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Clopidogrel for All – Or Tailored Therapy?

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  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. ASPIRIN x 5HT ADP ADP CLOPIDOGREL ATP ACTIVE METABOLITE x Dense granule P2Y 12 Thrombin generation Amplification Shape change Alpha granule x Aggregation a b IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GPIIB/IIIA ANTAGONISTS Platelet Activation and Therapeutic Options 5HT Thromboxane Coagulation Collagen ADP A 2 ATP GPVI 5HT Thrombin P2Y 2A 1 a TP P2X PAR4 PAR1 PLATELET ACTIVATION a b a b IIb 3 IIb 3 Storey RF. Current Pharmaceutical Design 2006

  4. COOCH3 N N S S Cl Cl Thienopyridines Ticlopidine (1st generation) Clopidogrel (2nd generation) Prasugrel (CS-747) (LY640315) (3rd generation) O N C H O 3 S F O

  5. Treatment Failure? Stent thrombosis Recurrent Chest Pain Recurrent CVA Recurrent MI Death Heterogonous Lab Test results? What Test? What Agonist? What Concentration? What definition? What is Clopidogrel Resistance?“Reduced response”

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

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

  8. Link between low response and stent thrombosis / ischemic events

  9. Tailoring Clopidogrel Therapy? Possible subgroups to target

  10. 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 < 2 h after clopidogrel loading -25 -20 -15 -10 0 -30 -5 -5 D Inhibition (%) Hochholzer et al

  11. 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 <65 yr old 6354 5.4 7.6 >65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes 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 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 0.6 0.8 1.0 1.2 0.4 Relative Risk (95% CI) Placebo Better Clopidogrel Better Yusuf S et al. N Engl J Med. 2001;345:494-502.

  12. Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute phase of treatment Long-term phase of treatment DM No-DM 80 P=0.001 P<0.0001 P=0.04 8% 14% 60 38% 56% 78% 6% 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 >30%) No-DM T2DM T2DM No-DM ADP 20 mol/L ADP 6 mol/L Angiolillo DJ et al. J Am Coll Cardiol 2006;48 298-304. Angiolillo DJ et al. Diabetes. 2005;54:2430-5.

  13. Putative Genetic Determinants of Clopidogrel Activity(Pharmacogenomics)

  14. Polymorphic Genes and Effect of Clopidogrel First Author Journal Year N Polymorphism Effect Trenk D Abstract 2006 749 CYP3A5A6986G 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 - 

  15. COOCH3 N S Clopidogrel Cl O CH3 O C N S O Cl 2-oxo Compound N HOOC O OCH3 * HS Cl Active Metabolite 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

  16. Main effects of CYP2C19*2 polymorphism on cardiovascular outcomes . MI survivors <45y, n=259 Collet JP et al. Lancet 2008

  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

  18. What to do about poor response?

  19. 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 2007;115:708-716

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

  21. 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

  22. 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 2008;1:631-638

  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 -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 Log rank p =0.007 MACE: CV death, MI, revascularization Bleeding 3 (4) 4(5) P=NS † p =0.059 * p =0.007 J Am Coll Cardiol 2008;51:1404-11

  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 ADP-Ag <70% Clopidogrel responders Excluded Abciximab N=74 Conventional therapy N=75 Cuisset et al JACC:CI, 2008:649-53

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

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

  31. Clopidogrel Responder* Clopidogrel Nonresponder Healthy Volunteer Crossover Study IPA (20 M ADP) at 24 H 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

  32. 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

  33. Thankyou