Primary Results From Genotype Information and Functional Testing A Prospective Pharmacogenomic Analysis of Clopidogrel Therapy GIFT ACC/i2 2011 Matthew J. Price MD , Sarah S. Murray PhD, Dominick J. Angiolillo MD, PhD, Elizabeth Lillie PhD, Nicholas Schork PhD, Paul S. Teirstein MD, Eric J. Topol MD
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Primary Results From Genotype Information and Functional Testing A Prospective Pharmacogenomic Analysis of Clopidogrel Therapy GIFT ACC/i2 2011 Matthew.
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Primary Results From Genotype Information and Functional Testing
A Prospective Pharmacogenomic Analysis of Clopidogrel Therapy
GIFTACC/i2 2011
Matthew J. Price MD, Sarah S. Murray PhD, Dominick J. Angiolillo MD, PhD, Elizabeth Lillie PhD, Nicholas Schork PhD,
Speaker Honoraria: DSI/Lilly, The Medicines Company, Quest, Nanosphere
Research Support: Bristol Meyers Squibb/sanofi-aventis, Quest Diagnostics, Accumetrics,
GIFT was supported through an investigator-initiated grant from BMS/sanofi aventis
GRAVITAS was sponsored by Accumetrics.
Background
• Loss of function (LoF) alleles of the CYP2C19 gene have been shown to influence clopidogrel pharmacokinetics and pharmacodynamics.
• The Plavix® boxed warning suggests alternative dosing regimens (150 mg daily) in CYP2C19 poor metabolizers based on a small PK/PD study in healthy subjects.
• The relationship between genetics, clopidogrel dosing and platelet function over time has not been examined within a prospective, multicenter, randomized trial.
Paraoxonase 1 (PON1): A Novel Determinant of Clopidogrel PK, PD, and Outcomes After PCI?
• No association between CYP2C19, platelet inhibition, and outcomes
• The role of PON1 needs confirmation by external validation
Bouman HJ, Schomig E, van Werkum JW, et al. Nature Medicine 2011; 17(1):110-6
Standard-Dose Clopidogrel†
clopidogrel 75-mg/dayStandard-Dose Clopidogrel†
clopidogrel 75-mg/day
High-Dose Clopidogrel†
clopidogrel 600-mg, thenclopidogrel 150-mg/day
PRU ≥ 230
High On-treatment Reactivity
Yes No
N = 1109 N = 586
Normal On-treatment Reactivity
Random SelectionR
N = 1105
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 moKey Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
†placebo-controlled All patients received aspirin (81-162mg daily)
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs
Price MJ et al , JAMA 2011
Elective or Urgent PCI with DES*
N=5429 VerifyNow P2Y12 Test 12-24 hours post-PCI
GRAVITAS Study Design
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Price MJ et al, JAMA. 2011;305(11):1097-1105
GRAVITAS: Pharmacodynamic Outcomes
Effect of study drug in patients with high OTR
• High-dose provided variable and modest reduction in on-treatment reactivity (OTR)• Post-hoc: “responders” with events had OTR clustered just below 230 PRU
Events in Patients Treated with 75 mg
Price MJ, AHA 2010
The GRAVITAS Genetic Sub-study: Objectives
To assess, in a multicenter, randomized, placebo-controlled setting:
• The genetic determinants of on-treatment reactivity (OTR) after PCI, including PON1, CYP2C19 and ABCB1
• Whether genotype influences the PD response to high-dose clopidogrel in patients with high on-treatment reactivity after PCI.
Sample Acquisition and Genotyping
• Samples (N=1,152) obtained at platelet function screening or during follow-up from patients participating in GRAVITAS at 42 participating sites
• 40 SNPs genotyped with Sequenom platform, including, but not limited to:
• CYP2C19: *2, *3, *4, *5, *6, *7, *8, *17
• PON1, ABCB1
• OTR assessed using VerifyNow P2Y12 test per GRAVITAS protocol
• Baseline: 12-24 hours post-PCI, after standard peri-procedural clopidogrel regimen
• 30±7 days
Classification of CYP2C19 Genotype and Predicted Metabolic Phenotype
2° endpoints: Rate of OTR ≥ 230 and OTR ≥ 208 PRU at 30 days
On-Treatment Reactivity at Screening (12-24 hrs post-PCI) N=1013
Co-dominant model, adjusted for tx and characteristics associated with OTR.
SNP R2
PON1 Q192R 0.2% P = 0.42
CYP2C19*2 6.5% P = 2.2 x 10-15
CYP2C19*17 0.5% P = 0.08
ABCB1 3435 CT 0.1% P = 0.61
Change in On-Treatment Reactivity at 30 days N=714
SNP R2
PON1 Q192R 0% P = 0.71
CYP2C19*2 5.1% P = 1.4 x 10-5
CYP2C19*17 1.2% P = 0.02
ABCB1 3435 CT 0% P = 0.40
Results: Influence of PON1, CYP2C19, and ABCB1 on the Primary Endpoint
P<0.0013 for statistical significance
Platelet Reactivity on Clopidogrel Post-PCI Is Associated With CYP2C19 Genotype & Phenotype
CYP2C19 genotype
Metabolic phenotype
Least squared means. P values compared to No LOF/Extensive. η2 : portion of variance explained by the genotype or phenotype in the multivariate generalized linear model
η2=6.7%
η2=6.7%
CYP2C19 LoF Allele Carriage Is A Major, Independent Predictor of High OTR Post-PCI
*Adjusted for BMI, gender, age, current smoking, CrCl<60 ml/min, DM, CHF, HTN, hyperlipidemia
N=1008
Predicted CYP2C19 Metabolic Phenotype Is A Major, Independent Predictor of High OTR Post-PCI
Ultra, Ultra-rapid; Ext, Extensive; Int, IntermediateAdjusted for BMI, gender, age, current smoking, CrCl<60 ml/min, DM, CHF, HTN, hyperlipidemia
N=1006
CYP2C19 LOF Allele Is Associated With Higher Risk of Persistently High OTR at 30 Days Regardless of Dose
Patients with OTR ≥ 230 PRU at 12-24 hours after PCI. Adjusted ORs.
N=273 N=277
ORs for PRU ≥ 208 at 30 Days
ORs for PRU ≥ 230 at 30 Days
CYP2C19 Genotype is Associated With the PD Effect of Clopidogrel at 30 Days In Patients with High OTR
Regardless of Dosing Strategy
High-dose: clopidogrel 600 re-load then 150 mg/day; Standard-dose: clopidogrel 75 mg/day. High OTR: ≥ 230 PRU at enrollment (12-24 hrs post-PCI)P values adjusted for multiple comparisons
Adjusted Hazard Ratios for CV Death, MI, or Stent Thrombosis According To CYP2C19 Genotype or