1. 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

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

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

4. 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

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

6. 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):

7. Adverse Clinical Outcomes
JAMA 2010; 304(10):

8. Adverse Clinical Outcomes
JAMA 2010; 304(10):

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

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

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

12. 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?

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

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

15. 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):
Pharmacotherapy 2012;32(4):

16. 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

17. 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

18. 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

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

20. 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):
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):
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):
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:
Jneid H, Anderson JL, Wright RS, et al 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):
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):
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):
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):

21. 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