STEEPLE: Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients: An International Randomized Evaluation

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).

Drugs/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, and aspirin in 85%. 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, 91.7% 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 6.0% of the enoxaparin 0.5 mg/kg group, 6.6% of the enoxaparin 0.75 mg/kg group, and 8.7% of the UFH group (p=0.014 for 0.5 mg/kg vs. UFH; p=0.052 for 0.75 mg/kg vs. UFH). The lower bleeding rate with enoxaparin was observed both in the strata of patients intended to be treated with GP IIb/IIIa inhibitors and those not intended to be treated with GP IIb/IIIa inhibitors, as well as in a per protocol analysis.

Major bleeding occurred in 1.2% of each of the enoxaparin groups and 2.8% of the UFH group (p=0.005 for 0.5 mg/kg vs. UFH; p=0.007 for 0.75 mg/kg vs. UFH). There was no difference in minor bleeding (4.9%, 5.4%, 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 7.2% of the 0.5 mg/kg group, 7.9% of the 0.75 mg/kg group, and 8.4% 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 was most likely 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.

Conditions

• Coronary heart disease

Therapies

• Anticoagulant
• Anticoagulant / Enoxaparin
• Anticoagulant / Heparin

Study Design
Randomized.
Patients Enrolled:3,528
Mean Follow-Up:30 days
Mean Patient Age:Mean age 64 years
% Female:25

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

Patient Population

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

References

Presented by Dr. Gilles Montalescot at the European Society of Cardiology Hot Line Session, September 2005.