A randomized controlled trial comparing venous stenting with conservative treatment in patients with Deep Venous Obstruction

Annually about 1-2 per 1000 people in Western European countries develop deep
venous thrombosis (DVT). The most frequent long-term complication of DVT is
development of a Post thrombotic syndrome (PTS). (1)
PTS consists of a range of symptoms that can occur in patients following a deep
vein
thrombosis. The definition of PTS is difficult to quantify but can be measured
best by the Villalta score. The higher the Villalta score, the more severe
complaints are. A score >15 indicates a severe PTS .
The pathological pathway of PTS is not completely understood but can be found
in altered haemodynamics. Virchow*s triad consisting of hypercoagulable state,
vascular wall damage and venous stasis explains the development of a deep vein
thrombosis. The first two mentioned causes are encountered in standardised
treatment nowadays. For the venous stasis no good treatment existed until
recently percutaneous angioplasty (PTA) and dedicated venous stents became
available. (2)
Patients with PTS experience symptoms related to chronic venous insufficiency
caused by obstruction and valve impairment leading to venous hypertension.
These symptoms may include pain, tired legs, venous claudication and cramps,
oedema, pigmentation or other skin changes finally leading to ulcera.
Patients with established PTS experience a significant impact on QoL with, in
several cases,
daily disabilities comparable to an impaired QoL in Chronic Obstrucive
Pulmonary Disease (COPD), congestive heart disease and diabetes. (3, 4)
PTS develops in 40-50 % of all patients with a history of a DVT depending on
anatomic position of deep venous thrombosis and involvement of collateral
system.(5-7) Whenever DVT occurs in iliofemoral or caval veins with obstruction
of collateral systems the outflow obstruction is greater than DVT*s in the calf
veins. One can understand this outflow obstruction will present more clinical
and invalidating symptoms. Other risk factors for severe PTS, found in a large
prospective trial, are morbidity included severity of venous symptoms at 1
month, recurrent ipsilateral DVT, high body mass index and higher age. Some of
these risk factors are modifiable while others are not. (8, 9)
Like mentioned before venous outflow obstruction is caused by inadequate
recanalization, extravascular compression or congenital abnormalities. The most
common cause of extravascular compression is called May Thurner syndrome (MTS).
May Thurner is defined as compression of the left iliac common vein by the
right iliac artery. Patients develop outflow obstruction and valve incompetence
which can lead to impaired venous outflow of the leg. This outflow obstruction
causes venous hypertension and consequently the symptoms related to this.
Patients with MTS have an increased chance of developing recurrent DVT because
of anatomical variance and blood stasis.

Conventional treatment of DVO to minimalize complaints consists of the use of
elastic compressions stockings, exercise, lymph drainage therapy and the use of
(pain) medication. For most patients the physician selects one or a combination
of the treatment modalities mentioned above in an attempt to reduce symptoms.
However this is not always effective.(10)
A definitive solution for DVO patients may be a revascularisation procedure and
stenting of
the affected tract. This can be achieved by endovascular or hybrid procedures
in which a
PTA is performed and a dedicated venous stent is placed. This procedure is
already being performed in various hospitals around the world with good results
on an individual basis. The goal of PTA and stenting is to prevent PTS (
whenever placed in acute settings) or recurrent DVT and associated expected
decrease in quality of life. Decreased life quality during treatment of DVO may
increase the socioeconomic burden and can eventually lead to loss of ability to
work.
Quality of life can be measured by numerous questionnaires. General
questionnaires and disease specific questionnaires have been developed.(11)
The VEINES-QoL/Sym questionnaire is a 100 point disease-specific scoring
questionnaire which can be used to evaluate the psychometric properties of
venous disease. It is a valid and reliable instrument which has been used to
evaluate outcomes in previous literature. (12)
Improvement on QoL has been reported after venous stenting in case series. (13,
14) However a randomized trial has never been performed.

Primary Objective:
Measure QoL (VEINES QoL/Sym) change in patients with DVO at one year after PTA
and stenting compared to conventional therapy (short class II elastic
compressions stockings, exercise, lymph drainage therapy and the use of (pain)
medication)

Secondary Objective(s):
Measure QoL change in patients with DVO at 6 weeks-three months after PTA and
stenting compared to conventional therapy (short class II elastic compressions
stockings, exercise, lymph drainage therapy and the use of (pain) medication)

Measuring changes in Villalta scores and VCSS classification compared in
patients after PTA and stenting compared to conventional therapy (short class
II elastic compressions stockings, possible exercise, lymph drainage therapy
and the use of (pain) medication) in patients with DVO

Measuring complication rates of PTA and stenting in patients with DVO

Measuring primary, primary assisted and secondary patency of stents in patients
with DVO treated by PTA and stenting in patients

Measuring recurrence of DVT in patients with MTS treated with PTA and stenting
or conventional treatment

We propose to conduct a prospective randomized controlled study comparing PTA
and stenting to conservative therapy for patients with DVO.
May Thurner syndrome is defined as chronic compression of left common iliac
vein by right common iliac artery resulting in compression of vein between
artery and vertebral column.
Post thrombotic syndrome is defined as a range of clinical symptoms with venous
claudication or Villalta score >5.

Patients with PTS or MTS who are referred to the department of venous
surgery will be recruited. All new patients with deep venous pathology, will
have imaging of the veins using duplex ultrasound (DUS) and magnetic resonance
venography (MRV) or computed tomography venography (CTV). With these modalities
the extent of the obstruction or occlusion of the veins will be assessed.
Eligible patients will be contacted and offered the opportunity to participate
in the study. After they have signed informed consent, patients will be
randomized to either conservative treatment or PTA and stenting.
Conservative treatment consists of either one or a combination of the
following items: therapeutic elastic stockings short (till knee) Class II, pain
medication, manual lymphatic drainage therapy and regular post thrombotic
anticoagulants therapy. The necessity of each treatment modality will be
evaluated on an individual basis in interaction with both the patient as well
as the treating physician.
The patients in the intervention group are treated with PTA and
stenting of the affected veins (for details about the procedure see section
8.c). All procedures will be performed by a team of dedicated vascular surgeons
and interventional radiologists. Only percutaneous procedures will be taken
into account.

On baseline and all follow up moments all patients will undergo a full
clinical examination to assess the extent of complaints and clinical
manifestations from DVO. The severity of complaints is being scored using the
Venous Clinical Severity Score (VCSS), venous claudication score and the
Villalta scale. Venous claudication is defined as experience of onset or
worsening of pain during exercise, which subsides during rest, especially when
sitting or lifting the leg.
To assess QoL the VEINES-QoL/Sym will be used for disease specific QoL.
In all patients blood samples are taken on first enrollment, after 6 weeks and
after 12 months for possible future examinations.
Questions about income and having a (paid) job will be asked and registered on
baseline and follow up.
All patients will visit the outpatient clinic at 9-12 months after
participation.
All these scorings and possible help in filling in the questionnaires will be
accompanied by an independent investigator which is blinded for intervention.
The patients in the intervention group will have visits at 2 weeks, 6 weeks, 3
months, and 6 months to assess the patency of the stents by duplex ultrasound.
After 12 months all patients in the intervention group will receive a CTV to
evaluate stent patency and stent position.

After inclusion patients will be stratified for PTS/ MTS group. Patients in the
intervention group will be scheduled and treated with PTA and stenting. For
this treatment patients should be administered to the patient ward for at least
24 hours. Patients will be treated percutaneous by punction of the femoral
vein, common femoral vein, popliteal or jugular vein. Patients with PTS will
receive sedation. Patients with MTS will be treated with local anaesthesia.
After punction of the vein an introducer sheet is introduced. A wire is passed
along the diseased segment. This segment is dilated with a balloon and stented.
Afterwards one or more stents will be placed into the vein and post dilatation
with a balloon will follow to optimize the geometry of the stent. Patients need
to lie down for at least 3 hours to optimal closure of the percutaneous
punction.
Whenever necessary, creatin, haemoglobin or INR control has to be performed.
With low haemoglobin levels a packed cell should be given.
INR levels above 4 should be treated with lowering the amount of used
anticoagulant tablets and can result in postpone of the procedure.
All patients will receive an infusion and the sedated patients will receive a
bladder catheter.

For patients who are randomized into the intervention arm of the study a
hospital stay for minimum 24 hours till 5 days is mandatory depending on the
extent of intervention. Risks associated with the intervention include:
bleeding, non-successful intervention, secondary thrombosis or infections of
wound, urinary tract or pulmonary tract.
After the intervention patients will receive anti-coagulant treatment for at
least 6 months. This is associated with an increased risk of bleeding. Most
patients however already receive anticoagulant therapy for previous thrombosis.
Expected benefits for the interventional group are an expected increase in QoL,
less loss of working days and thereby reducing costs for the health care and
social care system.
Clinical follow up will be performed at 9-12 month for both groups with
additional follow up at 2 weeks, 6 weeks, 3 and 6 months after intervention.

For patients who are randomized into the intervention arm of the study a
hospital stay for at least 24 hours is mandatory. Risks associated with the
intervention include: bleeding, technical or clinical non successful
intervention, no relieve of complaints, secondary thrombosis and infection of
wound, urinary tract or pulmonary tract.
After the intervention patients will receive anti-coagulant treatment for at
least 6 months. This is associated with an increased risk of bleeding. Most
patients however already receive anticoagulant therapy for previous thrombosis.
Expected benefits for the interventional group are an expected increase in
HRQoL, longer walking distance and pain reduction. Resulting therefrom health
and social care costs will decrease. Patients will use less frequent pain
medications and will less frequent see a doctor because of unexplainable pain.
The social costs will decrease because it is expected patients will have less
days off work and therefore less social services will be needed.
Clinical follow up will be matching usual care and be performed at 9-12 month
for both groups with usual follow up at 2 weeks, 6 weeks, 3 months and 6 months
after intervention with DUS.