Point of Care Platelet Function Testing

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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
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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.

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Platelet function testing Common testing devices
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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
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.
2009157562.e1-562.e9.
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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
N1001
N92
80
60
40
20
0
0
2
4
6
8
Time from loading dose to cath (h)
Gurbel P et al, Circulation 2003 1072908-2913
Hochholzer et al. Circulation 2005 1112560-2564
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Scripps Clinic Event Free survival in DES
patients with and without high post-treatment
reactivity (HPR)
N258
N122
Event Composite of CV death, MI, or stent
thrombosis HPR PRU 235
Price MJ et al . EHJ. 2008 29, 9921000
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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
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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 lt 230)
Clopidogrel High Dose N1109
Clopidogrel Standard Dose N1105
Price. AHA Scientific Sessions, Chicago 2010
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GRAVITAS Pharmacodynamics Effect of SD vs HD
clopidogrel
150-mg/d
75-mg/d
500
P 0.98
P lt 0.001
400
PRU 230 at 30 days PRU 230 at 30 days
Clopidogrel 75mg/d Clopidogrel 150mg/d
62 40
p lt 0.001 p lt 0.001
PRU value
300
200
100
0
N1013
N940
N1105
N1012
N944
N1109
6 mo
6 mo
Post-PCI
30 d
Post-PCI
30 d
ITT population
Price. AHA Scientific Sessions, Chicago 2010
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GRAVITAS Primary endpoint CV death, MI, or
stent thrombosis
2.3 vs. 2.3 HR 1.01 (95 CI 0.58-1.76) P0.98
Observed event rates are listed P value by log
rank test.
Price. AHA Scientific Sessions, Chicago 2010
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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
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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 lt 230)
Random selection
Clopidogrel Standard Dose N586
Clopidogrel High Dose N1109
Clopidogrel Standard Dose N1105
Non-Randomized Comparison
Price. AHA Scientific Sessions, Chicago 2010
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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
N1105
N 586
High Residual Reactivity
Not High Residual Reactivity
ITT population
Price. AHA Scientific Sessions, Chicago 2010
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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
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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
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(No Transcript)
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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 (N2466) 12 m Composite end point of death, MI, stroke, Urgent revascularization, ST Therapy based on MD test results
DANTE NCT00774475 Unstable or NSTEMI-PCI (N442) 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 (N2150) (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
20111615-12.e5
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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.