point of care platelet function testing is there still value? · verifynow ® and light...
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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.
Light transmittance aggregometry (LTA)Historical standardAggregation based, platelet rich plasma (PRP)ADP peak platelet aggregationCentral laboratory, trained technicians Time consuming
VerifyNow® P2Y12 assayAggregation based, whole bloodBedside test. fully automated
Multiplate ® (MULTIple PLATElet) function analyzerAggregation based, whole bloodBedside test. fully automatedSensitive for aspirin, ADP receptor inhibitor,
GP IIb/IIIa antagonists
Platelet function testing:Common testing devices
Adapted from Varenhorst C, et al. Am Heart J. 2009;157:562.e1-562.e9.
Association between PRU (from VerifyNow) and RPA (from LTA) induced with 20-μmol/L ADP after thienopyridinea
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.
Maintenance Dose
PRU (VN-P2Y12)
0-20
0
20
40
60
80
RPA
(%
) to
20
μM
AD
P
r = 0.79P<0.0001y = 9.839 + 0.177x
100 200 300 400
Comparison of Platelet Inhibition as Measured by VerifyNow ® and Light Transmission Aggregometry
Change in ADP-Induced Platelet Aggregation75 mg chronic dosing
0 2 4 6 8
0
20
40
60
80
100
Time from loading dose to cath (h)
Gurbel P et al, Circulation 2003; 107:2908-2913
Maximal aggregation 5 µmol/L ADP (%)following 600 mg loading dose
N=1001
Hochholzer et al. Circulation 2005 111;2560-2564
Variability in platelet reactivity with clopidogrel
N=92
Scripps Clinic: Event Free survival in DES patients with and without high post-treatment reactivity (HPR)
Platelet reactivity < 235 PRU
Platelet reactivity ≥ 235 PRU
Event – Composite of CV death, MI, or stent thrombosisHPR – PRU ≥ 235
Price MJ et al . EHJ. 2008; 29, 992–1000
N=122
N=258
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
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)
ClopidogrelHigh Dose
N=1109
ClopidogrelStandard Dose
N=1105
Price. AHA Scientific Sessions, Chicago 2010
GRAVITAS:Patient flow
500
400
300
200
100
0
PRU value
Post-PCI
150-mg/d
30 d 6 mo Post-PCI 30 d 6 mo
N=1013 N=940N=1105 N=1012 N=944N=1109
P = 0.98P < 0.001
ITT population
75-mg/d
Price. AHA Scientific Sessions, Chicago 2010
GRAVITAS:Pharmacodynamics: Effect of SD vs HD clopidogrel
PRU ≥ 230 at 30 days
Clopidogrel
75mg/d
Clopidogrel
150mg/d
62% 40%
p < 0.001
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.
GRAVITAS:Primary endpoint: CV death, MI, or stent thrombosis
Price. AHA Scientific Sessions, Chicago 2010
P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose
Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical interventionModerate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding
GRAVITAS:Bleeding events: Safety population
Price. AHA Scientific Sessions, Chicago 2010
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
ClopidogrelStandard Dose
N=1105
ClopidogrelStandard Dose
N=586
Non-Randomized Comparison
Random selection
GRAVITAS: HPR vs no HPR with clopidogrel 75-mg dailyPatient flow
Price. AHA Scientific Sessions, Chicago 2010
GRAVITAS: HPR vs no HPR with clopidogrel 75-mg dailyPRU and clinical outcome
Price. AHA Scientific Sessions, Chicago 2010
500
400
300
200
100
0
PRU 12 - 24 hrs post-PCI
High ResidualReactivity
Not HighResidual Reactivity
N=1105 N= 586
ITT population
Red dots: patients with CV death, MI, or stent thrombosis
230 PRU
• Compared with standard-dose therapy, high-dose clopidogrel (150-mg/d) achieved a modestpharmacodynamic 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.
GRAVITAS:Summary
Price. AHA Scientific Sessions, Chicago 2010
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
GRAVITAS:Possible interpretation of results
Mega. AHA Scientific Sessions, Chicago 2010
LD Phase and MD Phase VerifyNow® P2Y12
LD Phase MD Phase
PRINCIPLE
TIMI 44
LD=Loading Dose; MD=Maintenance Dose
Wiviott SD et al. Circulation 2007;116:2923-2932
P2Y
12
(% I
nh
ibit
ion
)
Clopidogrel 600 mg
0.5 hour 15 days
20
40
60
80
100
Prasugrel 10 mg
***P < 0.0001
6 hours
45.6***
89.5*** 83.3***
38.4
11.0
Prasugrel 60 mg
Clopidogrel 150 mg
65.1
0
Clopidogrel 600 mg
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)
(Prasugrel is licensed
for ACS patients
undergoing PCI)
6 m CV death,
nonfatal MI
Prasugrel
60/10 mg vs
Clopidogrel 600 mg/75 mg
On-going trials to test the hypothesis whether high levels of P2Y12 inhibition reduce events in HPR
Adapted from Collet J-P, et al. Am Heart J 2011;161:5-12.e5
• 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.
Point of Care Platelet Function Testing: Learnings from GRAVITAS