Psychometric Evaluation of a New Patient-Reported Outcome (PRO) Symptom Diary for Varicose Veins: VVSymQ(®) Instrument.

OBJECTIVE: To evaluate the psychometric properties of the VVSymQ(®) instrument, a new 5-item patient-reported outcome (PRO) measure for symptoms of varicose veins. METHOD: The VVSymQ(®) electronic daily diary was administered to outpatients who received routine treatment for varicose veins (N = 40). Compliance with diary administration and item score variability, reliability, construct validity, sensitivity to change, and clinically meaningful change were evaluated. RESULTS: Patients completed >97 % of scheduled diary assessments (at screening, baseline, and week 8). The VVSymQ(®) instrument captured patients' pre-treatment symptoms (all VVSymQ(®) symptoms were endorsed by ≥75 % of patients at baseline), and the change post-treatment (mean change in score -6.1), with a large Cohen effect size (1.6). Test-retest reliability was high (intraclass correlation coefficient 0.96); internal consistency was good (Cronbach's alpha ≥0.76; baseline, week 8). VVSymQ(®) scores were more strongly associated with PRO scores that reflect symptoms and symptom impact (the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms [VEINES-QOL/Sym] instrument and the Chronic Venous Insufficiency Quality-of-Life Questionnaire [CIVIQ-20]) than with PRO scores that reflect appearance (the Patient Self-Assessment of Appearance of Visible Varicose Veins [PA-V(3)]) or clinician-reported outcome scores (the Clinical-Etiology-Anatomy-Pathophysiology [CEAP] Classification of Venous Disorders and Venous Clinical Severity Score [VCSS]), demonstrating construct validity. Patients reporting that symptoms were "moderately" or "much improved" on the Patient Global Impression of Change (PGIC) anchor (i.e., >97 % of patients) had mean improvements of -6.3 VVSymQ(®) points, while a cumulative distribution curve showed that 50 % of patients improved by ≥-5.8 points; thus, a score change of approximately -6 demonstrated a clinically meaningful change in this study. The clinically meaningful change in the VVSymQ(®) score was greater in patients with a greater baseline VVSymQ(®) symptom burden, and the VVSymQ(®) instrument captured clinically meaningful treatment benefit even in patients with a low baseline symptom burden. CONCLUSION: The 5-item VVSymQ(®) instrument is a brief, psychometrically sound, useful tool for evaluating patient-reported varicose veins symptoms.

Benefits of polidocanol endovenous microfoam (Varithena®) compared with physician-compounded foams.

OBJECTIVE: To compare foam bubble size and bubble size distribution, stability, and degradation rate of commercially available polidocanol endovenous microfoam (Varithena®) and physician-compounded foams using a number of laboratory tests. METHODS: Foam properties of polidocanol endovenous microfoam and physician-compounded foams were measured and compared using a glass-plate method and a Sympatec QICPIC image analysis method to measure bubble size and bubble size distribution, Turbiscan™ LAB for foam half time and drainage and a novel biomimetic vein model to measure foam stability. Physician-compounded foams composed of polidocanol and room air, CO2, or mixtures of oxygen and carbon dioxide (O2:CO2) were generated by different methods. RESULTS: Polidocanol endovenous microfoam was found to have a narrow bubble size distribution with no large (>500 µm) bubbles. Physician-compounded foams made with the Tessari method had broader bubble size distribution and large bubbles, which have an impact on foam stability. Polidocanol endovenous microfoam had a lower degradation rate than any physician-compounded foams, including foams made using room air (p < 0.035). The same result was obtained at different liquid to gas ratios (1:4 and 1:7) for physician-compounded foams. In all tests performed, CO2 foams were the least stable and different O2:CO2 mixtures had intermediate performance. In the biomimetic vein model, polidocanol endovenous microfoam had the slowest degradation rate and longest calculated dwell time, which represents the length of time the foam is in contact with the vein, almost twice that of physician-compounded foams using room air and eight times better than physician-compounded foams prepared using equivalent gas mixes. CONCLUSION: Bubble size, bubble size distribution and stability of various sclerosing foam formulations show that polidocanol endovenous microfoam results in better overall performance compared with physician-compounded foams. Polidocanol endovenous microfoam offers better stability and cohesive properties in a biomimetic vein model compared to physician-compounded foams. Polidocanol endovenous microfoam, which is indicated in the United States for treatment of great saphenous vein system incompetence, provides clinicians with a consistent product with enhanced handling properties.

The role of clinically-relevant parameters on the cohesiveness of sclerosing foams in a biomimetic vein model.

We have recently reported on the development of a biomimetic vein model to measure the performance of sclerosing foams. In this study we employed the model to compare the commercially-available Varithena(®) (polidocanol injectable foam) 1% varicose vein treatment (referred to as polidocanol endovenous microfoam, or PEM) with physician compounded foams (PCFs) made using different foam generation methods (Double Syringe System and Tessari methods) and different foam formulations [liquid to gas ratios of 1:3 or 1:7; gas mixtures composed of 100% CO2, various CO2:O2 mixtures and room air (RA)]. PCFs produced using the DSS method had longer dwell times (DTs) (range 0.54-2.21 s/cm in the 4 mm diameter vein model) than those of the corresponding PCFs produced by the Tessari technique (range 0.29-0.94 s/cm). PEM had the longest DT indicating the best cohesive stability of any of the foams produced (2.92 s/cm). Other biomimetic model variables investigated included effect of vessel size, delayed injection and rate of plug formation (injection speed). When comparing the 4 and 10 mm vessel diameters, the DTs seen in the 10 mm vessel were higher than those observed for the 4 mm vessel, as the vein angle had been reduced to 5° to allow for foam plug formation. PCF foam performance was in the order RA > CO2:O2 (35:65) ≅ CO2:O2 (65:35) > CO2; PEM had a longer DT than all PCFs (22.10 s/cm) except that for RA made by DSS which was similar but more variable. The effect of delayed injection was also investigated and the DT for PEM remained the longest of all foams with the lowest percentage deviation with respect to the mean values, indicating a consistent foam performance. When considering rate of plug formation, PEM consistently produced the longest DTs and this was possible even at low plug expansion rates (mean 29.5 mm/s, minimum 20.9 mm/s). The developed vein model has therefore demonstrated that PEM consistently displays higher foam stability and cohesiveness when compared to PCFs, over a range of clinically-relevant operational variables.

A novel biomimetic analysis system for quantitative characterisation of sclerosing foams used for the treatment of varicose veins.

A novel analysis system for the quantification of sclerosing foam properties under clinically relevant conditions was developed with the purpose of establishing a robust methodology for comparative characterisation of different foam formulations and production strategies. The developed biomimetic-inspired model comprised of 4 or 10 mm inner diameter polytetrafluoroethylene tubing, filled with a blood substitute and fixed to a platform with an adjustable inclination angle. Sclerosing foams were produced by mixing polidocanol with either atmospheric air or 100 % CO2, using a double-syringe system method. Individual foams were injected into the tube, while videos were captured simultaneously. Videos were then transferred to an in-house computational foam analysis system (CFAS) which performed a sequence of semi-automated operations, allowing quantitative characterisation of sclerosing foam dynamic behaviour. Using CFAS, degradation rates of different foams were measured and the effect of gas composition, liquid sclerosant concentration and time delay between foam production and injection were evaluated.

Clinical significance of cerebrovascular gas emboli during polidocanol endovenous ultra-low nitrogen microfoam ablation and correlation with magnetic resonance imaging in patients with right-to-left shunt.

BACKGROUND: Foam generated by manual agitation of liquid sclerosant with air or gas is routinely utilized to treat refluxing veins. Although generally well tolerated, serious neurological events have been reported. The composition and properties of the foam, including bubble size and gaseous components, may contribute to the potential for microcirculatory obstruction and cerebral ischemia. We tested an ultra-low nitrogen polidocanol endovenous microfoam with controlled bubble size and density and hypothesized that patients at risk due to the presence of middle cerebral artery (MCA) bubble emboli during microfoam injection would not demonstrate evidence of clinical or subclinical cerebral infarction. METHODS: Patients with great saphenous vein incompetence were treated with ultra-low nitrogen (≤ 0.8%) polidocanol endovenous microfoam injected under ultrasound guidance. Patients with right-to-left shunt were included to evaluate the safety of cerebral arterial bubbles. All patients with MCA emboli detected by transcranial Doppler during endovenous microfoam ablation received intensive surveillance for microinfarction, including brain magnetic resonance imaging and measurement of cardiac troponin-I. RESULTS: MCA bubble emboli were detected in 60 of 82 treated patients; 22 patients had no detectable emboli. Among patients with MCA bubbles detected, 49 (82%) had ≤ 15 bubbles. No patients developed magnetic resonance imaging abnormalities, neurological signs, or elevated cardiac troponin. CONCLUSIONS: Patients treated with foamed liquid sclerosants are commonly exposed to cerebrovascular gas bubbles. In this series of 60 high-risk patients with MCA bubble emboli during or after treatment with ultra-low nitrogen polidocanol endovenous microfoam, there was no evidence of cerebral or cardiac microinfarction. The results of this study cannot be generalized to foams compounded using bedside methodologies, since the composition of these foams is substantially different.

What is the current role of foam sclerotherapy in treating reflux and varicosities?

Foam sclerotherapy is not a defined procedure nor is the product uniform or licensed for use but it is now accepted practice in most territories worldwide. Foam sclerotherapy has been used to treat a wide range of venous conditions from the closure of incompetent great saphenous trunk veins to telangiectasia and from venous malformations to hemorrhoids with good outcomes being reported. There is a rapidly expanding body of literature supporting its safety and efficacy as well as a few case histories of serious complications. This article will focus on the current role of foam sclerotherapy in the treatment of varicose veins.

High prevalence of right-to-left shunt in patients with symptomatic great saphenous incompetence and varicose veins.

BACKGROUND: Varicose veins are common and increasingly are being treated by less invasive endoscopic methods such as foam sclerotherapy. Patent foramen ovale (PFO) is also common, present in approximately one-quarter of adults. PFO allows bubbles introduced by foam sclerotherapy to cross into the general circulation, potentially causing cerebral artery gas embolization with unevaluated consequences. METHODS: Men and women aged 18 to 60 years with symptomatic varicose veins (CEAP C(3-5)) responded to an advertisement to recruit volunteers for a study on endovenous microfoam ablation (EMA). Participants' veins were screened by duplex ultrasound imaging, and those with isolated great saphenous vein (GSV) incompetence were tested for right-to-left (R-L) vascular shunt using transcranial Doppler (TCD) of the middle cerebral artery to detect the presence of bubble emboli after an injection of an agitated saline, blood, and air mixture as a contrast at rest and with the Valsalva maneuver. RESULTS: Of 221 participants tested for R-L shunt, 85 (38.5%) were positive at rest (95% confidence interval [CI], 32.5-45.2) and 114 (51.8%) were positive after the Valsalva maneuver (95% CI, 45.4-58.5). A total 130 patients (58.8%) were positive for R-L shunt at rest or after Valsalva (95% CI, 52.5%-65.1%). This is significantly higher than the reported 26% prevalence of PFO in the general population (95% CI, 24.4-30.1). CONCLUSIONS: The prevalence of R-L shunt in patients with GSV incompetence CEAP C(3-5) in this study was higher than expected in the general population. TCD does not differentiate between intracardiac shunts and intrapulmonary shunts, so this observation needs further investigation. This link between R-L shunt and varicose veins is novel and, whether etiologic or functional, may improve the understanding of both conditions. The findings have importance in the treatment of varicose veins with foam sclerotherapy and EMA.

The ESCHAR trial: should it change practice?

INTRODUCTION: Most leg ulcers are caused by venous disease, the most common cause of venous hypertension being superficial vein incompetence. The ESCHAR trial tested the value of superficial vein surgery combined with compression in the healing and recurrence of venous leg ulcers compared with compression alone. METHODS: A total of 500 patients with chronic venous leg ulcers, or recently healed ulcers, were randomized to superficial vein surgery and compression or compression alone. Vein surgery was saphenofemoral ligation and great saphenous stripping and phlebectomy or saphenopopliteal ligation and phlebectomy. RESULTS: Ulcer healing was virtually identical between the 2 groups at 65% at 24 weeks; subgroup analysis failed to show a benefit for surgery to promote ulcer healing. Ulcer recurrence rate was halved in those that underwent surgery regardless of the presence of deep vein incompetence. CONCLUSION: Superficial vein surgery should be considered in all leg ulcer sufferers to reduce ulcer recurrence rather than accelerate ulcer healing.