UPDATE DELLA PROFILASSI
ANTITROMBOTICA E MECCANICA
B. Cosmi
U.O. di Angiologia e Malattie della
Coagulazione
“Marino Golinelli”
Policlinico S. Orsola-Malpighi
Bologna
Evolution of Venous Thromboembolism Prophylaxis
•1940s Early mobilization
•1940s Heparin
•1950s Warfarin
•1960s Dextrans
•1970s Low-dose heparin (LDH)
•1980s Low Molecular Weight Heparins (LMWH)
•1990s Parenteral direct thrombin inhibitor (DTI)
•(hirudin)
•2002 Fondaparinux (Pentasaccharide)
•2008 Oral direct thrombin inhibitors
•???? Oral Factor Xa Inhibitors
• Profilassi del TEV nei paz. chirurgici con i
nuovi farmaci antitrombotici
• Profilassi meccanica
• Profilassi del TEV nel paz. medico
Obiettivi nello sviluppo di nuovi
anticoagulanti
• effetto dose risposta prevedibile
• assenza interazioni con cibo e farmaci
• possibilità di somministrazione a dosi
fisse senza monitoraggio di laboratorio
• semplificare terapia anticoagulante a
lungo termine
Stadi della ricerca clinica con i
nuovi anticoagulanti
• 1° stadio:
profilassi del tromboembolismo venoso in chirurgia
ortopedica maggiore
• 2° stadio:
terapia del tromboembolismo venoso
• 3° stadio :
sindromi coronariche acute e fibrillazione atriale
I nuovi farmaci
Anticoagulanti:
Indiretti (AT-mediati)
Diretti (anti IIa)
(anti Xa)
Fondaparinux
Idraparinux
Dabigatran
Rivaroxaban
Apixaban
PENTASACCHARIDES
Arixtra (fondaparinux)
(SanOrg34006)
idraparinux
Arixtra®
COONa
OSO3Na
OSO3Na
O
O
OH
OH
O
O
OSO3Na
O
COONa
OH
O
O
O
O
HO
OSO3Na
OH
NHSO3Na
NHSO3Na
OH
OMe
NHSO3Na
OSO3Na
SanOrg3 4006
• T1 /2 suitable to treat o/ week instea d of o/d
• More activity per mg administered
O SO 3 -
O Me
O S O 3-
C O O-
O
O
O
O S O 3-
O
O
O Me
10 Na+
O SO 3 -
O
O
C O OO Me
MeO
O Me
O Me
O S O 3-
O Me
O
O
O SO 3 -
O Me
O S O 3+
9N a
Fondaparinux :
The first of a new class of synthetic
selective inhibitors of factor Xa
•
•
•
•
•
•
•
Five saccharide units
Synthetic
Highly selective for AT3
Factor Xa inhibition
No binding with plasma proteins
No effect on platelet function
No thrombocytopenia
Meccanismo d’azione del Pentasaccaride
Fondaparinux
•
•
•
•
•
•
•
Molecular weight 1500 d
Rapid onset of action
Plasma half life 15-20 h
1 administration/day
Renal elimination
No monitoring
No specific antidote available, but the
effects are reversed by F. VIIa
EFFICACIA DEL FONDAPARINUX NELLA PROFILASSI DEL
TROMBOEMBOLISMO VENOSO IN CHIRURGIA ORTOPEDICA
Serious adverse events and
bleeding
From first injection to day 11 - All treated patients
Fondaparinux
Enoxaparin
NNH
Patients With
(N=3616)
(N=3621)
SAE
196 (5.4 %)
164 (4.5 %)
111
Fatal bleeding
0
1
Non-fatal bleeding in
critical organ
0
1
Bleeding leading
to re-operation
12 (0.33 %)
Bleeding with
transfusion ≥ 2 units
and/or hemoglobin
decrease ≥ 2g/dL
84 (2.3%)
52 (1.4 %)
111
109 (3.01%)
99 (2.73%)
357
Other Bleeding
9 (0.25 %)
125
Direct Thrombin Inhibition
Tissue
Factor
XII
XIIa
XI
XIa
VII
VIIa
IXa
IX
X
Xa
Factor II
Thrombin
(Prothrombin)
Lepirudin
Bivalirudin
Argatroban
Ximelagatran (oral)
Dabigatran (oral)
Fibrinogen
Fibrin
Ingelheim/Germany, 27 March 2008
Boehringer Ingelheim today
announced that the European
Commission has granted marketing
authorisation of the novel, oral
direct thrombin inhibitor,
Pradaxa® (dabigatran etexilate) in all
27 EU member states.
It is anticipated that Pradaxa® will
be launched in Germany and the
United Kingdom in the coming
weeks
Struttura del Dabigatran etexilate
Inibitore diretto della trombina, orale
Dabigatran etexilate versus enoxaparin for prevention of
venous thromboembolism after total hip replacement:
a randomised, double-blind, non-inferiority trial
Bengt I Eriksson BI et al RE-NOVATE
Lancet 2007; 370: 949–56
•
•
•
•
•
3494 patients
total-hip replacement were
Randomized
to one of two doses of dabigatran etexilate (220 mg
or 150 mg once daily) or enoxaparin (40 mg sc once
daily), given for one month.
The primary efficacy outcome was the composite of
total VTE (venographic or symptomatic) and death
from all causes during treatment.
RE-NOVATE: Major results
End point
Dabigatran
150 mg (%)
Dabigatran
220 mg (%)
Enoxaparin
40 mg (%)
Total VTE and 8.6
death from all
causes
6.0
6.7
Major
bleeding
2.0
1.6
1.3
Oral dabigatran etexilate vs. subcutaneous enoxaparin for
the prevention of venous thromboembolism after total knee
replacement: the RE-MODEL randomized trial.
Eriksson BI et al.
J Thromb Haemost. 2007 Nov;5(11):2175-7.
2076 patients
dabigatran etexilate, 150 mg or 220 mg once-daily, starting
with a half-dose 1-4 hours after surgery, or subcutaneous
enoxaparin 40 mg once-daily, starting the evening before
surgery, for 6-10 days.
Follow-up for 3 months
The primary efficacy outcome was a composite of total VTE
(venographic or symptomatic) and mortality during
treatment, and the primary safety outcome was the
incidence of bleeding events
Oral dabigatran etexilate vs. subcutaneous enoxaparin for
the prevention of venous thromboembolism after total knee
replacement: the RE-MODEL randomized trial.
Eriksson BI et al.
J Thromb Haemost. 2007 Nov;5(11):2175-7.
End point
Dabigatran
150 mg (%)
Total VTE,
40.5%
and all-cause
mortality
(primary end
point)
Major
1.3%
Bleeding
Dabigatran
220 mg (%)
Enoxaparin
40 mg (%)
36.4%
37.7%
1.5%
1.3%
“Dabigatran etexilate”
• Dose di
• 110 mg ( ½ cp) 1 - 4 h dopo chirurgia
• 220 mg/die
• 10 gg dopo protesi ginocchio
• 28-35 gg dopo protesi anca
• Se età > 75 aa o IRC moderata
• 150 mg
“Dabigatran etexilate”
• Studi in fase III (non-inferiorità verso TAO)
Re-COVER: TEV acuta, 5 gg LMWH poi
random. (doppio cieco) a Dab. (150 mg x 2) o
TAO x 6 mesi
Re-MEDY: prev. secondaria; dopo 3-6 m. di
TAO, random., cieco; Dab. (150 mg x 2) o
TAO x 18 mesi
Direct Factor Xa inhibition
XIIa
XIa
IXa
×
Xa
Factor II
(prothrombin)
Fibrinogen
Fibrin clot
Tissue
factor
VIIa
Rivaroxaban
Apixaban
DU-176b
YM150
LY517717
PRT-054021
Apixaban
• A highly potent, oral, direct FXa inhibitor (Ki 0.08 nM)
– Follow-up to razaxaban (development halted due to
bleeding concerns)
• Phase II study for VTE prevention after TKR: completed
– Double-blind; dose-ranging; three od and three bid
apixaban doses; comparator enoxaparin and warfarin;
target enrolment n=1202
• Phase II pilot study for VTE prevention in patients with
advanced metastatic cancer: ongoing
Struttura del Rivaroxaban
A Once-Daily, Oral, Direct Factor Xa Inhibitor,
Rivaroxaban (BAY 59-7939), for
Thromboprophylaxis After Total Hip Replacement
Eriksson et al. Circulation. 2006;114:2374-2381
Rivaroxaban bid (THR/TKR pooled):
Estimated incidence rate* (%)
40
DVT, PE, and all-cause mortality
Major bleeding
30
Efficacy: p=0.39
20
10
Safety: p<0.0001
0
0
5
10
20
30
40
50
60
Rivaroxaban (mg total daily dose)
*Estimated rates calculated by logistic regression adjusted for study, age, and gender
Enoxaparin
Rivaroxaban
• RECORD – REgulation of Coagulation in major
Orthopaedic surgery reducing the Risk of DVT
and PE
• Rivaroxaban 10 mg od will be compared with
enoxaparin in over 10,000 patients worldwide
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–
–
–
RECORD 1: THR, 5 weeks therapy
RECORD 2: THR, 5 weeks vs 10–14 days enoxaparin
RECORD 3: TKR, 10–14 days therapy
RECORD 4: TKR, 10–14 days therapy
Rivaroxaban
Rivaroxaban
Rivaroxaban
RECORD 3: Major safety end points
Outcome
Rivaroxaban
(%)
Enoxaparin
(%)
p
Major bleed
0.6
0.5
NS
Any bleed
4.9
4.8
NS
Lassen M et al. 2007 Congress of the International
Society on Thrombosis and Hemostasis; July 7-13,
2007; Geneva, Switzerland.
Nuovi anticoagulanti:
potenziali vantaggi
• Fondapar. Idrapar.
•
rapida azione; no controllo
no HIT
1 somm./die o 1/sett
Altri anti-Xa o anti-IIa
orali; no controllo
rapida azione
Nuovi anticoagulanti:
potenziali svantaggi
• No antidoti (eccetto SSR126517E)
• Difficile monitorare l’effetto (se
•
•
•
•
emorragia)
Non escludibili altri negativi effetti
Breve tempo di emivita
(vantaggi/svantaggi)
Difficile controllare la compliance
Costi
PROFILASSI MECCANICA
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Calze elastiche :
prevenzione distensione venosa con riduzione
stasi venosa nel polpaccio con miglioramento
ritorno venoso
CPI (compressione pneumatica intermittente; arto
o solo piede) con manicotti gonfiabil ad
intermittenza: solo paz. ospedalizzati
Stimolano e mantengono flusso pulsatile nel
circolo venoso profondo
CPI aumentano velocità flusso in v. femorale
comune dal 50 al 250% dei valori a riposo
ELASTIC COMPRESSION STOCKINGS FOR PREVENTION
OF DEEP VEIN THROMBOSIS
•
(Amaragiri SV, Lees TA, Cochrane Review,
Cochrane Library Issue 3, 2002)
Nove studi clinici randomizzati ( sia paz. Chirurgici
che medici)
CE da sole vs. controllo:
TVP 13% vs. 27%
RRR : 66%
•
Sette studi clinici randomizzati (paz. Chirurgici)
CE con altro metodo farmacologico:
TVP 2% vs. 15% RRR: 76%
• Nessuno studio ha incluso paz a basso rischio
• In associazione alla profilassi farmacologica se:
- sindrome varicosa
- insufficienza venosa cronica
- alto rischio
Intermittent pneumatic compression and deep vein
thrombosis prevention.
A meta-analysis in postoperative patients.
Urbankova et al. T& H, 2005; 2005 Dec;94(6):1181-5
RCT of IPC versus no prophylaxis,
2,270 patients in 15 eligible studies:
1,125 and 1,145 in the IPC and no prophylaxis
group, respectively.
The included studies formed a total of 16 treatment
groups and were conducted in orthopedic (5),
general surgical (4),oncologic (3), neurosurgical
(3) and urologic (1) patient populations.
In comparison to no prophylaxis,
IPC devices reduced the risk of DVT by 60%
(relative risk 0.40, 95% CI 0.29 - 0.56; p < 0.001).
• Foot pump livelli di compressione maggiori
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•
•
•
per aumentare flusso in v. femorale, più
efficaci se utilizzate in combinazione con CE
vs. CE sole
Pochi confronti tra i vari apparecchi
Non chiaro momento inizio e durata ottimali
Compliance del paz.
CPI > efficacia di CE in pz. A alto rischio in
combinazione con anticoagulanti o se
anticoagulanti controindicati
Efficacy outcomes during extended-duration enoxaparin
therapy in high-risk nonsurgical patients
End points
VTE events*
Symptomatic
VTE
Asymptomatic
VTE
Outcome,
extended
prophylaxis,
n=2052 (%)
2.8
0.3
Outcome,
placebo,
n=2062
(%)
4.9
1.1
RR
p
reduction
(%)
44
73
0.0011
0.0044
2.5
3.7
34
0.0319
*Primary efficacy end point: composite of asymptomatic DVT, symptomatic DVT,
symptomatic pulmonary embolism, or fatal pulmonary embolism. Asymptomatic DVT was
defined by compression ultrasonography, which was routinely performed.
VTE=venous thromboembolism
RR=relative risk
Hull RD et al. EXCLAIM 2007 Congress of the International Society on
Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
Safety outcomes during extended-duration randomized
therapy in high-risk nonsurgical patients
End point
Total bleeding
events*
Major bleeding
events
Minor bleeding
events
Extended
enoxaparin
prophylaxis,
n=2052 (%)
5.7
Placebo,
n=2062 (%)
p
3.8
0.007
0.6
0.15
0.019
5.2
3.7
0.024
*Primary safety end point
Hull RD et al. 2007 Congress of the International Society on
Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.