Y-a-t-il un avenir pour les tests plaquettaires ? Thomas Cuisset CHU Timone, Marseille

Un avenir pour les tests plaquettaires ? Mais Pour quoi faire ? Pour individualiser le traitement ?

Variabilité de Réponse au Clopidogrel 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 Number of patients Hyper répondeurs Hémorragie Non Répondeurs Risque ischémique ≤0 [10,20] [30,40] [50,60] [70,80] >90 Serebruany et al. JACC 2005

Definite or probable stent thrombosis Thrombose de stent 804 patients, Stent actif 100 98 96 94 92 90 88 86 84 82 80 98±1 – Non Réponse: ADP-Ag>70% = 90th percentile – ADP 10 µmol/L, LTA 91±3 Definite or probable stent thrombosis Responders Nonresponders Log rank p <0.001 0 30 60 90 120 150 180 Time (days) Non Réponse reliée à la thrombose de stent HR 3.08, 95% CI 1.32 to 7.16; p=0.009 Buonamici et al. JACC 2007

Hyper-réponse reliée au risque hémorragique 597 patients SCA, clopidogrel 600 mg, Saignements Q1: Hyperréponderus, ADP-Ag<40% ADP 10 µmol/L, LTA During the next minutes I would like to discuss with you some aspects of percutaneous interventions in patients with multivessel disease like ... Hyper-réponse reliée au risque hémorragique HR 5.3, 95% CI 1.9 to 14.9; p<0.01 Cuisset et al. Eurointervention 2009 5

Higher Platelet Inhibition Higher Platelet Reactivity Fenêtre Thérapeutique ? Hémorragie Ischémie Stent Thrombosis × 3 Major Bleed × 2 Higher Platelet Inhibition (HPI) Higher Platelet Reactivity (HPR)

donc…on teste tout le monde ? Preuve que le test est relié au pronostic ..ne veut pas dire que faire le test et traiter en fonction améliore le pronostic ‘Evidence’ pour traitement individualisé ??

60% Stable 10% NSTEMI/STEMI R Population bas risque Test en Post PCI Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 60% Stable 10% NSTEMI/STEMI Population bas risque Test en Post PCI R High-Dose Clopidogrel† clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months GRAVITAS enrolled patients undergoing elective or urgent PCI with a drug-eluting stent. Clopidogrel-naïve patients had to receive a 600-mg loading dose, and those already on chronic clopidogrel could not receive an additional load. This was designed to ensure that the effect of clopidogrel was at steady-state at the time of platelet function measurement. Platelet function was measured with the VerifyNow P2Y12 test 12 to 24 hours after PCI. With this test, platelet reactivity is reported in terms of PRU – the higher the PRU, the greater the level of residual reactivity on clopidogrel. In GRAVITAS, high reactivity was defined as a PRU greater than or equal to 230, a cutoff similar to that suggested by previous studies to provide the maximal sensitivity and specificity for subsequent cardiac events. Patients with high reactivity were randomized in a double-blind fashion to either 6 months of high dose clopidogrel or standard dose clopidogrel. The primary efficacy endpoint was a composite of cardiovascular death, non-fatal MI, or stent thrombosis at 6-months. The Key safety endpoint was GUSTO severe or moderate bleeding. Platelet reactivity was re-assessed at 30-days and 6 months in a blinded fashion, but no treatment decisions were made based upon the results of these tests. Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months Price et al, JAMA 2011 GRAVITAS study 8

Fortes doses vs. Doses standard Pas de bénéfice dans GRAVITAS Price et al, JAMA 2011 GRAVITAS study

Flow-chart TRIGGER-PCI Study Successful Elective PCI with DES without major complication and NO GPIIb/IIIa use Post-PCI VerifyNow P2Y12 Assay (PRU) 2 - 7 hours after MD of clopidogrel 75 mg at day 1 post-PCI N ~6500 Yes PRU > 208 No Non-Responder Responder Population bas risque Test en Post PCI A B C N = 1075 N = 1075 N = 4350 “Prasugrel arm” Prasugrel LD 60 mg Prasugrel MD 10 mg QD + Clopidogrel placebo “Clopidogrel arm” Placebo LD Clopidogrel MD 75 mg QD + Prasugrel placebo “Standard Therapy” Clopidogrel MD 75 mg QD Non-interventional study (Registry) N = 2,150  33% Clinical Follow-up and blinded VerifyNow Assessment at 90 days, 180 days Primary Endpoint: 6 month CV Death or MI Trenk et al, AHA Congress 2011

Efficacy endpoints TRIGGER-PCI Study Prasugrel N=212 Clopidogrel N=211 p=ns Days on study treatment(median) 174 - Primary composite efficacy EP: CV death or MI 1 (0.5%) Key secondary efficacy EPs: MI Rehospitalization for cardiac ischemic event 2 (0.9%) 4 (1.9%) Urgent TVR Definite ST Stroke CV death All cause death Trenk et al, AHA Congress 2011 LBCT V3_4 FinalTACW_Trial Protocol and Organization_Franz-Josef Neumann_V1.0_2010-08-27 TRIGGER-PCI TCT2011LBCT V3_4 FinalTACW_Trial Protocol and Organization_Franz-Josef Neumann_V1.0_2010-08-27 11 11 11 11 11

Conclusions de GRAVITAS/TRIGGER PCI Pas de bénéfice à ttt individualisé dans ICP ‘bas risque’ Pas de bénéfice à ttt individualisé après ICP (événements péri ICP ?) Bénéfice chez patients haut risque (SCA) avant ICP avec nouveaux inhibiteurs P2Y12 doit être évalué Price et al, JAMA 2011 - Trenk et al, AHA Congress 2011

Clinical Trials Identifier Primary Outcome Measure Study Clinical Trials Identifier Patients (n) Randomization Primary Outcome Measure Thienopyridine Therapy GRAVITAS Gauging responsiveness With A VerifyNow Assay-Impact on Thrombosis And Safety NCT00645918 ACS-PCI-DES (2783) Deem non responders defined according to a PRU≥230 6 month CV death, non-fatal MI or ST 75 mg qd vs 150mg qd or prasugrel 10mg ARCTIC Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy NCT00827411 Elective PCI –DES (2466) Use of VerifyNowTM assay for P2Y12 and aspirin 12 months Composite end point of death, M, stroke, Urgent revascularization, ST Therapy based on MD test results DANTE Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition NCT00774475 Unstable or NSTEMI –PCI (442) Deem non responders defined according to a PRU>? 6 and 12 months CV death, nonfatal MI, TVR by PCI or CABG 75 mg qd v 150mg qd TOPAS -1 Tailoring of Platelet Inhibition to Avoid Stent Thrombosis NCT00914368 Previous PCI or stenting for CAD (450) Not randomized VerifyNow P2Y12TM (PRU) 600mg LD 75mg qd for 6 months TRIGGER-PCI Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel NCT00910299 Coronary Artery Disease (CAD) –DES (2150) Deem non responders defined according to a PRU>208 or >162 6 months CV death, non fatal MI Prasugrel 60/10mg vs Clopidogrel 600mg/75mg TARGET-PCI Thrombocyte Activity Reassessment and GEnoTyping for PCI NCT01177592 Non emergent PCI (1500) Guided (gene & PD) versus non- guided One year death, M, stroke, Urgent revascularization, ST Clopidogrel (LD+MD) vs prasugrel (LD+MD) ETUDE NEGATIVE ETUDE NEGATIVE ETUDE ARRETEE 13

Limites actuelles du traitement individualisé Coût des tests Quand faire le test ? Aigu ? Plus tard ? 2 tests ! Place des tests avec nouvelles molécules ? Preuve scientifique +++ (ARCTIC)

Un avenir pour les tests plaquettaires ? présent Un avenir pour les tests plaquettaires ? Pour individualiser ? Pas en routine pour tous les patients Les tests plaquettaires restent un outil de recherche clinique Intéressants chez patients sélectionnés

During the next minutes I would like to discuss with you some aspects of percutaneous interventions in patients with multivessel disease like ... Wijns et al, EHJ 2010 16

Un avenir pour les tests plaquettaires ? Pour individualiser ? OUI ! Ou sera le curseur ?? …attendons les études en cours Quelques patients très sélectionnés Tous les patients

Un avenir pour les tests plaquettaires ? Mais Pour quoi faire ? Pour individualiser le traitement ? Encore tôt… Autre utilité ?

Autre intérêt des tests …? LA COMPLIANCE Prise contrôlée d’aspirine Non Réponse ? 100 75 AA-induced platelet aggregation (%) 50 25 Non Compliance Hospital 1 month Test plaquettaire pour aider à la détection de la Non Compliance ? Cuisset et al Am Heart J 2009

Registre Prasugrel: Paris-Marseille HPR 6.7% 3.5% 3.2% Cayla, Cuisset, Silvain, Montalescot et al, unpublished data

Merci