1. On behalf of the GRAVITAS Investigators
Primary Results of The Gauging Responsiveness with AVerifyNow Assay - Impact on Thrombosis And SafetyTrial
GRAVITAS
AHA 2010
Mr Chairman, ladies and gentlemen, I am honored to present, on behalf of my fellow investigators, the primary results of the GRAVITAS trial.
Matthew J. Price, MD
On behalf of the GRAVITAS Investigators

2. Disclosures
Consulting fees/honoraria: Bristol Meyers Squibb/sanofi-aventis, Accumetrics, DSI/Lilly, AstraZeneca, The Medicines Company, Cordis
Speaker Honoraria: DSI/Lilly, The Medicines Company, Boston Scientific, Medtronic
Research Support: Bristol Meyers Squibb/sanofi-aventis, Accumetrics
Off-label use of clopidogrel and VerifyNow P2Y12 test will be discussed in this presentation
Here are my disclosures

3. Platelet Reactivity Varies Widely Among Patients on Clopidogrel
Maximal aggregation 5 µmol/L ADP (%)
following 600 mg loading dose
Change in ADP-Induced Platelet Aggregation
75 mg chronic dosing
100
N=1001 80 60 40
A large body of data has demonstrated that the level of platelet reactivity on clopidogrel varies widely among patients – whether after a loading dose or in the, chronic, maintenance phase of therapy. 20 2 4 6 8
Time fromloading dose to cath (h)
Hochholzer et al. Circulation 2005
Gurbel P et al, Circulation 2003

4. Point-of-Care Platelet Function Testing: Current Status
At least 7 studies involving more than 3,000 patients have concluded that high residual platelet reactivity measured by the VerifyNow P2Y12 test is associated with poor clinical outcomes after PCI.
A treatment strategy for patients with high residual platelet reactivity has not been tested in a large, randomized, clinical trial.
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5. GRAVITAS: PrimaryHypothesis
High-dose clopidogrel for 6 months is superior to standard clopidogrel therapy for the prevention of adverse CV events after PCI in patients with high residual reactivity.
The primary goal of GRAVITAS was to test the hypothesis that high dose clopidogrel for 6 months is superior to standard clopidogrel therapy for the prevention of adverse cardiovascular events after PCI in patients with high residual reactivity.

6. Trial Organization Trial Leadership:
Matthew J. Price (Chair), Peter B. Berger, Christopher P. Cannon, J.F Tanguay (Canada PI), Paul S. Teirstein, Eric J. Topol
Sponsor:
Accumetrics (Project Leader, Jeffrey R. Dahlen)
Study Drug:
Provided by BMS/sanofiaventis through an investigator-initiated grant to Scripps Advanced Clinical Trials
Data Center and Site Management:
Synteract (Carlsbad, CA)
Data Safety and Monitoring Board:
David P. Faxon (chair), E Magnus Ohman, Charles S. Davis
Special Thanks: Robert Hillman
Here is the trial organization.GRAVITAS was funded by Accumetrics. Study Drug was provided by BMS/sanofiaventis through an investigator initiated grant.

7. Principal Investigators/Study Sites (Top 40 of 83)
D. Spriggs (Clearwater, FL)
S. Marshalko (Bridgeport, CT)
S. Puri (Moline, IL)
R. Waksman (Washington, DC)
M. Robbins (Nashville, TN)
C. O'Shaughnessy (Elyria, OH)
P. Teirstein (La Jolla, CA)
E. Fry (Indianapolis, IN)
K. Garratt (New York, NY)
D. Angiolillo (Jacksonville, FL)
O. Bertrand (Quebec, QC)
B. McLaurin (Anderson, SC)
M. Stillabower (Newark, DE)
S. Rao (Durham, NC)
J. Aragon (Santa Barbara, CA)
R. Gammon (Austin, TX)
E.D. Nukta (Fairview Park, OH)
Z. Jafar (Poughkeepsie, NY)
J.F. Tanguay (Montreal, QC)
G. Wong (Sacramento, CA)
Abbas (Troy, MI)
D. Cohen (Kansas City, MO)
T. Mann (Raleigh, NC)
J. Robb (Lebanon, NH)
W. Batchelor (Tallahassee, FL)
M. Lucca (Duluth, MN)
P. Gordon (Providence, RI)
S. Ward (Erie, PA)
M. Schweiger (Springfield, MA)
D. Rizik (Scottsdale, AZ)
M. Amine (Tomball, TX)
J. Wang (Baltimore, MD)
P. Berger (Danville, PA)
R. Minutello (New York, NY)
N. Chronos (Atlanta, GA)
E. Mahmud (San Diego, CA)
D. So (Ottawa, ON)
P.K. Cheung (Edmonton, AB)
R. Stoler (Dallas, TX)
M. Fugit (Sacramento, CA)
GRAVITAS involved more than 80 sites in the United States and Canada. I would like to thank all the investigators and research staff at the participating sites, who made this unique trial possible.

8. GRAVITAS Study Design R Elective or Urgent PCI with DES*
VerifyNowP2Y12 Test hours post-PCI
PRU ≥ 230 R
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
GRAVITAS tested the clinical efficacy of a treatment strategy of prolonged high-dose clopidogrel based upon the results of the VerifyNow P2Y12 test after PCI.
The trial enrolled patients undergoing elective or urgent PCI who received a peri-procedural clopidogrel regimen designed to ensure a steady-state level 12 to 24 hours after the procedure.
At that time, platelet function was assessed. The VerifyNow P2Y12 test provides a result is in terms of PRU – the higher the PRU, the greater the level of residual reactivity on clopidogrel.
In GRAVITAS, high reactivity was defined as a PRU greater than or equal to 230, a cutoff similar to what has been suggested by previous studies to provide the maximal sensitivity and specificity for subsequent cardiac events.
Patients with high reactivity were randomized in a double-blind fashion to either 6 months of high dose clopidogrel – that is, an additional loading dose followed by 150-mg a day – or standard dose clopidogrel – that is, 75-mg a day. Platelet reactivity was re-assessed at 30-days and 6 months in a blinded fashion, but no treatment decisions were made based upon the results of these tests. The primary efficacy endpoint was a composite of cardiovascular death, non-fatal MI, or stent thrombosis at 6-months. The Key safety endpoint was GUSTO severe or moderate bleeding.
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 hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)

9. DES for the treatment of stable or unstable CAD*
Inclusion and Exclusion Criteria
DES for the treatment of stable or unstable CAD*
Major Inclusion Criteria
Major Exclusion Criteria
Bleeding event prior to platelet function testing
Recent glycoprotein IIb/IIIainhibitor
The major inclusion criteria was the receipt of at least one DES for the treatment of stable or unstable CAD.
Major exclusion criteria included bleeding prior to platelet function testing, or recent receipt of a glycoprotein inhibitor, as such agents interfere with the VerifyNow P2Y12 test
* STEMI pts were permitted after a protocol modification during the trial

10. 50% risk reduction with high-dose clopidogrel
Power Analysis: Sample Size Estimate
Assumptions:
An event rate of 5% in patients on standard-dose clopidogrel at 6-months
50% risk reduction with high-dose clopidogrel
2200 patients needed to provide 80% power at a two-sided 0.05 significance level
To calculate the appropriate sample size, we assumed an event rate of 5% in high-reactivity patients treated with standard-dose clopidogrel.
This estimate was based on the findings of several previous studies of patients with high reactivity.
There was a paucity of data with which to estimate the potential risk-reduction with high dose-clopidogrel. In GRAVITAS, we selected the patients who would be biologically most likely to have the most powerful clinical response.
In addition, in the placebo-controlled trials of thienoypridine therapy in the bare metal stent era, the treatment effect was greater than 50%.
With this, we estimated that 2200 patients would be needed to provide an 80% power at a two-sided 0.05 significance level.

11. GRAVITAS Patient Flow 5429 patients screened with VerifyNow P2Y12
12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
(PRU ≥ 230)
3215 (59%) without high residual platelet reactivity
(PRU < 230)
We screened 5,429 patients with the VerifyNow test 12 to 24 hours after PCI – the largest cohort of patients to ever undergo platelet function testing in a single study.
41% of patients were categorized as having high residual reactivity according to a PRU greater than or equal to 230.
These 2,214 patients were randomly assigned to either high-dose or standard dose clopidogrel
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105

12. High-Dose Clopidogrel Standard-Dose Clopidogrel
Baseline Characteristics of the Randomized Groups
Characteristic
High-Dose Clopidogrel
(N=1109)
Standard-Dose Clopidogrel
(N=1105)
Residual platelet reactivity,
median (IQR)
282 PRU
( )
283 PRU
( )
Age, mean ± SD
64 ± 11
Male sex
65%
Diabetes Mellitus
44%
47%
Myocardial infarction
30%
29%
PCI
50%
45%
Cr Cl< 60 ml/min
40%
42%
Proton-Pump Inhibitor
Peri-procedural clopidogrel
Naïve/Clopidogrel 600-mg load
53%
Clopidogrel 75 mg/d> 7d
39%
37%
Clopidogrel Load + 75mg/d < 7d 8%
10%
Key baseline demographics were well balanced between the 2 groups.
The median PRU in the 2 groups was approximately 283.
The 2 groups had similar rates of PPI use and similar clopidogrel dosing regimens prior to platelet function assessment.

13. High-Dose Clopidogrel Standard-Dose Clopidogrel
Procedural Characteristics of the Randomized Groups
Characteristic
High-Dose Clopidogrel
(N=1109)
Standard-Dose Clopidogrel
(N=1105)
Indication for PCI
Stable angina or ischemia
60%
UA, no ST depression
24%
NSTE-ACS
UA, ST-dep, biomarker (-) 5%
Cardiac biomarker (+)
10%
ST-elevation MI
0.5%
0.2%
Treated lesions/patient
1.4 ± 0.6
1.4 ± 0.7
Stents/Patient
1.7 ± 1.0
1.6 ± 1.0
Total stented length (mm)
30 ± 23
29± 21
Key Procedural and lesion characteirstics were also well balanced.
The indication for the index procedure was stable CAD or low-risk unstable angina in 84% of patients.

14. Pharmacodynamics: Effect of SD vs HD Clopidogrel
Standard-Dose
High-Dose
500
P = 0.98
P < 0.001
400
Persistently high 30 days: 62% vs 40%, p<0.001
PRU
value
300
200
This slide shows the pharmacodynamic effect of standard-dose compared with high-dose clopidogrel in these patients with high residual reactivity after PCI.
The level of platelet reactivity decreased in both groups over the first 30-days -- by a median of 37 PRU in the standard dose group and 80 PRU in the high dose group. Therefore, compared with standard-dose, high-dose clopidogrel significantly reduced reactivity by approximately 40 PRUs at 30 days.
Platelet reactivity was fairly stable in both groups thereafter.
Compared with the standard dose regimen, The effect of high-dose clopidogrel resultedin a 22% absolute reduction in the frequency of patients with persistent high reactivity at 30 daysand a 24% reduction at 6 months.
100
N=1105
N=1013
N=940
N=1109
N=1012
N=944
Post-PCI
30 d
6 mo
Post-PCI
30 d
6 mo
ITT population

15. Primary Endpoint: CV Death, MI, Stent Thrombosis
Here are the primary results of the GRAVITAS trial.
At 6-months, the observed rate of the primary endpoint was 2.3% in the high-dose group compared with 2.3% in the standard dose group, resulting in a hazard ratio of 1.01 and a p value of There were a total of 50 eventswhich was lower than the 68 that we had anticipated.
Observed event rates are listed; P value by log rank test.

16. Bleeding Events: Safety Population
Consistent with its lack of effect in reducing thrombotic events, 6 months of high-dose clopidogrel in patients with high residual reactivity did not increase GUSTO bleeding.
Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical intervention
Moderate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding
P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose

17. GRAVITAS Patient Flow: Secondary Analysis
5429 patients screened with VerifyNow P2Y12
12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
(PRU ≥ 230)
3215 (59%) without high residual platelet reactivity
(PRU < 230)
Random selection
GRAVITAS also included a third, observational arm.
A cohort of patients without high residual reactivity – that is, with PRUs less than 230 – were randomly selected to be followed on standard clopidogrel in a double-blinded fashion.
Ofthe 3,215 patients without high reactivity, 586 were enrolled, and their outcomes compared in an observational, non-randomized fashion to the patients with high-reactivity that were randomized to standard dose clopidogrel.
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105
Clopidogrel
Standard Dose
N=586
Non-Randomized Comparison

18. Baseline Characteristics: Non-Randomized Comparison
SD – High RPR
N=1105
SD – Not High RPR
N=586 p
Residual platelet reactivity,
median (IQR)
283 PRU ( )
151 PRU ( )
<0.001
Age, years
64 ± 11
62± 10
<.0001
Male sex
65%
80%
Diabetes Mellitus
47%
29%
Body mass index (median) 31 29
Cr Cl< 60 ml/min
42%
27%
Proton pump inhibitor
30%
20%
Indication for PCI
0.41
Stable angina or ischemia
60%
56%
UA, no ST depression
24%
28%
NSTE-ACS
UA, ST-dep, biomarker (-) 5%
Cardiac biomarker (+)
10%
11%
As noted in previous, smaller studies, the characteristics of patients with and without high residual reactivity differed in many ways.

19. Secondary Comparison: High vs. Not High Reactivity
Here are the results of thisnon-randomizedcompariion of patients with and without high reactivity treated with clopidogrel 75-mg a day.
At 6 months, the observedrate of the composite endpoint was 2.3% in patients with high reactivity compared with 1.4% in patients without high reactivity, representing a hazard ratio of 1.7.
The difference in event rates did not reach statistical significance; note that the lower boundary of the 95% CI is less than one.
The point estimate of this large hazard ratio appears consistent with previous studies documenting a significant association between residual reactivity and cardiovascular events after PCI.
Observed event rates are listed. P value by log-rank test.

20. CV Events and Post-PCI PRU In Pts With High and Not High Reactivity Treated With Standard-Dose Clopidogrel
500
Red dots: patients with CV death, MI, or ST
400
PRU
hrs post-PCI
300
230 PRU
200
TheIn subjects without HRPR that had CV events, the post-PCI PRU was near the cutoff, not distributed throughout the range of observed PRU results
Consistent with prior reports that higher PRU is associated with increased risk of CV events
100
N=1105
N= 586
High Residual
Reactivity
Not High
Residual Reactivity
ITT population

21. GRAVITAS: Summary
Compared with standard-dose, high-dose clopidogrel achieved a modest pharmacodynamic effect in patients with high residual reactivity.
In patients with high reactivity measured after PCI, 6-months of high-dose clopidogrel did not reduce the rate of the primary endpoint and did not increase GUSTO severe or moderate bleeding.
In summary,

22. GRAVITAS: Possible Explanations
Underpowered: patients low-risk, low event rates.
Given HR of 1.01 after 2200 patients, unlikely that a larger trial would show a clinically meaningful benefit
Pharmacodynamic effect of the intervention was too weak?
Stronger intervention, goal-directed therapy with serial measurements merit study
Platelet reactivity is a non-modifiable risk factor?
To be further examined in TARGET-PCI, ARCTIC, TRIGGER-PCI
VerifyNow results not predictive of risk?
However, at least 7 studies involving more than 3,000 patients demonstrate a correlation with MACE

23. GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high reactivity identified by a single platelet function test after PCI.
Whatever the potential explanation, GRAVITAS does not support….