI (%)

Omp D1 Plac D1 Omp D7 Plac D7


P = NS

P < 0.0001

Figure 1.Figure 1.

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Study Results: Variation of PRIStudy Results: Variation of PRI

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-32

-70

-60

-50

-40

-30

-20

-10

0

PRI Variation (%)

Placebo Omp


P < 0.0001

Figure 2.Figure 2.

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Study Results: SummaryStudy Results: Summary

• Baseline demographic characteristics between the Omp and Baseline demographic characteristics between the Omp and placebo treated groups were statistically similar, Table 1.placebo treated groups were statistically similar, Table 1.

• Day 1, mean PRI was similar in both groups (83.9% vs. 83.2%), 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 but PRI on Day 7 was significantly higher in the Omp group (51.4% vs.. 39.8%), (p< 0.0001) Figure 1.(51.4% vs.. 39.8%), (p< 0.0001) Figure 1.

• Clopidogrel “poor” responders (defined as PRI >50%) were Clopidogrel “poor” responders (defined as PRI >50%) were more common in the Omp group 60.9% vs. 26.7% in the more common in the Omp group 60.9% vs. 26.7% in the placebo group (p < 0.0001).placebo group (p < 0.0001).

• The odds ratio of being a clopidogrel “poor” responder when The odds ratio of being a clopidogrel “poor” responder when treated with Omp was 4.31 (95% CI 2.0 to 9.2).treated with Omp was 4.31 (95% CI 2.0 to 9.2).


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Conclusions:Conclusions: 1.1. Omp significantly decreased the effect of clopidogrel on Omp significantly decreased the effect of clopidogrel on

platelet activation as tested by VASP phosphorylation.platelet activation as tested by VASP phosphorylation.

2.2. Clinical implications of this study suggest that 1/3 of Clinical implications of this study suggest that 1/3 of patients on clopidogrel alone are unprotected against patients on clopidogrel alone are unprotected against ACS (PRI > 50%) and that patients co-treated with Omp ACS (PRI > 50%) and that patients co-treated with Omp have double the risk of ACS (60.9% have PRI > 50%).have double the risk of ACS (60.9% have PRI > 50%).

3.3. The empiric prescription of Omp to prevent the potential The empiric prescription of Omp to prevent the potential of gastrointestinal bleeding caused by aspirin-clopidogrel of gastrointestinal bleeding caused by aspirin-clopidogrel antiplatelet therapy should be stopped. Risk stratification antiplatelet therapy should be stopped. Risk stratification for GI complications should guide Omp use in these for GI complications should guide Omp use in these patients.patients.


Reviewer CommentsGilard, 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.

PPI Primary Pathway (Secondary pathway)a. Omperazole CYP2C19 (CYP3A4)b. Esomperazole CYP3A4 (CYP2C19)c. Lansoprazole CYP3A4 (CYP2C19,CYP1A)d. Dexlansoprazole CYP2C19 (CYP3A4)e. Rabeprazole CYP2C19 + CYP3A4f. Pantoprazole CYP2C9 (CYP2C19sulfate

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;51:256-60.

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Reviewer CommentsReviewer Comments

1.1. Dr. Gilard and colleagues are commended for using a readily available Dr. Gilard and colleagues are commended for using a readily available clinical assay (VASP phosphorylation) to demonstrate the effects of clinical assay (VASP phosphorylation) to demonstrate the effects of Omp on clopidogrel inhibition of the ACS marker, PRI. Omp on clopidogrel inhibition of the ACS marker, PRI.

2.2. The study is well designed, the results striking and with important The study is well designed, the results striking and with important negative clinical implication for the coadministration of omp and negative clinical implication for the coadministration of omp and clopidogrel among patients at risk for ACS. clopidogrel among patients at risk for ACS.

3.3. This study design should be applied in a similar fashion to evaluate the 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 > effect of other PPIs on clopidogrel and the ACS risk measured by PRI > 50%.50%.

4.4. For now, we should all use restraint in the prescription of PPI among For now, we should all use restraint in the prescription of PPI among patients on clopidogrel and follow the current recommendation of the patients on clopidogrel and follow the current recommendation of the FDA until further studies are available. FDA until further studies are available.


http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htmhttp://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm

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http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htmhttp://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm

The identification of increased risk for Acute Coronary Syndrome when at risk The identification of increased risk for Acute Coronary Syndrome when at risk cardiac patients receiving clopidogrel are concomitantly given PPIs has lead to cardiac patients receiving clopidogrel are concomitantly given PPIs has lead to the Food & Drug Administration to issue the following warning:the Food & Drug Administration to issue the following warning:

““Healthcare providers should continue to prescribe and patients should Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.”attack or stroke.”

““Healthcare providers should re-evaluate the need for starting or continuing Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.”treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel.”

““Patients taking clopidogrel should consult with their healthcare provider if Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking PPI, including Prilosec OTC.”they are currently taking or considering taking PPI, including Prilosec OTC.”

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PowerPoint Presentation - Literature Review