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Growing evidence for the
effectiveness of FXa inhibition
Professor Cedric HERMANS MD, MRCP(UK), PhD
Division of HaematologyCliniques 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)
Contact Phase - FXII
FIX + FVIII
FX
Thrombin
Tissue Factor + FVIIa
Intrinsicpathway
Extrinsicpathway
Commonpathway
FXI
FIBRIN CLOT
FV
Classic theory of the coagulation cascade
PARENTERAL
Sites of action of new anticoagulants
DIRECT INDIRECT
Xa
IIa
FT/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
FondaparinuxIdraparinux
Antithrombin
Dabigatranand others
Rivaroxabanand others
ORAL
DIRECT
Pentasaccharide (Arixtra - Fondaparinux)
Olson ST, et al. J. Biol. Chem. 1992; 267:12528–12538.
IIaII
FibrinogenFibrin clot
Extrinsic pathway
Intrinsicpathway
3
ATIII Xa
1
ATIII ATIII
2
Arixtra
Xa
PentasaccharidePentasaccharide sequence of heparin (present in UFH sequence of heparin (present in UFH and LMWH) binds to AT causing conformational change and LMWH) binds to AT causing conformational change at its reactive centre accelerating 1000-fold its at its reactive centre accelerating 1000-fold its interaction with factor Xa.interaction with factor Xa.IIAPlatelets
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
Roehrig S et al. J Med Chem 2005;48:5900–8; Perzborn E et al. J Thromb Haemost 2005;3:514–21.
• ~ one-third excreted as unchanged active substance in urine
• Of the two-thirds metabolized: half eliminated renally, half eliminated by faecal route
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
– Low potential for drug-drug interactions, no drug-food interactions
– Potent antithrombotic effects are achieved by specifically blocking the activity of thrombin (both free and clot-bound)
Fibrin Clot
XII
Intrinsic
ExtrinsicXI
IX
VIII VII
Xa
V
IIa
I
Tissue Factor
-Dabigatran
NEW versus OLD anticoagulants
PradaxaLMWH + Vitamin K Antagonist
Synthetic
Per os
One or two tablet(s) / day
No monitoring
No or little food/drug interaction
Xarelto
Many targets for new anticoagulants: Why target Factor Xa?
TFPI (tifacogin)
FondaparinuxIdrabiotaparinux
RivaroxabanApixaban
YM150LY517717
Edoxaban (DU-176b)Betrixaban (PRT054021)
XimelagatranDabigatran
Oral Parenteral
DX-9065aOtamixaban
FactorXa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
AT
APC (drotrecogin alfa)sTM (ART-123)
TTP889
Adapted from Weitz & Bates. J Thromb Haemost 2005; Gross & Weitz. Arterioscler Thromb Vasc Biol 2008; Carriero & Ansell. Expert Opin Investig Drugs 2008
TF/FactorVIIa
FactorIIa
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)
Targets of new anticoagulants :FXa or FIIa (Thrombin)
TF ThrombinFVaFXaFVIIa
FibrinogenFibrinogen
Thrombus
Inhibition of 1 unit of Xa prevents generation of 1000 units of thrombin
Wessler & Yin. Circ 1973;47:671
Reason 2Specificity 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 better
Enoxaparin better
Exact 95% CIHip replacen = 3,411
Hip fracturen = 1,250
Knee replacen = 724
Overall odds reduction
-100 -80 -60 -40 -20 200 40 60 80 100
45.4%
63.1%
55.3%
[59.0; 27.6]
[73.4; 45.0]
[75.5; 44.8]
[63.2; 45.8]
61.6%
p = < 0.001
Fondaparinux vs enoxaparinin orthopedic surgery
% odds reduction
Turpie AGG. Arch Intern Med 2002;162:1833
Reason 3
Inhibition of thrombin could in theory have detrimental
consequences, even outside the clotting system
The limited functions of
Factor Xa
ProcoagulantProcoagulant Thrombin formation PAI – 1 release
Cell Prolif / InflammationCell Prolif / Inflammation Cytokine release Smooth muscle cell proliferation
From J. Ansell 2007
AnticoagulantAnticoagulant Protein C activation Prostacyclin formation
ProcoagulantProcoagulant Fibrin formation Platelet activation Feedback activation TAFI activation
InflammationInflammation P-selection expression Cell adhesion Chemotaxis
Cellular ProliferationCellular Proliferation Tissue repair Growth factor secretion Angiogenesis
The many functions of
Thrombin
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.
Furugohri et al. Eur J Pharmacol 2005;514:35 Morishima et al. Blood 2006;108:274a
Esmon Thromb Haemost 2008
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
haemostasisIeko et al. J Thromb Haemost 2004;2:612
0
20
40
60
80
100
120
0 50 100 150 200 250
Thrombin
FXa
Enzyme dilution in 1:4 Human Plasma
ClottingTime(s)
Dose Response: Xa vs IIa
C. Esmon
Clotting Time vs. Enzyme Concentration
28.5
16.6
13.1
24.0
0
10
20
30
100 mg 300 mg 450 mg Enoxaparin
Choice of Doses
Optimal Efficacy / Safety Balance
BISTRO II
2.6
8.3 8.4
4.6
0
2
4
6
8
10
100 mg 300 mg 450 mg Enoxaparin
Majo
r +
clin
ically
rele
van
t n
on
-majo
r b
leed
ing
(%
)
Safety
Dabigatran etexilate total daily doseDabigatran etexilate total daily dose
Efficacy
Tota
l V
TE (
%)
Eriksson et al. J Thromb Haemost 2005; 3:103
5
Efficacy and safety results
Hip surgery Knee surgery
Total venous thromboembolism and all-cause mortalityMajor, post-operative bleeding
600
10
20
30
40
50
60
0 10 50403020
Rivaroxaban total daily dose (mg)
Enoxaparin30 mg bid
Inci
den
ce (
%)
5Enoxaparin40 mg od
0 10 20 30 40 50 600
10
20
30
5
40
50
60
Rivaroxaban total daily dose (mg)
Total daily rivaroxaban doses of 5–20 mg had similar efficacy and safety to enoxaparin
Inci
den
ce (
%)
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