Best Endovenous Treatment, Including STenting, Versus Non-endovenous Treatment in Chronic Proximal Deep Venous Disease

Study Overview
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Brief Summary
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Chronic obstruction of the iliac veins or inferior vena cava can occur as a result of deep vein thrombosis (DVT), or due to extrinsic compression in non-thrombotic iliac vein lesions (NIVLs). This obstruction can manifest as post-thrombotic syndrome (PTS) after DVT or as chronic venous disease (CVD) in NIVL. Despite sparse evidence, rates of venous stenting for PTS and NIVLs are increasing. A pragmatic, observer-blind, multi-centre, randomised-controlled trial for adults with CVD secondary to either PTS or NIVLs randomised to either best endovenous therapy (including venoplasty and deep venous stenting) or standard therapy (compression +/- anticoagulation). Included participants will have chronic venous disease (CEAP classification 3 - 6) secondary to proximal deep venous disease. The primary outcome is severity of venous disease at 6 months as ascertained by the Venous Clinical Severity Score (VCSS).

Detailed Description
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Symptomatic chronic obstructive lesions of the iliac veins and inferior vein cava can be secondary to post-thrombotic lesions caused by a deep vein thrombosis (DVT) or due to non-thrombotic iliac vein lesions (NIVLs). DVT has an annual incidence of 148 per 100,000 person years in Europe. Following a DVT, up to 50% of patients develop post thrombotic syndrome (PTS), defined as chronic venous symptoms or signs secondary to DVT i.e. lifelong leg pain, oedema and skin changes. Furthermore, the subsequent rate of venous ulceration is high with up to 29% of those with PTS suffering from active or healed venous ulcers. The pathophysiology of PTS is thought to be sustained venous hypertension from a combination of venous outflow obstruction and valvular incompetence. NIVLs are due to external compression or intrinsic lesions that reduce the venous drainage through the iliac venous system. This, in turn, can lead to chronic venous insufficiency and also increase the risk of DVT. NIVLs contribute to the significant morbidity and cost associated with CVD. NIVLs can be demonstrated on imaging as a stenosed iliac vein or in an iliac vein of normal diameter with intrinsic lesions. Rates of venous stenting for PTS and NIVLs are rapidly increasing. However, sparse evidence exists to support the use of venous stenting and clinical guidelines reflect this. Endovenous stenting is being increasingly used as a treatment option for individuals with complications relating to chronic venous disease such as skin changes, ulceration, debilitating symptoms, and functional impairment. However, a recent systematic review of sixteen eligible studies, none of which were RCTs, concluded that: The quality of evidence to support the use of deep venous stenting to treat chronic obstructive disease is currently weak. The treatment does however appear promising and is safe and should therefore be considered as a treatment option while the evidence base is improved. Many of the studies employed stents which were not primarily designed for use in the venous system. The role of endovenous reconstruction in the context of patients with PTS and NIVLs, including deep venous stenting using modern stents designed specifically for use in the venous system, remains to be elucidated in a well-designed RCT. The rational for the proposed study is supported by both haemodynamic and clinical evidence. Retrospective cohorts of deep venous stenting in PTS and NIVLs have yielded promising results. Pre-clinical research suggests that common femoral vein pressure is increased in post thrombotic venous obstruction. It has been demonstrated that deep venous stenting improves mean ambulatory venous pressures and therefore should reduce the symptomology experienced by the individual. Furthermore, venous stents are specifically designed to be uncovered and rigid, aiming to keep the aspect ratio of the stent at a 1:1 ratio, to minimise outflow obstruction and increase venous return.

Official Title
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Best Endovenous Treatment, Including STenting, Versus Non-endovenous Treatment in Chronic Proximal Deep Venous Disease - the BEST Multi-centre Randomised Controlled Trial

Conditions
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Chronic Venous Insufficiency, Chronic Venous Thrombosis, Iliac Vein Stenosis, Iliac Vein Obstruction, Post Thrombotic Syndrome

Intervention / Treatment
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* Procedure: Deep venous stenting
* Combination Product: Best medical therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with chronic venous disease secondary to chronic proximal thrombotic or nonthrombotic stenosis or occlusion Disease in iliac and/or caval deep venous system(s) CEAP clinical C3, C4, C5, C6 or symptoms of venous claudication Anatomically suitable for endovenous reconstruction Exclusion Criteria: Contraindications to stenting (e.g. anatomically unsuitable, contrast allergy) Contraindications to prolonged anticoagulation Existing diagnosis of profound pro-thrombotic states (Beh et's, anti-phospholipid syndrome) Caval occlusion at or proximal to the level of the renal veins Open / hybrid open-endovascular deep venous intervention Pregnancy Inability to provide consent Need to intervene caudal to common femoral vein confluence to achieve inflow Participants that have tested positive for coronavirus within the last 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Superiority comparison using intention to treat analysis
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Best endovenous reconstruction + best medical treatment (compression +/- anti-thrombotic therapy).<br>The intervention arm consists of participants undergoing best endovenous reconstruction under the guidance of intra-vascular ultrasound in addition to best medical treatment (compression +/- antithrombotic therapy). | Procedure: Deep venous stenting<br>* Endovascular reconstruction encompasses balloon venoplasty and venous stenting. A dedicated venous stent will be used, the brand of which the individual interventionist will decide.<br>* Other names: Iliac vein stenting;Combination Product: Best medical therapy<br>* Compression stockings encompass a range of therapies used to provide an externally applied graduated-pressure up the length of the limb aiming to improve venous function and decrease lower limb swelling. Compression stockings can be classified by size and grade, i.e. the pressure the stockings applies to the limb. For the purpose of this trial Class II and Class III graduated compression stockings should be used, with the aim of providing Class III if tolerated. Antithrombotic agents include, but are not limited to: warfarin (titrated to international normalised ratio, INR), apixaban, rivaroxaban, aspirin, and clopidogrel.<br>|
| Active Comparator: Best medical treatment alone (compression +/- anticoagulation).<br>The comparator arm will consist of participants receiving best medical treatment alone. | Combination Product: Best medical therapy<br>* Compression stockings encompass a range of therapies used to provide an externally applied graduated-pressure up the length of the limb aiming to improve venous function and decrease lower limb swelling. Compression stockings can be classified by size and grade, i.e. the pressure the stockings applies to the limb. For the purpose of this trial Class II and Class III graduated compression stockings should be used, with the aim of providing Class III if tolerated. Antithrombotic agents include, but are not limited to: warfarin (titrated to international normalised ratio, INR), apixaban, rivaroxaban, aspirin, and clopidogrel.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous Clinical Severity Score (VCSS) at 6 months | Disease severity score. Venous clinical severity score (VCSS) encompasses nine hallmarks of chronic venous disease, each scored on a severity scale from 0 to 3. Min score 0, Max score 30. High score = worse severity of disease. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Re-intervention, number of participants requiring an additional procedure. | Dichotomous outcome, defined as additional procedure undertaken to maintain or re-establish stent patency, | 6 weeks, 3 months, 6 months, 12 months | 
| Stent patency, dichotomous outcome, number of participants with a patent stent at last follow-up. | Reported as primary, primary-assisted, secondary patency | 6 weeks, 3 months, 6 months, 12 months | 
| Cost-effectiveness of deep venous reconstruction | ICER | 12 months | 
| VEINES-QoL/Sym | Disease-specific quality of life measure. Standardised score, hence no meaningful min/max. High score = better quality of life. | 6 weeks, 6 months, 12 months | 
| Villalta score | Disease severity score. Min score 0, Max score 33. High score = worse severity of disease. | 6 weeks, 6 months, 12 months | 
| Ginsberg score, dichotomous outcome (Yes / No) | Diagnostic system for PTS (Yes /No). | 6 weeks, 6 months, 12 months | 
| Venous ulceration, dichotomous outcome | Presence of venous ulceration on clinical examination. | 6 weeks, 6 months, 12 months | 
| SF-36 | Quality of life measure. Standardised score, 0 - 100 per section. High score = better quality of life. | 6 weeks, 6 months, 12 months | 
| EQ-5D-5L | Quality of life measure. Scored 0 - 100 for VAS. High score = better quality of life. | 6 weeks, 6 months, 12 months | 
| Walking distance | Walking distance, metres, self-reported. | 6 weeks, 6 months, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep venous stenting, Intravascular ultrasound, Post thrombotic syndrome, Non-thrombotic iliac vein lesions, Proximal venous outflow obstruction, Chronic venous disease