Anticoagulants, old and inconvenient therapies?

Presentazione sul tema: "Anticoagulants, old and inconvenient therapies?"— Transcript della presentazione:

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

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

3 New agents in clinical development: The search for selectivity
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 Pathway Antithrombotics in development Tissue Factor Pathway Inhibitors TFPI, rNAPc2, VIIa inhibitors Initiation Thrombin generation activity TF/VIIa X IX IXa VIIIa Xa Va II IIa

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

5 SPECIFIC BINDING OF PENTASACCHARIDES
Fondaparinux

6 Pentasaccharides Targeted mechanism of action
Core slide 23 Specific inhibition of factor Xa via ATIII IIa II Fibrinogen Fibrin clot Extrinsic pathway Intrinsic pathway Xa 1 AT AT 2 3 AT Xa Key marketing messages As a synthetic and selective inhibitor of factor Xa, Org31540/SR90107A has a fully defined and reproducible action leading to effective anticoagulant control. By interrupting the cascade at its central step, factor Xa, Org31540/SR90107A provides an optimal efficacy/safety ratio. Because it reversibly binds to ATIII, Org31540/SR90107A need only be present in small quantities for a targeted and efficient action. pentasacharides Org31540/SR90107A is highly selective for inhibition of factor Xa, and is a potent reversible ligand of the main endogenous regulator of blood coagulation, ATIII. The selective binding of Org31540/SR90107A to ATIII modifies the conformation of the ATIII molecule. This conformational change results in a more than 500-fold potentiation of the natural inhibitory activity of ATIII against factor Xa. Each molecule of Org31540/SR90107A binds one molecule of ATIII and is released from the binding site on ATIII at the moment when a factor Xa molecule binds to ATIII. Consequently, each molecule of Org31540/SR90107A can bind several molecules of ATIII consecutively. In contrast, the conformational change to ATIII induced by Org31540/SR90107A is permanent and the binding of ATIII to factor Xa is covalent and irreversible. The inhibition of one factor Xa molecule by one molecule of ATIII blocks the formation of 1800 molecules of thrombin, thus achieving a high level of antithrombotic potency. Olson ST, et al. J. Biol. Chem. 1992; 267:12528–12538. The first selective inhibitor of factor Xa Catalytic activity at low doses High potency through action at an early stage of the coagulation cascade For further slides on this topic, see the CD-ROM databank: Slides P7–P11

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

8 Profilo farmacocinetico di fondaparinux
100% biodisponibile Cmax = 0.34 µg/mL (DS: 0.04) Tmax = 1.7 h (DS: 0.4) Cmax/2 = 25 minuti T1/2 = 17.2 ore (DS: 3.2) 0.35 0.3 0.25 plasmatica (µg/mL) Concentrazione 0.2 0.15 0.1 0.05 4 8 12 16 20 24 28 32 36 Ore Donat F, Thromb Haemost, 2001 (ISTH Abstract)

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

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

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

12 Fondaparinux : analisi cumulativa di efficacia
Enoxaparin meglio Fondaparinux meglio - 61.6% Penthifra Test di omogeneità p= 0.072 - 58.3% Ephesus - 28.1% Pentathlon 2000 RRR PER TEV: 55.2 % p < 0.001 - 63.1% Pentamaks - 55.2% Riduzione totale 40% 20% 0% -20% -40% -60% -80% Turpie, Arch Intern Med, 2002

13 Overall efficacy of Fondaparinux vs enoxaparin: Odds reduction per type of surgery and overall
Fondaparinux better Enoxaparin better Exact 95% CI Hip replacement n = 3,411 [59.0; 27.6] 45.4% Hip fracture n = 1,250 [73.4; 45.0] 61.6% Knee replacement n = 724 63.1% [75.5; 44.8] Overall odds reduction p = [63.2; 45.8] 55.3% % odds reduction -100 -80 -60 -40 -20 20 40 60 80 100 p value of homogeneity test of hip replacement studies = 0.068 p value of homogeneity test = 0.16 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) EP non fatale 9 (0.25%) 7 (0.2%) EP fatale 2 (< 0.1%) 3 (< 0.1%) Morte 15 (0.4%) 21 (0.6%)

15 Fondaparinux: profilo di tollerabilita’ rispetto ad enoxaparina nella profilassi del TEV in chirurgia ortopedica maggiore Sanguinamento Fondaparinux Studi di Fase III (N=3616) N (%) Enoxaparina Studi di Fase III (N=3621) N (%) PERIODO DI TRATTAMENTO (fino a 11 giorni) Emorragia fatale 1 Emorragia in un organo vitale 1 Emorragia che richiede un nuovo intervento 12 (0.3) 8 (0.2) Emorragia con un indice di sanguinamento* 2 84 (2.3) 53 (1.5) Infezione della ferita 37 (1.0) 29 (0.8) Complicanze in sede chirurgica che comportano un prolungamento della degenza od un ulteriore ricovero 52 (1.4) 52 (1.4) PERIODO DELLO STUDIO (fino a 49 giorni) Morte per qualsiasi causa 48 (1.3) 52 (1.4) * L’indice 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)]. Turpie, Arch Intern Med, 2002

16 The PENTHIFRA-Plus Study
Study Design n = 326 Fondaparinux 2.5 mg od INITIAL TREATMENT PERIOD (7 ± 1 DAYS) Double- Blind Fondaparinux HFS Total Treatment Duration 21 ± 2 Days R 2.5 mg od Placebo n = 330 Venogram Day 19–24 Post randomization PENTHIFRA-Plus Eriksson BI. Arch Int Med 2003

17 Primary analysis: All adjudicated VTE
40 35 % [28.7 ; 41.7] 35 30 RRR = 96% p = 4 X 10-22 A significant reduction of symptomatic VTE from 2.7% to 0.3% (RRR 89%) 25 % all VTE 20 15 10 1.4 % 5 [0.3 ; 4.2] Fondaparinux Placebo 3/208 77/220 PENTHIFRA-Plus Eriksson BI. Arch Int Med 2003

18 Secondary analysis: All adjudicated DVT
40 Fondaparinux 74/218 35 Placebo 30 25 % DVT 42/211 20 35/222 15 10 5 3/208 2/221 1/207 Any Proximal DVT Distal DVT only Any DVT PENTHIFRA-Plus Eriksson BI. Arch Int Med 2003

19 Adjudicated bleeding in treated patients
Arixtra Placebo n = 327 n = 329 Fatal bleeding Non-fatal bleeding in critical organ At surgical site leading to re-operation 2 (0.6%) 2 (0.6%) Bleeding index  2 6 (1.8%) 0 (0.0%) Minor bleeding only 5 (1.5%) 2 (0.6%) major bleeding, p = (ns) PENTHIFRA-Plus Eriksson BI. Arch Int Med 2003

20 Serious Adverse Events (SAE) and deaths after randomization
Arixtra Placebo n = 327 n = 329 SAE 24 (7.3%) 24 (7.3%) Drug-related SAE 1 (0.3%) 2 (0.6%) Fatal PE 2* (0.6%) Total deaths 6 (1.8%) 8* (2.4%) * One non fatal PE at day 24 became fatal 2 days after in the placebo group PENTHIFRA-Plus Eriksson BI. Arch Int Med 2003

21 Sviluppi del pentasaccaride
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 PEGASUS PEGASUS R Double-Blind Treatment 7 ± 2 Days Venogram Day 5–10
Fondaparinux 2.5 mg once-daily start 6 hrs post-op Double-Blind R Treatment 7 ± 2 Days Dalteparin 2500 U pre-op and post-op 5000 U once-daily post-op start 2 hrs pre-op Venogram Day 5–10 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 Follow-up Day 30 ± 2

23 PEGASUS Results (n=2927) All VTE 4.6% 6.1% Major bleed 3.4% 2.4%
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 32 4.6% 0.4% 0.8% 6.1% 0.3% 1.0% Major bleed 3.4% 2.4% Fatal bleed 0.1% Minor bleed 2.2% 1.6% Death 1.4% Spinal catheter use 35.5% 38.6%

24 Cancer Surgery Patients
PEGASUS Cancer Surgery Patients All VTE up to Day 10 Odds Reduction = 40.5% (95 %CI : 61.9; 7.24%) p = 0.02 9 8 7 6 % of VTE 5 7.7% 4 55/712 4.7% 3 33/696 2 1 Fondaparinux Dalteparin

25 ARTEMIS R Double-Blind Treatment 6–14 Days Fondaparinux
2.5 mg once-daily Double-Blind R Treatment 6–14 Days Placebo Venogram Day 6–15 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 Follow-up Day 32

26 Odds Reduction = 49.5% (95%CI: 72.1; 8.6)
Primary efficacy outcome VTE up to Day 15 Odds Reduction = 49.5% (95%CI: 72.1; 8.6) p = 0.029 12 10.5% 34/323 10 8 5.6% 18/321 % of VTE 6 4 2 Fondaparinux Placebo

27 Primary efficacy components
10 Fondaparinux 2.5mg n = 321 9.1% 9 8 Placebo n = 323 29 7 5.6% 6 % of outcomes 5 18 p = 0.029 4 3 1.5% 2 1 5 0% 0% 0% Any DVT Sympt. DVT/non-fatal PE Fatal PE

28 Safety outcomes in the treatment period
Fondaparinux Placebo n = n = 414 Major bleeding Fatal Surgical intervention Critical organ Bleeding Index  (0.2%) (0.2%) Minor bleeding (2.6%) (1.0%) Death (0.9%) (1.7%)

29 Sviluppi del pentasaccaride
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
Fondaparinux Phase II trial in VTE treatment: Efficacy assessed at 1 week with 3 month follow-up, parallel, double blind, randomized, n = 456 Dalteparin 100 IU/kg twice daily Fondaparinux fixed dose 5 mg once daily 7.5 mg once daily 10 mg once daily Randomization venous ultrasound & lung scan Day 7 +/- 1 change in venous ultrasound & lung scan Day 97 follow-up: recurrent VTE The Rembrandt Investigators. Circulation 2000;102:2726–2731.

31 The REMBRANDT study: Positive outcome = improved ultrasound +/or lung perfusion without worsening of either 0% 10% 20% 30% 40% 50% 60% 5 mg 7.5 mg Fondaparinux 10 mg Dalteparin Better No change Worse The REMBRANDT Study, Circulation 2000;102:2726–2731.

32 % of patients with a deterioration of the lung scan on day 7 ± 1
14% 8.1% 13.1% 8.5% 12.1% 0% 2% 4% 6% 8% 10% 12% 5 mg 7.5 mg 10 mg Dalteparin Fondaparinux The Rembrandt Investigators. Circulation 2000;102:2726–2731.

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

34 Matisse Study Designs 2200 patients with PE + DVT
. Matisse Study Designs  5 days IV UFH (aPTT ) + OAC (INR 2-3) 2200 patients with PE + DVT R Open-Label  5 days 7.5 mg fondaparinux* sc + OAC (INR 2-3) 2200 patients with DVT R Double-blind  5 days SC enoxaparin (1 mg/kg, bid) + OAC (INR 2-3) * 5 mg if body-weight < 50 kg 10 mg if body-weight > 100 kg 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

35 Primary efficacy outcome – 3 months -
Fondaparinux (N=1103) UFH (N=1110) Fondaparinux - UFH (95 % CI ) Matisse PE -1.2%  = 3.5% 0.5% -3.0% Fatal PE (1.5 %) (1.4 %) Non-fatal PE or DVT (2.4 %) (3.6 %) Total symptomatic recurrent VTE (3.8 %) (5.0 %) A T I S E M . Primary efficacy outcome – 3 months - Fondaparinux (N=1098) LMWH (N=1107) Matisse DVT Fatal PE (0.5 %) (0.5 %) Non-fatal PE or DVT (3.5 %) (3.6 %) Total symptomatic recurrent VTE (3.9 %) (4.1 %) -0.15 %  = 3.5% 1.5% -1.8% Fondaparinux - LMWH (95 % CI )

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

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

38 Sviluppi del pentasaccaride
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 Fondaparinux and Acute Coronary Syndromes
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

40 PENTALYSE: hypothesis for Pentasaccharide
Prolonged co-administration with alteplase in AMI could: 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.

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 PENTALYSE: Alteplase + Pentasaccharide / Heparin in STEMI
7.0% 0.9% 8.0% 2.3% 5 10 Heparin Pentas. % p a t i e n s P=.091 P=.065 TIMI 3  TIMI 0, 1 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:

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

44 Primary Efficacy Endpoint (Day 9)
n= n= n= n= n=76

45 Clinical Endpoint (Day 9) Death, AMI or Sympt. Rec. Ischemia
25 21,1 20 18,0 18,4 15,1 15 12,9 Incidence (%) 10 5 2.5 mg 4 mg 8 mg 12 mg enox Fondaparinux

46 Patients with Bleeding Event (Day 9)
Major Major and/or Minor 0,0 1,4 1,8 0,4 3,9 5,4 4,6 4,8 2 4 6 8 2.5mg 4mg 8mg 12mg enox Incidence (%) fondaparinux fondaparinux

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 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 Primary Efficacy Assessed within 48 hrs. All cause death MI re-infarction Urgent revascularization Need for bail-out 6PIIb/IIIa inhibitor Single injection of study drug 48 Fondaparinux 2.5 mg IV Stratum 1 with GPIIb/IIIa Fondaparinux 5.0 mg IV R UFH 100 IU/kg IV N=300 Fondaparinux 2.5 mg IV Fondaparinux 5.0 mg IV Stratum 2 without GPIIb/IIIa R UFH 100 IU/kg IV

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 Primary Efficacy Death MI Refractory ischemia Fondaparinux 2.5 mg S.C. o.d. + Placebo-Enoxaparin S.C. b.i.d. 1 2 3 4 5 6 7 8 9 R n=16,000 Daily administration or until hospital discharge Enoxaparin 1 mg/Kg S.C. o.d. + Placebo-Fondaparinux S.C. b.i.d. 1 2 3 4 5 6 7 8 9

49 MICHELANGELO - STEMI Stratum 1 Stratum 2
Inclusion Criteria Clinically and ECG Dx AMI (STEMI) Primary Efficacy Death Recurrent MI (STEMI) Fondaparinux* 2.5 mg S.C. o.d. Fondaparinux placebo S.C. b.i.d. 1 2 3 4 5 6 7 8 9 Stratum 1 “UFH not indicated” 1 2 3 4 5 6 7 8 9 *Daily administration or until hospital discharge Fondaparinux* + [UFH placebo (24-48 hrs)] UFH IV (24-48 hrs)+ Fondaparinux placebo Stratum 2 “UFH indicated” 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9

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 Pentasaccharide have been built to mimic the sequence in heparins, responsible for AT binding. First step was to copy this sequence as closely as possible Second was to improve “nature” by adding a sulphoxy at H3. Third was to make simpler, safer and cheaper alternatives and to further titrate the elimination half-life to once-a-week use. OCH3 OCH3

51 SanOrg 34006 (IDRAPARINUX): un nuovo antitrombotico a lunga emivita
ATIII-binding pentasaccharide sequence O CH2OSO3- OH NHR COO- OSO3- NHSO3- R = -SO3- or COCH3 Emivita: 130 ore somministrazione 1 vv/settimana

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

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

55 STUDIO PERSIST: Profilo di tollerabilità
Emorragie maggiori Tutte le emorragie P=0.029 Idraparinux (mg) Idraparinux (mg) 0 / / / / / 132 3 / / / / / 132

56 Conclusions PERSIST dose finding study and kinetic modelling
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

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

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

59 once weekly s.c. injection End of follow-up period
Study design 6-months once weekly s.c. injection 6-months follow up Idraparinux 1,700 PE or DVT patients who completed 6 months of treatment All patients untreated Day 183+7 Day 365+7 Randomization Placebo End of study treatment End of follow-up period

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

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

62 Complex Simple Treatment regimens Antithrombotic Drugs Few or none Fixed (?body wt ?renal function) Predictable Reproducible Targeted and specific New Variable sc or oral availability Frequent Laboratory tests Dose Dynamics Kinetics Anticoagulant effect Old