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Anticoagulants, old and inconvenient therapies? Heparins Standard heparin 1937Parenteral, monitoring LMWH 1982Parenteral, fixed or weight adjusted doses.

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Presentazione sul tema: "Anticoagulants, old and inconvenient therapies? Heparins Standard heparin 1937Parenteral, monitoring LMWH 1982Parenteral, fixed or weight adjusted doses."— Transcript della presentazione:

1 Anticoagulants, old and inconvenient therapies? Heparins Standard heparin 1937Parenteral, monitoring LMWH 1982Parenteral, fixed or weight adjusted doses Vitamin K antagonists Dicoumarol 1942 Oral, monitoring Warfarin 1953 Oral, monitoring First published clinical experience

2 Perché nuovi farmaci antitrombotici: caratteristiche dellanticoagulante ideale Perché nuovi farmaci antitrombotici: caratteristiche dellanticoagulante ideale Efficacia e sicurezza Efficacia e sicurezza Scarsità di effetti collaterali Scarsità di effetti collaterali Azione facilmente e rapidamente reversibile Azione facilmente e rapidamente reversibile Effetto prevedibile, monitoraggio non necessario Effetto prevedibile, monitoraggio non necessario Semplicità della via, della modalità e del numero delle sommistrazioni Semplicità della via, della modalità e del numero delle sommistrazioni Buona compliance del paziente (con conseguente ottimizzazione della efficacia e sicurezza) Buona compliance del paziente (con conseguente ottimizzazione della efficacia e sicurezza) Costo ragionevole Costo ragionevole

3 Thrombin Inhibitors: Hirudin, Bivalirudin, Argatroban, Melagatran, Ximelagatran IXa inhibitors Xa inhibitors: -Pentasaccharide - TAP, Antistasin, DX 9065a, YM60828, 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 New agents in clinical development: The search for selectivity

4 factor Xa AT Arg Lys Pentasaccharide sequence Extended chains capture other factors like thrombin thrombin Heparins thrombin factor Xa Pentasaccharides

5 SPECIFIC BINDING OF PENTASACCHARIDES Fondaparinux

6 Specific inhibition of factor Xa via ATIII 1 AT pentasacharides 3 Xa IIaII Fibrinogen Fibrin clot Extrinsic pathway Intrinsic pathway Xa AT 2 Mechanism of action Pentasaccharides Targeted mechanism of action

7 Fondaparinux: il primo di una nuova classe di inibitori sintetici e selettivi del fattore Xa Herbert, Cardiovasc Drug Rev, 1997 Van Boeckel, Angew Chem Int Ed Engl, 1993 Altamente selettivo nei confronti del suo bersaglio Effetto antitrombotico prevedibile e dose-dipendente Somministrazione solo parenterale Eliminazione renale Totale sintesi chimica

8 Concentrazione plasmatica (µg/mL) Donat F, Thromb Haemost, 2001 (ISTH Abstract) Ore 100% biodisponibile C max = 0.34 µg/mL (DS: 0.04) T max = 1.7 h (DS: 0.4) C max/2 = 25 minuti T 1/2 = 17.2 ore (DS: 3.2) 100% biodisponibile C max = 0.34 µg/mL (DS: 0.04) T max = 1.7 h (DS: 0.4) C max/2 = 25 minuti T 1/2 = 17.2 ore (DS: 3.2) Profilo farmacocinetico di fondaparinux Profilo farmacocinetico di fondaparinux

9 Turpie et al, N Engl J Med 2001;344:619-25

10 PENTHIFRA:Frattura danca (Europa, Sud America, Oceania) Oceania) 1,711 pazienti EPHESUS:Artroprotesi danca (Europa) 2,309 pazienti PENTATHLON 2000:Artroprotesi danca (Nord America, Oceania) (Nord America, Oceania) 2,275 pazienti PENTAMAKS:Chirurgia maggiore di ginocchio (Nord America) (Nord America) 1049 pazienti Fondaparinux : studi di fase III in chirurgia ortopedica maggiore

11 Sviluppo clinico di fondaparinux nella profilassi del TEV in chirurgia ortopedica: quattro studi di Fase III Dose unica di 2.5 mg/die, inizio post-chirurgico Trattamento in doppio cieco per 7 ± 2 giorni Due studi: 30 mg x 2/die, inizio post-chirurgico (Schema americano) Flebografia Giorno 5–11 Follow-up Giorno 42 ± 7 Enoxaparina Fondaparinux Due studi: 40 mg/die, inizio pre-intervento (Schema europeo) R

12 -80% -60%-40%-20%0%20% 40% Enoxaparin meglioFondaparinux meglio % Riduzione totale % Penthifra % Ephesus % Pentathlon % Pentamaks RRR PER TEV: 55.2 % p < Test di omogeneità Test di omogeneità p= p= Fondaparinux : analisi cumulativa di efficacia Turpie, Arch Intern Med, 2002

13 Fondaparinux betterEnoxaparin better p value of homogeneity test of hip replacement studies = p value of homogeneity test = 0.16 Exact 95% CI Hip replacement n = 3,411 Hip fracture n = 1,250 Knee replacement n = 724 Overall odds reduction % 63.1% 55.3% [59.0; 27.6] [73.4; 45.0] [75.5; 44.8] [63.2; 45.8] 61.6% p = Overall efficacy of Fondaparinux vs enoxaparin: Odds reduction per type of surgery and overall % odds reduction Turpie AGG, Haematologica 2001;86(Suppl):59-62.

14 End point di efficacia: EP e morte al giorno 11 Fondaparinux Enoxaparina (n=3616)(n=3621) 9 (0.25%) 2 (< 0.1%) 15 (0.4%) 7 (0.2%) 3 (< 0.1%) 21 (0.6%) EP non fatale EP fatale Morte

15 Fondaparinux: profilo di tollerabilita rispetto ad enoxaparina nella profilassi del TEV in chirurgia ortopedica maggiore * Lindice di sanguinamento è stato così calcolato: [numero di sacche di emazie o di sangue intero trasfuse + [(emoglobinemia pre-sanguinamento) - (emoglobinemia post- sanguinamento) (in g/dL)]. Fondaparinux Studi di Fase III (N=3616) N (%) Enoxaparina Studi di Fase III (N=3621) N (%) Emorragia fatale01 Emorragia in un organo vitale 01 Emorragia che richiede un nuovo intervento12 (0.3)8 (0.2) Emorragia con un indice di sanguinamento* 284 (2.3)53 (1.5) Infezione della ferita37 (1.0)29 (0.8) Complicanze in sede chirurgica che comportano un prolungamento della degenza od un ulteriore ricovero 52 (1.4) PERIODO DELLO STUDIO (fino a 49 giorni) Morte per qualsiasi causa 48 (1.3) 52 (1.4) Sanguinamento PERIODO DI TRATTAMENTO (fino a 11 giorni) Turpie, Arch Intern Med, 2002

16 Study Design Fondaparinux 2.5 mg od R Venogram Day 19–24 Post randomization Double- Blind Total Treatment Duration 21 ± 2 Days Placebo Fondaparinux INITIAL TREATMENT PERIOD (7 ± 1 DAYS) HFS n = 326 n = mg od Eriksson BI. Arch Int Med 2003 PENTHIFRA-Plus The PENTHIFRA-Plus Study

17 Primary analysis: All adjudicated VTE 35 % [28.7 ; 41.7] Placebo % all VTE 1.4 % [0.3 ; 4.2] Fondaparinux 3/208 77/220 RRR = 96% p = 4 X Eriksson BI. Arch Int Med 2003 PENTHIFRA-Plus A significant reduction of symptomatic VTE from 2.7% to 0.3% (RRR 89%)

18 Secondary analysis: All adjudicated DVT Any Proximal DVTDistal DVT onlyAny DVT Fondaparinux Placebo 35/222 1/207 42/211 3/208 74/218 2/221 % DVT Eriksson BI. Arch Int Med 2003 PENTHIFRA-Plus

19 Adjudicated bleeding in treated patients Arixtra n = 327 Placebo n = 329 Fatal bleeding00 Non-fatal bleeding in critical organ00 At surgical site leading to re-operation 2 (0.6%) Bleeding index 2 6 (1.8%)0 (0.0%) Minor bleeding only5 (1.5%)2 (0.6%) major bleeding, p = (ns) Eriksson BI. Arch Int Med 2003 PENTHIFRA-Plus

20 Arixtra n = 327 Placebo n = 329 SAE24 (7.3%) Drug-related SAE1 (0.3%)2 (0.6%) Fatal PE02* (0.6%) Total deaths6 (1.8%)8* (2.4%) * One non fatal PE at day 24 became fatal 2 days after in the placebo group Eriksson BI. Arch Int Med 2003 Serious Adverse Events (SAE) and deaths after randomization PENTHIFRA-Plus

21 Sviluppi del pentasaccaride Indicazione Campo applicazione Nome studio Indicazione Campo applicazione Nome studio Profilassi TEV Chir. Addominale Alto Rischio PEGASUS Profilassi TEV Medicina interna ARTEMIS Terapia TEV TVP REMBRANDT Terapia TEV TVP, embolia polmonare MATISSE(DVT-PE) Terapia SCA IMA trombolisato PENTALYSE Terapia SCA Angina Instabile PENTUA Terapia SCA SCA MICHELANGELO Profilassi TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH Profilassi TE Fibrillazione atriale AMADEUS

22 Dalteparin 2500 U pre-op and post-op 5000 U once-daily post-op Fondaparinux 2.5 mg once-daily R start 2 hrs pre-op start 6 hrs post-op Venogram Day 5–10 Follow-up Day 30 ± 2 Double-Blind Treatment 7 ± 2 Days PEGASUS Abdominal surgery (70% cancer) General anesthesia Duration surgery > 45 min Patients at risk for VTE: Age > 60 years or Age > 40 years with at least one risk factor for VTE

23 Results (n=2927) Fondaparinux (enrolled n= 1465) (evaluable for VTE n=1027) Dalteparin (enrolled n=1462) (evaluable for VTE n=1019) All VTE Symptomatic --at day 10 --at day % 0.4% 0.8% 6.1% 0.3% 1.0% Major bleed3.4%2.4% Fatal bleed0.1% Minor bleed2.2%1.6% Death1.0%1.4% Spinal catheter use35.5%38.6%

24 Cancer Surgery Patients All VTE up to Day 10 Odds Reduction = 40.5% (95 %CI : 61.9; 7.24%) p = /712 9 FondaparinuxDalteparin % 4.7% 33/696 % of VTE

25 Placebo Fondaparinux 2.5 mg once-daily R Venogram Day 6–15 Follow-up Day 32 Double-Blind Treatment 6–14 Days ARTEMIS Acutely ill medical patients: aged 60 years expected to require bed rest for 4 days hospitalized for: CHF (NYHA class III / IV) Acute respiratory illness in the presence of chronic lung disease Acute infectious or inflammatory disease

26 Odds Reduction = 49.5% (95%CI: 72.1; 8.6) p = Primary efficacy outcome VTE up to Day 15 Placebo Fondaparinux 5.6% 18/ % 34/ % of VTE

27 Primary efficacy components p = % of outcomes Fondaparinux 2.5mg n = 321 Placebo n = % 9.1% 1.5% Any DVT Sympt. DVT/non-fatal PE Fatal PE %

28 Fondaparinux Placebo n = 425 n = 414 Major bleeding Fatal 0 0 Surgical intervention 0 0 Critical organ 0 0 Bleeding Index 2 1 (0.2%) 1 (0.2%) Minor bleeding 11 (2.6%) 4 (1.0%) Death 4 (0.9%) 7 (1.7%) Safety outcomes in the treatment period

29 Sviluppi del pentasaccaride Indicazione Campo applicazione Nome studio Indicazione Campo applicazione Nome studio Profilassi TEV Chir. Addominale Alto Rischio PEGASUS Profilassi TEV Medicina interna ARTEMIS Terapia TEV TVP REMBRANDT Terapia TEV TVP, embolia polmonare MATISSE(DVT-PE) Terapia SCA IMA trombolisato PENTALYSE Terapia SCA Angina Instabile PENTUA Terapia SCA SCA ASPIRE/MICHELANGELO Profilassi sec TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH Profilassi TE Fibrillazione atriale AMADEUS

30 REMBRANDT study design Randomization venous ultrasound & lung scan Day 7 +/- 1 change in venous ultrasound & lung scan Day 97 follow-up: recurrent VTE Dalteparin 100 IU/kg twice daily 7.5 mg once daily 10 mg once daily Fondaparinux fixed dose Fondaparinux Phase II trial in VTE treatment: Efficacy assessed at 1 week with 3 month follow-up, parallel, double blind, randomized, n = 456 The Rembrandt Investigators. Circulation 2000;102:2726– mg once daily

31 The REMBRANDT study: Positive outcome = improved ultrasound +/or lung perfusion without worsening of either The REMBRANDT Study, Circulation 2000;102:2726– % 10% 20% 30% 40% 50% 60% 5 mg7.5 mg Fondaparinux 10 mgDalteparin BetterNo changeWorse

32 % of patients with a deterioration of the lung scan on day 7 ± 1 The Rembrandt Investigators. Circulation 2000;102:2726–2731. Fondaparinux

33 Symptomatic recurrent VTE up to Day 97 The Rembrandt Investigators. Circulation 2000;102:2726–31. Fondaparinux 1.8% 1.9% 3.3% 5.0% 0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% 5 mg 7.5 mg 10 mg Dalteparin

34 R 5 days IV UFH (aPTT ) + OAC (INR 2-3) 5 days IV UFH (aPTT ) + OAC (INR 2-3) 90 ± 7 Days 5 days 7.5 mg fondaparinux * sc + OAC (INR 2-3) 5 days 7.5 mg fondaparinux * sc + OAC (INR 2-3) 2200 patients with PE + DVT Open-Label 5 days SC enoxaparin (1 mg/kg, bid) + OAC (INR 2-3) 5 days SC enoxaparin (1 mg/kg, bid) + OAC (INR 2-3) Matisse Study Designs R Double-blind 2200 patients with DVT 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 * 5 mg if body-weight < 50 kg 10 mg if body-weight > 100 kg A T I S S E M

35 Fondaparinux (N=1098)LMWH (N=1107) Matisse DVT 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 %) % = 3.5% 0 1.5% -1.8% Fondaparinux - LMWH (95 % CI ) Fondaparinux (N=1103)UFH (N=1110) Fondaparinux - UFH (95 % CI ) Matisse PE -1.2% = 3.5% 0 0.5% -3.0% 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 %) A T I S S E M Primary efficacy outcome – 3 months -

36 Matisse DVT Fondaparinux LMWH 3.7 % 4.2 % Principal Safety Outcome - initial treatment - Fondaparinux UFH Matisse PE 4.5 % 6.3 % A T I S S E M Major bleedClinically relevant non-major bleed

37 Matisse DVT Fondaparinux LMWH 3.8 % 3.0 % Mortality - 3 months - Fondaparinux UFH Matisse PE 5.2 % 4.4 % A T I S S E M Cancer VTE/bleedingOther

38 Sviluppi del pentasaccaride Indicazione Campo applicazione Nome studio Indicazione Campo applicazione Nome studio Profilassi TEV Chir. Addominale Alto Rischio PEGASUS Profilassi TEV Medicina interna ARTEMIS Terapia TEV TVP REMBRANDT Terapia TEV TVP, embolia polmonare MATISSE(DVT-PE) Terapia SCA IMA trombolisato PENTALYSE Terapia SCA Angina Instabile PENTUA Terapia SCA SCA ASPIRE/MICHELANGELO Profilassi sec TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH Profilassi TE Fibrillazione atriale AMADEUS

39 Pentalyse Acute MI Completed Pentua Unstable angina Completed Aspire PCI Ongoing Michelangelo: -UA-NSTEMI (Oasis 5) Unstable angina Ongoing -STEMI (Oasis 6) ST Elevation MI Ongoing Fondaparinux and Acute Coronary Syndromes

40 PENTALYSE: hypothesis for Pentasaccharide Prolonged co-administration with alteplase in AMI could: Prevent reocclusion of the infarct- related artery, while Prevent reocclusion of the infarct- related artery, while Producing similar rates of early coronary artery revascularization as compared to a standard regimen of alteplase with unfractionated heparin. Producing similar rates of early coronary artery revascularization as compared to a standard regimen of alteplase with unfractionated heparin.

41 PENTALYSE: Fondaparinux in Acute Myocardial Infarction Dose-finding (4, 8, 12 mg PS) in AMI in combination with rt-PA vs UFH, 326 patients Results: Similar TIMI-3 flow at 90 min, a trend to lower rate of re-occlusion/re-vascularisation at 5-7 days

42 TIMI 3 TIMI 0, 1 P=.065 P=.091 TIMI 2, 3 TIMI 0, 1 Reocclusion rates on days 5 to 7 in patients with ΤΙΜΙ grade 3 flow or ΤΙΜΙ 2, 3 flow at 90 min who did not undergo a coronary intervention and were treated per protocol. Eur Heart J 2001;22: PENTALYSE: Alteplase + Pentasaccharide / Heparin in STEMI 7.0% 0.9% 8.0% 2.3% Heparin Pentas. % p a t i e n t s

43 Study design Unstable angina Non-Q wave MI ST or Trop + Unstable angina Non-Q wave MI ST or Trop + enoxaparin 1 mg/kg bid 2.5 mg fondaparinux 4 mg fondaparinux 8 mg fondaparinux 12 mg fondaparinux Randomization Treatment 3-7 days Day 9 48 h ECG Endpoint evaluation Day 30 Efficacy endpoint:Death + AMI + a-/symptomatic recurrent ischemia until day 9 Safety endpoint: Major bleeding until day 9 Pentua

44 Primary Efficacy Endpoint (Day 9) n=61 n=77 n=71 n=65 n=76 P < 0.05

45 Clinical Endpoint (Day 9) Death, AMI or Sympt. Rec. Ischemia 12,9 21,1 18,0 15,1 18, mg4 mg8 mg12 mgenox Fondaparinux Incidence (%) P =

46 MajorMajor and/or Minor fondaparinux Patients with Bleeding Event (Day 9)

47 ASPIRE A randomized blinded pilot trial of fondaparinux sodium vs. UFH in addition to standard therapy in a broad range of pts undergoing PCI Primary Efficacy Assessed within 48 hrs. All cause death MI re-infarction Urgent revascularization Need for bail-out 6PIIb/IIIa inhibitor Inclusion Criteria >21 yrs NSTEMI and STEMI Planned PCI Pre-treatment ASA mg o.d. p.o. + clopidogrel 75 mg o.d. p.o. continued 4 weeks Stratum 1 with GPIIb/IIIa N=300 Stratum 2 without GPIIb/IIIa Fondaparinux 2.5 mg IV Fondaparinux 5.0 mg IV UFH 100 IU/kg IV 0 48 R R Fondaparinux 2.5 mg IV Fondaparinux 5.0 mg IV UFH 100 IU/kg IV Single injection of study drug

48 MICHELANGELO - UA/NSTEMI Double blind-double dummy, placebo controlled, parallel arm study, of the efficacy and safety of Fondaparinux vs. enoxparin in acute treatment of UA/NSTEMI Inclusion Criteria >21 yrs UA NSTEMI < 24hrs onset Troponin T/I CK-MB ECG-ischemia Fondaparinux 2.5 mg S.C. o.d. + Placebo-Enoxaparin S.C. b.i.d. Enoxaparin 1 mg/Kg S.C. o.d. + Placebo-Fondaparinux S.C. b.i.d. R n=16, Primary Efficacy Death MI Refractory ischemia Daily administration or until hospital discharge

49 Fondaparinux* + [UFH placebo (24-48 hrs)] UFH IV (24-48 hrs)+ Fondaparinux placebo Fondaparinux* 2.5 mg S.C. o.d. Fondaparinux placebo S.C. b.i.d. MICHELANGELO - STEMI Inclusion Criteria Clinically and ECG Dx AMI (STEMI) *Daily administration or until hospital discharge Stratum 1 UFH not indicated Stratum 2 UFH indicated Primary Efficacy Death Recurrent MI (STEMI)

50 Pentasaccharides tailor made Fondaparinux (Arixtra ® ) MOST LIKE NATURAL Once-a-day (1987) Org31550 MORE POTENT A new binding site discovered Idraparinux, SanOrg34006 SIMPLIFIED (1992) Once-a-week OCH 3

51 SanOrg (IDRAPARINUX): un nuovo antitrombotico a lunga emivita SanOrg (IDRAPARINUX): un nuovo antitrombotico a lunga emivita O CH 2 OSO 3 - OH O O NHR COO - OH O O OH CH 2 OSO 3 - OSO 3 - O O NHSO 3 - CO O - OH O O OSO 3 - CH 2 OSO 3 - OHO O NHSO 3 - R = -SO 3 - or COCH 3 ATIII-binding pentasaccharide sequence Emivita: 130 ore somministrazione 1 vv/settimana

52 Sviluppi del pentasaccaride Indicazione Campo applicazione Nome studio Indicazione Campo applicazione Nome studio Profilassi TEV Chir. Addominale Alto Rischio PEGASUS Terapia TEV TVP REMBRANDT Terapia TEV TVP, embolia polmonare MATISSE(DVT-PE) Terapia SCA IMA trombolisato PENTALYSE Terapia SCA Angina Instabile PENTUA Terapia SCA SCA ASPIRE / MICHELANGELO Profilassi TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH Profilassi TE Fibrillazione atriale AMADEUS

53 PERSIST: Studio dose-finding con Idraparinux nella profilassi secondaria della TVP LMWH Randomization days 12 weeks ScreenAcute treatment 2.5 mg idraparinux o.w. 5 mg 7.5 mg 10 mg Open label INR-adjusted VKA Baseline: CUS + PLS Last assessment: CUS + PLS N=124 N=125 N=128 N=118 N=119 The Persist Investigators Group, Blood, 2002

54 Idraparinux (mg) STUDIO PERSIST: Profilo di efficacia STUDIO PERSIST: Profilo di efficacia 77 / 9 / 8 / 10 / / 2 / 0 / 3 / 2 / Complicanze tromboemboliche sintomatiche

55 Emorragie maggiori Tutte le emorragie Idraparinux (mg) STUDIO PERSIST: Profilo di tollerabilità STUDIO PERSIST: Profilo di tollerabilità 3 / / / / / / / / / / 132 P=0.029

56 Distinct dose-safety response No dose-efficacy response 2.5 mg idraparinux once-weekly has similar efficacy compared to warfarin with the potential for improved safety 2.5 mg idraparinux once-weekly dose is suitable regardless age and body-weight with only a reduced maintenance dose for patients with severe renal insufficiency Conclusions PERSIST dose finding study and kinetic modelling

57 Van Gogh Studies Treatment of: 1. DVT 2. PE, as well as 3. extended treatment beyond 6 months Vitamin-K antagonists Against the Non- Glycoaminoglycan Idraparinux on clinical Outcomes Greatly relevant in Hemodynamic stable VTE patients

58 Hep +VKA VKA only, 26 wks 2.5 mg idraparinux, 26 wks Study design PE (N=2,200) 2.5 mg idraparinux, 13 wks (LMW)Heparin at least for a total of 5 days and INR >2 for two consecutive days Any heparin 36 h before randomization Hep +VKA VKA only, 13 wks Randomization DVT (N=2,200) Hep +VKA VKA only, 26 wks 2.5 mg idraparinux, 26 wks 2.5 mg idraparinux, 13 wks Any heparin 36 h before randomization Hep +VKA VKA only, 13 wks Randomization (LMW)Heparin at least for a total of 5 days and INR >2 for two consecutive days

59 Study design Randomization 6-months once weekly s.c. injection End of study treatment Idraparinux Placebo 6-months follow up All patients untreated End of follow-up period 1,700 PE or DVT patients who completed 6 months of treatment Day Day 365+7

60 Dose finding study in DVT patients PERSIST Pharmacokinetic modelling Rationale for dose selection in the van Gogh studies

61 Patients with AF, eligible for VKA treatment Randomization 2.5 mg idraparinux o.w. INR-adjusted VKA Idraparinux sodium (SanOrg34006) Phase III Amadeus AF Treatment 6-24 months open-label EFFICACY:All strokes and non-CNS embolism SAFETY:All bleeding

62 ComplexSimpleTreatment regimens Antithrombotic Drugs Few or none Fixed (?body wt ?renal function) Predictable Reproducible Targeted and specific New Variablesc or oral availability FrequentLaboratory tests VariableDose VariableDynamics VariableKinetics ComplexAnticoagulant effect Old


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