Slide 32 Initially, intracoronary administration of streptokinase was shown to provide a substantial reduction in mortality, but the logistic limitations of this approach lead to the pursuit of IV fibrinolytic administration. Subsequently, several large-scale placebo-controlled trials established the unquestionable mortality benefit associated with IV fibrinolytic therapy. The GISSI trials demonstrated that streptokinase produced an 18% reduction in inhospital mortality versus standard therapy. 1 The TIMI trial showed a 60% patency rate in patients who received alteplase compared to 35% of those who received streptokinase (P<0.001). 1 In GUSTO-I, 54% of patients administered alteplase achieved TIMI-3 flow compared with 32% to those given streptokinase and IV heparin. 1 GUSTO-I was instrumental in defining the link of 90-minute epicardial flow and mortality reduction. Considering its widespread availability and the ability to administer it in the absence of highly trained specialists, fibrinolytic monotherapy is the current mainstay treatment for ST elevation MI. 1. Roberts C. Have we reached the therapeutic ceiling in acute myocardial infarction? Crit Care Nurse . 1999;(Suppl):7-11.
Slide 33 The GUSTO-I trial, comparing front-loaded alteplase with streptokinase and a streptokinase and alteplase combination was instrumental in defining the link of 90-minute epicardial coronary artery flow and mortality reduction. This study was fundamental in spurring the development of novel fibrinolytic agents with greater efficacy and longer half-lives, developments that have been facilitated by the advent of genetic technologies. 1,2 GUSTO-I compared front-loaded alteplase (15 mg bolus, 0.75 mg/kg for 30 minutes, then 0.5 mg/kg for 60 minutes) with streptokinase (1.5 million U with either IV or sub-Q heparin) or alteplase (1 mg/kg infusion for 60 minutes) plus streptokinase (1.0 million U) among 41021 patients with ST-segment-elevation MI. Beyond demonstrating a superior mortality reduction of front-loaded alteplase compared with streptokinase or the combination of streptokinase and alteplase, this study provided insights into the importance of time to treatment and the connection between infarct vessel patency, preservation of ventricular function, and mortality reduction. Patients treated within the first two hours of symptom onset experienced the lowest rate of 30-day mortality, (5.5% vs 9.0% among those treated after 4 hours). This equates to a 1% increase in mortality with each additional hour of delay between symptom onset and treatment initiation, between 2 to 6 hours. This association was confirmed within a subsequent meta-analysis demonstrating the greatest mortality gains (30% reduction in mortality at 30 days) associated with treatment within the first hour of symptom onset, with a progressive attenuation of 1.6 lives per 1000 lost with each hour of delay. 3 1. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med . 1993;329:673-682. 2. Weaver WD. The role of thrombolytic drugs in the management of myocardial infarction. Comparative clinical trials. Eur Heart J . 1996;17 Suppl F:9-F15. 3. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet . 1994;343:311-322.
Slide 78 Evidence is accumulating that platelet GP IIb/IIIa inhibition, specifically with abciximab, is effective in reducing adverse ischemic events in patients with AMI whether it is used in combination pharmacotherapy with fibrinolysis, periprocedurally before PCI, or with stenting. The clinical trials surveyed range from the mid-1990s through 2000.
Slide 79 In a substudy of patients from the EPIC trial who received direct or rescue PTCA for AMI, Lefkovits and coworkers reported significant reductions in the primary composite end point of death, reinfarction, repeat intervention, or bypass surgery. Outcomes were assessed at 30 days and 6 months. Baseline characteristics were similar in direct and rescue PTCA patients. In a pooling of the two patient groups, abciximab bolus and infusion reduced the primary composite end point by 83% (26.1% placebo vs 4.5% abciximab bolus and infusion, P =0.06). No reinfarctions or repeated urgent interventions occurred in the abciximab bolus and infusion patients at 30 days, although there was a trend toward more deaths in these patients. At 6 months, ischemic events were reduced from 47.8% with placebo to 4.5% with abciximab bolus and infusion ( P =0.002), particularly reinfarction ( P =0.05) and repeat revascularization ( P =0.002). The investigators concluded that adjunctive abciximab therapy during direct and rescue PTCA following AMI decreased acute ischemic events and clinical restenosis in this subset of patients from EPIC. 1 1. Lefkovits J, Ivanhoe RJ, Califf RM, et al. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. EPIC investigators. Am J Cardiol . 1996;77:1045-1051.
Slide 100 This slide shows the 30-day results in the composite end point of death, reMI or urgent TVR in RAPPORT. The composite end point was reduced by nearly half (48%) from 11.2% to 5.8%, an absolute reduction of 5.4%, which was significant. Death or recurrent MI was reduced from 5.8% to 4.6% ( P =NS). Urgent intervention was reduced from 6.6% to 1.7% ( P =0.007). 1,2 O’Shea C, Tcheng JE. Platelet glycoprotein IIb/IIIa integrin inhibition in acute myocardial infarction. J Invas Cardiol . 1999;11:494-499. Brener SJ, Barr LA, Burchenal JEB, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation . 1998;98:734-741.
Slide 44 Overall, while the several aspects of the combined fibrinolytic and GP IIb/IIIa inhibitor reperfusion strategy remain to be clarified, the paradigm shift towards platelet inhibition among reperfusion strategies for ST-elevation MI promises to provide clinically important reductions in mortality. Furthermore, therapies targeting platelet inhibition will also enable combined pharmacological and catheter-based reperfusion approaches, offering optimal treatment to a larger proportion of patients.
Slide 43 TIMI-14, SPEED, and other investigations have provided the foundation for GUSTO-V and other studies of reduced-dose fibrinolysis and GP IIb/IIIa inhibition currently being planned. The results from GUSTO-V are eagerly awaited and promise to provide the definitive link between fibrinolysis, platelet inhibition, microvascular perfusion, and mortality reduction. However, several issues remain to be clarified. First, while heparin (or alternate forms of antithrombin therapy) is an essential component of combination pharmacotherapy, it is also linked to bleeding risk. Evidence indicating the optimal dosing of unfractionated heparin added to combined fibrinolysis and GP IIb/IIIa inhibition is conflicting and may depend on the fibrin specificity of the fibrinolytic agent plus the ability of the GP IIb/IIIa inhibitor to suppress thrombin generation. 1,2 Secondly, the clinical importance of the differences among GP IIb/IIIa antagonists with respect to potency, effects on the other adhesion molecules such as MAC-1 and the vitronectin receptor, and efficacy in protecting the microvasculature are uncertain. 3 These issues may require study designs beyond that incorporated within GUSTO-V. Finally, the safety and efficacy of early invasive management is promised by a strategy founded on potent platelet inhibition. 4 Validation of this concept is still awaited. 1. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation . 1999;99:2720-2732. 2. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Circulation . 2000;101:2788-2794. Coller 3. Coller BS. Potential non-glycoprotein IIb/IIIa effects of abciximab. Am Heart J . 1999;138:S1-S5. 4. Brodie BR, Stuckey T, Hansen C, et al. Benefits of reperfusion prior to intervention un outcomes after primary angioplasty for acute myocardial infarction. Am J Cardiol . 1998;85:13-18 .
Slide 110 At 14-day follow-up, peak flow velocity was 18.1 for the stent-plus-abciximab group versus 10.4 for the stent-only group, while wall motion index was 0.44 versus 0.15, respectively. In addition, the stent-plus-abciximab patients had improved recovery in global LVEF (62% stent-plus-abciximab vs 56% stent-only; P =0.003). These observations suggest that suggest that abciximab enhanced microvascular perfusion and the recovery of contractile function in the distribution of the IRA. 1 1. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation . 1998;98:2695-2701.
Acute Myocardial Infarction are Thrombolitics Enough ?
Acute Myocardial Infarction are Thrombolitics Enough ? Augustin J. DeLago M.D.,F.A.C.C. Director,Catheterization Laboratory Director,Invasive Cardiology The Heart Institute Albany Medical Center
Management Strategies in AMI Early evidence of reduced mortality after IC SK Evidence of mortality benefit after IV SK (GISSI) <ul><li>GUSTO-I, TIMI: </li></ul><ul><li>Lytics, 90-min CBF reduce mortality </li></ul><ul><li>New lytics created </li></ul>
GUSTO-I: The Benefit of Reperfusion 8.9 4.4 TIMI 2 TIMI 0-1 30-day mortality (%) 7.4 TIMI 3 90-minute angiography P =0.08 P =0.009 Patency ~ Mortality Ross AM et al. N Engl J Med. 1993;329:1615–1622. <ul><li>The Open Artery Hypothesis </li></ul><ul><li>Reperfusion of the IRA results in LV preservation </li></ul><ul><li>Open the artery early to improve outcomes </li></ul>10 8 6 4 0 2
Innovations in the Management of AMI <ul><ul><li>• Mortality ceiling (6% to 7%) </li></ul></ul><ul><ul><li>• Successful reperfusion (45% to 60%) </li></ul></ul><ul><ul><li>• ICH risk (0.5% to 1.5%) </li></ul></ul><ul><ul><li>• Approximately 40% of patients do not achieve TIMI-3 flow at 90 minutes </li></ul></ul><ul><ul><li>• Critical time dependence for reperfusion to achieve optimal outcomes </li></ul></ul>Limitations of Fibrinolysis
GP IIb/IIIa Inhibitors Steric hindrance Nonspecific Binds with 3 chain on GP IIb/IIIa, v 3 Competitive blockade Highly specific for GP IIb/IIIa Mimic amino acid sequences Abciximab Small molecule Artist’s conception
<ul><li>Binding Competitive Competitive </li></ul><ul><li>Half-life Plasma ~2 h ~2 h <10 min Biologic ~2 h ~2 h Days </li></ul><ul><li>Clearance Renal Renal Renal/Spleen </li></ul>GP IIb/IIIa Inhibitors Eptifibatide Abciximab Tirofiban
GP IIb/IIIa Inhibitors Benefits of GP IIb/IIIa Inhibition in AMI: Review of Clinical Trials
EPIC: AMI Subset – Post Hoc Analysis Lefkovits J et al. Am J Cardiol. 1996;77:1045–1051. Death/re-MI/urgent TVR (%) 30 days 6 months 26.1 21.1 4.5 47.8 32.3 4.5 P =0.06 P =0.002 83% 91% 0 10 20 30 40 50 60 70 80 90 100 Placebo (n=23) Abciximab bolus (n=19) Abciximab bolus + infusion (n=22)
TIMI 3 Flow : 90 min TIMI 14 tPA + rPA Phases 215 148 88 tPA 50 mg rPA 5 + 5 U % Pts n = Full Dose Lytic 50% Lytic+ Abx 87 tPA 100 mg rPA 10 + 10 U p=0.014
Abciximab Improves ST Res-90 min de Lemos et al AHA 1999 Complete (> 70%) ST Res P<0.0005 N=179 N=329 tPA + rPA pooled TIMI 14
<ul><ul><li>GP IIb/IIIa Inhibitors in Primary PTCA </li></ul></ul><ul><li> RAPPORT </li></ul>Objective Evaluate safety and efficacy of abciximab as adjunctive therapy to primary PTCA <ul><li>End Points </li></ul><ul><li>Primary: Composite of </li></ul><ul><li>any-cause death, recurrent MI, repeat TVR within 6 months </li></ul><ul><li>Secondary: Composites of death, MI, urgent TVR at 7 days and 30 days </li></ul>Brener SJ et al. Circulation. 1998;98:734–741.
RAPPORT 30-Day End Points (Intent-to-Treat) P =0.03 % of Patients Death, re-MI, or urgent intervention Urgent intervention Death or re-MI P =0.52 P =0.006 11.2 5.8 5.8 4.6 6.6 1.7 Placebo (n=242) Abciximab (n=241) 48% 74% Brener SJ et al. Circulation. 1998;98:734–741. 0 5 10 15
PCI with Adjunctive GP IIb/IIIa N: 64 392/83 200 403 300 Random: No No Yes Yes Yes PCI: PTCA PTCA Stent PTCA Stent P : 0.06 0.04 0.03 <0.05 <0.05 26.1 4.5 9.7 3.6 9.2 2 11.2 5.8 15.3 7.3 0 10 20 30 Control Abciximab 30-d Mortality, MI, Urgent ReV Percent Trial EPIC GUSTO-III Neumann RAPPORT ADMIRAL .
Lysis vs Primary PTCA 6.5 2.6 7 1.0* 3.6 4.3 7 5.7 5.6 5.5 11.9 8.7* 6.5 4.4* PAMI ZWOLLE MAYO GUSTO-IIb MITI CCP Weaver Lytic PTCA * P <0.05 30-d Mortality or Discharge N 395 395 103 1138 3145 20,683 2606 Herrmann HC. Am J Cardiol. 2000;85:10C-16C. Percent 0 5 10 15
Reperfusion in AMI FIBRINOLYSIS PRIMARY PTCA <ul><li>Reduces mortality </li></ul><ul><li>Well studied </li></ul><ul><li>Widely available </li></ul><ul><li>Lower mortality </li></ul><ul><li>Anatomic definition </li></ul><ul><li>Avoids hemorrhage </li></ul>
Facilitated Percutaneous Coronary Intervention: Evidence for the Efficacy of a New Approach
Potential Benefits of Facilitated PCI <ul><li>May be cost-effective if combination pharmacologic therapy lessens the need for PCI </li></ul><ul><li>Improves patient stability during intervention </li></ul><ul><ul><li>Patients with open arteries have less shock, IABP, pacemaker, arrest </li></ul></ul><ul><ul><li>Higher technical success due to less hectic procedure, better distal vessel visualization </li></ul></ul><ul><li>Fuses best aspects of fibrinolysis and primary PCI </li></ul><ul><ul><li>Earlier and greater TIMI-3 flow rates </li></ul></ul><ul><ul><li>May improve myocardial tissue perfusion </li></ul></ul>
SPEED: Study Population Nonqualifying PCI (n=43) SPEED study (n=528) Primary end point = TIMI-3 flow Dose-finding (n=305) Confirmation (n=223) 60-90 min angiogram (n=466) No early PCI (n=162) Facilitated PCI (n=323) Abciximab + reteplase Abciximab + reteplase (5+5 U) vs full-dose reteplase (10+10 U) Herrmann HC et al. J Am Coll Cardiol . 2000;36:1489–1496.
TIMI Grade 3 Flow at 60-90 Min Angiographic Core Lab Reading r-PA Alone 60 U Hep Abciximab + r-PA 5 + 5 40 U Hep Abciximab + r-PA 5 + 5 p = 0.2 n = 107 n = 103 n = 75 n = 66 Abciximab Alone p = 0.06 SPEED ACC 1999: Oral Presentation
SPEED: Clinical Success Early PCI No Early PCI 0 10 20 30 94.4% 83.8% P <0.05 Percent Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496. Days Freedom From Mortality, MI, Urgent ReV at 30 days 80 85 90 95 100
Results in a Perspective 31% 54% 0% 25% 50% 75% 100% SK t-PA Abciximab r-PA 5 + 5 GUSTO-1 90-min Meta-analysis 60-min SPEED 60-min 23% 23% 14% p < 0.001 p = 0.06 ACC 1999: Oral Presentation
Trial Protocol (n = 16,600) ST , lytic eligible, < 6 h ASA No Abciximab 2 x 10 U bolus (30’) Reteplase Abciximab* Low Dose Heparin: 60 U/kg bolus followed by a 7 U/kg/h infusion 1º endpoint: mortality at 30 days 2º endpoint: clinical and safety events at 30 days 2 x 5 U bolus (30’) Reteplase Standard Heparin: 5,000 U bolus followed by either 800 U/hr (pts < 80 kg) or 1,000 U/hr (pts > 80 kg) infusion * 0.25mg/kg bolus followed by 0.125 g/kg/min infusion for 12 hours GUSTO-IV AMI
Suggested Treatment Strategy Abciximab Low Dose Heparin: 60 U/kg bolus followed by a 7 U/kg/h infusion Half Dose Lytic URGENT PCI IF PERSISTENT CHEST PAIN OR ST ELEVATION
Future Studies <ul><li>FASTER </li></ul><ul><li>ASSENT III </li></ul><ul><li>GUSTO V - MI </li></ul><ul><li>INTEGRITI </li></ul><ul><li>FINESSE </li></ul>TNK + Tirofiban Phase IIb [ Spring 2001 ] TNK + Abciximab TNK + heparin TNK + LMW heparin approx 6000 pts Phase IIb [ Spring 2001 ] r-PA + Abciximab r-PA + heparin 16,600 pts Phase III [ Spring 2001 ] TNK + Eptifibatide Phase IIb [ Starting now ] Abciximab + PCI Abciximab + r-PA + PCI 2700 pts; starting now
Summary <ul><li>Several aspects of combined fibrinolytic and GP IIb/IIIa inhibition reperfusion strategy remain to be clarified </li></ul><ul><li>Further reductions in mortality should be expected with more inclusion of platelet inhibition in reperfusion strategies for ST-elevation MI </li></ul><ul><li>Combined pharmacologic and catheter-based reperfusion approaches will offer optimal treatment to more patients </li></ul>
<ul><li>Increasing TIMI-3 flow rates prior to and post PCI </li></ul><ul><li>Improving cardiac function </li></ul><ul><li>Improving procedural success </li></ul><ul><li>Reducing short- and long-term ischemic events </li></ul>GP IIb/IIIa Inhibition Improves Primary PCI Outcomes by: Innovations in the Management of AMI
Reasons for Better Results With Contemporary Facilitated PCI <ul><li>Abciximab blocks platelet activation produced by fibrinolytic agents and PCI </li></ul><ul><ul><li>RAPPORT and ADMIRAL trials </li></ul></ul><ul><li>Intracoronary stents improve PTCA outcome by reducing dissection, reocclusion </li></ul><ul><ul><li>FRESCO, ZWOLLE, GRAMI, PAMI trials </li></ul></ul><ul><li>Increased operator experience </li></ul><ul><ul><li>PACT trial </li></ul></ul><ul><li>The specific fibrinolytic agent utilized (ie, reteplase) </li></ul><ul><ul><li>GUSTO-III—rescue PCI </li></ul></ul>
<ul><li>Optimal dosing of unfractionated heparin added to combined fibrinolysis and GP IIb/IIIa inhibition </li></ul><ul><li>Clinical importance of differences among GP IIb/IIIa antagonists in potency, effects on other adhesion molecules, and efficacy in protecting microvasculature </li></ul><ul><li>Validation of the safety and efficacy of early invasive management combined with potent platelet inhibition </li></ul>Evolving Questions
Hypothetical TIMI-3 Flow 0 10 20 30 40 50 60 70 80 90 100 – 30 0 30 60 90 Early Later Begin Rx Arrive ED Percent of patients with TIMI-3 flow Time (min) 86% Fac PCI 77% Combo Rx 70% Primary PTCA 60% Fibrinolysis
<ul><li>Optimal inhibition of platelet aggregation can be attained with GP IIb/IIIa receptor inhibitors </li></ul><ul><li>Target inhibition of the platelet GP IIb/IIIa receptor reduces ischemic events associated with PCI </li></ul><ul><li>The relative efficacy of GP IIb/IIIa receptor inhibitors is difficult to judge from different clinical trials, given the differences in study design and end-point adjudication </li></ul>GP IIB/IIIa Inhibitor Use in PCI: Summary
Munich Experience Primary Stenting With or Without Abciximab P =0.024 Change in peak flow velocity (cm/s) Neumann FJ et al. Circulation . 1998;98:2695–2701. P =0.007 P =0.003 10.4 18.1 56 62 0.15 0.44 (n=72) (n=80) (n=72) (n=79) (n=72) (n=79) No abciximab Abciximab Change in wall motion index (SD/chord) Global LVEF (%) 0 5 10 15 20 25 0 0.2 0.4 0.6 0.8 0 10 20 30 40 50 60 70 80
Facilitated PCI Trial FINESSE N 2700 Inclusion AMI (6 h) Exclusion Low risk Age <60 y and local inferior infarction Design Open-label Facilitated PCI Reteplase/abciximab Stent/clopidogrel Control Primary PCI + abciximab Heparin 60 U/kg Primary end point D/ReMI/CHF (30 d) Secondary end points ST segment resolution/ 1-y follow-up
SWIFT Trial of Anistreplase Survival Freedom from MI SWIFT Trial Study Group. Br Med J. 1991;302:550-560. Days from onset of symptoms Conventional care group Intervention group Patients surviving (%) Days from onset of symptoms Patients alive without reinfarction (%) 100 98 96 94 92 0 100 200 300 365 100 95 90 85 80 0 100 200 300 365
SPEED: Adverse Events at 30 Days Death ReMI UR Bleed Trans All 3.4 3.7 1.2 4.9* 1.6 9.3* 6.5 8.6 9.0 16.0* 15 30* 0 10 20 30 Early PCI (n=323) No Early PCI (n=62) * P <0.05 Percent Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489-1496.
GP IIb/IIIa Inhibitors in AMI Munich Experience (Neumann et al) Objective Evaluate cardiac function in pts given adjunctive abciximab + stenting vs pts given standard heparin only <ul><li>Conclusions </li></ul><ul><li>Improvements in cardiac </li></ul><ul><li>function significantly greater in stent pts receiving abciximab </li></ul><ul><li>vs heparin-only pts </li></ul><ul><li>Abciximab improved </li></ul><ul><li>microvascular reperfusion </li></ul><ul><li>Abciximab improved </li></ul><ul><li>restoration of LV function </li></ul><ul><li>in infarct area </li></ul>
GP IIb/IIIa Inhibitors in AMI ADMIRAL Objective Compare pts given abciximab vs placebo in primary stenting <ul><li>Conclusions </li></ul><ul><li>Significant improvement in LV function at 24 hours </li></ul><ul><li>TIMI-3 flow significantly </li></ul><ul><li>higher in abciximab-treated </li></ul><ul><li>group than placebo group prior to and post PCI </li></ul><ul><li>Significant reduction in death/MI/urgent TVR through 30 days </li></ul>
Thrombogenesis Platelet Aggregation GP IIb/IIIa Fibrinogen
Thrombogenesis Platelet Adhesion GP IIb/IIIa GP Ib/IX von Willebrand Factor Collagen GP Ia/IIa
Thrombogenesis Platelet Activation TxA 2 TxA 2 Prostaglandins G 2 /H 2 Arachidonic acid Phospholipase A 2 Strong Agonists TxA 2 thrombin collagen (high level) G protein Activated phospholipase C Calcium release PKC Weak Agonists Epinephrine, ADP, serotonin, collagen Activation of GP IIb/IIIa