Antiplatelet therapy in ACS/PCI. Thomas Cuisset, CHU Timone, Marseille DIU Cardiologie Interventionnelle Paris, Janvier 2013

Transcription

1 Antiplatelet therapy in ACS/PCI Thomas Cuisset, CHU Timone, Marseille DIU Cardiologie Interventionnelle Paris, Janvier 2013

2 Oral Antiplatelet therapy in ACS/PCI

3 Most Challenging Questions in Nov Aspirin / Clopidogrel Dosing in PCI/ACS? New P2Y12 blockers for which patients? Duration of Dual Therapy after DES? Platelet Monitoring in daily practice?

4 What is youraspirin Discharge Dosing after PCI/ACS? 1) < 100 mg for all patients 2) mg for all patients 3) According to patient risk profile 4) Tailored on Platelet Tests

5 Low dose of Aspirin Aspirin + Clopidogrel, NSTE ACS patients, CURE Study No ischemic benefit, Higher rate of bleeding complications Peters et al, Circulation 2003

6 Low dose of Aspirin p=0.61 p=0.04 No ischemic benefit, Higher rate of bleeding complications N=25086 patients, CURRENT OASIS 7 study Mehta et al, NEJM 2010

7 What is ouraspirin Discharge Dosing after PCI/ACS? 1) < 100 mg for all patients 2) mg for all patients 3) According to patient risk profile 4) Tailored on Platelet Tests

8 What is yourclopidogrel Regimen in PCI/ACS patients? 1) 300 mg LD and 75 mg daily 2) 600 mg and 15O mg daily one week 3) > 600 mg LD 4) Tailored on Platelet Function tests

9 Dual antiplatelet therapy in ACS = Gold Standard 11.8% 9.5% 20% RRR CURE trial, N Engl J Med 2001

10 Clopidogrel : An unreliable platelet inhibition! Number of patients Hypo Responders Ischemic Risk 0 [10,20] [30,40] [50,60] [70,80] >90 5µM ADP platelet aggregation (%) Serebruany et al. JACC 2005

11 Higher doses of Clopidogrel? Montalescot et al. JACC 2006 Cuisset et al. JACC 2006 Higher Dose Higher Platelet Inhibition / Lower Incidence of Resistance

12 Higher doses of clopidogrel? HR=1.26, p=0.03 p=0.30 No ischemic benefit, Higher rate of bleeding complications CURRENT OASIS 7 study, Mehta et al, NEJM 2010

13 N=25086 patients Benefit of High doses of Clopidogrel in PCI subgroup CURRENT OASIS 7 study Mehta et al, NEJM 2010

14 What is ourclopidogrel Regimen in PCI/ACS patients? 600 mg and 15O mg daily one week post PCI unless a New P2Y12 blockers is indicated in ACS

15 When do yougive new P2Y12 blockers in ACS? 1) All ACS patients 2) All ACS patients undergoing PCI 3) Only STEMI patients 4) Only Diabetic ACS patients 5) Only Clopidogrel Non Responders 6) None, Due to Risk of Bleeding

16 Prasugrel and Ticagrelor New P2Y12 blockers higher, faster and predictable platelet inhibition

17 Prasugrel

18 Prasugrel versus clopidogrel in patients with ACS ACS (STEMI or UA/NSTEMI) & planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy 12 months 1 o endpoint: CV death, MI, stroke 2 o endpoints: CV death, MI, stroke, rehosp-rec isch CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key substudies: Pharmacokinetic, genomic Wiviott SD et al. N Engl J Med 2007

19 15 TRITON: Balance of Efficacy and Safety CV Death / MI / Stroke Clopidogrel 12.1 HR 0.81 ( ) P= NNT = Prasugrel 9.9 Endpoint (%) 5 TIMI Major NonCABG Bleeds Prasugrel Clopidogrel HR 1.32 ( ) P=0.03 NNH = Days Wiviott SD et al. N Engl J Med 2007

20 Choice of P2Y12 inhibitors Ischemic Risk Bleeding Risk Selection of patients +++

21 Proportion of patients (%) Prasugrel in STEMI Time (Days) Clopidogrel Prasugrel Clopidogrel Prasugrel HR=0.79 ( ) p=0.02 RRR=21% Clopidogrel Prasugrel 2.4 p= HR=1.11 ( ) N=3534 Montalescot et al. Lancet 2009

22 Prasugrel in Diabetic Patients Endpoint (%) Clopidogrel 17.0 CV Death / MI / Stroke 12.2 Prasugrel TIMI Major Non CABG Bleeds Clopidogrel 2.6 Prasugrel Time (Days) HR 0.70 P<0.001 NNT = 23 NNH = 795 N=3146 Wiviott et al, Circulation 2007

23 Safety Concern in subgroups? Higher rate of bleeding if > 75 y.o or < 60 kg deleterious and CI if prior Stroke / TIA

24 Ticagrelor: PLATO study PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Wallentin et al, N Engl J Med 2010

25 Primary EP (CV death, MI or stroke) 13 Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.84 (95% CI ), p= Days after randomisation Wallentin et al, N Engl J Med 2010

26 9 8 Non-CABG and CABG-related major bleeding 7.4 NS 7.9 K-M estimated rate (% per year) p= p= NS 5.8 Ticagrelor Clopidogrel 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

27 7 Safety = Non-CABG related TIMI major bleedings Same Platelet Inhibition Same Bleeding Risk p=0.001 * p=0.03* p=0.025* +38% +32% +27% 3.7 ASA only NNH=167 NNH= Prasugrel Ticagrelor Clopidogrel 75 0 CURE 360 days TRITON 450 days PLATO 360 days Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010

28 Subgroup analysis? Same Than TRITON? Others?

29 Better results for Prasugrel in STEMI and Diabetic and ticagrelor?

30 PLATO: STEMI Subgroup 10.8 % 9.4 % =1.4 % p=0.07 STEMI, N=7544 TRITON: N=3534, =2.4 % for primary EP, p=0.02 Steg et al, Circulation 2010

31 PLATO: Diabetic Subgroup 16.2 % 14.1 % 10.8 % 9.4 % =2.1 % p=0.07 =1.4 % p<0.01 Diabetes, N=4662 TRITON: N=3146, =5.2 % for primary EP, p<0.001 James et al, Eur Heart J 2010

32 Better results for Prasugrel in STEMI and Diabetic not observed for ticagrelor!

33 PLATO: Impact of CKD 22 % 17.3 % =4.7 % p< % 7.9 % N=3237 with CC < 60ml/min James et al, Circulation 2010

34 Bad outcomes in patients with Prasugrel: -> 75 y.o - with prior stroke and ticagrelor?

35 PLATO: Patients > 75 y.o Benefit of Ticagrelor not affected by Age N=2878 Husted et al, Circulation 2012

36 PLATO: Patients with prior stroke / TIA Primary Endpoint Total Mortality Benefit of Ticagrelor not affected by prior history of stroke / TIA N=1152 Husted et al, Circulation 2012

37 Bad outcomes in patients with Prasugrel: -> 75 y.o - with prior stroke not observed for ticagrelor!

38 New Evidence for Prasugrel?

39 Covering the gaps of the TRITON study design! Study population: Broad ACS population in PLATO High Risk ACS patients medically managed TRILOGY Study with Prasugrel TRITON (prasugrel) ACS/PCI, No pre treatment PLATO (ticagrelor) «All High Risk ACS» Patients with Pre treatment before cathlab ACCOAST Study with Prasugrel

40 PLATO: ACS patients medically managed Planned non-invasive strategy Primary endpoint 12 % vs. 14.3%, p=0.04 Patients not included in TRITON Benefit of Ticagrelor in medically managed high risk ACS James et al, BMJ 2011

41 TRILOGY study (< 75 y.o, n=7243) ACS patients medically managed with prasugrel + 0.6% absolute Idem TRITON / PLATO at 1 year No benefit of Prasugrel in ACS patients medically managed Roe et al, NEJM 2012

42 ACCOAST study Study stopped by DSMB for excess bleeding / no ischemic benefit

43 Study population: Broad ACS population in PLATO TRITON (prasugrel) ACS/PCI, No pre treatment PLATO (ticagrelor) «All ACS» High Risk ACS patients medically managed TRILOGY Study with Prasugrel Negative study Patients with Pre treatmet before cathlab ACCOAST Study with Prasugrel Study stopped for excess bleeding /30 mg LD -No pre treatment in NSTE ACS with Prasugrel - No prasugrel in high-risk NSTE ACS medically managed

44 New P2Y12 blockers for each patients? Prasugrel or Ticagrelor?

45 First Question New P2Y12 blockers or Not?

46 Bleeding Risk High risk: Prior stroke/tia* Age > 75 y.o, Weight <60 kg Active bleeding Chronic OAC, Prior Bleeding Low risk Ischemic Risk ACS patients No prior stroke/tia/bleeding Age < 75 y.o Weight > 60 kg No Chronic OAC High risk Low risk ACS STEMI No ST changes Diabetes mellitus, CKD No Troponin elevation High-risk NSTE ACS (Tn + and/or ST changes) PCI for stable CAD Recurrent event on clopidogrel Stent Thrombosis (Patients not in Triton / Plato) Individual Decision Clopidogrel 600/150 New P2Y12 Blockers Clopidogrel 600/150 * CI Prasugrel

47 First Question New P2Y12 blockers or Not: YES Second Question Which One?

48 Good Candidates Selection of P2Y12 blockers in ACS Patients Prasugrel and Ticagrelor General Warning Contraindications High Risk NSTEMI (Both) Recurrent event/clopidogrel (Both) STEMI (Prasugrel) Diabetic patients (Prasugrel) Patients > 75 y.o (Prasugrel) Low Body Weight (< 60 kg) (Both) COPD, AV block (Ticagrelor) Chronic OAC (Both) Prior Stroke / TIA (Prasugrel) Active Bleeding Disease (Both) Patient with CKD (Ticagrelor) High Risk ACS medically treated (Ticagrelor) High ACS treated by CABG (Ticagrelor) High Risk ACS > 75 y.o or prior stroke (Tica)

49 My Practice for P2Y12 Blockers in ACS Low Bleeding Risk** STEMI High Bleeding Risk** NSTE ACS Risk Stratification: Ischemic* and Bleeding** Risks Prasugrel *** Clopidogrel Upstream LD : Clopidogrel 600 mg or Ticagrelor 180 mg Coronary Angiography / Risk stratification (2-72h) Primary PCI PCI: Ticagrelor, Clopidogrel or Prasugrel (DM) MED: Ticagrelor or Clopidogrel CABG: Ticagrelor or Clopidogrel * Tn + or significant T wave / ST changes ** OAC, age, prior/active bleeding *** Except prior stroke / TIA

50 What is yourduration of DAT after DES in your center? 1) 3 months 2) 6 months 3) 12 months 4) > 12 months 5) Tailored on PCI: Left Main? Bifurcations? Number stents? Stent Length? 6) Tailored on Patient Risk Profile: Diabetes, Previous ACS, Renal Failure

51 Data from Registries: first generation DES 3021 pts / DES / FU 18 m / 1.9 % ST 6816 pts / DES / FU 4 years / 1.2 % ST Airoldi et al. Circulation 2007 Schulz et al. EHJ 2009 No relationship after 6 months between discontinuation / ST

52 Any changes with new generation DES? Subsequent ST (ARC Def/Prob) (%) 2.0% 1.5% 1.0% 0.5% 0.68% 1.64% Never Interrupted* DAPT Interrupted 0.21% 0.0% N=10615 EES registry 0.0% First Interruption 0-3 Months First Interruption 3-12 Months No increased risk of ST if discontinuation > 3 month post PCI Oral Communication, EuroPCR 2012

53 Randomized Study: DES LATE 2701 pts / DES / FU 2 years 12 months vs > 12 months DAT No benefit of long term DAT No difference in TIMI Major bleedings Park et al. NEJM 2010

54 Randomized Study: EXCELLENT 1443 DES patients (EES vs SES) P<0.01 for non inferiority 6 m vs. 12 m DAT Non Inferiority study 4.7% 4.4% No benefit of long term DAT for TVF TVF (death, MI, TVR 12 months) No difference in TIMI Major bleedings HC Gwon, ACC 2011

55 PRODIGY Study Intent-to-stent 1:1:1:1 Balancing Randomization Xience V Taxus Endeavor BMS 30-Days Short DAPT 1:1 1 Endpoint Randomization Prologned DAPT Aspirin Clopidogrel Aspirin Clopidogrel 6 Mos * 24 Mos Valgimigli et al, Circulation 2012

56 PRODIGY Study % mo DAPT 6 mo DAPT 24 mo DAPT 6 mo DAPT Hazard Ratio: 0.98 ( ) P= Valgimigli et al, Circulation 2012

57 PRODIGY Study 24 mo DAPT 6 mo DAPT 12 % 8 P= Hazard Ratio: 0.46 ( ) P= Valgimigli et al, Circulation 2012

58 What is our usual duration of Dual Antiplatelet Therapy? 6 months is nowthe rule for PCI in stable CAD In some specific cases, longer DAT is given: PCI: Complexe Bifurcations, prior ST, N stents... Patient: ACS, Diabetic, recurrent event In some very specific cases, shorter DAT is given (3 m): Bleeding, Elderly, OAC

59 Do youthink Platelet Function Monitoring 1) Always Should be used in daily practice? 2) Never 3) In Few Selected High Risk Patients?

60 Clopidogrel :An unreliable platelet inhibition! Number of patients 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

61 Stent thrombosis and platelet reactivity 2.0 N=8575, drug eluting stent, 50% ACS and 50% stable CAD Definite/Probable ST (%) P2Y12 PRU > 208 (n=3607) P2Y12 PRU 208 (n=4834) HR=3.89 [1.90, 7.98] p <0.001 HR=3.91 (p=0.005) in ACS patients HR=1.49 (p=0.49) in non-acs patients 0.81% % Days ADAPT-DES study, Stone et al, TCT 2011

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

63 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

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

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

66 So let s test everybody and Tailor? Result of Test have clinical relevance for prognosis Doesn t mean that testing and tailored therapy improve clinical outcome!! Evidence for tailored therapy in 2013?

67 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

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

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

70 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 Non-Responder Yes PRU > 208 No Responder A N = 1075 Prasugrel arm Prasugrel LD 60 mg Prasugrel MD 10 mg QD + Clopidogrel placebo B N = 1075 Clopidogrel arm Placebo LD Clopidogrel MD 75 mg QD + Prasugrel placebo Low risk population Post PCI Platelet Testing C N = 4350 Standard Therapy Clopidogrel MD 75 mg QD N = 2,150 33% 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 Cardiol2012

71 Efficacy endpoints TRIGGER-PCI Study Prasugrel N=212 Clopidogrel N=211 Days on study treatment(median) Primary composite efficacy EP: CV death or MI 0 1 (0.5%) - Key secondary efficacy EPs: MI 0 1 (0.5%) - Rehospitalization for cardiac ischemic event 2 (0.9%) 4 (1.9%) Urgent TVR 2 (0.9%) 1 (0.5%) - Definite ST Stroke 0 1 (0.5%) - CV death p=ns All cause death 0 1 (0.5%) - Trenk et al, J Am Coll Cardiol2012 -

72 Conclusions from GRAVITAS/TRIGGER PCI No benefit of tailored therapy in low-risk PCI patients No benefit of tailored therapy after PCI (all peri PCI events missed!) Study needed with ACS patients, Rando. before testing

73 GRAVITAS / TRIGGER PCI Coronary angiogram Stent-PCI ARCTIC STUDY Coronary angiogram Rd Screening 24hrs after PCI with VerifyNow P2Y12 High platelet reactivity (PRU 230/208) Rd VerifyNow P2Y12 + ASA Drug (ASA, clopidogrel, prasugrel, GP2b3a I.) and Dose adjustments if high platelet reactivity Stent-PCI Standard of care Stent-PCI Clopi High Dose / Prasugrel 6-month FU Clopidogrel Standard Dose Stable CAD, Rando after Test Adjustment post PCI Drug and Dose adjustments if high platelet reactivity at Day month FU Standard of care 25% PCI for ACS, Test or Not Adjustment before PCI

74 Collet, Cuisset Montalescot et al, NEJM 2012

75 No benefit of monitoring compared with conventional treatment This does not support the routine use of Platelet testing (GM) Collet, Cuisset Montalescot et al, NEJM 2012

76 Limitations of ARCTIC Only 25% ACS patients Only 18% of prasugrel in patients with HPR on clopidogrel

77 Study GRAVITAS Gauging responsiveness With A VerifyNow Assay-Impact on Thrombosis And Safety Clinical Trials Identifier NCT Patients (n) ACS-PCI-DES (2783) Randomization Primary Outcome Measure Thienopyridine Therapy NEGATIVE STUDY Deem non responders defined according to a PRU 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 NCT months Elective PCI DES Use of VerifyNow TM assay for Composite end point of death, (2466) NEGATIVE STUDY P2Y and aspirin M, stroke, Urgent 12 revascularization, ST Therapy based on MD test results DANTE Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition TOPAS -1 Tailoring of Platelet Inhibition to Avoid Stent Thrombosis TRIGGER-PCI Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel NCT NCT NCT Unstable or NSTEMI PCI (442) Previous PCI or stenting for CAD (450) Coronary Artery Disease (CAD) DES (2150) Deem non responders defined according to a PRU>? Not randomized NEGATIVE STUDY Deem non responders defined according to a PRU>208 or >162 6 and 12 months CV death, nonfatal MI, TVR by PCI or CABG VerifyNow P2Y 12 TM (PRU) 6 months CV death, non fatal MI 75 mg qd v 150mg qd 600mg LD 75mg qd for 6 months Prasugrel 60/10mg vs Clopidogrel 600mg/75mg TARGET-PCI Thrombocyte Activity Reassessment and GEnoTyping for PCI NCT Non emergent PCI Guided (gene& PD) versus One year death, M, stroke, (1500) STUDY STOPPED non- guided Urgent revascularization, ST Clopidogrel (LD+MD) vs prasugrel (LD+MD)

78 Conclusion: Platelet Testing in daily practice Low Risk PCI / Stable CAD patients: - Less relationship platelet testing / clinical outcomes (ADAPT-DES ) - No benefit of tailored therapy / platelet testing (GRAVITAS, TRIGGER PCI) - No evidence for routine platelet testing, only very selected patients High Risk PCI / ACS Patients: - Relationship platelet testing / ischemic events with clopidogrel - High platelet inhibition required in High Risk Patients - New drug available with potent and predictable platelet inhibition - No Evidence for use of platelet testing (ARCTIC) - Test with new P2Y12 blockers or drug selection?

79 Use of Platelet Testing with new P2Y12 blockers?

80 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, Am J Cardiol 2012

81 Bleeding Risk Monitoring? 213 NSTE ACS patients, prasugrel 10 mg/d, post discharge bleeding Hyper Response: PRI VASP < 20% Patients with Hyper response to Prasugrel have twice higher risk of bleeding Cuisset et al, JACC int 2012

82 Do WeThink Platelet Function Monitoring Should be Mandatory? No evidence for routine use Platelet Monitoring not (yet?) ready for routine use in clinical practice, still research area But might be interesting in selected patients (stent thrombosis, bleeding event )

83 Aspirin/Clopidogrel Dosing in ACS? Aspirin < 100 mg and Clopidogrel 600/150 in PCI patients New P2Y12 blockers for which patients? According to bleeding and ischemic risk Duration of Dual Therapy after DES? 6 months is the rule Platelet Monitoring? Not Yet Ready for Routine Use

84 IV Antiplatelet therapy in ACS/PCI

85 Still Room for GPI during PCI in 2011? Elective PCI NSTE ACS STEMI

86 When do Weuse GPI for Elective PCI? 1)Bail-out therapy 2)20-50% of my Elective PCI 3)> 50% of my Elective PCI

87 Triple vs. Double therapy in NSTE ACS? Triple vs. Double therapy in STEMI?

88 Triple vs. Double therapy in NSTE ACS? Yes or no? When?

89 Benefit in old trials without P2Y12 blockers Boersma et al, Lancet 2002

90 Limitations of earlier studies No P2Y12 inhibitors: only ASA + Heparin Still room with clopidogrel loading?

91 ISAR REACT 2 study 2022 patients with High Risk NSTE ACS and Tn + or EKG changes requiring PCI Pre-treatment with high dose (600mg) clopidogrel > 2 h pre PCI Abciximab n=1012 Placebo n=1010 Primary Endpoint: death, MI, and urgent TVR within 30 days Secondary Endpoint: In-hospital major and minor bleeding Kastrati et al JAMA 2006

92 Benefit of GPIIbIIIa inhibitors on top of clopidogrel in high risk NSTE ACS patients undergoing PCI Kastrati et al JAMA 2006

93 GPI and new P2Y12 inhibitors? No scientific data available needed! High Risk NSTE ACS Pre-treatment with new P2Y12 blockers > 2 h pre PCI GPIIbIIIa inhibitors Placebo Primary Endpoint: death, MI, and urgent TVR within 30 days Secondary Endpoint: In-hospital major and minor bleeding

94 Platelet inhibition with Prasugrel n=352 Variability of response Inhibition of platelet activation / P2Y12 pathway Higher platelet inhibition with GPI in high risk patients

95 Triple vs. Double therapy in NSTE ACS? Yes or no? YES in selected high-risk patients When?

96 Triple vs. Double therapy in NSTE ACS? Yes or no? YES in selected high-risk patients When? Upstream Routine in CCU or in the cathlab (NB: Benefit of GPI only if PCI)

97 EARLY ACS Study Giugliano et al, NEJM 2009

98 In EARLY-ACS Very High Risk NSTE ACS: 84% Tn+, 62% ST changes, 30% DM Cathlab < 24h 60% patients undergoing PCI (40% without any benefit from GPI) Only 27% provisional use of GPI (< 50% patients with PCI) Giugliano et al, NEJM 2009

99 Primary Endpoint Death, MI, RIUR or TBO (%) Delayed provisional eptifibatide Routine early eptifibatide Time Since Randomization (Hours) P = % 9.3% Giugliano et al, NEJM 2009

100 Safety Results Bleeding (all patients, %) Routine Early Delayed Provisional Eptifibatide Eptifibatide (n=4686) (n=4643) TIMI major ( ) TIMI major or minor ( ) <0.001 GUSTO severe ( ) 0.97 GUSTO moderate or severe ( ) <0.001 PRBC transfusion ( ) OR (95% CI) P Giugliano et al, NEJM 2009

101 Conclusion from EARLY ACS Upstream Non Selective use of GPI in NSTE ACS: - Did Not Provide ischemic Benefit - Was associated with Higher bleeding risk These data support selective use downstream with Early Invasive Strategy

102 Wijns et al, EHJ 2010 Hamm et al, EHJ 2011

103 Triple vs. Double therapy in NSTE ACS? YES in selected high-risk patients In the cathlab before PCI selectively

104 Triple vs. Double therapy in NSTE ACS? Triple vs. Double therapy in STEMI?

105 Triple vs. Double therapy in STEMI? Yes or No? When?

106 Evidence for GPIIbIIIa in ppci Meta-analysis of 8 RCTs including 3949 pts Death at 6/12 months P= RRR 30% NNT 55 De Luca et al, JAMA 2005

107 Triple therapy for STEMI Still Room with new P2Y12 inhibitors?

108 Fabolus PRO Study 125 * * * * * %IPA to 20 µmol/l ADP Tirofiban 25µg/kg bolus ± 2 H infusion Prasugrel 60 mg P< for the trend 15' 30' 1 H 2 H 6 H H Time after Start of the Treatment 4-6 h before full prasugrel effect Primary PCI not covered Valgimigli M et al, J Am Coll Cardiol Intv 2012

109 Triple vs. Double therapy in STEMI? Yes or No? YES in most of patients (early presenters +++) No change with new P2Y12 blockers When?

110 Triple vs. Double therapy in STEMI? Yes or No? When? Prehospital or Cathlab: Facilitation?

111 Abciximab + Reteplase Abciximab No Facilitation, IIbIIIa in cathlab N=2452, FINESSE STUDY Ellis et al. NEJM 2008

112 N=2452, Abciximab Early vs. Abciximab + Half dose Lytic vs. Abciximab before PCI Ellis et al. NEJM 2008

113 Limitations FINESSE - Slow recruitment -Late STEMI (50% balloon inflation > 4h) -Long DTB delay (50% > 2h) - No P2Y12 inhibitors Ellis et al. NEJM 2008

114 High-Risk-Early Patients in FINESSE TIMI Risk Score > 3 And Delay < 4h Sub-Analysis of FINESSE Herrmann et al, JACC Int 2009

115 Risk stratification (TIMI risk score): Low Risk < 3 High Risk 3 Benefit of Facilitation in High-risk patients N=1086 Rakowski et al. AHJ 2009

116 Upstream IIbIIIa in STEMI? STEMI Guidelines, Steg et al, EHJ 2012 ESC Revasc. Guidelines Wijns et al, EHJ 2010

117 Triple vs. Double therapy in STEMI? Yes or No? When? Prehospital or Cathlab: Facilitation? Maybe: Clear Diagnosis Early (< 3-4h) High Risk (Anterior) Low Bleeding Risk / Radial No: Uncertain Diagnosis Late presentation (> 3h) Low Risk High Bleeding Risk

118 Optimal way of Administration: IC or IV?

119 154 STEMI < 12h, Randomized to IV Abciximab or IC Abciximab Primary Endpoint: Median Infarct Size with MRI % p= % 15.1% IV IC Leipzig study Thiele et al, Circulation 2008

120 AIDA-STEMI trial 2065 patients with suspected STEMI - STEMI with symptoms <12 h - Planned primary PCI - no contraindication for abciximab UFH IU/kg Aspirin 500 mg, Clopidogrel 600 mg/prasugrel 60 mg Abciximab bolus 0.25 mg/kg plus 12 h infusion µg/kg/min 1032 patients randomized to IC abciximab 1033 patients randomized to IV abciximab AIDA STEMI trial, Thiele et al, Lancet 2012

121 Clinical endpoint: Death, reinfarction, new CHF No benefit of IC administration, no harm neither AIDA STEMI trial, Lancet 2012

122 AIDA-STEMI: MRI sub-study Infarct size, %LV Infarct size Median [IQR] 16% [9, 25] p=0.52 Median [IQR] 17% [8, 25] Presence MO, % Microvascular obstruction p= % 47% 10 0 IC abciximab N=385 IV abciximab N=389 IC abciximab N=384 IV abciximab N=390 Thiele et al, TCT 2012

123 So... Hypothesis from retrospective analysis Supported by small studies / metaanalysis Not confirmed in RCT

124 Triple vs. Double therapy in STEMI? YES in most of patients regarless of oral therapy In the cathlab selectively before PCI, after angio IV or IC: No major difference

125 Thank You