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

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Presentation on theme: "Nye antikoagulantia Faktor Xa-hæmmere og trombinhæmmere LARS BORRIS OVERLÆGE ORTOPÆDKIRURGISK AFD. ÅRHUS SYGEHUS."— Presentation transcript:

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

2 Nye antikoagulantia Initiering Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin rNAPc2 fondaparinux idraparinux (razaxaban)apixaban BAY ………………..………………..……………….. (xi)melagatrandabigatran 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 Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin rNAPc2 BAY (rivaroxaban)(razaxaban)apixaban dabigatran 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 studiedesign T R K OP Screening Tid (dage) BehandlingFollow-up K = kontrolstof typisk LMWH T = teststof OP = THA og/eller TKA Screening: bilateral UE flebografi eller UL. AK behandling hvis PE eller DVT Dobbelt-blinding

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 Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin rNAPc2 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 Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin BAY (rivaroxaban) 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

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

15 Chemestry: BAY (rivaroxaban) MW daltons Formula: C 19 H 18 CIN 3 O 5 S

16 FEATURES OF BAY A reversible, direct oral FXa inhibitor Bioavailability: 60%-86% in dogs Rapid obsorption as tablet (C max 2-4 h) Intake with food increases C max by 40% Half-life:5-6 h Excretion: renal/bile

17 BAY has antithrombotic effects (venous thrombosis model) **P<0.01; ***P<0.001 Perzborn et al., ICT 2004 Venous thrombosis model – rat venous stasis model ** *** Thrombus reduction (%) BAY (mg/kg) i.v.

18 BAY does not affect bleeding times at an antithrombotic-effective dose (3 mg/kg) BAY (mg/kg p.o.) Prolongation of bleeding time (X-fold) Rat (n=10)Rabbit (n=5) 0.3ND1.4± ND1.7± ±0.11.6± ±0.2**ND ±0.2***ND Data are shown as mean±SEM **P<0.01; ***P<0.001; ND = not determined Perzborn et al., ICT 2004 Rat and rabbit bleeding models

19 BAY : 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  (ODIXa-Hip – a Phase IIa Dose Escalating Proof of Principle Trial) ODiXa Hip Oral Direct Factor Xa Inhibitor BAY in the Prevention of VTE in Patients Undergoing Total Hip Replacement  (ODIXa-Hip IIb - bid dosing) Controlled, Double-Blind, Randomized, Dose-ranging Study on the prevention of VTE in Patients Undergoing Elective Total Hip Replacement  (ODIXa-Knee – a Phase IIb Dose-ranging Trial – bid dosing) ODiXa Knee Oral Direct Factor Xa Inhibitor BAY in the Prevention of VTE in Patients Undergoing Total Knee Replacement

23 ODIXa-HIP Study (10942) (open) R D1 D6-10 D+30 THR venography Follow-up BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid BAY 20 mg bid BAY 30 mg bid BAY 30 mg od Enoxaparin

24 ODIXa-HIP II Study (10944) (double-blinded) R D1 D6-10D+30 THR venographyFollow-up BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid BAY 20 mg bid BAY 30 mg bid Enoxaparin

25 ODIXa-Knee Study (10945) (double-blinded) R D1 D6-10D+30 TKR venography follow-up BAY 2.5 mg bid BAY 5 mg bid BAY 10 mg bid BAY 20 mg bid BAY 30 mg bid Enoxaparin

26 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 safety endpoint 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

27 Results 3 bid studies Pooled analysis

28 Efficacy: Total VTE TKA

29 Major Bleeding

30 Net-Clinical Benefit (in %) major VTE and major bleedings OutcomeTreatment GroupSN 44+45SN Rate (%)95%-CIRate (%)95%-CI Net Clinical Benefit – modified ITT Population 2.5 mg bid BAY – – mg bid BAY – – mg bid BAY mg bid BAY mg bid BAY Enoxaparin – – 9.4 Note : Net Clinical Benefit is defined as Composite of Major VTE and Major Bleeding

31 1 Phase II od Study  (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) R D1 D6-10D+30 THR venography follow-up BAY 5 mg od BAY 10 mg od BAY 20 mg od BAY 30 mg od BAY 40 mg od Enoxaparin

33 Dose Trend Total VTE

34 Dose Trend Major Bleeding

35 Net Clinical Benefit Enox BAY , mg qd 5 10 % 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 Short-term prevention of VTE in TKA compared with enox 40 mg od or 30 mg bid Future development programme phase III Extended Prevention of VTE in THA 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 Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin (razaxaban)apixaban 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 Surgery Randomization Enoxaparin 30 mg sc bid Razaxaban 25 mg po bid Day 12±2 Follow-upVenography R Razaxaban 50 mg po bid Razaxaban 75 mg po bid Razaxaban 100 mg po bid Day 42±2Day 1 Razaxaban initiated 6-8 h after surgery Enoxaparin initiated h after surgery

41 RazaxabanEnoxaparin 50 mg bid25 mg bid 75 mg bid 100 mg bid 30 mg bid n=147n=123n=115n=121n= / / 7539 / 7647 / 7459 / Age (years) Mean and range Gender M/F BMI Mean and range Patient characteristics N=656

42 Result Summary ITT; all evaluable patients up to day 12±2 VTE RateBleeding 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 Propagation Trombin aktivitet VF/VIIa VIIIa IXa IX X Xa Va II IIa Fibrinogen Fibrin dabigatran efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

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

47 Oral administration of Dabigatran etexilate 150 mg - Healthy volunteers C max = 2 hours T 1/2 = h Bioavailbility = 3-5% C max = 2 hours T 1/2 = h Bioavailbility = 3-5%

48 Study Design BISTRO II Total 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 Venography Day 6–10 Follow-up 4-6 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

49 1973 Dabigatran Enoxaparin % evaluable % evaluable Total randomised Treatment group Randomized Non-treated or no surgery Underwent surgery Primary efficacy population Non-evaluable VTE assessment Patient Disposition

50 Baseline Characteristics Patient Characteristics Age (mean)65.9 yrs Females61% Weight (mean)79 kg Operation details Hips / Knees2:1 Regional Anaesthetic73% Study Drug Administration Time to first dose (mean) 2.6 hours Treatment duration (mean) 7 days

51 mg bid 150 mg bid 300 mg qd 225 mg bidEnoxaparin Distal DVT Proximal DVT PE p < VTE (%) p = VTE in all Patients Dabigatran etexilate p = 0.02 Eriksson BI et al. BISTRO II. J Thromb Haemost. 2005;3:103-11

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

53 Major bleeding in all Patients Major Bleeding (%) 50 mg bid 150 mg bid 300 mg qd 225 mg bidEnoxaparin p < 0.05 p < 0.05 p < ·3% 4·1% 4.7% 3.8% 2.0% 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

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