1 / 28

Evaluation of a novel, rationally designed, low-molecular-weight heparin during elective PCI: Results of the Phase 2 EM

Evaluation of a novel, rationally designed, low-molecular-weight heparin during elective PCI: Results of the Phase 2 EMINENCE Trial. Sunil V. Rao MD for the EMINENCE Investigators. EMINENCE Trial: Disclosures. Presenter disclosures

torsten
Download Presentation

Evaluation of a novel, rationally designed, low-molecular-weight heparin during elective PCI: Results of the Phase 2 EM

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Evaluation of a novel, rationally designed, low-molecular-weight heparin during elective PCI: Results of the Phase 2 EMINENCE Trial Sunil V. Rao MD for the EMINENCE Investigators

  2. EMINENCE Trial: Disclosures Presenter disclosures Research funding: Cordis Corporation, Momenta Pharmaceuticals, Portola Pharmaceuticals Off-label uses: Enoxaparin for PCI, fondaparinux for PCI The EMINENCE Trial was funded by Momenta Pharmaceuticals

  3. Unfractionated heparin Advantages: measurable, reversible, experience Disadvantages: platelet activation, HIT (TS), unreliable degree of antithrombin activity LMWH Advantages: more reliable anticoagulation Disadvantages: not measurable, platelet activation, some degree of discomfort during PCI Fondaparinux Advantages: similar efficacy to LMWH with less bleeding Disadvantages: not demonstrated to be safe during PCI, not easily reversible Bivalirudin Advantages: less bleeding, measurable, short half-life Disadvantages: not more efficacious than UFH, trends toward slightly more ischemic events Available Anticoagulant Options

  4. Undesired Sequences Eliminated and Active Binding Sites Positioned on Opposite Ends of Chain

  5. Low-molecular-weight heparin Increased anti-factor II activity compared with other LMWHs Constant Xa/IIa ratio over time Predictable PK/PD Effects are reversible or neutralized with protamine sulfate High bioavailability: IV and SC administration M118 Structure and Properties

  6. EMINENCE Study Design Randomized, open-label, active-controlled, dose-ranging design Patients undergoing elective PCI Pre-PCI antiplatelet (ASA, clopidogrel) therapy Planned GP IIb/IIIa not allowed Vascular sheaths removed 4 hours after last M118 dose or when ACT < 160 sec if assigned to UFH Closure devices allowed; transfemoral encouraged Phase A: 3 arms – 70 U/kg UFH, 75 IU/kg M118, 100 IU/kg M118 Qualitative review by DSMB after 5% of patients enrolled in 75 IU/kg M118 & UFH arms Phase B: 4 arms – 70 U/kg UFH, 50 IU/kg M118, 75 IU/kg M118, 100 IU/kg M118

  7. EMINENCE Study Design Low-risk patients with stable CAD undergoing elective PCI Pre-treat with ASA (325 mg) and clopidogrel 300 mg prior to PCI Baseline ACT measurement Cardiac catheterization Randomization; ASA + clopidogrel M118 50 anti-Xa IU/kg UFH 70 U/kg IV bolus M118 75 anti-Xa IU/kg M118 100 anti-Xa IU/kg 7-day telephone interview 14-day follow-up 30-day follow-up

  8. EMINENCE Primary End Point Composite of 30-day death, MI, repeat revascularization, catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, or all bleeding (REPLACE-2 scale*) *Major bleeding Transfusion of > 2 units whole blood or packed red blood cells, or Intracranial hemorrhage, or Retroperitoneal hemorrhage, or A fall in hemoglobin (Hgb) > 4 g/dL (or 12.5% of hematocrit) with no bleeding site identified despite attempts to do so, or Spontaneous or non-spontaneous blood loss associated with a Hgb drop > 3 g/dL (or 10% of hematocrit) *Minor bleeding: Any observed bleeding that does not meet major bleeding criteria

  9. EMINENCE Primary Statistical Analysis Primary end point analyzed on an intent-to-treat basis Main comparison: subjects randomized to UFH vs. subjects randomized to experimental therapy (all M118 doses combined) Primary analysis: non-inferiority analysis of UFH vs. pooled M118 doses Assume control (UFH) rate of 8% Goal to reject an absolute 8% increase in the primary outcome Non-inferiority will be achieved if the upper limit of the 95% CI is less than 0.08 A sample size of 600 patients (150/arm) provides 93% power at a one-sided alpha of 0.05

  10. EMINENCE: Secondary Comparisons Prespecified Primary end point Primary end point minus major bleeding 30-day death or MI 30-day death/MI/repeat revascularization Primary end point and bleeding comparisons between UFH and combined M118 without 50 IU/kg dose Post-hoc Composite of 30-day death/MI/repeat revascularization/24-hr major bleeding TIMI major and minor bleeding

  11. EMINENCE Trial Results: Demographics Background characteristics equally balanced across groups Mean age: 63.8 yrs Sex: 72.4% male, 27.6% female Race: 91.7% White (8.0% Hispanic) 5.8% Black 1.2% Asian 0.8% Other 0.6% Native American Median weight: 90.1 kg Mean 1.5 lesions treated across all groups

  12. EMINENCE: Concomitant Procedural Treatments

  13. Coagulation Parameters: Median ACTs

  14. Median ACTs at Time of Sheath Pull ACT is primarily influenced by anti-IIa (thrombin) activity. M118 exhibits a greater degree of anti-Xa activity relative to anti-IIa than UFH (Xa:IIa ratio of 1.4:1 vs. 1:1 for UFH). M118 would be expected to have greater anticoagulant activity at lower ACT values than UFH because the additional anti-Xa activity is not reflected in the measurement of ACT. *Protocol recommended sheath removal if ACT < 160 sec if randomized to UFH or at 4 hours postPCI if randomized to M118; “Per Protocol population

  15. EMINENCE Results: Primary End Point, ITT

  16. Primary and Secondary Efficacy Comparison* *Assumes missing end points were not end points per protocol and statistical analysis plan.

  17. EMINENCE Results: Prespecified Secondary End PointsPrimary End Point Excluding Minor Bleeding

  18. EMINENCE Results: Prespecified Secondary End PointsDeath, MI, or Repeat Revascularization

  19. EMINENCE Results: Prespecified Secondary End PointsDeath or MI

  20. Key Procedural End Point: Bailout GPIIb/IIIa Use

  21. EMINENCE: Protocol-defined Major BleedingREPLACE-2 Scale

  22. EMINENCE: Protocol-defined Minor BleedingREPLACE-2 Scale

  23. EMINENCE Bleeding: TIMI Scale (Post Hoc)

  24. EMINENCE Bleeding: Transfusions 0.0 0.0

  25. EMINENCE: Conclusions (1) M118 is a safe and feasible anticoagulant to administer during elective PCI M118 is comparable to weight-adjusted UFH at preventing a range of PCI-related complications The 75 IU/kg and 100 IU/kg M118 doses appear promising Lower rates of ischemic complications, similar rates of bleeding

  26. EMINENCE: Conclusions (2) Dose-related increase in ACT Similar rates of protocol-defined major bleeding but higher rates of minor bleeding (dose-dependent) The EMINENCE Phase 2 results form the basis for further evaluation of M118 for the treatment of ischemic heart disease

  27. EMINENCE Trial Steering Committee ChiaraMelloni MD MHS, Shelley Myles-DiMauroBSc RN, Samuel Broderick MS, Kristina Sigmon MS, AndrzejKosinski PhD, Neal S. Kleiman MD, Vladimir Dzavik MD, Jean Francois Tanguay MD, Ian Fier MBA, James Roach MD, and Richard C. Becker MD

  28. THANK YOU TO THE EMINENCE INVESTIGATORS AND THE PATIENTS WHO PARTICIPATED IN THE TRIAL

More Related