GPIIbIIIa inhibitors for Clopidogrel Non Responders undergoing Elective PCI T Cuisset, C Frere, J Quilici, MC Alessi, JL Bonnet Pôle Cardiovasculaire, CHU Timone, Marseille Inserm, U626, Faculté de Médecine, Marseille Printemps de la Cardiologie Nancy, Juin 2009 Session des Jeunes Cardiologues
Clopidogrel Response HypoResponders Ischemic Risk Serebruany et al, J Am Coll Cardiol 2005
Clinical Relevance of Clopidogrel Non Response Post-PCI Ischemic Events N Functional Parameter Clinical Relevance Matezky et al. Circulation 2004 Gurbel et al. JACC 2005 Gurbel et al. Circulation 2005 Cuisset et al. JTH 2006 Lev et al. JACC 2006 Cuisset et al. JACC 2006 Hocholzer et al. JACC 2006 60 platelet aggregation (4 th quartile) Post-primary PCI ischemic events (6 months) 192 periprocedrual platelet aggregation Post-PCI ischemic events (6 months) 120 periprocedrual platelet aggregation Myonecrosis and inflammation marker release 106 platelet aggregation Post-PCI ischemic events (30 days) 120 clopidogrel/aspirin-resistant patients Post PCI-myonecrosis 292 platelet aggregation Post-PCI ischemic events (30 days) 802 platelet aggregation (3 rd & 4 th quartiles) Post-PCI ischemic events (30 days) Geisler et al. Eur Heart J 2006 379 platelet inhibition Post-PCI ischemic events (3 months) Bliden et al. JACC 2007 100 platelet aggregation Post-PCI ischemic events (12 months) Angiolillo et al, Am J Cardiov Drugs 2007
Cuisset et al. JTH 2006 104 ACS patients, Coronary Stenting Non Response: ADP-Ag>70% Quartile Stratification Clopidogrel Non Response associated with higher risk of ischemic events
Buonamici et al, JACC 2007 804 patients, Coronary Stenting with DES Non Response: ADP-Ag>70% 90th Percentile of Controls Clopidogrel Non Response was associated with higher occurence of Stent Thrombosis HR 3.08, 95% CI 1.32 to 7.16; p 0.009
ST Free Survival Predictive Values of ADP-Ag for Stent Thrombosis Clopidogrel non responders Clopidogrel responders p=0.002 100 99.2% 598 patients, Stenting post ACS 95 95.7% Non Response: ADP-Ag>67% ROC curves analysis 90 0 10 20 30 Days Clopidogrel Non Response was associated with occurence of Stent Thrombosis 4.3% vs. 0.8%, OR 5.8, 95% CI 1.9 to 24.6; p=0.003 Cuisset et al, Am J Cardiol 2009, accepted for publication
How to Overcome the Variability of Response? Improved treatment for «non responders» Tailored Antiplatelet Therapy (Monitoring)? Improved Antiplatelet Therapy for all? To eradicate the non response
How to Overcome the Variability of Response? Improved treatment for «non responders» Tailored Antiplatelet Therapy (Monitoring)? Improved Antiplatelet Therapy for all? To eradicate the non response
Bonello et al, JACC 2007 Elective PCI or NSTE ACS VASP Index Clopi NR: VASP>50% 40% Non Responders Additional LD VASP-guided vs Control
Limitations: 8% non responders after 2400 mg and delayed PCI Bonello et al, JACC 2007
Objective We assessed in a prospective, randomized study the benefit of GPIIbIIIa antagonist for clopidogrel non responders undergoing elective PCI
Cuisset et al, JACC Int 2008 Methods Consecutive Patients undergoing elective PCI Loading dose of 600 mg of clopidogrel Clopidogrel Response with ADP 10 µmol-induced aggregation Non Responders (ADP-Ag>70%) randomized to Active strategy with Abciximab or Conventional strategy Endpoint: Combined endpoint of Death, Periprocedural MI, subacute definite or probable ST and recurrent ACS
Study Design Cuisset et al, JACC Int 2008
Cuisset et al, JACC Int 2008 Results 149 Non responders (ADP-Ag>70%) after 600 mg clopidogrel Randomized to Active strategy with Abciximab (n=74) or Conventional strategy (n=75)
Cuisset et al, JACC Int 2008 Results Characteristics Active strategy (n=74) Conventional strategy (n=75) P value Male 55(74) 58(77) 0.71 Age, (years) 66±9 64±8 0.68 Body Mass Index (kg/m²) 27±4 28±5 0.82 CV risk factors Hypertension 48(65) 45(60) 0.61 Characteristics Active strategy Conventional strategy (n=74) (n=75) P value Reference Diameter 2.8±0.5 2.6±0.4 0.47 Minimal Lumen Diameter 1.0±0.3 1.0±0.2 0.27 % Stenosis 64±9 66±10 0.38 Residual Stenosis, % 11±3 11±3 0.97 Total Stent Length, mm 24±9 25±7 0.66 Stent Diameter, mm 3±0.3 3±0.4 0.83 GPIIbIIIa antagonists 74 (100) 2 (3) <0.001 Diabetes mellitus 26(35) 30(40) 0.62 Smoker 22(30) 26(49) 0.60 Dyslipidemia 54(74) 57(76) 0.71 Familial history 14(19) 18(24) 0.55 Discharge Medications Statins B-Blocker ACE inhibitors 60(81) 41(55) 33(45) 62(83) 39(52) 36(48) 0.83 0.74 0.73 Ejection fraction 62±11 60±14 0.59 Biological data Creatinine, (mg/dl) 97±12 102±21 0.78 CRP (mmol/l) 2.5±0.8 2.7±0.7 0.70 Platelet count 211±33 225±43 0.60 ADP-induced aggregation 78±6 78±7 0.84
Primary Endpoint Cuisset et al, JACC Int 2008 Results Primary Endpoint: 40 % vs. 19 %, p=0.006
% Cuisset et al, JACC Int 2008 Results * * 40 30 Active Conventional 20 10 0 Death ST ACS PM I CV ev ents * p<0.01
Cuisset et al, JACC Int 2008 Conclusion The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GPIIbIIIa antagonist for clopidogrel non responders With ADP-Ag>70% to identify clopidogrel non responders
Cuisset et al, JACC Int 2008 Limitations - Small Sample Size - Benefit mainly driven by PMI reduction - No consensual definition of non response
Valgimigli et al, ESC Congress 2008 Tailoring Treatment with Tirofiban in patients with Resistance to aspirin and/or Resistance to clopidogrel Elective PCI or NSTE ACS Verify Now ASA NR: ARU>550 Clopi NR: % inhibition<40% Tirofiban vs Placebo
Limitations of «Tailored Therapy» - These studies compared for «non responders» Additional Therapy (LD, IIbIIIa) vs placebo - Monitoring: Test? Threshold? - 3 Studies: 3 Different tests, 3 definitions, 3 strategies
Randomisation avant implantation d un stent actif Groupe 1 : Bras Monitoré 1-Evaluation systématique de la réponse biologique à l aspirine et au clopidogrel avant la mise en place de l endoprothèse active. 2-Adaptation du traitement antiplaquettaire chez les hyporépondeurs au moment de l angioplastie 3-Réévaluation chez tous les patients à J14±3 de la réponse au traitement antiplaquettaire oral et ajustement du de la dose d entretien Groupe 2 : Bras Conventionnel 1- Pas d évaluation de la réponse biologique au traitement antiplaquettaire 2- La stratégie antiplaquettaire orale est laissée à la discrétion de l investigateur en fonction des pratiques habituelles Evaluation du critère primaire de jugement tous les 6 mois (6 jusqu à 18 mois) 1. Toute cause de mortalité 2. Infarctus du myocarde 3. Toute revascularisation urgente 4. Thrombose de stent nécessitant une revascularisation ou non 5. AVC ischémique nécessitant une nouvelle hospitalisation
How to Overcome the Variability of Response? Improved treatment for «non responders» Tailored Antiplatelet Therapy (Monitoring)? Improved Antiplatelet Therapy for all? To eradicate the non response
IPA at 24 hours (%) Interpatient Variability Interpatient Variability Healthy Volunteer Crossover Study 100 80 N=66 60 40 20 0 Clopidogrel Responder Clopidogrel Non-responder -20 Response to Clopidogrel 300 mg Response to Prasugrel 60 mg From Brandt JT AHJ 153: 66e9,2007
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