Thrombolysis in Myocardial Infarction Trial, Phase 14 - TIMI 14

Description:

Abciximab with thrombolytic therapy for coronary patency in acute MI.

Hypothesis:

To assess the effect of combination abciximab and thrombolytic therapy on TIMI-3 flow at 90 minutes for patients with myocardial infarction.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 301 (Dose confirmation phase)
Mean Follow Up: 90 minutes (angiographic)
Female: 0

Patient Populations:

Between the ages of 18 and 75 years
Presented within 12 hours of ischemic symptoms lasting at least 30 minutes
At least 1 mm elevation of the ST segment

Exclusions:

Prior coronary bypass surgery
Cardiogenic shock
Excess risk for bleeding
Thrombolytic therapy within the preceding 7 days

Primary Endpoints:

TIMI-3 flow at 60 and 90 minutes

Secondary Endpoints:

Major bleeding

Drug/Procedures Used:

The dose-finding phase of the study evaluated abciximab with t-PA, abciximab with streptokinase, and abciximab alone. Dose-confirmation phases assessed the effect of abciximab with 50mg t-PA combined with very-low-dose heparin regimens.

Concomitant Medications:

All patients received aspirin. All patients who received abciximab also received heparin.

Principal Findings:

Patients randomized to low-dose heparin with abciximab (either alone or with reduced-dose thrombolytic therapy) or standard-dose heparin (70 U/kg bolus followed by 15 U/kg/hr) with accelerated t-PA (up to 100mg). Patients who received abciximab (0.25 mg/kg bolus followed by 0.125 mcg/kg/min infusion for 12 hours) were further randomized to receive 1 of 12 thrombolytic doses, or no concomitant thrombolytic. Eight different t-PA regimens were tested, representing total doses of 20, 35, 50, and 65mg given as bolus, 30-, or 60- minute infusions. Four doses of streptokinase (500,000, 750,000, 1.25 million and 1.5 million units) were evaluated. A blinded core laboratory interpreted 90-minute angiograms for 98% of patients.

TIMI-3 flow at 90 minutes was achieved in 57% of patients given t-PA alone, compared to 32% of patients given abciximab alone. (For comparison, the TIMI-3 reperfusion rate was 30% for streptokinase alone in a meta-analysis of TIMI-1 and GUSTO-I results.)

Abciximab coupled with streptokinase produced TIMI-3 flow in 39-47% of patients. An arm combining abciximab with 1.5 million units of streptokinase arm was terminated early because of excess bleeding.

Abciximab therapy with t-PA produced TIMI-3 flow in 38-77% of patients. The most promising regimen used 50mg of t-PA: a 15mg t-PA bolus, followed by 35mg administered over 60 minutes.

Angiographic measurements of the speed and extent of thrombolysis were evaluated in terms of 60 and 90 minute TIMI-3 flow. The control (t-PA alone) arms had TIMI-3 flow in 45% of patients at 60 minutes and 57% of patients at 90 minutes, consistent with previous angiographic studies of t-PA. The best t-PA arm (bolus plus 60-minute infusion) had 65% TIMI-3 flow at 60 minutes (n=51) and 72% TIMI-3 flow at 90 minutes (n=101).

The rate of intracranial, retroperitoneal, or other major hemorrhage was 6% for the t-PA control, abciximab control, and pooled t-PA with abciximab arms. The major hemorrhage rate was 12% in the collective experience with streptokinase and abciximab.

In the dose-confirmation phase, the investigators examined the abciximab with 50mg t-PA regimen. Simultaneously, patients were randomized to low-dose heparin or very low-dose heparin (30 U/kg bolus with 4U/kg/hr infusion). TIMI-3 flow rates at 90 minutes were 63% for the control patients who received t-PA alone (n=208), compared to 77% for patients receiving abciximab with 50mg t-PA and low-dose heparin (n=93). The incidence of TIMI-3 flow was 68% for patients receiving abciximab, 50 mg t-PA, and very-low-dose heparin.

Interpretation:

Combination abciximab and reduced-dose t-PA therapy appears to produce TIMI-3 flow in more patients than either agent alone. The 77% incidence of TIMI-3 flow rivals the reperfusion rate observed for primary angioplasty in GUSTO IIb (73%). Reperfusion may be faster for combination therapy, although the percentage of patients with TIMI-3 flow at 60 minutes may simply reflect the greater proportion of patients that do reperfuse at 90 minutes. The bleeding risk in the dose-ranging phase appears to be acceptable for the combination regimen selected for further study. Further trials must examine the effect of combination antiplatelet and thrombolytic therapy on clinical outcomes.

References:

1. Presented at the XXth Congress of the European Society of Cardiology, Vienna, 1998

Clinical Topics: Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Lipid Metabolism

Keywords: Thrombolytic Therapy, Myocardial Infarction, Platelet Aggregation Inhibitors, Streptokinase, Heparin, Fibrinolytic Agents, Immunoglobulin Fab Fragments, Tissue Plasminogen Activator, Angioplasty


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