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)

Thrombin (IIa)

Fibrinogen Fibrin

Coagulation cascade

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

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

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)

Initiation

Amplification

Propagation…

Reason 1 Central role of FXa in the

coagulation cascade

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

Reason 4 Therapeutic window of anti-Xa inhibiton

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

Old versus new anticoagulantsAnti-Xa versus anti-IIa ?

PradaxaLMWH + Vitamin K Antagonist

Synthetic

Per os

One or two tablet(s) / day

No monitoring

No or little food/drug interaction

Xarelto