1. 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

2. 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

3. 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:

4. 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:

5. 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

6. 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

7. 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

8. 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

9. LESSON 3 TIMI 11B Death/MI/Urgent Revascularization at 14 Days % Days20
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: 8 10 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

11. 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:

12. TIMI Risk Score for STEMI
LESSON 4
(Continued)
TIMI Risk Score for STEMI
Historical
Age pts
>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

13. 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 Q Q Q Q4 Q5
Range < – – – >30
TIMI 17
Morrow DA, Lancet 2001;358:1571-5
P<
P<
P<

14. 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

15. 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:

16. 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=
TnT cut point = 0.01 ng/ml (54% of Pts TnT +)
TACTICS-TIMI 18
Morrow DA, JAMA 2001;286:

17. 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

18. 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

19. 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

20. 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:

21. 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

22. 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:

23. 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

24. LESSON 9 CLARITY – TIMI 28 Occluded Artery (or D/MI thru Angio/HD)
36%
Odds Reduction
Odds Ratio 0.64 (95% CI ) P=
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:

25. 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

26. 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 =
RR = 0.81
p =
Days
Days
ExTRACT-TIMI 25
Antman E, N Engl J Med
2006; 354: