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UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA B. Cosmi U.O. di Angiologia e Malattie della...
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Transcript of UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA B. Cosmi U.O. di Angiologia e Malattie della...
UPDATE DELLA PROFILASSI ANTITROMBOTICA E MECCANICA
B. CosmiU.O. di Angiologia e Malattie della
Coagulazione“Marino Golinelli”
Policlinico S. Orsola-MalpighiBologna
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) Fondaparinux
IdraparinuxDiretti (anti IIa) Dabigatran
(anti Xa) RivaroxabanApixaban
PENTASACCHARIDESArixtra (fondaparinux) idraparinux (SanOrg34006)
O
C O O -
O M e
O MeO
O
OS O 3-
OS O 3-
OS O 3-O M e
OC O O -
O M e
O M e
O
OS O 3-
OS O 3-
OS O 3-
OO
O
O
OS O 3-
M eO
O M e
O M e
9 N a+
Arixtra®
SanOrg34006
• T1/2 suitable to treat o/week instead of o/d• More activity per mg administered
O
HO
OH
NHSO3Na
OSO3Na
O
COONa
OH
OH
O
OSO3Na
NHSO3Na
OSO3Na
O
OSO3Na
COONaOH
O
OH
NHSO3Na
OSO3Na
OMeOO
OO
10 Na+
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 DELTROMBOEMBOLISMO VENOSO IN CHIRURGIA ORTOPEDICA
From first injection to day 11 - All treated patients
Patients WithFondaparinux
(N=3616)Enoxaparin NNH
(N=3621)
SAE 196 (5.4 %) 164 (4.5 %) 111
Fatal bleeding 0 1
Non-fatal bleeding incritical organ
0 1
Bleeding leading to re-operation
12 (0.33 %)
Bleeding withtransfusion ≥ 2 unitsand/or hemoglobindecrease ≥ 2g/dL
84 (2.3%) 52 (1.4 %) 111
Other Bleeding109 (3.01%) 99 (2.73%) 357
Serious adverse events and bleeding
9 (0.25 %) 125
Factor IIFactor II(Prothrombin)(Prothrombin)
FibrinogenFibrinogen
XII VII
X
XIIX
Direct Thrombin Inhibition
XIIaXIIa
ThrombinThrombin
VIIaVIIaXIaXIa
FibrinFibrin
IXaIXa
XaXa
Tissue Tissue FactorFactor
LepirudinLepirudinBivalirudinBivalirudinArgatrobanArgatroban
Ximelagatran (oral)Ximelagatran (oral) Dabigatran (oral)Dabigatran (oral)
Struttura del Dabigatran etexilateInibitore diretto della trombina, orale
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
Dabigatran etexilate versus enoxaparin for prevention ofvenous thromboembolism after total hip replacement:
a randomised, double-blind, non-inferiority trialBengt 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 death from all causes
8.6 6.0 6.7
Major bleeding
1.3 2.0 1.6
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 (%)
Dabigatran 220 mg (%)
Enoxaparin 40 mg (%)
Total VTE, and all-cause mortality (primary end point)
Major
Bleeding
40.5%
1.3%
36.4%
1.5%
37.7%
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
VIIa
Xa
IXa
XIa
XIIa
Direct Factor Xa inhibition
Tissue factor
Fibrinogen Fibrin clot
Factor II(prothrombin)
RivaroxabanApixabanDU-176b
YM150LY517717
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 ReplacementEriksson et al. Circulation. 2006;114:2374-2381
Rivaroxaban bid (THR/TKR pooled):
*Estimated rates calculated by logistic regression adjusted for study, age, and gender
Efficacy: p=0.39
Safety: p<0.0001
0 10 20 30 40 50 60 Enoxaparin
0
10
20
30
40
DVT, PE, and all-cause mortalityMajor bleeding
Est
imat
ed in
cid
ence
rat
e* (
%)
Rivaroxaban (mg total daily dose)5
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– 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
Lassen M et al. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
Outcome Rivaroxaban (%)
Enoxaparin (%)
p
Major bleed 0.6 0.5 NS
Any bleed 4.9 4.8 NS
Nuovi anticoagulanti: potenziali vantaggi
• Fondapar. Idrapar.rapida azione; no controllono HIT1 somm./die o 1/sett
• Altri anti-Xa o anti-IIaorali; 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
• 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 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
Hull RD et al. EXCLAIM 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
Efficacy outcomes during extended-duration enoxaparin
therapy in high-risk nonsurgical patients End points Outcome,
extended prophylaxis, n=2052 (%)
Outcome, placebo, n=2062 (%)
RR reduction (%)
p
VTE events* 2.8 4.9 44 0.0011
Symptomatic VTE
0.3 1.1 73 0.0044
Asymptomatic VTE
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 thromboembolismRR=relative risk
Safety outcomes during extended-duration randomized
therapy in high-risk nonsurgical patients
Hull RD et al. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.
End point Extended enoxaparin prophylaxis, n=2052 (%)
Placebo, n=2062 (%)
p
Total bleeding events*
5.7 3.8 0.007
Major bleeding events
0.6 0.15 0.019
Minor bleeding events
5.2 3.7 0.024
*Primary safety end point