nye antikoagulantia faktor xa-hæmmere og trombinhæmmere lars borris overlÆge ortopÆdkirurgisk...

Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere

LARS BORRISOVERLÆGE

ORTOPÆDKIRURGISK AFD.ÅRHUS SYGEHUS

Nye antikoagulantiaNye antikoagulantia

Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrin

rNAPc2rNAPc2

fondaparinux fondaparinux idraparinuxidraparinux

(razaxaban)(razaxaban)apixabanapixaban

BAY 59-7939BAY 59-7939………………………………....………………………………....………………………………....

(xi)melagatran(xi)melagatran

dabigatrandabigatran

efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

Udvælgelseskriterier

• Kirurgisk profylakse

• Ikke er eller har været markedsført

• Har gennemført fase II

• Offentliggjorte resultater

Nye antikoagulantiaNye antikoagulantia

Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrin

rNAPc2rNAPc2

BAY 59-7939BAY 59-7939(rivaroxaban)(rivaroxaban)


dabigatrandabigatran


Fokusområder for udvikling af nye stoffer

• Bedre effekt (VTE ) • Større sikkerhed (blødning )• Postoperativ start• Færre administrationer (fx 1 gang ugl.)• Oral administration• Lettere styrbarhed (ingen

monitorering)

Standard studiedesign

T

R

K OP Screening

Tid (dage)Behandling Follow-up

K = kontrolstof typisk LMWHT = teststofOP = THA og/eller TKA

Screening: bilateral UE flebografi eller UL. AK behandling hvis PE eller DVT

Dobbelt-blinding

Standard end-points• Major VTE: alle PE* (±død), alle DVT* (±

symptomer) samt død* af alle årsager• Major bleeding*: fatal blødning, blødning i

kritiske organer, blødning der fører til reoperation, blødning der medfører forlængelse af indlæggelse, blødning der medfører behandlingstop

*bedømt af uvildige blindede ekspertgrupper

Virkningssteder for nye antikoagulantia


Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrin

rNAPc2rNAPc2


Vævsfaktor/faktor VIIa hæmmere

rNAPc2Rekombinant nematode antikoagulant protein c2Findes naturligt i spyttet fra hageorm (Ancylostoma caninum)

Virkningsmekanisme:Hæmmer det kompleks der dannes mellem vævsfaktor og faktor VIIa i initieringsfasen

Stofprofil:Halveringstid>50 timerBiotilgængelighed: 90%-100% efter sc injektion

KLINISK DOKUMENTATION rNAPc2

Dose-finding studie. 293 knæalloplastik ptt. (åbent, ukontrolleret)5 forskellige regimer:1,5, 3 og 5 g/kg 6-12 timer PO og derefter dag 3,5 og evt. 7 1,5 eller 3 g/kg 1 time PO og derefter dag 3,5 og evt. 7RESULTAT:3 g/kg 1 time PO var mest effektiv med total DVT 12,2% (1,3% prox. DVT) og større blødning 2,3%

Ref.: Lee A et al. Circulation 2001; 104:74-8.



Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrin

BAY 59-7939BAY 59-7939(rivaroxaban)(rivaroxaban)


Direkte vs. indirekte Xa hæmmere

Indirekte hæmmere er heparinerne (UFH og LMH) samt de syntetiske pentasaccarider, som hæmmer Xa via binding til antithrombin

Direkte hæmmere f. eks. BAY 59 7939 hæmmer både frit Xa og bundet Xa

BAY 59-7939 inhibits free FXa, prothrombinase activity, and endogenous Factor Xa in plasma

Perzborn et al., ICT 2004

Chemestry: BAY 59 7939 (rivaroxaban)

• MW 435.89 daltons

• Formula: C19H18CIN3O5S

FEATURES OF BAY 59 7939

• A reversible, direct oral FXa inhibitor• Bioavailability: 60%-86% in dogs

• Rapid obsorption as tablet (Cmax 2-4 h)

• Intake with food increases Cmax by 40%

• Half-life:5-6 h• Excretion: renal/bile

BAY 59-7939 has antithrombotic effects (venous thrombosis model)

**P<0.01; ***P<0.001Perzborn et al., ICT 2004

Venous thrombosis model – rat venous stasis model

**

***100

80

60

40

20

0

0.03 0.10 0.30

Th

rom

bu

s re

du

ctio

n (

%)

BAY 59-7939 (mg/kg) i.v.

BAY 59-7939 does not affect bleeding times at an antithrombotic-effective dose (3 mg/kg)

BAY 59-7939

(mg/kg p.o.)

Prolongation of bleeding time

(X-fold)

Rat (n=10) Rabbit (n=5)

0.3 ND 1.4±0.7

1.0 ND 1.7±0.9

3.0 1.0±0.1 1.6±0.8

6.0 2.1±0.2** ND

10.0 2.7±0.2*** ND

Data are shown as mean±SEM

**P<0.01; ***P<0.001; ND = not determinedPerzborn et al., ICT 2004

Rat and rabbit bleeding models

BAY 59-7939: dose-dependent inhibition of Factor Xa

Healthy human subjects

Key points: pharmacodynamics

In healthy human subjects, BAY 59-7939:• Dose-dependently inhibits Factor Xa

– Factor Xa inhibition and plasma concentrations of

BAY 59-7939 correlate strongly

• Dose-dependently prolongs prothrombin time– Prothrombin time and plasma concentrations of BAY

59-7939 correlate strongly

• Does not affect antithrombin or ecarin-induced thrombin (Factor IIa) activity

• Prolongs time to thrombin generation, inhibits the maximum extent of thrombin generation, and the total amount of thrombin generated– Factor Xa inhibition and the maximum extent of

thrombin generation show good correlation

Once daily vs. twice daily dosing

• Phase I studies in healthy subjects showed that single doses of rivaroxaban have pharmacodynamic effects that persist for 24 hours

• Rivaroxaban significantly inhibited peak and total amounts of thrombin generated and prolonged thrombin generation time for 24 hours after dosing in healthy subjects

Harder et al. Phatophysiol Haemost Thromb 2004;33:P0078Kubitza et al. J Thromb Haemost 2005; 3: P 1704Kubitza et al. Clin Pharmacol Ther 2005; 78: 412-21

3 Phase II bid Studies

10942 (ODIXa-Hip – a Phase IIa Dose Escalating Proof of 10942 (ODIXa-Hip – a Phase IIa Dose Escalating Proof of Principle Trial)Principle Trial)

OOral DiDirect Factor XaXa Inhibitor BAY 59-7939 in the Prevention of VTE in Patients Undergoing Total HipHip Replacement

10944 (ODIXa-Hip IIb - bid dosing)10944 (ODIXa-Hip IIb - bid dosing)Controlled, Double-Blind, Randomized, Dose-ranging Study on the prevention of VTE in Patients Undergoing Elective Total Hip Replacement

10945 (ODIXa-Knee – a Phase IIb Dose-ranging Trial – bid 10945 (ODIXa-Knee – a Phase IIb Dose-ranging Trial – bid dosing)dosing)OOral DiDirect Factor XaXa Inhibitor BAY 59-7939 in the Prevention of VTE in Patients Undergoing Total KneeKnee Replacement

ODIXa-HIP Study (10942)(open)

R

D1 D6-10 D+30

THR venography Follow-up

BAY 2.5 mg bidBAY 5 mg bidBAY 10 mg bid

BAY 20 mg bidBAY 30 mg bidBAY 30 mg odEnoxaparin

ODIXa-HIP II Study (10944)(double-blinded)

R

D1 D6-10 D+30

THR venography Follow-up


BAY 20 mg bidBAY 30 mg bidEnoxaparin

ODIXa-Knee Study (10945)(double-blinded)

R

D1 D6-10 D+30

TKR venography follow-up


BAY 20 mg bidBAY 30 mg bidEnoxaparin

Study endpoints

Primary efficacy endpoint

Composite of any DVT (proximal and/or distal); non-fatal, symptomatic, objectively confirmed PE; and all-cause mortality

Secondary efficacy endpoint

Major VTE: composite of proximal DVT; non-fatal, symptomatic, objectively confirmed PE; and VTE-related death

Primary safetyendpoint

Major bleeding

Secondary safety endpoints

• Clinically relevant, non-major bleeding • Minor bleeding

Efficacy:evaluated 5–9 days after surgery

Safety: bleeding occurring after the first dose of study drug and no later than 2 days after the last dose

Results 3 bid studies

Pooled analysis

Efficacy: Total VTE

TKA

Major Bleeding

Net-Clinical Benefit (in %) major VTE and major bleedings

Outcome Treatment Group SN 44+45 SN 42+44+45

Rate (%) 95%-CI Rate (%) 95%-CI

Net Clinical Benefit – modified ITT Population

2.5 mg bid BAY 3.4 1.5 – 7.4 5.4 3.2 – 9.1

5.0 mg bid BAY 4.0 1.9 – 8.3 5.8 3.4 – 9.6

10 mg bid BAY 6.1 3.3 - 11.0 6.3 3.7 - 10.4

20 mg bid BAY 8.7 5.2 - 14.3 8.1 5.2 - 12.4

30 mg bid BAY 9.6 5.1 - 17.2 12.5 8.1 - 18.8

Enoxaparin 6.6 3.7 – 11.2 6.2 4.0 – 9.4

Note : Net Clinical Benefit is defined as Composite of Major VTE and Major Bleeding

1 Phase II od Study

11527 (ODIXa-OD.HIP – once daily dosing)11527 (ODIXa-OD.HIP – once daily dosing)Controlled, Double-Blind, Randomized, Dose-ranging Study of once-daily regimen of BAY 59-7939 in the Prevention of VTE in Patients Undergoing Elective Total Hip Replacement

ODIXa-OD.HIP Study (11527)(double-blinded)

R

D1 D6-10 D+30

THR venography follow-up

BAY 5 mg odBAY 10 mg odBAY 20 mg od

BAY 30 mg odBAY 40 mg odEnoxaparin

Dose Trend Total VTE

Dose Trend Major Bleeding

Net Clinical Benefit

5 10 20 30 40 Enox BAY 59-7939, mg qd

5

10

%11.1

3.5

6.1

8.08.8

5.2

major VTE

major bleed

Main conclusion

of dose-finding

Based on efficacy results (total VTE and major VTE) and bleeding results:

–Once-daily dosing in VTE-prevention seems to be benficial

–Optimal dose: 10 mg od

Short-term prevention of VTE in TKA Short-term prevention of VTE in TKA compared with enox 40 mg od or 30 compared with enox 40 mg od or 30 mg bidmg bid

Future development programme phase III

Extended Prevention of VTE in THAExtended Prevention of VTE in THA

Comparison of Extended Prevention Comparison of Extended Prevention with BAY 59-7939 given for 5-6 weekswith BAY 59-7939 given for 5-6 weekswith short-term prevention with enox.with short-term prevention with enox.in THAin THA



Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrin



FEATURES OF RAZAXABAN

• Direct Factor Xa inhibitor• Oral administration

Design of a phase II study in elective TKA

Surgery Randomization

Enoxaparin 30 mg sc bid

Razaxaban 25 mg po bid

Day 12±2

Follow-upVenography

R Razaxaban 50 mg po bid



Day 42±2Day 1

Razaxaban initiated 6-8 h after surgeryEnoxaparin initiated 12-24 h after surgery

Razaxaban Enoxaparin50 mg bid25 mg bid 75 mg bid 100 mg bid 30 mg bid

n=147 n=123 n=115 n=121 n=150

57 / 90 48 / 75 39 / 76 47 / 74 59 / 91

66 65 67 66 6535-82 37-85 33-86 41-84 35-84

31 31 31 31 3216-46 17-54 18-50 18-49 21-53

Age (years)Mean andrange

GenderM/F

BMI Mean andrange

Patient characteristics N=656

Result Summary ITT; all evaluable patients up to day 12±2

0

5

10

15

20

25

30

% R

ate

VTE Rate Bleeding Rate

25 50 75 100 30 25 50 75 100 Razaxaban Enoxaparin Razaxaban

Preferred dose:

25 mg bid

FUTURE DEVELOPMENT

continues with another molecule with a more reliable absorption:

apixaban

a phase III study in THA and TKA has already been finalized

results are expected in 2006



Initiering

Propagation

Trombin aktivitet

VF/VIIa

VIIIa

IXa

IXX

XaVa

II

IIa

Fibrinogen Fibrindabigatrandabigatran


• MW = 471.5 daltons

Dabigatran (BIBR 953)Thrombin inhibitor

Dabigatran etexilate (BIBR 1048)

• MW = 627.7 daltons

• Lipid water partition

coefficient = 3.7

N

N

CH3

N

NH

O

HN

NO

NH2

OH

x

O

SCH3

O

OH

N

N

CH3

N

N

O

H

O

O

CH3

N

NO

OCH3

NH2

Oral administration of Dabigatran etexilate 150 mg - Healthy

volunteers

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24

time [hours]

Dab

igat

ran

plas

ma

conc

. [ng

/mL]

CCmax max = 2 hours= 2 hours

TT1/2 1/2 = 14 - 17 h= 14 - 17 h

Bioavailbility = 3-5%Bioavailbility = 3-5%

CCmax max = 2 hours= 2 hours

TT1/2 1/2 = 14 - 17 h= 14 - 17 h

Bioavailbility = 3-5%Bioavailbility = 3-5%

Study Design BISTRO IITotal Hip &Total Knee Replacement study

Enoxaparin

Start 12 hours pre-operatively

Start 1-4 hours post-operatively

40 mg qd 400pat

50 mg bid 400 pat 150 mg bid 400 pat 300 mg qd 400 pat 225 mg bid 400 pat

Randomization Venograph

yDay 6–10

Follow-up4-6 weeks

Dabigatran

R

• 62 sites in 12 countries• Double-blind treatment allocation• Blinded event assessment• Central Adjudication Committee for efficacy and safety• 2000 patients - to have 1500 evaluable patients

19731973

DabigatrDabigatranan

EnoxapariEnoxaparinn

15715766

397397

1919 55

15315388

383383

11641164

73.9% 73.9% evaluableevaluable

300300

75.6% evaluable75.6% evaluable

Total Total randomisedrandomised

Treatment Treatment groupgroup

RandomizedRandomized

Non-treated or no Non-treated or no surgerysurgery

Underwent Underwent surgerysurgery

Primary efficacy Primary efficacy populationpopulation

Non-evaluable VTE Non-evaluable VTE assessmentassessment

374374 8383

Patient DispositionPatient Disposition

Baseline CharacteristicsPatient

CharacteristicsAge (mean) 65.9 yrsFemales 61%Weight (mean) 79 kg

Operation detailsHips / Knees 2:1Regional

Anaesthetic73%

Study Drug AdministrationTime to first dose

(mean)2.6 hours

Treatment duration (mean)

7 days

00

3030

2525

2020

1515

1010

55

50 mg50 mgbidbid

150 mg150 mgbidbid

300 mg300 mgqdqd

225 mg225 mgbidbid

EnoxaparEnoxaparinin

Distal DVTDistal DVT

Proximal DVTProximal DVT

PEPEp p < 0.0001< 0.0001VTE (%)VTE (%)

p p = 0.0007= 0.0007

VTE in all PatientsVTE in all Patients

Dabigatran etexilateDabigatran etexilate

p p = 0.02= 0.02

Eriksson BI et al. BISTRO II. J Thromb Haemost. 2005;3:103-11

23,6

13,4 13,1

8,3

14,9

39,4

27,223,9 23,7

44,6

0

10

20

30

40

50

50 mgbd

150 mgbd

300 mgbd

225 mgbd

LMWH 50 mgbd

150 mgbd

300 mgbd

225 mgbd

LMWH

HipHip KneeKnee

VTE in Individual Surgical VTE in Individual Surgical GroupsGroups

VTE (%)

pp < 0.05 < 0.05

p p < < 0.050.05


Major bleeding in all Patients

Major Bleeding (%)

50 mg50 mgbidbid

150 mg150 mgbidbid

300 mg300 mgqdqd

225 mg225 mgbidbid

EnoxaparEnoxaparinin

p p < 0.05< 0.05p p < 0.05< 0.05

0·3%

4·1%

4.7%

3.8%

2.0%

0

1

2

3

4

5


Conclusion BISTRO II

Compared with enoxaparin the VTE rate was significantly lower with the three highest doses,

major bleeding was greater with higher doses,

the final choise of dose has not yet been announced

nye antikoagulantia faktor xa-hæmmere og trombinhæmmere lars borris overlÆge ortopÆdkirurgisk...

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