Thrombolysis In Myocardial Ischemia trial, phase IIIA - TIMI 3A


Alteplase vs. placebo for angiographic outcomes in acute MI.


Thrombolytic therapy for unstable angina and the closely related syndrome of non-Q wave myocardial infarction (MI), particularly if the therapy were administered early, would be expected to reduce the severity of obstruction of the culprit lesion or of the tendency of a nonoccluded lesion to progress and thereby improve the clinical outcome.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 306
NYHA Class: not given
Mean Follow Up: 48 hours
Mean Patient Age: 58.5
Female: 25
Mean Ejection Fraction: not given

Patient Populations:

Greater than 5 minutes but less than 6 hours of chest pain occurring at rest, judged to be caused by ischemia, occurring within 12 hours of enrollment and accompanied by objective evidence of ischemic heart disease (as determined by ECG evidence of ischemia in at least two contiguous leads [either 0.1-mV transient ST-segment elevation of >30 minutes duration or 0.1-mV ST-segment depression 80 msec after the J-point or T-wave inversion]).
Documented history of previous MI.
>70% stenosis on a previous arteriogram.


>76 or <21 years of age
Had undergone coronary artery bypass graft (CABG) surgery
Experienced a MI within the preceding 21 days
Undergone percutaneous transluminal coronary angioplasty (PTCA) within six months
Pulmonary edema or shock
Contraindication to thrombolytic therapy or heparin
Coexistent illness
Left bundle branch block
Receiving oral anticoagulants

Primary Endpoints:

Measurable improvement in culprit lesion caliber of > 10% reduction of diameter stenosis or improvement in flow by at least two TIMI Perfusion flow grades between the baseline and the 18- to 48-hour studies.

Secondary Endpoints:

Frequency of substantial improvement (> 20% reduction of stenosis or two TIMI Perfusion grades), frequency of measurable worsening (> 10% stenosis or two TIMI grades).

Drug/Procedures Used:

rt-PA, 20mg IV bolus then 0.8 mg/kg, total maximum dose 80mg, or placebo; angiographic catheterization

Concomitant Medications:

Oxygen, anti-ischemic drugs including IV or sublingual nitrates, calcium antagonists, or beta-adrenergic blocking agents, either alone or in combination; heparin initiated at the same time as rt-PA, 5000 U IV and continuous infusion adjusted to maintain the activated partial thromboplastin time of 1.5-2.0 times laboratory control values

Principal Findings:

A non-Q wave myocardial infarction (MI) was diagnosed in 97 patients (32%) after entry. In the entire patient population, among t-PA- and placebo-treated patients, respectively, 25% vs. 19% (p = 0.25) of all culprit lesions achieved the primary study end point, measurable improvement (by a > 10% reduction of stenosis or two TIMI flow grades) at follow-up.

Substantial improvement (by a > 20% reduction of stenosis or two TIMI grades) was seen with t-PA in 15% of all culprit lesions vs. 5% with placebo (p < 0.003). Arteriographically apparent thrombus was present at baseline in the culprit lesion of 107 patients (35%).

Substantial improvement was more frequent with t-PA among lesions containing apparent thrombus (in 36% with t-PA vs. 15% with placebo; p < 0.01), as it was among patients evolving a non-Q wave MI (33% vs. 8%; p < 0.005).

By multivariate analysis, the significant, independent predictors of substantial improvement include apparent thrombus (p = 0.0001), non-Q wave MI (p = 0.003), and t-PA use (p = 0.01). Both non-Q wave MI status and thrombus had been specified a priori as important variables.

Fifty-three patients (14%) had no luminal diameter stenosis of a major coronary artery >60% on the baseline arteriogram. Compared with patients with unstable angina with an identifiable culprit lesion, patients without critical coronary obstruction were more likely to be women and non-white and less likely to have ST-segment deviation on the presenting electrocardiogram. Arteriography in such patients revealed no visually detectable coronary stenosis in half of the group; the remaining patients had noncritical coronary narrowing (i.e., < 60% luminal diameter stenosis) without morphologic features (ulceration or thrombus), suggestive of unstable or active coronary plaque.

Nearly one third of the patients without critical coronary stenosis had impaired angiographic filling, suggesting a possible pathophysiologic role for coronary microvascular dysfunction. These patients with unstable angina and no critical coronary obstruction had an excellent short-term prognosis; 2% died or had myocardial infarction compared with 18% of patients with critical obstruction.


Arteriographically apparent intraluminal thrombus and improvement of the culprit lesion with either of these regimens were only moderately frequent in patients with unstable angina or non-Q wave MI. Substantial improvement of culprit lesions was more frequent with t-PA than with placebo overall and in two prospectively defined subgroups. The clinical relevance of these observations was tested in the larger TIMI III B study, which failed to demonstrate a clinical benefit.


1. Circulation 1993;87:38-52. Early effects
2. Am J Cardiol 1994;74:531-37. Final results

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Implantable Devices, Lipid Metabolism

Keywords: Thrombolytic Therapy, Myocardial Infarction, Multivariate Analysis, Follow-Up Studies, Heart Conduction System, Constriction, Pathologic, Electrocardiography, Coronary Stenosis, Thrombosis, Catheterization, Tissue Plasminogen Activator

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