1. CYP2C19 Genotyping to Individualize Anti-platelet Therapy: Which one should we perform? How to interpret data? Is it ready for clinical practice?
Alan R. Shuldiner, M.D.
Associate Dean for Personalized Medicine
University of Maryland School of Medicine

2. Alan R. Shuldiner, MD
Consulting: USDS, Inc

3. Heritability of clopidogrel response = 0.7  GENETICS !
Variability of Clopidogrel Response: The Amish Pharmacogenomics of Antiplatelet Intervention (PAPI ) Study
668 healthy subjects treated with clopidogrel for 1 week
Platelet aggregation measured before and after therapy
The population “responds” to clopidogrel but there is great inter-individual variation in response
Heritability of clopidogrel response = 0.7  GENETICS !
Shuldiner et al (2009) JAMA

4. PAPI-1: Clopidogrel Response GWAS to Functional Variant to Clinical Outcome
~1/3 of individuals carry at least one CYP2C19*2 allele, which accounts for approximately 12% of the variation in clopidogrel response (platelet aggregation) and a 2.4-fold increased risk of a recurrent CV event.
HR = 3.4
HR = 2.4
Shuldiner et al (2009) JAMA

5. Highly consistent results for ACS/PCI patients in > 25 (retrospective) studies…
CYP2C19*2 associated with:
- Lower active metabolite levels (PK)
- Higher residual ex vivo platelet
aggregation (PD)
- Higher CV events in ACS/PCI (outcomes)
CYP2C19 genotype likely plays little or no role for other indications (e.g., afib, PVD, stroke)

6. Any CV Events *1/*2 or *2/*2 *1/*2 Only *2/*2 Only
Among patients treated with clopidogrel, hazard ratios (HRs) are reported for cardiovascular death, myocardial infarction, or ischemic stroke among carriers of 1 or 2 (panel A), 1 (panel B), or 2 (panel C) reduced-function CYP2C19 alleles vs noncarriers. Size of data markers reflects the statistical weight of the study in the meta-analysis. Data marker for the overall category indicates the 95% confidence interval (CI) for the overall HR. The number of events and of individuals at risk for events is presented for each study. Panel C, Studies with no adverse cardiovascular events among carriers of 2 reduced-function CYP2C19 alleles were excluded from analysis.
*2/*2 Only

7. Stent Thrombosis *1/*2 or *2/*2 *1/*2 Only *2/*2 Only
Among patients treated with clopidogrel, hazard ratios (HRs) are reported for cardiovascular death, myocardial infarction, or ischemic stroke among carriers of 1 or 2 (panel A), 1 (panel B), or 2 (panel C) reduced-function CYP2C19 alleles vs noncarriers. Size of data markers reflects the statistical weight of the study in the meta-analysis. Data marker for the overall category indicates the 95% confidence interval (CI) for the overall HR. The number of events and of individuals at risk for events is presented for each study. Panel C, Studies with no adverse cardiovascular events among carriers of 2 reduced-function CYP2C19 alleles were excluded from analysis.
*2/*2 Only

8. FDA Boxed warning: Plavix (3/20/2010):
WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
See full prescribing information for complete boxed warning.
Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)
FDA Boxed warning: Plavix (3/20/2010):

9. Why aren’t most cardiologists performing genetic testing?
Lack of prospective randomized clinical trials
Does pgx improve outcomes?
What is the optimal clinical algorithm for its application?
Is it cost effective? (Models suggest yes!)
Health care provider education (and expectations)
Logistics of genetic testing
Point-of-care, CLIA, etc.
Reimbursement
Ethical and legal considerations
Despite above: Patients ‘get it’ and want it!
Who will pay for an RCT?

10. Pharmacogenomics Research Network Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Genetic Testing in Patients Requiring Anti-Platelet Therapy (Scott et al, Clin Pharmacol Ther 2011) Disclaimer: CPIC CYP2C19 Guideline is more pro-active than current ACC/AHA consensus statement (Circulation, 2010; also see Roden and Shuldiner, Circulation, 2010)

11. CPIC Guidelines, Scott, et al., Clin Pharmacol Ther 2011
Assigning likely CYP2C19 phenotypes based on genotypes
Likely Phenotype*
Genotypes
Examples of Diplotypes
Ultrarapid Metabolizer (UM)
Normal or increased activity (~5-30% of patients)
An individual carrying two increased activity alleles (*17) or one functional allele (*1) plus one increased activity allele (*17)
*1/*17, *17/*17
Extensive Metabolizer (EM)
Homozygous wild-type or normal activity (~35-50% of patients)
An individual carrying two functional (*1) alleles
*1/*1
Intermediate Metabolizer (IM)
Heterozygote or intermediate activity (~18-45% of patients)
An individual carrying one functional allele (*1) plus one loss-of-function allele (*2-*8)
*1/*2, *1/*3, *2/*17
Poor Metabolizer (PM)
Homozygous variant, mutant, low, or deficient activity (~2-15% of patients)
An individual carrying two loss-of-function alleles (*2-*8)
*2/*2, *2/*3, *3/*3
* Asians have higher frequencies of loss-of function alleles than other populations
CPIC Guidelines, Scott, et al., Clin Pharmacol Ther 2011

12. CPIC Guidelines, Scott, et al., Clin Pharmacol Ther 2011
Suggested Clinical Algorithm for Genotype-Directed Anti-platelet Therapy in ACS/PCI Patients
CPIC Guidelines, Scott, et al., Clin Pharmacol Ther 2011

13. PGRN Translational Pharmacogenomics Project (TPP): Translating CPIC Guidelines into Clinical Practice
6 Implementation sites (more to come on-line later)
3 Pilots: TPMT/thiopurines; CYP2C19/clopidogrel; CYP2C9, CYP4F2 and VKORC1/warfarin; DMET/preemptive testing; custom panels
All testing in CLIA-approved environments
Develop decision support software for commonly used EMRs
Health care provider education programs
Collect implementation data metrics (test quality, turn around time, efficiency of adoption, provider feed back surveys/ focus groups)
Disseminate knowledge
Implementation Sites
University of Maryland
(Shuldiner – PI)
University of Florida
(Johnson)
Vanderbilt University
(Roden and Peterson)
CPIC (Relling) and
PharmGKB (Klein and Altman)
St Judes Children’s Research Hospital
(Relling)
CPIC
Guidelines
Educational
materials
Data
analysis
Decision support
Tools for EMR
Ohio State University
(Sadee)
Mayo Clinic
(Weinshilboum and Pereira)

14. University of Maryland Translational Genomics Laboratory Verigene® CYP2C19 Test Procedure
Offered to UMMC and BVAMC patients undergoing cardiac catheterization in whom anti-platelet therapy is likely
Blood sample sent to TGL before or during cath and CYP2C19 genotype is returned within 4 hours
Results (with treatment recommendation) reported to cath lab, placed in cath report/discharge summary for referring physician and letter sent to patient
Implementation outcomes tracked
(Future: Pragmatic clinical trial)

15. Conclusions: CYP2C19 Genotyping to Individualize Anti-platelet Therapy: Which one should we perform? How to interpret data? Is it ready for clinical practice?
CYP2C19*2 and *3 –real determinants of clopidogrel response (*17 less/unimportant; others variants rare)
Pro-drug activation, platelet aggregation AND clinical outcomes, especially in ACS/PCI patients
Despite lack of prospective RCTs, evidence base for indication-specific CYP2C19 guided therapy is strong
ACS undergoing PCI
Elective PCI
(Likely not medically managed ACS, afib, PVD, stroke, etc.)
CPIC provides reasonable guidelines for CYP2C19-guided anti-platelet therapy (Scott, et al., Clin Pharmacol Ther 2011
CYP2C19 genotype should be used in conjunction with clinical and other information to optimize therapy for each patient