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Vasoflux International Trial for Acute Myocardial Infarction Lysis - VITAL
Description:
Vasoflux International Trial for Acute Myocardial Infarction Lysis (VITAL) was a randomized, single-blind, phase 2, dose-escalating, multicenter trial of the vasoflux versus unfractionated heparin (UFH) in patients with acute ST-segment elevation myocardial infarction (MI) undergoing treatment with streptokinase. Vasoflux is a novel anticoagulant, derived from low-molecular-weight heparin and chemically modified to have decreased factor Xa activity and increased affinity for factor IXa and heparin cofactor II.
Hypothesis:
Vasoflux will be associated with improved angiographic patency of the infarct-related artery compared to UFH in patients undergoing thrombolytic therapy with streptokinase for treatment of ST-segment elevation MI.
Study Design
Study Design:
Patients Enrolled: 277
Mean Follow Up: 30 days
Female: ~20
Patient Populations:
Age >18 years, the presence of ischemic pain lasting >30 minutes associated with either >2 mm ST-segment elevation in two contiguous precordial leads or >1 mm in two contiguous limb leads or new left bundle branch block, and the ability to be randomized within six hours of onset of symptoms
Exclusions:
Uncontrolled hypertension, hemodynamic instability, known hepatic or renal failure, prior stroke, a history of bleeding disorders, or other conditions that may increase the risk of bleeding
Primary Endpoints:
Percentage of patients achieving TIMI-3 flow of the infarct-related vessel at 90-minute angiogram
Secondary Endpoints:
Corrected TIMI frame count at 60 and 90 minutes. Bleeding events, classified as severe or life-threatening if intracranial or if causing hemodynamic compromise requiring inotropic support, transfusion, fluid replacement, surgical intervention, or resuscitation; as moderate if requiring transfusion only without hemodynamic compromise; and as mild if not requiring transfusion and not causing hemodynamic compromise.
Drug/Procedures Used:
Patients were randomized to one of four doses of IV vasoflux or UFH. Vasoflux was given in four successive dose groups of 1, 4, 8, or 16 mg/kg followed by 1, 4, 8, or 16 mg/kg/h as continuous infusion. UFH was given at 70 IU/kg bolus followed by 14 IU/kg/h. Study drugs were administered until completion of a 90-minute angiogram.
After study drug completion, UFH could be resumed according to local practice. All patients received streptokinase at 1.5 million units over a 45-60 minute period. The study was open-label, but events were adjudicated in a blinded manner.
Concomitant Medications:
All patients received aspirin (150-350 mg) before study drug administration. Use of other antiplatelets or anticoagulants was not allowed.
Principal Findings:
A total of 277 patients were randomized (59 to UFH, 52 to 4 mg/kg, 63 to 8 mg/kg, and 66 to 16 mg/kg). The 1 mg/kg arm was terminated early, after 37 patients, because no excess in bleeding events occurred and efficacy was expected to be low. The groups were well-matched at baseline in terms of age, gender, diabetes, hypertension, and infarct-related vessel. Across all treatment groups, 92% of patients underwent angiography at 90 minutes to assess the primary endpoint.
For the primary endpoint, rates of TIMI-3 flow in the infarct-related vessel were similar across all groups (41% UFH, 36% 1 mg/kg, 35% 4 mg/kg, 36% 8 mg/kg, 42% 16 mg/kg, p=NS for all comparisons). Median corrected TIMI frame count was similar across all groups (37 UFH, 44 1 mg/kg, 38 4 mg/kg, 37 8 mg/kg, 36 16 mg/kg, p=NS for all comparisons). Major bleeding events were significantly increased in the vasoflux 16 mg/kg arm compared to UFH (28% vs. 8%, p=0.01). There was a trend toward increased major bleeding events in the 8 mg/kg arm compared to UFH (13% vs. 8%, p=0.58). Major bleeding events in the other vasoflux dosage arms were not significantly increased compared to UFH.
Mortality at 30 days was similar between groups (3% UFH, 0% 1 mg/kg, 2% 4 mg/kg, 5% 8 mg/kg, and 6% 16 mg/kg, p=NS), as was nonfatal reinfarction (3% UFH, 3% 1 mg/kg, 14% 4 mg/kg, 3% 8 mg/kg, and 2% 16 mg/kg, p=NS).
Interpretation:
Among patients with acute ST-segment elevation MI, vasoflux was not associated with improved vessel patency rates compared to UFH. Higher doses of vasoflux were associated with increased bleeding events compared to UFH. These findings suggest that targeting factor IXa and heparin cofactor II may not be a useful adjunct to thrombolysis.
References:
Peters RJ, Spickler W, Theroux P, et al. Randomized comparison of a novel anticoagulant, vasoflux, and heparin as adjunctive therapy to streptokinase for acute myocardial infarction: results of the VITAL study (Vasoflux International Trial for Acute Myocardial Infarction Lysis). Am Heart J 2001;142:237-43.
Keywords: Thrombolytic Therapy, Myocardial Infarction, Factor IXa, Heparin Cofactor II, Heparin, Fibrinolytic Agents, Pain, Single-Blind Method, Streptokinase, Bundle-Branch Block, Factor Xa, Hypertension, Diabetes Mellitus
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