1. Point of Care Platelet Function Testing – Is There Still Value?
Mark B. Effron, MD, FACC, FAHA, FCCP
Medical Fellow
US Medical Division – Cardiovascular/Critical Care
LillyUSA, LLC
Advanced Cardiovascular Intervention January 2011
London

2. Disclosures
Dr. Effron is an employee and holds equity in Eli Lilly and Company which markets ReoPro® (abciximab) and Efient ® (prasugrel).
Please be aware that some of the following presentations will include off-licence clopidogrel doses. 300mg/75mg is the licenced clopidogrel dose in the UK.

3. Platelet function testing: Common testing devices
Light transmittance aggregometry (LTA)
Historical standard
Aggregation based, platelet rich plasma (PRP)
ADP peak platelet aggregation
Central laboratory, trained technicians
Time consuming
VerifyNow® P2Y12 assay
Aggregation based, whole blood
Bedside test. fully automated
Multiplate ® (MULTIple PLATElet)
function analyzer
Aggregation based, whole blood
Bedside test. fully automated
Sensitive for aspirin, ADP receptor inhibitor,
GP IIb/IIIa antagonists

4. Comparison of Platelet Inhibition as Measured by VerifyNow ® and Light Transmission Aggregometry
Association between PRU (from VerifyNow) and RPA (from LTA) induced with 20-μmol/L ADP after thienopyridinea
Maintenance Dose
PRU (VN-P2Y12)
-20 20 40 60 80
RPA (%) to 20 μM ADP
r = 0.79
P<0.0001
y = x
100
200
300
400
Symbols represent individual simultaneous predose measurements on days 14 and 29. Correlation coefficient (r) was calculated by the Pearson method.
aTwo thienopyridines, clopidogrel (75 mg) and prasugrel (10 mg), were included in this study.
RPA = residual platelet aggregation.
Adapted from Varenhorst C, et al. Am Heart J. 2009;157:562.e1-562.e9. 4 4

5. Variability in platelet reactivity with 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
N=92 80 60 40 20 2 4 6 8
Time from loading dose to cath (h)
Hochholzer et al. Circulation ;
Gurbel P et al, Circulation 2003; 107:

6. Scripps Clinic: Event Free survival in DES patients with and without high post-treatment reactivity (HPR)
Platelet reactivity < 235 PRU
Platelet reactivity ≥ 235 PRU
N=258
N=122
Event – Composite of CV death, MI, or stent thrombosis
HPR – PRU ≥ 235
Price MJ et al . EHJ. 2008; 29, 992–1000

7. Survival free from primary endpoint
POPULAR:
Survival free from primary endpoint
Primary Endpoint – Composite of death, MI, definite stent thrombosis, or stroke
Breet N et al . JAMA. 2010; 303:

8. 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
Price. AHA Scientific Sessions, Chicago 2010

9. Pharmacodynamics: Effect of SD vs HD clopidogrel
GRAVITAS:
Pharmacodynamics: Effect of SD vs HD clopidogrel
75-mg/d
150-mg/d
500
P = 0.98
P < 0.001
400
PRU ≥ 230 at 30 days
Clopidogrel 75mg/d
Clopidogrel 150mg/d
62%
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
ITT population
Price. AHA Scientific Sessions, Chicago 2010

10. Primary endpoint: CV death, MI, or stent thrombosis
GRAVITAS:
Primary endpoint: CV death, MI, or stent thrombosis
2.3% vs. 2.3%
HR 1.01 (95% CI )
P=0.98
Observed event rates are listed; P value by log rank test.
Price. AHA Scientific Sessions, Chicago 2010

11. Bleeding events: Safety population
GRAVITAS:
Bleeding events: Safety population
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
Price. AHA Scientific Sessions, Chicago 2010

12. GRAVITAS: HPR vs no HPR with clopidogrel 75-mg daily 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)
Random selection
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105
Clopidogrel
Standard Dose
N=586
Non-Randomized Comparison
Price. AHA Scientific Sessions, Chicago 2010

13. GRAVITAS: HPR vs no HPR with clopidogrel 75-mg daily
PRU and clinical outcome
500
Red dots: patients with CV death, MI, or stent thrombosis
400
PRU
hrs post-PCI
300
230 PRU
200
100
N=1105
N= 586
High Residual
Reactivity
Not High
Residual Reactivity
ITT population
Price. AHA Scientific Sessions, Chicago 2010

14. GRAVITAS:
Summary
Compared with standard-dose therapy, high-dose clopidogrel (150-mg/d) 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 (150- mg/d) did not reduce the rate of cardiovascular death, non-fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding.
Price. AHA Scientific Sessions, Chicago 2010

15. Possible interpretation of results
GRAVITAS:
Possible interpretation of results
Study Population - Patients with high residual platelet reactivity (HRPR) may not benefit from tailoring antiplatelet therapy because HRPR is a risk marker and not a modifiable risk factor
Intervention – 150 vs 75 mg of clopidogrel - A projected 50% RRR may have been too robust for 150 mg vs 75 mg of clopidogrel. Alternatively, 150 mg of clopidogrel may not provide a sufficient difference in platelet inhibition.
Power – Too little power to show a difference between treatment arms
Mega. AHA Scientific Sessions, Chicago 2010

17. On-going trials to test the hypothesis whether high levels of P2Y12 inhibition reduce events in HPR
Acronym
Clinical Trials Identifier
Patient Population
Primary Outcome Measure
Thienopyridine therapy
ARCTIC
NCT
Elective and NSTEMI
PCI patients-DES
(N=2466)
12 m Composite
end point of death,
MI, stroke, Urgent
revascularization, ST
Therapy based on
MD test results
DANTE
NCT
Unstable or
NSTEMI-PCI
(N=442)
6 and 12 m CV death, nonfatal MI, TVR by PCI or CABG
75 mg qd vs
150 mg qd
TRIGGER-PCI
NCT
Coronary artery
disease (CAD)-DES
(N=2150)
(Prasugrel is licensed for ACS patients undergoing PCI)
6 m CV death,
nonfatal MI
Prasugrel
60/10 mg vs
Clopidogrel 600 mg/75 mg
Adapted from Collet J-P, et al. Am Heart J 2011;161:5-12.e5

18. Point of Care Platelet Function Testing:
Learnings from GRAVITAS
GRAVITAS does not support a treatment strategy of high-dose clopidogrel (150-mg/d) in low-risk patients with high residual platelet reactivity (HPR) identified by a single platelet function test after PCI.
However, GRAVITAS does not invalidate the hypothesis that use of an oral antiplatelet agent which can overcome HPR may improve clinical outcomes. Ongoing clinical trials will help determine the benefit and risk of such a strategy.