Role of Genotyping and Point of Care Role of Genotyping and Point-of-Care Testing in Clopidogrel, Prasugrel, Testing in Clopidogrel, Prasugrel, and Ticagrelor Ron Waksman, MD Ron Waksman, MD Professor of Medicine (Cardiology), Georgetown University Associate Director, Division of Cardiology , Washington Hospital Center
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Role of Genotyping and Point of Care Role of Genotyping and Point-of-Care Testing in Clopidogrel, Prasugrel, Testing in Clopidogrel, Prasugrel, and Ticagrelor
Ron Waksman, MD Ron Waksman, MD Professor of Medicine (Cardiology), Georgetown UniversityAssociate Director, Division of Cardiology, Washington Hospital Center
Pharmacogenomics, Metabolism, and Platelet Reactivityg y
Antiplatelet Drug Resistance / Response Variability: An Emerging Clinical ProblemAn Emerging Clinical Problem
Individual Response Variability to Dual Antiplatelet Individual Response Variability to Dual Antiplatelet Therapy in theTherapy in the Steady State PhaseSteady State Phase of Treatmentof TreatmentTherapy in the Therapy in the Steady State PhaseSteady State Phase of Treatmentof Treatment
•• PointPoint--ofof--carecareUltegra rapid platelet function analyzer (VerifyNow)Ultegra rapid platelet function analyzer (VerifyNow)Thromboelastagraph (TEG)Thromboelastagraph (TEG)PFAPFA--100100PlateletworksPlateletworksCone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)
•• Genetic testingGenetic testing
How does the VerifyNow Assay Work?• Whole blood, closed-tube sampling with no pipetting required• Assay results in less than 5 minutes (assay time)• Good correlation with LTA and VASP
Fibrinogen-coated beads Agglutinated beads aggregate in clusters
GRAVITAS Trial DesignGRAVITAS Trial DesignggGauging Responsiveness with a VerifyNow Assay Gauging Responsiveness with a VerifyNow Assay –– Impact on Impact on Thrombosis and Safety Thrombosis and Safety
• This trial is designed to evaluate whether tailored clopidogrel therapy, using a point-of-care platelet function assay, reduces major adverse cardiovascular events after DES implantation
Stable angina/ischemia or non-ST-elevation acute coronary syndrome undergoing PCI with DES
High Residual Platelet Reactivity on Clopidogrel Therapy 12 to 24 hours Post PCI
Not High Residual Platelet Reactivity on Clopidogrel Therapy 12 to 24 hours Post PCI py
Standard DosingClopidogrel 75 mg once
High DoseClopidogrel 450 mg loading dose followed by
p g py
• The primary end point is the time to first occurrence of cardiovascular death, nonfatal di l i f ti d fi it / b bl t t th b i
p g gdaily x 6 months
p g g g y150 mg once daily x 6 months
myocardial infarction, or definite/probable stent thrombosis.
Price MJ et al. Am Heart J. 2009;157:818-824.
Power Analysis: Sample Size Estimate
• Assumptions:
• An event rate of 5% in patients on standard-dose clopidogrel at 6-months
• 50% risk reduction with high-dose clopidogrelp g
2200 patients needed to provide 80% p ppower at a two-sided 0.05 significance levellevel
GRAVITAS Patient Flow
5429 patients screened with VerifyNow P2Y12 12 24 hours post PCI12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
3215 (59%) without high residual platelet reactivityp y
(PRU ≥ 230)p y
(PRU < 230)
ClopidogrelHi h D
ClopidogrelSt d d DHigh Dose
N=1109Standard Dose
N=1105
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Bleeding Events: Safety Population
Severe or life threatening: Fatal bleeding intracranial hemorrhage or bleeding that causes hemodynamic compromise requiring
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 Patient Flow: Secondary Analysis
5429 patients screened with VerifyNow P2Y12 12 24 hours post PCI12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
3215 (59%) without high residual platelet reactivityp y
Male sex 65% 80% <0.001Di b t M llit 47% 29% <0 001Diabetes Mellitus 47% 29% <0.001Body mass index (median) 31 29 <0.001Cr Cl< 60 ml/min 42% 27% <0.001Proton pump inhibitor 30% 20% <0.001Indication for PCI 0.41
Stable angina or ischemia 60% 56%Stable angina or ischemia 60% 56%UA, no ST depression 24% 28%NSTE-ACS
Secondary Comparison: High vs. Not High Reactivity
Observed event rates are listed. P value by log-rank test.
CV Events and Post-PCI PRU In Pts With High and Not High Reactivity Treated With Standard-Dose Clopidogrel
500
400Red dots: patients with CV death, MI, or ST
300PRU 12 - 24 hrs
200post-PCI 230 PRU
100
0
High Residual Not High
N=1105 N= 586
High ResidualReactivity
Not HighResidual Reactivity
ITT population
GRAVITAS: Possible Explanations
• Underpowered: patients low-risk, low event rates.Gi HR f 1 01 ft 2200 ti t lik l th t• Given HR of 1.01 after 2200 patients, unlikely that a larger trial would show a clinically meaningful benefit
• Pharmacodynamic effect of the intervention was too weak?• Stronger intervention, goal-directed therapy with serial
t it t dmeasurements merit study• Platelet reactivity is a non-modifiable risk factor?
• To be further examined in TARGET-PCI, ARCTIC, TRIGGER-PCI
• VerifyNow results not predictive of risk?• However, at least 7 studies involving more than 3,000
patients demonstrate a correlation with MACE
GRAVITAS does not support a pptreatment strategy of high-dose clopidogrel in low risk patients withclopidogrel in low-risk patients with high reactivity identified by a single g y y gplatelet function test after PCI.
P=0.046 for interaction between benefit of prasugrel vs. clopidogrel and CYP2C19 genotypeP 0.046 for interaction between benefit of prasugrel vs. clopidogrel and CYP2C19 genotype
Mega JL, Close SL, Wiviott SD et al. Circulation 2009; 119:2553-2560.
Mega JL. American Heart Association; November 2009; Orlando, Florida.
Pharmacogenomics of Antiplatelet TherapiesgCarriers vs Non-carriers of a Reduced-function CYP2C19 Allele
More Ischemic Less Ischemic
CLINICAL OUTCOMES
Prasugrel 0.89 P=0.27Events Events
Clopidogrel 1.53 P=0.01
0.046
Clopidogrel 1.53 P 0.01
3.5 3.0 2.5 2.0 1.5 1.0 0.5
Odds Ratio
Modified from: Mega JL et al. Circulation. 2009;119:2553-2560.* Data adapted from: Mega JL et al. N Engl J Med. 2009;360:354-362.
EventEvent--free Survival Over 1 Year of Followfree Survival Over 1 Year of Follow--upupIn Patients Treated with Clopidogrel Following PCI*In Patients Treated with Clopidogrel Following PCI*
No. of CYP2C19*2 allelesNo. of CYP2C19*2 alleles CYP2C19*2 variant accounts for 12% CYP2C19*2 variant accounts for 12% 0011
clopidogrel response variation of platelet clopidogrel response variation of platelet aggregation to ADP.aggregation to ADP.
ng E
vent
ng E
vent
3030
4040
5050 All patientsAll patients Patients taking Patients taking clopidogrel at time clopidogrel at time
of eventof event
Patients not taking Patients not taking clopidogrel at time clopidogrel at time
Proximal to phenotypeCaptures environmental & genetic
variability
GENETIC TESTING
FixedLifelong impact y
More difficult to assessVaries with time
gEasy to assess
Distanced from phenotype
Clopidogrel ReloadingAmong Genetic Carriers
Bonello et al JACC 2010
Tailoring Antiplatelet Therapy Based on Tailoring Antiplatelet Therapy Based on Platelet Function Testing and Genotyping
• Paul Gurbel, August 2010"The bottom line is we have no prospective studies at this time that alteration of therapy based on genotype or phenotype really affects patient outcomes”
• Whit P JACC 2010 (B ll /G b l t l)• White Paper, JACC 2010 (Bonello/Gurbel et al)“However, until the results of large scale trials of personalized antiplatelet therapy are available the routine use of platelet function measurements in the therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended”
• 2010 ACCF/ACG/AHA Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines"The role of either pharmacogenomic testing or platelet function testing in The role of either pharmacogenomic testing or platelet-function testing in managing therapy with thienopyridines and PPIs has not yet been established"
Conclusions• The CYP2C19 reduced function genotypes
are associated with worse outcomes in the setting of treatment with clopidogrel. Novel antiplatelets appear to be less so.
• ABCB1 and PON-1 may offer similar risk stratification.
• Genetics and platelet function appear to offer complementary information.
• Routine use of genetic and platelet function g ptesting for alteration of therapy is not ready for prime time