Mohan Sathyamoorthy, M.D., F.A.C.C.

Vice-Chief, Cardiovascular DivisionBaylor All Saints Medical Center, Fort Worth, TX

Adjunct Assistant Clinical Professor of MedicineVanderbilt Medical Center, Nashville, TN

Cardiologist, HeartPlace, Fort Worth, TX

Learning Objectives

Understand the key clinical data related to platelet function testing in clinical cardiovascular medicine

Understand the key controversies related to these data

Can one incorporate this data into your day to day clinical practice

Disclosures

Speakers Bureau for:Lantheus Medical ImagingGilead Biosciences

Consultant for:None

Active Research Grants:None

The Clinical Effectiveness of an Antiplatelet Agent….A Platelet’s Response to a Drug vs. A Drug’s Bioavailability to a Platelet

PLATELET

DRUG

Platelet Function Platelet Function TestingTesting

4) Does laboratory identification and treatment of high platelet reactivity benefit the patient?

4) Does laboratory identification and treatment of high platelet reactivity benefit the patient?

What Key Questions Would You Ask about Platelet Function Testing?

What does high on-treatment platelet reactivity mean to the patient?

What does high on-treatment platelet reactivity mean to the patient?

High platelet reactivity:quantifiable and modifiable

risk factor

High platelet reactivity:quantifiable and modifiable

risk factor

Can increasing anti-platelet agentdoses affect high platelet reactivity?Can increasing anti-platelet agentdoses affect high platelet reactivity?

What is the anti-platelet effect of clopidogrel, asa, and emerging agents?

What is the anti-platelet effect of clopidogrel, asa, and emerging agents?

ACS and “Coronary Injury” is a “Platelet-Centric Disease”

Shear Stress, PCIShear Stress, PCIPlaque RupturePlaque Rupture

PlateletPlatelet

ADPADP

TxATxA

22

Granule Secretion

Membrane Membrane PL’sPL’s

Platelet Platelet AggregationAggregation

Microaggregates

Myocardiall Infarction

GPIIb/IIIaGPIIb/IIIa

ActivationActivation

XX

XX XX

Initial Activation

Sustained Activation

P-selectin P-selectin CD-40LCD-40L

PLT-WBCPLT-WBCAggregation/Aggregation/MicroparticlesMicroparticles

Inflammation

CytokineCytokineReleaseRelease

Growth Growth Factor Factor ReleaseRelease

Restenosis

Stent Thrombosis

Procoagulant Procoagulant StateState

Hypercoagulability

ThrombinThrombin

TFTF

AspirinAspirin

ClopidogrelClopidogrel

GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor

TFTF

What Affects a Platelet’s Response to a Drug

Platelet BiologySurface Receptor Biology

○ P2Y12

○ TP (Thromboplastin)○ VW (VonWillenbrand. i.e. 2b3a)○ PAR (Protease Activated Receptors)

Granule Biology

Levels of Circulating Receptor Agonists

Central Role of Platelets and Interaction With Coagulation in the Genesis of Thrombosis

Shear, PCIShear, PCIPlaque RupturePlaque Rupture

Platelet

Initial Activation

ThrombinThrombinTissue FactorTissue Factor

CollagenvWF

TxA2

ADP

PAR-1

P2Y12

TPActivation

Granule Secretion

Amplification

Amplification

Amplification

Procoagulant State

COX-1

Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-1834.

X

X

X

X Platelet Platelet AggregationAggregation

GPIIb/IIIaGPIIb/IIIa

ActivationActivation

Fibrinogen

Fibrin+

Platelet -FibrinClot Formation

What Affects A Drug’s “Bio”Availability to A Platelet?

Absorption kineticsGut

Pharmacokinetics and dynamicsInitial and steady state

Concomitant MedicationsDrug-drug interactions

Metabolism, i.e. PharmacogeneticsLiver Cytochromes and SNPs

Clopidogrel Metabolism and Effect

P2Y12

GPIIb/IIIa ActivationGPIIb/IIIa ActivationPlatelet AggregationPlatelet Aggregation

X

PLC

cAMP

VASP-P

Ca++

Mobilization

ADP

AdenylylCyclase

Granule Secretion

ADP

GqG12

Shape Change

P2Y1

PI3-K

Rap-1bAkt

Rho Kinase

Gi

ADP Release

ClopidogrelPrasugrel

Intestinal Absorption

CYP P450Conversion

Active Thiol Metabolite

Irreversible Binding

Irreversible Binding

Gurbel PA et al. Gurbel PA et al. Nat Clin Pract Cardiovasc Med. 2006;3:387-395.

So How Do These Factors Relate to a Clinical Endpoint?

Both of these phenomenon ultimately DETERMINE…..

VARIABILITY OF RESPONSE TO THERAPY

i.e. hyporesponsiveness or “resistance”

Antiplatelet Drug “Resistance” / “Response Variability”

An Emerging Clinical Problem

-20-20

00

2020

4040

6060

8080

100100

IPA

at

24 h

ou

rs (

%)

Response to Prasugrel 60 mg

Response to Clopidogrel 300 mg

Clopidogrel ResponderClopidogrel Responder

Clopidogrel Non-responderClopidogrel Non-responder

Inte

rpat

ien

tIn

terp

atie

nt

Var

iab

ility

Var

iab

ility

Interp

atient

Interp

atient

Variab

ilityV

ariability

From Brandt JT AHJ 153: 66e9,2007

N=66

Baylor All Saints CV Conference 2010: Advances in CV Therapy, M. Sathyamoorthy, MD, FACC

Healthy Volunteer Crossover Study

Krasopoulos, G. et al. BMJ 2008;336:195-198

Risk of any cardiovascular event in aspirin resistant patients

Baylor All Saints CV Conference 2010: Advances in CV Therapy, M. Sathyamoorthy, MD, FACC

Krasopoulos, G. et al. BMJ 2008;336:195-198

Baylor All Saints CV Conference 2010: Advances in CV Therapy, M. Sathyamoorthy, MD, FACC

Risk of any cardiovascular event in aspirin or clopidrogel “resistant” patients

Assessing Platelet Function to Maximize a Therapeutic Response

BOTTOM LINE:

• Aspirin and clopidrogrel inhibit platelet aggregation but patients exhibit a variable response to both aspirin and clopidrogrel

CLINCIAL IMPLICATION:• Maximum anti-platelet effects of aspirin and clopidrogrel may not be obtained with standard dosage• Up to 30% of patients may be resistant to the effects of these drugs• Patient assessment may be required prior to initiation of procedures where clopidrogrel is given• Pre-surgical testing of platelet function may assess the risk of bleeding

Adapted from H. Aboul-Enein, Benha Faculty of Medicine

So how do we assess “Responsiveness” in 2011

We test PLATELET FUNCTION

We should now consider PHARMACOGENETIC TESTING i.e. liver cytochrome genotypes

Test Advantages Disadvantages ASA Thienopyridines 2B3A

Turbidometric PA (PFA-100)

“gold Standard”

ReproducibilityExpenseTimeSample

Yes Yes Yes

Impedance PA (MEA)

Whole blood ReproducibilityExpenseTimeSample

Yes Yes Yes

VerifyNow SimplePOCWhole Blood

No instrument adjustment

Yes Yes Yes

Plateletworks Whole Blood Not well studied Yes Yes Yes

TXAB2 COX-1 Indirect Yes No No

Urinary 2,3DHTb2

COX-1 IndirectRenal fcn

Yes No No

Clin Cardiol (Suppl. 1) 31.3.I-10-1-16 (2008)E Braunwald et al: Assessing the current role of platelet function testing

PLATELET FUNCTION TESTING in 2011

Baseline Platelet Reactivity* Determines Outcomes Following Coronary Stenting

1.0

0.9

0.8

0.7

0.6

0.5

0 100 200 300

Low Reactivity Group

High Reactivity Group

Time (Days)

Prob

abili

ty o

f Fre

edom

from

Eve

nt**

* Fibrinogen binding in response to 0.2 M ADP** Composite MI, UR, Revascularization

P = 0.01P = 0.006

P = 0.043

Kabbani SS et al. Kabbani SS et al. Am J CardiolAm J Cardiol. 2003;91:876-878.. 2003;91:876-878.

Studies Linking High Ex-Vivo Platelet Reactivity to ADP and Ischemic Events

Study Results Clinical Relevance

1. Barragan et al. (Catheter Cardiovasc Interv. 2003;59:295)

VASP-P levels Stent thrombosis

2. Ajzenberg et al. (J Am Coll Cardiol. 2005;45:1753)

Shear-induced aggregation Stent thrombosis

3. Gurbel et al. (CREST Study)(J Am Coll Cardiol. 2005;46:1827)

VASP-P levels ADP-LTA

Stimulated GP IIb/IIIa expressionStent thrombosis

4. Buonamici(J Am Coll Cardiol. 2007;49:2312)

ADP-LTA Stent thrombosis

5. Matzesky et al. (Circulation. 2005;109:3171)

∆ ADP-LTA Recurrent cardiac events

6. Gurbel et al. (Circulation. 2005;111:1153)

(J Am Coll Cardiol;2006;48:2186) ADP-LTA

Myonecrosis and inflammation

7. Bliden et al. (J Am Coll Cardiol. 2007;49:657)

pre-PCI ADP-LTA on chronic clopidogrel 1 year post-PCI events

8. Cuisset et al.(J Thromb Haemost. 2006;3:542)

ADP-LTA 30-day post-PCI events

9. Lev et al. (J Am Coll Cardiol. 2006;47:27)

ADP and AA-LTA Post-PCI myonecrosis

10. Cuisset et al. (J Am Coll Cardiol. 2006;48:1339)

ADP-LTA30-day post-PCI events600 mg – less events

11. Hochholzer et al.(J Am Coll Cardiol. 2006;48:1742)

ADP-LTA 30-day MACE

Aradi D , et al Am Heart J. 2010 Sep;160(3):543-51.

Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis. METHODS• Systematic review and meta-analysis

on the clinical relevance of HPR , observation studies 2003-2010

• Outcome measures : cardiovascular (CV) death, definite/probable stent thrombosis (ST), nonfatal myocardial infarction (MI), and a composite end point of reported ischemic events.

RESULTS• Twenty studies , 9,187 patients • High on-clopidogrel platelet reactivity

MI: 3.00 [2.26-3.99,

STEMI: 4.14 [2.74-6.25]

Composite:4.95 [3.34-7.34]

P < .00001 for all cases

CONCLUSIONS: According to the meta-analysis,

patients with HPR had a 3.4-fold higher risk for CV death compared with patients with normal ADP reactivity (odds ratio 3.35, 95% CI 2.39-4.70, P < .00001).

High on-clopidogrel platelet reactivity, measured by an ADP-specific platelet function assay, is a strong predictor of CV death, MI, and ST in patients after percutaneous coronary intervention.

ISSUES Methodology Definition of HPR between studies Meta-analysis/Review

LightSource

Platelets in whole blood maximally activated by

agonist in mixing chamber

Fibrinogen-coated beads

+Agonist

Agglutinated beads aggregate in clusters

MixingChamber

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

Agonists:

VerifyNow Assay

• Whole blood, closed-tube sampling with no pipetting required• Assay results in less than 5 minutes (assay time)• Good correlation with LTA and VASP

VerifyNow Point-of-Care Platelet Function Assay* Correlates with Clinical Outcomes Post-DES Deployment

0.80

0.85

0.90

0.95

1.00

Eve

nt-fr

ee S

urviv

al

0 50 100 150 200 Time (days)

Price et al. Eur Heart J. 2008;29:992.

Not high platelet reactivityHigh platelet reactivity

99.0%

P=0.004

91.5%

*pre-discharge

DES Thrombosis and Residual Platelet Reactivity

Perc

ent o

f pat

ient

s fr

ee fr

om

defin

ite o

r pro

babl

e ST

(%)

RespondersNonresponders*

*Residual platelet aggregation (10 µM ADP) ≥70%Buonamici P et al. J Am Coll Cardiol. 2007;49:2312-2317.

Time (Days)

98 198 1

91 391 3

Log rank P<0.001

0

20

40

60

80

75 mg 150 mg

Pla

tele

t in

hib

itio

n (

%)

p=0.009

P2Y

12 R

eact

ivit

y U

nit

s

0

50

100

150

200

250

300

75 mg 150 mg

p=0.007

OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) Impact of high clopidogrel maintenance dosing on platelet function in DM patients with suboptimal clopidogrel response

VerifyNow P2Y12 substudy

Angiolillo DJ et al. Circulation. 2007;115:708-16.

Angiolillo DJ et al. Am J Cardiol. 2008;101:440-5.

%IPA PRU

Primary Results of The Gauging Responsiveness with A VerifyNow Assay - Impact on Thrombosis And

Safety Trial

GRAVITASAHA 2010

 

Matthew J. Price, MDOn behalf of the GRAVITAS Investigators

Point-of-Care Platelet Function Testing: Current Status

• At least 7 studies involving more than 3,000 patients have concluded that high residual (on-clopidogrel) platelet reactivity measured by the VerifyNow P2Y12 test is associated with poor clinical outcomes after PCI.

• A treatment strategy for patients with high residual platelet reactivity has not been tested in a large, randomized, clinical trial.

GRAVITAS: Primary Hypothesis

• High-dose clopidogrel for 6 months is superior to standard-dose clopidogrel for the prevention of adverse CV events after PCI in patients with high residual reactivity.

Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months

High-Dose Clopidogrel†

clopidogrel 600-mg, thenclopidogrel 150-mg daily X 6 months

Elective or Urgent PCI with DES*

VerifyNow P2Y12 Test 12-24 hours post-PCI

PRU ≥ 230

RR

GRAVITAS Study Design

†placebo-controlled

Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 moKey Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo

Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months

All patients received aspirin (81-162mg daily)

*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs

Inclusion and Exclusion Criteria

•DES for the treatment of stable or unstable CAD*

* STEMI pts were permitted after a protocol modification during the trial

• Bleeding event or other major complication prior to platelet function testing

• Recent glycoprotein IIb/IIIa inhibitor

Major Inclusion Criteria

Major Exclusion Criteria

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

GRAVITAS Patient Flow

Primary Endpoint: CV Death, MI, Stent Thrombosis

Observed event rates are listed; P value by log rank test.

Bleeding Events: Safety Population

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

Secondary Comparison: High vs. Not High Reactivity Treated with Clopidogrel 75-mg daily

Observed event rates are listed. P value by log-rank test.

CV Events and Post-PCI PRU In Patients With High and Not High Reactivity Treated With Clopidogrel 75-mg Daily

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 ST

230 PRU

GRAVITAS: Summary

• Compared with standard-dose therapy, high-dose clopidogrel 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 did not reduce the rate of cardiovascular death, non-fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding.

GRAVITAS: Possible Explanations

• Underpowered: patients low-risk, low event rates?

• Given HR of 1.01 with more than 2,200 patients, unlikely that a larger trial would show a clinically meaningful benefit

• Pharmacodynamic effect of the intervention was too weak?

• Stronger intervention and/or goal-directed therapy with serial measurements merit study (TRIGGER-PCI; ARCTIC; TARGET-PCI)

GRAVITAS does not support a treatment strategy of high-dose clopidogrel in patients with high residual reactivity identified by a single platelet function test after PCI.

“Standard Therapy”

Clopidogrel 75 mg

“Clopidogrel arm” Placebo LD

Clopidogrel 75 mg MD+ Prasugrel placebo

“Prasugrel arm”Prasugrel 60 mg LDPrasugrel 10 mg MD

+ Clopidogrel placebo

Successful PCI with DES without major complication and NO GPIIb/IIIa use

Post-PCI VerifyNow P2Y12 Assay (PRU) 2 - 4 hours after 1st MD of clopidogrel 75 mg at day 1 post-PCI

Non-Responder

Clinical Follow-up and VerifyNow Assessment at 90 days, 180 days

Primary Endpoint: 6 month CV Death and MI

Yes No

N ~ 8800

N = 1075A

Random Selection

TRIGGER-PCI

“Clopidogrel arm” Placebo LD

Clopidogrel 75 mg MD+ Prasugrel placebo

“Prasugrel arm”Prasugrel 60 mg LD

Prasugrel 10 mg MD + Clopidogrel placebo

ResponderPRU ≥ 208?

PRU ≥ 140?

N = 1075B N = 550C N = 550D E

Platelet function substudy: VerifyNow Assessment at day 2 (2 – 4 h after 1st MD of study drug)

Courtesy of F.J. Neumann

ASCET (PFA-100) AHA

SS 11/2010

Primary Objective: Clinical outcome (composite USA+MI+CVA+Death) over 2 years in patients with “stable” symptomatic CAD on ASA therapy as related to initial aspirin response via PFA-100

Secondary Objective: Investigate the difference in composite event rate between patients treated with ASA vs Clopidrogel

ASCET (PFA-100) AHA SS

11/2010

Results Composite Endpoint

when ASA no RPR (n=373) 10.5% vs ASA high RPR (n=130) 13.1% p=0.44

Composite Endpoint with RPR on ASA when treated with ASA 13.1% (n=130) or Clopidrogel 7.8% (n=129) p=0.16

26% of patients had RPR while on ASA by PFA-100

ConclusionsNo difference in

composite endpointsRPR by PFA-100 did

NOT predict clinical outcome

Trend seems to indicate fewer endpoints using clopidrogel in patients with high RPR vs. ASA

Angiographic CAD w or w/o

PCIN=1001

Composite endpoint of

USA+MI+CVA+Death

ASA 160 mg QDN=503

Clopidrogel 75mg QD

N=503

ASCET STUDY DESIGN FLOWCHART

ASA 160 mg/d x 7 days then PFA-100

ASA compliance was measured by TXAB2 levels

Platelet reactivity after clopidrogrel treatment assessed with point-of-care analysis (MEA) and early drug-eluting stent thrombosis.

HYPOTHESIS:Does platelet reactivity to clopidogrel assessed with multiple electrode platelet aggregometry (MEA) correlate with the risk of early drug-eluting stent thrombosis?

METHODS: 2/07-2/08, 1608 patients Before PCI, all patients received 600

mg clopidogrel. The ADP-induced platelet aggregation was assessed in whole blood with a MEA.

The primary end point was definite ST at 30 days.

RESULTS: Compared with normal responders (n

= 1,285), low responders (MEA upper qunitile, n = 323) had a significantly higher risk of: definite ST within 30 days (2.2%

vs. 0.2%; odds ratio [OR]: 9.4; 95% confidence interval [CI]: 3.1 to 28.4; p < 0.0001)

Mortality rates were 1.2% in low versus 0.4% in normal responders (OR: 3.2; 95% CI: 0.9 to 11.1; p = 0.07).

Composite of death or ST was higher in low versus normal responders (3.1% vs. 0.6%; OR: 5.1; 95% CI: 2.2 to 11.6; p < 0.001).

CONCLUSIONS: Low response to clopidogrel assessed with MEA is significantly associated with an increased risk of ST. Further studies are warranted to evaluate the ability of MEA to guide antiplatelet therapy in patients undergoing PCI.

Sibbing D et al, J Am Coll Cardiol. 2009 Mar 10;53(10):849-56.

Clopidogrel response status assessed with Multi-plate point-of-care analysis (MEA) and the incidence and timing of stent thrombosis over six months following coronary stenting.

6 Month followup data from Sibbing D et al, J Am Coll Cardiol. 2009 Mar 10;53(10):849-56.

Cumulative incidence of definite ST within six months was significantly higher in low responders [2.5% vs. 0.4%; OR 6.5; 95% CI, 2.4-17.0; P<0.001].

The combined incidence of definite or probable ST was higher as well in low vs. normal responders [4.1% vs. 0.7%; OR 5.8; 95% CI, 2.8-12.3; P<0.0001].

A significant inverse correlation of MEA values and the timing of definite or probable ST (in days) was observed (Spearman coefficient = -0.45; P=0.04)

CONCLUSION MEA measurements are highly predictive for the occurrence of ST

during the first six months following coronary stenting. In the majority of clopidogrel low responders suffering ST, the ischemic

event occurs early in the course after the procedure.

Sibbing D, , et al Thromb Haemost. 2010 Jan;103(1):151-9. Epub 2009 Oct 26.

VASP Guided PCI

Mean ±SD Control VASP-guided p

VASP after first LD, % 68 ±11 69 ±10 0.4

VASP after adjustment, % 38 ±14* *<0.001

Bonello et al. J Am Coll Cardiol 2008

MACE: CV death, MI, revascularization

Log rank p =0.007

After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target.

Courtesy of Angiolillo

VASP and LTA: limitations Not-user friendly Time consuming Require experienced lab personnel Require expensive equipment Not universally available Overall,….expensive

Courtesy of Angiolillo

~30%75mg/day for 30days

Post-PCI

~30%-40% 75mg/day for 5-7days

volunteers

~30%-40%300 mg load

Post-PCI

~30%-50%600 mg load

Post-PCI

~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI3

Inhibition of Platelet Aggregation (Wide Response Variability)1

Mechanism of Clopidogrel Mechanism of Clopidogrel Response VariabilityResponse Variability

ClopidogrelBisulfate

Inactive Carboxylic Acid Metabolite

CYP3A4

CYP3A5

CYP2C19

Active Thiol Metabolite

P2Y12 Receptor

Limited absorption capacity with ceiling effect at 600mg loading doseLimited absorption capacity with ceiling effect at 600mg loading dose

Hepatic P450Cytochromes

lipophilic statins

Genetic polymorphisms

Genetic polymorphisms

Multistep Conversion

15%

Esterases

85%

1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9.

P-glycoprotein(MDR1 3435T genotype)2

?

Smoking, proton pump inhibitorsCYP1A2

CYP2B6, 2C19

Intestinal Absorption

Residual Platelet Aggregation Stratified by CYP2C19*2 Genotype

0

20

40

60

Baseline Before PCI Pre-discharge

CYP2C19 *1/*1CYP2C19 *1/*2CYP2C19 *2/*2

Trenk D et al. J Am Coll Cardiol. 2008:51:1925-1934.

Clopidogrel Non-ResponsivenessCorrelation With CYP3A4 Enzyme Activity

0

20

40

60

80

100

Aggr

egat

ion

(%)

80 980 9

37 2037 20

5.0

4.0

3.0

2.0

1.0

0

1.9 0.71.9 0.7

2.7 1.02.7 1.0

Platelet aggregation CYP3A4**4 hours post clopidogrel* activity

*450 mg PO (P=0.0002); **P=0.15

Nonresponders (25%)Nonresponders (25%)

14CO2 exhaled/h (%

)

Lau WC et al. J Am Coll Cardiol. 2003;41:225A.

Responders (75%)Responders (75%)

Hazard Ratio 1.53

(95% CI 1.07-2.19)

P=0.014

8.0

12.1

1064 1009 999 980 870 755 542

Number at Risk:

Days After Randomization

Non-Carrier

395 364 360 348 306 270 181Carrier

CV

Dea

th, M

I, o

r S

tro

ke (

%)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Non-carriers

Carriers

CYP2C19 and CVD, MI, or StrokeCLOPIDOGREL

* Carriers ~30% of the population

CYP2C19 Reduced-Function Allele Carriers

N=1,477

Hazard Ratio 0.89

(95% CI 0.60-1.31)

P=0.27

9.8

8.5

1048 991 982 951 849 750 541

407 383 376 364 320 276 188

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Number at Risk:

Days After Randomization

Non-Carrier

Carrier

CV

De

ath

, M

I, o

r S

tro

ke

(%

) Non-carriers

CarriersCYP2C19Reduced-Function

Allele Carriers

PRASUGREL

N=1,466

Pharmacogenetics of antiplatelet therapy

Mega et al. NEJM 2009Courtesy of Angiolillo

Strategies to Improve/Overcome Clopidogrel

Response Increase clopidogrel dose (What data do

we believe?? GRAVITAS implies NO!)

Prasugrel! New pharmacologic agents coming….(ticagrelor, AZD6140, cangrelor)

Is there a role for CYP inducers (St. John’s Wort, etc.) to enhance conversion?

Triple antiplatelet regimens (cilostazol, dipirydamole)?

Learning Objectives

Understand the key clinical data related to platelet function testing in guiding clinical decision makingOPTIMUSGRAVITASTRIGGER-PCIASCETMEA Studies (JACC 2010, TH 2010)Mega et al, NJEM 2009

Learning Objectives

Understand the key controversies related to these data…Is there really a standard definition of

“responsiveness or resistance”Cut points matter, and we fundamentally DO

NOT have a consensusWhat is the best test? Do we combine

platelet function testing and Genotype testing in a POC method?

Learning Objectives

Can one incorporate this data into your day to day clinical practice and do we have GUIDELINES supporting this?

ISTH Consensus Statement:Do not test ASA or clopidogrel resistance outside of clinical trials or to change therapy based on such testing.

Why? NO clinically meaningful, standardized definition of resistance based on data linking therapy-dependent laboratory tests to clinical outcomes .

Correct treatment of patients whose platelets are hyporesponsive to antiplatelet agents is unknown.

Guidelines Continued AHA/ACC/ASCI: Daily ASA therapy after PCI for patients without ASA

‘‘resistance,’’ but no definition of resistance is offered.

Class IIb, level C recommendation

For clopidogrel, the guidelines state that ‘‘ . . .in patients in whom stent thrombosis may be catastrophic or lethal. . . Platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.’’ What about GRAVITAS???

Method to assess platelet inhibition is not described.

We need adequately powered clinical trials to….

1. Determine what is the most simple, inexpensive, and rapid test of platelet function and/or metabolism genotyping that best predicts clinical outcomes ofantiplatelet therapy for specific patient subgroups? AND STICK TO IT….results in trials discussed seem to vary by assay!

2. Determine if individual outcomes are affected when treatment ischanged in response to the testing results. i.e. what is our “threshold” or “cutoff” values

3. What the benefit of supplementary treatment with an agent having a different mechanism of action in patients with known hypo-response to a given antiplatelet agent?

4. With emerging agents, is any of this ultimately going to matter?

Adapted from H. Aboul-Enein, Benha Faculty of Medicine

HOW DO WE MOVE FORWARD?