1. Insight into the Gauging Responsiveness with A VerifyNow Assay - Impact on Thrombosis And Safety (GRAVITS) Trial
Peter Berger, MD
Director, Center for Clinical Studies
Interventional Cardiologist
Geisinger Clinic
CRT Feb. 2011

2. Potential Conflicts of Interest
Consultant to Boehringer Ingelheim, Eli Lilly/Daiichi-Sankyo, AstraZeneca (each for less than $10,000).
Executive Steering Committee for the GRAVITAS trial for Acumetrics (Unpaid).
Equity in Lumen, Inc. (greater than $10,000).
Research funding to institution for which I am the PI: Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, The Medicines Company, Corgenix/Aspirinworks, Lilly/Daiichi-Sankyo (each for more than $10,000).

3. Point-of-Care Platelet Function Testing Current Status
At least 7 studies involving more than 3,000 patients reveal that high residual (on- clopidogrel) 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. 3

4. GRAVITAS: Primary Hypothesis
High-dose clopidogrel for 6 months is superior to standard-dose clopidogrel for the prevention of adverse CV events after PCI in patients with high residual reactivity. 4

5. GRAVITAS Study Design R Elective or Urgent PCI with DES*
VerifyNow P2Y12 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
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 protocol-mandated to ensure steady-state at hrs
†Placebo-controlled
All patients received aspirin (81-162mg daily) 5

6. GRAVITAS Study Design
Was GRAVITAS really designed to answer the question of whether platelet function testing provides clinically useful information?
Not ideally.
Couldn’t the study have been positive because 150 mg outperformed 75 in all pts regardless of responsiveness on the VerifyNow?
Yes it could have been. A positive study would not necessarily have proven the role of platelet function testing. 6

7. 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 or other major complication prior to platelet function testing
Recent glycoprotein IIb/IIIa inhibitor
* STEMI pts permitted after a protocol modification during the trial 7

8. 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 8

9. GRAVITAS Sample Size Estimate
Why was a 5% 6 mo event rate anticipated in pts on standard-dose clopidogrel? Why was a 50% risk reduction anticipated?
STARS: 30-day event rate 3.6% in BMS pts on aspirin vs. 0.5% in pts on DAP
Buonamici et al: 6 mo death/stent thrombosis rate 10.5% in clopidogrel non-responders vs 2.7% in responders
Price et al: 6 mo event rate 6.5% in pts with high post- treatment reactivity vs 1.0% in those without it
Large txmt effect anticipated since only pts identified to have biological potential for a large drug effect were enrolled 9

10. 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)
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105 10

11. GRAVITAS Study Design
Why was a PRU >230 selected as the cut-off distinguishing responders from hyporesponders?
Reactivity above this threshold (~1/3 of pts on clopidogrel) is associated with ischemic events after PCI. This PRU level are generally consistent with other definitions of clopidogrel non-responsiveness that are associated with poor outcomes using other measurement techniques
Gurbel PA et al. JACC 2005;46:
Hochholzer W et al. JACC 2006;48:
Bliden KP et al. JACC 2007;49:657-66
Price MJ et al. EHJ 2008;29(8):
Matetzky S et al. Circulation 2004;109(25):3171-5 11

12. Why was clopidogrel 150 mg chosen as the active treatment?
GRAVITAS Study Design
Why was clopidogrel 150 mg chosen as the active treatment?
At least 5 studies in differing populations (stable CAD, diabetics, hyporesponders, etc.) revealed that 150 mg is associated with significantly greater levels of inhibition of aggregation than 75 mg.
Prasugrel was not available at the time the study was designed or launched. 12

13. Baseline Characteristics of the Randomized Groups
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%
Hx of MI
30%
29%
STEMI
.5%
.2%
NSTEMI
10%
ACS with STE depression
5.0%
5.3%
Stable
85% 13

14. High risk pts were eligible. Were high risk pts enrolled?
GRAVITAS Study Design
High risk pts were eligible. Were high risk pts enrolled?
The study population generally consisted of low risk patients. The result of the trial (or any trial) should generally only be applied to patients who resemble patients enrolled in the trial.
*Large since the trial only enrolls individuals identified to have biological potential for a large drug effect. 14

15. 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
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 15

16. Pharmacodynamics: Effect of SD vs HD Clopidogrel
Standard-Dose
High-Dose
500
P = 0.98
P < 0.001
400
The difference in aggregability was significant but modest, and the variability in both groups was large
Persistently high 30 days: 62% vs 40%, p<0.001
PRU
value
300
200
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 16

17. Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test. 17

18. Bleeding Events: Safety Population
Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding causing 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 18

19. 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
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105
Clopidogrel
Standard Dose
N=586
Non-Randomized Comparison 19

20. 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
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% 20

21. 2o Comparison: High vs. Not High Reactivity
2o Comparison: High vs. Not High Reactivity Treated with Clopidogrel 75-mg Daily
Observed event rates are listed. P value by log-rank test. 21

22. Post Hoc Analysis: CV Events and PRU In Pts With and Without High Reactivity Trxted With Clopidogrel 75 mg Daily
500
Red dots: patients with CV death, MI, or ST
400
PRU
hrs post-PCI
300
230 PRU
200
100
N=1105
N= 586
High Residual
Reactivity
Not High
Residual Reactivity
ITT population 22

23. GRAVITAS: Summary
Compared with standard-dose therapy, high-dose clopidogrel achieved a modest pharmacodynamic effect in patients with high residual reactivity.
In patients with high residual reactivity measured after PCI, 6-months of high-dose clopidogrel did not reduce the rate of cardiovascular death, non- fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding. 23

24. GRAVITAS: Possible Explanations
Underpowered: patients low-risk, low event rates?
Given HR of 1.01 with more than 2,200 patients, unlikely that a clinically meaningful benefit would have been present even if a much larger trial identified modest clinical benefit.
Pharmacodynamic effect of the intervention was too weak?
A stronger intervention, or goal-directed therapy with serial measurements, might well have made a difference (TRIGGER-PCI; ARCTIC; TARGET-PCI) 24

25. GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after PCI. 25