anticoagulants, old and inconvenient therapies? heparins standard heparin 1937parenteral, monitoring...
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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
Eriksson BI. Arch Int Med 2003PENTHIFRA-Plus
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
Eriksson BI. Arch Int Med 2003PENTHIFRA-Plus
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)
Eriksson BI. Arch Int Med 2003PENTHIFRA-Plus
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
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 ASPIRE/MICHELANGELO Profilassi sec TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH
Profilassi TE Fibrillazione atriale AMADEUS
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
The Rembrandt Investigators. Circulation 2000;102:2726–2731.
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
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
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
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 ASPIRE/MICHELANGELO Profilassi sec TEV Profilassi secondaria TVP PERSIST Terapia/Profilassi secondaria TEV TVP, embolia polmonare VAN GOGH
Profilassi TE Fibrillazione atriale AMADEUS
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
8 mg fondaparinux8 mg fondaparinux
12 mg fondaparinux12 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
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
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
Sviluppi del pentasaccarideSviluppi 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
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)
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
+VKAVKA only, 13 wksR
ando
miz
atio
n
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
+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