Transcript CYP2C19 - Clinical Trial Results

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
Disclosures
Consulting fees/honoraria: Bristol-Myers Squibb/sanofiaventis, Accumetrics, DSI/Lilly & Co., Quest Diagnostics,
AstraZeneca, The Medicines Company, Medicure
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?
• PON1 QQ192 homozygotes: lower activity, lower concentration of AM, lower inhibition
• HR for ST = 12.92 (95% CI, 4.5-95.5)
• 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
Price MJ et al , JAMA 2011
GRAVITAS Study Design
Elective or Urgent PCI with DES*
VerifyNow P2Y12 Test 12-24 hours post-PCI
Yes
PRU ≥ 230
No
High On-treatment Reactivity
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg/day
Normal On-treatment Reactivity
Random Selection
R
N = 1109
N=5429
N = 1105
Standard-Dose Clopidogrel†
clopidogrel 75-mg/day
N = 586
Standard-Dose
Clopidogrel†
clopidogrel 75-mg/day
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)
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
Events in Patients Treated with 75 mg
• High-dose provided variable and modest reduction in on-treatment reactivity (OTR)
• Post-hoc: “responders” with events had OTR clustered just below 230 PRU
Price MJ, AHA 2010
The GRAVITAS Genetic Sub-study:
Objectives
To assess, in a multicenter, randomized, placebocontrolled 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 periprocedural clopidogrel regimen
• 30±7 days
Classification of CYP2C19 Genotype and
Predicted Metabolic Phenotype
Genotype
• CYP2C19 Loss-of-function allele: *2, *3, *4, *5,
*6, *7, or *8
Metabolic Phenotype
• Ultra-rapid: *1/*17, *17/*17
• Extensive: *1/*1
• Intermediate: *1/*2 thru*8, *17/*2 thru*8
• Poor: *2 thru *8/*2 thru *8
Analyses and Endpoints
• Baseline population (12-24 hrs post-PCI)
1° endpoint: OTR (PRU)
2° endpoints: Rate of OTR ≥ 230 and ≥ 208
PRU
• Response to study drug
1° endpoint: Δ OTR from baseline to 30 days
2° endpoints: Rate of OTR ≥ 230 and OTR ≥
208 PRU at 30 days
Results: Influence of PON1, CYP2C19,
and ABCB1 on the Primary Endpoint
P<0.0013 for statistical significance
On-Treatment Reactivity at Screening (12-24 hrs post-PCI) N=1013
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 CT
0.1%
P = 0.61
Change in On-Treatment Reactivity at 30 days N=714
SNP
PON1 Q192R
R2
0%
P = 0.71
CYP2C19*2
5.1%
P = 1.4 x 10-5
CYP2C19*17
1.2%
P = 0.02
0%
P = 0.40
ABCB1 3435 CT
Co-dominant model, adjusted for tx and characteristics associated with OTR.
Platelet Reactivity on Clopidogrel Post-PCI Is
Associated With CYP2C19 Genotype & Phenotype
CYP2C19 genotype
η2=6.7%
Metabolic phenotype
η2=6.7%
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
CYP2C19 LoF Allele Carriage Is A Major,
Independent Predictor of High OTR Post-PCI
N=1008
*Adjusted for BMI, gender, age, current smoking, CrCl<60 ml/min, DM, CHF, HTN, hyperlipidemia
Predicted CYP2C19 Metabolic Phenotype Is A
Major, Independent Predictor of High OTR Post-PCI
N=1006
Ultra, Ultra-rapid; Ext, Extensive; Int, Intermediate
Adjusted for BMI, gender, age, current smoking, CrCl<60 ml/min, DM, CHF, HTN, hyperlipidemia
CYP2C19 LOF Allele Is Associated With Higher Risk of
Persistently High OTR at 30 Days Regardless of Dose
N=273
ORs for
PRU ≥ 230
at 30 Days
ORs for
PRU ≥ 208
at 30 Days
Patients with OTR ≥ 230 PRU at 1224 hours after PCI. Adjusted ORs.
N=277
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
Metabolic Phenotype
Total # of Events= 14
Interpret with caution
Adjusted for prior MI, prior PCI, prior CABG, diabetes, CrCl < 60 ml/min, Beta-blocker use, stent length, ACS
Summary (1)
• In the multicenter, prospective, GIFT study:
• PON1 Q192R and ABCB1 3435 CT were
not associated with:
• On-clopidogrel platelet reactivity at
screening after PCI or at 30-day FU
• The change in platelet reactivity with highdose clopidogrel in patients with high OTR
at baseline.
Summary (2)
• CYP2C19 genotype was significantly associated w/OTR
after PCI.
• CYP2C19 genotype was an independent predictor of the
antiplatelet effect of clopidogrel 150 mg/d in patients with
high OTR post-PCI.
• Carriers of 1 or 2 LoF alleles substantially more likely to
have persistently high OTR at 30 days
• In carriers of 2 LoF alleles, the antiplatelet effect of 150
mg MD was similar to that of 75 mg MD.
• CYP2C19*17 was not associated with significantly lower
OTR after PCI, or an enhanced response to 150 mg MD
Conclusions
• GIFT does not support an effect of PON1 in clopidogrel
response variability.
• GIFT confirms the importance of CYP2C19 in
clopidogrel response over time, regardless of dosing
strategy.
• CYP2C19 genotype may complement a platelet
function-guided approach to individualized antiplatelet
therapy after PCI.
FUTURE DIRECTIONS
• Whole exome sequencing of the
GIFT cohort is ongoing
• allows an unbiased
investigation of the complete
protein-coding regions in the
genome
• comprehensive strategy to
define the gene variants
associated with clopidogrel
responsiveness (in all coding
elements of the genome)
Thanks to The GIFT Investigators
A. Abbas (Troy, MI)
M. Amine (Tomball, TX)
D. Angiolillo (Jacksonville, FL)
R. Applegate (Winston-Salem, NC)
J. Aragon (Santa Barbara, CA)
H. Aronow (Ypsilanti, MI)
W. Batchelor (Tallahassee, FL)
M. Buchbinder (San Diego, CA)
L. Cannon (Petoskey, MI )
N. Chronos (Atlanta, GA)
D. Cohen (Kansas City, MO)
E. Fry (Indianapolis, IN)
M. Fugit (Sacramento, CA)
R. Gammon (Austin, TX)
K. Garratt (New York, NY)
P. Gordon (Providence, RI)
Z. Jafar (Poughkeepsie, NY)
M. Lurie (Torrance, CA)
E. Mahmud (San Diego, CA)
A. Malik (Fort Worth, TX )
T. Mann (Raleigh, NC)
S. Manoukian (Nashville, TN)
B. McLaurin (Anderson, SC)
J.C. Merrit (Rome, GA)
E. Nukta (Fairview Park, OH)
C. O’Shaughnessy (Elyria, OH)
S. Plante (Ontario, Canada)
D. Purdy (Rapid City, SD)
S. Puri (Moline, IL)
D. Rizik (Scottsdale, AZ)
M. Robbins (Nashville, TN)
M. Schweiger (Springfield, MA)
D. Spriggs (Clearwater, FL)
R. Stoler (Dallas, TX)
P. Teirstein (La Jolla, CA)
R. Waksman (Washington, DC)
S. Ward (Erie, PA)
M. Warshofsky (Danbury, CT)
G. Wong (Sacramento, CA)