1. Clopidogrel for All – Or Tailored Therapy? Dr James Cotton MD FRCP Heart and Lung Centre Wolverhampton

2. Conflicts of interest Research Grants/Honoraria –Pfizer Advisory boards –Lilly –Daiichi Sankyo Travel Sponsorship –Lilly

3. Platelet Activation and Therapeutic Options Thrombin Thromboxane A 2 5HT ADPADPPLATELET ACTIVATION P2Y 1 5HT 2A PAR1 PAR4 Thrombingeneration Shapechange  IIb  3   3   3 Fibrinogen Aggregation Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP ADP5HT Dense granule ATP P2XASPIRINx GPIIB/IIIA ANTAGONISTS x Storey RF. Current Pharmaceutical Design 2006 P2Y 12 Amplification CLOPIDOGRELACTIVEMETABOLITE x

4. Thienopyridines Ticlopidine (1 st generation) N S Cl N S COOCH 3 N F O S O O CH 3 Clopidogrel (2 nd generation) Prasugrel (CS-747) (LY640315) (3 rd generation)

5. 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?

6. Factors affecting Clopidogrel activity Metabolism 1) Polymorphisms of CYP 450 System 2) Drug-drug interactions 3) Plasma esterase activity Absorption Multiple potential factors ABCB1 gene Platelet Increased resting state of activation. Diabetes, ACS Compliance Tolerability

7. Plus serum markers, urinary metabolites, Platelet surface markers, TEG etc

8. Link between low response and stent thrombosis / ischemic events End-pointAuthorJournal / yearn Stent thrombosisBarragan et al.CCI 200336 Gurbel et al.JACC 2005120 Ajenberg et al.JACC 200549 Buonamici et al.JACC 2007804 Blindt et al.TH 200799 Ischaemic eventsMatetzky et al.Circ 200460 Geiser et al.EHJ 2006379 Gurbel et al.JACC 2005192 Bliden et al.JACC 2007100 Cuisset et al.JTH 2006106 Hochholzer et al.JACC 2006802 Bonello et al.JTH 2007144

9. Tailoring Clopidogrel Therapy? Possible subgroups to target

10. Effect of Clopidogrel on Aggregometry 1,987 patients Age (per 10 years) Body weight (per 10 kg) Diabetes mellitus Severe CAD Family history of CAD < 2 h after clopidogrel loading  Inhibition (%) -25-15-20 -30 -10 0 -5 Weaker inhibition -5 Hochholzer et al

11. Placebo + ASA Characteristic No. of Patients Clopidogrel + ASA Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) 1.21.00.80.6 0.4 Yusuf S et al. N Engl J Med. 2001;345:494-502. Outcomes With Clopidogrel in Various Subgroups Overall125629.311.4 Associated MI328311.313.7 No associated MI92798.610.6 Male sex77269.111.9 Female sex48369.510.7 65 yr old620813.315.3 65 yr old620813.315.3 ST-segment deviation627511.514.3 No ST-segment deviation62877.08.6 Enzymes elevated at entry317610.713.0 Enzymes not elevated at entry93868.810.9 Diabetes284014.216.7 No diabetes97227.99.9 Low risk41875.16.7 Intermediate risk41856.59.4 High risk418416.318.0 History of revascularization22468.414.4 No history of revascularization103169.510.7 Revascularization after randomization457711.513.9 No revascularization after randomization79858.110.0

12. 78% 14% 8% P=0.04 Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Angiolillo DJ et al. Diabetes. 2005;54:2430-5. Non-responders (Platelet inhibition  10%) Low responders (Platelet inhibition 10-29%) Responders (Platelet inhibition >30%) 56% 6% 38% DM No-DM Acute phase of treatment Long-term phase of treatment 24 hrs post 300 mg LD Angiolillo DJ et al. J Am Coll Cardiol 2006;48 298-304. 0 20 40 60 80 Platelet aggregation (%) P=0.001 P<0.0001 ADP 20  mol/L ADP 6  mol/L T2DM No-DM T2DM No-DM

13. Putative Genetic Determinants of Clopidogrel Activity (Pharmacogenomics)

14. First Author Journal Year N Polymorphism Effect Trenk D Abstract 2006 749 CYP3A5 A6986G  MDR1 C3435T  Sibbing DJ Thromb Haem 2006 P2Y1 A1622G  Smith SM Platelets 2006 54 P2Y12  CYP 3A5 A6986G  2005 PAR-1 14 A>T  Angiolillo DJATVB 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 2005119 P2Y12 T744C  Angiolillo DJ Blood Coag Fibr 2004 44GP Ia C 807T  Angiolillo DJ Blood Coag Fibr2004 38 GP IIIa PlA2 -  Polymorphic Genes and Effect of Clopidogrel

15. Hepatic Metabolism Clopidogrel N S Cl COOCH 3 CYP 3A4(5) CYP 2C9 CYP 2C19 CYP 2B6 CYP 1A2 CYP 2B6 CYP 2C19 Inactive Metabolites carboxylic acid derivative (85% of ingested clopidogrel) Esterases Clopidogrel: Pro-drug to Active Metabolite Formation Active Metabolite HOOC * HS N O Cl OCH 3 CH 3 O N S O ClOC 2-oxo Compound HepaticMetabolism

16. OutcomesAdjusted 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 MI5.57 (1.94–16.01)0.001 Urgent revascularization3.24 (0.69–15.09)0.13 Collet JP et al. Lancet 2008 Main effects of CYP2C19*2 polymorphism on cardiovascular outcomes. MI survivors <45y, n=259

17. Predictors of death from any cause, nonfatal MI, or stroke among patients, 2208 AAMI patients Simon T et al. N Engl J Med 2009 Subgroup All patients, n=2208 (95% CI) ABCB1 alleles CC (wild-type)1.00 CT1.51 (1.09–2.10) TT1.72 (1.20–2.47) Any CYP2C19 loss-of-function alleles (*2, *3, *4, and *5) No variant alleles1.00 1 variant allele0.69 (0.51–0.93) 2 variant alleles1.98 (1.10–3.58) Any CYP2C19 loss-of-function alleles (*2, *3, *4, and *5) among PCI patients No variant alleles1.00 1 variant allele0.78 (0.50–1.21) 2 variant alleles3.58 (1.71–7.51)

18. What to do about poor response?

19. Angiolillo, D. J. et al. Circulation 2007;115:708- 716 Effect of double maintenance dose on platelet aggregation in 40 T2DM non clopidogrel responders Inhibition of max platelet aggregation

20. Aleil, B. et al. J Am Coll Cardiol Intv 2008;1:631-638 VASP-02 Study:153 elective PCI patients N=58 N=95 N=153 N=31

21. 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

22. 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 became Responders on 150 mg day

23. 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 2008;51:1404-11

24. STUDY 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 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

25. PLATELET MONITORING Mean ±SDControlVASP-guidedp VASP after first LD, %68 ±1169 ±100.4 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

26. PRIMARY-END POINT : EFFICACY MACE; n (%) Control (n=84) VASP-guided (n=78) Cardiovascular death2 (2)0 Acute and Sub-acute stent thrombosis 4 (5)†0 Revascularization2 (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

27. Abciximab in poor clopidogrel responders Elective PCI Aspirin 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 Abciximab N=74 ADP-Ag <70% Clopidogrel responders Excluded Conventional therapy N=75 Cuisset et al JACC:CI, 2008:649-53

28. Cuisset, T. et al. J Am Coll Cardiol Intv 2008;1:649-653 Kaplan-Meier Analysis for 30-Day Clinical Outcome According to Group

29. 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 CYP2C19*1-5 alleles? –Search for a new agent?

30. Worrall 2009 Poor specificity of clopidogrel activity tests P=0.0002

31. IPA (20  M ADP) at 24 H -20.0 0.0 20.0 40.0 60.0 80.0 100.0 Inhibition of Platelet Aggregation (%) Prasugrel 60 mg Clopidogrel 300 mg Clopidogrel Responder* Clopidogrel Nonresponder *Responder =  25% IPA at 4 and 24 h Healthy Volunteer Crossover Study N = 66 Brandt J et al. ACC 2005

33. 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

35. Thankyou