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Prof. Rosanna Abbate Univ.di Firenze. Commonly-used anticoagulant treatments affect several steps of coagulation pathway Clot Intrinsic pathwayExtrinsic.

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Presentation on theme: "Prof. Rosanna Abbate Univ.di Firenze. Commonly-used anticoagulant treatments affect several steps of coagulation pathway Clot Intrinsic pathwayExtrinsic."— Presentation transcript:

1 Prof. Rosanna Abbate Univ.di Firenze

2 Commonly-used anticoagulant treatments affect several steps of coagulation pathway Clot Intrinsic pathwayExtrinsic pathway TM TF Ca 2+ Xa TFPI PCa PC PS X II IX XI XIIXIIa FibrinFibrinogen Xa Va PL Ca 2+ IIa VII Inhibition by heparins Inhibition by Vitamin K antagonists Coagulation mechanisms Xa Endogenous anticoagulant ATIII XIa VIIa VIIIa Ca 2+ PL IXa Legend

3 Anticoagulant drugs currently used Heparins (standard unfractionated, low molecular weight) Oral anticoagulants (warfarin, acenocumarol) Hirudin (in Italy only for HIT)

4 Thrombin Inhibitors: DS, Hirudin, Bivalirudin, Argatroban, Melagatran, Ximelagatran IXa inhibitors Xa inhibitors: Pentasaccharide TAP, Antistasin, DX 9065a, DPC 906 Protein C Activators aPC, Thrombomodulin Coagulation PathwayAntithrombotics in development Tissue Factor Pathway Inhibitors TFPI, rNAPc2, VIIa inhibitors Initiation Thrombin generation Thrombin activity TF/VIIa IIa II Xa IXa IXX VIIIa Va i New agents in clinical development: The search for selectivity

5 Platelet activation Fibrin formation F XIII activation F V and F VIII activation Protein C activationVascular release of TPA TAFI Cellular migration Vascular tone regulation Mitogenic activity Thrombin functions

6 THROMBIN FIBRINOGEN Catalytic site Anion binding exosite I fibrinogen binding site Anion binding exosite II heparin binding site TROMBINA: siti funzionali

7 COMPARISON OF INHIBITORY EFFECTS OF HEPARIN ON FLUID-PHASE ( ) AND FIBRIN-BOUND THROMBIN ( )

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10 THROMBIN MELAGATRAN BSF BIBR 1048 MS HIRUGEN LU AT III Farmaci antitrombinici HIRUDIN HIRULOG HEPARIN

11 Ximelagatran Weitz, et al. Thrombosis Research 106; 2002 The drug has a half-life of about 3 h mandating twice daily administration. The active agent, melagatran, is primarily eliminated via the kidneys. Consequently, its half-life is prolonged in the elderly, reflecting their reduced renal function. The pharmacokinetics and pharmacodynamics of ximelagatran are not influenced by aspirin and ximelagatran does not interfere with drugs that are metabolized by the P450 isozymes CYP2C19, CYP2C9 or CYP3A4

12 XIMELAGATRAN (H 376/95) pro-drug oral administration melagatran t max melagatran h half life of melagatran h(healthy vol.) bioavailability of melagatran of approx 20% low variability in melagatran exposure dose, time, gender independent no food interaction (minor decrease in AUC <10%)

13 MELAGATRAN subcutaneous dosing bid rapidly and complete absorption subcutaneously low volume of distribution 0.2 L/kg plasma protein binding <15% not metabolised clearance mainly (80%) renal t max 0.5 h half life h(healthy subjects) inter-individual variability of AUC low (CV; about 15%) NOT suitable for oral dosing

14 Melagatran LMW selective direct thrombin inhibitor EXOSITE 1 (also binding site of fibrin) THROMBIN ACTIVE SITE Synthetic compound - molecular weight of approx 400

15 Melagatran Synthetic compound - mol w of approx Directed to the Active Site of Thrombin Hirulog Exosite 1 Thrombin (with binding to active site) Thrombin (with binding to active site) Thrombin (with indirect blocked active site) Exosite 1 Melagatran Hirudin Exosite 1 Adapted from Lefkovits. Circulation 1994;90:1522–1536. also binding site of fibrin

16 Melagatran

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19 Melagatran e il metabolita attivo di Ximelagatran Biodisponibilita 20% (dose orale 60 mg, n=12) Time (h) Plasma conc. (µmol/l) Melagatran Ximelagatran - t max 1.5 h - emivita 3 h - eliminazione renale Eriksson, Blood, 1999

20 Thrombus size (AU) Total bleeding time (min) Melagatran Effect Bleeding Warfarin Dose (µmol/kg/h), (µmol/kg/day) Elg M et al, Thromb Res 1999;94:187 Antithrombotic effect and bleeding in a rat model

21 Melagatran/ximelagatran Studi clinici sperimentali Fase I TEV profilassi FA TEV terapia SCA Melagatran - 22 studi H 376/ studi TR TR METHRO I METHRO II MASCOT I 203 (USA) METHRO III PLATINUM EXPRESS EXULT A EXULT B TR THRIVE I THRIVE IV THRIVE III THRIVE II THRIVE V SPORTIF II SPORTIF III SPORTIF IV SPORTIF III SPORTIF V ESTEEM

22 EXPRESS: disegno dello studio Tempo -12 h 0 h 12 h 24 h 8-11 gg. 4-6 sett sera op sera Enoxaparina 40 mg sc qd (ogni sera) Ximelagatran orale 24 mg bid (mattino e sera) M e l a g a t r a n sc 2 mg3 mg flebografia follow-up Eriksson, JTH 2003 Each administered with matched placebo Treatment: 7-12 days F-up: 4-6 wks 2835 THR/ TKR pts

23 THR interventi EXPRESS: TVP Prossimale + PE RRR=67% TKR Interventi RRR = 60% melagatran (sc) and ximelagatran (po) enoxaparina(sc ) % event THR+TKR Interventi RRR=63.2% Eriksson, JTH 2003

24 EXPRESS: TEV totali RRR=29% RRR=21% THR Interventi TKR Interventi melagatran (sc) and ximelagatran (po) enoxaparina(sc ) % eventi THR+TKR Interventi RRR=23.6% Eriksson, JTH 2003 VTE sintomatico raro

25 EXPRESS: Emorragie Maggiori SurgeryBleeding CategoryEnoxaparinMelagatran/ Ximel. THR+ITT population TKR-Fatal Bleeding00 -Critical Site00 -Severe1.2%3.1% -Other 7.0%9.2% -Non wound related transfusion > 2 units00.2% -Requiring re-operation # 0.4% 0.5% -Blood transfusions61.7%66.8%* May have occurred during the entire study period * Difference significant for THR, not for TKR Eriksson, JTH 2003

26 Treatment/ Preoperative dose Proximal DVT/PE, % (95% Cl) Total DVT/PE, % (95% Cl) Bleeding, % (95% Cl) Blood loss during surgery, mL (95% Cl) Melagatran/0 mg (METHRO III) 5.7 (4.4;7.2) 31.0 (28.3;33.7) 1.4 (0.9;2.2) (190.3;235.7) Melagatran/2 mg (EXPRESS) 2.3 (1.5;3.3) 20.2 (17.9;22.7) 3.3 (2.4;4.4) (175.5;217.6) Melagatran/3 mg (METHRO II) 2.4 (1.0;4.9) 15.1 (11.1;19.8) 4.8 (2.8;7.4) (175.0;264.2) LMWH (pooled data) 6.3 (5.4;7.3) 27.1 (25.4;28.8) 1.5 (1.1;2.0) (191.6;220.9) Efficacy and safety of (xi)melagatran for prevention of VTE after THR or TKR: analysis of 3 randomized, double-blind studies, to evaluate the influence of time and dose A. T. Cohen, ISTH 2003

27 EXULT A TRIAL (++North-America) TKR Ximelagatran (24 mg bid) Ximelagatran (36 mg bid) Warfarin (INR 1.8-3) Each administered with matched placebo Treatment: 7-12 days F-up: 4-6 wks Warfarin initiated the evening of the day of surgery Ximelagatran initiated 12 hrs or more after surgery Francis NEJM 2003

28 EXULT A - Efficacy end points End point Warfarin (95% CI) Ximelagatran 24 mg (95% CI) Ximelagatran 36 mg (95% CI) Total VTE and death 27.6% ( ) 24.9% ( ) 20.3% ( )* Proximal VTE and death 4.1% ( ) 2.5% ( ) 2.7% ( ) *p=0.003 RRR 26.4% ARR 7.3% Symptomatic DVT or death < 1% in each group Francis NEJM 2003

29 EXULT A: Safety end points End pointWarfarin (95% CI) Ximelagatran 24 mg (95% CI) Ximelagatran 36 mg (95% CI) Major bleeding 0.7% ( )0.8% ( ) Major or minor bleeding Minor bleeding 4.5% ( ) 4.0% 4.8% ( ) 4.7% 5.3% ( ) 4.7% No statistically significant differences for perioperative indicators of bleeding, or wound drainage or appearance Francis NEJM 2003

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31 EXULT B TRIAL (++North-America) TKR Ximelagatran (36 mg bid) Warfarin (INR 1.8-3) Study design very close to EXULT A 2303 pts enrolled, 2299 received at least one dose, 1949 had adequate venography Weitz ISTH 2003

32 EXULT B: Total VTE and all-cause mortality End pointWarfarin (%) Ximelagatran (%) RRR (%) p Total VTE and all- cause mortality event rate <0.001 Colwell CW et al. American Society of Hematology; December 6-9, 2003; San Diego, CA. ARR 9.3% (95% CI ) NNT 11 (8-18) A trend was observed to reduction of proximal DVT (4% vs 3.5%)

33 EXULT B: Bleeding events End pointWarfarin (%) Ximelagatran (%) p Major bleeding NS Minor bleeding NS Colwell CW et al. American Society of Hematology; December 6-9, 2003; San Diego, CA. No relevant alterations in liver function tests as in EXULT A

34 (Xi)melagatran in chirurgia ortopedica maggiore Xi 24 mg x2 = enoxa 30 x2 in TKR Xi 24 mg x2 = W in TKR Xi 24 mg x2 < enoxa 30 x2 in THR Xi 36 mg x2 > W in TKR (EXULT) M 3 mg pre e 3mg post + Xi 24 mg x2 > dalte 5000 x1 ma > emorragie in THR+TKR M 2 mg pre e 3mg post + Xi 24 mg x2 > enoxa 40 x1 in THR+TKR (EXPRESS) M 3mg post + Xi 24 mg x2 = enoxa 40 x1 in THR+TKR USA Europa D Prisco 2004

35 Quadratic fit for study OR for DVT vs. the number of hrs from surgery for the first dose of the antithrombotic regimen. Peak efficacy ranges between 2 h preop and 6-8 h postop. Timing of initial administration of prophylaxis against deep vein thrombosis in patients following hip or knee surgery (Hull 2003)

36 R n=68 n=65 n=73 n=71 n=73 Ximelagatran 24 mg oral bid Ximelagatran 36 mg oral bid Ximelagatran 48 mg oral bid Ximelagatran 60 mg oral bid Dalteparin sc + warfarin DVT treatment, THRIVE I - Study design Day 3-5Day 6-9Day 12-16Day 26-32Pre-entry Phlebography Follow-upAdv Ev Visit 1 Visit 2 Visit 3 Visit 14 Visit 5 Multicentre, randomised, controlled, parallel group, dose-finding Eriksson H et al. J Thromb Haemost 2003; 1: N=350 DVT pts

37 THRIVE I - treatment of patients with DVT Ximelagatran ( mg bid) vs warfarin + dalteparin 24 mg 36 mg 48 mg 60 mg W/D <-5[-5 to +5]>5 Patients % Total bleeding: Ximelagatran (12 %, no dose response), W/D (10 %) Efficacy: Change in Marder score units at 14 days (n=295) Eriksson H et al. J Thromb Haemost 2003; 1: 41-7.

38 THRIVE I- Conclusions: H 376/95 in DVT Flat dose-response Broad therapeutic interval No severe bleedings Use without monitoring supported

39 THRIVE II: design of the study Placebo H 376/95 + Warfarin/Enoxaparin R Objective confirmation of DVT and/or PE End of Treatment H 376/95 36 mg b.i.d. + Placebo Warfarin/Enoxaparin 6 Month E Until INR 2.0 at two consecutive measurements ( days of Enoxaparin ) 14 days follow up max 14 days onset of symptoms of DVT of lower limbs +/- PE 24 hours stratification Enoxaparin (1 mg/Kg bid) Warfarin or H 376/95 n= 1241 n= % enrolled pts with PE

40 THRIVE II: results EventXimelagatran n (%*) Enoxa/warfarin n (%*) Absolute difference ximel: enoxa/w (%*; 95% Cl) Recurrent VTE (ITT)26 (2.1%)24 (2.0%)+0.2%** (-1.0%; + 1.3%) Recurrent VTE (OT)23 (2.0%)17 (1.5%)+0.5% (-0.6%; + 1.6%) All-cause mortality (ITT) 28 (2.3%)42 (3.4%)-1.0%** (-2.4%; + 0.2%) Major bleeding (OT)14 (1.3%)25 (2.2%)-0.9% (-2.0%; + 0.2%) Recurrent VTE and/or major bleeding (OT) 37 (3.2%)42 (3.6%)-0.4% (-1.9%; + 1.1%) * Estimated cumulative risk; **rounded figures; CI = confidence interval; ITT = intention-to-treat; OT = on- treatment

41 Volume 349: October 30, 2003 Number 18 Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran Sam Schulman, M.D., Karin Wåhlander, M.D., Torbjörn Lundström, M.D., Solveig Billing Clason, M.Sc., Henry Eriksson, M.D., for the THRIVE III Investigators

42 R 18 months Placebo E 6 ±1 months Ximelagatran Ximelagatran (24 mg, b.i.d., p.o.) Initial VTE event Stratification - malignancy 2 weeks follow up Study treatment INR<1.5 Stop of study treatment 617 patients 616 patients Schulman, NEJM 2003 THRIVE III: disegno dello studio Standard anticoagulation ITTpopulation n=612 n=611 Leg US scan + perfusion lung scan at baseline

43 THRIVE III: TEV totali - TVP e/o EP ( ITT population) Months Ximelagatran Placebo P< HR=0.16 (95%CI 0.09; 0.30) Estimated cumulative risk (%) 2.8% 12.6% 9.8%9.8% Schulman, NEJM 2003

44 THRIVE III: Emorragie maggiori e minori (ITT population) 21.0% 23.9% 18 Months P= (NS) HR=1.19 (95%CI 0.93; 1.53) Estimated cumulative risk (%) Ximelagatran Placebo Schulman, NEJM 2003

45 Ridker PM et al, N Engl J Med 2003

46 THRIVE III PlaceboXimelagatran Emorragie maggiori * 0.8%1.0% Morti Morti +TEV 1.2% 13.3% 1.0% 3.9% HR 0.23 Aumento ALT (>3 x limite superiore normale) 1.2%6.4%** HR 6.5 *nessuna fatale o intracranica ** Senza iperbilirubinemia, massimo valore osservato 25 x, mesi, transitorio, andamento indipendente da sospensione ximelagatran o meno, non segni o sintomi, non spiegabile con caratteristiche di pazienti o farmaci associati Schulman, NEJM 2003

47 Time Courses of Elevations in the Alanine Aminotransferase Level in Patients Receiving Ximelagatran in Whom the Values Exceeded Three Times the Upper Limit of Normal at Least Once Diamonds represent the last observation in a given patient; dotted lines represent patients in whom treatment with ximelagatran was discontinued. The highest peak shows the maximal elevation in a patient with positive serologic-test results for Epstein–Barr virus infection. The outlying peak near 360 days shows the maximal elevation in a patient with a gall-bladder concrement. Schulman, NEJM 2003

48 Fibrillazione atriale – Fase III ® Ximelagatran36 mg bid Warfarin Fino a 27 mesi 3000 paz. resto del mondo open label, : SPORTIF III 3000 paz. USA & Canada double-blind, double-dummy, sham INR : SPORTIF V

49 Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF III) Lancet 2003;362:

50 The SPORTIF III Study Randomised, parallel group, open-label treatment allocation, blinded event assessmentRandomised, parallel group, open-label treatment allocation, blinded event assessment 23 countries, 259 centers23 countries, 259 centers Exposure: mean 17 months, 4941 patient-years and 96 primary endpoints. Adjusted-doseWarfarin (INR 2-3) Fixed-doseximelagatran (36 mg b.i.d.) Nonvalvular atrial fibrillation patients with at least one aditional risk factor for stroke n=3 407 Primary objective: To establish the non-inferiority of ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

51 Paragone di vari eventi compositi SPORTIF III, Lancet 2003;362:

52 SPORTIF III Stroke e/o embolia sistemica (intention to treat) p= Durata (mesi) Warfarin Ximelagatran Eventi cumulativi (%) 56 eventi (2.3%/anno) 40 eventi (1.6%/anno) Presented at ACC 2003

53 4.6% Eventi (% per anno) Eventi primari + emorragie maggiori + morte 6.1% RRR=25% p = Eventi avversi maggiori (on treatment analysis) Ximelagatran Warfarin Presented at ACC 2003

54 Eventi (%) ALT >3x limite sup. norma p < % 0.7% Altri eventi avversi Aumento enzimi epatici Ximelagatran Warfarin Presented at ACC 2003

55 The SPORTIF V Study Randomised, double-blind, double-dummy, sham INR, blinded endpoint assessment USA and Canada, 409 centers Exposure: mean 20 months, 6405 patient-years and 88 primary endpoints. Adjusted-doseWarfarin (INR 2-3) Fixed-doseXimelagatran (36 mg bid) Nonvalvular atrial fibrillation patients with at least one aditional risk factor for stroke n=3 922 Primary objective: To establish the non-inferiority of fixed-dose ximelagatran compared to dose-adjusted warfarin (INR ) for prevention of all strokes and/or systemic embolic events in patients with nonvalvular paroxysmal or persistent atrial fibrillation and 1 adjunctive risk factor for stroke

56 SPORTIF V - Stroke ed embolismo sistemico (Intention to treat) Ximelagatran Warfarin Ximelagatran Warfarin Mesi 51 events (1.6%/anno) 37 eventis (1.2%/anno) Eventi cumulativi (%/anno) p=0.13

57 SPORTIF (Analisi intention to treat) SPORTIF III SPORTIF V Differenza assoluta nella frequenza di eventi (Ximelagatran – Warfarin) Ximelagatran meglioWarfarin meglio Pooled -0.03

58 SPORTIF V - Emorragie (Analisi on treatment) 3.1% 47% 0.1% 2.4% 37% Cerebrali Maggiori Maggiori + minori Warfarin Ximelagatran Eventi (% /anno) p< p=0.16 NS

59 SPORTIF V - aumento transaminasi ALT >3 x val. normale WarfarinXimelagatran Mesi Numero di pazienti

60 Oral ximelagatran for secondary prophylaxis after myocardial infarction. The ESTEEM randomised controlled trial Wallentin L et al, Lancet 2003; 362:789-97

61 Dose-finding, doppio cieco, controllato con placebo in 1883 pazienti con recente infarto del miocardio Ximelagatran 24 mg, 36 mg, 48 mg, or 60 mg 2 volte/die, per 6 mesi Tutti i pazienti ricevevano anche ASA 160 mg Obiettivi primari: mortalità generale, infarto non fatale, recidiva ischemica grave ESTEEM Study Wallentin L et al. Lancet 2003; 362: 789–97

62 Rischio cumulativo di morte, infarto e stroke. Pool di tutte le dosi di ximelagatran, analisi intention-to-treat

63 ESTEEM- Emorragie Wallentin L et al. Lancet 2003; 362: 789–97

64 ESTEEM - Conclusioni Wallentin L et al, Lancet 2003; 362: Lassociazione ximelagatran-ASA è più efficace del solo ASA nella prevenzione di eventi cardiovascolari maggiori nei 6 mesi successivi ad infarto del miocardio

65 What will the future bring us? Studies so far demonstrate that (xi)melagatran has predictable pharmacokinetic characteristics in volunteers and in patients and has a wider therapeutic window than warfarin. (Xi)melagatran treatment does not need any lab monitoring However, no antidote is available for overdosage and the relevance of increase in ALT has to be clarified


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