sunil v. rao md for the eminence investigators evaluation of a novel, rationally designed,...
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Sunil V. Rao MD
for the EMINENCE Investigators
Evaluation of a novel, rationally Evaluation of a novel, rationally designed, low-molecular-weight designed, low-molecular-weight
heparin during elective PCI: heparin during elective PCI: Results of the Phase 2 Results of the Phase 2
EMINENCE TrialEMINENCE Trial
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
Available Anticoagulant OptionsAvailable Anticoagulant Options
Unfractionated heparinUnfractionated heparin Advantages: measurable, Advantages: measurable,
reversible, experiencereversible, experience Disadvantages: platelet Disadvantages: platelet
activation, HIT (TS), activation, HIT (TS), unreliable degree of unreliable degree of antithrombin activityantithrombin activity
LMWHLMWH Advantages: more reliable Advantages: more reliable
anticoagulationanticoagulation Disadvantages: not Disadvantages: not
measurable, platelet measurable, platelet activation, some degree of activation, some degree of discomfort during PCIdiscomfort during PCI
FondaparinuxFondaparinux Advantages: similar Advantages: similar
efficacy to LMWH with efficacy to LMWH with less bleedingless bleeding
Disadvantages: not Disadvantages: not demonstrated to be safe demonstrated to be safe during PCI, not easily during PCI, not easily reversiblereversible
BivalirudinBivalirudin Advantages: less Advantages: less
bleeding, measurable, bleeding, measurable, short half-lifeshort half-life
Disadvantages: not more Disadvantages: not more efficacious than UFH, efficacious than UFH, trends toward slightly trends toward slightly more ischemic eventsmore ischemic events
Undesired Sequences Eliminated and Active Binding Sites Positioned on Opposite Ends of Chain
M118 Structure and PropertiesM118 Structure and Properties
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
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
Low-risk patients with stable CAD undergoing elective PCIPre-treat with ASA (325 mg) and clopidogrel 300 mg prior to PCI
Baseline ACT measurement
UFH 70 U/kg IV bolus
M118 75 anti-Xa IU/kg
M118 100 anti-Xa IU/kg
Cardiac catheterization
Randomization; ASA + clopidogrel
7-day telephone interview
14-day follow-up
30-day follow-up
M118 50 anti-Xa IU/kg
EMINENCE Study Design
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
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
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
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
EMINENCE: Concomitant Procedural Treatments
UFH 70N=151
M118 50N=44
M118 75N=152
M118 100N=156
M118 AllN=352
DES 83.3% 80.5% 84.1% 83.8% 83.5%
Closure device
53.0% 43.2% 55.3% 55.2% 53.7%
Clopidogrel < 300 mg
6.8% 7.0% 8.6% 5.3% 6.9%
Clopidogrel ≥ 300 mg
93.2% 93.0% 91.4% 94.7% 93.1%
Coagulation Parameters: Median ACTs
UFH 70N=151
M118 50N=44
M118 75N=152
M118 100N=156
No closure device* 155 158 160 169
With closure device 251 206 237 271
*Protocol recommended sheath removal if ACT < 160 sec if randomized to UFH or at 4 hours postPCI if randomized to M118; “Per Protocol population
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.
EMINENCE Results: Primary End Point, ITT
Primary End Point
31.1
22.7
28.330.1
28.4
0
5
10
15
20
25
30
35
UFH 70 M118 50 M118 75 M118 100 M118 Combined
%
M118 Group for Comparison w/ UFH
M118 Event Rate
UFH Event Rate
Upper 95% Confidence Limit
in Event Rates
Is M118 Event Rate <UFH +
Delta?
Primary - M118 combined
28.4% 31.1% 4.6% Yes
M118 50 IU 22.7% 31.1% 3.7% Yes
M118 75 IU 28.3% 31.1% 5.8% Yes
M118 100 IU 30.1% 31.1% 7.7% Yes
*Assumes missing end points were not end points per protocol and statistical analysis plan.
Primary and Secondary Efficacy Comparison*
EMINENCE Results: Prespecified Secondary End PointsPrimary End Point Excluding Minor Bleeding
Primary End Points (Excluding Minor Bleeds)
17.9
11.4
12.5
14.1
13.1
0
2
4
6
8
10
12
14
16
18
UFH 70 M118 50 M118 75 M118 100 M118 Combined
%
EMINENCE Results: Prespecified Secondary End PointsDeath, MI, or Repeat Revascularization
Death, MI, Revascularization
8.6
11.4
7.9
6.4
7.7
0
2
4
6
8
10
12
UFH 70 M118 50 M118 75 M118 100 M118 Combined
%
EMINENCE Results: Prespecified Secondary End PointsDeath or MI
Key Procedural End Point: Bailout GPIIb/IIIa Use
EMINENCE: Protocol-defined Major BleedingREPLACE-2 Scale
Bleeding Complications: Major Bleeds
1.3
2.3
0.7
1.3
0
0.5
1
1.5
2
2.5
UFH 70 M118 50 M118 75 M118 100
%
EMINENCE: Protocol-defined Minor BleedingREPLACE-2 Scale
Bleeding Complications: Minor Bleeds
15.9
11.4
17.1
19.9
0
2
4
6
8
10
12
14
16
18
20
UFH 70 M118 50 M118 75 M118 100
%
EMINENCE Bleeding: TIMI Scale (Post Hoc)
EMINENCE Bleeding: Transfusions
0.0 0.0
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
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
EMINENCE Trial Steering CommitteeEMINENCE Trial Steering Committee
Chiara Melloni MD MHS, Chiara Melloni MD MHS, Shelley Myles-DiMauro BSc RN, Samuel Shelley Myles-DiMauro BSc RN, Samuel
Broderick MS, Kristina Sigmon MS, Andrzej Broderick MS, Kristina Sigmon MS, Andrzej Kosinski PhD, Neal S. Kleiman MD, Kosinski PhD, Neal S. Kleiman MD,
Vladimir Dzavik MD, Jean Francois Tanguay Vladimir Dzavik MD, Jean Francois Tanguay MD, Ian Fier MBA, James Roach MD, and MD, Ian Fier MBA, James Roach MD, and
Richard C. Becker MD Richard C. Becker MD
THANK YOU TO THE EMINENCE THANK YOU TO THE EMINENCE INVESTIGATORS AND THE INVESTIGATORS AND THE
PATIENTS WHO PARTICIPATED IN PATIENTS WHO PARTICIPATED IN THE TRIALTHE TRIAL