1. Gauging Responsiveness with A VerifyNow assay - Impact on Thrombosis And Safety
The GRAVITAS trial
Matthew J. Price MD, FACC, FSCAI
Director, Cardiac Catheterization Laboratory, Scripps Clinic
Director, Interventional Cardiology Research, Scripps Genomic Medicine
La Jolla, California

2. Matthew J. Price, MD DISCLOSURES Consulting Fees Honoraria
Accumetrics, Inc., Daiichi Sankyo, Inc., AstraZeneca, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
Honoraria
Daiichi Sankyo, Inc. and Eli Lilly and Company
Grants/Contracted Research
Sanofi-Aventis U.S. LLC, Portola Inc.
Ownership Interest (Stocks, Stock Options or Other Ownership Interest)
I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation.
I intend to reference clopidogrel

3. Background
There is significant variability in the inhibitory response to clopidogrel among individuals.
Patients with high platelet reactivity on clopidogrel treatment appear to have a higher risk of ischemic events after PCI.
Higher-dose clopidogrel regimens improve inhibition (decrease platelet reactivity) in patients who have high on-treatment reactivity with standard dosing.
The safety and efficacy of tailored clopidogrel therapy based on platelet function testing has not been examined in a prospective, randomized fashion.

4. Background Clinically derived cut-offs for the VerifyNow P2Y12 device
Study N
Device
Primary Endpoint
Cutoff
Method
Price et al
380
VN P2Y12
6M CV death, MI, ST
PRU > 235
ROC curve
Patti et al
160
30-day CV death, MI, TVR
PRU > 240
Marcucci et al
683
1 yr CV death, MI
Breet et al
1052
1 yr death, MI, ST, CVA
PRU > 236
Marcucci et al, Circulation 2009; 20;119(2):237-42
Patti, G. et al. J Am Coll Cardiol 2008;52:
Price MJ et al. Eur Heart J 2008; 29(8):
Adapted from Price MJ, Circulation 2009 May 19;119(19):

5. G R A V T A S Primary Hypothesis:
Adjusting the dose of clopidogrel in patients with high on-treatment reactivity after PCI with DES will reduce the hazard rate for ischemic events (CV death, non-fatal MI, and stent thrombosis) in the six months after randomization.
Secondary Hypothesis:
The hazard rate for ischemic events in patients with high on-treatment reactivity with the standard clopidogrel 75-mg/day will be significantly greater than similarly treated patients without high on-treatment reactivity.

6. G R A V T A S
Successful PCI with DES without major complication or GPIIb/IIIa use
VerifyNow P2Y12 Assay hours post-PCI
PRU ≥ 230?
Yes No
Normal On-treatment Reactivity
High On-treatment Reactivity
Random Selection R
ACS A B C
N = 1100
N = 1100
N = 583
“Tailored Therapy”
clopidogrel 600-mg*, then
clopidogrel 150-mg/day
“Standard Therapy”
placebo loading dose, then clopidogrel 75mg +placebo/day
“Standard Therapy”
placebo loading dose clopidogrel 75mg +placebo/day
Clinical Follow-up And Platelet Function Assessment at 30 days, 6M
Primary Endpoint: 6 month CV Death, Non-Fatal MI, ARC definite/prob ST
Safety Endpoint: GUSTO Moderate or Severe Bleeding
*total first day dose
Price MJ et al, Am Heart J 2009

7. Clopidogrel, Genotype, and Clinical Outcomes in ACS
TRITON Results According to Carriage of Reduced Fxn CYP2C19 Allele in ACS Patients Receiving Clopidogrel
12.1%
Carriers
P= 0.01
8.0%
Non-carriers
However, the CYP2C19*2 genotype accounts for only 12% of the variation in clopidogrel response (Shuldiner et al, JAMA 2009)
Mega JL et al, NEJM 2009;360:354-62

8. Exploring the Synergy Between Genetic and Platelet Function Testing
In addition to CYP2C19 status, what are the independent predictors of clopidogrel non-responsiveness?
Does genotype influence the incremental response to high dose maintenance clopidogrel?
E.g., can high-dose maintenance therapy provide further platelet inhibition in patients with high on-treatment reactivity who are carriers of CYP2C19 loss-of-function alleles?

9. CYP2C19 CYP3A5 CYP2B6 CYP3A4 ABCB1 P2RY12 IRS-1 PAR-1
Exploring the Synergy Between PFT and Genetic Testing: The Effect of Genotype on Incremental Inhibition Provided by High-dose Clopidogrel
PLATELET FUNCTION: VerifyNow P2Y12 at GRAVITAS index procedure (post standard dose clopidogrel) and after 30 days, 6 months of study drug
AND
GENOTYPE: Genetic panel from blood sample drawn at time of GRAVITAS platelet function testing or follow-up
CYP2C19 CYP3A5 CYP2B6 CYP3A4 ABCB1 P2RY12 IRS-1 PAR-1
Baseline clinical characteristics (e.g., DM)
Concomitant Meds (e.g., PPIs)
Independent determinants of residual platelet reactivity (PRU) on standard clopidogrel therapy
Effect of genetics, e.g., CYP2C19*2 carriage, on the incremental response to high-dose clopidogrel in non-responders to standard Rx
ClinicalTrials.gov Identifier NCT

10. G R A V T A S
GRAVITAS is the first large scale, randomized, placebo controlled clinical trial to examine whether adjustment of clopidogrel therapy on the basis of platelet function testing safely improves outcomes after DES implantation.
GRAVITAS is currently enrolling at 70 U.S. and 10 Canadian sites, and enrollment should be complete in the coming weeks.
GIFT, a sub-study of GRAVITAS, will assess the independent predictors of platelet reactivity including genotype, and will assess the influence of genotype on the functional response to high-dose clopidogrel maintenance therapy.