Thrombolysis In Myocardial Ischemia trial, phase IIIB - TIMI 3B


Early invasive vs. early conservative strategies after acute coronary syndromes.


To determine the effects of thrombolytic therapy and of an early invasive strategy on clinical outcome after unstable angina or non-Q wave MI.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 1,473
Mean Patient Age: 59
Female: 33

Patient Populations:

Chest discomfort at rest judged to be caused by ischemia, lasting ≥5 minutes but ≤6 hours
Discomfort must have occurred within 24 hours of enrollment
Objective evidence of ischemic heart disease by ECG in at least two contiguous leads (≥0.1-mV ST segment elevation lasting <30 minutes, transient or persistent ≥0.1-mV ST segment depression, or T-wave inversion during an episode of rest pain within the prior 7 days). Alternatively, previous documented coronary artery disease (a history of previous myocardial infarction or a ≥70% luminal diameter stenosis on a previous coronary arteriogram or a positive exercise thallium scintigram).


Pulmonary edema
Systolic arterial pressure >180 mm Hg or a diastolic pressure >100 mm Hg
Contraindication to thrombolytic therapy or heparin
Left bundle branch block
Treatable cause of unstable angina
Myocardial infarction within the preceding 21 days
Coronary arteriography within 30 days
Percutaneous transluminal coronary angioplasty (PTCA) within 6 months
Previous coronary artery bypass grafting (CABG)
Coexistent severe illness
Woman of child-bearing potential
Oral anticoagulants

Primary Endpoints:

For the comparison between tPA and placebo: "unfavorable outcome" at 6 weeks (death, postrandomization nonfatal myocardial infarction or reinfarction) or failure of initial therapy
For the comparison between the early invasive and early conservative strategies: death, postrandomization myocardial infarction, or an unsatisfactory ETT performed at 6 weeks.

Secondary Endpoints:

Differences in treatment effect (tPA versus placebo) or strategies (invasive versus conservative) for death or myocardial infarction for several subgroups.

Drug/Procedures Used:

In a 2 x 2 factorial design, tPA or placebo as well as an early invasive or early conservative management strategy.

The total dose of tPA or placebo was 0.8 mg/kg (maximum, 80mg). One third of the total dose but no more than 20mg was given ini

Concomitant Medications:

All patients were treated with bed rest, anti-ischemic medications, aspirin, and heparin

Principal Findings:

tPA vs Placebo
At six weeks, an "unfavorable outcome" end point occurred in 54.2% of the tPA-treated patients and 55.5% of the placebo-treated patients (P=NS).

By 42 days the occurrence of MI was higher in patients receiving tPA than in patients receiving placebo (7.4% vs. 4.9%; P = 0.04).

After 1 year, the incidence of death or nonfatal infarction for the t-PA- and placebo-treated groups remained similar (12.4% vs. 10.6%, p = 0.24).

Invasive vs Conservative strategies
At 6 weeks, the principal end point for comparison of the two strategies occurred in 16.2% of the patients randomized to the early invasive strategy versus 18.1% of those assigned to the early conservative strategy (P=NS).

Average length of initial hospitalization, incidence of rehospitalization within 6 weeks, and days of rehospitalization all were significantly lower (P<0.01) for the early invasive strategy.

At 1 year, the incidence of death or nonfatal infarction was similar for the early invasive and early conservative strategies (10.8% vs. 12.2%, p = 0.42).

Revascularization by 1 year was common, but was slightly more common with the early invasive than the early conservative strategy (64% vs. 58%, p < 0.001). This result was related entirely to a small difference in angioplasty rates (39% vs. 32%, p < 0.001).


A lower dose of tPA (average, 63 mg) was used in this trial compared with the usual dose used in the treatment of patients presenting with ST segment elevation and evolving Q-wave infarction. Nevertheless, intracranial hemorrhage occurred in 0.55% of TPA-treated patients. Based on the absence of net clinical benefit, tPA is not recommended for routine use in patients with unstable angina or NQMI, such as those enrolled in this trial.

For early invasive compared with early conservative strategy, the groups did not differ in clinical outcome, although the early invasive strategy resulted in shorter initial hospitalization and rehospitalization rates. This trial preceded the use of stents and glycoprotein 2b3a inhibitors as well as thienopyridines. Nearly 8 years later, the more modern TACTICS-TIMI 18 trial has now reinvestigated the relative benefits of invasive vs conservative management and demonstrated that an early invasive strategy employed on top of a background of upstream tirofiban therapy was associated with improved clinical outcomes.


1. Circulation 1994;89:1545-56. Final results

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Thrombolytic Therapy, Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Constriction, Pathologic, Fibrinolytic Agents, Electrocardiography, Angioplasty, Tyrosine, Thienopyridines, Stents, Intracranial Hemorrhages, Coronary Angiography

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