Treatment of Superficial Vein Thrombosis with
intermediate doses of Tinzaparin: Lessons learnt
from the SEVEN study
Athanasios D. Giannoukas MD, MSc(Lond.), PhD(Lond.), FEBVS
Professor of Vascular Surgery
Faculty of Medicine, School of Health Sciences, University of Thessalia, Greece
Chairman, Dept. of Vascular Surgery, University Hospital of Larissa
Larissa, Greece
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Conflict of Interest Disclosure Form
I have no potential conflict of interest to report
I have the following potential conflict(s) of interest to report:
Type of affiliation / financial interestName of commercial company
Receipt of grants/research supports: Leo, Sanofi, Bayer, Glaxo
Receipt of honoraria or consultation fees: Leo, Sanofi, Bayer, Servier
Participation in a company sponsored speaker’s bureau:
Bayer, Leo, Servier
Stock shareholder: -
Spouse/partner: -
Other support (please specify): -
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CALISTO study
The primary efficacy outcome (death from any cause orsymptomatic PE, symptomatic DVT, or symptomatic extensionto the saphenofemoral junction or symptomatic recurrence ofDVT at day 47) occurred in 0.9% of patients in thefondaparinux group and 5.9% in the placebo group (P < 0.001).The rate of PE or DVT was 85% lower in the fondaparinuxgroup. Similar risk reductions were observed at day 77. Nodifference was observed in major bleeding between the twogroups.
Decousus H et al. CALISTO Study Group. N Engl J Med 2010;363:1222–1232
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Goldman and Ginsberg. NEJM 2010;363:1278
Historical comparisons have shown extremely low mortality
among untreated pts with SVT, which support an initial “no
anticoagulation treatment” approach unless conservative
measures fail to resolve symptoms or DVT develops
Treatment with Fondaparinux for 45 days may be reasonable
in case of severe symptoms, thrombosis in the proximal
saphenous vein, or in recurrent disease
Cost-effectiveness issues
Therapy with Fondaparinux 2.5 mg daily for 45 days costs
$2,124 to $7,380
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ACCP GuidelinesFebruary 2012; 141(2_suppl)
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines6
Guidelines (From International Consensus)
All patients with STP should have bilateral duplex
scanning to exclude DVT (Grade 1b)
LMWH in intermediate doses for at least one month is
recommended (Grade 2a )
Fondaparinux 2.5 mg daily for at least 4 weeks is an
effective treatment (Grade 1b)
Surgery is not better than LMWHs (Grade 2b)
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SeVEN Study
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TITLE: «Superficial venous thrombosis: A
retrospective multicentre study of complications,
treatment and patient profile in Greece
Sponsored by Leo Pharma Hellas
Study design
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Multicenter, non-interventional observational study with
RETROSPECTIVE analysis of MEDICAL RECORDS
7 sites in Greece (adoption of similar approach in diagnosis and
treatment)
250 patients (statistical estimation for meaningful results)
The collection of data period of 16 months (Q4 2014 – Q4 2015)
Patient data was collected from hospital records for a period of 12
weeks after enrollment visit
Inclusion criteria
Outpatients ≥18 years old, with symptomatic superficial venous
thrombosis ≥5 cm, as confirmed by imaging methods.
Onset of symptoms within 10 days prior to treatment onset.
Patients treated with low molecular weight heparin (Tinzaparin 0.5
ml – 10,000 antiXa iu once daily) for at least 14 days, in accordance
with the recommendations of their physician.
Treatment could be extended according to the treating physician
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Exclusion criteria
Patient medical history of deep vein thrombosis and/or pulmonary
embolism within 6 months prior to study inclusion.
Presentation of superficial venous thrombosis due to sclerotherapy
or insertion of a venouscatheter within 1 month prior to study
inclusion or within 3cm of the SFJ or SPJ .
BMI > 35 kg/m2
Patients receiving medication that affect blood coagulation e.g.
acetylosalicylic acid, vitamin K antagonists, dextrane.
Significant surgical procedure within 3 months prior to study
inclusion.
Patients subjected to spinal or epidural anaesthesia within 48 hours
prior to study inclusion.
Patients who within the past month experienced cerebral bleeding,
trauma and/or recently underwent CNS surgery.12
FLOW CHART OF DATA COLLECTION
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AssessmentVisit 1 –
week 0
Visit 2 –
week 2
Visit 3 –
week 12
Inclusion/exclusion criteria X
Demographics: gender, age, height,
weightX
Medical history X
VTE episodes up to 6 mths prior to
current eventX
Co-morbidities X
Recent or chronic immobility X
VVs in X
SVT: onset of symptoms/diagnosis X
Previous treatment for SVT in the past
(>6 mths from current episode)X
Clinical examination X
Blood tests X
Lower limb colour Doppler X X
Treatment X X X
New episodes of SVT X X
Recording new episodes of VTE X X
Study Objectives
Primary end-point Recurrence of VTE or death within the study
period (12 weeks) in patients with superficial
venous thrombosis treated with Tinzaparin
(Tinzaparin 0.5 ml – 10,000 antiXa iu once
daily)
Secondary Objectives 1. The evaluation of treatment duration in respect
to the presentation of the primary end-point.
2. The evaluation of treatment safety (bleeding
complications etc).
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Time plan for data collection
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Notes: FSI, First Subject InLSI, Last Subject InLSO, Last Subject Out
2014 2015
Q1-Q2 Q3-Q4Q3 Q4 Q1-Q2
Study sites initiations and FSI
LSI: Q3 2015
Data collection period
DB lock:Q4 2015
2016
Q3-Q4
Publication: Q1 2016
Gender Male/ Female107 (36.1%) / 189
(63.9%)
Weight Mean (SD) 78.7 (13.1)
Height (cm) Mean (SD) 168.4 (9.0)
BMI UNKNOWN 23 (7.8%)
Normal 70 (23.6%)
Obese 203 (68.6%)
VTE EPISODES 79 (26.7%)
DVT 14 (4.8%)
PE 0 (0%)
Family history 2 (0.6%)
PTS 1 (0.4%)
SVT 74 (25%)
Co-morbidities 17 (5.7%)
Heart of respiratory failure 5 (1.6%)
Autoimune disease 10 (3.4%)
Soft tissue infection 2 (0.6%)
Chronic or recent immobility 96 (32.4%)
Hospitalisation 6 (2%)
Local trauma 7 (2.4%)
Sedentary habit 22 (7.4%)
Long-haul flight 7 (2.4%)
Bed-bound 16 (5.4%)
Long-standing 51 (17.2%)
VVs 240 (81%)
Previous treatment for SVT more
than 6 mnths from current event65 (22%)
Elastic/non-elastic
compression44 (14.8%)
Leg elevation 23 (7.8%)
Other (non pharmaceutical
treatment)6 (2%)
Local/P.O. Anti-
iflammatory drugs16 (5.4%)
Anticoagulants 42 (14.2%)
Anti-vitamin K 2 (0.6%)
Basic characteristics of the patients
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0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440
0
10
20
30
40
50
Perc
ent
thr
Length of thrombus at visit 1
19
Reasons for treatment
termination at visit 2
22
Symptoms relief 90
Patient’s decision 3
Treatment modification 1
Bleeding (minor) 2
Allergic reaction 1
Length of thrombus at visit 2 in
comparison at visit 1
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400
0
5
10
15
20
25
30
Perc
ent
thr
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440
0
10
20
30
40
50
Per
cent
thr
Visit 1
Visit 2
23
Type of treatment among patients with
continuing treatment after visit 2
24
Status
4
184
2
Αρ
ιθμ
ός α
σθ
ενώ
ν
0
20
40
60
80
100
120
140
160
180
200
Επίσκεψη 2
Ίδια δόση Άλλο σκεύασμα Μεγαλύτερη δόση
Nu
mb
er
of
pa
tie
nts
Visit 2
Same
regime &
dose
Other regime Same regime but
higher dose
Factors associated with
treatment continuation
Thrombosis at the above knee segment (p=0.002)
Reduced daily activity / mobilisation (p=0.005)
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After 3.5 months in follow-up 94.1% of patients were event free*
*Data censored at 3.5 months as per protocol procedures
VTE RECURRENCE
VTE recurrence during treatment
Γράφημα 1. Συχνότητα επεισοδίων
3
1 1
14
Συχνότη
τα ε
πει
σοδίω
ν
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
event_new1
Υποτροπή επιπολήςφλεβικής θρόμβωσης
Εν τω βάφει φλεβικήθρόμβωση
Επέκταση της φλεβικήςθρόμβωσης στη σαφηνομηριαία
συμβολή
Κλινικά μη-μείζονα αιμοραγία(κατά ISTH-Παράρτημα 2)
Average time to event= 47,9 days(min=1 day, max=120 days)
Αρ
ιθμ
ός
ασ
θεν
ών
SVT Recurrence DVT SVT extension to SFJ Minor bleeding (ISTH)
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5%
8%
0%
2%
4%
6%
8%
10%
Διέκοψαν Συνεχίσαν
VTE recurrence in relation to the
duration of treatment
Treatment termination at
visit 2
Treatment continuation after
visit 2
p=0.46
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Timing of VTE recurrence
N %
Weekly event distribution
2 11.11st
3rd 1 5.6
>4 wks 15 83.3
Total 18 100.0
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30
p-value=0.1442
*Data censored at 3.5 months as per protocol procedures
VTE recurrence in relation to presence of
VVs/vein reflux
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p-value=0.3350
*Data censored at 3.5 months as per protocol procedures
VTE recurrence in relation to history of
previous VTE events
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WeightTreatment duration
≤ 2 weeksp-value
≤70 36.5 0.5981
70-88 29.8
>88 32.9
Duration of treatment in relation to
body weight
Conclusions
Tinzaparin in intermediate dose (0.5 ml, 10.000 antiXa iu/daily) is
an effective and safe treatment for SVT
Most of the patients (64%) received longer duration treatment (36.9
days) but a considerable fraction of of patients (36%) required
short duration treatment (16.2 days)
Thrombus location (above knee) and not immediate full
mobilisation were factors associated with longer duration of
treatment
VTE recurrence was not related to the duration of treatment,
body weight and to the presence of venous reflux/ VVs in the
limb
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Future research
The findings of SEVEN study should be tested prospectively in a larger
size of patients
Not all patients require long treatment. Thus, identification of factors
that help determine those who need shorter duration of treatment is
important
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