Study program to Evaluate the Prevention of Ischemia with direct AntiXa inhibition: SEPIAACS1 TIMI 4

1
Study program to Evaluate the Prevention of
Ischemia with direct Anti-Xa inhibitionSEPIA-AC
S1 TIMI 42
A randomized, double-blind, triple-dummy,
dose-ranging study to evaluate the clinical
efficacy and safety of OTAMIXABAN in patients
with NSTEACS and planned early invasive strategy
Marc S. Sabatine, MD, MPHon behalf of the
SEPIA-ACS1 TIMI 42 Investigators
M Sabatine has received honoraria and consulting
fees from sanofi-aventis and honoraria from
Bristol-Myers Squibb.
1
SEPIA-ACS1 TIMI 42 was supported by a research
grant from sanofi-aventis
2
Coagulation Cascade

• OTAMIXABAN
• Specific, Direct, IV, Factor Xa Inhib
• Proximal inhib of coag cascade
• Small molecule
• Inhibits clot-bound factor Xa,which is
  inaccessible tolarge molecule indirect
  inhibitors
• Favorable PK/PD profile
• Short-acting (half-life 30 min)
• Wt-based bolus infusion
• No need for monitoring
• No significant renal elimination

Extrinsic Pathway Tissue factor, FVII
Intrinsic Pathway FXII, FXI, FIX, FVIII, PL, Ca2
Common Pathway Factor X ? Factor Xa
Factor V
Thrombin (F IIa)
Prothrombin (F II)
Fibrin Formation Platelet Aggregation
2
3
Clinical Efficacy Composite
SEPIA-PCI
947 patients undergoing non-urgent PCI Greater
reduction in thrombin generation w/ OTAM vs. UFH
mg/kg/hr
3
Cohen M et al. Circulation 20071152642
4
Study DesignPhase II, Dose-Ranging
Mod-to-High Risk NSTE ACS (ST deviation or ?
biomarker)w/ Planned Early Invasive Strategy
Aspirin Clopidogrel
R
at or before randomization
double-blind
Blinded bail-out eptifibatide if rec. ischemia or
thrombotic complic. during PCI
OTAM 0.035 (n125)
OTAM 0.070 (n676)
OTAM 0.140 (n658)
OTAM 0.175 (n671)
OTAM 0.105 (n662)
UFH Eptifi. (n449)
Coronary angiography ? PCI within 3 days
OTAM / UFH until end of PCI (or longer if
indic) Eptifibatide until 18-24 h after end of PCI
1 EP Death, MI, Urgent Revasc, Bail-out
IIb/IIIa thru 7 d
Follow-up at Day 30, Day 90, Day 180
4
5
Major Exclusion Criteria

• Treatment with anticoagulant during index
  presentation for gt24 h prior to randomization
• Requirement for treatment with an oral
  anticoagulant
• Contraindications to eptifibatide
• bleeding w/in previous 30 days or known bleeding
  diathesis
• severe hypertension (SBP gt200 mmHg or DBP gt110
  mmHg)
• major surgery or trauma in the past 6 wks
• history of stroke in the past 30 d or any history
  of hemorrhagic stroke
• creatinine clearance lt30 ml/min or dependence on
  renal dialysis
• Platelet count lt100,000/ul INR ?2
• Prior PCI within 30 days of randomization
• Cardiogenic shock

5
6
Trial Organization
6
7
Steering Committee
7
8
Worldwide Participation
3241 Patients Randomized
125
15
157
115
25
35
5
91
391
220
71
43
28
98
19
11
65
169
8
93
161
73
19
171
129
102
88
112
10
3
24
69
252
151
196 Sites 36 countries
64
8
9
Baseline Characteristics
No clinically relevant imbalances between
treatment arms
9
10
Medications
10
Patients could have received more than 1 type of
anticoagulant prior to study med
11
Cardiac Procedures
99
Coronary Treatment
Med Rx(34)
PCI(63)
CABG(3.6)
Hospital Day
11
12
Primary Efficacy EndpointDeath, MI, Urg Revasc,
or Bailout GP IIb/IIIa
RR vs UFH(95 CI)
n125
n676
n662
n658
n671
n449
mg/kg/hr
12
P0.34 for trend across OTAM Dose Arms
13
Primary Endpoint over 180 Days
OTAM 0.035
UFHEptifi
OTAM 0.175
OTAM 0.070
OTAM 0.140
OTAM 0.105
Cumulative incidence
13
14
Death or MI
RR vs UFH(95 CI)
n125
n676
n662
n658
n671
n449
mg/kg/hr
14
15
Urgent Revascularization
n125
n676
n662
n658
n671
n449
mg/kg/hr
15
16
Bailout GP IIb/IIIa Inhibitor
RR vs UFH(95 CI)
n125
n676
n662
n658
n671
n449
mg/kg/hr
16
17
Thrombotic Complications
PCI Subset, n2032 (63)
Defined as abrupt or side branch closure, distal
embolization or no/slow reflow, or new thrombus
RR vs UFH(95 CI)
n81
n417
n419
n396
n433
n286
mg/kg/hr
17
18
Primary Safety EndpointTIMI Major or Minor Bleed
unrelated to CABG(defined as bleed with ? in Hgb
of ?3 g/dL or ICH)
RR vs UFH(95 CI)
P0.0001 for trendacross OTAM Dose Arms
n122
n669
n651
n651
n664
n448
mg/kg/hr
18
19
TIMI Minimal Bleeding (defined as any overt
bleed with ? in Hgb of lt3 g/dL)
n122
n669
n651
n651
n664
n448
mg/kg/hr
19
20
RBC Transfusion
n122
n669
n651
n651
n664
n448
mg/kg/hr
20
21
Conclusions
We achieved our goal of defining the optimaldose
range of otamixaban for future study
Otamixaban 0.105-0.140 mg/kg/h appears to be best
range for further study as a replacement for UFH
GP IIb/IIIa
21
22
THE LANCET
Available at www.thelancet.com
Presentation slides available at www.timi.org
22