Speaker s name: Thomas Cuisset, MD, PhD

Transcription

1 Speaker s name: Thomas Cuisset, MD, PhD X I have the following potential conflicts of interest to report: x Consulting: Daiichi Sankyo, Eli Lilly Employment in industry Stockholder of a healthcare company Owner of a healthcare company x Others: Lecture Fee Abbott Vascular, Astra Zeneca, Biotronik, Boston Scientific, Cordis, Daichi Sankyo, Sanofi, Edwards, Eli Lilly, Medtronic I do not have any potential conflict of interest

2 Antiplatelet therapy should be guided by platelet response tests: Pro Thomas Cuisset, Marseille, FR ESC Congress 2012, Munich

3 Why Platelet Function Monitoring Should be Mandatory? To Improve Patients Outcome!

4 How platelet testing could improve prognosis?

5 How platelet testing could improve prognosis? Low Response to Clopidogrel risk of ischemic events Platelet Test for tailored Therapy in non responders

6 Number of patients Clopidogrel :An unreliable platelet inhibition! [10,20] [30,40] [50,60] [70,80] >90 5µM ADP platelet aggregation (%) Serebruany et al. J Am Coll Cardiol 2005

7 Predictors of low response to clopidogrel Clinical factors Non compliance Underdosing Drug-drug interaction Acute coronary syndrome Diabetes mellitus High BMI Renal failure Elderly patient Genetic factors CYP2C19*2 +++ Low response to clopidogrel Cellular factors High platelet turnover Lower CYP activity Increased ADP exposure

8 Number of patients Clopidogrel :An unreliable platelet inhibition! HypoResponders Ischemic Risk? 0 [10,20] [30,40] [50,60] [70,80] >90 5µM ADP platelet aggregation (%) Serebruany et al. J Am Coll Cardiol 2005

9 Higher incidence of MACE in clopidogrel non responders Hochholzer, Trenk et al. J Am Coll Cardiol 2006

10 Definite/Probable ST (%) Stent thrombosis and platelet reactivity 2.0 N=8575, drug eluting stent, 50% ACS and 50% stable CAD P2Y12 PRU > 208 (n=3607) P2Y12 PRU 208 (n=4834) HR=3.89 [1.90, 7.98] p < % % Days ADAPT-DES study, Stone et al, TCT 2011

11 What Did we learn from Platelet Testing? - Variability of clopidogrel Response - Clinical consequences - Optimized therapy needed in High Risk Patients! - Evidence for Tailored therapy?

12 Repeated Loading doses in Non Responders? Elective PCI or NSTE ACS (50/50) N=162, 600 mg clopidogrel VASP Index HPR defined as PRI VASP>50% Additional 600 mg Loading dose VASP-guided vs. Control Significant benefit of tailored therapy on PR Bonello et al J Am Coll Cardiol 2007

13 Repeated Loading doses in Non Responders? Significant clinical benefit of tailored therapy Limitations: 8% non responders after 2,400 mg and delayed PCI Bonello et al J Am Coll Cardiol 2007

14 GPIIbIIIa inhibitors in Non Responders? 600 mg Clopidogrel, elective PCI, n=149 Elective PCI LTA Clopi NR: ADP-Ag>70% Abciximab vs Placebo Composite endpoint: 40 % vs 17 %, p<0.01 Periprocedural MI (Troponin > N): 35 % vs 18 %, p<0.01 Cuisset et al J Am Coll Cardiol Int 2008

15 GPIIbIIIa inhibitors in Non Responders? 300 or 600 mg Clopidogrel, n=263 Elective PCI or ACS Verify Now ASA NR: ARU>550 Clopi NR: % inhibition<40% Tirofiban vs Placebo Periprocedural MI (Troponine > N): 35 % vs 20 %, p<0.01 Valgimigli et al, Circulation 2009

16 However Results from small studies 3 Studies: 3 tests, 3 definitions, 3 strategies No consensual definition: test? Threshold? Timing? Large RCT s needed

17 Elective or Urgent PCI with DES* VerifyNow P2Y12 Test hours post-pci Low risk population Post PCI Platelet Testing PRU 230 R 60% Stable CAD 10% NSTEMI/STEMI High-Dose Clopidogrel clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel clopidogrel 75-mg daily X 6 months 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 GRAVITAS study Price et al, JAMA 2011

18 High dose vs. standard dose Clopidogrel: Primary Endpoint: CV death, MI, stent thrombosis n=1109 n=1105 GRAVITAS study Price et al, JAMA 2011

19 Limitations of GRAVITAS Tailoring Based on single measurement Test performed after PCI Very Low Risk Population Adjusted strategy inappropriate (no new P2Y12 blockers)

20 Flow-chart TRIGGER-PCI Study Successful Elective PCI with DES without major complication and NO GPIIb/IIIa use N ~6500 Post-PCI VerifyNow P2Y12 Assay (PRU) 2-7 hours after MD of clopidogrel 75 mg at day 1 post-pci A Prasugrel arm Prasugrel LD 60 mg Prasugrel MD 10 mg QD + Clopidogrel placebo Non-Responder N = 1075 B Yes N = 1075 Clopidogrel arm Placebo LD Clopidogrel MD 75 mg QD + Prasugrel placebo PRU > 208 No Low risk population Post PCI Platelet Testing N = 2,150 33% Responder C N = 4350 Standard Therapy Clopidogrel MD 75 mg QD Non-interventional study (Registry) Clinical Follow-up and blinded VerifyNow Assessment at 90 days, 180 days Primary Endpoint: 6 month CV Death or MI Trenk et al, J Am Coll Cardiol 2012

21 TRIGGER-PCI : platelet testing Benefit of tailored therapy with prasugrel Trenk et al, J Am Coll Cardiol 2012

22 TRIGGER-PCI : clinical outcomes No clinical benefit of tailored therapy Trenk et al, J Am Coll Cardiol 2012

23 Bad news for tailored therapy in the study? Benefit on platelet inhibition without clinical benefit but. 1) Patient selection: Very Low risk population 2) Small sample size / number of events 3) Post PCI platelet testing (peri PCI optimization needed!) No definite conclusion derived from this study

24 How platelet testing could improve prognosis? Low Response to Clopidogrel risk of ischemic events Platelet Test for tailored Therapy in non responders High Platelet inhibition Higher Bleeding Risk Platelet Test for bleeding risk prevention

25 Number of patients Clopidogrel :An unreliable platelet inhibition! HyperResponders Bleeding Risk? HypoResponders Ischemic Risk 0 [10,20] [30,40] [50,60] [70,80] >90 5µM ADP platelet aggregation (%) Serebruany et al. J Am Coll Cardiol 2005

26 Platelet Reactivity and Bleeding 597 NSTE ACS patients, clopidogrel 600 mg, Post discharge bleeding Q1: Hyperresponders, ADP-Ag<40% ADP 10 µmol/l, LTA Higher Clopidogrel Response Higher Risk of Bleeding HR 5.3, 95% CI 1.9 to 14.9; p<0.01 Cuisset et al. Eurointervention 2009

27 Use of Platelet Testing with new P2Y12 blockers?

28 French Registry: Paris - Marseille n=444 patients, ACS patients undergoing PCI % 3.5% 3.2% VASP PRI (%) PRU RPA (%) Predictable degree of platelet inhibition, low rate of HPR Cayla, Cuisset, Silvain, Montalescot et al, submitted

29 Bleeding Risk Monitoring? 213 NSTE ACS patients, prasugrel 10 mg/d, post discharge bleeding Hyper Response: PRI VASP < 17% (quartile distribution) Patients with Hyper response to Prasugrel have twice higher risk of bleeding Cuisset et al, JACC int 2012, accepted for publication

30 Bleeding Events Therapeutic Window? Ischemic Events Major Bleed 2 Optimal Therapeutic Range Stent Thrombosis 3 Higher Platelet Inhibition (HPI) Higher Platelet Reactivity (HPR)

31 How platelet testing could improve prognosis? 1) Low Response to Clopidogrel risk of ischemic events Platelet Test for tailored Therapy in non responders 2) High Platelet inhibition Higher Bleeding Risk Platelet Test for bleeding risk prevention 3) Lack of Compliance to DAPT Higher Risk of ST Platelet Test for non compliance detection / education

32 3 centres / 2229 pts / FU 9 mois / 1.3% ST Iakovou et al JAMA 2005

33 Aspirin Response 450 pts, PCI for non ST ACS Aspirin 250 mg in hospital and 75mg daily Assessment of Aspirin Response Hospital 1 month 2% >10% 30% 30% Non Response Response

34 AA-induced platelet aggregation (%) Resistance or Non Compliance? 136 pts / PCI for non ST ACS/ Aspirin 75 mg % Resistance? Non Compliance? 25 0 Hospital 1 month Controlled Intake of Aspirin Cuisset et al Am Heart J 2009

35 AA-induced platelet aggregation (%) 100 Non Response? Controlled Intake of Aspirin Hospital 1 month Non Compliance Platelet Testing to Identify Non Compliance Education +++ Cuisset et al Am Heart J 2009

36 New P2Y12 inhibitors More Nuisance Bleeding associated with Non Compliance Roy et al, AJC 2008 Ticagrelor: Twice Daily Compliance?

37 New P2Y12 inhibitors Plavix Prasugrel Ticagrelor Compliance? 70%

38 Why Platelet Function Monitoring Should be Mandatory? To Improve Patients Outcome!

39 Bleeding Events Antiplatelet Monitoring: Why? Ischemic Events Major Bleed 2 Optimal Therapeutic Range Stent Thrombosis 3 HyperResponders Improve Outcome HypoResponders Non Compliance

40 Thank You