Servier – Phlebolymphology

III. Deep venous system session:
chronic venous outflow/ obstruction/
acute DVT treatment/ deep venous
reflux

Optimizing pathways for acute DVT treatment
Prakash Saha (London, UK)
Deep vein thrombosis (DVT) is a common medical condition that occurs in 1 UK resident out of 1000 every year, and the iliofemoral venous segment is involved in 10% to 15% of cases. DVT results in a postthrombotic syndrome in 30% of all cases and costs the National Health Service about 1 billion pounds per year. Improving the outcomes of DVT requires providing appropriate management of these patients in an ambulatory setting with around-the-clock ultrasound imaging and early initiation of anticoagulation, as well as detecting those patients who require an interventional treatment. Three issues are essential to the optimization of acute DVT treatment: identification, management, and surveillance. The most important aspects of identifying DVT involves an appropriate use of the Wells score and D-dimer analysis, providing ultrasound examination within 4 hours if the clinical probability is high, and having access to cross-sectional imaging, such as CT and MR venography (MRV), especially in patients with iliocaval DVT. Modern MRV with special data processing not only verifies the diagnosis, but also assesses the age of the thrombus, which distinguishes acute and chronic venous obstruction and predicts lysis ability. The most important points of DVT management involves providing adequate information to the patients (including the use of special smartphone applications), conservative management with appropriate limb elevation, elastic compression, and lowmolecular- weight heparin, vitamin K antagonists, or direct oral anticoagulants, as well as thrombophilia testing and cancer screening. The interventional options, such as catheterdirected thrombolysis, pharmacomechanical thrombectomy, intravascular ultrasound, venous stenting, and hybrid surgery, should be used in all appropriate patients at the high-volume centers. To choose the right patient for catheter-directed thrombolysis, certain factors should be taken into account, such as bleeding risk (B), life expectancy (L), anatomy (A), severity (S), and timing (T) of DVT (ie, according to the BLAST tool). The venous stenting and robust anticoagulation protocol are crucial after an interventional treatment. Treatment outcome surveillance depends on good hematological management (duration and type of anticoagulation), ultrasound follow-up for vein patency by choosing appropriate criteria for reintervention and long-term clinical outcomes assessment using the Villalta score and patient-reported quality of life scores. Finally, optimal DVT treatment could be carried out by the multidisciplinary team and involve primary care, nursing specialists, ultrasonography specialists, interventional radiologists, hematologists, and vascular surgeons.

Optimal outcomes assessment after acute DVT thrombolysis
Raghu Kolluri (Columbus, OH, US)
The outcomes after deep vein thrombosis (DVT) contain end points and factors that influence the end points. The general requirements for a proper end point include measurability and clinical relevance for physicians as well as for patients. The main efficacy outcomes for acute iliofemoral DVT may include immediate relief of symptoms, absence of longterm sequelae, and recurrences. Immediate symptoms could be measured by leg pain scores, leg circumference, and functional tests, such as a 6-minute walk test or time on the treadmill. The immediate anatomic outcomes may be assessed with a venographic Marder score, intravascular ultrasound of the iliocaval DVT, or by duplex ultrasound and specific obstruction scores (venous segmental disease score) in femoropopliteal DVT. The long-term outcomes may be assessed by patient self-reported questionnaires (generic [eg, short-form 36] or disease-specific [eg, VEINES QOL]), by the CEAP classification or severity scores, such as the venous clinical severity score (VCSS) or the Villalta score. It is important to remember that most of these instruments were developed to assess chronic venous insufficiency in general and were not specified for postthrombotic syndrome. The well-known Villata score is properly validated for postthrombotic syndrome, but it cannot distinguish between postthrombotic changes and primary venous disease. Among 288 patients with a chronic venous disease without any history of DVT, 70% were classified as having postthrombotic syndrome and 33% as having severe postthrombotic syndrome. In addition, the Villalta score does not mention venous claudication, the very important long-term sequel of iliofemoral DVT. The factors that could affect the end points include the presence of reflux before the index DVT, the fact and type of compression therapy, elevated central venous pressure, and other causes of edema and anticoagulation management.

CAVA trial
Cees Wittens (Maastricht, Netherlands)
The CAVA trial (CAtheter Versus Anticoagulation) is an open-label, assessor-blind, multicenter, randomized controlled trial that is comparing the efficacy and safety of additional ultrasound-accelerated catheter-directed thrombolysis (UACDT with an EKOS® device) versus standard anticoagulation therapy in patients with their first acute iliofemoral deep vein thrombosis (DVT) with complaints for less than 14 days. The primary outcome of the study was the proportion of postthrombotic syndrome measured using the Villalta score at the 1-year follow-up. The secondary end points include the proportion of postthrombotic syndrome by International Society on Thrombosis and Haemostasis (ISTH) criteria, the severity of postthrombotic syndrome, and the health-related and generic quality of life scores. The safety outcome was major bleeding. A total of 184 patients were allocated to either UACDT (n=91) or conventional treatment (n=93). Of those patients allocated to EACDT vs conventional treatment, 74 vs 71, respectively, completed the 12-month followup, 77 vs 75, respectively, were analyzed in an intention-to-treat (ITT) modality, and 58 vs 57, respectively, were analyzed per protocol. The baseline characteristics of the patients were similar in both groups. The mean duration of symptoms before UACDT was 11.0 days and the venous stenting rate was 45%. The primary outcome at 12 months was registered in 29.3% of patients after UACDT and in 35.1% of patients after conventional treatment with no statistically significant difference. In addition, there was no difference in secondary outcomes. The subanalysis showed a successful lysis with restored vein patency of _90%; however, only 53.2% of patients in the UACDT group achieved restored vein patency. Compared with those after unsuccessful lysis, these patients had a significantly higher stenting rate (75.6% vs 11.1%) and better outcomes: less moderate-to-severe postthrombotic syndrome (7.5% vs 25.7%), lower Villata (3.35±3.10 vs 4.72±3.19) and VCSS (3.50±2.57 vs 4.88±2.25) scores, and better quality of life parameters.

Where next after ATTRACT and CAVA?
Mitchell Silver (Columbus, OH, US)
The discouraging results of the ATTRACT trial (Acute venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis) may be related to the study limitations (eg, only 1 patient out of 50 screened patients was randomized and the total enrollment in 56 clinical centers took 5 years) and that the study was underpowered to look at the higher-risk population, as only 57% of the patients had iliofemoral deep vein thrombosis (DVT), only 68% of patients in the control group were followed to 24 months, no intravascular ultrasound (IVUS) was used during the intervention, only 20% of patients had a venous duplex ultrasound at 1 year, and the median duration of lysis was 21 hours, which could be reflected with the higher risk of major bleeding. The main limitations of the CAVA trial (CAtheter Versus Anticoagulation) are represented by a long enrollment time (7 years for 184 patients), a low rate of successful lysis (53.2%), an absence of duplex ultrasound follow-up, and the long duration of the lysis procedure (48 hours).

All of these limitations should be overcome by the CLEAR DVT study (Contemporary Endovascular Therapies in Treatment of Acute Iliofemoral DVT). The study will occur over 2 phases. During phase 1, the initial cohort of 65 patients after an endovascular venous intervention will be compared with the propensity-matched medical therapy group of the ATTRACT trial with a primary end point of postthrombotic syndrome, which will be assessed by the Villalta score at 24 months after the intervention. Only iliofemoral DVT with symptom duration of up to14 days will be included. The thrombolysis will be performed using the AngioJet^TM system with mandatory IVUS and venous stenting in all cases where there is a cross-sectional area reduction of ≥50%. After the intervention, a standardized anticoagulation regimen will be prescribed. The 6-minute walk test will be used as a functional end point, a mandatory duplex ultrasound will be performed at 12 months, and health economics will be calculated. In addition, the study aims to evaluate the prevalence of mechanical abnormalities of the iliac veins, to correlate functional parameters (Villalta and quality of life scores) with posttreatment thrombus burden, recurrent DVT, and vein patency. The results of the phase 1 study will be used for construction of the phase 2 study, ie, the randomized clinical trial.

Complications and disasters during deep venous stenting procedures
Gerard O’Sullivan (Galway, Ireland)
Vein rupture during endovascular iliac vein reconstruction is rare and associated with prior vein surgery, radiotherapy, and vessel catheterization. However, it does not depend on age, sex, the duration, length, or nature of the obstruction, or the presence of cancer. In one example, a 47-year-old woman with endometrial cancer underwent a hysterectomy that was complicated by injury and further repair of pelvic vessels, and then she developed leg swelling with demonstrated difficulties and dangers of iliac vein endovascular reconstruction. The iliac vein obstruction was verified only by CT venography with a direct injection of the contrast agent into the foot. Attempts at a standard balloon angioplasty led to vein rupture and internal bleeding. The implantation of a bare venous stent in case of a previous dissection is not able to stop bleeding; on the contrary, a stent placed in the zone of inelastic scars can play a role of good conduit and increase blood leakage. Therefore, the woman was transferred to the operating room and the rupture was fixed with an open surgical procedure. To perform an endovascular procedure with a high risk of rupture, it is recommended to have general anesthesia, a urethral catheter, an arterial line, 3-point access, large balloons, and the correct size sheet and stent grafts in the operating room.

An update on stent trials and the role of IVUS
Erin Murphy (Charlotte, NC, US)
The portfolio of venous products is now changing worldwide. There are several ongoing and finished trials aimed at assessing the efficacy and safety of venous stenting with different products: VIRTUS (Evaluation of the VICI™ Venous Stent System in Patients With Chronic Iliofemoral Venous Outflow Obstruction) for the VICI Venous Stent® by Boston Scientific, VIVO (Prospective European Study of the Zilver® Vena^TM Venous Stent in the Treatment of Symptomatic Iliofemoral Venous Outflow Obstruction) for the Zilver® Vena^TM stent by Cook Medical, VERNACULAR (BARDR The VENOVO™ Venous Stent Study for Treatment of Iliofemoral Occlusive Disease) for the VENOVOTM stent by Bard, and ABRE (Evaluation of the safety and effectiveness of the ABRE™ venous self-expanding stent system) for the ABRE^TM stent by Medtronic. All studies have similar aims and designs, with only a few differences. The primary end point is stent patency assessed by venogram, duplex ultrasound, or intravascular ultrasound. Only the ABRE study uses intravascular ultrasound to assess the degree of baseline venous obstruction and vein patency at 12 months, while others use only venogram findings. For all studies, the threshold for venous obstruction at baseline is ≥50%. VIRTUS and VERNACULAR have already shown good results in terms of efficacy (84.0% and 88.3%, respectively) and safety (98.8% and 93.5%, respectively, of patients without major adverse events for 30 days). Both studies demonstrated a significant decrease in the venous clinical severity score and an improvement in quality of life. The results from VIVO and ABRE should be reported in 2020 and 2012.

The challenge of inflow – how can we assess it and what to look for
Houman Jalaie (Aachen, Germany)
Venous inflow is probably the most important predictor of outcomes after venous recanalization. It could be affected by many factors, such as body position, breathing, state of inflow conduit, outflow possibilities (collaterals), and there are no exact measures because volume flow determination is prone to error. Inflow should be a mandatory assessment prior to vein recanalization with special attention being paid to the anatomical extension of the lesion below the inguinal ligament, the involvement of the main inflow vessels, the degree of lumen reduction in the common femoral, femoral, and deep femoral veins (more than a 50% reduction should be considered as hemodynamically relevant), and collateral veins. For this purpose, duplex ultrasound, CT or direct CT venography, MR or direct MR venography, phlebography, and IVUS may be used. Duplex ultrasound combines anatomical and hemodynamic data, and it is inexpensive and noninvasive, but it requires a learning curve. CT venography is fast, but holds the patient in the supine position, and it is associated with radiation exposure and does not provide any hemodynamic information. MR venography is more time consuming and expensive compared with CT. According to the literature, air plethysmography is not able to determine patient who will benefit from the treatment and those who will not. Direct CT venography defines the dominant vein inflow. Phlebography may be used to choose the better landing zone with the best inflow, even if it is infrainguinal. However, the most appropriate way to assess venous inflow is duplex ultrasound performed in a supine and upright position compared with the contralateral side, as it reports the postthrombotic changes from the knee up to the inferior vena cava, measures the flow volume at the common femoral vein, and provides a precise venous map. Based on preliminary results, a flow of 200 mL/min measured at the common femoral vein may be a threshold of adequate inflow. Combination of duplex ultrasound and CT/MR venography is the proper way to assess the inflow preoperatively.

What is next when stents fail?
Stephen Black (London, UK)
The patency of a venous stent depends on technical issues (stent choice and position of placing), blood flow (inflow, stenosis), and clotting abnormalities (antiphospholipid antibody syndrome, Bechet disease, vessel wall status, etc). If the stent fails during longterm follow-up, it is important to consider the reason for stenting in the first place, what caused the stent to fail, and what is the aim for further treatment. Only patients with severe symptoms, such as leg ulceration, may be considered for further interventions. Patients with mild and moderate symptoms do not require any additional surgery. The surgical options for failed stents are venous bypass or endophlebectomy with an arteriovenous fistula. It is important to provide good inflow by opening a deep femoral vein. When applying a fistula, arterial inflow should provide enough inflow for the stent, but does not overload the venous system, otherwise, there will be no improvement in terms of venous insufficiency. When applying a venous bypass in patients with a venous ulcer, antibacterial prophylaxis is crucial to prevent graft infection. However, most of the patients with failed stents during the long-term follow-up do not require intervention.

The challenge of the femoral vein – treating post-thrombotic syndrome with normal iliac outflow
Steve Elias (Englewood, NJ, US)
Among the 950 000 cases of deep vein thrombosis (DVT) per year in the USA, 55% account for a femoropopliteal lesion that reflects with postthrombotic syndrome in 30% to 40% of all cases. Standard care is usually not enough, which is why the intervention should restore flow, decrease venous pressure, and improve the symptoms. The surgical options are venous bypass, venous stenting, and open endophlebectomy. A modern option considers using angioplasty with possible thrombolysis. The efficacy and safety of such a modality were assessed recently in the ACCESS PTS trial (ACCElerated thrombolySiS for Post Thrombotic Syndrome) that included 78 patients with iliofemoral DVT diagnosed ≥6 months ago, a Villalta score of ≥8, and in whom conservative treatment had failed for 3 months. They underwent balloon angioplasty for the occlusive vein segments, EKOS thrombolysis with an infusion of tissue plasminogen activator (0.5-1.0 mg/hour for ≥12 hours) and repeated balloon angioplasty after that. The primary end point, reduction in the Villalta score of ≥4 points, was achieved in 67% of patients with a mean decrease in the Villalta score of 34% at 30 days. One major bleeding event occurred within 72 hours after the intervention and one pulmonary embolism event occurred during 30 days of observation. The modification of this technique is called GESSTA (Gasparis/Elias Single Session Thrombolysis/Angioplasty), which suggests sequential segmental tissue plasminogen activator exposure and balloon angioplasty of occluded veins through a specially designed balloon catheter with perforation within one session. The preliminary results showed ulcer healing in 10 of 16 treated patients. The suggested method is more simple, safe, and less expensive than the approach with EKOS, but needs to be studied in randomized clinical trials.

Latest advances with percutaneous deep venous valves
Steven Dubenec (Sydney, Australia)
Chronic deep vein insufficiency may be represented by obstruction, reflux, and the combination of obstruction and reflux. Reflux in deep veins appears due to an absence of valves or to their destruction, resulting in leg ulceration. Standard compression therapy is moderately effective, but ulcer recurrence occurs in 20% of all cases. The option for surgical valve repair included valvuloplasty, external banding, and valve transplantation and transposition. However, endovascular techniques are more attractive, but their efficacy is limited with a small number of animal studies. The novel option is a BlueLeaf technique that constructs neovalves similar to the open technique described by Oscar Maleti. The device is introduced through the large 16 Fr common femoral vein access in the retrograde direction. It provides the construction of subintimal valves by vein wall hydrodissection and nitinol arm separation under intravascular ultrasound visualization. It allows for the creation of monocuspid or bicuspid valves at different levels of the femoral vein. The preliminary results contain data from 11 patients, where 1 to 3 monocuspid valves were created in 10 of these patients. Therefore, technical success was achieved in 91% of the patients. No occlusive deep vein thromboses were registered, but, in 4 patients, mural thrombi were observed, which resolved during the 90 days of observation. Adverse events were represented with one symptomatic arteriovenous fistula, which resolved with compression, and 6 cases with access site complications, where 1 patient required surgical intervention. The patients were followed for 1 to 12 months with a significant reduction in the venous clinical severity score. The device is now undergoing further updates.

Endovascular rescue strategies for in-stent thrombus lining and occlusion
Erin Murphy (Charlotte, NC, US)
In-stent thrombosis (acute or chronic) may be related to physiologic (low inflow, stent mismatch), anticoagulation, or mechanical issues. The intervention is usually indicated in case of recurrence of initially improved symptoms, the persistence of some mechanical issues occluding the stent, or if the stent diameter is less than 3 to 5 mm (threatens the stent). The standard intervention for such cases is a venoplasty, but, in acute cases, catheter-directed thrombolysis or pharmacomechanical thrombectomy may be optional. Chronic stent occlusion may be difficult to resolve even after a few weeks. The main candidates for intervention are young and symptomatic patients with sufficient inflow and the ability to receive anticoagulation. It is important to consider that the stent may not open or stay open after treatment and that it may require multiple interventions. Laser recanalization may be optional in chronic stent occlusion. The anticoagulation management after reintervention depends on the reason for stent thrombosis. In case of a mechanical issue, the minimal 6-month duration of anticoagulation is indicated with the final decision being based on thrombophilia screening and stent status. In the case of nonmechanical issues, evaluation of compliance, thrombophilia screening, change or escalation of anticoagulation regimen, permanent anticoagulation, and hematologist consultation is indicated.

Meeting the challenges of upper limb venous outflow obstruction
Rick de Graaf (Friedrichshafen, Germany)
Upper extremity venous outflow obstruction may be manifested as Paget-Schroetter syndrome (venous thrombosis on the background of venous thoracic outlet syndrome) or chronic central venous obstruction due to compression or fibrosis. There are no valid instruments to assess the clinical impact of upper limb venous obstruction. The Villalta scale is inadequate for this issue. The incidence of postthrombotic syndrome after upper limb deep vein thrombosis is reported in wide ranges (7% to 46%), but skin ulceration is very rare. The different approach to upper limb interventions compared with lower limb interventions is caused by anatomical differences (bone structures, the significance of inflow veins), etiology of the lesions (structural and anatomical, iatrogenic due to central venous catheters), and physiology of venous return (dependence of flow on exercises). Therefore, the recanalization of upper extremity veins is usually more challenging, and lower extremity knowledge is not transferrable to the upper limbs. For recanalization, hydrophilic wires and catheters, sharp needles, and radiofrequency may be used. Thrombolysis or pharmacomechanical thrombectomy is a good option for acute upper limb deep vein thrombosis. Venous stenting is not well established and there is no good evidence on what kind of stents (dedicated venous or specified upper extremity) should be used. It is important to consider decompressive surgery, such as first rib resection, and additional angioplasty for residual lesions. The main challenge in the treatment of upper limb venous obstruction is selecting the right patients.

Central vein obstruction – stenting in the SVC and IVC
Narayanan Thulasidasan (London, UK)
The obstruction of the superior vena cava may be related to either malignant (bronchogenic, lymphoma) or nonmalignant (central venous catheter, pacemaker, fibrosis) factors. The same factors are present for the inferior vena cava: retroperitoneal metastasis, lymphoma, or thrombosis/postthrombosis, fibrosis, filter-related, or congenital (atresia, agenesis). Recanalization of the superior vena cava depends on the etiology of the obstruction and expectations from the intervention. In the case of postcatheterization obstruction or dialysis fistula, the main aim is to restore dialysis access and avoid stenting unless it is asymptomatic. In the case of an implanted pacemaker, the main reason is to reinsert wires through the stent. Practical advice for superior vena cava recanalization include a careful cross with multiple projections, use of laser or radiofrequency only if sure, predilate stepwise to avoid rupture, avoid aggressive postdilatation, choose a cephalad stent landing zone carefully to avoid kinking of the brachiocephalic vein, have a cardiothoracic surgeon in the same building and a pericardial drainage kit in the same room.

To cross the occluded or absent inferior vena cava, it is practically important to:

• Identify any residual intraluminal microchannels;
• Use stiff straight hydrophilic wire to “drill” through the occluded vessel;
• Cross in a bidirectional manner through the common femoral and internal jugular veins;
• Use the back end of the guidewire for sharp dissections across short segments; use an arterial chronic total occlusion reentry device or trans-septal needles to bridge between antegrade and retrograde dissection tracts;
• Preserve as much native vein as possible;
• Use heparin after crossing;
• Mandatory use of intravascular ultrasound to confirm successful crossing, assess required proximal and distal landing zones, and choose the proper stent size;
• Make predilation to facilitate deployment of stents to near-nominal length and diameter; use stent constructs that consist of large-bore caval stents with doublebarreled iliac stents inside and throughout;
• Ensure sufficient overlap;
• Identify renal drainage and avoid shuttering inflow with multiple layers of overlapping stents if significant drainage into the inferior vena cava is identified;
• Provide postdilation;
• Remove the inferior vena cava filter when possible, but can also leave and stent through; and
• Ensure adequate inflow and provide proper anticoagulation.

Self-expanding nitinol stents are best to deal with repetitive compressive stresses in the inferior vena cava during respiration, trunk flexion, and nearby arterial pulsation. According to the literature, the experience with inferior vena cava reconstruction contains more 400 cases with a patency rate of 57% to 95% and clinical success in 40% to 80% of cases. Therefore, inferior vena cava reconstruction is a feasible and safe procedure that can be technically challenging in patients with advanced postthrombotic syndrome and long-segment occlusions.

Strategies and pitfalls for venous stents for the upper limb
Steven Dubenec (Sidney, Australia)
Upper limb deep vein thrombosis (ULDVT) range from 2% to 4% of all venous thrombi; they are complicated by a pulmonary embolism in approximately 10% of cases. Primary ULDVT develops as Paget-Schroetter syndrome due to physical effort and has no association with disease or trauma. It accounts for about 20% of all cases. Secondary ULDVT appears more frequently in association with malignancy, trauma, thrombophilia, or central venous catheters. Paget- Schroetter syndrome usually occurs in young, active patients around 30 years old and predominantly on the right side on the background of mechanical abnormalities at the thoracic outlet. It is usually provoked by repetitive activity. Initial vein damage leads to a thrombogenic surface and recurrent trauma leads to fibrosis of the vein and development of rib-bypass collaterals. To date, there are no randomized clinical trials showing the best treatment modality for ULDVT. With anticoagulation alone, about 60% of all patients have recurrent symptoms. Catheter-directed thrombolysis is an alternative option to restore limb function, but without decompressive surgery, it leads to DVT recurrence in 30% of patients at 30 days. The suggested approach contains catheter-directed thrombolysis with possible angioplasty, first rib resection, and venous stenting. The analyzed data contains information on 24 limbs after catheter-directed thrombolysis in 21 patients with a mean age of 40 years; 8 had acute DVT and 3 had a rib resection performed with a mean time after lysis of 64 days. All of the veins were stented. The primary stent patency during the 24-month follow-up was 55%, the primaryassisted patency was 95%, and the secondary patency was 100%. When stenting the upper limb, it is important to: (i) choose an appropriate type and size for the stent, taking into account that not every one of them can accommodate the upper extremity forces; (ii) use dual access for crossing difficult lesions and occlusions; (iii) use high-pressure ultra-noncompliant balloons; (iv) be prepared for balloon rupture; (v) place a stent after rib resection or perform a rib resection as soon as possible after stenting; and (vi) use intravascular ultrasound to identify the diseased segment, to assess the diameter of the vein, to work out the stent length required, and to check appropriate stent deployment. All performed upper limbs stents require ultrasound follow-up. However, restenosis is usually symptomatic.