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Continuous Infusion Versus Double-Bolus Administration of Alteplase - COBALT
Description:
Front-loaded vs. double-bolus alteplase for 30-day mortality in acute MI.
Hypothesis:
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.
Exclusions:
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.
Interpretation:
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.
References:
1. N Engl J Med 1997;337:1124-30. Final results
Keywords: Shock, Cardiogenic, Stroke, Intracranial Hemorrhages, Streptokinase, Brazil, Chest Pain, Coronary Disease, Fibrinolytic Agents, Electrocardiography, Tissue Plasminogen Activator
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