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Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients: An International Randomized Evaluation - STEEPLE
Description:
The goal of the study was to evaluate the safety and efficacy of intravenous (IV) enoxaparin compared with intravenous unfractionated heparin (UFH) in patients undergoing nonemergent percutaneous coronary intervention (PCI).
Study Design
Study Design:
Patients Enrolled: 3,528
Mean Follow Up: 30 days
Mean Patient Age: Mean age 64 years
Female: 25
Patient Populations:
Age ≥18 years undergoing nonemergent single or multivessel PCI, which is performed with a femoral approach
Exclusions:
Thrombolytic therapy within the prior 24 hours; primary PCI for ongoing ST-segment elevation MI; rescue PCI after failed thrombolysis; any other elective PCI scheduled within the following 30 days after the index PCI; increased bleeding risk (e.g., ischemic stroke within the last year or any previous hemorrhagic stroke, intracranial tumor or aneurysm, trauma or major surgery, bypass surgery in prior month, active bleeding), uncontrolled arterial hypertension, recent (<48 hours) or planned spinal/epidural anesthesia or puncture, impaired hemostasis, history of hypersensitivity or contraindication to heparin or low molecular weight heparin, treatment with oral anticoagulant therapy within 72 hours prior to inclusion or current need for vitamin K antagonist therapy, treatment with a direct thrombin inhibitor, low molecular weight heparin, or UFH during the 24 hours prior to enrollment, use of abciximab within the prior seven days, or tirofiban or eptifibatide within the prior 12 hours before PCI
Primary Endpoints:
Non-CABG related major and minor bleeding by 48 hours post-PCI
Secondary Endpoints:
Percent of patients reaching target anticoagulation levels at the start and end of the procedure
Composite of non-CABG major bleed through 48 hours, all-cause mortality, MI, and urgent target vessel revascularization at 30 days
Drug/Procedures Used:
Patients were randomized in an open-label manner to IV enoxaparin 0.5 mg/kg (n=1,070), IV enoxaparin 0.75 mg/kg (n=1,228), or an activated clotting time (ACT)-adjusted UFH regimen (n=1,230). The target ACT in the UFH group was 300-350 without use of a glycoprotein (GP) IIb/IIIa (70-100 IU) dose, or 200-300 with use of a GP IIb/IIIa (50-70 IU) dose. Randomization was stratified by the investigator's intended use of GP IIb/IIIa inhibitor.
Principal Findings:
Enrollment in the enoxaparin 0.5 mg/kg dose was stopped prematurely by the Data Safety Monitoring Committee near the end of the trial at the objection of the Steering Committee due to a difference in mortality between the three groups (three-way p=0.02); however, there was no significant difference in mortality between the enoxaparin 0.5 mg/kg dose group and the UFH group when compared directly (p=0.15), leading to the Steering Committee's objection.
Drug-eluting stents were used in 57% of patients, and multivessel PCI was performed in 16% of patients. GP IIb/IIIa inhibitors were used in 41% of patients. The percentage of patients meeting target Xa levels both before and at the end of the PCI was higher in both enoxaparin arms than the percentage of patients meeting the target ACT levels in the UFH arm (78.8% for 0.5 mg/kg, 91.8% for 0.75 mg/kg, 19.7% for UFH; p<0.001 for each enoxaparin group vs. UFH).
The primary endpoint of non-CABG major or minor bleeding by 48 hours occurred in 5.9% of the enoxaparin 0.5 mg/kg group, 6.5% of the enoxaparin 0.75 mg/kg group, and 8.5% of the UFH group (p=0.01 for 0.5 mg/kg vs. UFH; p=0.051 for 0.75 mg/kg vs. UFH).
Major bleeding occurred in 1.2% of each of the enoxaparin groups and 2.8% of the UFH group (p=0.004 for 0.5 mg/kg vs. UFH; p=0.007 for 0.75 mg/kg vs. UFH). There was no difference in minor bleeding (4.8%, 5.3%, and 5.9%, respectively). The composite of non-CABG major bleed through 48 hours, all-cause mortality, myocardial infarction (MI), or urgent target vessel revascularization at 30 days occurred in 6.9% of the 0.5 mg/kg group, 7.7% of the 0.75 mg/kg group, and 8.2% of the UFH group (p=NS). There was also no difference in death or MI individually.
Interpretation:
Among patients undergoing nonemergent PCI, treatment with reduced dose enoxaparin was associated with lower rates of major or minor bleeding by 48 hours post-PCI compared with treatment with ACT-driven UFH.
Prior smaller trials have evaluated reduced doses of enoxaparin as an alternative to UFH in patients undergoing PCI. However, none have been adequately powered to fully assess safety. Use of enoxaparin in the catheterization laboratory may not only offer a potential safety advantage with the lower bleeding events, but it can also be easier to use, as it does not require dose adjustment based on ACT monitoring and can facilitate quicker sheath removal.
Indeed, the present trial demonstrated as a secondary endpoint that more patients in the enoxaparin groups met target Xa levels than the UFH group met target ACT levels. While enrollment in the lower enoxaparin dose group was stopped prematurely due to a slight excess in mortality across the three groups (although not different from UFH for the individual comparison), further examination of the data by the trial group showed the result may have been spurious, given that there was no consistent cause of death or increased risk for other endpoints such as MI or urgent target vessel revascularization. Additionally, at the end of the trial with full 30-day data, mortality did not differ between the three groups.
References:
Montalescot G, et al. Enoxaparin versus Unfractionated Heparin in Elective Percutaneous Coronary Intervention. N Engl J Med 2006;355:1006-17.
Presented by Dr. Gilles Montalescot at the European Society of Cardiology Hot Line Session, September 2005.
Keywords: Cause of Death, Myocardial Infarction, Enoxaparin, Drug-Eluting Stents, Research Personnel, Catheterization, Heparin, Platelet Membrane Glycoprotein IIb, Percutaneous Coronary Intervention, Platelet Glycoprotein GPIIb-IIIa Complex
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