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

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

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

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)

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?

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

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

Link between low response and stent thrombosis / ischemic events End-pointAuthorJournal / yearn Stent thrombosisBarragan et al.CCI Gurbel et al.JACC Ajenberg et al.JACC Buonamici et al.JACC Blindt et al.TH Ischaemic eventsMatetzky et al.Circ Geiser et al.EHJ Gurbel et al.JACC Bliden et al.JACC Cuisset et al.JTH Hochholzer et al.JACC Bonello et al.JTH

Tailoring Clopidogrel Therapy? Possible subgroups to target

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 (%) Weaker inhibition -5 Hochholzer et al

Placebo + ASA Characteristic No. of Patients Clopidogrel + ASA Percentage of Patients with Event Placebo Better Clopidogrel Better Relative Risk (95% CI) Yusuf S et al. N Engl J Med. 2001;345: Outcomes With Clopidogrel in Various Subgroups Overall Associated MI No associated MI Male sex Female sex yr old yr old ST-segment deviation No ST-segment deviation Enzymes elevated at entry Enzymes not elevated at entry Diabetes No diabetes Low risk Intermediate risk High risk History of revascularization No history of revascularization Revascularization after randomization No revascularization after randomization

78% 14% 8% P=0.04 Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Angiolillo DJ et al. Diabetes. 2005;54: 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; Platelet aggregation (%) P=0.001 P< ADP 20  mol/L ADP 6  mol/L T2DM No-DM T2DM No-DM

Putative Genetic Determinants of Clopidogrel Activity (Pharmacogenomics)

First Author Journal Year N Polymorphism Effect Trenk D Abstract CYP3A5 A6986G  MDR1 C3435T  Sibbing DJ Thromb Haem 2006 P2Y1 A1622G  Smith SM Platelets P2Y12  CYP 3A5 A6986G  2005 PAR-1 14 A>T  Angiolillo DJATVB CYP 3A4 IVS10+12G>A (+) 4 other CYP 3A4  Hulot JS Blood CYP2C19 *1/*2 – Lev EI Thromb Res GP IIIa PlA  P2Y12 T744C  P2Y1 1622A>G  Angiolillo DJ Thromb Res P2Y12 T744C  Angiolillo DJ Blood Coag Fibr GP Ia C 807T  Angiolillo DJ Blood Coag Fibr GP IIIa PlA2 -  Polymorphic Genes and Effect of Clopidogrel

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

OutcomesAdjusted hazards ratio (95% CI) p Death, nonfatal MI, urgent revascularization (primary end point) 5.38 (2.32–12.47)< 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

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 alleles 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 alleles variant allele0.78 (0.50–1.21) 2 variant alleles3.58 (1.71–7.51)

What to do about poor response?

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

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

Aleil, B. et al. J Am Coll Cardiol Intv 2008;1: Platelet Reactivity Index at 2 Weeks According to the Maintenance Dose of Clopidogrel

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

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:

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

PLATELET MONITORING Mean ±SDControlVASP-guidedp VASP after first LD, %68 ±1169 ±100.4 VASP after adjustment, %  38 ±14**< 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:

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

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

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

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?

Worrall 2009 Poor specificity of clopidogrel activity tests P=0.0002

IPA (20  M ADP) at 24 H 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

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

Thankyou