Disclosure Information… The following relationships exist related to this presentation: Michael R. Lassen Consulting Fees sanofi-aventis Modest Level Dirk Zielske Employee sanofi-aventis Significant Level Ola Dahl Consulting Fees sanofi-aventis Modest Level Patrick Mismetti Consulting Fees sanofi-aventis Modest Level A. Graham TurpieConsulting Fees sanofi-aventis Modest level SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study
21
Embed
Disclosure Information … The following relationships exist related to this presentation:
SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study. Disclosure Information … The following relationships exist related to this presentation:. - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Disclosure Information…The following relationships exist related to this presentation:
Michael R. Lassen Consulting Fees sanofi-aventis Modest Level
Ola Dahl Consulting Fees sanofi-aventis Modest Level
Patrick Mismetti Consulting Fees sanofi-aventis Modest Level
A. Graham Turpie Consulting Fees sanofi-aventis Modest level
SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total Hip Replacement Surgery – DRIVE: a Dose Ranging Study
SR123781A, a New Synthetic Anticoagulant for the Prevention of Venous Thromboembolism in Total
Hip Replacement Surgery – DRIVE: a Dose Ranging Study
Michael Rud LassenHørsholm Hospital, University of Copenhagen, Denmark
On behalf of Ola Dahl, Patrick Mismetti, Dirk Zielske, A.Graham Turpie, and the DRIVE Investigators
SR123781A
▲ Synthetic hexadecasaccharide
▲ Mixed profile of antithrombin-dependent anti-Factor Xa
and anti-factor IIa activities
▲ Completely absorbed after subcutaneous injection
▲ Half-life 11–16 h
▲ Dose-proportional and linear PK over doses studied,
0.8–18 mg
Antithrombin domainSpacerThrombin domain
OO
O
O O
O
O OO
O
OO
O
O
SO3-
SO3-
SO3-
SO3-
SO3-
-OOC
-OOC
SO3-
OMeO MeO
MeO
MeOOMe O OMe
OMe
MeOOO
O O
O
SO3-
SO3-
SO3-
OO
O
O O
O
SO3-
SO3-
SO3-
O
O O
O
SO3-
SO3-
SO3-
O
-O3SO
O
MeOMeO
OO
MeOMeO
OMe
O
OMeO
O
MeO MeO
OMe
MeO
OMe
-O3S 3
19 Na+
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
Sulphatedtetrasaccharide
PentasaccharideSulphated
tetrasaccharidePentasaccharide
SR123781ASynthetic Hexadecasaccharide
T domain =Tetrasaccharide
sequence
factor Xa
AT
ArgArgLys
A domain =Pentasaccharide
sequence
neutralspacer
Inhibition of activated Factor X
T domain =Tetrasaccharide
sequence
AT
ArgArgLys
A domain =Pentasaccharide
sequence
thrombin
neutralspacer
Inhibition of activated Factor II (Thrombin)
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
DRIVE: graphical study design
Day 30 ±3
Patients 18 years
Undergoing elective
total hip replacement
surgery
End of treatment visit
Mandatory bilateral venography
Randomization (Day-1)
Surgery (Day1)
SR123781A 0.25 mg
enoxaparin 40 mg
Follow-up period
SR123781A 0.5 mg
SR123781A 1.0 mg
SR123781A 2.0 mg
SR123781A 4.0 mg
5 – 10 daysDouble blind, double dummy
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
Day 5 – 11
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)
DRIVE populations
SR123781A Enox
0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg
All randomized 172 164 172 170 176 169
Safety population 171 163 170 168 171 166
Primary efficacy population
118 124 126 128 114 126
DRIVE demographics
BMI: body mass index; CrCL: creatinine clearance
SR123781A Enox
0.25 mg 0.5 mg 1 mg 2 mg 4 mg 40 mg
Median age, years 59 60 60 60 58 59
Age range, years 25–86 18–86 33–83 25–90 23–86 28–83
Age ≥75 years, % 9.9 11.7 8.2 8.9 7.0 9.0
Female, % 58.5 58.9 58.8 58.3 57.9 61.4
BMI ≥30 kg/m2, % 33.5 22.1 34.1 26.8 29.2 28.9
Baseline CrCL, %
<30 mL/min 1.2 0.6 1.2 0 0 1.2
≥30 – <50 mL/min 5.3 4.3 5.9 7.7 7.6 4.2
Surgical characteristics and treatment exposure
SR123781A Enox0.25 mgN=171
0.5 mgN=163
1 mgN=170
2 mgN=168
4 mgN=171
40 mgN=166
Mean duration of surgery ± SD, min 92 ± 44 87 ± 34 89 ± 36 91 ± 39 95 ± 44 89 ± 36
Use of cement, % 39.8 39.3 42.4 36.5 36.8 37.3
Anesthesia type, %
General only 19.9 17.2 15.9 13.8 15.8 15.7
Regional only 77.8 81.6 82.4 83.8 81.3 82.5Post-op treatment exposure, median (range), days
*Fatal bleeding; **encephalopathic brain hypoxia unrelated to bleeding or VTE
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