Evaluation of M118 IN pErcutaNeous Coronary intErvention - EMINENCE

Description:

This was a phase II trial comparing three doses of intravenous M118 (a novel synthetic anticoagulant with both antithrombin and anti Xa activity) with unfractionated heparin (UFH) in patients undergoing elective percutaneous coronary intervention (PCI).

Hypothesis:

M118 would be noninferior to UFH as an anticoagulant in patients undergoing elective PCI. The upper limit of non-inferiority was defined as an absolute increase of 8% in the primary endpoint in the combined M118 arms, assuming an event rate of 8% in the UFH arm.

Study Design

  • Parallel

Patients Enrolled: 503
Mean Follow Up: 30 days
Mean Patient Age: Median: 63.8 years
Female: 28

Patient Populations:

  • Age ≥19 years
  • Stable coronary artery disease amenable to PCI

Exclusions:

  • ACT >200 seconds before study drug administration
  • Hemoglobin <10 mg/dl="">
  • Platelet count <100,000 or="">600,000/mm3
  • Creatinine clearance <30 ml/min="">
  • Baseline aspartate aminotransferase/alanine aminotransferase >upper limit of normal
  • MI within 7 days of index procedure
  • Known allergy to heparin, pork, or pork-related contents
  • Suspected aortic dissection
  • Stroke/transient ischemic attack within 3 months of index procedure
  • Active bleeding or bleeding diathesis (including need for oral anticoagulant therapy)
  • Hemodynamic instability at the time of PCI
  • Trauma or major surgery in the 30 days before index PCI, or planned surgery within 30 days of PCI
  • Receipt of LMWH within the 12 hours before PCI if creatinine clearance is >60 ml/min or within 24 hours before PCI if creatinine clearance is &le;60 ml/min
  • Planned use of GP IIb/IIIa inhibitors, or atherectomy
  • Target vessel is unprotected left main coronary artery, or chronic total occlusion present for &ge;3 months

Primary Endpoints:

  • Composite of death/MI/repeat revascularization/stroke/24-hour thrombocytopenia/24-hour major + minor bleeding/bailout use of GP IIb/IIIa inhibitors during the index PCI/catheter-related thrombus formation during index PCI at 30 days
  • Protocol defined major and minor bleeding

Secondary Endpoints:

  • Primary endpoint excluding bleeding
  • Death or MI
  • Death, MI, or revascularization
  • Death, MI, revascularization, or major bleeding

Drug/Procedures Used:

Study drug was administered as an intravenous bolus before the coronary guidewire crossed the lesion. For patients assigned to UFH, the initial dose was 70 U/kg (maximum 5000 U), and a minimum activated clotting time (ACT) of 200 seconds was necessary before the lesion could be crossed. Additional boluses of 20 U/kg could be administered if the ACT value before or during PCI was &le;200. Patients randomized to the M118 arms received either 50, 75, or 100 IU/kg of M118.

Because the optimal ACT value for M118 during PCI has not been established, additional M118 boluses were guided by procedure duration and not by specific ACT values: An additional bolus of one-half of the initial M118 dose was given (25, 37.5, or 50 IU/kg) if the procedure was not completed 30 minutes after the initial bolus. Further boluses at one-half the initial dose were given at subsequent 30-minute intervals if needed.

Concomitant Medications:

All patients were required to receive 325 mg of aspirin within 12 hours of the index PCI and &ge;300 mg of clopidogrel within 6 hours of the index PCI. Aspirin was then continued at a dose of 75-325 mg daily for &ge;30 days. Similarly, clopidogrel was continued at a dose of 75 mg daily for 30 days.

Principal Findings:

A total of 503 patients were randomized, 151 to UFH, 44 to 50 IU/kg M118, 152 to 75 IU/kg of M118, and 156 to 100 IU/kg M118. The 50 IU/kg arm was added after the trial was started, but then terminated after 44 patients were enrolled, based on Data Safety and Monitoring Board recommendations (due to an unexplained death from multisystem organ failure in this arm, with concerns for causality). Baseline characteristics were fairly similar between the arms. About 33% had diabetes, 34.4% had prior myocardial infarction (MI), 17% had prior coronary artery bypass grafting, and 9.5% had a history of congestive heart failure. The predominant vascular access approach was transfemoral (99.6%) with 6F sheaths. Angiographically, about 12% had three-vessel disease.

ACTs demonstrated a dose-dependent response in all M118 arms at all time points. Procedural success was noted in 95% of the patients. Drug-eluting stents were deployed in about 83% of the patients. Immediate complications included abrupt closure (0.5%), new thrombus (0.2%), and dissection (2%). The incidence of the primary endpoint at 30 days (death/MI/repeat revascularization/stroke/24-hour thrombocytopenia/24-hour major + minor bleeding/bailout use of glycoprotein [GP] IIb/IIIa inhibitors during the index PCI/catheter-related thrombus formation during index PCI) was similar between the UFH and 50, 75, and 100 IU/kg M118 arms (31.1% vs. 22.7% vs. 28.3% vs. 30.1%, p

The individual endpoints including 30-day mortality (0% vs. 2.3% vs. 0.7% vs. 0%) were similar between the four arms. The composite endpoint of death, MI, repeat revascularization, or major bleeding was also similar (8.6% vs. 11.4% vs. 8.6% vs. 7.7% vs. 8.5%) between the four arms. Protocol-defined major bleeding was similar (1.3% vs. 2.3% vs. 0.7% vs. 1.3%), whereas minor bleeding showed a dose-related response in the M118 arms (15.9% vs. 11.4% vs. 17.1% vs. 19.9%) .

Interpretation:

The results of this phase 2 trial indicate that M118 is noninferior to UFH for ischemia and bleeding-related outcomes in patients undergoing elective PCI, although minor bleeding seems to be higher with higher doses. It also seems to be well tolerated, and shows a dose-dependent increase in ACT.

M118 is a novel synthetic anticoagulant, with action against both thrombin (factor IIa), similar to bivalirudin, and factor Xa, similar to low molecular weight heparin (LMWH) (ratio of activity = 1:1.4). It thus has several exciting properties and potential benefits. The safety and efficacy of M118 for the treatment of higher-risk patients and in combination with GP IIb/IIIa inhibitors and other emerging antiplatelet agents will need to be evaluated in adequately powered phase 3 trials.

References:

Rao SV, Melloni C, Myles-Dimauro S, et al., on behalf of the EMINENCE Investigators. Evaluation of a new heparin agent in percutaneous coronary intervention: results of the phase 2 evaluation of M118 IN pErcutaNeous Coronary intErvention (EMINENCE) Trial. Circulation 2010;121:1713-21.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and Heart Failure, Lipid Metabolism, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Thrombin, Platelet Aggregation Inhibitors, Drug-Eluting Stents, Heparin, Low-Molecular-Weight, Hirudins, Platelet Membrane Glycoprotein IIb, Percutaneous Coronary Intervention, Thrombosis, Heart Failure, Recombinant Proteins, Peptide Fragments, Factor Xa, Coronary Artery Bypass, Diabetes Mellitus, Thrombocytopenia


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