Point of Care Platelet Function Testing – Is There Still Value? Mark B. Effron, MD, FACC, FAHA, FCCP Medical Fellow US Medical Division – Cardiovascular/Critical

Point of Care Platelet Function Testing – Is There Still Value?

Mark B. Effron, MD, FACC, FAHA, FCCPMedical 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

(%) t

o 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 80

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 endpointPrimary 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


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


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


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


N=1105


N=586

Non-Randomized Comparison

Random selection

GRAVITAS: HPR vs no HPR with clopidogrel 75-mg dailyPatient flow


GRAVITAS: HPR vs no HPR with clopidogrel 75-mg dailyPRU and clinical outcome


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 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.

GRAVITAS:Summary


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 DoseWiviott 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

100Prasugrel 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 Compositeend point of death,MI, stroke, Urgent

revascularization, ST

Therapy based onMD test results

DANTE NCT00774475 Unstable orNSTEMI-PCI

(N=442)

6 and 12 m CV death, nonfatal MI, TVR by PCI or CABG

75 mg qd vs150 mg qd

TRIGGER-PCI NCT00910299 Coronary arterydisease (CAD)-DES

(N=2150)(Prasugrel is licensed

for ACS patients undergoing PCI)

6 m CV death,nonfatal MI

Prasugrel60/10 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

Documents

Point of Care Platelet Function Testing – Is There Still Value? Mark B. Effron, MD, FACC, FAHA, FCCP Medical Fellow US Medical Division – Cardiovascular/Critical