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Assessment of the Safety and Efficacy of a New Thrombolytic Regimen - ASSENT 3 PLUS
Description:
The goal of the ASSENT 3 PLUS trial was to examine the use of the low molecular weight heparin enoxaparin versus unfractionated heparin in combination with TNK in the pre-hospital setting for ST-segment elevation myocardial infarction (STEMI).
Hypothesis:
The efficacy of treatment with enoxaparin plus TNK will be superior to treatment with unfractionated heparin (UFH) plus TNK in the pre-hospital setting for STEMI.
Study Design
Study Design:
Patients Enrolled: 1,639
Mean Follow Up: 30 days
Female: 23
Patient Populations:
Age >=18 years, symptom onset <6 hours prior to randomization, ST-segment elevation of 0.1 mV in 2 limb leads or left bundle-branch block.
Exclusions:
Systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg; use of glycoprotein IIb/IIIa inhibitors within the preceding 7 days; major surgery, biopsy of a parenchymal organ, or substantial trauma within the preceding 2 months; any head or other trauma occurring after onset of current myocardial infarction; any known history of stroke, transient ischemic attack, or dementia; any known structural damage to the central nervous system; current therapy with oral anticoagulants; treatment with UFH >5000 U or a therapeutic subcutaneous dose of LMWH within the previous 6 hours; known thrombocytopenia (<100 000 cells/µL); known renal insufficiency (serum creatinine >2.5 mg% for men and >2.0 mg% for women); sustained cardiopulmonary resuscitation (>10 minutes) in the previous 2 weeks; pregnancy, lactation, or parturition in the previous 30 days; active participation in another investigative drug or device study in the previous 30 days; previous enrollment in this study; any other disorder that would place the patient at increased risk; and inability to follow the protocol and to comply with the follow-up requirements.
Primary Endpoints:
Efficacy: composite of 30-day death and in-hospital MI or refractory ischemia. Efficacy plus safety: composite of 30-day death and in-hospital MI, refractory ischemia, ICH, or major bleed.
Secondary Endpoints:
Individual components of composite endpoints: 30-day death and in-hospital MI, refractory ischemia, ICH, major bleed.
Drug/Procedures Used:
Patients were evaluated at home or in the ambulance by the emergency medical team. A 12-lead ECG was transmitted to the Emergency Department from the ambulance, myocardial infarction was assessed, randomization was assigned, and treatment was begun during transport. Patients were randomized to enoxaparin (n=818) (30 mg bolus plus 1 mg/kg SC every 12 hours until hospital discharge or 7 days) with full dose TNK or UFH (n=821) (60 IU/kg plus infusion of 12 IU/kg/hr for 48 hours with a target PTT of 50-70 seconds) with full dose TNK.
Concomitant Medications:
TNK
Principal Findings:
The composite efficacy endpoint (death at 30 days or in-hospital myocardial infarction [MI] or refractory ischemia) trended lower in the enoxaparin arm compared with the UFH arm, but did not reach statistical significance (14.2% vs 17.4%, p=0.080). The efficacy plus safety endpoint (efficacy endpoint plus intracranial hemorrhage [ICH] or major bleed) did not differ between the 2 arms (18.3% enoxaparin vs 20.3% UFH, p=0.30). Among the individual components of the composite endpoint, recurrent MI was lower in the enoxaparin arm (3.55% vs 5.85%, p=0.028) as was refractory ischemia (4.40% vs 6.46%, p=0.067). However, the enoxaparin arm had a higher rate of stroke (2.93% vs 1.34%, p=0.026) and ICH (2.20% vs 0.97%, p=0.047), and a trend toward a higher rate of major bleed (4.04% vs 2.8%, p=0.168). The 30-day mortality rate was 7.49% in the enoxaparin arm and 5.99% in the UFH arm (p=0.234). In a subgroup analysis, the efficacy endpoint was lower in the enoxaparin arm in patients age <=75 (11.2% vs 15.2%, p=0.033) but no difference was seen in the age >75 group (35.6% vs 33.3%, p=0.694). There was a significant interaction with age and enoxaparin treatment for ICH (p=0.04), with an ICH rate of approximately 7% in the enoxaparin arm vs <1% in the UFH arm (p=0.01). Compared with the ASSENT 3 trial, the time to treatment was approximately 45 minutes shorter with the pre-hospital treatment regimen in ASSENT-3 PLUS. However, there were other baseline differences in the two populations.
Interpretation:
In the pre-hospital setting, treatment of STEMI patients with enoxaparin plus TNK was not associated with a significant reduction in the primary composite efficacy endpoint of 30 day death and in-hospital MI or refractory ischemia compared UFH plus. Subgroup analysis suggests that in younger patients (age <=75), the enoxaparin treatment may prove beneficial. However, this interpretation should be drawn cautiously, as it is derived from a subgroup analysis. There was a significant interaction between age and enoxaparin treatment for ICH. Given this finding, further study of a reduced or weight-adjusted dosing of enoxaparin may be warranted in elderly and low weight patients. Use of reduced dose enoxaparin in addition to TNK will be further investigated in the upcoming EXTRACT-TIMI 25 trial. Additionally, it is important to note that the ASSENT-3 PLUS study was conducted in the pre-hospital setting, and extrapolation of the data to the hospital setting may not be valid.
References:
Circulation. 2003;108:r1-r8. Presented at AHA 2002, late breaking clinical trials.
Keywords: Time-to-Treatment, Myocardial Infarction, Stroke, Intracranial Hemorrhages, Enoxaparin, Heparin, Low-Molecular-Weight, Bundle-Branch Block, Emergency Service, Hospital, Electrocardiography, Hemorrhage
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