Il Tromboembolismo Venoso. La Terapia della TVP

Transcript

1 Il Tromboembolismo Venoso La Terapia della TVP

2 A chi conviene la terapia domiciliare della TVP? Paziente? Azienda ospedaliera? Medico di medicina generale? Case farmaceutiche e farmacisti? Sistema Sanitario Nazionale?

3 Terapia della TVP 1960: primo primo trial randomizzato che dimostra l efficacia dell eparina per via endovenosa (Barrit et al, Lancet 1:301;1960) 1992: dimostrata pericolosità della terapia iniziale con solo acenocumarolo (Brandjes et al, N Engl J Med 327:1485:1992) 1996: due studi dimostrano efficacia e sicurezza delle eparine a basso peso molecolare, anche a domicilio (Koopman et al; Levine et al; N Engl J Med 334;1996)

4 Terapia del tromboembolismo Eparina per almeno 5 giorni Anticoagulanti orali (warfarin o acenocumarolo) dal primo giorno, per almeno 3 mesi Sospendere Eparina almeno 48 ore dal raggiungimento dell INR terapeutico ( )

5 Terapia della TVP acuta condotta pratica della terapie con eparina standard Emorragie Antidoto:solfato o cloridrato di protamina: 1 mg/100 U eparina Controlli aptt ogni 6-8 ore Osteoporosi

6 Prandoni et al ; Lancet, 1992 Risultati Tromboembolia recidivante (a 6 mesi) Miglioramento score venografico N casi % di pazienti P= Nadroparina Eparina Nadroparina Eparina

7 A Meta-analysis Comparing LMWH With Unfractionated Heparin in the Treatment of Venous Thromboembolism Dolovich L.R., Arch. Intern. Med. Jan 2000 Nr. studi Tromboembolismo venoso Dalteparina vs UFH 4 Enoxaparina vs UFH 2 Nadroparina vs UFH 4 Reviparina vs UFH 1 Tinzaparina vs UFH 2 Embolia Polmonare Dalteparina vs UFH 4 Enoxaparina vs UFH 2 Nadroparina vs UFH 4 Reviparina vs UFH 1 Tinzaparina vs UFH 2 Confronto tra differenti LMWH e UFH LMWH migliori Pooled Relative Risch UFH migliore

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9 Vantaggi delle LMWH Efficacia almeno sovrapponibile all eparina standard anche infusionale Facilità di gestione della terapia Riduzione dei tempi di ospedalizzazione rispetto al periodo di trattamento con eparina standard

10 Vantaggi delle LMWH Ottima maneggevolezza e sicurezza Buona farmacocinetica. Biodisponibilità più elevata SC. Emivita più lunga. Dosaggio fisso pro-kg senza monitoraggio di laboratorio Compatibile con i trattamenti a lungo termine. Può essere usata in gravidanza

11 Terapia con eparine a basso peso molecolare EBPM Nadroparina Enoxaparina Tinzaparina Dalteparina Reviparina Dose (fase acuta) 90 U/Kg/12 ore 100 U/Kg/12 ore 175 U/Kg/24ore 200 U/Kg/24 ore 90 U/Kg/12 ore Lensing et al Lancet 1999; 353: 479

12 Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home Tasman Study N Engl J Med 1996;334:682-7 Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis Canadian Study N Engl J Med 1996;334:677-81

13 Koopman et al; New England J.M., 1996 Risultati Giorni medi di ospedalizzazione , ,7 2 0 Eparina Nadroparina

14 Koopman et al; New England J.M., 1996 Risultati Riduzione dei tempi di ospedalizzazione : Il 36% dei pazienti trattati con Nadroparina non è stato ricoverato Il 40% è stato ricoverato per un breve periodo (1-2 gg) Riduzione del 67% dell ospedalizzazione per i pazienti trattati con Nadroparina (2,7 vs 8,1 gg)

15 Trattamento domiciliare della TVP Recidive TEV EBPM ENF Emorragie maggiori EBPM ENF Levine NEJM % 6.7% 2.0% 1.2% Koopman TASMAN study NEJM % 8.6% 0.5% 2.0% TOTALE 6% 7.5% 1.3% 1.6% Percentuale pazienti trattati per intero a domicilio = Koopman 36% e Levine 49%. Costi: ridotti dell 83 % i giorni di ricovero nei pazienti trattati con enoxaparina

16 A Meta-analysis Comparing LMWH With Unfractionated Heparin in the Treatment of Venous Thromboembolism Dolovich L.R., Arch. Intern. Med. Jan 2000 Nr. studi Tromboembolismo venoso ospedalizzati 10 a domicilio 3 Embolia Polmonare ospedalizzati a domicilio Sanguinamenti maggiori ospedalizzati a domicilio Mortalità totale ospedalizzati a domicilio Confronto tra pazienti trattati in ospedale e pazienti trattati a domicilio LMWH vs UFH LMWH migliori Pooled Relative Risch UFH migliore

17 Valutazione economica di terapia domiciliare o in ospedale nello studio Koopman Van den Belt et al, Thomb Haemost 79:259;1998 L attuazione della terapia domiciliare deve essere preceduta da una prudente valutazione dello spostamento di risorse e da un adeguata fase organizzativa

18 TERAPIA DOMICILIARE diagnosi certa istruzione del paziente accesso telefonico privilegiato per consigli ed efficaci strutture di supporto controllo emocromo in 5^ giornata controllo TP/INR a giorni alterni fino a quando INR è > di 2 per due controlli consecutivi Follow-up condiviso e organizzato

19 Terapia domiciliare della TVP: rischi da evitare Sottovalutazione di una malattia potenzialmente grave Diagnosi affrettata, non strumentale Inadeguata valutazione delle condizioni cliniche del paziente Mancata ricerca delle cause della TVP Carico di responsabilità e spese per paziente, famigliari, medico curante Mancato rilevamento delle complicanze

20 Terapia domiciliare della TVP: aspetti soggettivi ed economici Frank et al, J Suisse Med 1998 Meglio a casa: Decorso clinico (score) Costi Peggio a casa: Sensazione di benessere Percezione del dolore Interpretazione: 1) Insufficienti misure accessorie (deambulazione forzata, calze elastiche) 2) Ansia per il timore di complicanze

21 TERAPIA DOMICILIARE criteri esclusione Quali pazienti non trattare a domicilio? Monreal M, Thromb Haemost 81:996;1999 -Scarsa compliance o motivi logistici -Comorbidità -TVP estesa a vena iliaca a -Sintomi evocativi e persistenti di EP -Alto rischio emorragico (anziani = 5%/anno, neoplasie)

22 Terapia della trombosi venosa nella fase post-acuta: terapia anticoagulante orale Monitoraggio della terapia Intensità dell anticoagulazione (INR 2-3) Durata ottimale del trattamento

23 Terapia della TVP cose che servono Posizione antideclive degli arti inferiori durante il riposo Calze elastiche (classe 2) Ricerca di eventuali cause (stati trombofilici, neoplasie)

24 Il Tromboembolismo Venoso La Terapia della TVP

25 Terapia di Supporto Cardiaca Mantenere la PVC mmhg Supportare l attività inotropa biventricolare, incrementando le pressioni di perfusione senza aumentare l afterload polmonare e/o peggiorare il mis-match ventilazione /perfusione = - Dobutamina-Noradrenalina o - Levosimendan Mantenere il RS (CVE, amiodarone) Evitare acidosi, ipossia, ipercapnia. Angelo Ghirarduzzi,

26 Terapia di Supporto Respiratoria Ventilazione meccanica con: - Pressioni intrapolmonari < 30 cm/h PEEP ottimale - Bassi volumi 6 ml/kg e frequenze adeguate ( non sovradistensione polmonare). Vieillard-Baron A, Crit care Med 2001 Angelo Ghirarduzzi,

27 Terapia di Supporto Considerare catetere urinario O 2 Terapia = 5l/m = po 2 60 mmhg Morfina 1-4 mg ev in 5 ripetibili ogni 3 ore (?): no in caso di ipotensione Angelo Ghirarduzzi,

28 Current Treatments for Patients with Acute VTE Unfractionated or low-molecular-weight heparin followed by variable periods of oral anticoagulant therapy Thrombolytic treatment and/or thrombo-embolectomy in selected patients with critical pulmonary embolism Intracaval filter in selected patients with contraindications to antithrombotic drugs Angelo Ghirarduzzi,

29 Treatment of VTE Initial treatment 5 to 7 days LMWH or UFH or PTS Long-term therapy > 3 months Vitamin K antagonist (INR )

30 UFH 5000 UI bolo Infusione continua U/h in infusione con pompa con monitoraggio aptt ratio secondo nomogramma durata5-7 giornicirca Angelo Ghirarduzzi,

31 Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials Quinlan DJ, McQuillan A, Eikelboom JW Ann Intern Med 2004; 140:

32 Recurrent VTE in patients with symptomatic PE

33 LMWH e PTS Enoxaparina = 1 mg/kg/bid o 1.5 mg/kg/die Dalteparina = 200 antixa/kg/die Fondaparinux = 5 mg (< 50 kg), 7.5 mg ( Kg), 10 mg (> 100 Kg) Nadroparina = 160 UI/Kg/bid Tinzaparina = 175 UI/Kg/die * Dosaggio anti Xa in pazienti obesi (> 150 Kg), o piccole taglie (< 40 Kg), gravide, IRC. ** Fondaparinux da non usare se clearance creat < 30 ml/min Angelo Ghirarduzzi,

34 TERAPIA CON EPARINA NON FRAZIONATA: QUANDO E ANCORA INDICATA? Pazienti con insufficienza renale (creatininemia > 2 mg/dl) Pazienti obesi (peso > 100 kg) Pazienti ad elevato rischio emorragico (infusione ev): - immediato postoperatorio? - ripresa della terapia anticoagulante postemorragia maggiore Angelo Ghirarduzzi,

35 Treatment of Cancer Patients with Venous Thrombosis

36 CANCER AND VTE 3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni Blood 2002; 100: 3484) LMWH vs. warfarin: LMWH Monotherapy reduces recurrence and bleeding, compared with warfarin Lee AYY. NEJM 2003; 349: 146.

37 LMWH MONOTHERAPY REDUCES RECURRENCE IN PATIENTS WITH VTE AND CANCER (N=676) Probability of Recurrent Venous Thromboembolism (%) No. at Risk Dalteparin Oral anticoagulant Lee AYY. NEJM 2003; 349: 146.

38 Cancer patients: CLOT Study (%) HR=0.48; P= % Dalteparin (N=336) OAT (N=336) % 5.6% 3.6% Recurrent VTE Major bleeding Lee et al, NEJM 2003

39 Practical implications Based on available evidence, cancer patients with venous thrombosis should be treated with full-dose LMWH for one month followed by two/thirds of the initial treatment for as long as cancer is active

40 Thrombolysis vs heparin for PE Pros Early reperfusion Reduced mortality in patients with PE and haemodinamic instability Cons Bleeding complications

41 Thrombolysis vs heparin for PE Author Study design n Treatment Follow-up UPET, 1973 Randomized 82 UK* 78 Heparin 14 days Tibbutt, 1974 Randomized 13 SK i.p.* 17 Heparin i.p. 72 hours Ly, 1978 Randomized 14 SK* 11 Heparin 72 hours Marini, 1988 Randomized 20 UK* 10 Heparin 12 months PAIMS-2, 1992 Randomized 20 rtpa* 16 Heparin 20 days Goldhaber, 1993 Randomized 46 rtpa* 55 Heparin 14 days Jerjes-Sanchez, 1995 Randomized 4 SK* 4 Heparin In-hospital PIOPED, 1990 Randomized, double-blind 9 rtpa* 4 Heparin In-hospital Levine et al, 1990 Randomized 33 rtpa* 10 days double-blind 25 Heparin

42 LYSIS META-ANALYSIS RECURRENT PE/DEATH (Circulation 2004) Study Thrombo bolysis Heparin OR 95% CI UPET, /82 14/ Tibbut, /13 1/ Ly, /14 2/ Dotter, /15 3/ Marini, /20 0/ PIOPED, /9 0/ Levine, /33 0/ Dalla Volta, /20 1/ Goldhaber, /46 4/ Jerjes-Sanchez, /4 4/ Kostantinides, /118 7/ TOTAL 25/374 36/ Favors Thrombolysis Favors Heparin

43 Cumulative Probability of Event-free Survival Probability of event-free survival (%) UFH plus alteplase (n=118) UFH alone (n=137) Event = in-hospital death or clinical deterioration requiring an escalation of treatment Days Konstantidines S et al. N Engl J Med 2002;347:

44 PE Lysis: Major Bleeding at BWH n=104 Major Bleeding (N=20) Fatal bleeding 1 (5%) Transfuse > 3 Units (35%) Hypotension 7 (35%0 Reoperation 1 (5%) Independent predictors of major hemorrhagw: catecholamines (p, 0.001), cancer (p=0.004), diabetes (p=0.010), high INR (p=0.012) (Am J Cardiol 2006; 97: )

45 Thrombolysis versus heparin for PE - II Thrombolysis Heparin OR n/n n/n (95% CI) Rec & death 25/374 36/ (6.7) (9.6) Rec & death Massive PE 12/128 24/ (9.4) (19) Rec & death smassive PE 13/246 12/ (5.3) (4.8) Circulation 2004

46 Thrombolysis in submassive PE remains controversial. A multinational European clinical trial (85 centers/ 12 countries) will enroll about 1,100 submassive PE patients with normal BP, elevated Troponin, and RV enlargement on ECHO.

47 Agenti Trombolitici Streptochinasi Urochinasi Alteplase Reteplase Tenecteplase U in 30 min U/ora per ore o U in 2 ore 4400 U/kg in 10 min U/Kg in ore o U in 2 ore 100 mg in 2 ore 0.6 mg/kg in 15 min 1^ bolo 10 U, 2^ bolo 1) U dopo 30 min Bolo di U in 10 sec (< 60 Kg = 30 U e > 90 Kg = 50 U)

48 Agenti Trombolitici: controindicazioni Controindicazioni Assolute: - pregresso stroke emorragico - stroke ischemico negli ultimi 6 mesi -neoplasiacerebrale - trauma nelle ultime tre settimane - emorragie in atto Controindicazioni Relative: -TIA negliultimi6 mesi -TAO - gravidanza o puerperio - punture in sedi non comprimibili - rianimazione traumatica - ipertensione refrattaria - cirrosi epatica - endocardite infettiva - ulcera peptica con recente sanguinamento

49 ANGIOJET CATHETER FOR RHEOLYTIC THROMBECTOMY

50 EMBOLECTOMIA CHIRURGICA Miglioramento tecniche chirurgiche In PE massive molto compromesse, TROMBOSI ATRIALE DESTRA, Chiusura forame ovale Sopravvivenza a 48 mesi del 76-83% Digonnet A, Throac Surg 2007, Van Putte BP, Interact CardioVasc Thrac Surg 2008, Kadner A, J Thorac Cardiovasc Surg 2008

51 PE RX PLAN RISK STRATIFY Normal BP; Normal RV Low BP, or BP OK + High Troponin + RV Dysfx or Enlarged UFH, LMWH, PTS + 2^ Prevention 1^ Therapy IVC Filter? Anticoagulation Thrombolysis Embolectomy

52 I NUOVI ANTITROMBOTICI NELLA PROFILASSI e TERAPIA DELLA MALATTIA TROMBOEMBOLICA VENOSA Angelo Ghirarduzzi

53 ACCP 2008 Treatment of Venous Thromboembolism UFH (iv, sc, sc fixed doses LMWH Fondaparinux Thrombolysis Initial treatment VKAs INR 2-3 VKAs INR 2-3 or Long-term treatment Extended treatment 5 days At least 3-mo Indefinite With re-assessment of the individual riskbenefit at periodic intervals

54 Current problems in prophylaxis and treatment of venous thromboembolism Need for s.c. injections and overlapping therapy Monitoring and dose adjustment of vitamin K antagonists Efficacy excellent (4-5% recurrences al 3-mo), but safety requires improvement (10% bleeding in 3 months) Optimal duration is unknown Need for regimens utilizing one drug for initial treatment and secondary prophylaxis

55 Warfarin 1940s: Warfarin synthesized Warfarin at least 5 times more potent than dicoumarol More predictable 1948: Rodenticide 1953: First clinical studies of warfarin

56 VKAs Drawbacks that limit their effectiveness and safety. Anticoagulant effects by reducing the functional levels of Factors II, VII, IX, X. Difficulty in predicting the anticoagulant effect.

57 Warfarin: inter-individual variability Prothrombin ratio µg/ml Total plasma warfarin

58 Warfarin: Narrow therapeutic window Antithrombotic Effect and Bleeding in a Rat Model Thrombus Size (AU) Effect Bleeding Warfarin Total Bleeding Time (min) Dose (µmol/kg/day) Elg et al. Thromb Res. 1999;94:

59 Limitations of VKAs Delayed onset of action Monitoring assays difficult to standardize Food and drug interactions A high adverse event profile Overlap with parenteral anticoagulant INR monitoring and complex organization of management needed for optimal outcomes Frequent monitoring when introducing new drugs

60 Targets for Anticoagulant Drugs Intrinsic pathway (surface contact) Extrinsic pathway (tissue damage) XII XIIa Tissue factor XI XIa IX IXa VIIa VII VIII VIIIa Heparins and LMWH Vitamin K antagonists Direct thrombin inhibitors: Dabigatran Factor Xa inhibitors Direct: Rivaroxaban & Apixaban Indirect: Fundaparinux, Idraparinux X V II Va Fibrinogen Xa IIa (Thrombin) Fibrin

61 Phase 2-3 oral anticoagulants ORAL PARENTERAL TTP889 INITIATION FX FV/VIIa FIX TFPI (tifacogin) NAPc2 Rivaroxaban Apixaban YM150 DU-176b Betrixaban PROPAGATION FVIII FIXa FV TAPC (drotecogin alfa) stm (ART-123) Hirudin, Argatroban Dabigatran AZD0837 THROMBIN ACTIVITY FXa IIa AT Fondaparinux Idraparinux DX-9065a

62 The antithrombotic pipeline is heavy of novel agents Anticoagulants Thrombollytics Antiplatelets Phase I Phase II Phase III

63 Target profile of an ideal antithrombotic Oral and subcutaneous administration Low PK and PD variability Low potential for food or drug interactions Once daily administration Wide therapeutic window (effect vs. bleeding) No coagulation monitoring

64 Classical Pathway of the Evaluation of New Antithrombotics FIRST = SECOND = THIRD = treatment of established venous thrombosis treatment of established venous thrombosis atrial fibrillation and acute coronary syndromes

65 Factor Xa or Thrombin: which is the better target? VKAs have drawbacks that limit their effectiveness and safety. VKAs exert their anticoagulant effects by reducing the functional levels of Factors II, VII, IX, X. These fact may contribute to the difficulty in predicting the anticoagulant effect.

66 Factor Xa or Thrombin: which is the better target? New oral anticoagulants in development have targeted action against individual coagulation factors: specifically direct factor Xa and IIa inhibitors.

67 Why target FXa? FX occupies a critical juncture in the coagulation cascade and controls thrombin generation Activation of one molecule of FX results in the generation of 1000 molecules of FIIa (concept of amplification). FXa is more thrombogenic than thrombin (inhibition earlier in the sequence of coagulation factor interactions). Response curve of Xa suggests a wider therapeutic window with Anti-Xa inhibitors

68 FX functions Principal mediator of thrombin generation from prothrombin via the prothrombinase complex. Limited other functions - Weak proinflammatory and proliferative activities -Nodirect effect on platelet activation

69 LMWHs varies in anti-xa/anti-iia activity Clinical studies suggest that LMWH with the highest anti-fxa/iia activity are more effective and safer. Fondaparinux indirect but specific Fxa inhibitor has provided strong clinical proof supporting that specific Xa inhibition provides more effective and safer (?) therapy (Turpie AGG, Arch Int Med 2002, OASIS- 5 Trial Group, NEJM 2006).

70 Why target FII? Thrombin is the final effector of blood coagulation Activates FXIII making fibrin resistant to fibrinolysis Thrombin amplifies its own generation by activating FV e FVIII key factors for intrinsic tenase and prothrombinase (feed back activation).

71 FII functions Procoagulant - Fibrin formation - Platelet activation - Feedback activation - TAFI activation Anticoagulant - Protein C activation - Prostacyclin formation Inflammation - P-selectin expression -Celladhesion -Chemotaxis Cellular Proliferation - Tissue repair -Growfactor secretion - Angiogenesis

72 Thrombin as principal activator of platelets Interaction withprotease activated receptors PAR1 e PAR4 Recruits platelets to the site of vascular injury Platelets provide an anionic surface onto which coagulaton complexes assemble

73 Why don t target FII? Low doses of a direct thrombin inhibitor allowed increased thrombin generation Potential rebound hypercoagulability Low levels of thrombin are sufficient, when thrombin is generated via the intrinsic FXI-mediated pathway and plus thrombomodulin, to stimulate activation of TAFI about 1250-fold. Response curve for thrombin is narrow suggesting a less wide therapeutic window with thrombin inhibitors

74 Factor Xa Inhibitors Non selective and Indirect UFH LMWHs Selective Indirect Fondaparinux Idraparinux Direct TAP Antistasin Rivaroxaban Apixaban YM 456 LY

75 Pentacaccharide Sanorg = Fundaparinux inhibitor of factor Xa.

76 Pentasaccharide Sanorg A targeted mechanism of action Intrinsic pathway Extrinsic pathway ATIII ATIII ATIII X a X a Pentasaccharide II IIa Fibrinogen Fibrin clot Il Fundaparinux si lega selettivamente alla molecola di AT in cui induce una modificazione che aumenta la sua attività inibitrice di 300 volte

77 Fundaparinux Studio Rembrandt = Studio Fase II in TVP prox Studio Matisse DVT = Studio Fase III in TVP prox Studio Matisse PE = Studio Fase III in PE

78 THE REMBRANDT INVESTIGATORS Treatment of proximal deep vein thrombosis with a novel synthetic compound A phase II evaluation Circulation 2000

79 THE REMBRANDT INVESTIGATORS Efficacia paragonabile a quella di Dalteparina per dosi di 5-10 mg die od Circulation 2000

80 The Matisse Studies

81 PS IN THE INITIAL TREATMENT OF VTE = Phase III studies MATISSE DVT MATISSE PE Ann Intern Med 2004; 140: NEJM 2003, 349: PS VS ENOXAPARIN PS VS UFH

82 A T I S S..... E. M. Matisse Study Designs 5 days IV UFH (aptt ) + OAC (INR 2-3) patients with PE + DVT R Open-Label 5 days 7.5 mg fondaparinux * sc + OAC (INR 2-3) patients with DVT R Double-blind blind * 5 mg if body-weight < 50 kg 10 mg if body-weight > 100 kg 5 days SC enoxaparin (1 mg/kg, bid) + OAC (INR 2-3) 2 90 ± 7 Days Primary Efficacy Outcome (3 months) Fatal PE / unexplained death Recurrent symptomatic non-fatal PE or DVT Principal Safety Outcome (initial treatment) Major bleed Clinically relevant non-major bleed

83 A T I S S..... E M.. Primary efficacy outcome 3 months - Matisse PE Fondaparinux (N=1103) UFH (N=1110) Fatal PE 16 (1.5 %) 15 (1.4 %) Non-fatal PE or DVT 26 (2.4 %) 41 (3.6 %) Total symptomatic recurrent VTE 42 (3.8 %) 56 (5.0 %) -3.0% Matisse DVT -1.2% 0 0.5% Fondaparinux - UFH (95 % CI ) Fondaparinux (N=1098) = 3.5% LMWH (N=1107) Fatal PE 5 (0.5 %) 5 (0.5 %) Non-fatal PE or DVT 38 (3.5 %) 40 (3.6 %) Total symptomatic recurrent VTE 43 (3.9 %) 45 (4.1 %) -1.8% 0 1.5% % Fondaparinux - LMWH (95 % CI ) = 3.5%

84 A T I S S..... E M.. Principal Safety Outcome - initial treatment - Matisse PE Fondaparinux 1.3% 3.2% 4.5 % UFH 1.1% 5.2% 6.3 % 0% 2% 4% 6% 8% Major bleed Clinically relevant non-major bleed Matisse DVT Fondaparinux 1.1% 2.6% 3.7 % LMWH 1.2% 3.0% 4.2 % 0% 2% 4% 6% 8% Major Bleeding Non-major Bleeding

85 A T I S S..... E M.. Mortality -3 months - Matisse PE Fondaparinux 2.6% 1.6% 1.1% 5.2 % UFH 2.0% 1.5% 0.9% 4.4 % 0% 2% 4% 6% Cancer VTE/bleeding Other Matisse DVT Fondaparinux 2.2% 0.9% 0.6% 3.8 % LMWH 1.7% 0.5% 0.8% 3.0 % 0% 2% 4% 6%

86 Idraparinux Studio Persist = Studio Fase II in TVP prox Studio Van Gogh DVT = Studio Fase III in TVP prox Studio Van Gogh PE = Studio Fase III in PE Studio Van Gogh Extension = Studio Fase III su durata ottimale terapia

87 The PERSIST Study on the dose-effect relationship of once weekly idraparinux versus o/d warfarin in the treatment and secondary prophylaxis of venous thromboembolism J Thromb Haemost 2004

88 Study Design enoxaparin days screen Acute treatment Randomization Open label warfarin INR INR enoxaparin mg mgidraparinux o.w. o.w. 5 mg mgidraparinux o.w. o.w mg mgidraparinux o.w. o.w mg mgidraparinux o.w. o.w. 12 weeks Committees: Steering Committee Central Adjudication Committee Data and Safety Monitoring Committee

89 Persist: Thrombotic burden: deterioration (ITT) = A-symptomatic + Symptomatic VTE + unexplained death 15 Overall dose trend p= Incidence (%) / / / mg 5 mg 7.5 mg 10 mg warfarin idraparinux OK

90 Bleeding Events Major Any bleeding mg 5mg 7.5mg 10mg warfarin 2.5mg 5mg 7.5mg 10mg warfarin idraparinux idraparinux OK Incidence (%)

91 IDRAPARINUX IN THE TREATMENT OF VTE Phase III studies VAN GOGH DVT VAN GOGH PE IDR VS ENOXAPARIN IDR VS UFH

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97 Biotinylated idraparinux Biotinylated idraparinux SSR E Idraparinux active moiety responsible for pharmacological activity for both molecules Biotinylated part allows neutralization by avidin (extracted from white part of the eggs) Bioequipotency of 3 mg biotinylated idraparinux with 2.5 mg idraparinux after a single injection

98 Biotinylated Idraparinux ongoing Prevention VTE No studies Treatment of VTE - Equinox (DVT) - Cassiopea (PE) Atrial fibrillation - Borealis Bioequipotency Phase III Phase III

99 Equinox Study design 700 patients with DVT Objectives: bioequipotency, efficacy-safety, neutralization M6 M9 M12 D1 D183/D185/D188 D274 Biotinylated idraparinux 3.0 mg s.c. Once a week n = 350 Bioequipotency N = 220 Randomization Confirmed acute symptomatic DVT n = 350 Idraparinux 2.5 mg s.c. once a week Avidin/placebo iv N = 70 Enrollment completed in April 2007 (757 patients)

100 CASSIOPEA study design 3,200 patients with PE 6 m 3-6 m Symptomatic PE, with or without symptomatic DVT Enoxa > 5 d Enoxa > 5 d Placebo warfarin Biotinylated Idraparinux Placebo warfarin Biotinylated Idraparinux Obs Obs 3-mo 6-mo R 3 m 3-6 m 6 m 3-6 m Enoxa > 5 d Placebo Biotinylated Idraparinux Placebo warfarin Obs 6-mo Enoxa > 5 d Placebo Biotinylated Idraparinux Obs 3-mo Placebo warfarin Enoxaparin 1 mg/kg bid 3 m 3-6 m

101 Xabani

102 Rivaroxaban Odixa DVT = fase II in TVP prossimale Einstein Study II = fase II in TVP prossimale Einstein III DVT = fase III in TVP prossimale Einstein III PE = fase III in PE Einstein Extension

103 Rivaroxaban Xarelto Oxazolidone derivative with more than 80% bioavailability after oral administration. It is cleared mainly via the liver (66% renal elimination)

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105 Rivaroxaban Xarelto INHIBITS FIBRIN-BOUND FACTOR Xa Does not require a cofactor No direct effect on thrombin No direct effect on agonist-induced platelet aggregation

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107 Rivaroxaban Xarelto : Clinical program overview: : 50,000 patients to be enrolled VTE prevention VTE prevention in hospitalized medically ill patients VTE treatment Stroke prevention in atrial fibrillation Secondary prevention of acute coronary syndrome Phase II ODIXa-HIP1 ODIXa-HIP2 ODIXa-KNEE ODIXa-OD-HIP ODIXa-DVT EINSTEIN-DVT ATLAS Phase III RECORD RECORD1 RECORD2 RECORD3 RECORD4 MAGELLAN EINSTEIN-DVT EINSTEIN-PE EINSTEIN-EXT ROCKET AF Japanese Phase III Study

108 Rivaroxaban Odixa DVT = fase II in TVP prossimale Einstein Study II = fase II in TVP prossimale Einstein III DVT = fase III in TVP prossimale Einstein III PE = fase III in PE Einstein Extension

109 Rivaroxaban Xarelto Thromboprophylaxis in major orthopaedic surgery. Evaluated in four phase III large-scale studies for thromboprophylaxis following major orthopaedic surgery Dose of 10 mg o.d. starting 6 hours postoperatively.

110 RECORD:efficacy endpoints RECORD3 (TKR) RECORD1 (THR) RECORD2 (THR) % n Enoxaparin 40 mg od days Rivaroxaban 10 mg od prphylaxis Enoxaparin 40 mg od 5 weeks Rivaroxaban 10 mg od prophylaxis Enoxaparin 40 mg od days Rivaroxaban 10 mg od 5 weeks Total VTE 18.9% 166/ % 79/824 RRR 49% P< % 59/ % 18/1595 RRR 70% P< % % 17/864 RRR 79% P<0.001 Major VTE 2.6% 24/ % 9/908 RRR 62% P< % 33/ % 4/1686 RRR 88% P< % 49/ % 6/961 RRR 88% P<0.001 Sympt. VTE 2.0% 24/ % 8/`1201 RRR 66% P< % 11/ % 6/2193 RRR 45% P= % 15/ % 3/1212 RRR 80% P=0.004 Eiksson Blood 2007, Kakkar Blood 2007, Lassen Blood 2007

111 RECORD: safety endpoints RECORD3 (TKR) RECORD1 (THR) RECORD2 (THR) % n Enoxaparin 40 mg od days Rivaroxaban 10 mg od prphylaxis Enoxaparin 40 mg od 5 weeks Rivaroxaban 10 mg od prophylaxis Enoxaparin 40 mg od days Rivaroxaban 10 mg od 5 weeks Major bleeding 0.5% 6 0.6% 7 0.1% 2 0.3% 6 < 0.1% 1 < 0.1% 1 Nonmajor bleeding 4.4% % % % % % 80 Eiksson Blood 2007, Kakkar Blood 2007, Lassen Blood 2007

112 RECORD3 TKR: summary Total VTE RRR 49% Majior VTE RRR 62% RRR 66% Symptomatic VTE Major bleeding Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily Lassen Blood 2007

113 RECORD4 TKR: summary RRR 31% Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily 0 Total VTE Majior VTE Symptomatic VTE Major bleeding

114

115

116

117

118

119 Apixaban (BMS ) Direct inhibitor of Factor Xa: does not require AT Potent and selective: FXa Ki = 0.08 nm Produces concentrationdependent prolongation of prothrombin time and APTT higher concentration Effective in preclinical models of venous and arterial thrombosis in rabbits, rats, and dogs Preclinical pharmacokinetic profile characterized by very low clearance, low volume of distribution, and multiple elimination patways.

120 Apixaban Other phase III studies DVT Treatment Botticelli Study = Studio Fase II in TVP prossimale e Amplify Study = studio fase III in TVP prossimale ed PE (4800 pts) Atrial Fibrillation = ARISTOTLE STUDY ( pts) Post ACS 2^ Prevention CV (1800 pts)

121 Study Apixaban Phase 3 DVT Prevention Program Advance I -034 Advance III -047 Advance II -035 ADOPT -036 Study drug dose and duration 2.5 mg BID 12 days Init: h 2.5 mg BID 12 days Init: h 2.5 mg BID 35 days Init: h 2.5 mg BID 30 days Init: < 48h Comparator dose and duration Enox 30 BID days Init: h Enox 40 OD 5 weeks Init: 12 ± 3h before surgery Enox 40 OD days Init: 12 ± 3h before surgery Enox 40 OD While hospitalized (> 6 days) then Pbo Knee knee HIP MEDICAL Binding Double-blind Double-dummy Primary endpoint VTE-death Venogram VTE-death Venogram VTE-death Venogram VTE-death CUS Sample size Statistical design Superiority Superiority NI; then Superiority Superiority

122 Apixaban Dose Finding in treatment for VTE Botticelli Study JT&H 2008 Bleeding Events Major or clinically relevant nonmajor bleeding Event rate (%) 95% CI Major bleeding Event rate (%) 95% CI Apixaban 5 mg bid (n=128) , , 4.3 Apixaban 10 mg bid (n=133) , , 2.7 Apixaban 20 mg od (n=124) , , 4.4 LMWH = VKA (n=126) , 2.9

123 Thrombin Inhibitors Non selective and Indirect UFH LMWHs Danaparoid Selective Indirect Dermatan Sulfate Direct Hirudin, Hirulog Argatroban\ Ximelagatran Dabigatran Napsagatran Inogatran Efegatran

124 Ximelagatran Used in higher dose for primary and secondary treatment of VTE and for stroke prevention in patients with AF. Vs Warfarin In VTE similar efficacy (recurrent VTE in 2%) with less major bleeding (1.3% vs 2.2%) In AF similar efficacy (primary event rate 1.6%) with combined rate of major+minor bleeding lower (32% vs 39%)

125 Dabigatran Etexilate Dabigatran etexilate is an oral direct thrombin inhibitor exhibiting: Predictable anticoagulant effect Fixed dose Acts on clot blound and free thrombin Fast onset and offset Pro-drug

126 Dabigatran Etexilate: : the capsule

127 Dabigatran Etexilate: pharmacodynamic profile Close correlation between dabigatran plasma conc and effects on blood coagulation parameters: aptt, INR, ECT and TT Dose response relationship with activated partial thromboplastin time (aptt) Low inter-individual variability of ECT and TT: aptt prolongation and INR display higher variability Stanger J Clin Pharmacol 2005

128 Dabigatran Etexilate: : PK in humans Dabigatran etexilate plasma concentration time profiles after single 150 mg dose (t 3 hours post surgery for orthopedic surgery patients) Cmax - in healthy volunteers = 2.0 h - after orthopaedic surgery - 6 h initial dose - 2 h steady state Stanger J Clin Pharmacol 2005 T 1/2 - in healthy volunteers = h - after orthopaedic surgery steady state

129 Dabigatran Etexilate Type Company Half-life Bioavailability Elimination DTI Boehringer- Ingelheim % renal 20% biliary Dosage Od (in 2 tablets)

130 Active Site-Directed DTIs Dabigatran Exosite 1 Fibrinogen Recognition Site Exosite 1 Active (catalytic) Site Thrombin Exosite 2 Heparin Binding Site

131 Ximelagatran and Dabigatran Hirudin Hirulog Exosite 1 Exosite 1 Exosite 1 Dabigatran Thrombin (with indirect blocked active site) Thrombin (with binding to active site) Thrombin (with binding to active site)

132 Free thrombin Dabigatran IIa Clot-bound thrombin Dabigatran IIa

133 Dabigatran etexilate ongoing Prevention VTE in elective hip/knee (Renovate I e II; Remodel, Remobilize) Treatment of VTE (Recover I e II; Remedy, Resonate) Phase III Phase III ACS (Redeem) Atrial fibrillation (Rely) Phase III

134 RE-VOLUTION TRIAL PROGRAM OVERVIEW = more than patients involved

135 Enoxa BISTRO II Efficacy and Major bleeding P=0.06 P=0.02 P= Total VTE % Major Bleeding mg bid 150 mg bid 300 mg qd 225 mg bid Enoxa mg bid 150 mg bid 300 mg qd 225 mg bid

136 RENOVATE STUDY DESIGN: Non-inferiority PATIENTS UNDERGOING THR Start 12 hours pre-op Enoxaparin 40 mg qd R Start 1-4 hours post-op Dabigatran Etexilate 75 / 150 mg qd 110 / 220 mg qd Venography Day F-UP weeks 3330 Randomized Total Hip Replacement Patients; 1110 per group

137 RENOVATE: Primary Efficacy Outcome Endpoint Total VTE and all cause mortality % Absolute Difference vs Enoxaparin % (95% CI) P-value for non - inferiority Dabigatran 220mg 150 mg N=880 N= (-2.9, 1.6) (-0.6, 4.4) <0.05 <0.05 Enoxaparin N=

138 RENOVATE: Bleeding Outcomes Endpoint Major Bleeding (%) Major Bleeding Plus Clinically Relevant Bleeding (%) Dabigatran 220mg 150 mg N=880 N= Enoxaparin N= Any Bleeding (%)

139 RENOVATE: Bleeding Outcomes Endpoint Major Bleeding (%) Major Bleeding Plus Clinically Relevant Bleeding (%) Dabigatran 220mg 150 mg N=880 N= Enoxaparin N= Any Bleeding (%)

140 RENOVATE: Primary Outcome Eriksson Lancet 2007 Dabigatran better Enoxaparin better -7.7% -0.7% 220 mg + 0.7% 150 mg + 1.9% Equivalence -0.8% % Difference in Absolute Event Rates (Dagigatran enoxaparin 95% CI)

141 REMODEL STUDY DESIGN: Non-inferiority PATIENTS UNDERGOING TKR Start 12 hours pre-op Enoxaparin 40 mg qd R Start 1-4 hours post-op Dabigatran Etexilate 75 / 150 mg qd 110 / 220 mg qd Venography Day F-UP 2-14 weeks CAC for all efficacy and safety outcomes

142 REMODEL: Primary Efficacy Outcome Eriksson J Thromb Haemost 2007 Endpoint Total VTE and all cause mortality % Absolute Difference vs Enoxaparin % (95% CI) P-value for non - inferiority Dabigatran 220mg 150 mg N=503 N= (-7.3, 4.6) (-3.1, 8.7) <0.05 <0.05 Enoxaparin N=

143 Study Design: Non inferiority Patients undergoing TKR Dabigatran better Enoxaparin better -9.2% -1.3% 220 mg + 9.2% + 2.8% 150 mg Equivalence -10% % Difference in Absolute Event Rates (Dagigatran enoxaparin 95%CI)

144 Conclusions Results of RE-NOVATE and RE-MODEL Both doses of dabigatran proved efficacious and comparable to enoxaparin for the prevention of major VTE in orthopedic surgery Showed a low rate of bleeding, comparable with enoxaparin Showed no difference in ACS events or liver enzyme changes in either of the dabigatran etexilate doses compared to enoxaparin Offered fixed oral dosing without coagulation monitoring

145 REMOBILIZE STUDY DESIGN: 2510 Randomized patients: : 670 / group Start hours post-op Enoxaparin 30 mg bid R Start 6-12 hours post-op Dabigatran Etexilate 75 / 150 mg qd 110 / 220 mg qd Venography Day F-UP 2-14 weeks CAC for all efficacy and safety outcomes

146 REMOBILIZE: Primary Efficacy Outcome Endpoint Total VTE and all cause mortality % Absolute Difference vs Enoxaparin % (95% CI) P-value for non - inferiority Dabigatran 220mg 150 mg N=604 N= (-0.8, 10.8) (-3.4, 13.3) Enoxapari n N=

147 Study Design: Non inferiority Patients undergoing TKR Dabigatran better Enoxaparin better -9.2% + 5.8% 220 mg + 9.2% + 8.4% 150 mg Equivalence -15% 0 +15% Difference in Absolute Event Rates (Dagigatran enoxaparin 95%CI)

148 Conclusions Dabigatran etexilate versus enoxaparin 60 mg/day in prevention of venous thromboembolism following Total Knee Arthroplasty Dabigatran etexilate was not as effective as enoxaparin for preventing venous thromboembolism and all-cause mortality - Possible reasons: -Highercomparatordose - Later start with the first dabigatran dose Showed a low rate of bleeding, comparable with enoxaparin Showedelevatedliverenzymecomparablewith enoxaparin Offered fixed oral dosing without coagulation monitoring

149 Dabigatran etexilate: Recover I Objectives Study Design Patient Population Treatment Endpoints Treatment Groups EndpointsNumber of Subjects (Total) Efficacy and safety od Dabigatran Etexilate 150 mg bid vs warfarin for 6 month treatment of acute symptomatic VTE Randomized, double-blind, parallel, active,controlled trial Male and female patients with confirmed symptomatic DVT or PE 6 months Primary: recurrent symptomatic VTE and deaths related to VTE. Secondary: DVT, PE, all deaths 18 months Safety: Bleedings events, ACS, Discontinuations Dabigatran Etexilate 150 mg bid vs Warfarin INR 2-3 Target enrolment of 1275 patients per treatment group

150 Phase II dose rangin studies of direct oral factor Xa and factor IIa inhibitors with LMWH as comparator Total VTE Major VTE Major Bleeding Rivaroxaban mg/die 15.9% 2.2% 1.8% Rivaroxaban mg/die 12.3% 2.0% 4.2% Apixaban 5-10 mg/die 9.3% 1.4% 1.4% Apixaban 20 mg/die 6.8% 2.2% 3.9% Dabigatran mg/die 22.7% 4.0% 2.3% Dabigatran 450 mg/die 13.1% 1.7% 3.8% Enoxaparin 40 mg /die 22.3% 4.4% 1.1%

151 Potential VTE Management Landscape Agent Half life (hrs) Bioavailability Elimination Dosing/Class APIXABAN % 25% renal 70% hepatic Bid oral direct axa RIVAROXABAN 5-13 > 80% 30% renal qd oral 70% hepatic direct axa IDRAPARINUX % renal Once weekly sc indirect axa DABIGATRAN % 80% renal Qd oral DTI

152 THRIVE Treatment Incidence of ALAT elevations >3 x ULN 4 enoxaparin/warfarin ximelagatran Incidence (%) Week Francis CW et al, Blood 2003; 102: Abstract #7

153 Il Tromboembolismo Venoso La durata ottimale della Terapia

154 Time Course of VTE Recurrence % VTE recurrence Recurrences related to the index VTE (90% ipsilateral DVT) Dependent by acute episode treatment Recurrences not related to the index VTE (50% controlateral DVT) Dependent by the patient s intrinsic risk Index event Time

155 LA RECIDIVA DI TVP/EP A 5 anni = 15-30% dei pts con VTE non provocato o con fattori di rischio permanenti ha una recidiva dopo aver completato la terapia antitrombotica. La frequenza non cambia in base al tipo di durata intermedia della terapia anticogulante (3-24 mesi) A 5 anni = 5-10% nei pts con fattori di rischio temporanei (Prandoni, Ann Intern Med 1996; Zurich Study, Circulation 1996; Hansson P-O, Arch Int Med 2000; Heit, Arch Int Med 2000).

156

157 LA RECIDIVA DI TVP/EP Il rischio di decesso per EP fatale = / 100 person / years Il case-fatality rate della recidiva di PE = 3.8-9% - DVT = % - PE = % - PE+DVT = % 1^ anno = incidenza % anni successivi = / 100 persone / anno età (HR 2.12 CI, ); TEV non provocata (HR 2.42 CI, ); PE vs TVP n.s.

158 Duration of Long-Term Treatment of VTE: until its benefit (reduction of VTE) outweight its risk (Bleeding) VTE Risk Bleeding Risk

159 Cover.gif

160 LINEE GUIDA VIII ACCP Evidenced-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy Chest, 2008

161 Treatment of VTE Initial treatment 5 to 7 days LMWH or UFH Long-term therapy (early phase) > 3 months Vitamin K antagonist (INR )

162 Long-Term Treatment of VTE Treatments continued after initial therapy (heparin or thrombolytic agents) has been completeted) Two goals: Early phase (first three months): to complete treatment of the acute episode Late phase (after the first three months): to prevent new episodes of VTE not directly related to the acute event

163 Options after the initial VKA treatment Withdraw Rx with low risk of recurrence = select patients with acceptable recurrence rate Extend VKA in moderate-high risk of recurrence Indefinite Duration of Anticoagulant Treatment Withdraw Rx with High clinical burden (bleeding) = select patients with not acceptable management burden (bleeding) = intermediate duration of treatment or low-intensity of anticoagulant effect

164 ? BASSO RISCHIO TEV

165 Temporary vs No Temporary Risk Factor Op dur RCTs California Epidem Minnesota Epidem Prandoni cohort Hansson (2000) Baglin (2003) Palareti (2003) Christiansen (2005) My overall estimate 0.5 Reduced Increased

166 Reversible provoking factors Major Factors - Surgery - Hospitalization - Plaster cast immobilization Minor Factors - estrogen therapy - pregnancy - prolonged travel (> 8 h) - Major factor occurred 1-3 months before VTE diagnosis Within 1 month The greater strengh of risk factor, the lower expected risk of recurrence after stopping VKA therapy (Baglin T Lancet 2003)

167 Distale (sintomatica)/prossimale Si estende al circolo prossimale nel % dei casi Kakkar, Lancet 1969 Lohr, Br J Surg, 1995 Se non trattata può provocare EP (4% sintomatica e 30% asintomatica) Clarke-Pearson, Am J Obstet Gynecol, 1984 Doyle, Annals Int Med, 1987 Le recidive a distanza di tempo sono meno frequenti che nelle TVP prossimali. (1) Schulman, NEJM, 1995 (2) Hansson, Arch Intern Med, 2000 (3) Pinede, (DOTAVK), Circulation, 2001

168 DURAC 1 Analisi sottogruppo: i pazienti con TVP distale possono essere trattati con sicurezza per sole 6 settimane di terapia

169 Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proxymal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf-vein thrombosis (DOTAVK) 736 pazienti, 34% distali, 30% con EP, 44% idiopatici. (no cancro) Follow up 72 settimane Pinede L, Circulation, 2001

170 ? MODERATO-ALTO RISCHIO TEV

171 Trials and different duration of VKA therapy of VTE Most of these studies excluded patients with active cancer because they were judge to require long-term VKA (high risk of recurrence) Earlier Trials (Levine MN Thromb Haemost 1995, Schulman S NEJM 1995, Prandoni P Ann Intern Med 1996, ) identified that the risk od recurrent VTE was much lower in provoked-vte Three major categories of patients with VTE Provoked by reversible risk factor Unprovoked Active Cancer

172 TVP/EP... Dopo una EP le recidive sono EP nel 60% dei casi e la probabilità di morte da EP fatale è circa 3-4 volte rispetto all esordio come TVP, sia dopo 3 mesi sia dopo 1 anno. Douketis JD, Risk of Fatal Pulmonary Embolism in Patients with Treated VTE. JAMA, Murin, Comparison of outcomes after Hospitalization for DVT or PE. Thromb Haemost, White, The Epidemiology of VTE, Circulation Suppl June Dopo una TVP le recidive sono TVP nell 80% dei casi, nei primi 6 mesi prevalentemente nello stesso arto, poi ugualmente ripartite in entrambi. Schulman, Comparison of 6 w with 6 m od OAT after first episdode of VTE. NEJM, Prandoni P, The Long Term Clinical Course of Acute Deep Venous Thrombosis. Ann Inter Med, Lindmarker, The risk of ipsilateral vs contralateral recurrent DVT in the leg. J Internal Med, Kearon, Natural Hystory of VTE, Circulation Suppl July 2003.

173 Recidive di MTV con 1^ evento TVP prossimale (n 562 paz.) o con 1^ evento EP (n 354 paz.) 6% 1% 11% 28% 4% 7% 47% 25% TVP omo TVP control TVP omo + EP TVP cont + EP EP isolata TVSI 71% TVP EP TVSI

174 VTE Recurrence First Episode Annual Rate of recurrence Recommended OAC duration Idiopathic (Unprovoked) ~5% > 3 months* Associated with reversible risk factors cancer Recurrent episode 2-3% 10% 10% 3 months** Indefinite Indefinite Ridker PM, NEJM 2003 Schulman S, NEJM 2003

175 Long-Term Treatment of VTE Optimal Duration of treatment (VKA) Definite Scheduled Stop Date Indefinite No scheduled Stop Date (treatment may be stopped because of a subsequent increase in the risk of bleeding)

176 Short (4-6 weeks) vs Intermediate (3-6 months) duration of Therapy Five trials First VTE episode

177 STUDIO DURAC 1 18% 9% RR 0.5% CI, ) 443/454 Unselected patients with proximal DVT / PE Schulman, NEJM 1995

178 Different Intermediate (3 months vs 6-12 months) Durations of Therapy Two studies 3 vs 6 months (DOTAVK, Campbell) Two studies 3 vs 12 months (WODIT- DVT, WODIT-PE) First VTE episode

179 STUDIO WODIT-DVT DVT 8.3% 3% At the end of the first year, recurrent VTE was less frequent in group on anticoagulant treatment, but at the end of extended follow up a similar risk of recurrence is expected Agnelli, NEJM 2001

180 WODIT Durante la TAO i pazienti sono protetti dalle recidive Indipendentemente dalla durata del trattamento, circa il 15% dei pazienti con primo episodio di TVP idiopatica presentano una recidiva alla sospensione del trattamento (RR 0.95; 95% CI, ).

181 Indefinite vs Intermediate Durations of Therapy Four Trials - Schulman S, NEJM 1997 (2 nd episode) - Kearon C, NEJM 1999 (unprovoked) - Ridker PM, NEJM 2003 (unprovoked) - Palareti G, NEJM 2006 (unprovoked + DD pos.)

182 STUDIO DURAC II P<0,001 RRR 87% 111/116 pts 25% 3% Randomization to indefinite treatment with VKA (target INR 2.5) reduces recurrent VTE by 90% --- Incidence of major bleeding = 3%/yr --- VTE + MB = 28% vs 12% Schulman, NEJM 2003

183 STUDIO LAFIT Kearon, NEJM 1999

184 STUDIO PROLONG

185 STUDIO PROLONG Risk of Major Bleeding = 1% per patient/year

186 Rate of Major Bleeding during the extended phase of anticoagulation for VTE Ost D, JAMA 2005 metaanalysis on 1571 pts 1.1% per patient-years vs 0.6% per patients/years without anticoagulation RR, % CI,

187 Bleeding in patients receiving VKA for VTE A meta-analysis of randomized, controlled trials Entire period of anticoagulation Initial 3 months of therapy After initial 3 months Case-fatality rate of major bleeding 9.4 ( ) 9.3 ( ) 9.1 ( ) Rate of intracranial bleeding 1.15% pts-y ( ) 1.48% pts-y ( %) 0.65% pts-y ( )

188 Cumulative Incidence of Recurrent VTE 20 VTE Bleeding Cumulative incidence Of events (%) Cancer No cancer Time (months) Prandoni P et al. Blood 2002;100:3484 8

189 New Strategies Modulate intensity of Anticoagulant effect LMWH New antithrombotics

190 ELATE Results: : low-intensity VKA treatment did not provide advantages 1.9% Target INR HR 3.3; 95%, CI, % Target INR 2.5 MB 0.96% vs 0.93% MB+mb 4.9% vs 3.9% Kearon C et al, NEJM 2003;349:631-9

191 PREVENT Results Recurrent VTE Composite endpoint Cumulative rate of events (%) P< % Pts / yr Placebo HR 0.36; 95%, CI, Low-intensity warfarin 2.6% Pts / yr Cumulative rate of events (%) P=0.01 Placebo Low-intensity warfarin Years of follow-up Years of follow-up Ridker PM et al. N Engl J Med 2003;348:

192 Elate & Prevent Low-intensity warfarin is much more effective than placebo but it is less effective than conventional-intensity treatment It does not reduce the incidence of bleeding The monitoring can be semplified (less frequent INR monitoring)

193 ACCP recommendations For patients with DVT secondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A)

194 ACCP recommendations For patients with unprovoked DVT, we recommend treatment with a VKA for at least 3 months (Grade 1A). We recommend that after 3 months of anticoagulant therapy, all patients with unprovoked DVT should be evaluated for the risk-to-benefit ratio for long-term therapy (Grade 1C) For patients with a first unprovoked VTE that is proximal, and in whom risk factors for bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment (Grade 1A). For patients with a second episode of unprovoked (.and provoked?) VTE (proximal? distal?), we recommend long-term treatment (Grade 1A) For patients with a first isolated distal DVT that is unprovoked (.and provoked?), we suggest that 3 months of anticoagulant therapy is sufficient rather than indefinite therapy (Grade 2B)

195 ACCP recommendations For patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant treatment (Grade 1A). For these patients, we recommend subsequent anticoagulant therapy with VKA or LMWH indefinitely or until cancer is resolved (Grade 1C)

196 ACCP recommendations For patients who received long-term anticoagulant treatment, the risk-benefit ratio of continuing such treatment should be reassessed in individual patient at periodic intervals (Grade 1C)

197 DURATA DELLA TERAPIA ANTICOAGULANTE ORALE PER TVP (ACCP, CHEST 2008) TVP distale secondaria a FR reversibile e/o temporaneo????? TVP (1 episodio) secondaria a FR reversibile e/o temporaneo (Grado 1A) TVP distale non provocata (Grado 1C) TVP non provocata (1 episodio) con alto rapporto rischio emorragico/rischio di recidiva di TEV TVP non provocata (1 episodio) con basso rapporto rischio emorragico/rischio di recidiva di TEV EP non provocata? TVP e/o EP secondo episodiotvp Neoplasia? < 3 mesi? 3 mesi 3-24 mesi Indefinita

198 ACCP recommendations In patient with DVT, we recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (range, ) for all treatment durations (Grade 1A) For patients with unprovoked DVT who have a strong preference for less frequent INR testing to monitor their therapy, after the first 3 months of conventional-intensity anticoagulation, we recommend low-intensity therapy (INR range ) with less frequent INR monitoring over stopping-treatment (Grade 1A) We recommend against high intensity VKA therapy (INR range, 3.1 to 4.0) compared to an INR range of (Grade 1A)

199 Options after the initial VKA treatment Withdraw Rx with low risk of recurrence = select patients with acceptable recurrance rate Extend VKA in moderate-high risk of recurrence Withdraw Rx with High clinical burden (bleeding) = select patients with not acceptable management burden (bleeding) = intermediate duration of treatment or lowintensity of anticoagulant effect Indefinite duration of Anticoagulant treatment New Strategies LMWH or New Antithrombotics

200 Duration of Long-Term Treatment of VTE: until its benefit (reduction of VTE) outweight its risk (Bleeding) Previus episodes VTE > 2 (RR 1.5) Antiphospholipid Antibodies (RR 2.0) Hereditary thrombophilia (RR 1.5) Males (RR 1.6) Residual thrombosis in the proximal veins (RR 1.5) Indefinite treatment Withdrawal Treatment Isolated Calf Vein Thrombosis (RR 0.5) Negative D-dimer findings 1 months after withdrawal of WKA (RR 0.4) Asian ethnicity (RR 0.8) Age > 75 years Previous GI bleeding (not reversible cause) Previous non cardio-embolic trokes Chronic renal or hepatic disease Concomitant antiplatelet therapy Poor anticoagulant control