Anne Masich, PharmD PGY1 Resident University of Maryland Outcomes for Clopidogrel Genotyping in Acute Coronary Syndrome (ACS): Absence of Clinical Evidence or Evidence of Clinical Absence Anne Masich, PharmD PGY1 Resident University of Maryland

Disclosure There are no actual or potential conflicts of interest related to the content of this presentation.

Objectives Distinguish antiplatelet response between the different CYP2C19 metabolizers Identify appropriate antiplatelet therapy in poor and intermediate CYP2C19 metabolizers

Patient Case KT is 45 year old male with radiating chest pain Past Medial History: diabetes, hypertension, and dyslipidemia Electrocardiogram (EKG) showed ST-Elevation Myocardial Infarction (STEMI) Underwent percutaneous coronary intervention (PCI) and received clopidogrel 600 mg PO once 3 drug eluting stents placed

Clopidogrel Activation Pathway LIVER CELL Clopidogrel CYP2C19 CYP1A2 CYP2B6 2-oxo-clopidogrel CYP2C9 CYP3A4 CYP2B6 CYP2C19 Inactive Metabolite Active Metabolite P2Y12 PLATELET ELIMINATION

Genetic Polymorphisms Phenotype Implications Ultra-rapid ↑ platelet inhibition ↓ residual platelet aggregation Extensive Normal platelet inhibition Normal residual platelet aggregation Intermediate ↓ platelet inhibition ↑ residual platelet aggregation Poor ↓↓platelet inhibition Poor – carrying 2 loss-of-function alleles Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417

Adverse Clinical Outcomes JAMA 2010; 304(10):1821-1830.

Adverse Clinical Outcomes JAMA 2010; 304(10):1821-1830.

Who should we genotype? Recurrent ACS despite clopidogrel therapy Stent thrombosis High risk PCI Extensive cardiovascular history with multiple revascularizations

Patient Case KT’s CYP2C19 genotyping results show he is an intermediate metabolizer (IM) of clopidogrel. What antiplatelet regimen is appropriate for KT?

Pharmacotherapy Management Clopidogrel 75 mg PO daily Prasugrel 10 mg PO daily Ticagrelor 90 mg PO BID

Patient Case The team doesn’t want to give KT standard dose clopidogrel KT’s insurance doesn’t cover ticagrelor or prasugrel He cannot afford to pay cash Is there another option for KT?

Pharmacotherapy Management Clopidogrel 75 mg PO daily Prasugrel 10 mg PO daily Ticagrelor 90 mg PO BID Clopidogrel 225 mg PO daily

High Dose Clopidogrel Cumulative Kaplan-Meier Estimates of the Time to First Adjudicated Occurrence of the Primary Efficacy End Point JAMA 2010; 304(10):1821-1830

Genotyping Cost-Effectiveness ↓ adverse events and ↓ costs Australian study: CYP2C19 genotype guided P2Y12 inhibitor therapy was more cost-effective compared to universal clopidogrel usage Universal ticagrelor is most effective Pharmacogenomics 2013; 14(6):2013-2021 Pharmacotherapy 2012;32(4):323-332

Practices at UMMC On site translational genomics lab Most patients with STEMI or high risk features will get CYP2C19 genotype testing If affordable, poor/intermediate metabolizers are switched to ticagrelor Genetics data can be utilized to justify need for insurance coverage

Question What is an appropriate P2Y12 inhibitor maintenance regimen for a patient undergoing PCI who is an intermediate CYP2C19 metabolizer? Ticagrelor 90 mg PO BID Clopidogrel 75 mg PO daily Clopidogrel 225 mg PO daily Prasugrel 10 mg PO daily

Take Away Poor/intermediate CYP2C19 metabolizers are at higher risk of adverse clinical outcomes Current guidelines don’t recommend routine genotyping Consider genotyping in high risk or recurrent ACS

Take Away Ticagrelor or prasugrel are preferred in poor/intermediate CYP2C19 metabolizers Consider triple dose clopidogrel when ticagrelor or prasugrel isn’t affordable

References M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. Pharmacogenomics knowledge for personalized medicine. Clinical Pharmacology & Therapeutics 2012; 92(4):414-417 Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010; 304(10):1821-1830. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition on high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010; 56(12):919-933. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527-533. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am coll cardiol 2012; 60(7):645-681. Mega JL, Hochholzer W, Frelinger AL, et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011;306(20):2221-2228. Reese ES, Mullins CD, Beitelshees AL, Onukwugha E. Cost-effectiveness of cytochrome P450 2C19 enotype screening for selection of antiplatelet therapy with clopidogrel or prasugrel. Pharmacotherapy 2012;32(4):323-332. Sorich MJ, Horowitz JD, Sorich W, Wiese MD, et al. Cost-effectiveness of using CYP2C19 genotype to guide selection of clopidogrel or ticagrelor in Australia. Pharmacogenomics 2013; 14(16):2013-2021.

Outcomes for Clopidogrel Genotyping in Acute Coronary Syndrome: Absence of Clinical Evidence or Evidence of Clinical Absence Anne Masich, PharmD PGY1 Pharmacotherapy Resident University of Maryland