in High-risk PCI Patients?

Transcription

1 Lunchtime Activities Is Potent t Oral P2Y 12 Inhibitor Enough to Prevent Thrombotic Events in High-risk PCI Patients? Young-Hoon Jeong, MD M.D., PhD Ph.D. Department of Internal Medicine, Gyeongsang National University Hospital and Gyeongsang National University School of Medicine, Jinju, Korea.

2 Disclosures Research Grants/Support Otsuka Accumetrics Boehringer-Ingelheim Haemonetics Dong-A Pharmaceutical Han-Mi Pharmaceutical Honoraria/Consulting Otsuka Sanofi-Aventis Daiichi Sankyo Inc Astrazeneca Nanosphere Haemonetics Han-Dok Pharmaceutical

3 3-Year Mortality According to Periprocedural MI 23,604 pts from 8 Korean RCTs and 3 registries (ASP+CLPD) (CK-MB > x3) HR, 1.47; P < ** HR, 1.20; p = 001: 0.01: : Adjusted for study, age, sex, DM, history of MI, PVD, CKD, ACS, EF, MVD, LM disease, bifurcation disease, stent type, and # stents. Park DW et al. Eur Heart J 2013;Feb 12.

4 Post-PCI Thrombosis is a Platelet-centric Event: Ischemic Outcomes Reduced Best by Most Potent and Reliable Agents PCI-induced Plaque Rupture Pl R t Tissue Thrombin Factor Fibrinogen Collagen vwf X Amplification Initial Activation Amplification PAR-1 ADP TxA 2 P2Y 12 TP X X Granule Secretion Activation COX-1 X GPIIb/IIIa Activation Fibrin + Platelet Aggregation Platelet-Fibrin Clot Formation Amplification Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:

5 - Variable, moderate, slow - Inhibition of P2Y12 receptor only X X Uniform potent reversible - Uniform, potent, reversible - Immediate inhibition of all agonist-induced aggregation including thrombin

6 Available Strategies of P2Y 12 Inhibition Therapeutic profile not affected by CYP, ABCB1 genetic variation Schömig A. N Engl J Med 2009;361:

7 Prasugrel vs. Clopidogrel in Stable CAD Patients Prasugrel 60 mg LD vs. Clopidogrel 600 mg LD (> 12hr before PCI) 52.9% 1.9% HPR (PRU>208) PMI (Troponin I): 23% vs. 44% P = Hamilos et al. ESC 2012.

8 GPIIb/IIIa Inhibitors Elective PCI in Era of Routine Stents and Thienopyridines: Meta-Analysis 22 studies, n=10,113 patients, routine use of thienopyridines; 30-day outcomes 30-day MI Abciximab i b Small Molecule Overall p< day Mortality Abciximab Small Molecule Overall p= day Major Bleeding Abciximab Small Molecule Overall p=0.22 Winchester DE et al. J Am Coll Cardiol. 2011;57: Minor Bleeding (GPI vs. control) = 3.0 vs. 1.7%, RR=1.70, p<0.001

9 Personalized GPIIb/IIIa Inhibitor Therapy: 3T/2R Study HPR patients n = 147 CLPD NR (< 40% inhibition) n = 23 ASA NR (ARU > 550) n = 93 ASA and CLOP NR ~ 70%: stable CAD

10 Valgimigli M et al. Circulation 2009;119:

11

12 Bivalirudin Bivalent Synthetic Direct Thrombin Inhibitor Bivalirudin Specifically inhibits Fluid phase thrombin Clot-bound thrombin Thrombin-mediated platelet aggregation g (blocks activation of PAR-1 and PAR-4 receptors): weak potency Reversible T minutes Topol EJ: Textbook of Interventional Cardiology

13 Pharmacodynamics of P2Y12 Inhibitor vs. GPI vs. Bivalirudin CLEAR PLATELETS-1 Gurbel PA et al. Circulation. 2005;111: CLEAR PLATELETS-2 Gurbel et al. J Am Coll Cardiol. 2009;53: ADP, Max) IPA (%; 20 M P-Induced ion (%) 5 M M TRAP Aggregati * Baseline * Hours * 600 mg C+B 75 mg C+B 75 mg C+B+GPI 600 C+B +GPI PRICIPLE TIMI-44 Wiviott SD et al, Circulation. 2007;116: ONSET/OFFSET Gurbel PA et al, Circulation. 2009;120: ADP, Max) IPA (%; 20 M Prasugrel 60 mg p< for each time point Clopidogrel 600 mg Hours IPA (%; 20 M ADP, Final) Ticagrelor 180mg p< for each time point 40 Clopidogrel 600 mg Hours

14 Impact of Bivalirudin vs. Abciximab in NSTEMI Patients with HPR ISAR-REACT 4 Platelet Substudy HPR: Multiplate 468 AU x min * Bivalirudin: no protective effect on post-pci events in AMI Sibbing et al. J Am Coll Cadiol 2012;60:

15 Impact of Bivalirudin vs. Abciximab+Heparin in STEMI Patients (HORIZONS-AMI) 2/3 received Pre randomization heparin. 3,602 pts with STEMI with symptom onset 12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) R 1:1 Bivalirudin monotherapy ( provisional GP IIb/IIIa) Emergent angiography, followed by triage to primary PCI, CABG or medical therapy 3006 pts eligible for stent randomization R 1:3 Paclitaxel-eluting eluting TAXUS stent Bare metal EXPRESS stent Stone GW. New Engl J Med. 2008;358: Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years

16 HORIZON AMI: Primary Outcome Measures Time in Days Time in Days 30-Day Events (% %) Heparin +GPI Bivalirudin Monotherapy ot Net Adverse Clinical Events MACE 12.2% 9.3% HR=0.75;p= Day Events (%) 5.5% 5.5% HR=1.00;p=0.98 Non-CABG Major Bleeding Mortality 30-Day Events (%) 8.4% 5.0% HR=0.59;p< Day Events (%) 31% 3.1% 2.1% HR=0.66;p=0.048

17 Definite /Probable Stent Thrombosis in HORIZONS-AMI Bivalirudin monotherapy Heparin + GPIIb/IIIaIIIa inhibitor 3 1 Day 4 1 Year 3.6% 2 HR =5.93, p = % 1.5% 2 HR =1.13, p = % 1 0.3% Time in Hours Time in days * Bivalirudin: less MACE driven by less bleeding more early stent thrombosis/pmi * How to maximize the benefit of GPI treatment? - radial approach - bolus or short-time time infusion

18 ACUITY Trial: Bivalirudin reduces Major bleeding only in femoral access Hamon M, et al. EuroIntervention. 2009;5:

19 Bolus-only or Short Infusion vs. Prolonged Infusion Study BRIEF PCI EASY Kini et al Study Type RCT, n=624 RCT, n=1005 Retrospective, n=2629 GPI Type Eptifibatide Abciximab Eptifibatide (72%) Abciximab (28) Study Population ACS or Stable CAD ACS or Stable CAD ACS or Stable CAD 32% Troponin + 20% Troponin + 14% Troponin + B2/C Coronary Lesion (%) 63% 47% 80% Duration of Infusion <2h vs. 18h bolus only vs. 12h bolus only vs h Adequate Clopidogrel 70% 92% 54% Load Before PCI (%) Bolus only or Short Infusion vs. Prolonged Infusion Death/MI/Urgent TVR at 4.8% vs. 4.5%, p= % vs. 1.8%, p=ns 3.2% vs. 3%, p= days Major Bleeding 1.0% vs. 4.2%, p= % vs. 0.2% p=ns 0.8% vs. 1.6%; p=0.09 Minor Bleeding 17.6% vs. 21.2%, 2% p=0.31 N/A 1.1% 1%vs. 2.2%; 2%;p= Hanna EB et al. J Am Coll Cardiol Intv. 2010; Fung AY et al. J Am Coll Cardiol. 2009;53: (BRIEF-PCI) Bertard OF et al. Circulation 2006;114: (EASY) Kini AS et al. Am Heart J. 2008;156:513-6

20 Characteristics of Glycoprotein IIb/IIIa Inhibitors Kristensen et al. Thromb Haemost 2012;107:

21 (High-dose bolus, HDB)

22 Reversibility of Glycoprotein IIb/IIIa Inhibitors Small Molecules vs. Abciximab 100 ation (%) et Aggrega Platele Eptifibatide (~4hrs) Tirofiban (~4 hrs) Abciximab (~36 hrs) Hours drug discontinuation Adapted from Tantry US and Gurbel PA. Future Cardiol. 2006;2:

23 Abciximab vs. HDB Tirofiban in Primary PCI STEMI all-comer Patients Aspirin + Clopidogrel + UFH Before Arterial Sheath Insertion 1:1 Valgimigli et al, JAMA 2008 Tirofiban* Abciximab 1:1 1:1 SES BMS SES BMS Coronary Angiography PCI Clinical FU 1, 4, 8 ms, 1yr and then yearly up to 5 Stenting was the default strategy in pts with a RVD 2.5 mm at visual estimation *: given as a bolus of 25 g/kg, followed by an hour infusion at 0.15 g/kg/min

24 30-Day Outcomes 4% 4 Stent P=0.85 Efficacy Endpoints (CEC adjudicated) di d) Abciximab P=0.98 Tirofiban Stent Thrombosis (ARC) 25%2. 2.5% 5 P=0.59 P=0.22 P=0.56 1% 1 MACE Death/MI utvr Definite Def/Prob -0.5

25 30-Day Outcomes 8 8% 6 6% Safety Endpoints (DSMB adjudicated) di d) P=0.40 Abciximab Tirofiban P= % P=0.44 P=0.82 P= % 0%0 Major Minor TIMI-Bleeding RBC Tranfusion Severe Any Thrombocytopenia -2

26 Small Molecule vs. Abciximab Administration Primary PCI: Meta-Analysis 6 RTs, n=1086 abciximab vs small molecules (only high-dose bolus and infusion) 30-day Mortality 30-day Secondary Outcomes OR (95% CI) Reinfarction 0.94 (0.44, 2.04) Post-procedural TIMI flow Grade (0.80, 1.39) ST-segment resolution 0.96 (0.78, 1.17) De Luca et al. J Am Coll Cardiol. 2009;53:

27 Pharmacodynamics of 600mg Clopidogrel LD in STEMI Pts Undergoing PPCI VASP-P P assay between 6 ~ 12 h after 600mg clopidogrel LD STEMI Pts = Non-responder to P2Y 12 Inhibitor Predictors of HPR OR Age 1. Splanchnic and liver (per hypoperfusion 10 yr) by hemodynamic HPR instability: BMI (kg/m2) % drug dugabsopto absorption and metabolism 95% CI P < Diabetes Omeprazole Catecholamine release and use: STEMI (vs. platelet baseline reactivity 2.14 and 1.30 turn-over SAP UA/NSTEMI STEMI (n=344) (n=339) (n=150) N=344 N=339 N=150 UA/NSTEMI) Fibrinogen < Bonello L, et al. Thromb Haemost Apr 26;108(1).

28 Ticagrelor vs. Prasugrel in STEMI Patients (180 mg LD/90 mg bid MD vs. 60 mg LD/10 mg QD MD) (180 mg LD/90 mg bid MD vs. 60 mg LD/10 mg QD MD) PPCI HPR point Alexopoulos D, et al. Circ CV Interv 2012;5:

29 Pharmacodynamic Effect of Prasugrel Alone vs. Prasugrel + HDB Tirofiban Infusion in STEMI Pts FABOLUS PRO Study (n = 100): Prasugrel 60mg LD Tirofiban 25 µg/kg bolus Tirofiban 0.15 µg/kg/min 2 hr infusion Prasugrel LD + GPI bolus obviates the need of continuous infusion and almost completely abolishes platelet activation. Valgimigli M, et al. JACC Cardiovasc Interv. 2012;5:

30 Eptifibatide IC vs. IV in STEMI (ICE Trial) IC versus IV bolus (2 x Bolus within 10 min. 180 μg/kg Eptifibatide), Followed by 2 μg/kg/min continuous infusion i.v. for 18 h IPA periphery (20 μmol/l ADP) GPIIb/IIIa receptor-blockade P= P=0.013 P=0.995 P<0.001 P=0.001 %IPA IC Eptifibatide n=21 30 IV Eptifibatide n=19 % Receptor-Blo ockade Baseline 15 min 30 min 60 min 0 post Bolus post Bolus post Bolus Bolus 1 Bolus 2 Bolus 1 Bolus 2 Peripheral blood Coronary sinus blood Deibele et al. Circulation 2010;121:

31 IC Bolus-only vs. IV Bolus+Infusion Tirofiban in STEMI Patients Tirofiban 25 μg/kg IC bolus only versus IV bolus+ 0.15μg/kg/min infusion IV for 18 h IMR ctfc 50 P=0.08 IC Tirofiban n=25 IV Tirofiban n=24 P= Kirma et al. Cath Cardio Interv 2012;79:59 67.

32 IC vs. IV Abciximab Infusion in STEMI All-cause Death 7 studies, n=3,311 patients, median follow-up of 3 months Recurrent MI Kubica et al. Cardiol J 2012;19:

33 INFUSE-AMI Trial 452 pts with anterior STEMI Anticipated i t Sx to PCI <5 hrs, TIMI 0-2 2fl flow in prox or mid idlad Primary PCI with bivalirudin anticoagulation Pre-loaded with aspirin and clopidogrel 600 mg or prasugrel 60 mg Manual aspiration R 1:1 Stratified by symptoms to angio <3 vs 3 hrs, and prox vs mid LAD occlusion No aspiration R 1:1 R 1:1 IC Abcx No Abcx IC Abcx No Abcx Primary endpoint: Infarct size at 30 days (cmri) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30d 30d, 1 yr) Stone et al. JAMA 2012;307:

34 Infarct size at 30 days by CMR Median [IQR] 15.1% [6.8, 22.7] Median [IQR] 17.9% [10.3, 25.4] %LV rct size, % Infar P=0.03 Localized infusion of IC abciximab bolus only through the drug delivery balloon (ClearWay rx) reduced d infarct size: 15.6% versus no abciximab arms IC abciximab N=188 No abciximab N=184 N=184 Stone et al. JAMA 2012;307:

35 Conclusions * Common indications for GPI use during PCI Clinical setting Indications Non-acute patients NSTE-ACS STEMI No pretreatment with or Poor response to P2Y12 inhibitor Bail-out situations (thrombus formation, vessel closure, etc.) No pretreatment with or Poor response to P2Y12 inhibitor High-risk patients (complex lesions, large thrombi, elevated troponin levels). Bail-out situations (thrombus formation, vessel closure, etc.) High-risk patients (early phase after antiplatelet therapy LD, complex lesions, large thrombi, haemodynamically compromised patients). In the era of potent P2Y 12 receptor inhibitor, GPI bolus (through IC delivery system) +/- short-term term IV infusion in high-risk patients: post-pci ischemic events w/o serious bleeding

36 Interaction of Haemostatic Components for PCI-related Thrombosis 100% Most thrombogenic environment: Intensified control will save lives! Activity Stent-Artery t At Interaction ti Platelet Activation Procoagulant Activity Inflammation Early Late Very Late Balanced Control Safety & Biologic i Control