CASS (CyanoAcrylate closure versus Surgical Stripping for incompetent saphenous veins) study: a randomized controlled trial comparing clinical outcomes after cyanoacrylate closure and surgical stripping for the treatment of incompetent saphenous veins

This is an open-label, multicenter, prospective, randomized controlled trial that will evaluate whether the clinical outcomes after cyanoacrylate closure are non-inferior to surgical stripping for the treatment of incompetent saphenous veins (Clinical Research Information Service (CRIS), KCT0003203). After baseline measurements, participants will be randomly allocated into the cyanoacrylate closure group or the surgical-stripping group. Participating centers are in Korea of which Kyung Hee University Hospital at Gangdong, Seoul National University Bundang Hospital, Wonkwang University Hospital, Yeungnam University Medical Center, and Seoul Metropolitan Government-Seoul National University Boramae Medical Center and will participate in patient recruitment and data collection.

Patients will be eligible for inclusion in the study if they require treatment for incompetent saphenous veins and have one or more of the following symptoms related to the incompetent saphenous vein: aching, throbbing, heaviness, fatigue, pruritus, night cramps, restlessness, discomfort, or swelling. To be eligible for randomization, patients must have identifiable reflux in the great saphenous vein (GSV) for greater than 0.5 s after distal compression and release or Valsalva’s maneuver in the standing or reverse Trendelenburg position. Patients must also have a Clinical, Etiologic, Anatomic, and Pathophysiologic (CEAP) classification score of C2 through C5. Other inclusion and exclusion criteria are listed in Table 1.

All patients with symptomatic incompetent GSVs will be treated by either cyanoacrylate closure or surgical stripping and followed up for a total of 24 months after treatment. A brief flowchart of the study is presented in Table 2.

Outcomes are recorded at 3 days and 1, 3, 6, 12, and 24 months after treatment (Table 2). The participants should return to the clinic 3 days after treatment and clinical information is collected. This includes the participants’ reporting of perioperative pain using a Visual Analog Scale (VAS); the investigator’s assessment of the presence of ecchymosis, rated using a 0- to 5-point scale (0, none; 1, involving < 25% of the treatment area; 2, 25–50%; 3, 50–75%; 4, 75–100%; 5, extension above or below the treatment segment); and the result of duplex ultrasound. The participants should also return 1 month, 3 months, 6 months, 12 months, and 24 months after treatment in order for clinical information to be collected; this includes the Venous Clinical Severity Score (VCSS) and the evaluation of the participants’ quality of life assessed by the Aberdeen Varicose Vein Questionnaire (AVVQ) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Duplex ultrasound follow-up is also performed at 3 months, 12 months, and 24 months. Other health problems and all adverse events are monitored at each study visit. The trial follow-up will continue until 24 months after index treatment.

The primary endpoint of the study is to evaluate the complete closure of the target vein; this is defined as vein closure along the entire treated vein segment with no discrete segments of patency exceeding 5 cm after cyanoacrylate closure, and the absence of venous reflux or residual venous tissue after surgical stripping. These endpoints will be measured by duplex ultrasound performed by a qualified vascular technologist or investigator at 3 months after treatment. The secondary outcomes include perioperative pain, postoperative ecchymosis, VCSS score, AVVQ, and EQ-5D at each scheduled follow-up visit; all adverse events during the 24-month follow-up period; and the complete closure rate and absence of venous reflux or residual venous tissue at the 12- and 24-month follow-ups.

Adverse events in clinical trials refer to all adverse events observed in the study subjects and do not necessarily have a causal relationship with treatment. The recording of serious adverse events (SAEs) will conform to the Good Clinical Practice standards and the Research Governance Framework 2005. The analysis of safety-related data will be performed with respect to the frequency of SAEs, including all-cause death, life-threatening events, need for hospitalization, need to extend hospital stay, and permanent significant function impairment. SAEs must be reported by the attending physician to the principal investigator within 24 h after the SAE becomes known.

The purpose of this study is to evaluate the non-inferiority of cyanoacrylate closure to surgical stripping in the treatment of incompetent saphenous veins. A sample size of 73 in each group will achieve 80% power to detect a non-inferiority margin difference between the group proportions of 96% in the cyanoacrylate group and 93% in the surgical-stripping group, assuming a dropout rate of 20%. Randomization will be performed by an independent statistical core at Kyung Hee University Hospital. The allocation of treatment will be done via a web-based randomization system, which returns the treatment group after the input of a participant’s study ID and inclusion/exclusion criteria.

The participants’ characteristics will be summarized using mean and standard deviation for continuous variables and frequency and percentage for categorical variables. A two-sided 95% confidence interval for a difference in occlusion rate between the two treatment groups will be calculated; then, whether the upper limit of confidence interval falls within the pre-determined margin of non-inferiority will be evaluated in order to prove the non-inferiority of cyanoacrylate closure to surgical stripping. Among the secondary outcomes, adverse events will be analyzed using chi-squared tests or Fisher’s exact tests as appropriate. SAEs will be compared using log-rank tests and survival curves constructed using Kaplan-Meier methods.