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

UNDERSTANDING ANTIPLATELET UNDERSTANDING ANTIPLATELET RESPONSE VARIABILITYRESPONSE VARIABILITYRESPONSE VARIABILITYRESPONSE VARIABILITY

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

2020

1515

ents

ents Bleeding riskBleeding risk Ischemic riskIschemic risk

1010

er o

f Pat

ieer

of P

atie gg

55Num

beN

umbe

97 597 592.592.5

87 587 582.582.5

77 577 572.572.5

67 567 562.562.5

57 557 552.552.5

47 547 542.542.5

37 537 532.532.5

27 527 522.522.5

17 517 512.512.5

7 57 52.52.5

00

% Platelet Aggregation (LTA% Platelet Aggregation (LTA--ADP 20ADP 20µµmol/L)mol/L)97.597.587.587.577.577.567.567.557.557.547.547.537.537.527.527.517.517.57.57.5

Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Baseline Platelet Reactivity* Determines Clinical Baseline Platelet Reactivity* Determines Clinical Outcomes** Following Coronary StentingOutcomes** Following Coronary Stenting

1 01.0

0.9 Low Reactivity Group

0.8

y p

0.7

0 6

High Reactivity Group

0.6

0.5P=0.01

P=0.006 P=0.043

0 100 200 300 Time (Days)

* Fibrinogen binding in response to 0.2 µM ADP** Composite MI, UR, RevascularizationKabbani SS et al. Am J Cardiol. 2003;91:876-878.

Non-responsiveness to Clopidogrel Is a Predictor of p p gStent Thrombosis in Patients Receiving a DES

I 804 ti t d i • In 804 patients undergoing stenting, stent thrombosis was found to be more prevalent in 96

98

100

mbo

sis

98±1

found to be more prevalent in patients with post-treatment platelet aggregation ≥70% in 90

92

94

babl

e st

ent t

hrom 91±3

Responders

Nonresponders

platelet aggregation ≥70% in response to 10 µM ADP

• The incidence of stent 82

84

86

88

Def

inite

or p

rob

Log rank P <0.001

The incidence of stent thrombosis was 8.6% in nonresponders and 2.3% in

80

82

0 30 60 90 120 150 180Time (days) nonresponders and 2.3% in

responders (P <0.001).

Buonamici P et al. J Am Coll Cardiol. 2006;49:2312-2317.

Interindividual Variability in Platelet Reactivity to Clopidogrel in Patients Undergoing Coronary Stenting

2 HoursResistance = 31%

20ResistanceResistance = 63%Resistance

24

24 HoursClopidogrel in Patients Undergoing Coronary Stenting

10

20Resistance

tients

(%)

12

≤ -30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Pa

≤ -30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

5 DaysResistance = 15%

28Resistance = 31%Resistance

22

30 Days

Resistance14

atien

ts (%

)

11

≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60

Pa

≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60

Gurbel PA et al. Circulation. 2003;107:2908-2913.

∆ Aggregation (%)

30(-30,-20]

( 20, 10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

60

∆ Aggregation (%)

( ] ( ] ( ] ( ] ( ] ( ] ( ]

Platelet Function TestsPlatelet Function Tests•• Platelet Aggregation Platelet Aggregation

Light transmittance aggregometry (LTA)Light transmittance aggregometry (LTA) gold standardgold standardImpedance platelet aggregationImpedance platelet aggregation

•• Flow CytometryFlow CytometryGPIIb/IIIa receptor activationGPIIb/IIIa receptor activationPP--selectin expressionselectin expressionMonocyteMonocyte--platelet aggregatesplatelet aggregatesMonocyteMonocyte--platelet aggregatesplatelet aggregatesVasodilatorVasodilator--associated stimulated phosphoprotein (VASP)associated stimulated phosphoprotein (VASP)

•• 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

Mixing

LightSource

MixingChamber

Aspirin Assay – AAP2Y12 assay – ADP + PGE1GpIIbIIIa assay – iso-TRAP

Agonists:

+Agonist

Platelets in whole blood maximally activated by

agonist in mixing chamber

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

(PRU ≥ 230)p y

(PRU < 230)

Random selection

ClopidogrelHi h D

ClopidogrelSt d d D

ClopidogrelStandard Dose

Random selection

High DoseN=1109

Standard DoseN=1105

Standard DoseN=586

Non-Randomized Comparison

Baseline Characteristics: Non-Randomized Comparison

CharacteristicSD –

High RPRN 1105

SD – Not High RPR

N 586 pN=1105 N=586 p

Residual platelet reactivity, median (IQR)

283 PRU (255 - 321)

151 PRU (105 - 191) <0.001

Age, years 64 ± 11 62± 10 <.0001

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

UA, ST-dep, biomarker (-) 5% 5%Cardiac biomarker (+) 10% 11%

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.

UNDERSTANDING PLATELET GENOMICSUNDERSTANDING PLATELET GENOMICS

Pharmacogenomics, Metabolism, and Platelet Reactivityg y

Mechanism of Action of Prasugrelg

Bhatt DL. N Engl J Med. 2009;361:940-942.

Ticagrelor: Ticagrelor: PharmacologyPharmacologygg

A P2Y i t t i t • A P2Y12 purinoceptor antagonist • Does not require cytochrome P450

metabolic activation to exert its inhibitory yeffects on platelet aggregation

• No active metaboliteR id t f ti• Rapid onset of action

• Reversibly binds to the P2Y12 receptor– Potential advantage if needing to g g

discontinue therapy due to surgery• Compared with clopidogrel, produces a

greater and more consistent inhibition of greater and more consistent inhibition of ADP-induced platelet aggregation

Adapted from: Owen RT et al. AZD6140. Drugs of the Future. 2007;32:845-853.

Effects of CYP2C19*2 and *17 Combined

N=445 patients; 24 hours post 600-mg clopidogrel loading doseSl

Normal

Slow

Fast Normal

PRI=platelet reactivity index; VASP=vasodilator-stimulated phosphoprotein.Frére C, et al. J Thromb Haemost. 2009;7(8):1409-1411.

Frequency 3% 3.5%

CYP2C19 and CVD, MI, or Stroke

N=1477 ACS/PCI Subjects Treated with Clopidgrel in TRITON-TIMI 38

12.112

13

14

CarriersCYP2C19 Reduced-Function Allele Carriers Hazard Ratio 3.09(95% CI 1.19-8.00)

(%)

4

8.0

or S

trok

e (%

)

7

8

9

10

11

Non-carriers

P=0.015

2.6

Sten

tThr

ombo

sis

(

2

3

CarriersCYP2C19 Reduced-Function Allele Carriers

Hazard Ratio 1.53(95% CI 1 07 2 19)

CV

Dea

th, M

I, o

3

4

5

6

7

0.8

finite

or P

roba

ble

S

1

2

Non-carriers

(95% CI 1.07-2.19)P=0.014

Days After Randomization

0

1

2

0 30 90 180 270 360 450

Def

00 30 90 180 270 360 450

Days After Randomization

1064 1009 999 980 870 755 542

Number at Risk:

Non-Carrier

395 364 360 348 306 270 181Carrier

1014 1004 1001 989 885 765 547375 368 366 359 316 279 186

Number at Risk:Non-CarrierCarrier

* Carriers ~30% of the population

Mega JL, Close S, Wiviott SD et al. N Eng J Med. 2009; 360:354-62.

CYP2C19*2 and Outcomes

al (%

)en

t-Fre

eas

c) S

urvi

vul

ativ

e Ev

erg

ent R

eva

Cum

uea

th, M

I, U

r(D

e

Collet JP et al. Lancet 2009;373:309-317.

Stent Thrombosis:(HR 6.02, 95% CI 1.81-20.04, P=0.0009)

CYP2C19*2 and Outcomes

1.98 (1.10-3.58)

0.69 (0.51-0.93)

1.00

P=0.003

Simon T et al. N Eng J Med. 2009; 360:363-375.

CYP2C19 and Treatment with ClopidogrelPredominantly for PCI

CVD, MI, or Stroke

1 2 CYP2C19 RFA N C i

Hazard Ratio (95% CI) P Value

1 57 (1 13 2 16) 0 006

N=9,68591.5% PCI

y

1 or 2 CYP2C19 RFA vs Non-Carriers 1.57 (1.13-2.16) 0.006

1 CYP2C19 RFA vs Non-Carriers 1.55 (1.11-2.17) 0.011 CYP2C19 RFA vs Non Carriers 1.55 (1.11 2.17) 0.01

2 CYP2C19 RFA vs Non-Carriers 1.76 (1.24-2.50) 0.002

Stent Thrombosis

1 or 2 CYP2C19 RFA vs Non-carriers 2.81 (1.81-4.37) <0.0001

N=5,894

1 CYP2C19 RFA vs Non-Carriers 2.67 (1.69-4.22) <0.001

2 CYP2C19 RFA vs Non-Carriers 3.97 (1.75-9.02) 0.001

Risk Higher withCYP2C19 Variant

Risk Lower withCYP2C19 Variant

21.0 105

RFA=reduced-function allele

Mega JL, Simon T, Collet JP et al.JAMA 2010;304(16):1821-30 .

CURE Genetics Substudy

No association seen between CYP2C19and outcomes inand outcomes in clopidogrel arm.

BUT patients treatedBUT, patients treated conservatively (only ~15% rate of PCI).

Pare et al. NEJM 2010; 363(18):1704-14.

Magnitude of PGx Interaction Will Depend R l ti B fit f Cl id lon Relative Benefit of Clopidogrel

Conservatively managed Invasively managedy g

Placebo0 12

0.14

y g

Aspirin Monotherapy

Stro

ke 0.10

0.12

85% Risk

20% Risk

Clopidogrel

eath

, MI,

S

0.06

0.08 85% Risk Reduction

20% Risk Reduction

CV

De

0.02

0.04 Dual Antiplatelet Therapy

Months of follow-up0 3 6 9 12

0.0

CURE. NEJM 2001;345:494-502 STARS. NEJM 1998; 339: 1665.

CYP2C19 and Treatment with ClopidogrelCVD, MI, or Stroke:Carriers of 1 or 2 CYP2C19 Variants vs Non-Carriers

Meta-Analysis (91.5% PCI)

Est. Hazard Ratio (95% CI)

1.57 (1.13-2.16)Meta Analysis (91.5% PCI) 1.57 (1.13 2.16)

PLATO (66% l d PCI)PLATO (66% planned PCI)

Meta-Analysis + PLATO 1.43 (1.11-1.84)

CURE (15.5% PCI)

CHARISMA (stable CAD or risk factors)

M t A l i PLATOMeta-Analysis + PLATO + CURE + CHARISMA 1.32 (1.07-1.63)

Risk Higher withCYP2C19 Variant

Risk Lower withCYP2C19 Variant

1.51.0 3.00.5Mega JL, Simon T, Collet JP et al.JAMA 2010;304(16):1821-30 .

Alternative Treatments: Pharmacodynamics

500100100 PrasugrelClopidogrel

4008080

300235

6060

%)

%)

200

235PRU

PRU

4040IPA

(%IP

A (%

10000

2020

Clopidogrel Responder

Cl id l Ti l0--2020

00Clopidogrel Non-responder

*Responder = ≥25% IPA at 4 and 24 h

Storey RF, et al. JACC 2010; 122(11):1056-67.

Clopidogrel Ticagrelor

Peak

Brandt JT et al., Am Heart J 2007;153:e9-e16.

TRITON-TIMI 38 Genetic Substudy1477 Pts w/ ACS and Planned PCI

Clopidogrel1466 Pts w/ ACS and Planned PCI

Prasugrel

12.1

11

12

13

14

CarriersCYP2C19 Reduced-Function

Allele Carriers

%)

11

12

13

14

Non-carriers of a CYP2C19reduced function allele%

)

8.0

I, or

Str

oke

(%)

7

8

9

10

Non-carriersNon-carriers

or S

trok

e (% 9.8

8.57

8

9

10

I, or

Str

oke

(%) Non-carriers

Carriers

reduced function allele

Carriersor S

trok

e (%

Hazard Ratio 1.53(95% CI 1 07 2 19)

CV

Dea

th, M

I

3

4

5

6

HR 1.53(95% CI 1 07 2 19)V D

eath

, MI,

Hazard Ratio 0.89(95% CI 0 60 1 31)

3

4

5

6

CV

Dea

th, M

V D

eath

, MI,

(95% CI 1.07-2.19)P=0.014

Days After Randomization

0

1

2

0 30 90 180 270 360 450

(95% CI 1.07-2.19)P=0.014

CV (95% CI 0.60-1.31)

P=0.27

0

1

2

0 30 90 180 270 360 450Days After Randomization

CV

1064 1009 999 980 870 755 542

Number at Risk:y

Non-Carrier

395 364 360 348 306 270 181Carrier1048 991 982 951 849 750 541407 383 376 364 320 276 188

Number at Risk:ays te a do at o

Non-CarrierCarrier

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.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm#ds

STENT THROMBOSIS (n=4905)Odds Ratio, fixed model

Bilateral CI, 95% for trials, 95% for MA

2C19*2 2C19*12C19*2 better 2C19*2 orse 2C19*2 2C19*1

10/375 8/1014

2C19*2 better 2C19*2 worse

Mega et al. (0.26)

8/73 4/186

g ( )

Collet et al. (0.15)

13/247 11/525

10/680 7/1805

Giusti et al. (0.34)

Sibbing et al (0 24) 10/680 7/1805

41/1375 30/3530Total

Sibbing et al. (0.24)

events / sizeOdd R ti

OR 3.45 95% CI: 2.14‐5.57, p<0.001, phet=0.78

/Odds Ratio

J Am Coll Cardiol 2010; 56(2):134-143

Collaborative Meta‐analysis: CYP2C19 and S Th b i i P i Cl id lStent Thrombosis in Patients on Clopidogrel

C i

Risk Ratio(95% CI) P value

Carriers vsNoncarriers

2.81 (1.81‐4.37) < .0001

Heterozygotes vs Wild Type

2.67 (1.69‐4.22) < .0001

Homozygotes vs Wild Type

3.97 (1.75‐9.02) < .001

0.5 1.0 15.0

N = 5772 Risk Higher WithCYP2C19 V i t

Risk Lower WithCYP2C19 Variant5 CYP2C19 VariantCYP2C19 Variant

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

of eventof event

% E

xper

ienci

% E

xper

ienci 3030

1010

2020

%%

9090 18018000

DaysDays

270270 360360 9090 180180 270270 360360 9090 180180 270270 36036000

DaysDays DaysDays

00

yy yy yy

0 0 158 154 150 144 143 66 64 62 58 57 92 90 88 87 861 1 67 61 56 53 50 27 23 18 17 16 40 38 38 36 33

No. at riskNo. at riskNo. of CYP2C19*2 allelesNo. of CYP2C19*2 alleles

Shuldiner A et al. JAMA. 2009;302:849-858.

* CYP2C19*2 variant accounts for 12% of clopidogrel response variation of platelet aggregation to ADP

TRITON-TIMI 38ABCB1 and CYP2C19 Polymorphisms DiminishTRITON-TIMI 38ABCB1 and CYP2C19 Polymorphisms DiminishABCB1 and CYP2C19 Polymorphisms DiminishClopidogrel Antiplatelet EffectABCB1 and CYP2C19 Polymorphisms DiminishClopidogrel Antiplatelet Effect

Both polymorphisms =highest risk 14

12MI, 12·6

13·6

12

10

8r dea

th,

e (%

)11·5

8

6

4vasc

ular

or s

trok

e

6·3

4

2

0

Car

diov o

— CYP2C19 reduced-function carrier and ABCB1 3435 TT— CYP2C19 reduced-function non-carrier and ABCB1 3435 TT— CYP2C19 reduced-function carrier and ABCB1 3435 CC/CT— CYP2C19 reduced-function non-carrier and ABCB1 3435 CC/CT

No polymorphisms = lowest risk

00 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450

Days from randomisationp=0·0018 across genotype.

Mega JL, et al. Lancet. 2010;376:1312-1319.CC = ABCB1 normal function; C→T = ABCB1 reduced function; Post-hoc analysis.

p g yp

Genetic and Platelet Function Testing

GENOME TRANSCRIPTOME PHENOTYPEPROTEOME

ENVIRONMENT

GENOME TRANSCRIPTOME PHENOTYPE

post-translationmodificationtranscription translation

PROTEOME

p

~2×104

genes

~105

proteins~106

modifiedproteins

>105

~107 SNPs

10transcripts

PLATELET FUNCTION TESTING

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