Transcript 1210_Gillet_0195

Perseus study
TREATMENT OF ACUTE SUPERFICIAL VEIN THROMBOSIS
OF LOWER LIMBS IN VASCULAR MEDICINE IN FRANCE
JL Gillet1, MA Sevestre2, D Pouchain3, P Blin4,5
1. French Society of Phlebology, Bourgoin-Jallieu, France,
2. Department of Vascular Medicine, Amiens, France,
3. Department of General Practice, Tours, France,
4. Bordeaux PharmacoEpi, Bordeaux, France
5. Nukleus, Paris, France
American College of Phlebology’s 30th Annual Congress, Nov 3-6, 2016, Anaheim, CA
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CONFLICT OF INTEREST
• Study requested by the French Health Technology Assessment
agency (HAS) at the time of fondaparinux reimbursement
process in the superficial vein thrombosis (SVT) indication
• Study funded by the market authorization holder (first GSK and
then Aspen Pharmacare Holdings) and carried out by Nukleus,
an independent CRO
• The four authors received fees from the sponsor of the study
for their participation in the steering committee
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BACKGROUND
• SVT is a common condition, often associated with deep-vein thrombosis
(DVT) and pulmonary embolism, and with a significant risk of subsequent
DVT and pulmonary embolism (ACCP guidelines, CHEST 2012)
• SVT therapeutics have low-grade validation or even not validated, except
for fondaparinux that demonstrated its efficacy with the CALISTO study
• Fondaparinux approved in Europe (not in US) for the treatment of adults
with acute symptomatic spontaneous SVT of the lower limbs without
concomitant deep vein thrombosis (DVT), at a recommended dose of 2.5mg
once a day for between 30-45 days;
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OBJECTIVES
• To describe treatment pattern of patients with an isolated SVT
of the lower limbs
• To describe patients and SVT characteristics
• To estimate venous thromboembolism event (VTE) and major
bleeding incidence according to treatment prescribed at
inclusion
• To assess VTE prognostic factors
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METHODS (1)
• Observational cohort study designed to prospectively include
–
–
1,000 patients enrolled and followed-up for 3 months
by a non-selected sample of 200 vascular physicians during daily practice
• Patients inclusion criteria
–
Adult patients (≥ 18 years) vising for a symptomatic acute spontaneous isolated SVT of
the lower limbs, confirmed by compression ultrasonography
• Patients exclusion criteria
–
–
–
–
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Secondary SVT to sclerotherapy or venous catheter
Concomitant DVT or pulmonary embolism
Patients with anti-coagulant for another reason than SVT
Patients who refused to participate or who were participating in a clinical trial or who
could not be followed for 3 months
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METHODS (2)
• Main outcomes (confirmed by adjudication committee)
– VTE (SVT extension, SVT recurrence, DVT, pulmonary embolism)
– Major bleeding
• Statistical analysis according to the drug prescribed at inclusion
– Fondaparinux,
– Low molecular weight heparin or unfractionated heparin
(LMWH/NFH),
– Other anticoagulant,
– None (within 48 hours after inclusion)
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RESULTS: FLOW CHART OF THE STUDY
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RESULTS: DRUG PRESCRIBED AT INCLUSION
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n
% total
Fondaparinux (first dose)
Missing
2.5 mg
5 mg
7.5 mg
10 mg
735
4
574
9
145
3
75.2%
0,4%
58,7%
0,9%
14,8%
0,3%
LWMH / Heparin
Tinzaparin
Enoxaparin
Heparin
127
99
26
2
13.0%
10.1%
2.7%
0.2%
None (within 48 hours after inclusion)
88
9.0%
Other treatment
rivaroxaban
acetylsalicylic acid
fluindione
clopidogrel
28
17
8
2
1
2.9%
1.7%
0.8%
0.2%
0.1%
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RESULTS: FONDAPARINUX DOSE
2.5 mg
n = 574
> 2.5mg
n = 157
1.4%
12.5%
7.5%
57.1%
13.9%
7.5%
3.2%
37.6%
7.0%
31.8%
10.8%
9.6%
fondaparinux (treatment group)
<= 7 days
8 - 23 days
24 - 29 days
30 - 45 days
46-52 days
> 52 days
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RESULTS: PATIENT CHARACTERISTICS
Fondaparinux
LMWH/NFH
Other anticoagulants
None*
n = 735
n = 127
n = 28
n = 88
n
n
n
Gender
(%)
462 (62.9)
n
(%)
92 (72.4)
(%)
17 (60.7)
(%)
p*
57 (64.8)
ns
Age groups (years)
ns
< 50
144 (19.6)
21 (16.5)
7 (25.0)
27 (30.7)
50-69
318 (43.3)
60 (47.3)
8 (28.6)
28 (31.8)
≥ 70
273 (37.1)
46 (36.2)
13 (46.4)
33 (37.5)
184 (25.2)
31 (25,5)
8 (28.6)
18 (20.9)
ns
Varicose veins
641 (87.2)
110 (86.6)
16 (57.1)
76 (86.4)
< 0.001
SVT History
292 (39.7)
56 (44.1)
13 (46.4)
39 (44.3)
ns
DVT history
113 (15.4)
25 (19.7)
10 (35.7)
13 (14.8)
0.02
21 (2.9)
6 (4.7)
2 (7.1)
6 (6.8)
0.08
Body-mass index ≥ 30 kg/m2
VTE History
Pulmonary embolism history
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RESULTS: RISK FACTORS
Fondaparinux
LMWH/NFH
Other anticoagulants
None*
n = 735
n = 127
n = 28
n = 88
641 (87.2)
110 (86.6)
16 (57.1)
76 (86.4)
< 0.001
History of cancer
45 (6.1)
17 (13.4)
1 (3.6)
3 (3.4)
0.01
Active cancer
20 (2.7)
7 (5.5)
1 (3.6)
1 (1.1)
ns
Recent prolonged travel
(> 6 hours in car or in plane)
42 (5.7)
6 (4.7)
1 (3.6)
7 (8.0)
ns
Prolonged immobilization
31 (4.2)
8 (6.3)
2 (7.1)
4 (4.5)
ns
Recent major surgery
(< 3 months before inclusion)
15 (2.0)
10 (7.9)
1 (3.6)
0
(-)
0.002
2 (0.3)
8 (6.3)
0
(-)
4 (4,5)
<0.001
Oral contraceptive / hormonereplacement therapy
26 (3.5)
3 (2.4)
0
(-)
9 (10.2)
0.017
Known thrombophilia
16 (2.2)
3 (2.4)
3 (10.7)
1 (1.1)
0.07
Varicose veins
Pregnancy or post-partum
(< 3 months after delivery)
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RESULTS: SVT CHARACTERISTICS
Fondaparinux
LMWH/NFH
Other anticoagulants
None*
n = 735
n = 127
n = 28
n = 88
n
n
n
(%)
n
(%)
(%)
(%)
SVT in Varicose veins
622 (84.7)
103 (81.1)
15 (53.6)
73 (83.0)
<0.001
Bilateral Thrombus
100 (13.6)
11 (8.7)
4 (14.3)
6 (6.8)
ns
Length of the thrombus
Missing
<0.001
4
2
0
0
< 5 cm
100 (13.7)
17 (13.6)
6 (21.4)
38 (43.2)
5-9 cm
152 (20.8)
19 (15.2)
5 (17.9)
13 (14.8)
10-24 cm
306 (41.9)
50 (40.0)
9 (32.1)
24 (27.3)
≥ 25 cm
173 (23.7)
39 (31.2)
8 (28.6)
13 (14.7)
32 (4.9)
14 (13.0)
5 (19.2)
4 (5.4)
≤ 3 cm from the saphenofemoral junction
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P*
<0.001
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RESULTS: OTHER TREATMENTS PRESCRIBED
Fondaparinux
LMWH/NFH
Other anticoagulants
None*
n = 735
n = 127
n = 28
n = 88
Compression stockings
692 (94.1)
118 (92.9)
25 (89.3)
68 (77.3)
<0.001
Topical NSAIDs
193 (26.3)
42 (33.1)
7 (25.0)
41 (46.6)
<0.001
NSAIDs or COX-2 inhibitors
31 (4.2)
15 (11.8)
2 (7.1)
20 (22.7)
<0.001
Analgesic agents
71 (9.7)
12 (9.4)
4 (14.3)
7 (8.0)
ns
Other treatment at inclusion
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RESULTS: VTE THROUGHOUT THE STUDY
% [95%CI]
N
n
Fondaparinux
725
24
LMWH/H
127
7
5.5 [2.3-11.0]
Other anticoagulants
28
1
3.6 [0.1-18.3]
None
88
1
1.1
[0-6.2]
Fondaparinux
725
6
0.8
[0.3-1.8]
LMWH/H
127
3
2.4
[0.5-6.7]
Other anticoagulants
28
1
3.6 [0.1-18.3]
None
88
1
1.1
[0-6.2]
Fondaparinux
725
18
2.4
[1.5-3.8]
LMWH/H
127
4
3.1
[0.9-7.9]
Other anticoagulants
28
0
0
[0-12.3]
None
88
0
0
[0-4.1]
During the 3-month follow-up period
3.3
[2.1-4.8]
During first drug prescribed exposure
During post exposure period
0
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6
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10
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RESULTS: VTE THROUGHOUT THE STUDY
SVT
SVT
extension recurrence
VTE
DVT
N
n (%)
IC95%
n
n
n
Fondaparinux
725
24 (3.3)
[2.1-4.8]
10
14
5
LMWH & heparin
127
7 (5.5)
[2.3-11.0]
2
3
5
Other anti-coagulants
28
1 (3.6)
[0.1-18.3]
1
0
0
None (first 48 hours)
88
1 (1.1)
[0-6.2]
1
0
0
During the 3-month follow-up
During first drug prescribed exposure (+ 2 days)
Fondaparinux
725
6 (0.8)
[0.3-1.8]
3
2
1
LMWH & heparin
127
3 (2.4)
[0.5-6.7]
2
0
3
Other anti-coagulants
28
1 (3.6)
[0.1-18.3]
1
0
0
None (first 48 hours)
88
1 (1.1)
[0-6.2]
1
0
0
Fondaparinux
725
18 (2.4)
[1.5-3.8]
7
12
4
LMWH & heparin
127
4 (3.1)
[0.9-7.9]
0
3
2
Other anti-coagulants
28
0
[0-12.3]
0
0
0
None (first 48 hours)
88
0
[0-4.1]
0
0
0
During post exposure period
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VTE RISK FACTORS
• During treatment exposure
– Too low incidence to perform multivariable analysis
• During post exposure period
independent risk factors
– Thrombus ≤ 3 cm from the SF junction
– SVT history
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OR
95%CI
7.77
2.50
[2.43-24.8]
[1.03-6.05]
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OTHER MAJOR EVENTS
No pulmonary embolism, or major bleeding, or death
in any group throughout the study
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DISCUSSION
• Low overall VTE incidence
• VTE Incidence during treatment exposure
– Same magnitude than in the CALISTO study for fondaparinux (0.9% of
symptomatic VTE or death)
– Large confidence interval for other groups
• VTE Incidence during post exposure period
– Patients with SVT very close to the safenofemoral junction should be
treated as a DVT with a higher dose and possibly longer duration
– Some patients with SVT history could benefit from a longer duration of
treatment to avoid relapses some weeks after the end of treatment
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CONCLUSION
This real-world cohort study shows that fondaparinux is
now the first drug prescribed for SVT in France and
its benefit-risk for unselected patients in daily practice is
on the same magnitude than the CALISTO study
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