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

Anticoagulants, old and inconvenient therapies?

HeparinsStandard heparin 1937 Parenteral, monitoring

LMWH 1982 Parenteral, fixed orweight adjusted doses

Vitamin K antagonistsDicoumarol 1942 Oral, monitoring

Warfarin 1953 Oral, monitoring

First publishedclinical experience

Perché nuovi farmaci antitrombotici: Perché nuovi farmaci antitrombotici: caratteristiche dell’anticoagulante “ideale”caratteristiche dell’anticoagulante “ideale”

• EfficaciaEfficacia e e sicurezzasicurezza

• Scarsità di Scarsità di effetti collateralieffetti collaterali

• Azione facilmente e rapidamente Azione facilmente e rapidamente reversibilereversibile

• Effetto prevedibile, Effetto prevedibile, monitoraggio non necessariomonitoraggio non necessario

• SemplicitàSemplicità della via, della modalità e del numero della via, della modalità e del numero

delle sommistrazionidelle sommistrazioni

• Buona Buona compliancecompliance del paziente (con conseguente del paziente (con conseguente

ottimizzazione della efficacia e sicurezza) ottimizzazione della efficacia e sicurezza)

• Costo Costo ragionevoleragionevole

Thrombin Inhibitors: Hirudin, Bivalirudin, Argatroban,Melagatran, Ximelagatran

IXa inhibitors Xa inhibitors: Xa inhibitors:

-Pentasaccharide-Pentasaccharide

-TAP, Antistasin, DX 9065a, YM60828, DPC 906

Protein C Activators aPC, Thrombomodulin

Coagulation Pathway Antithrombotics in development

Tissue Factor Pathway InhibitorsTFPI, rNAPc2, VIIa inhibitors

Initiation

Thrombingeneration

Thrombinactivity

TF/VIIa

IIa

II

Xa

IXa

IXX

VIIIa

Va

New agents in clinical development:The search for selectivity

factor Xa

AT

ArgArgLys

Pentasaccharide sequence

Extended chains capture other factors like thrombin

thrombin

Heparins

thrombin

factor Xa

Pentasaccharides

SPECIFIC BINDING OF PENTASACCHARIDES

Fondaparinux

Specific inhibition of factor Xa via ATIII

1

AT

pentasacharidespentasacharides

3

AT Xa

IIaII

Fibrinogen Fibrin clot

Extrinsic pathway

Intrinsicpathway

XaAT

2

Mechanism of actionMechanism of actionPentasaccharides

Targeted mechanism of action

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 bersaglioEffetto antitrombotico prevedibile e dose-dipendente Somministrazione solo parenterale Eliminazione renale

Totale sintesi chimica

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Con

cent

razi

one

plas

mat

ica

(µg/

mL)

0 4 8 12 16 20 24 28 32 36

Donat F, Thromb Haemost, 2001 (ISTH Abstract)

Ore

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)

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)

Profilo farmacocinetico di Profilo farmacocinetico di fondaparinux fondaparinux

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

PENTHIFRA:PENTHIFRA: Frattura d’anca (Europa, Sud America,Frattura d’anca (Europa, Sud America, Oceania)Oceania)

1,711 pazienti 1,711 pazienti

EPHESUS:EPHESUS: Artroprotesi d’anca (Europa)Artroprotesi d’anca (Europa)2,309 pazienti2,309 pazienti

PENTATHLON 2000:PENTATHLON 2000: Artroprotesi d’anca Artroprotesi d’anca (Nord America, Oceania)(Nord America, Oceania)

2,275 pazienti 2,275 pazienti

PENTAMAKS:PENTAMAKS: Chirurgia maggiore di ginocchioChirurgia maggiore di ginocchio (Nord America)(Nord America)

1049 pazienti1049 pazienti

FondaparinuxFondaparinux : studi di fase III in : studi di fase III in chirurgia ortopedica maggiorechirurgia ortopedica maggiore

Sviluppo clinico di fondaparinux nella Sviluppo clinico di fondaparinux nella profilassi del TEV in chirurgia profilassi del TEV in chirurgia

ortopedica: quattro studi di Fase IIIortopedica: 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)

FlebografiaGiorno 5–11

Follow-upGiorno 42 ± 7

Enoxaparina

Fondaparinux

Due studi: 40 mg/die, inizio pre-intervento (Schema europeo)

R

-80%-60%-40%-20%0%20%40%

Enoxaparin meglio Fondaparinux meglio

- 55.2%Riduzione totale

- 61.6%Penthifra

- 58.3%Ephesus

- 28.1%Pentathlon 2000

- 63.1%Pentamaks

RRR PER TEV: 55.2 %RRR PER TEV: 55.2 %p < 0.001p < 0.001

Test di omogeneità Test di omogeneità p= 0.072p= 0.072

Fondaparinux : Fondaparinux : analisi cumulativaanalisi cumulativa di efficacia di efficacia

Turpie, Arch Intern Med, 2002

Fondaparinux better Enoxaparin better

p value of homogeneity test of hip replacement studies = 0.068p value of homogeneity test = 0.16

Exact 95% CI

Hip replacementn = 3,411

Hip fracturen = 1,250

Knee replacementn = 724

Overall odds reduction

-100 -80 -60 -40 -20 200 40 60 80 100

45.4%

63.1%

55.3%

[59.0; 27.6]

[73.4; 45.0]

[75.5; 44.8]

[63.2; 45.8]

61.6%

p = 10 -17

Overall efficacy of Fondaparinux vs enoxaparin:Odds reduction per type of surgery and overall

% odds reduction

Turpie AGG, Haematologica 2001;86(Suppl):59-62.

End point di efficacia: End point di efficacia:

EP e morte al giorno 11EP e morte al giorno 11

FondaparinuxFondaparinux EnoxaparinaEnoxaparina

(n=3616)(n=3616) (n=3621)(n=3621)

9 (0.25%)9 (0.25%)

2 (< 0.1%)2 (< 0.1%)

15 (0.4%)15 (0.4%)

7 (0.2%)7 (0.2%)

3 (< 0.1%)3 (< 0.1%)

21 (0.6%)21 (0.6%)

EP non fataleEP non fatale

EP fataleEP fatale

Morte Morte

Fondaparinux: profilo di tollerabilita’ Fondaparinux: profilo di tollerabilita’ rispetto ad enoxaparina nella profilassi rispetto ad enoxaparina nella profilassi del TEV in chirurgia ortopedica maggioredel TEV in chirurgia ortopedica maggiore

* 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)].

FondaparinuxStudi di Fase III(N=3616) N (%)

EnoxaparinaStudi di Fase III

(N=3621) N (%)

Emorragia fatale 0 1

Emorragia in un organo vitale 0 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)

Sanguinamento

PERIODO DI TRATTAMENTO (fino a 11 giorni)

Turpie, Turpie, Arch Intern MedArch Intern Med, 2002, 2002

Study Design

Fondaparinux2.5 mg od

R

Venogram Day 19–24Post randomization

Double- Blind

Total Treatment Duration

21 ± 2 Days

Placebo

FondaparinuxFondaparinux

INITIAL TREATMENT PERIOD

(7 ± 1 DAYS)

HFS

n = 326

n = 330

2.5 mg od

Eriksson BI. Arch Int Med 2003PENTHIFRA-Plus

The PENTHIFRA-Plus Study

Primary analysis: All adjudicated VTE

35 %[28.7 ; 41.7]

0

5

10

15

20

25

30

35

40

Placebo

% all VTE

1.4 %[0.3 ; 4.2]

Fondaparinux3/208 77/220

RRR = 96%p = 4 X 10-22


A significant reduction of symptomatic VTE from 2.7% to 0.3% (RRR 89%)

Secondary analysis: All adjudicated DVT

0

5

10

15

20

25

30

35

40

Any Proximal DVT Distal DVT only Any DVT

Fondaparinux

Placebo

35/222

1/207

42/211

3/208

74/218

2/221

% DVT


Adjudicated bleeding

in treated patients

Arixtran = 327

Placebon = 329

Fatal bleeding 0 0

Non-fatal bleeding in critical organ 0 0

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 = 0.063 (ns)


Arixtran = 327

Placebon = 329

SAE 24 (7.3%) 24 (7.3%)

Drug-related SAE 1 (0.3%) 2 (0.6%)

Fatal PE 0 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

Eriksson BI. Arch Int Med 2003

Serious Adverse Events (SAE) and deaths after randomization

PENTHIFRA-Plus

Sviluppi del pentasaccarideSviluppi 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

Dalteparin2500 U pre-op and post-op5000 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

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 32

4.6%

0.4%

0.8%

6.1%

0.3%

1.0%

Major bleed 3.4% 2.4%

Fatal bleed 0.1% 0.1%

Minor bleed 2.2% 1.6%

Death 1.0% 1.4%

Spinal catheter use 35.5% 38.6%

Cancer Surgery Patients All VTE up to Day 10

Odds Reduction = 40.5% (95 %CI : 61.9; 7.24%)

p = 0.02

55/712

9

Fondaparinux Dalteparin0

1

2

3

4

5

6

7

8

7.7%

4.7%33/696

% o

f V

TE

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 diseaseAcute infectious or inflammatory disease

Odds Reduction = 49.5%(95%CI: 72.1; 8.6)

p = 0.029

Primary efficacy outcomeVTE up to Day 15

Placebo Fondaparinux

5.6%18/321

10.5%34/323

0

2

4

6

8

10

12

% o

f V

TE

Primary efficacy components

p = 0.029

% o

f ou

tcom

es

Fondaparinux 2.5mg n = 321

Placebo n = 323

10

5.6%

9.1%

1.5%

0

1

2

3

4

5

6

7

8

9

Any DVT Sympt. DVT/non-fatal PE

Fatal PE

18

29

50% 0% 0%

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



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


REMBRANDT study design

Randomizationvenous ultrasound

& lung scan

Day 7 +/- 1change in venous

ultrasound & lung scan

Day 97follow-up: recurrent

VTE

Dalteparin100 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;102:2726–2731.

5 mg once daily

The REMBRANDT study: Positive outcome = improved ultrasound +/or lung

perfusion without worsening of either

The REMBRANDT Study, Circulation 2000;102:2726–2731.

0%

10%

20%

30%

40%

50%

60%

5 mg 7.5 mg

Fondaparinux

10 mg Dalteparin

Better No change Worse

% of patients with a deterioration of the lung scan on day 7 ± 1


Fondaparinux

14%

8.1%

13.1%

8.5%

12.1%

0%

2%

4%

6%

8%

10%

12%

5 mg 7.5 mg 10 mg Dalteparin

Symptomatic recurrent VTE up to Day 97


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

R

5 days IV UFH (aPTT 1.5-2.5) + OAC (INR 2-3)5 days IV UFH (aPTT 1.5-2.5) + OAC (INR 2-3)

90 ± 7 Days90 ± 7 Days

5 days 7.5 mg fondaparinux5 days 7.5 mg fondaparinux** sc + OAC (INR 2-3) sc + OAC (INR 2-3)

2200 patients 2200 patients with PE with PE ++ DVT DVT

Open-LabelOpen-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-blindDouble-blind2200 patients 2200 patients with DVTwith 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

AT

I S SE

M ... . . .

.

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 %)

-0.15 %

= 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 %)

AT

I S SE

M ... . . .

. Primary efficacy outcome – 3 months -Primary efficacy outcome – 3 months -

Matisse DVT

Fondaparinux

LMWH 1.2%

1.1%

3.0%

2.6%

0% 2% 4% 6% 8%

Major Bleeding Non-major Bleeding

3.7 %

4.2 %

Principal Safety Outcome

- initial treatment -

Fondaparinux

UFH

Matisse PE

1.1%

1.3%

5.2%

3.2%

0% 2% 4% 6% 8%

4.5 %

6.3 %

AT

I S SE

M ... . . .

.

Major bleed Clinically relevant non-major bleed

Matisse DVT

Fondaparinux

LMWH

1.7%

0.9%

0.8%

2.2%

0.5%

0.6%

0% 2% 4% 6%

3.8 %

3.0 %

Mortality- 3 months -

Fondaparinux

UFH

Matisse PE

2.0%

2.6%

1.5%

1.6%

0.9%

1.1%

0% 2% 4% 6%

5.2 %

4.4 %

AT

I S SE

M ... . . .

.

Cancer VTE/bleeding Other



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


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

PENTALYSE: hypothesis for Pentasaccharide

Prolonged co-administration with alteplase Prolonged co-administration with alteplase in AMI could:in AMI could:

Prevent reocclusionPrevent reocclusion of the infarct-related of the infarct-related artery, whileartery, while

Producing Producing similar rates of early coronary similar rates of early coronary artery artery revascularizationrevascularization as compared to a as compared to a standard regimen of standard regimen of alteplase with alteplase with unfractionated heparinunfractionated heparin..

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

TIMI 3 TIMI 0, 1

P=.065 P=.091

TIMI 2, 3 TIMI 0, 1

Reocclusion rates on daysReocclusion rates on days 5 5 to to 7 7 in patients with in patients with ΤΙΜΙ ΤΙΜΙ grade grade 3 3 flow or flow or ΤΙΜΙ 2, 3ΤΙΜΙ 2, 3 flow at flow at 90 90 min who did not undergo a coronary intervention min who did not undergo a coronary intervention and were treated per protocol.and were treated per protocol.

Eur Heart J 200Eur Heart J 20011;22:1716-1724;22:1716-1724

PENTALYSE:PENTALYSE: AlteplaseAlteplase + + PentasaccharidePentasaccharide / / Heparin Heparin in STEMIin STEMI

PENTALYSE:PENTALYSE: AlteplaseAlteplase + + PentasaccharidePentasaccharide / / Heparin Heparin in STEMIin STEMI

7.0%

0.9%

8.0%

2.3%

0

5

10

Heparin

Pentas.

% patients

Study design

Unstable anginaNon-Q wave MI

ST or Trop +

Unstable anginaNon-Q wave MI

ST or Trop +

enoxaparin 1 mg/kg bidenoxaparin 1 mg/kg bid

2.5 mg fondaparinux 2.5 mg fondaparinux

4 mg fondaparinux4 mg fondaparinux



Ra

nd

om

iza

tio

nR

an

do

miz

ati

on

Treatment 3-7 daysTreatment 3-7 days

Day 9Day 9

48 h ECG

Endpoint evaluationEndpoint evaluation

Day 30Day 30

Efficacy endpoint: Death + AMI + a-/symptomatic recurrent ischemia until day 9

Safety endpoint: Major bleeding until day 9

Pentua

Primary Efficacy Endpoint (Day 9)

30,0

43,541,0

34,8

40,2

0

10

20

30

40

50

2.5 mg 4 mg 8 mg 12 mg enoxfondaparinux

Inci

den

ce (

%)

n=61 n=77 n=71 n=65 n=76

P < 0.05

Clinical Endpoint (Day 9)

Death, AMI or Sympt. Rec. Ischemia

12,9

21,1

18,0

15,1

18,4

0

5

10

15

20

25

2.5 mg 4 mg 8 mg 12 mg enoxFondaparinux

Inci

den

ce

(%

)

P = 0.03

210 185 183 199 206

Major Major and/or Minor

fondaparinux fondaparinux

Patients with Bleeding Event (Day 9)

0,0

1,41,8

0,40,0

3,9

5,4 5,4

4,6 4,8

0

2

4

6

8

2.5mg 4mg 8mg 12mg enox 2.5mg 4mg 8mg 12mg enox

Inci

den

ce (

%)

ASPIREA randomized blinded pilot trial of fondaparinux sodium vs. UFH in addition

to standard therapy in a broad range of pts undergoing PCIPrimary 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 80-325 mg o.d. p.o. + clopidogrel 75 mg o.d. p.o. continued 4 weeks

Stratum 1with GPIIb/IIIa

N=300

Stratum 2without GPIIb/IIIa

Fondaparinux 2.5 mg IV


UFH 100 IU/kg IV

0 48

R

R



UFH 100 IU/kg IV

Single injection of study drug

MICHELANGELO - UA/NSTEMIDouble 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.

Rn=16,000

1 2 3 4 5 6 7 8 9

1 2 3 4 5 6 7 8 9

Primary Efficacy• Death• MI• Refractory ischemia

Daily administration

or until hospital discharge

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)

1 2 3 4 5 6 7 8

*Daily administration

or until hospital

discharge

1 2 3 4 5 6 7 8 9

Stratum 1

“UFH not indicated”

Stratum 2

“UFH indicated”

1 2 3 4 5 6 7 8

1 2 3 4 5 6 7 8 9

9

9

Primary Efficacy• Death• Recurrent MI (STEMI)

PentasaccharidesPentasaccharidestailor madetailor made

O O

O O

O O

O

OH

OH

COO-

O

OSO3-

OH

HNSO3-

HO O

O

OSO3-

OSO3-

HNSO3-

O

O

OH

OSO3-

COO-

O

OSO3-

OSO3-

HNSO3-

O

O

OH

OSO3-

COO-

OOSO3

-

OSO3-

OCH3

HNSO3-

O

OH

OH

COO-

O

OSO3-

OH

HNSO3-

HO O

O

OCH3

OCH3

COO-

O

OSO3-

OCH3

OSO3-

H3CO O

O

OSO3-

OSO3-

OSO3-

O

O

OCH3

OSO3-

COO-

OOSO3

-

OSO3-

OCH3

OSO3-

OOSO3

-

OHOCH3

HNSO3-

Fondaparinux (Fondaparinux (ArixtraArixtra® ® ))MOST LIKE NATURALMOST LIKE NATURALOnce-a-day (1987)Once-a-day (1987)

Org31550Org31550MORE POTENTMORE POTENTA new binding site discoveredA new binding site discovered

Idraparinux,Idraparinux, SanOrg34006 SanOrg34006 SIMPLIFIED (1992)SIMPLIFIED (1992)Once-a-weekOnce-a-week

OCH3OCH3

SanOrg 34006 (IDRAPARINUX): un SanOrg 34006 (IDRAPARINUX): un nuovo antitrombotico a lunga emivitanuovo antitrombotico a lunga emivita

OO

CHCH22OSOOSO

33--

OHOH

OO

OO

NHRNHR

COOCOO--

OHOH

OO

OO

OHOH

CHCH22OSOOSO

33--

OSOOSO33

--

OO

OO

NHSONHSO33

--

COCOOO--

OHOH

OO

OO

OSOOSO33

--

CHCH22OSOOSO

33--

OHOH

OO

OO

NHSONHSO33

--

R = -SOR = -SO33

--

oror

COCHCOCH33

ATIII-binding pentasaccharide sequenceATIII-binding pentasaccharide sequence

Emivita: 130 ore somministrazione 1 vv/settimana



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


PERSIST: Studio dose-finding con Idraparinux nella profilassi secondaria

della TVP

LMWH

Ra

nd

om

iza

tio

n

1-2 5-7 days

12 weeks

Screen Acute 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

0,0 1,5 0,0 1,6 3,8

25,728,6

52,6

2,5

0

10

20

30

40

50

60

2,5 5

7,5 10

VKA

Cochra

ne 2

001

Hull 1

979

Lager

sted

t 198

5

Barrit

t 196

0

Inci

den

ce (

%)

Idraparinux (mg)

STUDIO PERSIST: Profilo di efficaciaSTUDIO PERSIST: Profilo di efficacia

77 / 9 / 8 / 10 /2016 35 28 19

0 / 2 / 0 / 3 / 2 /125 128 118 119 124

Complicanze tromboemboliche sintomatiche

0,0

3,0

1,5

6,9

0,8

2,3

11,9

13,8

15,3

8,3

0

2

4

6

8

10

12

14

16

2,5 5 7,5 10 VKA 2,5 5 7,5 10 VKA

Inci

den

ce (

%)

Emorragie maggiori Tutte le emorragie

Idraparinux (mg) Idraparinux (mg)

STUDIO PERSIST: Profilo di tollerabilitàSTUDIO PERSIST: Profilo di tollerabilità

3 / 131 16 / 135 18 / 130 20 / 131 11 / 132 0 / 131 4 / 135 2 / 130 9 / 131 1 / 132

P=0.029

• 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

Van Gogh Studies

Treatment of:1. DVT 2. PE, as well as3. extended treatment beyond 6 months

Vitamin-K antagonistsAgainst theNon-Glycoaminoglycan Idraparinux on clinicalOutcomesGreatly relevant inHemodynamic stable VTE patients

Hep

+VKA VKA only, 26 wks

2.5 mg idraparinux, 26 wks

Study designPE (N=2,200)


(LMW)Heparin at least for a total of 5 days and INR >2 for two consecutive days

Any heparin 36 h before randomization

Hep

+VKAVKA only, 13 wksR

ando

miz

atio

n

DVT (N=2,200)

Hep

+VKA VKA only, 26 wks



Any heparin 36 h before randomization

Hep

+VKAVKA only, 13 wksR

ando

miz

atio

n

(LMW)Heparin at least for a total of 5 days and INR >2 for two consecutive days

Study design

Ran

dom

izat

ion

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 D

ay 1

83+7

Day

365

+7

• Dose finding study in DVT patients PERSIST

• Pharmacokinetic modelling

Rationale for dose selection in the van Gogh studies

Patients with AF, eligible for VKA

treatmentR

ando

miz

atio

n2.5 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

ComplexSimpleTreatment regimens

Antithrombotic Drugs

Few or none

Fixed (?body wt ?renal function)

Predictable

Reproducible

Reproducible

Targeted and specific

New

Variablesc or oral availability

FrequentLaboratory tests

VariableDose

VariableDynamics

VariableKinetics

ComplexAnticoagulant effect

Old

Documents

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