Continuous Infusion Versus Double-Bolus Administration of Alteplase - COBALT


Front-loaded vs. double-bolus alteplase for 30-day mortality in acute MI.


Evaluate therapeutic equivalence between front-loaded and double-bolus alteplase therapy.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 7,169
Mean Patient Age: 63
Female: 24

Patient Populations:

Ischemic chest pain for at least 20 minutes.
Presented to the hospital within 6 hours after the onset of symptoms.
Electrocardiogram showed ST-segment elevation of at least 0.1 mV in two or more limb leads, ST-segment elevation of at least 0.2 mV in two or more contiguous precordial leads, or both.


Active bleeding.
Stroke or structural damage of the central nervous system.
Recent noncompressible vascular puncture.
Major surgery or trauma within the preceding 6 months.
Current participation in any other study of experimental drugs or devices.
Previous enrollment in this study.
Pregnancy, or lactation or parturition within the preceding 30 days.
A systolic blood pressure of ≥180 mm Hg, a diastolic blood pressure of ≥110 mm Hg, or both, in spite of treatment, were considered a relative contraindication to enrollment.

Primary Endpoints:

Mortality from any cause at 30 days

Drug/Procedures Used:

Accelerated infusion of alteplase 100mg or alteplase 50mg bolus over 1 to 3 minutes followed 30 minutes later by a second bolus of 50mg (or 40mg for patients who weighed less than 60kg).

Principal Findings:

The COBALT trial was designed to test therapeutic equivalence between two alteplase dosing strategies. Double-bolus alteplase was to be considered at least equivalent to accelerated infusion if the upper boundary of the one-sided 95 percent confidence interval of the difference in 30-day mortality did not exceed 0.40 percentage point. This value represented the lower 95 percent confidence limit of the 1 percent absolute difference in 30-day mortality between an accelerated infusion of alteplase and streptokinase that was observed in the GUSTO I trial.

On January 5, 1996, the trial was stopped because of higher rates of death, stroke, and cardiogenic shock in the double-bolus group than in the accelerated-infusion group.

Thirty-day mortality was higher in the double-bolus group than in the accelerated-infusion group: 7.98 percent as compared with 7.53 percent. The absolute difference was 0.44 percent, with a one-sided 95 percent upper boundary of 1.49 percent, which exceeded the prespecified upper limit of 0.40 percent to indicate equivalence in 30-day mortality between the two regimens.

The rate of any stroke and the rate of hemorrhagic stroke with the double-bolus regimen were 1.92 percent and 1.12 percent, as compared with 1.53 percent and 0.81 percent for the accelerated-infusion group (P = 0.24 and P = 0.23, respectively).

A subgroup of 225 patients enrolled in Brazil had angiographic outcomes evaluated. There were no significant differences in rates of TIMI-3 grade flow in this small series.

A subgroup of 2,282 patients was reviewed for electrocardiographic signs of reperfusion. Three groups of ST-segment resolution were defined: 1. Complete resolution (resolution > 70%), 2. Partial resolution (<70% and >30%), 3. No resolution (<30%). Patients with complete resolution of ST-segment elevation had a lower mortality compared to the other two groups.


Double-bolus alteplase was not shown to be equivalent, according to the prespecified criteria, to accelerated infusion with regard to 30-day mortality. There was also a slightly higher rate of intracranial hemorrhage with the double-bolus method. Therefore, accelerated infusion of alteplase over a period of 90 minutes remains the preferred regimen.


1. N Engl J Med 1997;337:1124-30. Final results

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Acute Heart Failure

Keywords: Shock, Cardiogenic, Stroke, Intracranial Hemorrhages, Streptokinase, Brazil, Chest Pain, Coronary Disease, Fibrinolytic Agents, Electrocardiography, Tissue Plasminogen Activator

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