Clopidogrel for All

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Clopidogrel for All Or Tailored Therapy?

• Dr James Cotton MD FRCP
• Heart and Lung Centre
• Wolverhampton

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Conflicts of interest

• Research Grants/Honoraria
• Pfizer
• Advisory boards
• Lilly
• Daiichi Sankyo
• Travel Sponsorship
• Lilly

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Platelet Activation and Therapeutic Options
5HT
Thromboxane
Coagulation
Collagen
ADP
A
2
ATP
5HT
GPVI
Thrombin
P2Y
2A
1
TP
a
P2X
PAR4
PAR1
PLATELET
ACTIVATION
a
b
a
b
IIb
3
IIb
3
Storey RF. Current Pharmaceutical Design 2006
4
Thienopyridines
Ticlopidine (1st generation)
Clopidogrel (2nd generation)
Prasugrel (CS-747) (LY640315) (3rd generation)
O
N
C
H
O
3
S
F
O
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What is Clopidogrel Resistance?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?

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Factors affecting Clopidogrel activity
Compliance Tolerability
Absorption Multiple potential factors ABCB1 gene
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Plus serum markers, urinary metabolites, Platelet
surface markers, TEG etc
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Link between low response and stent thrombosis /
ischemic events
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Tailoring Clopidogrel Therapy?

• Possible subgroups to target

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Effect of Clopidogrel on Aggregometry 1,987
patients
Weaker inhibition
Age (per 10 years) Body weight (per 10
kg) Diabetes mellitus Severe CAD Family history
of CAD lt 2 h after clopidogrel loading  
-25
-15
-20
-10
-30
0
-5
-5
D Inhibition ()
Hochholzer et al
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Outcomes With Clopidogrel in Various Subgroups
Percentage of Patients with Event
No. ofPatients
Placebo ASA
Clopidogrel ASA
Characteristic
Overall 12562 9.3 11.4 Associated
MI 3283 11.3 13.7 No associated
MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female
sex 4836 9.5 10.7 lt65 yr old 6354 5.4 7.6 gt65 yr
old 6208 13.3 15.3 ST-segment deviation 6275 11.5
14.3 No ST-segment deviation 6287 7.0 8.6 Enzyme
s elevated at entry 3176 10.7 13.0 Enzymes not
elevated at entry 9386 8.8 10.9 Diabetes 2840 14.
2 16.7 No diabetes 9722 7.9 9.9 Low
risk 4187 5.1 6.7 Intermediate
risk 4185 6.5 9.4 High risk 4184 16.3 18.0 Histo
ry of revascularization 2246 8.4 14.4 No history
of revascularization 10316 9.5 10.7 Revasculariza
tion after randomization 4577 11.5 13.9 No
revascularization after randomization 7985 8.1 10.
0
1.2
1.0
0.8
0.6
0.4
Relative Risk (95 CI)
Placebo Better
Clopidogrel Better
Yusuf S et al. N Engl J Med. 2001345494-502.
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Influence of Diabetes Mellitus on
Clopidogrel-induced Antiplatelet Effects
Acute phase of treatment
Long-term phase of treatment
DM
No-DM
80
P0.001
Plt0.0001
P0.04
8
14
60
38
56
78
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Platelet aggregation ()
40
24 hrs post 300 mg LD
20
Non-responders (Platelet inhibition ?10)
Low responders (Platelet inhibition 10-29)
0
Responders (Platelet inhibition gt30)
No-DM
T2DM
T2DM
No-DM
ADP 20 ?mol/L
ADP 6 ?mol/L
Angiolillo DJ et al. J Am Coll Cardiol 200648
298-304.
Angiolillo DJ et al. Diabetes. 2005542430-5.
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Putative Genetic Determinants of Clopidogrel
Activity(Pharmacogenomics)
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Polymorphic Genes and Effect of Clopidogrel
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 AgtT ? Angiolillo DJ ATVB
2006 45 CYP 3A4 IVS1012GgtA () 4
other CYP 3A4 ? Hulot JS Blood 2006 28
CYP2C19 1/2 Lev EI Thromb Res 2006 120
GP IIIa PlA ? P2Y12 T744C ? P2Y1
1622AgtG ? 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 - ?
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Clopidogrel Pro-drug to Active Metabolite
Formation
Esterases
Inactive Metabolites carboxylic acid
derivative (85 of ingested clopidogrel)
CYP 1A2 CYP 2B6 CYP 2C19
Hepatic Metabolism
CYP 3A4(5) CYP 2C9 CYP 2C19 CYP 2B6
Hepatic Metabolism
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Main effects of CYP2C192 polymorphism on
cardiovascular outcomes . MI survivors lt45y, n259
Collet JP et al. Lancet 2008
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Predictors of death from any cause, nonfatal MI,
or stroke among patients, 2208 AAMI patients
Simon T et al. N Engl J Med 2009
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What to do about poor response?
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Effect of double maintenance dose on platelet
aggregation in 40 T2DM non clopidogrel responders
Inhibition of max platelet aggregation
Angiolillo, D. J. et al. Circulation
2007115708-716
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VASP-02 Study153 elective PCI patients
N95
N31
N153
N58
Aleil, B. et al. J Am Coll Cardiol Intv
20081631-638
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Platelet Reactivity Index at 2 Weeks According to
the Maintenance Dose of Clopidogrel
Aleil, B. et al. J Am Coll Cardiol Intv
20081631-638
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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 became Responders on 150
mg day
Aleil, B. et al. J Am Coll Cardiol Intv
20081631-638
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VASP 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 2008511404-11
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STUDY DESIGN
Non-emergent PCI ACS and Stable angina (n406)
Loading dose (LD) ASA 250mg
Clopidogrel 600mg
VASP 50
Randomization (n162)
CONTROL (n84)
VASP-guided LD (n78)
Up-to 3 additional LD of 600 mg every 24 hours
until VASP lt 50 before PCI
Maintenance 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
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PLATELET MONITORING
-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 2008511404-11
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PRIMARY-END POINT EFFICACY
Log rank p 0.007
MACE CV death, MI, revascularization
Bleeding 3 (4) 4(5) PNS
p 0.059 p 0.007
J Am Coll Cardiol 2008511404-11
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Abciximab in poor clopidogrel responders
Elective PCI Aspirin 250 mg Clopidogrel 600
mg N643
ADP induced aggregation (ADP-AG) 10 µmol/l
ADP-AG gt70 Clopidogrel Non responders,
n149 Randomise 11
ADP-Ag lt70 Clopidogrel responders Excluded
Abciximab N74
Conventional therapy N75
Cuisset et al JACCCI, 2008649-53
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Kaplan-Meier Analysis for 30-Day Clinical Outcome
According to Group
Cuisset, T. et al. J Am Coll Cardiol Intv
20081649-653
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Summary

• Should we
• Double dose of clopidogrel in diabetics?
• Screen all PCI patients for clopidogrel response?
• What test ?
• What cost?
• Genotype all PCI patients for CYP2C191-5
  alleles?
• Search for a new agent?

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Poor specificity of clopidogrel activity tests
P0.0002
Worrall 2009
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IPA (20 ?M ADP) at 24 H
Healthy Volunteer Crossover Study
100.0
80.0
60.0
Inhibition of Platelet Aggregation ()
40.0
20.0
0.0
Responder ? 25 IPA at 4 and 24 h
N 66
-20.0
Prasugrel60 mg
Clopidogrel 300 mg
Brandt J et al. ACC 2005
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Recommendations 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

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Thankyou