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 2011
26 January 2011
London
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.
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
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
80
RPA (%) to 20 μM ADP
60
40
20
0
r = 0.79
P<0.0001
y = 9.839 + 0.177x
-20
0
100
200
300
PRU (VN-P2Y12)
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.
400
Variability in platelet reactivity with clopidogrel
Maximal aggregation 5 µmol/L ADP (%)
following 600 mg loading dose
100
Change in ADP-Induced
Platelet Aggregation
75 mg chronic dosing
N=1001
N=92
80
60
40
20
0
0
2
4
6
8
Time from loading dose to cath (h)
Hochholzer et al. Circulation 2005 111;2560-2564
Gurbel P et al, Circulation 2003; 107:2908-2913
Scripps Clinic: Event Free survival in DES patients with and
without high post-treatment reactivity (HPR)
N=258
N=122
Platelet reactivity ≥ 235 PRU
Platelet reactivity < 235 PRU
Event – Composite of CV death, MI, or stent thrombosis
HPR – PRU ≥ 235
Price MJ et al . EHJ. 2008; 29, 992–1000
POPULAR:
Survival free from primary endpoint
Primary Endpoint – Composite of death, MI, definite stent thrombosis, or stroke
Breet N et al . JAMA. 2010; 303: 754-762
GRAVITAS:
Patient flow
5429 patients screened with VerifyNow P2Y12
12-24 hours post-PCI
2214 (41%) with high residual
platelet reactivity
(PRU ≥ 230)
Clopidogrel
High Dose
N=1109
3215 (59%) without high
residual platelet reactivity
(PRU < 230)
Clopidogrel
Standard Dose
N=1105
Price. AHA Scientific Sessions, Chicago 2010
GRAVITAS:
Pharmacodynamics: Effect of SD vs HD clopidogrel
75-mg/d
500
150-mg/d
P = 0.98
P < 0.001
400
PRU
value
PRU ≥ 230 at 30 days
300
200
Clopidogrel
75mg/d
Clopidogrel
150mg/d
62%
40%
p < 0.001
100
0
ITT population
N=1105
N=1013
N=940
N=1109
N=1012
N=944
Post-PCI
30 d
6 mo
Post-PCI
30 d
6 mo
Price. AHA Scientific Sessions, Chicago 2010
GRAVITAS:
Primary endpoint: CV death, MI, or stent thrombosis
2.3% vs. 2.3%
HR 1.01 (95% CI 0.58-1.76)
P=0.98
Observed event rates are listed; P value by log rank test.
Price. AHA Scientific Sessions, Chicago 2010
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
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
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
12 - 24 hrs
post-PCI
300
230 PRU
200
100
0
N=1105
High Residual
Reactivity
ITT population
N= 586
Not High
Residual Reactivity
Price. AHA Scientific Sessions, Chicago 2010
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 (150mg/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
GRAVITAS:
Possible interpretation of results
1. 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
2. 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.
3. Power – Too little power to show a difference
between treatment arms
Mega. AHA Scientific Sessions, Chicago 2010
LD Phase and MD Phase
VerifyNow ® P2Y12
89.5***
P2Y12 (% Inhibition)
100
80
PRINCIPLE
TIMI 44
Prasugrel 60 mg
45.6***
83.3***
Prasugrel 10 mg
60
65.1
Clopidogrel 150 mg
40
38.4
20
Clopidogrel 600 mg
Clopidogrel 600 mg
11.0
***P < 0.0001
0
0.5 hour
6 hours
LD Phase
LD=Loading Dose; MD=Maintenance Dose
Wiviott SD et al. Circulation 2007;116:2923-2932
15 days
MD Phase
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
NCT00827411
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
NCT00774475
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
NCT00910299
Coronary artery
disease (CAD)-DES
(N=2150)
6 m CV death,
nonfatal MI
Prasugrel
60/10 mg vs
Clopidogrel 600 mg/75 mg
(Prasugrel is licensed
for ACS patients
undergoing PCI)
Adapted from Collet J-P, et al. Am Heart J 2011;161:5-12.e5
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.