International Study of Infarct Survival-3 - ISIS-3


Streptokinase vs. alteplase for mortality in acute MI.


To determine the balance between the benefits and risks of different antithrombotic regimens and of different fibrinolytic regimens

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 41,299

Patient Populations:

Within 24 hours of the onset of symptoms of suspected or definite acute myocardial infarction (MI), with or without ECG changes
No contraindications to SK, rt-PA, or APSAC


Not specified by the protocol (determined by responsible physician)

Primary Endpoints:


Secondary Endpoints:

Hemorrhagic strokes, cerebral hemorrhage, other bleeds

Drug/Procedures Used:

SK, 1.5 x 106 U IV over 1 hour
rt-PA, 0.6 x 106 U/kg over 4 hours
APSAC, 30 U IV over 3 minutes
Aspirin, 162.5 mg/day, or aspirin (same dose) plus heparin, 12,500 U bid subcutaneously for 7 days

Principal Findings:

The addition of heparin to aspirin was associated with an excess of major non-cerebral bleeds, and with definite or probable cerebral hemorrhage. No significant difference was seen with respect to total stroke.

During the heparin treatment period, there were slightly fewer deaths in the aspirin plus heparin group. Some of this early benefit may be lost when heparin treatment ceases.

No significant mortality advantage was observed in days 0-35 or during the 2-month follow-up.

The incidence of allergy and a slight excess of strokes (most attributed to cerebral hemorrhage) in the APSAC group, compared to the SK group.

The rate of reinfarction was similar for both the APSAC group and SK group as was the survival rate after six months.

There was a significant excess of strokes in the rt-PA group compared to the SK group, many of which were reported soon after treatment started and were attributed to cerebral hemorrhage.

Fewer reinfarctions were observed in the rt-PA group than in the SK group.

There was no significant difference in mortality between day 0 and day 35 and no difference in 6-month survival between the SK and rt-PA groups.


Any mortality differences between different fibrinolytic regimens are small. Mortality differences may well involve no more than a few deaths per thousand. The corollary of this is that differences of a few thousand patients in fatal or disabling side-effects (such as excess of stroke seen with rt-PA and APSAC) need to be taken seriously.

It is important not to let uncertainty as to which antithrombotic or fibrinolytic regimen to use routinely engender uncertainty as to whether to use antithrombotic or fibrinolytic therapies routinely.

Although no difference was detected between streptokinase and t-PA in ISIS-3, the dosing of concomitant heparin was suboptimal. The GUSTO I trial revealed that t-PA had better efficacy than SK with optimal heparin dosing.


1. Lancet 1992;339:753-770. Final results
2. New Engl J Med 1998;338:8-14. Gender subgroups

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: Uncertainty, Thrombolytic Therapy, Myocardial Infarction, Stroke, Follow-Up Studies, Heparin, Streptokinase, Survival Rate, Hypersensitivity, Anistreplase, Tissue Plasminogen Activator, Risk Assessment, Cerebral Hemorrhage

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