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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 1

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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): -

2

2010;363:1222–1232

3

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

4

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

5

ACCP GuidelinesFebruary 2012; 141(2_suppl)

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical

Practice Guidelines6

7

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)

8

SeVEN Study

9

TITLE: «Superficial venous thrombosis: A

retrospective multicentre study of complications,

treatment and patient profile in Greece

Sponsored by Leo Pharma Hellas

Study design

10

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

11

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

13

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).

14

Time plan for data collection

15

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

16

Recruited patients in each center

17

Age of patients

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

18

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

Time interval between the visits

20

Duration of treatment: Continuation/termination

at visit 2

21

64%

36%

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)

25

26

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)

27

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

28

Timing of VTE recurrence

N %

Weekly event distribution

2 11.11st

3rd 1 5.6

>4 wks 15 83.3

Total 18 100.0

29

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

31

p-value=0.3350

*Data censored at 3.5 months as per protocol procedures

VTE recurrence in relation to history of

previous VTE events

32

p-value=0.3157

VTE recurrence in relation to body weight

33

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

34

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

35

Thanks for the attention

36

Thank you

for your attention