Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
La Profilassi del
Tromboembolismo Venoso
Davide Imberti
U.O. Medicina Interna - Centro Emostasi e Trombosi
Ospedale di Piacenza
Patients Undergoing Major Orthopedic Surgery:
Total Hip Arthroplasty (THA), Total Knee Arthroplasty
(TKA)
2.1.1. In patients undergoing total hip arthroplasty
(THA) or total knee arthroplasty (TKA), we recommend
use of one of the following for a minimum of 10 to 14
days rather than no antithrombotic prophylaxis: lowmolecular-weight heparin (LMWH), fondaparinux,
apixaban, dabigatran, rivaroxaban, low-dose
unfractionated heparin (LDUH), adjusted-dose vitamin K
antagonist (VKA), aspirin (all Grade 1B), or an
intermittent pneumatic compression device (IPCD)
(Grade 1C).
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
Patients Undergoing Major Orthopedic Surgery:
Total Hip Arthroplasty (THA), Total Knee Arthroplasty
(TKA)
2.3.1. In patients undergoing THA or TKA, irrespective of the
concomitant use of an IPCD or length of treatment, we suggest
the use of LMWH in preference to the other agents we have
recommended as alternatives: fondaparinux, apixaban,
dabigatran, rivaroxaban, LDUH (all Grade 2B), adjusted-dose
VKA, or aspirin (all Grade 2C).
2.7. In patients undergoing major orthopedic surgery and who
decline or are uncooperative with injections or an IPCD, we
recommend using apixaban or dabigatran (alternatively
rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are
unavailable) rather than alternative forms of prophylaxis (all
Grade 1B).
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
Patients Undergoing Major Orthopedic Surgery:
Total Hip Arthroplasty (THA), Total Knee Arthroplasty
(TKA)
Remarks:
Limitations of alternative agents include the possibility of
increased bleeding (which may occur with fondaparinux,
rivaroxaban, and VKA), possible decreased efficacy (LDUH,
VKA, aspirin, and IPCD alone), and lack of long-term safety
data (apixaban, dabigatran, and rivaroxaban).
Furthermore, patients who place a high value on avoiding
bleeding complications and a low value on its inconvenience
are likely to choose an IPCD over the drug options.
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
Patients Undergoing Major Orthopedic Surgery:
Hip Fracture Surgery (HFS)
2.1.2. In patients undergoing hip fracture surgery
(HFS), we recommend use of one of the following rather than
no antithrombotic prophylaxis for a minimum of 10 to 14 days:
LMWH, fondaparinux, LDUH, adjusted-dose VKA, aspirin (all
Grade 1B) , or an IPCD (Grade 1C).
2.3.2. In patients undergoing HFS, irrespective of the
concomitant use of an IPCD or length of treatment, we suggest
the use of LMWH in preference to the other agents we have
recommended as alternatives: fondaparinux, LDUH (Grade 2B),
adjusted-dose VKA, or aspirin (all Grade 2C).
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
Isolated Lower-Leg Injuries
Distal to the Knee
3.0. We suggest no prophylaxis rather
than pharmacologic thromboprophylaxis
in patients with isolated lower-leg
injuries requiring leg immobilization
(Grade 2C).
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
Knee Arthroscopy
4.0. For patients undergoing knee
arthroscopy without a history of prior VTE,
we suggest no thromboprophylaxis rather
than prophylaxis (Grade 2B).
Pavia Spring Meeting on Thrombosis
21-22 Giugno 2012
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
Fondaparinux vs Enoxaparina nella prevenzione del
TEV in Chirurgia Ortopedica Maggiore
Complicanze emorragiche maggiori
Fondaparinux
migliore
Fondaparinux
Enoxaparina
Chirurgia maggiore
dell’anca
47/1140 (4.1%)
32/1133 (2.8%)
Chirurgia maggiore
dell’anca
20/1128 (1.8%)
11/1129 (1.0%)
Frattura dell’anca
18/831 (2.2%)
19/842 (2.3%)
Chirurgia maggiore
del ginocchio
11/517 (2.1%)
1/517 (0.2%)
Dati riuniti
96/3616 (2.7%)
63/3621 (1.7%)
Enoxaparina
migliore
1.54 (1.11- 2.16)
Odds Ratio (95% CI)
Bounameaux, Lancet, 2002
Fondaparinux: profilo di tollerabilita’
sovrapponibile ad enoxaparina nella profilassi
del TEV in chirurgia ortopedica maggiore
Fondaparinux
Studi di Fase III
(N=3616) N (%)
Enoxaparina
Studi 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)
48 (1.3)
52 (1.4)
Sanguinamento
PERIODO DI TRATTAMENTO (fino a 11 giorni)
PERIODO DELLO STUDIO (fino a 49 giorni)
Morte per qualsiasi causa
* 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
Efficacy: total VTE *
RRR 49%
20
rivaroxaban
enoxaparin
Incidence of total VTE %
16
P<0.001
P<0.001
P<0.0001
12
P=0.012
RRR 31%
RRR 79%
8
RRR 70%
4
0
RECORD1
RECORD2
RECORD3
RECORD4
RRR 54%; P< 0.00001
* Any DVT, non fatal PE, death from any cause
Imberti, Int Emerg Med, 2009
Rivaroxaban for the prevention of VTE
after hip and knee arthroplasty
Pooled analysis of four studies
Day 12±2 active
treatment pool
Day 1
Hip
Hip
Knee
Knee
Total treatment
duration pool
Day 12
(10–14)
Total study
duration
pool
Day 35
(31–39)
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Rivaroxaban
Enoxaparin
Placebo
Follow-up
Follow-up
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Rivaroxaban
Enoxaparin
Follow-up
Follow-up
Day 12
(10–14)
Follow-up
Day 65
(61–65)
Follow-up
Day 42
(42–47)
Turpie, Thromb Haemost, 2011
Primary efficacy outcome
Day 12±2 active treatment pool
Symptomatic VTE + all-cause mortality
2.0
Incidence (%)
52% reduction
1.5
HR=0.48 (95% CI: 0.31–0.75)
p=0.001
1.0
1.0%
0.5
0.5%
0
Enoxaparin
regimens
Rivaroxaban
regimens
60/6,200
29/6,183
Homogeneity test, p=0.431; safety population, n=12,383
Turpie, Thromb Haemost, 2011
Treatment-emergent* bleeding
Day 12±2 active treatment pool
n (%)
Major bleeding
Major bleeding
including
surgical site
Any clinically-relevant
non-major bleeding
Major + clinically
relevant
non-major bleeding
Any bleeding
Enoxaparin
regimens
(n=6,200)
13 (0.21)
Rivaroxaban
regimens
(n=6,183)
21 (0.34)
84
(1.35)
108
(1.75)
0.082
139
(2.24)
159
(2.57)
0.249
152
(2.45)
176†
(2.85)
0.186
384
(6.19)
409
(6.61)
0.376
0.175
Follow-up
Rivaroxaban
Enoxaparin
p-value#
Placebo
Follow-up
Follow-up
Active treatment
Day 12±2
*After first intake of study medication up to 2 days after last dose of study medication
#Analyzed using a Cox regression model;
†Patients may have had more than one type of event; safety population, n=12,383
Turpie, Thromb Haemost, 2011
Treatment-emergent bleeding
Total treatment duration pool
n (%)
Major bleeding
Major bleeding including
surgical site
Any clinically relevant
non-major bleeding
Major + clinically
relevant
non-major bleeding
Any bleeding
Enoxaparin
regimens
(n=6,200)
13 (0.21)
Rivaroxaban
regimens
(n=6,183)
24 (0.39)
p-value#
0.076
85
(1.37)
111
(1.80)
0.063
145
(2.34)
177
(2.86)
0.076
158
(2.55)
197†
(3.19)
0.039
401
(6.47)
434
(7.02)
0.255
Treatment duration
Rivaroxaban
Follow-up
Enoxaparin
Placebo
Follow-up
Follow-up
Active
treatment
#Analyzed
†Patients
using a Cox regression model
may have had more than one type of event; safety population, n=12,383
Turpie, Thromb Haemost, 2011
NOACs in management on thromboembolism
in orthopedics surgery
*
P< 0.00001
* Total VTE and all-cause mortality
** Symptomatic DVT: RR 0.41; 95% CI, 0.18-0-95)
Eriksson, Ann Rev Med, 2011
NOACs in management on thromboembolism
in orthopedics surgery
*
P=0.21
* Major bleeding
Eriksson, Ann Rev Med, 2011
PENTHIFRA : fondaparinux nella profilassi
del TEV nella chirurgia per frattura d’anca
p=2.6x10-8
TEV (%)
RRR: 56.4%
30
19.1%
20
10
8.3%
119/624
52/626
0
Fondaparinux
Enoxaparina
TEV: tromboembolismo venoso; RRR: riduzione relativa del rischio a favore di fondaparinux
Eriksson, N Engl J Med, 2001
Fondaparinux vs Enoxaparina nella prevenzione del
TEV in Chirurgia Ortopedica Maggiore
Complicanze emorragiche maggiori
Fondaparinux
migliore
Fondaparinux
Enoxaparina
Chirurgia maggiore
dell’anca
47/1140 (4.1%)
32/1133 (2.8%)
Chirurgia maggiore
dell’anca
20/1128 (1.8%)
11/1129 (1.0%)
Frattura dell’anca
18/831 (2.2%)
19/842 (2.3%)
Chirurgia maggiore
del ginocchio
11/517 (2.1%)
1/517 (0.2%)
Dati riuniti
96/3616 (2.7%)
63/3621 (1.7%)
Enoxaparina
migliore
1.54 (1.11- 2.16)
Odds Ratio (95% CI)
Bounameaux, Lancet, 2002
Deep vein thrombosis after knee
arthroscopy: a meta-analysis
• Sei studi prospettici relativi alla incidenza di TVP in assenza di profilassi
• 684 pazienti in totale
Autore
N
Diagnosi
62
US
4.8%
0
Demers
184
Flebo
18%
4.9%
Durica
161
Flebo
3.1%
1.2%
Delis
102
US
7.8%
0
Wirth
111
US
4.5%
0
Michot
64
US
15.6%
0
Williams
TVP tot TVP prox
Incidenza di TVP totale 9.9 % (95% CI 8.1%-11.7%),
prossimale 2.1 % (95% CI 1.2%-3%)
Ilahi, Arthroscopy, 2005
Efficacia e sicurezza della profilassi del TEV
in artroscopia di ginocchio
Calza elastica
(660)
EBPM
7 gg. (657)
EBPM
14 gg. (444)
p
End point
primario*
21 (3,2%)
6 (0,9%)
4 (0,9%)
0,005
End point
secondario**
31 (4,7%)
12 (1,8%)
11 (2,5%)
0,005
2 (0,3%)
6 (0,9%)
2 (0,5%)
n.s.
Emorragia
maggiore o
rilevante
* Incidenza cumulativa di TVP prossimale asintomatica, TEV sintomatico e morte a 3 mesi
** end point primario + incidenza cumulativa di TVP distale asintomatica a 3 mesi
Camporese, Ann Intern Med, 2008
LMHW for prevention of VTE in patients
with lower-leg immobilization
Testroote, Cochrane Review, 2009
LMHW for prevention of VTE in patients
with lower-leg immobilization
Testroote, Cochrane Review, 2009