LESSON 1 LESSON 1 Establishment of: The universally used coronary flow grading system to assess epicardial reperfusion, and demonstration of correlation between TIMI flow grade and survival in patients with STEMI The TIMI Frame Count to enhance reproducibility of the angiographic assessment of coronary blood flow The TIMI Myocardial Perfusion Grade to assess tissue level reperfusion with demonstration of independent effects of these measures on survival Criteria for grading the degree of hemorrhage A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. LESSON 1

LESSON 1 TIMI 1 TIMI 0 Complete occlusion TIMI Flow Grade Mortality at 42 Days TIMI 0 Complete occlusion TIMI 1 Penetration of obstruction by contrast but no distal perfusion TIMI 2 Perfusion of entire artery but delayed flow TIMI 3 Full perfusion, normal flow P < 0.005 A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. TIMI 1 Flygenring BP, J Am Coll Cardiol 1991;17:275A

LESSON 1 TIMI 4 & 10 cTFC p = 0.015 (Continued) Corrected TIMI Frame Count TIMI Grade 3 Flow Overall Mortality: 13% TIMI Grade 2 Flow Overall Mortality: 27% cTFC p = 0.015 TIMI 4 & 10 Gibson CM, Circulation. 1999;99:1945-50

Epicardial TIMI Grade 3 Flow Epicardial TIMI Grade 2/1/0 LESSON 1 (Continued) Myocardial Perfusion Grade Epicardial TIMI Grade 3 Flow Overall Mortality: 3.7% Epicardial TIMI Grade 2/1/0 Overall Mortality: 7% 5 way p = 0.007 Myocardial Perfusion Grade 3 Myocardial Perfusion Grade 2 Myocardial Perfusion Grades 0/1 Myocardial Perfusion Grade 3 Myocardial Perfusion Grades 2/1/0 TIMI 10B Gibson CM, Circulation. 1999;99:1945-50

LESSON 1 TIMI 2 Major Hemorrhage: Minor Bleeding: (Continued) Major Hemorrhage: 1. Any intracranial or retroperitoneal bleeding 2. Clinically overt bleeding associated with a drop in Hgb of > 5g/dL (or absolute drop in Hct of  15%). A transfusion is counted as 1 g/dL or 3% Hct. Minor Bleeding: Clinically overt bleeding associated with a drop in Hgb of 3 to  5g/dL (or absolute drop in Hct of 9 to < 15%) and does not meet criteria for major hemorrhage TIMI 2 Bovill EG, Ann Intern Med 1991;115:256-65

LESSON 2 The first demonstration of the superiority of tissue plasminogen activator over streptokinase in the successful reperfusion of occluded coronary arteries in patients with STEMI. A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. LESSON 2

LESSON 2 70 62 43 31 TIMI 1 t-PA SK * *P<0.001 Reperfusion of occluded arteries Patency at 90 minutes 20 40 60 80 % of Patients t-PA SK *P<0.001 * In TIMI 1, 290 patients with acute MI underwent initial coronary angiography followed by treatment with either SK or tPA with significantly higher rates of reperfusion evident in the tPA (yellow) arm. TIMI 1 TIMI Study Group, N Engl J Med 1985;312:932-36

LESSON 3 Demonstration of the superior efficacy of enoxaparin over unfractionated heparin in patients with unstable angina or non-ST elevation MI. A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. LESSON 3

LESSON 3 TIMI 11B Death/MI/Urgent Revascularization at 14 Days % Days 20 UFH 16.7 % 18 ENOX 14.5 % 16 14 % 14.2 % 12 12.4 % 10 P=0.048 RRR 15 % P=0.029 RRR 15 % 8 6 In the TIMI 11B acute phase, a significant reduction in the composite primary endpoint was observed at pre-specified timepoints of 8 and 14 days. Note that the curves remain separated, with the enoxaparin group experiencing a stable 15% relative risk reduction that was statistically significant at both timepoints. 4 2 2 4 6 8 10 12 14 Days TIMI 11B Antman EM, Circulation 1999;100:1593-1601 8 10 10 10

LESSON 4 Demonstration that simple risk scores (TIMI Risk Scores for UA/NSTEMI and STEMI) derived from baseline clinical information are powerful predictors of clinical outcomes and can improve therapy in patients with UA, NSTEMI, and STEMI. A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. LESSON 4

TIMI Risk Score for UA/NSTEMI LESSON 4 One Point for each of: Age > 65 y > 3 CAD Risk Factors Prior Stenosis > 50 % ST deviation > 2 Anginal events < 24 h ASA in last 7 days Elevated Cardiac Markers TIMI Risk Score for UA/NSTEMI % D/MI/Urgent Revascularization Vs TRS TIMI 11B Antman EM, JAMA 2000;284:835-842

TIMI Risk Score for STEMI LESSON 4 (Continued) TIMI Risk Score for STEMI Historical Age 65-74 2pts >75 3pts DM/HTN/Angina 1pt Exam SBP < 100 mmHg 3pts HR > 100 bpm 2pts Killip II – IV 2pts Weight < 67 kg 1 pt Presentation Anterior STE or LBBB 1 pt Time to Rx > 4hr 1pt ------------------------------------ Risk Score = Total (0-14) Mortality at 30 d vs. STEMI TRS TIMI 17 Morrow DA, Circulation 2000;102:2031-7

Simple Risk Score for STEMI LESSON 4 (Continued) Simple Risk Score for STEMI Simple Risk Score Heart Rate x [Age/10]2 SBP Mortality (%) 30-day mortality  by 43% for every 5 point  in risk score Quartile Q1 Q2 Q3 Q4 Q5 Range <12.5 12.5–17.5 17.5–22.5 22.5–30 >30 TIMI 17 Morrow DA, Lancet 2001;358:1571-5 P< 0.0001 P< 0.0001 P< 0.0001

LESSON 5 Demonstration that an early invasive strategy results in improved clinical outcomes for patients presenting with UA/NSTEMI treated with GP IIb/IIIa inhibitor. A grading system (left panel) for coronary perfusion was developed to carefully compare fibrinolytic agents in the TIMI 1 trial. As shown in the right panel, the TIMI flow grade showed a striking inverse correlation with mortality at 6 weeks. LESSON 5

Death, MI, Rehosp for ACS at 6 Months LESSON 5 Death, MI, Rehosp for ACS at 6 Months 19.4% 15.9% 1 2 3 4 5 6 Time (months) 8 12 16 20 % Patients O.R 0.78 95% CI (0.62, 0.97) p=0.025 CONS INV TACTICS-TIMI 18 Cannon CP, N Engl J Med 2001;344:1879-87

Death, MI, Rehosp for ACS at 6 Months LESSON 5 Death, MI, Rehosp for ACS at 6 Months CONS INV * p=NS OR=0.55 *p<0.001 Interaction P=0.013 (%) N= 426 414 480 506 TnT cut point = 0.01 ng/ml (54% of Pts TnT +) TACTICS-TIMI 18 Morrow DA, JAMA 2001;286:2405-12

LESSON 6 Demonstration that with a multimarker approach, troponin, hs-CRP, and BNP provide independent and complementary prognostic information in patients with UA/NSTEMI. LESSON 6

LESSON 6 TACTICS-TIMI 18 RR of D/MI/CHF at 6 months Assign patients 1 point for the presence of each elevated biomarker (TnI > 0.1 ng/ml, CRP > 1.5 mg/dl, BNP > 80 pg/ml). RR of D/MI/CHF at 6 months 1.0 0.2 0.5 2 5 OR & 95% CI for D/MI/CHF by 6 months Age (per year) Diabetes Prior MI Prior CHF ST deviation 0 Biomarkers 1 Biomarker 2 Biomarkers 3 Biomarkers TACTICS-TIMI 18 Sabatine MS, Circulation 2002;105:1760-3

LESSON 7 Demonstration that patients recently hospitalized for an acute coronary syndrome benefit from early, aggressive, and continued lowering of LDL-C to levels substantially below current target levels. LESSON 7

LESSON 7 DEATH, NON-FATAL MI, OR URGENT REVASCULARIZATION 20 Pravastatin 40 mg 15 16.7% Percent patients with events 10 Atorvastatin 80 mg 12.9% RRR 25% 5 P=0.0004 6 12 18 24 30 Months of Follow-up PROVE IT-TIMI 22 Cannon CP, N Engl J Med 2004;350:1495-1504

LESSON 8 Demonstration that atorvastatin 80 mg results in a greater depression of C-reactive protein than pravastatin 40 mg, independent of LDL-C reduction, indicating that the anti-inflammatory actions of statins are of critical importance in reducing clinical events. LESSON 8

LESSON 8 C-reactive protein (hsCRP) levels by treatment Risk of Death or MI after Day 30   Pravastatin 40mg (n=1873) Atorvastatin 80mg (n=1872) P value Randomization 12 mg/L 0.6 30 days 2.4 mg/L 1.7 mg/L <0.001 120 days 2.0 mg/L 1.3 mg/L Study end 2.1 mg/L       P=0.005 for prava P=0.6 for atorva PROVE IT-TIMI 22 Ridker PM, JACC 2005;45:1644-1648

LESSON 9 Demonstration that the addition of clopidogrel improves infarct-related artery patency and reduces death and ischemic complications in STEMI patients receiving standard fibrinolytic therapy including aspirin. LESSON 9

LESSON 9 CLARITY – TIMI 28 Occluded Artery (or D/MI thru Angio/HD) 36% Odds Reduction Odds Ratio 0.64 (95% CI 0.53-0.76) P=0.00000036 n=1752 0.4 0.6 0.8 1.0 1.2 1.6 n=1739 Clopidogrel better Placebo better Clopidogrel Placebo CLARITY – TIMI 28 Sabatine MS, N Engl J Med 2005;352:1179-89

LESSON 10 Demonstration that in patients receiving fibrinolysis for STEMI, a strategy of enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours for preventing death or reinfarction but there is an increase in major bleeding. Net clinical benefit is significantly improved with the enoxaparin strategy. LESSON 10

LESSON 10 ExTRACT-TIMI 25 Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days Primary Endpoint: Death or non-fatal re-MI by 30 days UFH UFH 14.5 12.0 11.7 9.9 ENOX ENOX % % RR = 0.83 p = 0.000003 RR = 0.81 p = 0.000001 Days Days ExTRACT-TIMI 25 Antman E, N Engl J Med 2006; 354:1477-88