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

Nye antikoagulantia Initiering VF/VIIa IX X IXa VIIIa Propagation Xa rNAPc2 IX X fondaparinux idraparinux (razaxaban) apixaban BAY 59-7939 ……………….. 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

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

Nye antikoagulantia Initiering VF/VIIa IX X IXa VIIIa Propagation Xa rNAPc2 IX X BAY 59-7939 (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

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 OP 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

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 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

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

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.

Virkningssteder for nye antikoagulantia Initiering VF/VIIa IX X IXa BAY 59-7939 (rivaroxaban) VIIIa Propagation Xa Va II Trombin aktivitet IIa Fibrinogen Fibrin efter Weitz JI, Hirsh J. New antithrombotic drugs. Chest 2001;119:95S-107S

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) Venous thrombosis model – rat venous stasis model ** *** 100 80 60 40 20 0.03 0.10 0.30 Thrombus reduction (%) BAY 59-7939 (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 59-7939 (0.03, 0.10, or 0.30 mg/kg) or solvent. Pretreatment with BAY 59-7939 (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 59-7939 in the prevention of thrombus formation Perzborn E et al. Antithrombotic effects of BAY 59-7939, 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, 2004. Poster no. PO053 **P<0.01; ***P<0.001 Perzborn et al., ICT 2004

Prolongation of bleeding time BAY 59-7939 does not affect bleeding times at an antithrombotic-effective dose (3 mg/kg) Rat and rabbit bleeding models 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 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 59-7939 did not significantly affect rat tail-bleeding time and rabbit ear-bleeding time at antithrombotic-effective doses (up to 3 mg/kg) Therefore, BAY 59-7939 has a favorable antithrombotic activity:bleeding risk ratio Perzborn E et al. Antithrombotic effects of BAY 59-7939, 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, 2004. Poster no. PO053 Data are shown as mean±SEM **P<0.01; ***P<0.001; ND = not determined Perzborn et al., ICT 2004

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:P0078 Kubitza et al. J Thromb Haemost 2005; 3: P 1704 Kubitza et al. Clin Pharmacol Ther 2005; 78: 412-21

3 Phase II bid Studies 10942 (ODIXa-Hip – a Phase IIa Dose Escalating Proof of Principle Trial) Oral Direct Factor Xa Inhibitor BAY 59-7939 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 59-7939 in the Prevention of VTE in Patients Undergoing Total Knee Replacement

ODIXa-HIP Study (10942) (open) D1 D6-10 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

ODIXa-HIP II Study (10944) (double-blinded) D1 D6-10 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

ODIXa-Knee Study (10945) (double-blinded) D1 D6-10 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

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

Results 3 bid studies Pooled analysis

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

Major Bleeding

Net-Clinical Benefit (in %) major VTE and major bleedings Outcome Treatment Group SN 44+45 SN 42+44+45 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) 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) D1 D6-10 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

Dose Trend Total VTE

Dose Trend Major Bleeding

Net Clinical Benefit major VTE major bleed % 10 5 5 10 20 30 40 Enox BAY 59-7939, mg qd 5 10 % 11.1 3.5 6.1 8.0 8.8 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

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 59-7939 given for 5-6 weeks with short-term prevention with enox. in THA

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

FEATURES OF RAZAXABAN Direct Factor Xa inhibitor Oral administration

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 12-24 h after surgery

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

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

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

Dabigatran etexilate (BIBR 1048) Dabigatran (BIBR 953) Thrombin inhibitor MW = 471.5 daltons Dabigatran etexilate (BIBR 1048) MW = 627.7 daltons Lipid water partition coefficient = 3.7

Oral administration of Dabigatran etexilate 150 mg - Healthy volunteers Cmax = 2 hours T1/2 = 14 - 17 h Bioavailbility = 3-5%

Study Design BISTRO II Total Hip &Total Knee Replacement study Enoxaparin 40 mg qd 400pat Start 12 hours pre-operatively Dabigatran 50 mg bid 400 pat 150 mg bid 400 pat R Start 1-4 hours post-operatively 300 mg qd 400 pat 225 mg bid 400 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

Patient Disposition 1973 Total randomised Treatment group Randomized Dabigatran Enoxaparin Randomized 1576 397 Non-treated or no surgery 19 5 Underwent surgery Dabigatran etexilate - 194 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

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

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

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

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

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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