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UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA B. Cosmi U.O. di Angiologia e Malattie della Coagulazione Marino Golinelli Policlinico S. Orsola-Malpighi.

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Presentazione sul tema: "UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA B. Cosmi U.O. di Angiologia e Malattie della Coagulazione Marino Golinelli Policlinico S. Orsola-Malpighi."— Transcript della presentazione:

1 UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA B. Cosmi U.O. di Angiologia e Malattie della Coagulazione Marino Golinelli Policlinico S. Orsola-Malpighi Bologna

2 Evolution of Venous Thromboembolism Prophylaxis 1940s Early mobilization 1940s Heparin 1950s Warfarin 1960s Dextrans 1970s Low-dose heparin (LDH) 1980s Low Molecular Weight Heparins (LMWH) 1990s Parenteral direct thrombin inhibitor (DTI) (hirudin) 2002 Fondaparinux (Pentasaccharide) 2008 Oral direct thrombin inhibitors ???? Oral Factor Xa Inhibitors

3 Profilassi del TEV nei paz. chirurgici con i nuovi farmaci antitrombotici Profilassi meccanica Profilassi del TEV nel paz. medico

4 Obiettivi nello sviluppo di nuovi anticoagulanti effetto dose risposta prevedibile assenza interazioni con cibo e farmaci possibilità di somministrazione a dosi fisse senza monitoraggio di laboratorio semplificare terapia anticoagulante a lungo termine

5 Stadi della ricerca clinica con i nuovi anticoagulanti 1° stadio: profilassi del tromboembolismo venoso in chirurgia ortopedica maggiore 2° stadio: terapia del tromboembolismo venoso 3° stadio : sindromi coronariche acute e fibrillazione atriale

6 I nuovi farmaci Anticoagulanti: Indiretti (AT-mediati) Fondaparinux Idraparinux Diretti (anti IIa) Dabigatran (anti Xa) Rivaroxaban Apixaban

7 PENTASACCHARIDES Arixtra (fondaparinux) idraparinux (SanOrg34006)

8 Fondaparinux : The first of a new class of synthetic selective inhibitors of factor Xa Five saccharide units Synthetic Highly selective for AT3 Factor Xa inhibition No binding with plasma proteins No effect on platelet function No thrombocytopenia

9 Meccanismo dazione del Pentasaccaride

10 Fondaparinux Molecular weight 1500 d Rapid onset of action Plasma half life h 1 administration/day Renal elimination No monitoring No specific antidote available, but the effects are reversed by F. VIIa

11 EFFICACIA DEL FONDAPARINUX NELLA PROFILASSI DEL TROMBOEMBOLISMO VENOSO IN CHIRURGIA ORTOPEDICA

12 From first injection to day 11 - All treated patients Patients With Fondaparinux (N=3616) Enoxaparin NNH (N=3621) SAE 196 (5.4 %) 164 (4.5 %) 111 Fatal bleeding 01 Non-fatal bleeding in critical organ 01 Bleeding leading to re-operation 12 (0.33 %) Bleeding with transfusion 2 units and/or hemoglobin decrease 2g/dL 84 (2.3%)52 (1.4 %) 111 Other Bleeding 109 (3.01%)99 (2.73%) 357 Serious adverse events and bleeding 9 (0.25 %) 125

13 Prophylaxis in fractured hip surgery Arixtra 2.5 mg od R Venogram Day 19–24 Double- Blind Total Treatment Duration 21 ± 2 Days Placebo Arixtra 2.5 mg od INITIAL TREATMENT PERIOD (7 ± 1 DAYS) HFS n = 326 n = 330 Pentifra-plus

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15 Il Fondaparinux non provoca HIT - Non reazione crociata di Fondaparinux con gli anticorpi associati allHIT negli studi in vitro - Non casi di HIT negli studi clinici di fase II e III - Non casi di HIT nellanalisi dei dati di esposizione al farmaco nel periodo 07/12/2001 al 31/12/2005 riferita a pazienti (Periodic Safety Update Report di fondaparinux relativi al periodo 05Dic Dic2005)

16 Factor II (Prothrombin) Fibrinogen XII VII X XI IX Direct Thrombin Inhibition XIIa Thrombin VIIa XIa Fibrin IXa Xa Tissue Factor Lepirudin Bivalirudin Argatroban Ximelagatran (oral) Dabigatran (oral) Dabigatran (oral)

17 Struttura del Dabigatran etexilate Inibitore diretto della trombina, orale Ingelheim/Germany, 27 March 2008 Boehringer Ingelheim today announced that the European Commission has granted marketing authorisation of the novel, oral direct thrombin inhibitor, Pradaxa ® (dabigatran etexilate) in all 27 EU member states. It is anticipated that Pradaxa ® will be launched in Germany and the United Kingdom in the coming weeks

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19 Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial Bengt I Eriksson BI et al RE-NOVATE Lancet 2007; 370: 949– patients total-hip replacement were Randomized to one of two doses of dabigatran etexilate (220 mg or 150 mg once daily) or enoxaparin (40 mg sc once daily), given for one month. The primary efficacy outcome was the composite of total VTE (venographic or symptomatic) and death from all causes during treatment.

20 RE-NOVATE: Major results End pointDabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin 40 mg (%) Total VTE and death from all causes Major bleeding

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22 Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. Eriksson BI et al. J Thromb Haemost Nov;5(11): patients dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Follow-up for 3 months The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events

23 Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. Eriksson BI et al. J Thromb Haemost Nov;5(11): End pointDabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin 40 mg (%) Total VTE, and all-cause mortality (primary end point) Major Bleeding 40.5% 1.3% 36.4% 1.5% 37.7% 1.3%

24 Combined analysis of dabigatran trials End pointDabigatran 150 mg (%) Dabigatran 220 mg (%) Enoxaparin (%) Major VTE and VTE- related death Major bleeding

25 Dabigatran etexilate Dose di 110 mg ( ½ cp) h dopo chirurgia 220 mg/die 10 gg dopo protesi ginocchio gg dopo protesi anca Se età > 75 aa o IRC moderata 150 mg

26 Dabigatran etexilate Studi in fase III (non-inferiorità verso TAO) Re-COVER: TEV acuta, 5 gg LMWH poi random. (doppio cieco) a Dab. (150 mg x 2) o TAO x 6 mesi Re-MEDY: prev. secondaria; dopo 3-6 m. di TAO, random., cieco; Dab. (150 mg x 2) o TAO x 18 mesi

27 VIIa Xa IXa XIa XIIa Direct Factor Xa inhibition Tissue factor Fibrinogen Fibrin clot Factor II (prothrombin) Rivaroxaban Apixaban DU-176b YM150 LY PRT ×

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29 Apixaban A highly potent, oral, direct FXa inhibitor (K i 0.08 nM) –Follow-up to razaxaban (development halted due to bleeding concerns) Phase II study for VTE prevention after TKR: completed –Double-blind; dose-ranging; three od and three bid apixaban doses; comparator enoxaparin and warfarin; target enrolment n=1202 Phase II pilot study for VTE prevention in patients with advanced metastatic cancer: ongoing

30 Struttura del Rivaroxaban

31 A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY ), for Thromboprophylaxis After Total Hip Replacement Eriksson et al. Circulation. 2006;114:

32 Rivaroxaban bid (THR/TKR pooled): *Estimated rates calculated by logistic regression adjusted for study, age, and gender Efficacy: p=0.39 Safety: p< Enoxaparin DVT, PE, and all-cause mortality Major bleeding Estimated incidence rate* (%) Rivaroxaban (mg total daily dose) 5

33 Rivaroxaban

34 RECORD – REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE Rivaroxaban 10 mg od will be compared with enoxaparin in over 10,000 patients worldwide –RECORD 1: THR, 5 weeks therapy –RECORD 2: THR, 5 weeks vs 10–14 days enoxaparin –RECORD 3: TKR, 10–14 days therapy –RECORD 4: TKR, 10–14 days therapy

35 Rivaroxaban

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38 Lassen M et al Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. RECORD 3: Major efficacy end points End pointRivaroxaban (%) Enoxaparin (%) Relative risk reduction (%) p DVT, nonfatal PE, all-cause mortality <0.001 Major VTE (proximal DVT, nonfatal PE, and VTE-related death)

39 RECORD 3: Major safety end points Lassen M et al Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. OutcomeRivaroxaban (%) Enoxaparin (%) p Major bleed0.60.5NS Any bleed4.94.8NS

40 Nuovi anticoagulanti: potenziali vantaggi Fondapar. Idrapar. rapida azione; no controllo no HIT 1 somm./die o 1/sett Altri anti-Xa o anti-IIa orali; no controllo rapida azione

41 Nuovi anticoagulanti: potenziali svantaggi No antidoti (eccetto SSR126517E) Difficile monitorare leffetto (se emorragia) Non escludibili altri negativi effetti Breve tempo di emivita (vantaggi/svantaggi) Difficile controllare la compliance Costi

42 PROFILASSI MECCANICA Calze elastiche : prevenzione distensione venosa con riduzione stasi venosa nel polpaccio con miglioramento ritorno venoso CPI (compressione pneumatica intermittente; arto o solo piede) con manicotti gonfiabil ad intermittenza: solo paz. ospedalizzati Stimolano e mantengono flusso pulsatile nel circolo venoso profondo CPI aumentano velocità flusso in v. femorale comune dal 50 al 250% dei valori a riposo

43 ELASTIC COMPRESSION STOCKINGS FOR PREVENTION OF DEEP VEIN THROMBOSIS (Amaragiri SV, Lees TA, Cochrane Review, Cochrane Library Issue 3, 2002) Nove studi clinici randomizzati ( sia paz. Chirurgici che medici) CE da sole vs. controllo: TVP 13% vs. 27% RRR : 66% Sette studi clinici randomizzati (paz. Chirurgici) CE con altro metodo farmacologico: TVP 2% vs. 15% RRR: 76% Nessuno studio ha incluso paz a basso rischio In associazione alla profilassi farmacologica se: - sindrome varicosa - insufficienza venosa cronica - alto rischio

44 Intermittent pneumatic compression and deep vein thrombosis prevention. A meta-analysis in postoperative patients. Urbankova et al. T& H, 2005; 2005 Dec;94(6): RCT of IPC versus no prophylaxis, 2,270 patients in 15 eligible studies: 1,125 and 1,145 in the IPC and no prophylaxis group, respectively. The included studies formed a total of 16 treatment groups and were conducted in orthopedic (5), general surgical (4),oncologic (3), neurosurgical (3) and urologic (1) patient populations. In comparison to no prophylaxis, IPC devices reduced the risk of DVT by 60% (relative risk 0.40, 95% CI ; p < 0.001).

45 Foot pump livelli di compressione maggiori per aumentare flusso in v. femorale, più efficaci se utilizzate in combinazione con CE vs. CE sole Pochi confronti tra i vari apparecchi Non chiaro momento inizio e durata ottimali Compliance del paz. CPI > efficacia di CE in pz. A alto rischio in combinazione con anticoagulanti o se anticoagulanti controindicati

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47 Hull RD et al. EXCLAIM 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. Efficacy outcomes during extended-duration enoxaparin therapy in high-risk nonsurgical patients End pointsOutcome, extended prophylaxis, n=2052 (%) Outcome, placebo, n=2062 (%) RR reduction (%) p VTE events* Symptomatic VTE Asymptomatic VTE *Primary efficacy end point: composite of asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or fatal pulmonary embolism. Asymptomatic DVT was defined by compression ultrasonography, which was routinely performed. VTE=venous thromboembolism RR=relative risk

48 Safety outcomes during extended-duration randomized therapy in high-risk nonsurgical patients Hull RD et al Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland. End pointExtended enoxaparin prophylaxis, n=2052 (%) Placebo, n=2062 (%) p Total bleeding events* Major bleeding events Minor bleeding events *Primary safety end point


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