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Updated Guideline of Glycoprotein Iib/Iiia Inhibitor for Acute Coronary Syndrome

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Updated Guideline of Glycoprotein Iib/Iiia Inhibitor for Acute Coronary Syndrome Updated Guideline of Glycoprotein IIb/IIIa Inhibitor for Acute Coronary Syndrome Young-Hak Kim, MD, PhD Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 1 Disclosure Information Honorarium from Handok Corp Clinical Classification of ACS Acute Coronary Syndrome Hx EKG No ST Elevation ST Elevation Cardiac Biomarker Final Unstable Non- Dx STEMI Angina STEMI 3 Platelet Activation Epinephrine Collagen ADP Thrombin AA Thienopyridines Aspirin Platelet TxA2 GP IIb/IIIa Platelet GPIIb/IIIa inhibitors Membrane Fibrinogen Target Sites of Antiplatelet Therapy Disruption of Shear Stress, Prostaglandins Endothelium Binding of Agonists: Direct GPlb/vWF Platelet l Thrombin Antithrombins Antagonists, Adhesion Dipyridamole Serotonin l Serotonin Antagonists Platelet Activation Clopidogrel l ADP Ticlopidine Aspirin, Platelet TxS Inhibitors Release TXA Receptor l TXA 2 2 Antagonists l Others GPllb/llla Platelet GP = Glycoprotein Antagonists Aggregation vWF = von Willebrand factor TxS = Thromboxane synthase TXA2 = Thromboxane A2 Schafer AI. Am J Med. 1996;101:202. Parenteral GP IIb/IIIa inhibitors Antibody • abciximab (ReoProâ, Centocor/Lilly) Cyclic peptide • eptifibatide (INTEGRILIN®, COR/Key) Nonpeptide • tirofiban HCI (Aggrastatâ, Merck) GP IIb/IIIa Receptor Antagonists Abciximab Tirofiban Eptifibatide (ReoPro®) (Aggrastat®) (Integrilin®) Fab portion of Pharma chimeric monoclonal Synthetic non-peptide Cyclic heptapeptide antibody Half-life 30 minutes 1.8 hours 2.5 hours Renal Adj. No Yes Yes Dosage 0.25 mcg/kg bolus 0.4 mcg/kg/min for 30 180 mcg/kg bolus (x2) followed by minutes followed by followed by 0.125 mcg/kg/min drip 0.1 mcg/kg/min drip 2.0 mcg/kg/min drip (max 10 mcg/min) for for 48-96 hours for 18-24 hours 12-24 hours Early Abciximab PCI Trials Death, MI, Urgent Revascularization – 30 Days EPIC EPILOG EPISTENT Placebo 12.8 12 Bolus Placebo 11.7 Placebo + Stent 10.8 8 8.3 Abciximab + PTCA 6.9 Bolus + Infusion Abciximab 5.2 Abciximab + Stent 5.3 4 Absolute - 4.5% Absolute - 6.5% Absolute - 5.5% Relative – 35% Relative – 55% Relative – 51% p = 0.008 p < 0.001 p < 0.001 0 30 30 30 0 Days 0 Days 0 Days NEJM 1994; 330:956-61 NEJM 1997; 336:1689-96 Lancet 1998; 352:87-92 For STEMI Primary PCI 30 Day Death, MI or Urgent TVR 20 ¯ 48% ¯ 52% ¯ 52% ¯ 30% ¯ 57% p = 0.03 p = 0.04 p = 0.01 p = 0.02 p = 0.02 14.6 15 11.2 10.5 10.5 10 6.9 6.0 5.8 5.0 4.5 4.5 % ofPatients % 5 0 RAPPORT ISAR-2 ADMIRAL CADILLAC* ACE** n = 483 n = 401 n = 300 n = 2082 n = 400 Circ 1998; JACC 2000; NEJM 2001; NEJM 2002; 98:734-41. 35:915-21. 41:1895-03. 346:957-66 Placebo Abciximab FINESSE – 90-Day Endpoints 12 10.710.5 9.8 10 8.9 8 7.5 7.4 6 5.5 5.2 4.5 Percent 4 2.9 2.2 1.9 2 0 Composite* Death MI Comp CHF Primary PCI (806) PCI+Abcix (818) PCI+Abcix+Reteplase (828) *All-cause mortality; rehosp or ED visit for CHF; VF >48 hours after randomization; cardiogenic shock. N=2452. Ellis S. ESC N Engl J Med 2008;358:2205 FINESSE – 90-Day Bleeding *** ** *** ** 16 14.5 14 12 10.1 * 9.7 10 8 6.9 6 Percent 6 4.8 4.1 4.3 4 2.6 2 0 Overall TIMI Major TIMI Minor Primary PCI (806) PCI+Abcix (818) PCI+Abcix+Reteplase (828) * p= 0.025. ** p < 0.01. *** p < 0.001 Ellis S. ESC N Engl J Med 2008;358:2205 CARESS Abciximab with ½ Dose Reteplase P=0.001 P=0.032 14 12.2 12 11.1 10 8 7.4 6 5 Percent 4.1 4.4 3.7 4 3.1 1.7 2 2 0.3 0.7 0 Composite Death Re-MI Ischemia Bleed Transfuse Immediate PCI (N=298) Rescue PCI (N=300) Composite = 30-day Death, Re-MI, Refractory ischemia. N=600 Di Mario C. Lancet 2008; 371: 559–68 On-TIME 2: Study Design STEMI diagnosed in ambulance or N=984 Jun 2006–Nov 2007 referral center ASA + 600 mg clopidogrel + UFH Placebo HDB Tirofiban* Transportation Angiogram PCI center Angiogram Provisional PCI Tirofiban HDB Tirofiban cont’d *Bolus: 25 µg/kg and 0.15 µg/kg/min infusion. van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46 BRAVE-3 Abciximab before Primary PCI 30-day Death, MI, Revas, and Stroke Mehilli et al. Circulation. 2009;119 On-TIME 2 Pre-hospital High Dose Tirofiban ST-Resolution Time P=0.033 P=0.020 P=NS P=NS P=NS Pre-treated with aspirin, heparin & 600 mg clopidogrel (Complete) post-PCI Bleeding Composite: death, recurrent MI, urgent revascularization Lancet. 2008;372:537 IIB/IIIa Meta-regression 30-Day Mortality De Luca G. et al. Eur Heart J 2009;30:2705 GP IIb/IIIa Guideline for STEMI 2009 Early invasive / PCI Medical Management ACC / AHA ESC ACC / AHA ESC Class IIa Class I Class IIb Class III Abciximab Without stenting Abciximab with half-dose lytic for patients age < 75 years Class IIb Class IIa Tirofiban, With stenting eptifibatide GPI = glycoprotein IIb/IIIa inhibitor For UA / NSTEMI Medical vs Interventional Therapy 30-day Death or MI – No Early PCI 20% p=NS Placebo 2b3a Inhibitor 15.6% 14.5% 15% p=NS P=NS 11.3% 10.8% p=NS 10.1% 10% 8.7% 7.8% 8.0% 5% 0% PURSUIT PRISM PLUS PARAGON B GUSTO-IV ACS Medical vs Interventional Therapy 30-day Death or MI – Early PCI P<0.05 Placebo 20% p=0.01 18.5% 16.7% 2b3a Inhibitor 15% p=NS 11.6% 11.6% p=0.03 10.2% 10% 9.0% 5.9% 4.8% 5% 0% PURSUIT PRISM PLUS PARAGON B CAPTURE ISAR-REACT PCI for Low-risk SA Patients – 30 Days Placebo Abciximab 10% p=NS p=NS p=NS p=NS 5% 3.8% 3.7% 4.0% 4.0% 0.9% 0.3% 0.3% 0.6% 0% Death MI Death/MI Urg Revac NEJM 2004;350:232-8 ISAR-REACT 2 PCI for Higher-risk ACS Patients – 30 Days p=0.06 p=0.03 11.5% Placebo (1012) 10.5% Abciximab (1010) 10% 8.6% p=0.34 8.1% p=0.64 5% 1.6% 1.1% 1.2% 1.0% 0% Death MI Death/MI Urg Revac JAMA 2006;295:1531-38 ISAR-REACT 2 Higher-risk Patients (ACS) – 30 Days JAMA 2006;295:1531-38 EVEREST: Study Design • Angina at rest within 12 h of admission • Unequivocal changes on ECG during angina High-risk • cTnI elevation NSTEMI ACS “In-Lab” “In-Lab” “Upstream” Tirofiban Abciximab HDB Tirofiban ASA/heparin ASA/heparin ASA/heparin thienopyridine thienopyridine thienopyridine tirofiban Intent to PTCA/stent Intent to PTCA/stent Intent to PTCA/stent 24 - 48 hours 24 - 48 hours 24 - 48 hours + Abciximab + HDB tirofiban HDB, high dose bolus J Am Coll Cardiol. 2006;47(3):522-528. EVEREST Tissue-Level Perfusion by TMPG Pre-PCI Post-PCI n=93 P=.0009 P=.015 TMPG 0/1 (%) TMPG 0/1 (%) Upstream HDB Abciximab Upstream HDB Abciximab Tirofiban Tirofiban Tirofiban Tirofiban TMPG, TIMI perfusion grade Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522. EVEREST Tissue-Level Perfusion by Myocardial Contrast Echocardiography MCE score index Normal tissue-level n=93 perfusion by MCE P=.04 P=.012 MCE ScoreMCE Index Patients Perfused (%) Upstream HBD Abciximab Upstream HBD Abciximab Tirofiban Tirofiban Tirofiban Tirofiban Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522-528. EVEREST Peak cTnI Levels Post-PCI n=93 P=.0002 P=.015 ng/mL Upstream HBD Abciximab Tirofiban Tirofiban Bolognese L, et al. J Am Coll Cardiol. 2006;47(3):522-528. ACUITY Timing Moderate-high risk ACS undergoing invasive strategy (N=13,800) PCI in 57% JAMA. 2007;297:591 ACUITY Timing Ischemic Composite Ischemic Death MI Unplanned rev composite for ischemia JAMA. 2007;297:591 ACUITY Timing Major Bleeding JAMA. 2007;297:591 EARLY-ACS: Primary Endpoint Invasive Strategy 15 Death, MI, Urgent revasc., Thrombotic events Delayed provisional Early routine eptifibatide eptifibatide N 4684 4722 # Events 469 439 10.0% 10 Delayed provisional eptifibatide 9.3% P = 0.23 (stratified for intended early 5 clopidogrel use) Early routine eptifibatide Death, MI, RIUR or TBO(%) MI,RIUR Death, or 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 Time Since Randomization (Hours) Giugliano et al. N Engl J Med 2009;360 Early-ACS: 30-day Death or MI 15 39% use of eptifibatide 12.4% Delayed provisional eptifibatide 10 11.2% P = 0.079 (stratified for intended early clopidogrel use) Death or (%) MI Death Early routine eptifibatide 5 Delayed provisional Early routine eptifibatide eptifibatide N 4684 4722 # Events 578 528 Days to Event 2.1 (1.0, 5.8) 2.7 (1.0, 4.9) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Time Since Randomization (Days) Giugliano et al. N Engl J Med 2009;360 GP IIb/IIIa Guideline for UA / NSTEMI 2009 Early invasive / PCI Medical Management ACC / AHA ESC ACC / AHA ESC Class I Class I Class I Class II Either GPI or clopidogrel in (high risk) If subsequent recurrent (high risk) addition to aspirin should be symptom/ischemia, heart failure, or initiated before angiography serious arrhythmia occur, angiography should be performed with upstream Class IIa use of either clopidogrel or GPI Reasonable to initiate antiplatelet therapy with both Class IIa GPI and clopidogrel If recurrent ischemic discomfort with clopidogrel, it is reasonable to add a GPI before angiography Class IIb May be reasonable to add GPI to oral antiplatelet and anticoagulant therapy GPI = glycoprotein IIb/IIIa inhibitor ICE Trial Intracoronary Injection of Eptifibatide 180-g/kg eptifibatide IC bolus Pre-PCI Post-PCI Circulation.
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