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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