Clopidogrel for All – Or Clopidogrel for All – Or Tailored Therapy?Tailored Therapy?

Dr James Cotton MD FRCP

Heart and Lung Centre

Wolverhampton

Conflicts of interestConflicts of interest

• Research Grants/Honoraria– Pfizer

• Advisory boards– Lilly– Daiichi Sankyo

• Travel Sponsorship– Lilly

Platelet Activation and Platelet Activation and Therapeutic OptionsTherapeutic Options

ThrombinThrombin

ThromboxaneThromboxaneAA22

5HT5HT

ADPADP ADPADP

PLATELETPLATELETACTIVATIONACTIVATION

P2Y15HT2A

PAR1

PAR4

ThrombinThrombingenerationgeneration

ShapeShapechangechange

IIb3 IIb3

IIb3

FibrinogenFibrinogen

AggregationAggregation

Alphagranule

Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators

TP

CoagulationCoagulation

GPVI

CollagenCollagen

ATPATP

ADPADP

5HT5HT

Densegranule

ATPATP

P2X

ASPIRINASPIRIN

xx

GPIIB/IIIA ANTAGONISTSGPIIB/IIIA ANTAGONISTS

xx

Storey RF. Current Pharmaceutical Design 2006

P2Y12

AmplificationAmplification

CLOPIDOGRELCLOPIDOGREL

ACTIVE ACTIVE METABOLITEMETABOLITE

xx

Thienopyridines

Ticlopidine

(1st generation)

N

SCl

N

SCl

COOCH3

N

F

O

SO

OC H3

Clopidogrel

(2nd generation)

Prasugrel (CS-747) (LY640315)

(3rd generation)

What is Clopidogrel Resistance?What is Clopidogrel Resistance?“Reduced response”“Reduced response”

• Treatment Failure?

• Stent thrombosis• Recurrent Chest Pain• Recurrent CVA• Recurrent MI• Death

• Heterogonous Lab Test results?

• What Test?• What Agonist?• What Concentration?• What definition?

Factors affecting Clopidogrel Factors affecting Clopidogrel activityactivity

Metabolism1) Polymorphisms of CYP 450 System2) Drug-drug interactions3) Plasma esterase activity

AbsorptionMultiple potential factorsABCB1 gene

Platelet Increased resting state of activation.Diabetes, ACS

ComplianceTolerability

Plus serum markers, urinary metabolites,

Platelet surface markers, TEG etc

Link between low response and Link between low response and stent thrombosis / ischemic eventsstent thrombosis / ischemic events

End-point Author Journal / year n

Stent thrombosis Barragan et al. CCI 2003 36

  Gurbel et al. JACC 2005 120

  Ajenberg et al. JACC 2005 49

  Buonamici et al. JACC 2007 804

Blindt et al. TH 2007 99

Ischaemic events Matetzky et al. Circ 2004 60

  Geiser et al. EHJ 2006 379

  Gurbel et al. JACC 2005 192

  Bliden et al. JACC 2007 100

  Cuisset et al. JTH 2006 106

  Hochholzer et al. JACC 2006 802

  Bonello et al. JTH 2007 144

Tailoring Clopidogrel Tailoring Clopidogrel Therapy?Therapy?

Possible subgroups to target

Effect of Clopidogrel on Aggregometry1,987 patients

Age (per 10 years)

Body weight (per 10 kg)

Diabetes mellitus

Severe CAD

Family history of CAD

< 2 h afterclopidogrel loading  

Inhibition (%)

-25 -15-20-30 -10 0-5

Weaker inhibition

-5

Hochholzer et al

Placebo Placebo + ASA+ ASACharacteristicCharacteristic

No. ofNo. ofPatientsPatients

Clopidogrel Clopidogrel + ASA+ ASA

Percentage of Patients with EventPercentage of Patients with Event

Placebo BetterPlacebo BetterClopidogrel BetterClopidogrel Better

Relative Risk (95% CI)Relative Risk (95% CI)1.21.21.01.00.80.80.60.60.40.4

Yusuf S et al. N Engl J Med. 2001;345:494-502.

Outcomes With Outcomes With Clopidogrel in Various SubgroupsClopidogrel in Various Subgroups

OverallOverall 1256212562 9.39.3 11.411.4

Associated MIAssociated MI 32833283 11.311.3 13.713.7No associated MINo associated MI 92799279 8.68.6 10.610.6

Male sexMale sex 77267726 9.19.1 11.911.9Female sexFemale sex 48364836 9.59.5 10.710.7

<<65 yr old65 yr old 63546354 5.45.4 7.67.6>65 yr old>65 yr old 62086208 13.313.3 15.315.3

ST-segment deviationST-segment deviation 62756275 11.511.5 14.314.3No ST-segment deviationNo ST-segment deviation 62876287 7.07.0 8.68.6

Enzymes elevated at entryEnzymes elevated at entry 31763176 10.710.7 13.013.0Enzymes not elevated at entryEnzymes not elevated at entry 93869386 8.88.8 10.910.9

DiabetesDiabetes 28402840 14.214.2 16.716.7No diabetesNo diabetes 97229722 7.97.9 9.99.9

Low riskLow risk 41874187 5.15.1 6.76.7Intermediate riskIntermediate risk 41854185 6.56.5 9.49.4High riskHigh risk 41844184 16.316.3 18.018.0

History of revascularizationHistory of revascularization 22462246 8.48.4 14.414.4No history of revascularizationNo history of revascularization 1031610316 9.59.5 10.710.7

Revascularization after randomizationRevascularization after randomization 45774577 11.511.5 13.913.9No revascularization after randomizationNo revascularization after randomization 79857985 8.18.1 10.010.0

78%

14%

8%PP=0.04=0.04

Influence of Diabetes Mellitus on Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Clopidogrel-induced Antiplatelet

EffectsEffects

Angiolillo DJ et al. Diabetes. 2005;54:2430-5.

Non-responders (Platelet inhibition Non-responders (Platelet inhibition 10%) 10%)

Low responders (Platelet inhibition 10-29%) Low responders (Platelet inhibition 10-29%)

Responders (Platelet inhibition >30%) Responders (Platelet inhibition >30%)

56%6%

38%

DMDM No-DMNo-DM

Acute phase of treatmentAcute phase of treatment Long-term phase of treatmentLong-term phase of treatment

24 hrs post 300 mg LD24 hrs post 300 mg LD

Angiolillo DJ et al. J Am Coll Cardiol 2006;48 298-304.

00

2020

4040

6060

8080

Pla

tele

t ag

gre

gat

ion

(%

)P

late

let

agg

reg

atio

n (

%)

PP=0.001=0.001PP<0.0001<0.0001

ADP 20 ADP 20 mol/Lmol/L ADP 6 ADP 6 mol/Lmol/L

T2DMT2DMNo-DMNo-DM T2DMT2DM

No-DMNo-DM

Putative Genetic Determinants Putative Genetic Determinants of of

Clopidogrel ActivityClopidogrel Activity

(Pharmacogenomics) (Pharmacogenomics)

First Author Journal Year N Polymorphism Effect

Trenk D Abstract 2006 749 CYP3A5 A6986G

MDR1 C3435T

Sibbing D J Thromb Haem 2006 P2Y1 A1622G

Smith SM Platelets 2006 54 P2Y12

CYP 3A5 A6986G

2005 PAR-1 14 A>T

Angiolillo DJ ATVB 2006 45 CYP 3A4 IVS10+12G>A

(+)4 other CYP 3A4

Hulot JS Blood 2006 28 CYP2C19 *1/*2

–Lev EI Thromb Res 2006 120 GP IIIa PlA

P2Y12 T744C

P2Y1 1622A>G

Angiolillo DJ Thromb Res 2005 119 P2Y12 T744C

Angiolillo DJ Blood Coag Fibr 2004 44 GP Ia C 807T

Angiolillo DJ Blood Coag Fibr 2004 38 GP IIIa PlA2 -

Polymorphic Genes and Effect of Clopidogrel

HepaticMetabolism

Clopidogrel

N

SCl

COOCH3

CYP 3A4(5)CYP 2C9

CYP 2C19CYP 2B6

CYP 1A2CYP 2B6

CYP 2C19

Inactive Metabolitescarboxylic acid derivative

(85% of ingested clopidogrel)

Esterases Esterases

Clopidogrel: Pro-drug to Clopidogrel: Pro-drug to Active Metabolite FormationActive Metabolite Formation

Active Metabolite

HOOCHOOC

* HS* HS

NN

OO

ClCl

OCHOCH33

CHCH33

OONN

SS

OO

ClCl

OOCC

2-oxo Compound

HepaticHepaticMetabolismMetabolism

Outcomes Adjusted hazards ratio (95% CI)

p

Death, nonfatal MI, urgent revascularization (primary end point)

5.38 (2.32–12.47) <0.0001

Definite stent thrombosis (secondary end point)

6.04 (1.75–20.80) 0.004

MI 5.57 (1.94–16.01) 0.001

Urgent revascularization 3.24 (0.69–15.09) 0.13

Collet JP et al. Lancet 2008

Main effects of Main effects of CYP2C19*2CYP2C19*2 polymorphism on cardiovascular polymorphism on cardiovascular

outcomes . MI survivors <45y, n=259outcomes . MI survivors <45y, n=259

Predictors of death from any cause, nonfatal Predictors of death from any cause, nonfatal MI, or stroke among patients, 2208 AAMI MI, or stroke among patients, 2208 AAMI

patientspatients

Simon T et al. N Engl J Med 2009

Subgroup All patients, n=2208 (95% CI)

ABCB1 alleles

•CC (wild-type) 1.00

•CT 1.51 (1.09–2.10)

•TT 1.72 (1.20–2.47)Any CYP2C19 loss-of-function alleles(*2, *3, *4, and *5)

•No variant alleles 1.00

•1 variant allele 0.69 (0.51–0.93)

•2 variant alleles 1.98 (1.10–3.58)Any CYP2C19 loss-of-function alleles(*2, *3, *4, and *5) among PCI patients

•No variant alleles 1.00

•1 variant allele 0.78 (0.50–1.21)

•2 variant alleles 3.58 (1.71–7.51)

What to do about poor What to do about poor response?response?

Angiolillo, D. J. et al. Circulation 2007;115:708-716

Effect of double maintenance dose Effect of double maintenance dose on platelet aggregation in 40 T2DM on platelet aggregation in 40 T2DM

non clopidogrel respondersnon clopidogrel responders

Inhi

bitio

n of

max

pla

tele

t ag

greg

atio

n

Aleil, B. et al. J Am Coll Cardiol Intv 2008;1:631-638

VASP-02 Study:153 elective PCI VASP-02 Study:153 elective PCI patientspatients

N=58

N=95

N=153

N=31

Aleil, B. et al. J Am Coll Cardiol Intv 2008;1:631-638

Platelet Reactivity Index at 2 Weeks According to the Maintenance Dose of Clopidogrel

Aleil, B. et al. J Am Coll Cardiol Intv 2008;1:631-638

Effect of Increasing the Maintenance Dose of Clopidogrel From 75 to 150 mg/day in Low Responders to 75 mg/day

(n = 31)

63% of low Responders becameResponders on150 mg day

VASP Guided multiple loading dosesVASP Guided multiple loading doses

L Bonello, L Camoin-Jau, S Arques, C Boyer, D Panagides, O Wittenberg, MC Siméoni, P Barragan, F Dignat-George, F Paganelli.

J Am Coll Cardiol 2008;51:1404-11

STUDY DESIGNSTUDY DESIGN

Non-emergent PCI : ACS and Stable angina (n=406)

Loading dose (LD) ASA 250mg Clopidogrel 600mg

VASP ≥ 50%

Randomization(n=162)

CONTROL (n=84) VASP-guided LD (n=78)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose ASA 160 mg

Clopidogrel 75 mg

1° endpoint: MACE (CV death, MI, revascularization) at 30 days

2° endpoints: TIMI major and minor bleeding at 30 days

PLATELET MONITORINGPLATELET MONITORING

Mean ±SD Control VASP-guided p

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

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

-Each additionnal bolus of 600 mg of clopidogrel decreased the number of patients with low response from 35 to 49%.

-Despite 2400 mg of clopidogrel 11 (14%) patients remained low-responders.

J Am Coll Cardiol 2008;51:1404-11

PRIMARY-END POINT : PRIMARY-END POINT : EFFICACYEFFICACY

 MACE; n (%)Control(n=84)

VASP-guided(n=78)

Cardiovascular death 2 (2) 0

Acute and Sub-acute stent thrombosis 4 (5)† 0

Revascularization 2 (2) 0

Overall MACE 8 (10)* 0

† p =0.059

* p =0.007

MACE: CV death, MI, revascularization

Log rank p =0.007

J Am Coll Cardiol 2008;51:1404-11

Bleeding 3 (4) 4(5) P=NS

Abciximab in poor clopidogrel Abciximab in poor clopidogrel respondersresponders

Elective PCIAspirin 250 mg + Clopidogrel 600 mg

N=643

ADP induced aggregation (ADP-AG)10 µmol/l

ADP-AG >70 %Clopidogrel Non responders, n=149

Randomise 1:1

AbciximabN=74

ADP-Ag <70%Clopidogrel responders

Excluded

Conventional therapyN=75

Cuisset et alJACC:CI, 2008:649-53

Cuisset, T. et al. J Am Coll Cardiol Intv 2008;1:649-653

Kaplan-Meier Analysis for 30-Day Clinical Outcome Kaplan-Meier Analysis for 30-Day Clinical Outcome According to GroupAccording to Group

SummarySummary

• Should we– Double dose of clopidogrel in diabetics?– Screen all PCI patients for clopidogrel

response?• What test ?• What cost?

– Genotype all PCI patients for CYP2C19*1-5 alleles?

– Search for a new agent?

NSTEMI N=248

0

100

200

300

400

500

CYP2C19 CYP2C19*2

PR

U V

erify

No

w P

RU

Worrall 2009

Poor specificity of clopidogrel Poor specificity of clopidogrel activity testsactivity tests

P=0.0002

IPA (20 IPA (20 M ADP) at 24 HM ADP) at 24 H

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

PrasugrelPrasugrel60 mg60 mg

Clopidogrel Clopidogrel 300 mg300 mg

Clopidogrel ResponderClopidogrel Responder**Clopidogrel NonresponderClopidogrel Nonresponder

*Responder = *Responder = 25% IPA at 4 and 24 h 25% IPA at 4 and 24 h

Healthy Volunteer Crossover Healthy Volunteer Crossover StudyStudy

N = 66N = 66

Brandt J et al. ACC 2005

Recommendations for 2009Recommendations for 2009

• Remember that clopidogrel works and stent thrombosis is rare!

• ? Measure clopidogrel response – Proven SAT– Patients who need to prematurely discontinue

aspirin– Patients with irremediably poor stent results

ThankyouThankyou