1. TIMI IIIA Protocol Design 391 Patients with Unstable Angina / NQWMI
IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockers
Angio Exclusion:
no CAD or LMain
Baseline Angio
Randomize
Placebo
t-PA
0.8 mg/kg over 90 mins
TIMI 3A evaluated 391 patients with unstable angina or non-Q wave MI with baseline coronary angiography and then randomized patients without left main CAD between treatment with tPA or placebo. F/U angiography was performed at hours to assess the effects of therapy on lesion severity.
Primary Endpoint:
Death, MI,
Positive ETT 6 weeks
Angio hrs
Follow-up 6 weeks
Circulation 1993;87:38-52 7 7 7

2. TIMI IIIA Primary Results Effects of tPA on Coronary Lesions
BASELINE ANGIORAPHY:
Apparent thrombus
No thrombus
35%
35%
Possible thrombus
TIMI 3A angiographically evaluated 391 patients with unstable ischemic discomfort and documented CAD and found definite thrombus in only 35% or mural opacities/eccentric lesions classified as possible thrombus in 30%. Notably, this proportion of patients with visible thrombus was much lower than anticipated from prior reports. After randomization to therapy with either front-loaded tPA or placebo, angiography showed no difference in the degree of lesion improvement between the two treatment arms.
30%
ANGIORAPHY AFTER tPA:
Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NS
TIMI IIIA Investigators. Circulation 1993;87:38-52.

3. TIMI IIIB Protocol Design 1473 Patients with Unstable Angina / NQWMI
ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockers
Randomize
Early Conservative:
ST Holter, ETT Thallium
Cath/PTCA if +ischemia
Early Invasive:
Cath h
PTCA/CABG prn
2x2 Factorial:
t-PA vs. Placebo
In light of the impressive benefits of thrombolytic therapy for ST elevation AMI and uncertainty regarding role and timing of invasive therapy for non-ST elevation acute coronary syndromes, TIMI 3B evaluated both of these therapeutic modalities for patients with unstable angina and non-Q wave MI.
All 1473 patients received five-drug medical therapy with aspirin, intravenous heparin, beta-blockers (unless contraindicated), nitrates, and calcium antagonists (diltiazem) if clinically appropriate. Then, in a 2x2 factorial design patients were randomized to receive either tPA or placebo and to follow either an early invasive (routine angiography followed by PTCA if appropriate) or a conservative strategy (cardiac catheterization only if recurrent ischemia). The primary endpoint was a composite of death, post-randomization infarction, or documented recurrent ischemia through 6 weeks.
1o Endpoint Inv-Cons:
Death, MI,
Positive ETT - 6 weeks
ETT 6 weeks
1o Endpoint t-PA:
Death, MI, Rec Isch,
+ ETT, Thallium
or ST Holter
Circulation 1994;89:
Follow-up 1 year 7 7 7

4. TIMI IIIB Investigators. Circulation 1994;89:1545-56
Primary Results
tPA vs. Placebo in Non-ST Elevation ACS
Composite Endpoint
Death or MI
ICH
% of Patients
Here we see the primary analysis of the efficacy of the tPA vs. placebo in TIMI IIIB. As depicted in the far left panel, there was no difference in the primary composite endpoint of death, post-randomization infarction, or documented recurrent ischemia through 6 weeks. Further, patients treated with tPA were at higher risk of death or MI (middle), as well as intracranial hemorrhage by 42 days (far right).
P = NS
P = 0.05
P = 0.05
TIMI IIIB Investigators. Circulation 1994;89:

5. TIMI IIIB Investigators. Circulation 1994;89:1545-56
Primary Results
Early Invasive vs. Conservative Strategy
Events at 42d Invasive Conservative p value
No. Pts
Death (%) NS
MI (%) NS
D/MI/+ETT (%) NS
Rehosp Angina (%) <0.001
D/MI/Rehosp (%)
LOS (days) <0.001
# Days rehosp <0.001
In the primary comparison of the early invasive vs. conservative strategies for management of non-ST elevation acute coronary syndromes in TIMI 3B, there was no difference in the composite outcome of death, post-randomization infarction or positive stress test at 6 weeks. Among patients following the invasive strategy, 61% underwent a revascularization procedure by 6 weeks. In comparison, by six weeks, 64% of those in the conservative arm had coronary angiography performed for recurrent angina at rest, or high risk results in non-invasive testing for ischemia leading to 49% having some form of revascularization. In reviewing secondary endpoints, we find a statistically significant reduction in the proportion of patients requiring re-hospitalization for recurrent angina in the invasive compared with the conservative strategy group.
TIMI IIIB Investigators. Circulation 1994;89:

6. TIMI III REGISTRY Protocol Design
All consecutive patients admitted with unstable angina were screened.
Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI
Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure
Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year.
The TIMI 3 registry was designed to complement the TIMI IIIA and B trials with the goal of delineating the clinical profile and outcomes of all patients with non-ST elevation acute coronary syndromes. Over 9500 patients with ACS were screened and 3316 included in the registry.

7. TIMI III REGISTRY Risk Stratification
Admission ECG as a prognostic indicator
ST deviation >0.1 mV _
LBBB
Tw change
No ECG changes 25
22.9
Death or MI 20 15 11
% of Patients 10
8.2
6.6
6.8
Among the 3316 patients with unstable angina and non-Q wave MI included in the TIMI III registry, the admission ECG was found to be a strong prognostic indicator with respect to the composite outcome of death or myocardial infarction. ST deviation in particular was associated with adverse outcomes at one year compared with those with no ST deviation whereas new T wave inversions did not add to the clinical history in predicting outcome.
3.6
3.7
3.7 5
2.6
1.6
1.6
0.8
In-Hospital
6 Weeks
1 Year
Stone PH, TIMI III Registry Study Group. JAMA 1996;275:
Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:

8. TIMI IIIB Risk Stratification cTnI to Predict Risk of Mortality in ACS
Enrolled 0-6 hrs
Enrolled 6-24 hrs
Enrolled 0-24 hrs
P<0.001
P <0.05
P<0.001
1404 patients enrolled in TIMI 3B had baseline samples available for measurement of cardiac troponin I. This serum marker substudy from TIMI 3B demonstrated a near linear gradient of mortality risk with rising concentration of cTnI. This risk relationship persisted after multivariate adjustment for traditional clinical markers of cardiovascular risk. Further as depicted in this figure, cTnI was predictive of mortality at 6 weeks even among patients with normal CK-MB. Consistent with prior data regarding cardiac troponin T, the association between cTnI and mortality was not as strong among patients presenting early after symptom onset. However, for patients presenting over 6 hours after symptom onset, a negative cTnI correlated with low mortality risk.
P <0.05
Antman et al. NEJM 1996; 335:1342-9