SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip R - PowerPoint PPT Presentation

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SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip R

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Title: SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip R


1
SR123781A, a New Synthetic Anticoagulant for the
Prevention of Venous Thromboembolism in Total Hip
Replacement Surgery DRIVE a Dose Ranging Study
Disclosure InformationThe following
relationships exist related to this presentation
Michael R. Lassen Consulting Fees sanofi-aventis
Modest Level Dirk Zielske Employee sanofi-av
entis Significant Level Ola Dahl Consulting
Fees sanofi-aventis Modest Level Patrick Mismetti
Consulting Fees sanofi-aventis Modest Level A.
Graham Turpie Consulting Fees sanofi-aventis Modes
t level
2
SR123781A, a New Synthetic Anticoagulant for the
Prevention of Venous Thromboembolism in Total Hip
Replacement Surgery DRIVE a Dose Ranging Study
  • Michael Rud Lassen
  • Hørsholm Hospital, University of Copenhagen,
    Denmark
  • On behalf of Ola Dahl, Patrick Mismetti, Dirk
    Zielske, A.Graham Turpie, and the DRIVE
    Investigators

3
SR123781A
  • Synthetic hexadecasaccharide
  • Mixed profile of antithrombin-dependent
    anti-Factor Xa and anti-factor IIa activities
  • Completely absorbed after subcutaneous injection
  • Half-life 1116 h
  • Dose-proportional and linear PK over doses
    studied, 0.818 mg

4
SR123781ASynthetic Hexadecasaccharide
Antithrombin domain
Spacer
Thrombin domain
Sulphated tetrasaccharide
Pentasaccharide
Sulphated tetrasaccharide
Pentasaccharide
The 2 functional domains are separated by a
central, non sulphated, heptasaccharide This
"spacer" has been introduced to create charge
"clusters" to minimize non-specific interactions
5
Inhibition of activated Factor X
neutral spacer
T domain Tetrasaccharidesequence
A domain Pentasaccharidesequence
factor Xa
Arg
Arg
Lys
AT
6
Inhibition of activated Factor II (Thrombin)
T domain Tetrasaccharidesequence
neutral spacer
A domain Pentasaccharidesequence
thrombin
Arg
Arg
Lys
AT
7
Study Aim
  • The objective of this study was to assess the
    dose-response of SR123781A for the prevention of
    venous thromboembolism in patients undergoing
    total hip replacement.
  • To investigate a 16-fold dose range of SR123781A
    (0.25 mg 4.0 mg once daily)
  • To use 40 mg of enoxaparin once daily as
    calibrator

8
DRIVE graphical study design
Follow-up period
5 10 days
Double blind, double dummy
SR123781A 0.25 mg
SR123781A 0.5 mg
Patients ?18 years Undergoing elective total hip
replacement surgery
SR123781A 1.0 mg
SR123781A 2.0 mg
SR123781A 4.0 mg
enoxaparin 40 mg
Day 30 3
Day 5 11
End of treatment visit Mandatory bilateral
venography
Randomization (Day-1) Surgery (Day1)
All regimens injected subcutaneously once
daily SR123781A administration to be started 8 1
hours post-operatively, enoxaparin 12 1 hours
pre-operatively, or post-operatively in case of
loco-regional anesthesia
9
Main endpoints
  • Efficacy
  • Composite of any deep-vein thrombosis (DVT),
    non-fatal pulmonary embolism (PE), venous
    thromboembolism (VTE)-related death up to Day11
  • Safety Major bleeding
  • Surgical site bleeding leading to intervention
  • Non-surgical site bleeding retroperitoneal or
    intracranial or into a critical organ, or leading
    to intervention, or overt bleeding with a
    bleeding index ? 2
  • Fatal bleeding
  • All outcomes were confirmed by an independent and
    blinded Adjudication Committee (Hamilton, Canada)

10
DRIVE populations
11
DRIVE demographics
BMI body mass index CrCL creatinine clearance
12
Surgical characteristics and treatment exposure
13
Primary efficacy endpoint
Significant dose response p-value 0.0001

14
Primary efficacy endpoint
15
Secondary efficacy endpoints
Significant dose response in proximal DVT( p
0.0001)

No Symptomatic VTE were observed in any of the
groups
16
Bleeding assessment
Significant dose response in major bleeding
p-value 0.0037
any bleeding p-value lt 0.0001
Fatal Surgical site leading to intervention
Non-surgical with bleeding index 2 5 and 5
17
DRIVE summary of results
35
30
25
20
Any VTE ()
15
10
5
0
0.25
0.5
1
2
4
40
Enoxaparin (mg)
SR123781A (mg)
18
DRIVE summary of results
35
30
25
20
Major bleeding ()
15
10
5
0
0.25
0.5
1
2
4
40
Enoxaparin (mg)
SR123781A (mg)
19
DRIVE summary of results
20
Safety evaluation
Fatal bleeding encephalopathic brain hypoxia
unrelated to bleeding or VTE
21
DRIVE conclusions
  • SR123781A displayed
  • A highly significant dose-response in the
    prevention of VTE over a 16-fold dose range
  • A significant dose-response for any bleeding and
    major bleeding
  • SR123781A doses ranging 1.5 2.5 mg demonstrated
    a reasonable risk-to benefit ratio for the
    prevention of VTE in patients undergoing major
    orthopedic surgery
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