MALATTIE TROMBOEMBOLICHE
Daniela Tormene
Anatomic theatre, Padua University
Brandjes DPM, Heijboer H, Büller HR, et al.
Acenocoumarol and heparin
compared with acenocoumarol
alone in the initial treatment of
proximal-vein thrombosis
(A.T.H.O.S.)
N Engl J Med 1992
A.T.H.O.S. STUDY
Results
_______________________________________________
Sintrom
(N=60)
Hep. + Sintrom
(N=60)
_______________________________________________
Symptomatic VTE
Asympt. DVT extens.
Major bleeding
20%
39.6%
5.0%
6.7%
8.2%
3.0%
_______________________________________________
Different heparin dosage
regimens in venous thrombosis
___________________________________________________
Starting U/24 h
High
Low
Recurrent VTE
(%)
High
Low
___________________________________________________
Brandjes, 1992
Hull, 1986
Raschke, 1993
30,000
0
6.7
30,000 iv 30,000 sc 5.2
30,240
24,000
5.0
20.0
19.8
25.0
___________________________________________________
Heparin nomogram
(Cruikshank et al., 1991)
Bolus: 5000 U followed by 1280 U/h. First APTT after 6h
___________________________________________________
APTT
(sec)
< 50
50-59
60-85
89-95
96-120
> 120
Bolus
(U)
5,000
0
0
0
0
0
Hold
(min)
0
0
0
0
30
60
Rate change Rep. APTT
(U/h)
+ 120
6h
+ 120
6h
0
next morning
- 80
6h
- 80
6h
- 160
6h
Current Treatments for Patients
with Acute VTE
• Unfractionated or low-molecular-weight heparin
followed by 3–6 months of oral anticoagulant
therapy
• Thrombolytic treatment in selected patients with
critical PE
• Intracaval filter in selected patients with
contraindications to antithrombotic drugs
Buller HR et al. Chest 2004
Efficacy and safety of LMWH in
comparison to UFH
Effects of LMWH vs Unfractionated Heparin (UFH) in
the Treatment of Acute VTE
(22 studies, 8867 symptomatic patients)
Thrombus reduction
OR=0.69 (0.59-0.81)
Recurrent VTE
OR=0.68 (0.55–0.84)
Major bleeding
OR=0.57 (0.39–0.83)
Total mortality
OR=0.76 (0.62–0.92)
0.0
0.5
Favours LMWH
1.0
1.5
2.0
RR Favours UFH
Cochrane
Review System
2004
New Therapeutic Opportunities
•
•
•
•
•
•
Home treatment of DVT
Treatment of PE
HIT and Osteoporosis
Treatment of DVT in cancer patients
Treatment of SVT
The potential of new drugs
Home treatment of suitable patients with
DVT
Outpatient DVT treatment with LMWH
TASMAN and North-American studies
TASMAN
North-American
LMWH
UFH
LMWH
UFH
(n=202)
(n=198)
(n=247)
(n=253)
Recurrent VTE
14 (6.9%) 17 (8.6%) 13 (5.3%) 17 (6.7%)
Major bleeding
1 (0.5%)
Mortality
14 (6.9%) 16 (8.1%) 11 (4.4%) 17 (6.7%)
4 (2.0%)
5 (2.0%)
3 (1.2%)
Ambulatory treatment with LMWH
Author
Grau ‘98
Harrison ‘98
Mattiasson ‘98
Wells ‘98
Kovacs ‘00
Labas ‘01
Lapidus ‘02
Beer ’03
Wells ’05
LMWH
Nadroparin
Dalt/Tinzap
Dalteparin
Dalteparin
Dalteparin
Enoxaparin
Tinzaparin
Nadroparin
Daltep/Tinzap
Setting
DVT
DVT
DVT
DVT/PE
PE
DVT
DVT
PE
DVT/PE
Pts
39
89
240
184
108
96
332
104
505
Wells PS, Kovacs MJ, Bormanis J,
Forgie MA, Goudie D, Morrow B,
Kovacs J
Expanding eligibility for outpatient
treatment of deep venous thrombosis
and pulmonary embolism with lowmolecular-weight heparin
Arch Intern Med 1998
Study design
Prospective long-term evaluation of a
wide series of patients with a broad
spectrum of venous thromboembolic
presentations treated at home with
dalteparin (200 U/Kg every 24 hours)
for a minimum of 5 days
Patients treated at home
 Patients considered
 Patients excluded
- concomitant med. problems:
- massive pulmonary embolism
- cost considerations
- active bleeding
- phlegmasia coerulea dolens
 Patients treated on a home basis
233
39
20
6
6
4
3
194
Features of home treated patients
Characteristics
Homecare
(N=95)
Mean age
63.5 + 16
Proximal DVT
77
Pulmonary embolism
16
Arm DVT
2
Idiopathic
28
Cancer
32
Previous DVT
14
DVT due to risk factors
21
Self-injection
(N=99)
63.1 + 17
77
18
4
32
29
15
23
Prospective 3-month evaluation
of clinical outcomes
Events
Homecare
(N=95)
Self-injection
(N=99)
Recurrent VTE
Major bleeding
3 (3.2%)
2 (2.1%)
4 (4.0%)
2 (2.0%)
Mortality*
6 (6.3%)
8 (8.0%)
* due to cancer in 11 patients
Conclusions
More than 80% of patients with acute
venous thromboembolism can be
treated at home with a low-molecularweight heparin
Patients can safely and effectively
perform self-injection of the
anticoagulant drug
Treatment of Pulmonary
Embolism
NEJM 1997: COLUMBUS and
THESEE studies. Main results
COLUMBUS
THESEE
LMWH
UFH
LMWH
UFH
(n=510)
(n=511)
(n=304)
(n=308)
Recurrent VTE
27 (5.3%) 25 (4.9%)
5 (1.6%)
6 (1.9%)
Major bleeding
16 (3.1%) 12 (2.3%)
6 (2.0%)
8 (2.6%)
Mortality
36 (7.1%) 39 (7.6%)
12 (3.9%) 14 (4.5%)
Low-molecular-weight heparin compared
with intravenous unfractionated heparin for
treatment of pulmonary embolism: a metaanalysis of randomized, controlled trials
Quinlan DJ, McQuillan A, Eikelboom JW
Ann Intern Med 2004; 140: 175-83
Recurrent VTE in patients with symptomatic PE
Short- and Long-term Outcome of
Patients with PE
Konstantinides S et al. Circulation 1997;96:882–8
Goldhaber SZ et al. Lancet 1999;353:1386–9
Ribeiro A et al. Circulation 1999;10:1325–30
Grifoni S et al. Circulation 2000;101:2817–22
Pengo V et al. N Engl J Med 2004; 350: 2257-64
Heparin Plus Alteplase
Compared with Heparin Alone
in Patients with Submassive
Pulmonary Embolism
• Konstantinides S, Geibel A, Heusel G,
Heinrich F, Kasper W
Konstantinides S et al. N Engl J Med 2002;347:1143–50
Probability of event-free survival (%)
Cumulative Probability
of Event-free Survival
100
UFH plus alteplase (n=118)
90
80
70
UFH alone (n=137)
Event = in-hospital death or clinical deterioration
requiring an escalation of treatment
5
10
15
Days
20
25
30
Konstantidines S et al. N Engl J Med 2002;347:1143–50
HIT and Osteoporosis
Reduction of HIT and osteoporosis?
• Likely but not conclusively demonstrated
• At least in medical patients, the rate of LMWHrelated HIT is not negligible (0.80%, Prandoni et
al, Blood 2005)
• In patients requiring the long-term administration
of heparin, the use of UFH is associated with a
higher rate of bone fractures than LMWH
(Monreal et al, Thromb Haemost 1994)
Potential benefit of LMWHs on
survival in cancer patients
Generation of the hypothesis
(Prandoni et al, Lancet 1992)
LMWH
(n=85)
UFH
(n=85)
6-month mortality
5 (5.9%)
9 (10.6%)
Cancer-related mortality
1/15 (6.7%)
8/18 (44.4%)
… although this is a post-hoc finding, it is
interesting that 44% of the cancer patients in
the standard heparin group died, compared
with only 7% of cancer patients in the LMWH
group. This difference is statistically unusual
(p=0.021) if these treatments had no effect on
the likelihood of succumbing to cancer …
Prandoni et al, Lancet 1992
Meta-analyses of DVT treatment studies
Author
Year
No. of
studies
Cancer mortality
UFH
LMWH
OR
Green
1992
2
7/62 (11%)
21/67 (31%)
0.28
Siragusa
1995
13
10/74 (14%)
23/81 (28%)
0.39
Hettiarachchi
1999
9
47/306 (15%)
71/323 (22%)
0.61
Gould
1999
11
22/132 (17%)
38/147 (26%)
0.57
Clinical trials addressing the value of
LMWH on cancer survival
• FAMOUS (J Clin Oncol 2004)
• MALT (J Clin Oncol 2005)
• CLOT 2 (J Clin Oncol 2005)
• TURKISH STUDY (J Thromb Haemost 2004)
Persisting indications for UFH in the
treatment of patients with VTE
• Renal insufficiency
• Relative contraindications to heparin
• Suspicion of PE in patients with critical
presentation
The Potential of New Drugs
Pentasaccharides
Factor Xa, the
only target
Pentasaccharide
Arg
Lys
AT
Arg
Factor Xa
Fondaparinux in Comparison
to (Low Molecular Weight)
Heparin for the Initial Treatment
of Patients with Symptomatic
Deep Venous Thrombosis or
Pulmonary Embolism
T.
A.
M .
I. S. S
.
E.
• The Matisse studies
The Matisse Investigators. Blood 2002;100:A302
I. S. S.
T.
A.
E.
M.
Matisse: Primary Efficacy
Outcome at 3 Months
Matisse PE
Fondaparinux (n=1103)
UFH (n=1110)
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%)
-3.0%
-1.2%
 = 3.5%
0 0.5%
Fondaparinux - UFH (95% CI )
Matisse DVT
Fondaparinux (n=1098)
Fatal PE
LMWH (n=1107)
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%)
-1.8%
0
-0.15 %
1.5%
 = 3.5%
Fondaparinux - LMWH (95% CI )
The Matisse Investigators. Blood 2002;100:A302
I. S. S.
T.
A.
E.
M.
Matisse: Principal Safety
Outcome: Initial Treatment
Matisse PE
Fondaparinux
UFH
1.3%
1.1%
0%
2%
LMWH
1.1%
4%
6%
8%
Clinically relevant non-major bleed
3.7%
2.6%
1.2%
0%
6.3%
5.2%
Major bleed
Matisse DVT
Fondaparinux
4.5%
3.2%
4.2%
3.0%
2%
Major Bleeding
4%
6%
8%
Non-major Bleeding
The Matisse Investigators. Blood 2002;100:A302
Pentasaccharides
tailor made
OSO3
O
(Arixtra®
Fondaparinux
MOST LIKE NATURAL
Once-a-day
)
Org31550
MORE POTENT
A new binding site discovered
-
OH
OSO3
O
O
OH
O
HO
HNSO3
OSO3
O
-
-
OH
COO
-
O
HO
OSO3
O
OCH3
-
-
OH
COO
-
OSO
OCH3 3
OSO3
O
OCH3
OSO3
-
OSO3
O
O
O
OCH3
-
OSO3
-
HNSO3
-
COO
OH
-
-
OSO3
O
O
O
O
OSO3
-
OSO3
-
-
-
-
HNSO3
-
O
OSO3
-
OCH3
-
-
-
OH
O
OSO3
O
O
O
-
HNSO3
-
OCH3
COO
OH
OSO3
O
O
OH
OSO3
-
HNSO3
O
OH
H3CO
-
O
HNSO3
Idraparinux, SanOrg34006
SIMPLIFIED
Once-a-week
COO
COO
OCH3
OSO3
O
O
O
OSO3
-
-
-
OCH3
-
OSO
OCH33
OSO3
-
PERSIST: Thrombotic Burden:
Deterioration (ITT Population)
Asymptomatic + symptomatic VTE + unexplained death
Incidence (%)
15
Overall dose trend P=0.062
12.6
3/119
10
6.3
4.8
2/128
2.5 mg
5 mg
5
7.3
6.8
2/124
0
7.5 mg
10 mg
Warfarin
Idraparinux
ITT = intent to treat
Persist Investigators. Blood 2002;100:A301
PERSIST: Bleeding Events
Any bleeding
Incidence (%)
Major bleeding
16
14
12
10
8
6
4
2
0
5
2.
15.3
13.8
11.9
8.3
6.9
3.0
1.5
0.0
g
m
2.3
5
g
m
5
7.
g
m
Idraparinux
10
0.8
m
g
W
f
ar
in
r
a
5
2.
g
m
5
g
m
5
7.
g
m
10
m
g
W
in
r
fa
r
a
Idraparinux
Persist Investigators. Blood 2002;100:A301
IDRAPARINUX IN THE TREATMENT OF VTE
Phase III studies
VAN GOGH DVT
VAN GOGH PE
IDR VS ENOXAPARIN OR UFH FOLLOWED BY VKA
Conclusions
• Home treatment of DVT with LMWH is feasible, safe and
cost-effective for selected patients
• Patients with acute PE and right-ventricular dysfunction
might benefit from a combination of heparin and
thrombolytic drugs to a greater extent than from heparin
alone
• LMWH is more effective than oral anticoagulants for
prevention of recurrent VTE in cancer patients
• Among the categories of emerging new compounds, for
the time being only fondaparinux is an alternative to
conventional anticoagulation, but can only be used for the
initial VTE treatment
VTE treatment: study designs
RE-COVER I1
RE-COVER II2
EINSTEIN-DVT3
EINSTEIN-PE4
AMPLIFY5
Hokusai-VTE6
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Study design*
Double-blind
Open-label
Double-blind
Double-blind
Prerandomization
heparin
NR
<48 hrs
<36 hrs
<48 hrs
Heparin lead-in
At least 5 days
None
None
At least 5 days
150 mg BID
15 mg BID x 3
wk then 20 mg
QD
10 mg BID x 7 d
then 5 mg BID
60 mg QD
30 mg QD†
Dose reduction
NONE
NONE
NONE
18%
Randomized
population
2,5641
2,5682
3,4493
4,8334
5,400
8,292
6 months
Pre-specified
3, 6, 12 months
6 months
Flexible
3 to 12 months
Study drug
Dose
Treatment
duration
*Comparator was warfarin in each case
†Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteria
NR=not reported
1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Blood 2011;118:Abstract 205
3. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
5. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 6. The Hokusai-VTE Investigators. N Engl J Med 2013