Download Thrombin = anticoagulant

Growing evidence for the
effectiveness of FXa inhibition
Professor Cedric HERMANS
MD, MRCP(UK), PhD
Division of Haematology
Cliniques universitaires Saint-Luc
1200 Brussels
Conflicts of interests
Participation in advisory
boards and consulting activities for
anti-Xa and anti-IIa anticoagulants
(Bayer Schering Pharma, Boehringer Ingelheim)
Coagulation cascade
Thrombin (IIa)
Fibrinogen
Fibrin
Classic theory of
the coagulation cascade
Contact
Phase - FXII
Tissue Factor
+ FVIIa
FXI
FIX + FVIII
Intrinsic
pathway
Extrinsic
pathway
FX
FV
Thrombin
FIBRIN CLOT
Common
pathway
Sites of action of new anticoagulants
FT/VIIa
ORAL
PARENTERAL
X
IX
VIIIa
DIRECT
Va
Rivaroxaban
and others
IXa
INDIRECT
Antithrombin
Fondaparinux
Idraparinux
Xa
II
DIRECT
Dabigatran
and others
IIa
Fibrinogen
Fibrin
Pentasaccharide (Arixtra - Fondaparinux)
Intrinsic
pathway
1
2
ATIII
Extrinsic
pathway
3
ATIII
Arixtra
ATIII
Xa
Xa
II
IIa
Fibrinogen
Platelets
IIA
Fibrin
clot
Pentasaccharide sequence of heparin (present in UFH
and LMWH) binds to AT causing conformational change
at its reactive centre accelerating 1000-fold its
interaction with factor Xa.
Olson ST, et al. J. Biol. Chem. 1992; 267:12528–12538.
Coagulation cascade and
targets of new oral anticoagulants
Rivaroxaban (XARELTO – Bayer Schering):
Anti-Xa
•
Direct, specific, competitive Factor Xa
inhibitor
•
Inhibits free and fibrin-bound Factor
Xa activity and prothrombinase
activity
•
Inhibits thrombin generation
•
No direct effect on platelet
aggregation, and thus, on primary
haemostasis
•
Bioavailibility: 80–100 %
•
Cmax at 2–4 h
•
~ one-third excreted as unchanged
active substance in urine
•
Of the two-thirds metabolized: half
eliminated renally, half eliminated
by faecal route
Roehrig S et al. J Med Chem 2005;48:5900–8; Perzborn E et al. J Thromb Haemost 2005;3:514–21.
Dabigatran etexilate (Pradaxa – Boehringer Ingelheim) :
Anti-IIa (Thrombin)
– After oral administration, the prodrug dabigatran
etexilate is rapidly converted to dabigatran, a potent
reversible Direct Thrombin Inhibitor (DTI)
– Absolute bioavailability ~ 6.5 %
– Fast onset of action (Cmax within 2h)
– Not metabolized by CYP450 / Renal excretion ~80%
– Half life 12-17 hours
Intrinsic
XII
XI
Extrinsic
Tissue Factor
IX
VII
VIII
– Low potential for drug-drug interactions,
no drug-food interactions
Xa
V
Dabigatran
-
IIa
I
– Potent antithrombotic effects are achieved by
specifically blocking the activity of thrombin (both free
and clot-bound)
Fibrin Clot
NEW versus OLD anticoagulants
LMWH + Vitamin K Antagonist
Pradaxa
Xarelto
Synthetic
Per os
One or two tablet(s) / day
No monitoring
No or little food/drug
interaction
Many targets for new anticoagulants:
Why target Factor Xa?
Oral
Parenteral
TF/Factor
VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban
Apixaban
YM150
LY517717
Edoxaban (DU-176b)
Betrixaban (PRT054021)
Ximelagatran
Dabigatran
Fibrinogen
IX
VIIIa
Va
Factor
Xa
APC (drotrecogin alfa)
sTM (ART-123)
IXa
AT
Fondaparinux
Idrabiotaparinux
DX-9065a
Otamixaban
II
Factor
IIa
Fibrin
Adapted from Weitz & Bates. J Thromb Haemost 2005; Gross & Weitz. Arterioscler Thromb Vasc Biol 2008;
Carriero & Ansell. Expert Opin Investig Drugs 2008
Why is FXa an attrative target
for new anticoagulants?
• LOCATION of FXa in the coagulation cascade
• Arixtra > LMWH > UFH (degree of inhibition of FXa)
• Inhibition of thrombin = deleterious consequences
• Larger therapeutic window with Xa inhibition ?
• Results of clinical trials ?
BUT no head-to-head comparison (anti-Xa versus anti-IIa)
Reason 1
Central role of FXa in the
coagulation cascade
Initiation
Amplification
Propagation…
Targets of new anticoagulants :
FXa or FIIa (Thrombin)
Fibrinogen
TF FVIIa
FXa
FVa
Thrombin
Thrombus
Inhibition of 1 unit of Xa prevents
generation of 1000 units of thrombin
Wessler & Yin. Circ 1973;47:671
Reason 2
Specificity of FXa inhibtion and
antithrombotic activity
Higher selectivity for FXa inhibition with heparins is
associated with a more potent anticoagulant effect :
Fondaparinux > LMWH > UFH
Fondaparinux : anti-Xa
LMWH : anti-FXa > anti-IIa
UFH : anti-FXa = anti-IIa
Fondaparinux vs enoxaparin
in orthopedic surgery
Enoxaparin
better
Fondaparinux
better
Hip replace
n = 3,411
[59.0; 27.6]
45.4%
Hip fracture
[73.4; 45.0]
61.6%
n = 1,250
Exact 95% CI
Knee replace
n = 724
Overall odds
reduction
% odds
reduction
[75.5; 44.8]
63.1%
-100
p = < 0.001
55.3%
-80
-60
-40
-20
0
20
40
60
80
[63.2; 45.8]
100
Turpie AGG. Arch Intern Med 2002;162:1833
Reason 3
Inhibition of thrombin could
in theory have detrimental
consequences, even outside
the clotting system
Procoagulant
Thrombin formation
PAI – 1 release
Cell Prolif / Inflammation
Cytokine release
Smooth muscle cell proliferation
The limited
functions of
Factor Xa
From J. Ansell 2007
Procoagulant
Fibrin formation
Platelet activation
Feedback activation
TAFI activation
Anticoagulant
Protein C activation
Prostacyclin formation
The many
functions of
Thrombin
Inflammation
P-selection expression
Cell adhesion
Chemotaxis
Cellular Proliferation
Tissue repair
Growth factor secretion
Angiogenesis
Factor Xa = an attractive target
for inhibition
• The only known functions of Factor Xa are either procoagulant
or proinflammatory
• Thrombin has both of these activities and indirect anticoagulant,
anti-inflammatory and anti-apoptotic activities
Thrombin = anticoagulant
Thrombin is essential for the activation of protein C.
Activated protein C inactivates FVa and FVIIIa.
Inhibition of thrombin impairs the activation of protein C and thereby the inhibition of FVa and
FVIIIa.
Esmon Thromb Haemost 2008
Furugohri et al. Eur J Pharmacol 2005;514:35 Morishima et al. Blood 2006;108:274a
Thrombin = anticoagulant
Inhibition of FXa does not interfere with
the PC/PS anticoagulant pathway.
Direct inhibition of FXa allows the
generation of small amount of thrombin
and the activation of protein C into
activated protein C.
Is the protein C anticoagulant pathway
still needed when thrombin procoagulant
activity is inhibited ???
Esmon Thromb Haemost 2008
Thrombin = potent platelet agonist
• FIIa is a potent platelet agonist.
• FXa does not activate platelets.
• Thrombin inhibition could increase the risk of bleeding.
• Direct FXa inhibitors allow the generation of small amounts of
thrombin necessary to activate platelets and preserve primary
haemostasis
Ieko et al. J Thromb Haemost 2004;2:612
Reason 4
Therapeutic window
of anti-Xa inhibiton
Dose Response: Xa vs IIa
Clotting Time vs. Enzyme Concentration
120
100
Thrombin
80
Clotting
Time(s)
FXa
60
40
20
0
0
50
100
150
200
250
Enzyme dilution in 1:4 Human Plasma
C. Esmon
Choice of Doses
BISTRO II
Safety
Efficacy
30
28.5
Total VTE (%)
24.0
20
16.6
13.1
10
0
100 mg
300 mg
450 mg
Enoxaparin
Major + clinically relevant
non-major bleeding (%)
10
8.3
8.4
8
6
4.6
4
2.6
2
0
Dabigatran etexilate total daily dose
100 mg
300 mg
450 mg
Dabigatran etexilate total daily dose
Optimal Efficacy / Safety Balance
Eriksson et al. J Thromb Haemost 2005; 3:103
Enoxaparin
Efficacy and safety results
Hip surgery
Knee surgery
60
60
50
50
Incidence (%)
Incidence (%)
Total venous thromboembolism and all-cause mortality
Major, post-operative bleeding
40
30
20
40
30
20
10
10
0
0
0 5 10
20
30
40
50
Rivaroxaban total daily dose (mg)
60
Enoxaparin
40 mg od
0
5 10
20
30
40
50
Rivaroxaban total daily dose (mg)
60
Enoxaparin
30 mg bid
 Total daily rivaroxaban doses of 5–20 mg had similar
efficacy and safety to enoxaparin
5
Factor Xa = an attractive target
for inhibition
• Factor Xa has a shallower dose–response curve than thrombin
• This suggests that maintaining the appropriate dose range for
Factor Xa inhibitors should be easier than for thrombin inhibitors
Conclusions
• Several reasons suggest that factor Xa might be a
more appopriate target than IIa.
• The reasons are theoretical and speculative.
• Recent clinical studies in orthopaedic surgery indirectly
support experimental observations.
Conclusions
• Clinical trials with oral FIIa and FXa inhibitors are
ongoing and following parallel paths.
• Which class of drugs will be better ?
– This question will remain unanswered until the appropriate
head-to-head clinical trials are performed.
– At the moment, both classes appear promising.
Head-to-head comparison between
anti-IIa and anti-Xa inhibitors
Even if we have a study which shows that the
cost-benefit ratio is superior with one compound
versus another one, this will be true :
a) only for these two particular drugs
b) and only in one well-defined clinical situation
Old versus new anticoagulants
Anti-Xa versus anti-IIa ?
LMWH + Vitamin K Antagonist
Pradaxa
Xarelto
Synthetic
Per os
One or two tablet(s) / day
No monitoring
No or little food/drug
interaction