Primary PCI – The Preferred Reperfusion Therapy for AMI Victor Guetta, M.D. Sheba Medical Center, Tel-Hashomer VG Why does fibrinolysis work? Restores patency of IRA Salvages myocardium Prevents unfavorable remodeling Diminishes electrical instability Preserves collateral potential Universally available VG Early mortality in AMI 10 9 8 7 6 % 5 4 3 2 1 0 8.8 7 3.7 TIMI 0/1 TIMI 2 TIMI 3 Anderson, AJC, 1996 VG Redefining the Standard of Acute Angiography Meta-analysis of 60-minute angiography 12 trials 1989–1998 1613 patients SK, r-PA and t-PA Weighted pooled analysis with 95% confidence intervals VG Redefining the Standard of Acute Angiography 100% 60 minutes 90 minutes 75% 61% 57% 45% 50% 22% 51% 31% * 25% 0% SK *GUSTO-I angio at 90 minutes t-PA r-PA VG Redefining the Standard of Acute Angiography 100% 100% GUSTO-I 90-min 60-min 23% 75% Meta-analysis 75% 23% 54% 50% 45% 50% 31% 25% 25% 22% p < 0.001 0% 0% SK t-PA —NEJM 1993 SK t-PA VG Intracranial Hemorrhage Thrombolytic therapy induces a relatively high rate of intracerebral hemorrhage: 1 in 100 to 200 treated patients (~0.7%) VG Procoagulant Effects of Thrombolytic Therapy Fibrin-Thrombin Platelets Fibrin-Thrombin Fibrinolytic Thrombin begets thrombin Resistance to fibrinolysis PAI-1 Thrombin increases platelet aggregation Platelets PAI-1 No response to fibrinolytic VG Adapted with permission from Topol EJ. Circulation. 1998;97:211-218. Combination therapy in AMI Completed studies On-going studies TIMI 14 FASTER SPEED ENTIRE INTRO-AMI INTEGRITI GUSTO V AMI ASSENT III VG Breaking the ceiling of fibrinolysis Combination fibrin and platelet lysis has been shown to enhance arterial patency in AMI 180/90/1.33 VG GUSTO V 5.91% 5.62% mortality (%) 6 OR=0.95 [0.83–1.08] p=0.45 4 2 reteplase (n=8260) abciximab+reteplase (n=8328) 0 0 5 10 15 days 20 25 30 VG Why does fibrinolysis not work? Minimal thrombus in 15%-25% Reocclusion Platelet activation Thrombin Vasomotor instability Resistance to lysis - time and composition Does not alleviate flow-limiting fixed stenoses Does not restore tissue perfusion in 20%30% (TIMI 0-I) VG DESCRIPTION OF THE TRIALS COMPARING PRIMARY PTCA AND INTRAVENOUS THROMBOLYSIS VG Death and nonfatal reinfarction at the end of study period VG Mortality at the end of study period VG 10 trials 2606 patients 74 mins to primary PTCA Overview of Primary PTCA versus Thrombolytic Therapy Relative Reduction p # Events Prevented/1000 Pts Treated Mortality 32% 0.02 21 Reinfarction 45% 0.04 24 IC Bleed 91% < 0.001 10 —Weaver, JAMA 1997 VG Reperfusion therapy for AMI 30-d outcome Weaver,JAMA 1997;278:2093 VG Acute MI PTCA vs Lysis – 6 Month Mortality (% ) 20 15 Thrombolysis PTCA 24% RRR 10 8.2% 6.2% 5 p=0.04 0 00 11 RCTs (2725 patients) 2 4 Months Months from from Randomization Randomization 6 PCAT Collaborative Group, 2001 VG Acute MI PTCA vs Lysis – 6 Month Death + MI (% ) 20 15 Thrombolysis PTCA 16.1% 37% RRR 10.2% 10 5 p<0.0001 0 0 11 RCTs (2725 patients) 2 4 Months from Randomization 6 PCAT Collaborative Group, 2001 VG Acute MI PTCA vs Lysis – 6 Month Subgroups n PTCA (%) Treatment Delay (mins)** < 35 724 4.7 35-55 1152 7.9 > 55 733 8.3 Site Volume ‡ Low 1533 8.7 Medium 601 5.8 High 501 3.6 Lytic (%) 15.7 12.5 12.1 p = 0.06 12.7 14.0 13.5 p = 0.03 ** average time difference between commencing thrombolytic therapy and performing first balloon inflation at an individual site level. ‡ Site volume on-study only, classified by number of patients randomized to PTCA per site per year: Low = < 15 patients/site year Medium = 15-30 patients/site/year High = > 30 patients/site/year 11 RCTs (2725 patients) Relative Risk (95% Cl) 0.1 0.2 0.5 1.0 Favours PTCA 2.0 5.0 10.0 Favours Lytic PCAT Collaborative Group, 2001 VG Acute MI PTCA vs Lysis – 6 Month Mortality In-hospital 30 days 6 months Re-MI In-hospital 30 days 6 months Death + Re-MI In-hospital 30 days 6 months Total Stroke In-hospital 30 days PTCA (%) Lytic (%) 4.0 4.3 6.2 6.3 6.9 8.2 2.5 3.2 4.8 6.4 7.6 9.8 6.1 7.0 10.2 11.7 12.9 16.1 0.22 0.66 1.45 1.88 Relative Risk (95% Cl) 0.02 11 RCTs (2725 patients) 0.05 0.1 0.1 0.2 0.2 0.5 0.5 1.0 1.0 2.0 2.0 5.0 5.0 10.0 10.0 Favours PTCA Favours Lytic PCAT Collaborative Group, 2001VG Acute MI PTCA vs Lysis – 6 Month Subgroups Age < 60 60-70 > 70 Sex Male Female Diabetes Yes No Prior MI Yes No MI location Anterior Non-anterior n PTCA (%) Lytic (%) 1178 852 605 4.3 6.3 13.3 8.2 12.8 23.6 2043 591 5.7 11.7 12.2 16.4 367 2151 9.2 6.5 19.3 11.8 383 2250 9.7 6.6 22.7 11.5 1153 1469 8.2 6.2 14.5 12.0 Relative Risk (95% Cl) 0.1 0.2 0.5 Favours PTCA 11 RCTs (2725 patients) 1.0 2.0 5.0 10.0 Favours Lytic PCAT Collaborative Group, 2001 VG Acute MI PTCA vs Lysis Subgroups Pulse rate n PTCA (%) Lytic (%) < 65 65-75 75-85 ≥ 85 678 513 536 690 5.3 8.2 6.6 8.2 13.4 9.7 12.9 14.6 < 115 115-130 130-150 ≥ 150 595 480 737 612 10.5 5.3 7.8 4.5 17.4 10.3 10.4 14.0 Low Intermediate High 1186 758 691 2.9 8.0 13.1 7.2 12.7 24.1 0-<2 2-<4 4-<6 ≥ 6 hrs 838 1035 347 265 5.6 8.2 6.0 8.5 11.6 12.6 15.6 21.3 SBP(mmHg) Risk group Presentation time Relative Risk (95% Cl) 0.1 11 RCTs (2725 patients) 0.2 0.5 1.0 2.0 5.0 10.0 Favours PTCA Favours Lytic PCAT Collaborative Group, 2001 VG Advances in reperfusion Stents Anti-platelet agents As adjunct to primary angioplasty In combination with fibrinolysis As precursor to facilitated angioplasty Combination VG Stents in primary PCI VG Reperfusion in AMI Schomig, NEJM 2000;343:385 VG Effective reperfusion in AMI Schomig, NEJM 2000;343:385 VG Myocardial salvage index Time from symptom onset to reperfusion Schomig, NEJM 2000;343:385 VG Abciximab in primary angioplasty 30-day death/MI/urgent TVR P<0.01 for all VG CADILLAC [ Presentation of acute safety / outcome data ] • No difference between groups in mortality, stroke • Trend toward fewer reinfarctions in stent pts • Trend toward less ischemia-driven TVR in stent pts • No difference between groups in ICH Stent/A Stent/P PTCA/A PTCA/P TIMI 3 flow 96.7% 92.1% 95% 94.8% Rec isch 1.2% 3.9% 1.4% 4% Bleeding 4.5% 3.5% 5.1% 3.1% Stone. Oral presentation. AHA 1999. CADILLAC MACE at 6 Months Incidence (%) 20% 19.3% 15% 15.2% 10% 10.9% 10.8% 5% 0% 0 30 60 90 120 150 180 Days to event PTCA, no abx PTCA, abx Stent, no abx Stent, abx VG Stone et al. Circ 2000; 102: II-664 ADM IRAL and CADILLAC Stone et al. Circ 2000; 102: II-664, Barragan et al Circ 2000; 102: II-662 TIMI 3 Flow Incidence (%) 100 87.6 93.8 96.1 93.1 75 p = NS p = 0.04 50 p = NS 20.3 23.8 p = 0.01 25 16.8 5.4 0 Baseline Final ADMIRAL Stent, No Abx Baseline Final CADILLAC Stent, Abx VG ADM IRAL and CADILLAC Stone et al. Circ 2000; 102: II-664, Barragan et al Circ 2000; 102: II-662 6 Month Mortality 10 Incidence (%) 7.3 5 3.5 3.3 3.0 55% 14% ADMIRAL CADILLAC 0 No Abx Abx VG ADMIRAL vs CADILLAC ADMIRAL (n=300) CADILLAC (n=2082) AMI < 12 hrs AMI < 12 hrs Double Blind Yes No Pre-PCI Abx? >25% High risk anatomy not excluded (Stents in 85%) Patient Population Clinical High Risk Yes No (per protocol) High risk anatomy excluded (Stents in 99.5%) No Killip IV (Mortality > 80%) 8% Excluded from Trial TIMI 3 Flow at Baseline (Pre-Abx) 5.6% (Placebo Arm) 22% (Average) 11% 2% Angiographic Exclusion Prior CABG VG Primary Stenting With or Without Abciximab P=0.024 20 18.1 15 10.4 10 5 0 n=72 n=80 0.8 80 P=0.007 P=0.003 70 global LVEF (%) 25 D wall motion index (SD/CHORD) D peak flow velocity (cm/s) Cardiac Function Parameters at 14 Days 0.6 0.44 0.4 0.2 0.15 62 56 60 50 40 30 20 10 0 0 n=72 no abciximab n=79 n=72 n=79 abciximab VG Neumann FJ. Circulation. 1998; 98:2695-2701. Meta-analysis of abciximab benefit in AMI A P 684 685 0.64 30d Death 2.8% P=0.14 4.2% 0.57 30d D/MI 4.2% P=0.02 7.2% 0.61 6m Death 4.2% P=0.04 6.7% 0.57 6m D/MI 7.0% P=0.003 11.7% 0 1 2 Khot, ACC 2001 VG Facilitated PCI PCI soon after pharmacotherapy, with or without persistent ischemia VG SPEED-Facilitated PCI Freedom from D/MI/UR MACE at 30 days Hermann, JACC 2000; 36:1489 VG Arterial patency before PCI P<0.0001 P=0.02 Brodie, AJC 2000;85:13 VG SPEED - Facilitated PCI N=99 N=195 Hermann, JACC 2000; 36:1489 VG Evaluation of Myocardial Perfusion 1. ST Resolution: Schröder JACC 26: 1657,1995 Complete (>70%) Partial (30-70%) None (< 30%) 2. TIMI Myocardial Perfusion Grade (MPG) TMP Grade 0 No or minimal blush TMP Grade 1 Stain present. Blush persists on next injection CM Gibson Circulation 1999 TMP Grade 2 Dye strongly persistent at end of washout. Gone by next injection TMP Grade 3 Normal ground glass appearance of blush. Dye mildly persistent at end of washout VG Microvascular obstruction Fibrinolysis/PCI MVO Platelets Plaque TIMI 3 flow ST elevation High cTFC MCO defect MRI defect VG Tissue reperfusion after fibrinolysis TMP and 30-day mortality Gibson, Circulation 2000 VG “A union in reperfusion” …”Open vasculature hypothesis” is now a more appropriate term than “open artery hypothesis”…It would be logical to offer the best of the two complementary strategies…. Gibson, JACC 2000;36:1497 VG Preventing Distal Embolization 34 y.o. female presenting with acute anterior MI less than 2 hours from symptoms onset VG Preventing Distal Embolization Give ASA and Heparin (ACT 200-250 sec) Start GP IIb/IIIa inhibitors VG Preventing Distal Embolization Use X-Sizer or Insert embolic protective device Check the flow VG Preventing Distal Embolization Treat the artery – Direct stenting if possible VG Preventing Distal Embolization Final result VG New paradigm of reperfusion Improves speed and quality of reperfusion Prevents and attenuates consequences of distal embolization of plaque and thrombus Facilitates immediate revascularization Prevents reocclusion and reinfarction Do Facilitated Primary PCI !! VG יש לך אוטם שריר הלב ,האם תרצה צנתור או טיפול טרומבוליטי ? STK ICH VG