Emerging Anticoagulants
for VTE Prevention
and Treatment:
Is change upon us?
Amanda C. Walker, PharmD
Clinical Pharmacist
University of Utah
University Thrombosis Service
Objectives
Describe the pharmacology and mechanism of
action for new and emerging anti-thrombotic
agents
Discuss and review current randomized
controlled trials for new and emerging anti-
thrombotic agents for VTE prevention and
treatment
Evaluate the adverse drug reactions and side
effects associated with these new agents
Current Limitations
Limitations Consequences
► Parenteral ► Inconvenient for
UFH ► Unpredictable due to long term use
unspecific binding ► Monitoring of
► Risk of HIT aPTT required
► Parenteral ► Inconvenient and
LMWH ► Risk of HIT expensive for long term
use
► Monitoring of platelets
► Unpredictable ► Regular monitoring and
VKAs ► Slow onset of action dose adjustments
► Narrow therapeutic window ► Risk of adverse events
► Food and drug interactions
(bleeding)
► Parenteral ► Inconvenient and
Fondaparinux
expensive for long term
use
Lassen MR. Vasc Health Risk Manag. 2008;4(6):1373-86.
New and Emerging
Anticoagulants
Anti – Xa : direct Anti – IIa
Rivaroxaban (oral) Dabigatran (oral)
Apixaban (oral) Odiparcil (oral)
Betrixiban (oral)
Flovagatran (parenteral)
Edoxaban (oral)
Pegmusirudin (parenteral)
Otamixaban (parenteral)
Peg Hirudin
LY – 517717 (oral)
DU – 176B (oral) Desiruidin
DX – 9065a (parenteral)
PRT054021 (oral)
Anti – Xa : indirect
Idraparinux biotinylated
(parenteral)
Site of Action for New
Anti-thrombotic Agents
Intrinsic XII Extrinsic
XI Tissue Factor
IX
VIII VII
Indirect Xa Direct Xa Inhibitors
Inhibitors AT X
“-xaban”
“-parinux”
V
Direct Thrombin
Inhibitors
warfarin II
“-gatran”
Fibrinogen
Fibrin Clot
Factor Xa vs. Factor IIa
Factor Xa Factor IIa
One Xa forms many Supports feedback
IIa amplification through
Limited role in Factor V, Factor VIII,
diversity of action and Factor IX
outside of coagulation Has many cellular
cascade effects
Clinical effectiveness inflammation
Fondaparinux Clinical effectiveness
Argatroban
Hirudins
Direct Factor Xa Inhibitors
Intrinsic XII
XI Extrinsic
TF
IX
VIII VII
Direct Xa Inhibitors
X “-xaban”
V
II
Fibrinogen
Fibrin Clot
Apixaban
Oral tablet
Bioavailability: 50%
Eliminated via
Peak Plasma Levels multiple pathways
= 3 hrs No laboratory
Half-life ~ 12 hours monitoring required
Metabolized in liver Manufactured by
via CYP3A4 and Bristol-Myers
CYP independent Squibb/Pfizer
mechanisms Plan to submit for
U.S. approval in
2009-2010
Apixaban Efficacy
Outcomes in TKR (Phase II)
Incidence of VTE and all-cause death (%)
40
35
30 Duration =
10 -14 days
25
20
15
10
5
0
5 2.5 10 5 20 10 Enox Warf
QDay BID QDay BID QDay BID 30mg BID
(n=152) (n=153)
Apixaban (mg) (n = 933)
Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.
Apixaban Safety
Outcomes in TKR (Phase II)
Incidence of bleeding events (%)
18
16
14
12
10
8
6
4
2
0
5 2.5 10 5 20 10 Enox Warf
QDay BID QDay BID QDay BID 30mg BID
(n=152) (n=153)
Apixaban (mg) (n = 933)
Apixaban Phase III Trials
Medically
Knee Knee Hip
Ill
# Patients 3058 3058 4022 6524
ADVANCE-1 ADVANCE-2 ADVANCE-3 ADOPT
Est. Completion March
Oct 2008 May 2009 Feb 2009
Date 2009
Apixaban Apixaban
Apixaban 2.5mg BID x
Apixaban 2.5mg BID
2.5mg BID 30 days
2.5mg BID vs vs
Study Arms vs
vs Enox Enox
30mg BID Enox Enox 40mg
40mg 40mg QDay QDay x 6-14
QDay days
ADVANCE – 1: Results of Efficacy
vs. Enoxaparin 30 mg BID
RR: 1.02 (95% CI: 0.78 to 1.32) P=0.06 for non-inferiority
Absolute Difference: 0.1% (95% CI: -2.22 to 2.44) P80%) No dosage adjustment
Onset of action 2-4 for gender, age, extreme
hours body weight
Half-life 9-12 hours Approved by Europe and
No observed effects on Canadian agencies, and
agonist-induced platelet under FDA review
aggregation currently
Rivaroxaban in VTE Prevention:
RECORD 3 - TKA
2531 patients
% %6
20 No Difference
18 5
16
RRR 4
14
12 RRR 62%
3
10 49%
8 2
6
4 1
2
0 0
Rivarox 10 Enox 40 Qday Rivarox 10 Enox 40 Qday
Qday x 14 d x 14 days Qday
Composite Major VTE Major Bleed Any Bleed
Rivaroxaban in VTE
Prevention:
3034 patients
RECORD 4 - TKA
Rivarox: RRR % 3.5
% 10 31%; ARR 3.2%
3 Not Significant
8 2.5
6 2
4 1.5
1
2
0.5
0
Rivarox 10 mg Enox 30 mg BID 0
Qday Rivarox 10 mg Enox 30 mg BID
Qday
Composite
Major Bleed Any Bleed
Symptomatic VTE and all-cause mortality
Turpie, et al. Lancet 2009;373:1673 – 80.
Rivaroxaban Ongoing
Phase III Clinical Trials
DVT PE DVT/PE
Einstein-DVT Einstein-PE Einstein-Extension
Rivarox 15mg BID x 3 Rivarox 15mg BID x 3 Rivarox 20mg Qday
wks then 20mg Qday wks then 20mg Qday vs
vs vs Placebo
Enox/VKA Enox/VKA
AF Medically Ill
Rivarox 20 mg Qday
vs Rivarox 10mg Qday x 35 days
Warfarin vs
Enox 40mg Qday x 10 days
Indirect Factor Xa
Inhibitors
Intrinsic XII
XI Extrinsic
TF
IX
VIII VII
Indirect Xa
Inhibitors AT
X
“-parinux” V
II
Fibrinogen
Fibrin Clot
Idraparinux
Once weekly SC injection
100% SC bioavailability
Half-life ~ 96-130 hours
Renal elimination
No monitoring required
Manufactured by
Sanofi-Aventis
Plan to file for U.S.
approval in 2009
Van Gogh Trials
Idraparinux 2.5 mg SC qweek vs standard therapy (heparin/LMWH + VKA)
DVT Study PE Study VTE Extended Study
Idraparinux vs placebo
2904 patients 2215 patients 1215 patients
↔ 3- and 6-month ↑ 3- and 6-month ↓ recurrent events
recurrence recurrence ↑ bleeding
↓ bleeding at 3 mo ↓ bleeding at 3 and ↔ mortality
↔ bleeding at 6 mo 6 mo
↔ mortality ↑ mortality
Amadeus Trial
4576 patients
Non-valvular atrial
fibrillation
Idraparinux 2.5 mg
SC qweek vs VKA
Trial stopped early
due to excess
clinically relevant
bleeding with
idraparinux
Idraparinux Biotinylated
MeO
N
OSO 3 a
N
OSO 3 a S
NaO 3 O
NaO 3 O
S O
O
NaOOC
O O O
O Idraparinux sodium
O OM e
e
MO O O NaOOC S
NaO 3 O
MeO MeO M eO OM e OM e NaO SO
3
N
OSO 3 a
M eO
O SO 3Na
N
O SO 3 a S
NaO 3 O
N aO 3 O
S O
O O O O
NaO OC O
MO
e O O N aO O C
O
N aO 3 O
S
OM e Idraparinux
O M e N aO SO
Biotinylated
M eO HN M eO OM e 3
N
O SO 3 a
O S
Avidin
H
N NH
HN
O O
Biotin arm with spacer
•No pharmacological effect
•IV injection
•Short half-life (10-16 min)
Phase III Clinical Trials with
Idraparinux Biotinylated
Idraparinux
biotinylated
3 mg weekly
vs
warfarin
in 6-month PE
treatment
(3200 patients)
Idraparinux biotinylated
3 mg weekly
vs
BOREALIS-AF
idraparinux
2.5 mg weekly Idraparinux biotinylated 3 mg weekly
in 6-month DVT tx vs
(700 patients) warfarin
in AF (9600 patients)
Direct Thrombin Inhibitors
Intrinsic XII
XI Extrinsic
TF
IX
VIII VII
X
V
Direct Thrombin
II Inhibitors
“-gatran”
Fibrinogen
Fibrin Clot
COMPANY NEWS; COMPANY NEWS;
F.D.A. PANEL F.D.A. REJECTS
VOTES AGAINST ASTRAZENECA'S
BACKING DRUG BY ANTI-CLOTTING
ASTRAZENECA DRUG
Published: September 11, 2004 Published: October 9, 2004
AstraZeneca failed to win AstraZeneca said yesterday
backing from a federal that federal regulators did not
government panel for its approve its anti-clotting drug,
Exanta blood thinner, a Exanta.
possible first alternative to the
drug Coumadin in more than
50 years.
Dabigatran
Oral capsule No dietary/food
Rapid onset of action interactions
Half-life 12-17 hours Brand name Rendix™
or Pradaxa®,
Renal elimination Boehringer-Ingelheim
No routine monitoring Approved in Europe
required March 2008; plans
P-gp substrate—use are to obtain U.S.
with caution when FDA approval by
administered 2010
concomitantly with P-
gp inhibitors
Dabigatran in TKR:
RE-MODEL (Phase II)
% Total VTE & Death % Adverse Events
41 12
n=1541 patients
40
treated 6-10
days, followed
10
for 3 months
8
39 post-surgery
6
38
4
37 2
36 0
150 mg 220 mg Enox 40
35
Qday Qday Qday
34
Dabigatran
150 mg 220 mg Enox 40
Qday Qday Qday
Major Bleeding Minor Bleeding
Dabigatran
LFT > 3xULN
Dabigatran in THR:
RE-NOVATE (Phase II)
% Total VTE & Mortality % Adverse Events
n=2651 patients
10 treated 28-35 7
days, followed 6
9 for 3 months
post-surgery 5
8 4
7 3
6 2
5 1
4 0
3 150 mg 220 mg Enox 40
2 Qday Qday Qday
1
Dabigatran
0
150 mg 220 mg Enox 40
Qday Qday Qday
Major Bleeding Minor Bleeding
LFT >3xULN
Dabigatran
Eriksson BI et al. Lancet 2007;370:949-56.
Dabigatran: RE-VOLUTION
Trial Program (Phase III)
AF and Secondary
Acute VTE Stroke VTE Secondary VTE
Treatment Prevention Prevention Prevention
RE-COVER RE-MEDY
RE-LY RE-SONATE
# Patients 2554 18000 1800 2004
Est
Completion Dec 2009 June 2009 October 2009 January 2011
Date
Dabigatran
Dabigatran 100 mg BID Dabigatran Dabigatran
150 mg BID and 150 mg 150 mg BID 150 mg BID
Study Arms BID
vs vs vs
warfarin vs placebo warfarin
warfarin
Summary
Time to Market for New Anti-Thrombotic Agents
Apixaban
Dabigatran
Otomaxiban
Idraparinux
Rivaroxaban
biotinylated
2010 2011 2012 2013
Property Rivaroxaban Apixaban Idraparinux Dabigatran
Target Factor Xa Factor Xa Factor Xa Thrombin
(indirect)
ROA Oral Oral Subcutaneous Oral
Prodrug No No Yes Yes
Bioavailability > 80% > 50% 100% 6%
Time to peak 3 3 ___ 2
Half-life 9 hrs 9 – 14 hrs 80 hrs 14 – 17 hrs
Frequency of Qday BID Q Week Qday or BID
Administration
Drug Potent CYP3A4 & Potent CYP3A4 & ___ P-glycoprotein
P-glycoprotein P-glycoprotein inhibitors
Interactions inhibitors inhibitors
Renal 66% 25% Yes 80%
excretion
Safe in No No Unknown No
pregnancy
Antidote No No No No
Adapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.
Potential Limitations of
New Anticoagulants
Antidotes
None of the newer agents has a specific antidote
Monitoring
Adverse Drug Events
Compliance
Cost
Clinical Trials vs. Actual Clinical Practice
Patient populations not even studied (i.e.
Cancer)
Conclusion
Several oral and parenteral Anti Xa and Anti IIa
drugs are under development at this time
Rivaroxaban and Dabigatran are approved in
the European Union and Canada for the
prophylaxis of DVT and awaiting FDA
review/approval
Safety issues are of prime importance in the
development of these drugs and will be
strongly scrutinized upon review
What about RE-LY?
Dabigatran versus Warfarin in Patients with
Atrial Fibrillation
Non-inferiority trial
Over 18,000 patients
Followup = 2 years
Dabigatran 110 mg and 150mg
vs.
Adjusted dose warfarin