1. Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere
LARS BORRIS
OVERLÆGE
ORTOPÆDKIRURGISK AFD.
ÅRHUS SYGEHUS

2. Nye antikoagulantia Initiering VF/VIIa IX X IXa VIIIa Propagation Xa
rNAPc2 IX X
fondaparinux idraparinux
(razaxaban)
apixaban
BAY
………………..
IXa
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
(xi)melagatran
dabigatran
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

3. Udvælgelseskriterier
Kirurgisk profylakse
Ikke er eller har været markedsført
Har gennemført fase II
Offentliggjorte resultater

4. Nye antikoagulantia Initiering VF/VIIa IX X IXa VIIIa Propagation Xa
rNAPc2 IX X
BAY
(rivaroxaban)
(razaxaban)
apixaban
IXa
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
dabigatran
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

5. 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)

6. Standard studiedesignOP
Screening K R T
Dobbelt-blinding
Tid (dage)
Behandling Follow-up
K = kontrolstof typisk LMWH
T = teststof
OP = THA og/eller TKA
Screening: bilateral UE flebografi eller UL.
AK behandling hvis PE eller DVT

7. 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

8. Virkningssteder for nye antikoagulantia
Initiering
VF/VIIa
rNAPc2 IX X
IXa
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

9. Vævsfaktor/faktor VIIa hæmmere
rNAPc2
Rekombinant nematode antikoagulant protein c2
Findes naturligt i spyttet fra hageorm (Ancylostoma caninum)
Virkningsmekanisme:
Hæmmer det kompleks der dannes mellem vævsfaktor og faktor VIIa i initieringsfasen
Stofprofil:
Halveringstid>50 timer
Biotilgængelighed: 90%-100% efter sc injektion

10. 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. 7
RESULTAT:
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.

11. Virkningssteder for nye antikoagulantia
Initiering
VF/VIIa IX X
IXa
BAY
(rivaroxaban)
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

12. 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 hæmmer både frit Xa og bundet Xa

14. BAY 59-7939 inhibits free FXa, prothrombinase activity, and endogenous Factor Xa in plasma
Perzborn et al., ICT 2004

15. Chemestry: BAY 59 7939 (rivaroxaban)
MW daltons
Formula: C19H18CIN3O5S

16. 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

17. BAY 59-7939 has antithrombotic effects (venous thrombosis model)
Venous thrombosis model – rat venous stasis model **
***
100 80 60 40 20
0.03
0.10
0.30
Thrombus reduction (%)
BAY (mg/kg) i.v.
A venous (fibrin rich, platelet poor) thrombus was formed by a combination of stasis and thrombogenic challenge (tissue factor) in the vena cava of anesthetized rats after intravenous (i.v.) administration of BAY (0.03, 0.10, or 0.30 mg/kg) or solvent.
Pretreatment with BAY (0.03, 0.10, or 0.30 mg/kg i.v.) reduced thrombus mass dose dependently, with an ED50 of 0.1 mg/kg compared with solvent, demonstrating a potential use for BAY in the prevention of thrombus formation
Perzborn E et al. Antithrombotic effects of BAY , an oral, direct Factor Xa Inhibitor, in
models of thrombosis and bleeding time in rats and rabbits. Poster presentation at the 18th
International Congress on Thrombosis, Ljubljana, Slovenia, June 20–24, Poster no.
PO053
**P<0.01; ***P<0.001
Perzborn et al., ICT 2004

18. Prolongation of bleeding time
BAY does not affect bleeding times at an antithrombotic-effective dose (3 mg/kg)
Rat and rabbit bleeding models
BAY
(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
1.7±0.9
3.0
1.0±0.1
1.6±0.8
6.0
2.1±0.2**
10.0
2.7±0.2***
Oral BAY did not significantly affect rat tail-bleeding time and rabbit ear-bleeding time at antithrombotic-effective doses (up to 3 mg/kg)
Therefore, BAY has a favorable antithrombotic activity:bleeding risk ratio
Perzborn E et al. Antithrombotic effects of BAY , an oral, direct Factor Xa Inhibitor, in
models of thrombosis and bleeding time in rats and rabbits. Poster presentation at the 18th
International Congress on Thrombosis, Ljubljana, Slovenia, June 20–24, Poster no.
PO053
Data are shown as mean±SEM
**P<0.01; ***P<0.001; ND = not determined
Perzborn et al., ICT 2004

19. BAY 59-7939: dose-dependent inhibition
of Factor Xa
Healthy human subjects

20. Key points: pharmacodynamics
In healthy human subjects, BAY :
Dose-dependently inhibits Factor Xa
Factor Xa inhibition and plasma concentrations of
BAY correlate strongly
Dose-dependently prolongs prothrombin time
Prothrombin time and plasma concentrations of BAY 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

21. 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:P0078
Kubitza et al. J Thromb Haemost 2005; 3: P 1704
Kubitza et al. Clin Pharmacol Ther 2005; 78:

22. 3 Phase II bid Studies
10942 (ODIXa-Hip – a Phase IIa Dose Escalating Proof of Principle Trial)
Oral Direct Factor Xa Inhibitor BAY in the Prevention of VTE in Patients Undergoing Total Hip Replacement
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 dosing)
Oral Direct Factor Xa Inhibitor BAY in the Prevention of VTE in Patients Undergoing Total Knee Replacement

23. ODIXa-HIP Study (10942) (open)
D D D+30
BAY 2.5 mg bid
BAY 5 mg bid
BAY 10 mg bid R
BAY 20 mg bid
BAY 30 mg bid
BAY 30 mg od
Enoxaparin
THR venography Follow-up

24. ODIXa-HIP II Study (10944) (double-blinded)
D D D+30
BAY 2.5 mg bid
BAY 5 mg bid
BAY 10 mg bid R
BAY 20 mg bid
BAY 30 mg bid
Enoxaparin
THR venography Follow-up

25. ODIXa-Knee Study (10945) (double-blinded)
D D D+30
BAY 2.5 mg bid
BAY 5 mg bid
BAY 10 mg bid R
BAY 20 mg bid
BAY 30 mg bid
Enoxaparin
TKR venography follow-up

26. Study endpoints Efficacy: evaluated 5–9 days after surgery
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
Safety: bleeding occurring after the first dose of study drug and no later than 2 days after the last dose
Major post-operative bleeding: fatal bleeding; bleeding into a critical organ (retroperitoneal, intracranial, intraocular, intraspinal); overt bleeding warranting treatment cessation; bleeding leading to reoperation; clinically overt bleeding associated with a fall in Hb 2g/dL or leading to transfusion of 2 units
Clinically relevant, non-major bleeding: multiple-source bleeding; spontaneous haematoma >25cm2; excessive wound haematoma; epistaxis >5 mins, macroscopic haematuria; spontaneous rectal bleeding, gingival bleeding >5 mins, haemoptysis, haematemesis; prolonged bleeding (>5 mins) after venipuncture
Minor bleeding events: those that did not fulfill criteria for major or clinically relevant non-major bleeding
Primary safety endpoint
Major bleeding
Secondary safety endpoints
Clinically relevant, non-major bleeding
Minor bleeding

27. Results 3 bid studies Pooled analysis

28. Efficacy: Total VTE TKA
curves not identical to those presented for the individual studies –age and gender adjustment and enox patients contribute to model

29. Major Bleeding

30. Net-Clinical Benefit (in %) major VTE and major bleedings
Outcome
Treatment Group
SN 44+45 SN
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
6.3
20 mg bid BAY
8.7
8.1
30 mg bid BAY
9.6
12.5
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

31. 1 Phase II od Study 11527 (ODIXa-OD.HIP – once daily dosing)
Controlled, Double-Blind, Randomized, Dose-ranging Study of once-daily regimen of BAY in the Prevention of VTE in Patients Undergoing Elective Total Hip Replacement

32. ODIXa-OD.HIP Study (11527) (double-blinded)
D D D+30
BAY 5 mg od
BAY 10 mg od
BAY 20 mg od R
BAY 30 mg od
BAY 40 mg od
Enoxaparin
THR venography follow-up

33. Dose Trend Total VTE

34. Dose Trend Major Bleeding

35. Net Clinical Benefit major VTE major bleed % 10 5 5 10 20 30 40 Enox
BAY , mg qd 5 10 %
11.1
3.5
6.1
8.0
8.8
5.2
major VTE
major bleed

36. 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

37. Future development programme phase III
Extended Prevention of VTE in THA
Short-term prevention of VTE in TKA compared with enox 40 mg od or 30 mg bid
Comparison of Extended Prevention
with BAY given for 5-6 weeks
with short-term prevention with enox.
in THA

38. Virkningssteder for nye antikoagulantia
Initiering
VF/VIIa IX X
IXa
(razaxaban)
apixaban
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

39. FEATURES OF RAZAXABAN
Direct Factor Xa inhibitor
Oral administration

40. Design of a phase II study in elective TKA
Day 1
Day 12±2
Day 42±2
Enoxaparin 30 mg sc bid
Razaxaban 25 mg po bid R
Razaxaban 50 mg po bid
Razaxaban 75 mg po bid
Razaxaban 100 mg po bid
Surgery
Randomization
Venography
Follow-up
Razaxaban initiated 6-8 h after surgery
Enoxaparin initiated h after surgery

41. Patient characteristics N=656
Razaxaban
Enoxaparin
50 mg bid
25 mg bid
75 mg bid
100 mg bid
30 mg bid
n=147
n=123
n=115
n=121
n=150
Gender
M/F
57 / 90
48 / 75
39 / 76
47 / 74
59 / 91
Age (years) 66 65 67 66 65
Mean and
range
35-82
37-85
33-86
41-84
35-84 31 31 31 31 32
BMI
Mean and
range
16-46
17-54
18-50
18-49
21-53

42. Result Summary ITT; all evaluable patients up to day 12±2
VTE Rate
Bleeding Rate
Razaxaban Enoxaparin Razaxaban

43. Preferred dose: 25 mg bid

44. 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

45. Virkningssteder for nye antikoagulantia
Initiering
VF/VIIa IX X
IXa
VIIIa
Propagation Xa Va II
Trombin aktivitet
IIa
dabigatran
Fibrinogen
Fibrin
efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

46. Dabigatran etexilate (BIBR 1048)
Dabigatran (BIBR 953)
Thrombin inhibitor
MW = daltons
Dabigatran etexilate (BIBR 1048)
MW = daltons
Lipid water partition
coefficient = 3.7

47. Oral administration of Dabigatran etexilate 150 mg - Healthy volunteers
Cmax = 2 hours
T1/2 = h
Bioavailbility = 3-5%

48. Study Design BISTRO II Total Hip &Total Knee Replacement study
Enoxaparin
40 mg qd pat
Start 12 hours pre-operatively
Dabigatran
50 mg bid pat
150 mg bid pat R
Start 1-4 hours post-operatively
300 mg qd pat
225 mg bid pat
Randomization
Venography
Day 6–10
Follow-up
4-6 weeks
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

49. Patient Disposition 1973 Total randomised Treatment group Randomized
Dabigatran
Enoxaparin
Randomized
1576
397
Non-treated or no surgery 19 5
Underwent surgery
Dabigatran etexilate Venography not performed, 136 Venography could not be evaluated, 5 Inconclusive venography data
Enoxaparin - 36 Venography not performed, 44 Venography could not be evaluated, 2 Inconclusive venography data
1538
383
Non-evaluable VTE assessment
374 83
Primary efficacy population
1164
73.9% evaluable
300
75.6% evaluable

50. Baseline Characteristics
Patient Characteristics
Age (mean)
65.9 yrs
Females
61%
Weight (mean)
79 kg
Operation details
Hips / Knees
2:1
Regional Anaesthetic
73%
Study Drug Administration
Time to first dose (mean)
2.6 hours
Treatment duration (mean)
7 days

51. VTE in all Patients Distal DVT Proximal DVT VTE (%) PE 30 25 20 15 10
There was a significant dose dependent decrease in the frequency of VTE with increasing doses of dabigatran etexilate (p<0·0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily (absolute difference -6·6%, p=0·04), 300 mg once daily (-7·4%, p=0·02), and 225 mg twice daily (-10·9%, p=0·0007) 5
50 mg
bid
150 mg
bid
300 mg qd
225 mg
bid
Enoxaparin
Dabigatran etexilate
Eriksson BI et al. BISTRO II. J Thromb Haemost. 2005;3:103-11

52. VTE in Individual Surgical Groups
Hip
Knee
VTE (%)
p < 0.05
p < 0.05
Eriksson BI et al. BISTRO II. J Thromb Haemost. 2005;3:103-11

53. Major bleeding in all Patients
0·3%
4·1%
4.7%
3.8%
2.0% 1 2 3 4 5
50 mg
bid
150 mg
bid
300 mg qd
225 mg
bid
Enoxaparin
Eriksson BI et al. BISTRO II. J Thromb Haemost. 2005;3:103-11

54. 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

55. SLUT