Placement of closed-cell designed venous stents in a mixed cohort of patients with chronic venous outflow obstructions – short-term safety, patency, and clinical outcomes
Abstract
Abstract.Background: To evaluate the performance of a closed-cell designed venous stent for the treatment of chronic ilio-femoral venous outflow obstruction (VOO) in the shortterm. Patients and methods: Safety, stent patency and clinical outcome after placement of the Vici Venous Stent® in patients with chronic ilio-femoral venous obstruction were assessed retrospectively. Stent patency was evaluated by duplex ultrasound scanning, and clinical outcome was determined using the revised Venous Clinical Severity score (rVCSS). Results: 75 patients (49 % female; median age 57 years; 82 limbs) with symptomatic significant VOO had stents placed in the ilio-femoral veins. Lower limb venous skin changes including ulcers (C-class in CEAP 4–6) were found in 31 patients (41 %). Nonthrombotic iliac vein lesions (NIVLs) and post-thrombotic obstruction (PTO) were found in 40 and 42 limbs, respectively. There were no safety issues. Cumulative primary, assisted-primary, and secondary stent patency in the entire cohort at 12 months were 94 %, 94 % and 96 %, respectively. Five limbs presented with stent occlusion. Two limbs had no intervention, 2/3 remained patent after reintervention. Clinical improvement (a decrease ≥ 2 rVCSS points) was observed in 81 %, 81 %, and 77 % of patients at 1 month, 6 months, and 12 months, respectively. There was a marked drop in the frequency of more marked pain and swelling (VCSS ≥ 2) from 62 % to 5 % and 93 % to 19 %, respectively. Four limbs had venous ulcers, three healed during the follow-up. Cumulative pri- mary stent patency at 12 months was 100 % and 87 % in patients with NIVL and PTO, respectively (p= 0.032). There was no statistical difference in clinical outcome between these subgroups. Conclusions: The Vici Venous Stent® placed in the ilio-femoral vein segment in patients with symptomatic VOO revealed no safety issues, had excellent primary patency and substantial symptom improvement. Long-term studies are needed to evaluate the durability of this stenting procedure.
Introduction
Endovenous stent placement has become the preferred choice to treat chronic femoro-ilio-caval venous outflow obstruction (VOO) of the lower extremities [1]. Venous stent placement is a safe procedure with low morbidity and mortality (< 1 %) and good stent patency with substantial symptom relief [2]. Stents designed for arteriosclerotic obstructions, most frequently Wallstent® (Boston Scientific, Natick, MA, USA), have been used in veins. The venous obstructive lesions are, however, different from those found in arteries. Most importantly, venous obstruction is found in vessels with larger diameters and is frequently caused by external compression at vessel crossings. In addition, post-thrombotic obstructions are due to severe fibrosis (the end-stage after acute thrombosis), not arteriosclerosis, and frequently cross the inguinal ligament. These observations have implications on the design features of stents dedicated to treat VOO, e. g. providing high radial strength but also allowing sufficient flexibility.
The Vici Venous Stent® (Veniti, Inc., Fremont, CA, USA) is a recently developed venous-dedicated self-expandable nitinol stent. It has a unique closed-cell design creating a balance between high crush resistance and flexibility. It is approved for use in Europe and is currently under assessment in a U. S. Food and Drug Administration Investigational Device Exemption trial. This study was primarily undertaken to evaluate the short-term safety and stent patency after placement of this new stent in patients with chronic ilio-femoral venous obstruction for the treatment of venous outflow obstruction. Clinical outcome is reported as available.
Patients and methods
Patient cohort
From November 2014 to July 2016, 82 lower limbs in 75 patients with chronic post-thrombotic (PTO) and non-thrombotic ilio-femoral venous outflow lesion (NIVL – defined as non-thrombotic common and external iliac venous obstructive lesions at the artery vessel crossings in the pelvis) were treated by placement of one or more Vici Venous Stents®. Although the patients had a standardized follow-up, the data was collected and analysed retrospectively. The obstructive lesion was considered thrombotic when the patient had a known history of previous ilio-femoral DVT or when post-thrombotic changes were found at the ilio-femoral anatomical site on imaging. Patients with post-thrombotic disease extending into the inferior vena cava (IVC) were excluded. The clinical severity of diseased limbs was classified using the C-class of the CEAP classification according to the reporting standards of the Society for Vascular Surgery (SVS) [3]. Only patients with C-class 3–4 and/or ≥ 2 points for pain in the revised Venous Clinical Severity Scoring (rVCSS) [4] had stent placement. Patients with acute DVT, early clot removal and subsequent stent placement were not included in the study. This study was approved by the local ethics committee and patient consent was obtained for the procedure, but not required for inclusion in this retrospective study.
Imaging
Chronic venous obstruction was diagnosed prior to treatment with duplex ultrasound scanning (DUS), computed tomography venography, and/or magnetic resonance venography. During the stenting procedure multi-plane venography with digital subtraction was routinely performed pre- and post-stent placement. In patients with NIVL, this investigation was complemented with intravascular ultrasound (IVUS) to confirm the presence of significant morphological outflow obstruction. Selective use of IVUS was chosen since the degree of the non-thrombotic compression stenoses are often underestimated [5]. Only patients with ≥ 50 % reduction of lumen diameter were stented.
Stenting procedure
The procedure was performed under local anaesthesia for patients with non-thrombotic obstruction and under monitored conscious sedation and local anaesthesia or general anaesthesia for patients with chronic post-thrombotic obstructions. The access site was chosen based upon the extent of the disease. In most cases, the femoral vein was used, but in some patients with NIVL the common femoral vein was accessed. The vein was punctured under ultrasound guidance. After venography, the lesion was traversed using a variety of guiding catheters and guidewires. In patients with NIVL, an IVUS evaluation was performed. Although the instructions for use of the Vici Venous Stent® do not make pre-dilation of the vein prior to stent placement obligatory, it is recommended by those familiar with the stent. Experience has shown that the target vein segments need to be pre-dilated before insertion of all venous nitinol stents need to be dilated before insertion, especially those with open-cell design, to prevent suboptimal expansion of the stent. Pre-dilation of all obstructions was performed with a high-pressure balloon in all patients to the nominal diameter of the stent to be placed and along the entire length of the diseased anatomical site. The combination of stents to cover the entire lesion was then decided. In the NIVL obstruction, the IVUS derived normal reference vessel diameter was used to size the stent diameter. When no normal reference vessel was found in the post-thrombotic obstructions, stent selection was based mainly on literature-reported reference vessel diameters. Stent diameters were 14 or 16 mm; lengths ranged from 60, 90, to 120 mm. If more than one stent was used, the stents overlapped by at least 1 cm. The Vici Venous Stent® has a uniform radial strength along the entire stent contrarily to the Wallstent® (Boston Scientific, Natick, MA, USA), which due to its braided design has poor radial strength at its ends. In addition, this closed-cell designed stent has minimal foreshortening in situ as compared to the Wallstent® with balloon dilation after initial placement. Therefore, this stent only needs to protrude minimally into the IVC (> 5 mm) and can be placed exactly at the ends of the lesion (> 5 mm). The stents were post-dilated to ensure complete expansion of the stent. After stent deployment, a repeated venogram/IVUS was performed to ensure patency, adequate adaptation to the wall, and coverage of the entire lesion. When bilateral disease was present, the preferred technique was to place stents in a “double-barrel” fashion into the IVC.
All patients received 5,000 units of unfractionated heparin intravenously intra-operatively. Post-procedure anticoagulation was started immediately following the completion of the procedure. Patients were initially given full-dose low-molecular weight heparin for at least 24 hours post-procedure and transitioned to vitamin K antagonists for continuous therapy. Anticoagulation was continued for a minimum of six months in patients with non-thrombotic obstructions and for at least six to 12 months in patients with post-thrombotic lesions. Patients with a history of two or more deep vein thromboses remained on anticoagulation indefinitely.
Follow-up
Patients were evaluated for stent patency by DUS at one, six, and 12 months. Patency was defined as absence of a ≥ 50 % lumen diameter stenosis of the stent. rVCSS was repeated at clinical follow-up.
Statistics
Continuous variables are presented as median and as range. Categorical data are presented as absolute number and percentage. Primary, assisted-primary (patency after preemptive intervention), and secondary patency (patency after intervention for occlusion) rates as defined by the reporting standards of the SVS [6] were calculated using survival analysis with the Kaplan-Meier method and Logrank test was used to compare cumulative curves using SPSS v. 22 (SPSS, IBM Corporation, Armonk, NY). Cumulative patency rates were only reported if the standard of error was < 10 %. rVCSS results were compared using Wilcoxon signed rank test for paired observations. Statistical significance was assumed when the two-tailed p-value was < 0.05.
Results
Stent placement was performed in 82 limbs in 75patients (49 % female, median age 57 years, range: 19–84). Bilateral disease was present in seven (9 %) patients. A full list of patient characteristics is presented in Table I. Thrombophilia was known in four patients (three heterozygous Factor V Leiden and one factor II mutation) but it is unknown how many had had thrombophilia testing performed.
Lower limb venous skin changes including ulcers (C-class 4–6) were found in 31 patients (41 %). Only one patient had a C-class 2 and was stented because of significant pain. Lower extremity pain and or swelling was reported in 99 % of 82 limbs. The rVCSS pain and swelling grade were ≥ 2 in 62 and 93 % of limbs, respectively. Most limbs were treated with compression therapy prior to stenting (80/82, 98 %).
Of the 82 stented limbs, 42 limbs had post-thrombotic (26 had occlusion and 16 non-occlusive obstruction) and 40 limbs non-thrombotic obstruction. Most lesions were on the left side (61/21, 74 %). A total of 107 stents were placed with a median of one stent per patient (range: one to three per limb). Obstructive lesions were confined to the common iliac vein in 34 limbs (42 %); 19 lesions (23 %) involved both the common iliac and external iliac veins, while 16 limbs (20 %) had lesions extending into the femoral vein (Table II).
The procedure had no major complication or major adverse events. One patient developed a small haematoma at the puncture site, which did not require intervention. There were no stent migration or symptomatic pulmonary embolisms. All stented patients had a patent stent system on discharge. Six patients were lost to follow-up. One additional patient died of a fatal myocardial infarction, unrelated to the procedure, before returning for follow-up.
Stent outcome
The median follow-up for stent patency was 164 days (range: 0–569 days). Stent patency was defined as presence of antegrade flow with ≤ 50 % lumen diameter reduction. Cumulative primary, primary-assisted, and secondary patency rates of all stented limbs were 99, 99, and 99 % at one month and 94, 94, and 96 %, at 6 and 12 months respectively, post-procedure (Figure 1). Thrombotic occlusion of the stent occurred in six limbs (in five patients) (median 89 days, range: 23–437 days). Four out of six occlusions occurred within six months post-stenting. All occlusions occurred in stents were placed in patients with post-thrombotic obstruction. Two patients (three limbs) with occlusions did not have significant symptoms and were observed without reintervention (remained occluded). Three patients had an attempt of thrombus removal by mechanical debulking with a 10F Aspirex device (Straub Medical, Wangs, Switzerland) followed by balloon angioplasty. In two patients, the stent was reopened, while in one patient, the stents remained occluded. The presence of stent fracture during the follow-up was not intentionally assessed, however, there were no cases of stent fracture associated with any reintervention.
Clinical outcome
The median clinical follow-up of stented limbs was 167 days (range: 0–598 days). The median rVCSS at the last follow-up was statistically significantly lower at five (range: 1–19) compared to before stenting at eight (range: 4–27) (p < 0.001). The rVCSS at one, six, and 12 months are given in Table III. The median rVCSS at each follow-up visit were statistically significantly lower compared to the score prior to stent placement. Symptomatic improvement ( ≥ 2-point improvement in rVCSS) was observed in 61 limbs (81 %), 35 limbs (81 %), and 17 limbs (77 %) at one, six, and 12 months, respectively. At the last follow-up of each patient, 59 limbs (79 %) showed symptomatic improvement. Five patients experienced symptomatic deterioration during the follow-up period: one patient had a late loss of primary patency and one patient’s rVCSS improved later. At pre-stent assessment, 50 of 82 limbs (62 %) complained of pain ≥ 2 points and 76 of 82 limbs (93 %) exhibited venous swelling ≥ 2 points. At the last follow-up, the number of exhibiting pain and swelling had dropped to four out of 75 limbs (5 %) and 14 out of 75 limbs (19 %), respectively. There were four limbs (three patients) with active ulcers prior to the stenting procedure. During the follow-up three of four venous ulcers had healed.
Post-thrombotic vs. non-thrombotic obstructions
Of the total patient population, 40 patients (42 limbs) treated were determined to have post-thrombotic obstruction (PTO), while 35 patients (40 limbs) had a non-thrombotic lesion (NIVL). Cumulative primary stent patency rate in patients with NIVL at 12 months was 100 %. Cumulative primary, assisted-primary, and secondary patency rates at 12 months for the stents placed in patients with post-thrombotic obstruction were 87, 87, and 91 %, respectively. Primary patency rates were significantly different between the two groups at 12 months (p = .032, Figure 2). The median rVCSS in the post-thrombotic patients and those with NIVL prior to stenting was 8.5 (range: 5–20) and 8 (range: 4–27) and at the last follow-up 5 (range: 1–19) and 5 (range: 2–15), respectively. There was no statistical difference between the two groups at pre-stent assessment or in the extent of decrease between pre-stent and last follow-up scores. The rVCSS at one, six, and 12 months for the two groups are given in Table III. The rVCSS for both groups decreased significantly at each follow-up interval when compared to prior stent placement, but the fall was similar in the two groups. Figure 3 and 4 show case examples of patients treated with Vici Venous Stents®
Discussion
The Vici Venous Stent® was safe to place with no mortality or morbidity. In a meta-analysis, the rate of early thrombotic events (< 30 days) for venous stenting was < 3 %, with most patients stented with Wallstent® [7]. The present study reported no early thrombotic events. Cumulative primary and secondary stent patency rates of the entire cohort at 12 months were 94 and 96 %l, respectively. In the feasibility phase of an international, multicentre investigational device exemption study of 30 patients with chronic VOO treated with the same stent, the corresponding cumulative stent patency rates at 12 months were 93 and 100 % [8].
Beside of the stent in this study, there are currently five dedicated venous stents on the market in Europe: The sinus-Venous and sinus-Obliquus stents (OptiMed, Ettlingen, Germany), the Zilver® Vena™ Venous Self-Expanding Stent (Cook Medical, Bloomington, IN), Venovo™ Venous Stent System (Bard, Tempe, AZ), and the Abre™ venous stent (Medtronic, Minneapolis, Minnesota, USA). The latter two stents have recently been introduced to the market and have not yet been reported on. de Wolf and colleagues reported a 12-months cumulative primary patency rate of 92 % for the sinus-Venous stent in patients with chron- ic VOO [9]. Stuck and colleagues evaluated the sinus-Obliquus stent in 20 patients with chronic and acute VOO and found a primary patency rate of 92 % at six months and 83 % at 10 months [10]. O’Sullivan et al. have shown that the Zilver® Vena™ stent has a so-called “clinical” patency rate of 85 % at a short median follow-up of 55 days [11]. This cohort included patients with acute ilio-femoral thrombosis (70 %) and half of the patients had advanced malignancy. In the feasibility phase of an IDE study of the Zilver® Vena™ stent in Europe, 35 patients with acute and chronic VOO were analysed [12]. A lumen diameter improvement > 100 % immediately after stent insertion was observed. Freedom of occlusion at 12 months was 88 %, but no standard cumulative patency analysis was presented with the presently accepted definition of stent patency. The present study shows stent patency rates which are non-inferior with other dedicated venous stents.
There has been no direct comparison between stents of different designs. It is difficult to compare stent patency rates in various reports, because the patency rates are highly influenced by the aetiology and severity of the disease [13]. Extensive post-thrombotic occlusive disease with poor inflow to the stent system do worse than focal non-thrombotic iliac vein lesions. Therefore, it is important to know what type of patients are included in the studies reporting on stent patency rates. Venous stent patency rates are markedly different in PTO and NIVL patients. In a study by Neglen et al., primary, assisted-primary, and secondary cumulative patency rates in 303 patients with PTO and 302 patients with NIVL patients were 79, 100, and 100 %, and 57, 80, and 86 % at 72 months, respectively [14]. In that study, Wallstents® were used exclusively. A recent meta-analysis of 1,122 patients with NIVL and 1,118 patients with PTO by Razavi et al. showed a primary patency rate at 12 months of 96 % and 79 %, respectively [2]. Wallstents® were used in 78 % of studies analysed. The cumulative primary and secondary patency rates remained higher in non-thrombotic patients than in the post-thrombotic patients throughout five years (primary patency at five years approximately 90 and 65 %, respectively).
While the older studies present results for patients treated with arterial stents, the same trend is seen in series using dedicated venous stents. Cumulative primary patency rates at 12 months with the sinus-Venous stent were 100 and 85 % for NIVL and PTO patients, respectively [9]. In the present study, there were also no stent occlusions in the non-thrombotic group compared to six in the PTO group, resulting in 12-month cumulative primary patency rates of 100 and 86 %, respectively. For comparison, the cumulative primary patency rates in the same groups in the Neglen et al. study using only Wallstents® at 12 months were 93 and 85 %, respectively [14].
The beneficial clinical response in this study is similar to those reported in other studies. The mean rVCSS decreased by 56–60 % in the reported studies of the sinus-Obliquus and Zilver® Vena™ stents [10, 12]. The median reduction of rVCSS using the sinus-Venous stent in patients with post-thrombotic and non-thrombotic obstructions were 38 and 33 %, respectively [9]. In this study, the pre-stent median rVCSS decreased from 8 (range: 4–27) to 4 (1–19) at 12 months in the entire cohort. There was a marked drop in the frequency of more severe pain and swelling (VCSS ≥ 2) from 62 to 5 % and 93 to 19 %, respectively. The response in each sub group was of similar magnitude.
Limitations
This study is limited by the decline of patients for clinical follow-up. The clinical response may be affected by the presence of reflux, perhaps explaining the reasons for clinical deterioration in five patients. Data is unfortunately not available. However, the main goal of this paper is to assess the safety and patency rate of the stent in the short-term, and not the clinical impact.
Conclusions
The Vici Venous Stent® is safe to use and associated with excellent primary patency rates with concomitant satisfactory symptomatic improvement with no device-related adverse events in the short-term follow-up. Further studies are necessary to confirm continuous efficacy in the long term.
Conflicts of interest: MKWL, WFS and RdG receives speaker honoraria from VENITI, Inc. PN is a stockholder and member of SAB and a proctor for Veniti.
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