Current practice of cyanoacrylate endovenous ablation: American vein and lymphatic society position statement.

BACKGROUND: Cyanoacrylate endovenous ablation and closure of incompetent saphenous veins have become increasingly utilized since its approval for use in the United States in 2015. This increase in usage necessitates a societal update to guide treatment and ensure optimal and consistent patient outcomes. METHOD: The American Vein and Lymphatic Society convened an expert panel to write an updated Position Statement with explanations and recommendations for the appropriate use of cyanoacrylate endovenous ablation for patients with venous insufficiency. RESULT: A Position Statement was produced by the expert panel with recommendations for appropriate use, treatment technique, outcomes review, and potential adverse events. Their recommendations were reviewed, edited, and approved by the Guidelines Committee of the Society. CONCLUSION: This societal Position Statement provides a useful document for reference for physicians and venous specialists to assist in the appropriate use of cyanoacrylate endovenous ablation in the treatment of patients with venous insufficiency.

Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

Five-year extension study of patients from a randomized clinical trial (VeClose) comparing cyanoacrylate closure versus radiofrequency ablation for the treatment of incompetent great saphenous veins.

OBJECTIVE: The proprietary cyanoacrylate closure (CAC) system vs radiofrequency ablation (RFA) trial (VenaSeal Sapheon Closure System Pivotal Study [VeClose]) showed that CAC, a nontumescent, nonthermal, nonsclerosant ablation technique, was effective and noninferior to RFA in vein closure with good 36-month outcomes. Conducted under a separate protocol, the aim of this extended follow-up was to assess the long-term safety and effectiveness of CAC and RFA for the treatment of incompetent great saphenous veins (GSV) at 5 years (60 months) of follow-up. METHODS: This 60-month extension study was conducted for all patients who completed the randomized VeClose study and who were willing to participate. The pivotal VeClose study included patients with symptomatic moderate to severe varicosities (Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] class C2-C4b) and symptomatic GSV incompetence who were randomly assigned (1:1) to either CAC or RFA. The primary outcome measure of this 60-month extension study was complete closure of the target vein, with planned exploratory analysis of noninferiority. Secondary outcomes included CEAP class; completion of the Venous Clinical Severity Score, EuroQol-Five Dimension survey, and Aberdeen Varicose Vein Questionnaire; patient satisfaction with treatment; adverse events (AEs) related to target GSV; and details of adjunctive procedures. RESULTS: A total of 89 patients completed the 60-month visit, which included 47 from the CAC group, 33 from the RFA group, and 9 CAC roll-in patients. No new recanalization events have been observed in the groups between 36 and 60 months of follow-up. At 60 months, Kaplan-Meier estimates for freedom from recanalization in the randomized CAC and RFA groups were 91.4% and 85.2%, respectively, demonstrating noninferiority of CAC compared with RFA. Both groups demonstrated sustained improvements in EuroQol-Five Dimension and quality of life measures through 60 months. Whereas patients assigned to C0 or C1 clinical class were excluded from the original study, more than half of all returning patients (64% [57/89]) were now assigned to C0 or C1, suggesting an improved clinical class from baseline. Furthermore, 41.1% of returning CAC patients and 39.4% of returning RFA patients are presently at least two CEAP clinical classes lower than at baseline. No long-term device- or procedure-related serious AEs occurred in either group between 36- and 60-month follow-up. CONCLUSIONS: CAC and RFA were effective in achieving complete target vein closure of the GSV at long-term follow-up, with CAC demonstrating continued noninferiority to RFA. CAC was also associated with sustained improvements in symptoms and quality of life, lower CEAP class, and high level of patient satisfaction without serious AEs between 36 and 60 months.

Twenty-four month results from a randomized trial of cyanoacrylate closure versus radiofrequency ablation for the treatment of incompetent great saphenous veins.

OBJECTIVE: We previously reported 3-month and 12-month occlusion rates after treatment of clinically symptomatic saphenous vein reflux with either cyanoacrylate closure (CAC) using the VenaSeal Closure System (Medtronic, Dublin, Ireland) or radiofrequency ablation (RFA) in a randomized, multicenter, clinical trial, VenaSeal Sapheon Closure System vs Radiofrequency Ablation for Incompetent Great Saphenous Veins (VeClose). Herein we report the 24-month follow-up results of the VeClose trial. METHODS: There were 222 patients with symptomatic great saphenous vein (GSV) incompetence who were randomly assigned to receive either CAC (n = 108) or RFA (n = 114). Patients were not allowed to receive adjunctive treatment of tributary varicosities until after the 3-month visit. Duplex ultrasound of the target vein was performed at day 3 and months 1, 3, 6, 12, and 24 after treatment, and closure was assessed by ultrasound by the treating physician. Overall 24-month success rates were compared; in addition, time to first reopening of the target vein was evaluated using survival analysis. End points such as Venous Clinical Severity Score, EuroQoL-5 Dimension, and Aberdeen Varicose Vein Questionnaire were evaluated. RESULTS: Of 222 randomized patients, 171 completed the 24-month follow-up, which included 87 from the CAC group and 84 from the RFA group. The 24-month complete closure rate was 95.3% in the CAC group and 94.0% in the RFA group, demonstrating continued noninferiority of CAC compared with RFA (P = .0034). Symptoms and quality of life improved similarly in both groups. No clinically significant device- or procedure-related late adverse events occurred. CONCLUSIONS: Both CAC and RFA were effective in closure of the target GSV, resulting in similar and significant improvements in the patient's quality of life through 24 months. These results suggest that CAC of the GSV is safe and durable out to 2 years.

VeClose trial 12-month outcomes of cyanoacrylate closure versus radiofrequency ablation for incompetent great saphenous veins.

OBJECTIVE: Endovenous cyanoacrylate closure (CAC) is a new U.S. Food and Drug Administration-approved therapy for treatment of clinically symptomatic venous reflux in saphenous veins. The device is indicated for the permanent closure of lower extremity superficial truncal veins, such as the great saphenous vein (GSV). Early results from a randomized trial of CAC have been reported previously. Herein we report 1-year outcomes. METHODS: There were 222 subjects with symptomatic GSV incompetence randomly assigned to receive either CAC (n = 108) or radiofrequency ablation (RFA; n = 114). After the month 3 visit, subjects could receive adjunctive therapies aimed at treating visible varicosities and incompetent tributaries. Vein closure was assessed at day 3 and months 1, 3, 6, and 12 using duplex ultrasound. Additional study visit assessments included the Venous Clinical Severity Score; Clinical, Etiology, Anatomy, and Pathophysiology classification; EuroQol-5 Dimension; and Aberdeen Varicose Vein Questionnaire. Both time to closure and time to first reopening of the target vein were evaluated using survival curve analysis. Adverse events were evaluated at each visit. RESULTS: Of 222 enrolled and randomized subjects, a 12-month follow-up was obtained for 192 (95 CAC and 97 RFA; total follow-up rate, 192/222 [86.5%]). By month 1, 100% of CAC subjects and 87% of RFA subjects demonstrated complete occlusion of the target vein. By month 12, the complete occlusion rate was nearly identical in both groups (97.2% in the CAC group and 97.0% in the RFA group). Twelve-month freedom from recanalization was similar in the CAC and RFA groups, although there was a trend toward greater freedom from recanalization in the CAC group (P = .08). Symptoms and quality of life improved equally in both groups. Most adverse events were mild to moderate and not related to the device or procedure. CONCLUSIONS: In patients with incompetent GSVs, treatment with both CAC and RFA results in high occlusion rates. Time to complete occlusion was faster with CAC, and freedom from reopening was higher after CAC. Quality of life scores improved equally with both therapies.

Proposal for a national coverage determination for the treatment of varicose veins and venous disease due to disparate Centers for Medicare and Medicaid Services local coverage determination policies.

Varicose veins and chronic venous disease are common problems in the United States. Persons with these conditions often have an adversely affected quality of life. There are a number of proven interventions to treat varicose veins and to improve patients' life quality, but these interventions are often restricted by the Centers for Medicare and Medicaid Services and private third-party payers. The Centers for Medicare and Medicaid Services have private contractors that administer Medicare policies in 10 jurisdictions across the United States. There is no national policy or coverage for the treatment of varicose veins; rather, there are multiple, disparate regional policies written by the contractors that cover the same Medicare beneficiary population. These disparate policies are not evidence based and provide unfair coverage of the same disease to the Medicare population, depending on where they live. Our proposal is for a national coverage determination policy for the treatment of varicose veins.

A multicenter, randomized, placebo-controlled trial of endovenous thermal ablation with or without polidocanol endovenous microfoam treatment in patients with great saphenous vein incompetence and visible varicosities.

Objectives * Varithena 017 Investigator Group: Michael Vasquez, MD, Venous Institute of Buffalo, Amherst, NY; Antonios Gasparis, MD, Stony Brook University Medical Center, Stony Brook, NY; Kathleen Gibson, MD, Lake Washington Vascular, Bellevue, WA; James Theodore King, MD, Vein Clinics of America, Oakbrook Terrace, IL; Nick Morrison, MD, Morrison Vein Institute, Scottsdale, AZ; Girish Munavalli, MD, Dermatology, Laser & Vein Specialists of the Carolinas, Charlotte, NC; Eulogio J. Sanchez, MD, Batey Cardiovascular Center, Bradenton, FL. Varithena® is a trademark of Provensis Ltd, a BTG International group company. To determine the efficacy and safety of polidocanol endovenous microfoam (PEM 0.5%, 1.0%) and placebo each administered with endovenous thermal ablation. Methods A multicenter, randomized, placebo-controlled, blinded study was conducted in patients with great saphenous vein incompetence and symptomatic and visible superficial venous disease. Co-primary endpoints were physician-assessed and patient-assessed appearance change from Baseline to Week 8. Results A total of 117 patients received treatment (38 placebo, 39 PEM 0.5%, 40 PEM 1%). Physician-rated vein appearance at Week 8 was significantly better with PEM ( p = 0.001 vs. placebo); patient-assessed appearance trended similarly. Polidocanol endovenous microfoam provided improvements in clinically meaningful change in patient-assessed and physician-assessed appearance ( p < 0.05), need for additional treatment ( p < 0.05), saphenofemoral junction reflux elimination, symptoms, and QOL. In PEM recipients, the most frequent adverse event was superficial thrombophlebitis (35.4%) Conclusions Endovenous thermal ablation + PEM significantly improved physician-assessed appearance at Week 8, increased the proportion of patients with a clinically meaningful change in appearance, and reduced need for additional treatment. www.clinicaltrials.gov (NCT01197833).

Multicenter assessment of the repeatability and reproducibility of the revised Venous Clinical Severity Score (rVCSS).

BACKGROUND: The Venous Clinical Severity Score (VCSS) was designed and validated as an objective measure of disease severity in patients with chronic venous disease (CVD). Recently, a revision of the VCSS (rVCSS) was performed to resolve ambiguity in the clinical descriptors and improve clarity and ease of use. This new revised VCSS requires validation to determine its repeatability and reproducibility in clinical evaluation of patients with varying levels of CVD. METHODS: A prospective multicenter protocol was designed to enroll patients undergoing evaluation for CVD at venous practices with experience using the original VCSS. At the time of initial evaluation, two clinicians independently assessed both lower extremities to determine the rVCSS and the CEAP clinical score. Between 1 and 6 weeks, patients returned and received repeat assessment of the rVCSS by the same two clinicians independently. Patients were excluded if any venous intervention occurred between the two separate evaluation visits. Scores were compared to determine inter- and intra-observer variability overall and within each CEAP clinical class. RESULTS: Seven centers enrolled a total of 136 limbs yielding 248 paired evaluations for interobserver variability and 258 paired evaluations for intraobserver variability. The mean interobserver rVCSS difference was 1.4 ± 1.7 and the mean intraobserver variability was 1.3 ± 1.6. Statistical assessment with weighted kappa yielded good repeatability (κ = 0.68; P < .0001) and good reproducibility (κ = 0.72; P < .000001) for the rVCSS. The rVCSS correlated well with the CEAP clinical class with significant differences between rVCSS in increasing classes. (P < .0001). CONCLUSIONS: In this multicenter evaluation, the rVCSS was demonstrated to be a reliable and reproducible instrument for documentation of the severity of symptoms in patients with lower extremity venous insufficiency.

The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.

The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis. The document also includes recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases (CVDs), including edema, skin changes, or venous ulcers. Recommendations of the Venous Guideline Committee are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system as strong (GRADE 1) if the benefits clearly outweigh the risks, burden, and costs. The suggestions are weak (GRADE 2) if the benefits are closely balanced with risks and burden. The level of available evidence to support the evaluation or treatment can be of high (A), medium (B), or low or very low (C) quality. The key recommendations of these guidelines are: We recommend that in patients with varicose veins or more severe CVD, a complete history and detailed physical examination are complemented by duplex ultrasound scanning of the deep and superficial veins (GRADE 1A). We recommend that the CEAP classification is used for patients with CVD (GRADE 1A) and that the revised Venous Clinical Severity Score is used to assess treatment outcome (GRADE 1B). We suggest compression therapy for patients with symptomatic varicose veins (GRADE 2C) but recommend against compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation (GRADE 1B). We recommend compression therapy as the primary treatment to aid healing of venous ulceration (GRADE 1B). To decrease the recurrence of venous ulcers, we recommend ablation of the incompetent superficial veins in addition to compression therapy (GRADE 1A). For treatment of the incompetent great saphenous vein (GSV), we recommend endovenous thermal ablation (radiofrequency or laser) rather than high ligation and inversion stripping of the saphenous vein to the level of the knee (GRADE 1B). We recommend phlebectomy or sclerotherapy to treat varicose tributaries (GRADE 1B) and suggest foam sclerotherapy as an option for the treatment of the incompetent saphenous vein (GRADE 2C). We recommend against selective treatment of perforating vein incompetence in patients with simple varicose veins (CEAP class C(2); GRADE 1B), but we suggest treatment of pathologic perforating veins (outward flow duration ≥500 ms, vein diameter ≥3.5 mm) located underneath healed or active ulcers (CEAP class C(5)-C(6); GRADE 2B). We suggest treatment of pelvic congestion syndrome and pelvic varices with coil embolization, plugs, or transcatheter sclerotherapy, used alone or together (GRADE 2B).

Revision of the venous clinical severity score: venous outcomes consensus statement: special communication of the American Venous Forum Ad Hoc Outcomes Working Group.

In response to the need for a disease severity measurement, the American Venous Forum committee on outcomes assessment developed the Venous Severity Scoring system in 2000. There are three components of this scoring system, the Venous Disability Score, the Venous Segmental Disease Score, and the Venous Clinical Severity Score (VCSS). The VCSS was developed from elements of the CEAP classification (clinical grade, etiology, anatomy, pathophysiology), which is the worldwide standard for describing the clinical features of chronic venous disease. However, as a descriptive instrument, the CEAP classification responds poorly to change. The VCSS was subsequently developed as an evaluative instrument that would be responsive to changes in disease severity over time and in response to treatment. Based on initial experiences with the VCSS, an international ad hoc working group of the American Venous Forum was charged with updating the instrument. This revision of the VCSS is focused on clarifying ambiguities, updating terminology, and simplifying application. The specific language of proven quality-of-life instruments was used to better address the issues of patients at the lower end of the venous disease spectrum. Periodic review and revision are necessary for generating more universal applicability and for comparing treatment outcomes in a meaningful way.

The importance of uniform venous terminology in reports on varicose veins.

There is a need for a standardized consistent language in vascular surgery that allows easy flow of information and comparison of results among clinicians. Beginning with current nomenclature, a common language serves as a framework for more detailed efforts. Understanding the outcomes assessment tools available provides the opportunity for universal outcomes reporting. Data collected at widespread points can then be fairly compared, and common goals of therapy can be determined. Common outcomes that have demonstrated verifiable trends and reproducibility should be subjected to the rigors of evidence-based questioning. The resultant standards of care and expectations of therapy are then confidently presented for everyday practice and ongoing research.

Sorting of the neuroendocrine secretory protein Secretogranin II into the regulated secretory pathway: role of N- and C-terminal alpha-helical domains.

Secretogranin II (SgII) belongs to the granin family of prohormones widely distributed in dense-core secretory granules (DCGs) of endocrine, neuroendocrine, and neuronal cells, including sympathoadrenal chromaffin cells. The mechanisms by which secretory proteins, and granins in particular, are sorted into the regulated secretory pathway are unsettled. We designed a strategy based on novel chimeric forms of human SgII fused to fluorescent (green fluorescent protein) or chemiluminescent (embryonic alkaline phosphatase) reporters to identify trafficking determinants mediating DCG targeting of SgII in sympathoadrenal cells. Three-dimensional deconvolution fluorescence microscopy and secretagogue-stimulated release studies demonstrate that SgII chimeras are correctly targeted to DCGs and released by exocytosis in PC12 and primary chromaffin cells. Results from a Golgi-retained mutant form of SgII suggest that sorting of SgII into DCGs depends on a saturable sorting machinery at the trans-Golgi/trans-Golgi network. Truncation analyses reveal the presence of DCG-targeting signals within both the N- and C-terminal regions of SgII, with the putative alpha-helix-containing SgII-(25-41) and SgII-(334-348) acting as sufficient, independent sorting domains. This study defines sequence features of SgII mediating vesicular targeting in sympathoadrenal cells and suggests a mechanism by which discrete domains of the molecule function in sorting, perhaps by virtue of a particular arrangement in tertiary structure and/or interaction with a specific component of the DCG membrane.

The utility of the Venous Clinical Severity Score in 682 limbs treated by radiofrequency saphenous vein ablation.

OBJECTIVES: The goal of endovenous ablation is to reduce the symptoms associated with chronic venous insufficiency. This prospective study was designed to apply the venous clinical severity score to limbs before and after endovenous saphenous vein radiofrequency ablation and to identify risk factors associated with treatment failure. METHODS: Between September 2003 and March 2005, 499 patients underwent 682 saphenous vein radiofrequency ablation procedures. Preoperative venous clinical severity scores were documented. Follow-up clinical and duplex examinations were performed at 4 days, 4 weeks, and 4 months after saphenous vein radiofrequency ablation and at > or=6 months thereafter. Venous clinical severity scoring was repeated at follow-up visits, and patients were asked to evaluate their level of satisfaction with the procedure. RESULTS: The mean +/- standard deviation age of the patients was 53.5 +/- 13.3 years (range, 28 to 86 years), and 68% were women. Pretreatment CEAP clinical class C3/C4 comprised 80% of limbs (520/682). Preoperative, 4-day, 4-week, and 4-month venous clinical severity scores were, respectively, 8.8 +/- 3.7 in 648 limbs, 5.2 +/- 3.0 in 629, 4.1 +/- 2.4 in 530, and 3.3 +/- 1.6 in 479 limbs. Saphenous vein radiofrequency ablation significantly reduced pain related to lower extremity venous disease from 95.7% to 15.2% (P < .0001) and edema from 92.4% to 17.0% (P < .0001). Before treatment, venous stasis ulcers were present in 52 limbs and healed at a rate of 86%. Complications in 633 limbs at last follow-up included superficial thrombophlebitis in 12.0%, paresthesia in 0.3%, and nonocclusive thrombus extension in 0.2%. No skin thermal injury was observed. Fewer than 2% of patients reported dissatisfaction with their procedural outcome. Age (relative risk, 0.98; P = .06), female sex (relative risk, 0.19; P < .0001), and tumescent volume >250 mL (relative risk, 0.59; P = .06) were associated with higher rates of occlusion. The overall occlusion rate was 87.1%. CONCLUSIONS: As determined by the venous clinical severity score, treatment of saphenous vein reflux with endovenous radiofrequency ablation results in the clinical improvement of symptoms and aids in the healing of venous ulcers. Age, female sex, and tumescent volume are associated with high success rates of occlusion. We found the venous clinical severity score to be an excellent stand-alone tool for assessing outcomes after saphenous vein radiofrequency ablation.