BACKGROUND
Venous Reflux/Venous Insufficiency

The venous system of the lower extremities consists of the superficial veins (this includes the great and small saphenous and accessory, or duplicate, veins that travel in parallel with the great and small saphenous veins), the deep system (popliteal and femoral veins), and perforator veins that cross through the fascia and connect the deep and superficial systems. One-way valves are present within all veins to direct the return of blood up the lower limb. Because the venous pressure in the deep system is generally greater than that of the superficial system, valve incompetence at any level may lead to backflow (venous reflux) with pooling of blood in superficial veins. Varicose veins with visible varicosities may be the only sign of venous reflux, although itching, heaviness, tension, and pain may also occur. Chronic venous insufficiency secondary to venous reflux can lead to thrombophlebitis, leg ulcerations, and hemorrhage. The CEAP classification of venous disease considers the clinical, etiologic, anatomic, and pathologic characteristics of venous insufficiency, ranging from class 0 (no visible sign of disease) to class 6 (active ulceration).

Treatment of Saphenous Veins and Tributaries

Saphenous veins include the great and small saphenous and accessory saphenous veins that travel in parallel with the great or small saphenous veins. Tributaries are veins that empty into a larger vein. Treatment of venous reflux has traditionally included the following:

• Identification by preoperative Doppler ultrasonography of the valvular incompetence
• Control of the most proximal point of reflux, traditionally by suture ligation of the incompetent saphenofemoral or saphenopopliteal junction
• Removal of the superficial vein from circulation, eg, by stripping of the great and/or small saphenous veins.
• Removal of varicose tributaries (at the time of the initial treatment or subsequently) by stab avulsion (phlebectomy) or injection sclerotherapy.

Thermal Ablation

Radiofrequency ablation is performed using a specially designed catheter inserted through a small incision in the distal medial thigh to within 1 to 2 cm of the saphenofemoral junction. The catheter is slowly withdrawn, closing the vein. Laser ablation is performed similarly; a laser fiber is introduced into the great saphenous vein under ultrasound guidance; the laser is activated and slowly removed, along the course of the saphenous vein. Cryoablation uses extreme cold. The objective of endovenous techniques is to injure the vessel, causing retraction and subsequent fibrotic occlusion of the vein. Technical developments since thermal ablation procedures were initially introduced include the use of perivenous tumescent anesthesia, which allows successful treatment of veins larger than 12 mm in diameter and helps to protect adjacent tissue from thermal damage during treatment of the small saphenous vein.

Sclerotherapy

The objective of sclerotherapy is to destroy the endothelium of the target vessel by injecting an irritant solution (either a detergent, osmotic solution, or chemical irritant), ultimately occluding the vessel. Treatment success depends on accurate injection of the vessel, an adequate injectate volume and concentration of sclerosant, and compression. Historically, larger veins and very tortuous veins were not considered good candidates for sclerotherapy due to technical limitations. Technical improvements in sclerotherapy have included the routine use of Duplex ultrasound to target refluxing vessels, luminal compression of the vein with anesthetics, and a foam/sclerosant injectate in place of liquid sclerosant. Foam sclerosants are produced by forcibly mixing a gas (eg, air or carbon dioxide) with a liquid sclerosant (eg, polidocanol or sodium tetradecyl sulfate). Physician-compounded foam is produced at the time of treatment. A commercially available microfoam sclerosant with a proprietary gas mix is available that is proposed to provide smaller and more consistent bubble size than what is produced with physician-compounded sclerosant foam.

Endovenous Mechanochemical Ablation

Endovenous mechanochemical ablation uses both sclerotherapy and mechanical damage to the lumen. Following ultrasound imaging, a disposable catheter with a motor drive is inserted into the distal end of the target vein and advanced to the saphenofemoral junction. As the catheter is pulled back, a wire rotates at 3500 rpm within the lumen of the vein, abrading the lumen. At the same time, a liquid sclerosant (sodium tetradecyl sulfate) is infused near the rotating wire. It is proposed that mechanical ablation allows for better efficacy of the sclerosant, and results in less pain and risk of nerve injury without the need for the tumescent anesthesia used with endovenous thermal ablation techniques (radiofrequency ablation, endovenous laser ablation).

Cyanoacrylate Adhesive

A cyanoacrylate adhesive is a clear, free-flowing liquid that polymerizes in the vessel via an anionic mechanism (ie, polymerizes into a solid material on contact with body fluids or tissue). The adhesive is gradually injected along the length of the vein in conjunction with ultrasound and manual compression. The acute coaptation halts blood flow through the vein until the implanted adhesive becomes fibrotically encapsulated and establishes chronic occlusion of the treated vein. Cyanoacrylate glue has been used as a surgical adhesive and sealant for a variety of indications, including gastrointestinal bleeding, embolization of brain arteriovenous malformations, and surgical incisions or other skin wounds.

Transilluminated Powered Phlebectomy

Transilluminated powered phlebectomy is an alternative to stab avulsion and hook phlebectomy. This procedure uses two instruments: an illuminator, which also provides irrigation, and a resector, which has an oscillating tip and suction pump. Following removal of the saphenous vein, the illuminator is introduced via a small incision in the skin and tumescence solution (anesthetic and epinephrine) is infiltrated along the course of varicosity. The resectoris then inserted under the skin from the opposite direction, and the oscillating tip is placed directly beneath the illuminated veins to fragment and loosen the veins from the supporting tissue. Irrigation from the illuminator is used to clear the vein fragments and blood through aspiration and additional drainage holes. The illuminator and resector tips may then be repositioned, thereby reducing the number of incisions needed when compared with stab avulsion or hook phlebectomy. It has been proposed that transilluminated powered phlebectomy might decrease surgical time, decrease complications such as bruising and lead to a faster recovery than established procedures.

Regulatory Status

In 2015, the VenaSeal Closure System (Sapheon, part of Medtronic) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval (P140018) process for the permanent closure of clinically significant venous reflux through endovascular embolization with coaptation. The VenaSeal Closure System seals the vein using a cyanoacrylate adhesive agent. FDA product code: PJQ.

In 2013, Varithena(R)(formerly Varisolve), a sclerosant microfoam made with a proprietary gas mix, was approved by the FDA under a new drug application (205-098) for the treatment of incompetent great saphenous veins, accessory saphenous veins, and visible varicosities of the great saphenous vein system above and below the knee.

The following devices were cleared for marketing by the FDA through the 501(k) process for endovenous treatment of superficial vein reflux:

In 1999, the VNUS Closure(R) System, a radiofrequency device, was cleared by the FDA through the 510(k) process for "endovascular coagulation of blood vessels in patients with superficial vein reflux." In 2005, the VNUS RFS(R) and RFSFlex(R) devices were cleared by the FDA for "use in vessel and tissue coagulation including treatment of incompetent (ie, refluxing) perforator and tributary veins." In 2008, the modified VNUS ClosureFast(R) Intravascular Catheter was cleared by the FDA through the 510(k) process. FDA product code: GEI.

In 2002, the Diomed 810 nm surgical laser and EVLT(R) (endovenous laser therapy) procedure kit were cleared by the FDA through the 510(k) process ".....for use in the endovascular coagulation of the great saphenous vein of the thigh in patients with superficial vein reflux." FDA product code: GEX.

In 2005, a modified Erbe Erbokryo cryosurgical unit (Erbe USA) was approved by the FDA for marketing. A variety of clinical indications are listed, including cryostripping of varicose veins of the lower limbs. FDA product code: GEH.

In 2003, the Trivex system (InaVein), a device for transilluminated powered phlebectomy, was cleared by the FDA through the 510(k) process for "ambulatory phlebectomy procedures for the resection and ablation of varicose veins." FDA product code: DNQ.

In 2008, the ClariVein Infusion Catheter (Vascular Insights) was cleared by the FDA through the 510(k) process (K071468) for mechanochemical ablation. The FDA determined that this device was substantially equivalent to the Trellis Infusion System (K013635) and the Slip-Cath Infusion Catheter (K882796). The system includes an infusion catheter, motor drive, stopcock, and syringe, and is intended for the infusion of physician-specified agents in the peripheral vasculature. FDA product code: KRA

Regulatory Status

• None

A. Treatment of the great or small saphenous veins by surgery (ligation and stripping), endovenous thermal ablation (radiofrequency or laser), microfoam sclerotherapy, or cyanoacrylate adhesive is considered medically necessary for symptomatic varicose veins/venous insufficiency when the following criteria have been met:

1. There is demonstrated saphenous reflux and CEAP [Clinical-Etiology-Anatomy-Pathophysiology] class C2 or greater; AND

2. Copies of original medical records submitted either hard copy or electronically documenting one or more of the following indications:

• Ulceration secondary to venous stasis; OR
• Recurrent superficial thrombophlebitis; OR
• Hemorrhage or recurrent bleeding episodes from a ruptured superficial varicosity; OR
• Persistent pain, swelling, itching, burning, or other symptoms associated with saphenous reflux, AND the symptoms significantly interfere with activities of daily living, AND conservative management including compression therapy for at least 3 months has not improved the symptoms.
B. Treatment of great or small saphenous veins by surgery, endovenous radiofrequency or laser ablation, microfoam sclerotherapy, or cyanoacrylate adhesive that does not meet the criteria described above is considered cosmetic and not medically necessary.

A. Treatment of accessory saphenous veins by surgery (ligation and stripping), endovenous radiofrequency or laser ablation, microfoam sclerotherapy, or cyanoacrylate adhesive is considered medically necessary for symptomatic varicose veins/venous insufficiency when the following criteria have been met:

1. Incompetence of the accessory saphenous vein is isolated; AND

2. There is demonstrated accessory saphenous reflux; AND

3. Copies of original medical records submitted either hard copy or electronically documenting one or more of the following indications:

• Ulceration secondary to venous stasis; OR
• Recurrent superficial thrombophlebitis; OR
• Hemorrhage or recurrent bleeding episodes from a ruptured superficial varicosity; OR
• Persistent pain, swelling, itching, burning, or other symptoms associated with saphenous reflux, AND the symptoms significantly interfere with activities of daily living, AND conservative management including compression therapy for at least 3 months has not improved the symptoms.
B. Concurrent treatment of the accessory saphenous veins along with the great or small saphenous veins is considered medically necessary when criteria is met for each vein and there is documentation of anatomy showing that the accessory saphenous vein discharged directly into the common femoral vein.

C. Treatment of accessory saphenous veins by surgery, endovenous radiofrequency or laser ablation, microfoam sclerotherapy, or cyanoacrylate adhesive that do not meet the criteria described above is considered cosmetic and not medically necessary.

A. The following treatments are considered medically necessary as a component of the treatment of symptomatic varicose tributaries when performed either at the same time or following prior treatment (surgical, radiofrequency or laser, microfoam sclerotherapy, or cyanoacrylate adhesive) of the saphenous veins (none of these techniques has been shown to be superior to another):
• Stab avulsion
• Hook phlebectomy
• Sclerotherapy
• Transilluminated powered phlebectomy

[NOTE: According to the REACTIV trial, a small proportion of patients may present with tributary varicosities in the absence of saphenous reflux. In this situation, treatment of symptomatic varicosities without prior or concurrent treatment of the saphenous veins is considered medically necessary when (1) the veins are visible and protruding above the surface of the skin; (2) the tributary varicosities are at least 2 mm in diameter; (3) the symptoms significantly interfere with activities of daily living; AND (4) conservative management including compression therapy for at least 3 months has not improved the symptoms.

Based on information from an article by Lee DK, et al (Ultrasonography 2017) on ultrasonography of the lower extremity veins: anatomy and basic approach, tributaries of the great saphenous vein (GSV) are variable between individuals. Despite attempts to standardize the terminology, various terms have been used and many of the tributaries are difficult to name. There are, however, general rules for naming them. If the course of the tributary is parallel to the GSV, it is called an accessory GSV (e.g., anterior accessory GSV, posterior accessory GSV). When a tributary courses obliquely, it is called the circumflex vein (e.g., posterior thigh circumflex vein, anterior calf circumflex vein).

The small saphenous vein (SSV) arises from the dorsal pedal arch and ascends posterolaterally from behind the lateral malleolus. It ascends along the middle of the calf and ends in the popliteal vein in the posterior knee. However, there are many variations in the termination of the SSV. It may end without connection to the popliteal vein. It may also branch out a cranial extension (the vein of Giacomini) that goes upward to join the GSV through the posterior thigh circumflex vein. The Giacomini vein is commonly described as a thigh extension of the SSV.]

B. Treatment of symptomatic varicose tributaries when performed either at the same time or following prior treatment of saphenous veins using any other techniques than noted above is considered investigational.

A. Surgical ligation (including subfascial endoscopic perforator surgery) or endovenous radiofrequency or laser ablation of incompetent perforator veins is considered medically necessary as a treatment of leg ulcers associated with chronic venous insufficiency when the following conditions have been met:
• There is demonstrated perforator reflux; AND
• The superficial saphenous veins (great, small, or accessory saphenous and symptomatic varicose tributaries) have been previously eliminated; AND
• Ulcers have not resolved following combined superficial vein treatment and compression therapy for at least 3 months; AND
• The venous insufficiency is not secondary to deep venous thromboembolism.
B. Ligation or ablation of incompetent perforator veins performed concurrently with superficial venous surgery is not medically necessary.

Treatment of telangiectasia such as spider veins, angiomata, and hemangiomata is considered cosmetic and not medically necessary.

Techniques for conditions not specifically listed above are investigational, including, but not limited to:
• Sclerotherapy techniques, other than microfoam sclerotherapy, of great, small, or accessory saphenous veins
• Sclerotherapy of perforator veins
• Sclerotherapy of isolated tributary veins without prior or concurrent treatment of saphenous veins (please see note under policy statement III.A.)
• Stab avulsion, hook phlebectomy, or transilluminated powered phlebectomy of perforator, great or small saphenous, or accessory saphenous veins
• Endovenous radiofrequency or laser ablation of tributary veins
• Endovenous cryoablation of any vein
• Mechanochemical ablation of any vein.

Table PG1. Clinical Portion of the CEAP Classification System

Class	Definition
C0	No visible or palpable signs of venous disease
C1	Telangiectasies or reticular veins
C2	Varicose veins
C2r	Recurrent varicose veins
C3	Edema
C4	Changes in skin and subcutaneous tissue secondary to CVD
C4a	Pigmentation and eczema
C4b	Lipodermatosclerosis or atrophie blanche
C4C	Corona phlebectatica
C5	Healed
C6	Active venous ulcer
C6r	Recurrent active venous ulcer
S	Symptomatic
A	Asymptomatic

Adapted from http://www.veinforum.org/uploadDocs/1/Revised-CEAP-Classification---May-2004.pdf.
CEAP: Clinical, Etiologic, Anatomic, Pathophysiologic classification system.

It should be noted that the bulk of the literature discussing the role of ultrasound guidance refers to sclerotherapy of the saphenous vein, as opposed to the varicose tributaries. When ultrasound guidance is used to guide sclerotherapy of the varicose tributaries, it would be considered either not medically necessary or incidental to the injection procedure.

Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that Treatment of Varicose Veins/Venous Insufficiency is covered when LCD L34924 criteria are met. Please refer to Novitas Solutions Inc, LCD Treatment of Varicose Veins and Venous Stasis Disease of the Lower Extremities for eligibility and coverage information. Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

Local Coverage Article: Treatment of Varicose Veins and Venous Stasis Disease of the Lower Extremities (A55229). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

The number of medically necessary sclerotherapy injection sessions varies with the number of anatomical areas that have to be injected, as well as the response to each injection.

More than 20 injections per leg, per session is noncovered

It is not expected that more than the following numbers of services are medically necessary:

· Three injections per vessel treated.
· Three sclerotherapy sessions for each leg.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Treatment of Saphenous Veins
Clinical Context and Therapy Purpose

Treatment of venous reflux/venous insufficiency seeks to reduce abnormal pressure transmission from the deep to the superficial veins. Conservative medical treatment consists of elevation of the extremities, graded compression, and wound care when indicated. Conventional surgical treatment consists of identifying and correcting the site of reflux by ligation of the incompetent junction followed by stripping of the vein to redirect venous flow through veins with intact valves. While most venous reflux is secondary to incompetent valves at the saphenofemoral or saphenopopliteal junctions, reflux may also occur at incompetent valves in the perforator veins or the deep venous system. The competence of any single valve is not static and may be pressure-dependent. For example, accessory saphenous veins may have independent saphenofemoral or saphenopopliteal junctions that become incompetent when the great or small saphenous veins are eliminated, and blood flow is diverted through the accessory veins.

The following section addresses the efficacy of the conventional treatments, specifically on the appropriate length of a trial of compression therapy and evaluation of recurrence rates for surgical treatment (ie, ligation and stripping) compared with compression therapy.

Compression Therapy

A Cochrane review by O'Meara et al (2009) evaluated compression for venous leg ulcers included 39 RCTs with 47 different comparisons.^1, This review was updated in 2012 and included 48 RCTs with 59 different comparisons.^2, Most RCTs were small. Measures of healing were the time to complete healing, the proportion of ulcers healed within the trial period (typically 12 weeks), the change in ulcer size, and the rate of change in ulcer size. Evidence from eight trials indicated that venous ulcers healed more rapidly with compression than without. Findings suggested that multicomponent systems (bandages or stockings) were more effective than single-component compression. Also, multicomponent systems containing an elastic bandage appeared more effective than those composed mainly of inelastic constituents. Although these meta-analyses did not include time to healing, studies included in the review reported the mean time to ulcer healing was approximately two months, while the median time to healing in other reports was three to five months.

A Cochrane review by Shingler et al (2011) assessed compression stockings as initial treatment for varicose veins in patients without venous ulceration.^3, Selected were 7 studies involving 356 participants with varicose veins without healed or active venous ulceration (CEAP [Clinical, Etiology, Anatomy, Pathophysiology] class C2-C4). Six studies compared different types or pressures of stockings. Subjectively, participants' symptoms improved, but results were not compared with a control arm. Due primarily to inadequate reporting, the methodologic quality of the selected trials was unclear. Meta-analyses were not performed due to inadequate reporting and suspected heterogeneity. Reviewers concluded that there was insufficient high-quality evidence to determine whether compression stockings were effective as the sole and initial treatment of varicose veins in patients without venous ulceration, or whether any type of stocking was superior to another type.

Ligation and Stripping

Systematic literature reviews have indicated a similar healing rate of venous ulcers with superficial vein surgery and conservative compression treatments but a reduction in ulcer recurrence rate with surgery.^4,5,In general, recurrence rates after ligation and stripping are estimated at 20% in short-term follow-up. Jones et al (1996) reported on the results of a trial that randomized 100 patients with varicose veins to ligation alone or ligation plus stripping.^6, At 1 year, reflux was detected in 9% of patients, rising to 26% at 2 years. Rutgers and Kitslaar (1994) reported on the results of a trial that randomized 181 limbs to ligation and stripping or to ligation plus sclerotherapy.^7, At 2 years, Doppler ultrasound demonstrated reflux in approximately 10% of patients after ligation and stripping, increasing to 15% at 3 years.

Alternatives to Ligation and Stripping

The purpose of endovenous thermal ablation (radiofrequency or laser), microfoam sclerotherapy, mechanochemical ablation (MOCA), cyanoacrylate adhesive (CAC), or cryoablation in patients who have varicose veins/venous insufficiency and saphenous vein reflux is to provide a treatment option that is an alternative to or an improvement on existing treatments.

The question addressed in this policy is: Do these alternative treatments improve the net health outcome in individuals who have varicose veins/venous insufficiency and saphenous vein reflux?

The following PICO was used to select literature to inform this policy.

Patients

The relevant populations of interest are those who have varicose veins/venous insufficiency and saphenous vein reflux.

Interventions

The therapies being considered are endovenous thermal ablation (radiofrequency or laser), microfoam sclerotherapy, mechanochemical ablation, cyanoacrylate adhesive, or cryoablation.

Comparators

Established treatments for varicose veins/venous insufficiency and saphenofemoral junction reflux are conservative therapy with compression bandages and ligation and stripping, with which the endovenous thermal procedures are compared. The less invasive endovenous thermal ablation (radiofrequency or laser) have become the standard treatments by which the newer treatments are compared. Endovenous thermal ablation techniques require tumescent anesthesia, which involves multiple injections along the vein and is associated with moderate pain. Compression stockings and avoidance of strenuous activities are recommended. Procedures that have more recently been developed (MOCA, CAC, and cryotherapy) do not require tumescent anesthesia are now compared with the thermal ablation procedures.

Outcomes

Outcomes of interest for venous interventions include healing and recurrence, recanalization of the vein, and neovascularization. Recanalization is the restoration of the lumen of a vein after it has been occluded; this occurs more frequently following treatment with endovenous techniques. Neovascularization is the proliferation of new blood vessels in tissue and occurs more frequently following vein stripping. Direct comparisons of the durability of endovenous and surgical procedures are complicated by these mechanisms of recurrence. Relevant safety outcomes include the incidence of paresthesia, thermal skin injury, thrombus formation, thrombophlebitis, wound infection, and transient neurologic effects.

Specific measures may include the visual analog score (VAS) for pain, the Venous Clinical Severity Score (VCSS), and the Aberdeen Varicose Veins Questionnaire (AVVQ). AVVQ scores range from 0 to 100 (worst possible quality of life). Follow-up at one and two years from RCTs is of interest to monitor treatment success (vein occlusion and recanalization), with follow-up to five years to assess durability of the treatment.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

A Cochrane review by Nesbitt et al (2014) compared endovenous ablation (radiofrequency and laser) with foam sclerotherapy or ligation and stripping for saphenous vein varices.^8, Included in the review were 13 randomized studies (total n=3081 patients). The overall quality of the evidence was moderate. There was no significant difference between sclerotherapy and surgery in the rate of recurrence, as rated by clinicians (odds ratio [OR], 1.74; p=0.06) or for symptomatic recurrence (OR=1.28). For endovenous laser ablation vs surgery, there were no significant differences between the treatment groups for clinician-reported or symptomatic recurrence, or for recanalization. Neovascularization and technical failure were reduced in the laser group (OR=0.05, p<0.001; OR=0.29, p<0.001, respectively). For endovenous radiofrequency ablation (RFA) versus surgery, there were no significant differences between groups in clinician-reported recurrence, recanalization, neovascularization, or technical failure. Reviewers concluded that sclerotherapy, endovenous laser ablation, and RFA are at least as effective as surgery in the treatment of great saphenous varicose veins.

A Cochrane review by Paravastu et al (2016) compared endovenous laser ablation or RFA with surgical repair for short saphenous veins with reflux at the saphenopopliteal junction.^9, Three RCTs identified compared endovenous laser ablation with surgery. There was moderate-quality evidence that recanalization or persistence of reflux at 6 weeks occurred less frequently after endovenous laser ablation than after surgery (OR=0.07; 95% confidence interval [CI], 0.02 to 0.22), and low-quality evidence that recurrence of reflux was lower after endovenous laser ablation at 1 year (OR=0.24; 95% CI, 0.07 to 0.77).

Randomized Controlled Trials

The largest RCT was reported by Brittenden et al (2014) and compared foam sclerotherapy, endovenous laser ablation, and surgical treatment in 798 patients.^10, The trial was funded by the U.K.'s National Institute for Health Research. Veins greater than 15 mm in diameter were excluded from the trial. At the 6-week follow-up visit, patients assigned to treatment with foam or laser had the option of treatment with foam for any residual varicosities; this optional treatment was performed in 38% of patients in the foam group and 31% of patients in the endovenous laser ablation group. Disease-specific quality of life was similar for the laser and surgery groups. The frequency of procedural complications was similar for the foam sclerotherapy (6%) and surgery (7%) groups but was lower for the laser group (1%).

The 2012 Comparable effectiveness of endovenous laser ablation and high ligation with stripping of the great saphenous vein (RELACS) study randomized 400 patients to endovenous laser ablation performed by a surgeon at 1 site or to ligation and stripping performed by a different surgeon at a second location.^11, At two-year follow-up, there were no significant differences between groups for clinically recurrent varicose veins, medical condition measured on the Homburg Varicose Vein Severity Score, or disease-related quality of life. Saphenofemoral reflux was detected by ultrasonography more frequently after endovenous laser treatment (17.8% vs 1.3%). The follow-up rate at five years was 81%.^12, Same-site recurrences were more frequent in the endovenous laser ablation group (18% with endovenous laser ablation vs 5% with surgery, p=0.002), but different-site recurrences were more frequent in the surgically treated group (50% with surgery vs 31% with endovenous laser ablation, p=0.002). Overall, there was no significant difference in recurrence rates between groups. There were also no significant differences between groups in disease severity or quality of life at five years.

Christenson et al (2010) compared endovenous laser ablation with ligation and stripping in 200 limbs (100 in each group).^13, At 1-year follow-up, 98% of the limbs were reported to be free of symptoms. At two-year follow-up, the endovenous laser ablation group had two veins completely reopened and five partially reopened, which was significantly greater than in the ligation and stripping group. In the 2013 Comparative Study of the Treatment of Insufficient Greater Saphenous Vein: Surgery vs Ultrasound Guided Sclerotherapy With Foam and Endovenous Laser Therapy (MAGNA) trial, 223 consecutive patients (240 legs) with great saphenous vein reflux were randomized to endovenous laser ablation, ligation and stripping, or foam sclerotherapy.^14, At one-year follow-up, the anatomic success rates were similar for endovenous laser ablation (88.5%) and stripping (88.2%), which were both superior to foam sclerotherapy (72.2%). Ten percent of the stripping group showed neovascularization. At five years, health-related quality of life and CEAP classification improved in all groups with no significant differences among them.^15, Grade I neovascularization was higher in the conventional surgery group (27% vs 3%, p<0.001), while grade II neovascularization did not differ significantly between surgical (17%) and endovenous laser ablation (13%) groups.

Wallace et al (2018) published the five-year outcomes of an RCT consisting of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins comparing surgery and endovenous laser ablation (EVLA) as treatments for symptomatic great saphenous varicose veins.^16, Data from 218 patients were available at 5-year follow-up. The clinical recurrence rate was 34.4% for the surgery group and 20.9% for EVLA (p=0.010). Patients-quality of life, assessed using EuroQol Five Dimensions (EQ-5D) and AVVQ, was significantly improved from baseline for both surgery (EQ-5D: 0.859 to 1.0, p=0.002; AVVQ: 13.69 to 4.59, p<0.001) and EVLA (EQ-5D: 0.808 to 1.0, p=0.002; AVVQ: 12.73 to 3.35, p<0.001). Technical success assessed by duplex ultrasound examination was 85.4% for surgery and 93.2% for EVLA (p=0.074).

The primary limitation of all of the studies was the lack of blinding.

Table 1. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Brittenden (2014)10,	UK	11	2008-2012	Individuals with primary varicose veins	Foam sclero-therapy (n=286) or EVLA (n=210)	Surgical treatment (n=289)
Rass (2012);11,RELACS	US	2	2004-2007	Individuals with GSV insufficiency	EVLA (n=185)	Surgical treatment (n=161)
Wallace (2018)16,	UK	1	2004-2009 1	Individuals with GSV insufficiency	EVLA (n=108)	Surgical treatment (n=110)

RCT: randomized controlled trial; GSV: great saphenous vein; EVLA: endovenous laser ablation.
¹ Date of original intervention study

Table 2. Summary of Key RCT Results

Study	AVVQ Score at Baseline; 6 Months	Frequency of Procedural Complications	Rate of Same-Site Recurrence	Clinically Recurrent Varicose Veins	AVVQ Score at Baseline; 5 years
Brittenden (2014)10,
Foam	17.69.9; 9.17.9	6%
Laser	17.89.1; 7.98.4	1%
Surgery	18.29.1; 7.87.5	7%
P-value		<0.001
Rass (2012)11, RELACS
Laser			18%	16.2%
Surgery			5%	23.1%
P-value			0.002	0.15
Wallace (2018)
Laser				20.9%	13.69; 4.59
Surgery				34.3%	12.73; 3.35
P-value				0.010	<0.001

AVVQ: Aberdeen Varicose Veins Questionnaire; RCT: randomized controlled trial; RELACS: A prospective, Randomised, two-centre study to evaluate surgical treatments of great saphenous vein insufficiency: Endovenous LAser treatment versus Crossectomy and Stripping.

The literature on the isolated treatment of the anterior accessory saphenous vein is limited. In a study by Theivacumar et al (2009), outcomes from a cohort of 33 patients who underwent endovenous laser ablation of the anterior accessory saphenous vein were compared with 33 matched controls undergoing endovenous laser ablation of the great saphenous vein.^17, For 21 (64%) of the patients in the accessory saphenous vein group, there had been no previous treatment of the great saphenous vein. At 12-month follow-up, there was no evidence of reflux in these patients, and the treated accessory saphenous vein was not visible with ultrasound. AVVQ scores had improved in both groups, with no significant difference between them. Patient satisfaction scores were also similar.

Subsection Summary: Endovenous Thermal Ablation (Laser or Radiofrequency)

There are multiple large RCTs and systematic reviews of RCTs assessing endovenous ablation using radiofrequency or laser energy of the saphenous veins. Comparison with ligation and stripping at 2- to 5-year follow-up has indicated similar recurrence rates for the different treatments. Evidence has suggested that ligation and stripping may lead to neovascularization, while thermal ablation may lead to recanalization, resulting in similar outcomes for endovenous thermal ablation and surgery. Laser ablation and RFA have similar success rates.

Treatment of Saphenous Veins: Sclerotherapy
Physician-Compounded Sclerotherapy
Review of Evidence

Hamann et al (2017) conducted a meta-analysis of RCTs reporting 5-year follow-up.^18, The meta-analysis (3 RCTs, 10 follow-up studies) included 611 legs treated with endovenous laser ablation, 549 treated with high ligation and stripping, 121 with sclerotherapy, and 114 with high ligation and endovenous laser ablation. Ultrasound-guided sclerotherapy had significantly worse outcomes than the other 3 treatments, with anatomic success rates of 34% for sclerotherapy compared with 83% to 88% for the other 3 treatments (p<0.001).

In the 2013 MAGNA trial (previously described), 223 consecutive patients (240 legs) with great saphenous vein reflux were randomized to endovenous laser ablation, ligation and stripping, or physician-compounded foam sclerotherapy (1 mL aethoxysclerol 3%: 3 cc air).^14, At 1-year follow-up, the anatomic success rate of foam sclerotherapy (72.2%) was inferior to both endovenous laser ablation (88.5%) and stripping (88.2%). Twenty-one patients in the sclerotherapy group had partial occlusion with reflux, though the clinical complaint was completely relieved. At 5-year follow-up, obliteration or absence of the great saphenous vein was observed in only 23% of patients treated with sclerotherapy compared with 85% of patients who underwent conventional surgery and 77% of patients who underwent endovenous laser ablation.^15, Thirty-two percent of legs treated initially with sclerotherapy required one or more reinterventions during follow-up compared with 10% in the conventional surgery and endovenous laser ablation groups. However, clinically relevant grade II neovascularization was higher in the conventional surgery (17%) and endovenous laser ablation (13%) groups than in the sclerotherapy group (4%). EQ-5D scores improved equally in all groups.

Vahaaho et al (2018) published a study looking at the 5-year follow-up of patients with symptomatic great saphenous vein (GSV) insufficiency.^19, Between 2008 and 2010, 166 individuals were randomized to receive open surgery, EVLA, or ultrasound-guided foam sclerotherapy. The GSV occlusion rate was 96% (95% CI: 91-100%) for open surgery, 89% (95% CI: 82-98%) for EVLA, and 51% (95% CI: 38-64%) for ultrasound-guided foam sclerotherapy (p<0.001). For patients with no additional treatment during follow-up, occlusion rates for open surgery, EVLA, and ultrasound-guided foam sclerotherapy were 96%, 89%, and 41%, respectively. The study was limited by the lack of blinding and by non-standardized foam application.

A noninferiority trial by Shadid et al (2012) compared foam sclerotherapy with ligation and stripping in 430 patients.^20,The analysis was per protocol. Forty (17%) patients had repeat sclerotherapy. At 2 years, the probability of clinical recurrence was similar in both groups (11.3% sclerotherapy vs 9.0% ligation and stripping), although reflux was significantly more frequent in the sclerotherapy group (35% vs 21%). Thrombophlebitis occurred in 7.4% of patients after sclerotherapy. Two serious adverse events in the sclerotherapy group (deep venous thrombosis, pulmonary emboli) occurred within one week of treatment. Lam et al (2018) reported 8-year follow-up with 53% of the patients in the original trial.^21, All measures of treatment success (eg, symptomatic GSV reflux, saphenofemoral junction failure, and recurrent reflux in the GSV) were lower in the physician-compounded sclerotherapy group compared to the ligation and stripping group.

Microfoam Sclerotherapy
Review of Evidence

In 2013, polidocanol (Varithena) microfoam was approved under a new drug application for the treatment of varicose veins. Efficacy data derived from two randomized, blinded, multicenter studies.^22, One compared polidocanol at 0.5%, 1.0%, and 2.0% with endovenous placebo or a subtherapeutic dose of polidocanol foam. The primary endpoint was an improvement in symptoms at week eight, as measured by the Varicose Vein Symptoms Questionnaire. The improvement in symptoms was greater in the pooled polidocanol treatment group (p<0.001) and in each of the individual dose-concentration groups compared with vehicle alone. Secondary and tertiary endpoints (appearance, duplex ultrasound response, quality of life) were also significantly better for the polidocanol groups compared with controls. This second study, called to evaluate the efficacy and safety of polidocanal endovenous microfoam 0.5% and 1.0% compared to placebo for the treatment of saphenofemoral junction incompetence (VANISH-2), was published by Todd et al (2014)^23, At the 8-week assessment, there was elimination of reflux and/or occlusion of the previously incompetent vein in 85.6% of the combined 0.5% and 1.0% groups, 59.6% of patients in the 0.125% group, and 1.8% of the placebo group. Analysis of data from both studies showed a dose-response from 0.5% to 2.0% for improvement in appearance and from 0.5% to 1.0% for Duplex responders. The polidocanol 1.0% dose was selected for the U.S. Food and Drug Administration (FDA) approval. Safety analysis found deep vein thrombosis detected by ultrasound in 2.8% of polidocanol-treated patients, with 1% of patients having proximal symptomatic thrombi; these patients were treated with anticoagulants. There was no sign of an increase in neurologic adverse events, and there were no adverse cardiac or cardiopulmonary effects following treatment with polidocanol injectable foam. Rates of occlusion with Varithena are similar to those reported for endovenous laser ablation or stripping. A randomized trial comparing endovenous laser ablation and stripping with this new preparation of foam sclerotherapy is needed to evaluate its comparative effectiveness. Evaluation out to five years is continuing.

Vasquez et al (2017) reported on a double-blinded RCT that evaluated the addition of polidocanol microfoam to endovenous thermal ablation.^24, A total of 117 patients who were candidates for both endovenous thermal ablation and treatment of visible varicosities received endovenous thermal ablation plus placebo (n=38) or polidocanol 0.5% (n=39) or 1% (n=40). At 8-week follow-up, physician-blinded vein appearance was significantly better with the combined polidocanol groups (p=0.001), but the improvement in patient ratings was not statistically significant. At 6-month follow-up, the percentages of patients who achieved a clinically meaningful change were significantly higher in both physician (70.9% vs 42.1%, p=0.001) and patient (67% vs 50%, p=0.034) ratings. The proportion of patients who received additional treatment for residual varicosities between week 8 and month 6 was modestly reduced (13.9% for the polidocanolvs 23.7% for placebo, p=0.037).

Subsection Summary: Sclerotherapy

For physician-compounded sclerotherapy, there is high variability in success rates of the procedure and some reports of serious adverse events. Results of a noninferiority trial of physician-compounded sclerotherapy indicated that once occluded, recurrence rates at two years are similar to those of ligation and stripping. By comparison, rates of occlusion with the FDA-approved microfoam sclerotherapy (polidocanol 1%) are similar to those reported for endovenous laser ablation or stripping.

Treatment of Saphenous Veins: Mechanochemical Ablation
Review of Evidence
Randomized Trials

Four RCTS with over 100 patients each (range, 132 to 213) have been identified that compared MOCA to thermal ablation. Study characteristics and study results are presented in Tables 3 and 4. Study limitations are described in Tables 5 and 6.

Two publications (Bootun et al [2016], Lane et al [2017]) reported on early results from an RCT of 170 patients that compared ClariVein with RFA.^25,26, Maximum visual analog scale pain scores (out of 100) during the procedure were significantly lower in the MOCA group (median, 15 mm) than in the RFA group (median, 34 mm; p=0.003). Average visual analog scale pain scores during the procedure were also modestly lower in the MOCA group (median, 10 mm) than in the RFA group (median, 19.5 mm; p=0.003). Occlusion rates, clinical severity scores, disease-specific quality of life, and generic quality of life scores were similar between groups at one and six months. Limitations of this study are described in Tables 5 and 6. Only 71% of patients were available for follow-up at 6 months, limiting the evaluation of closure rates at this time point (see Table 6).

Vahaaho et al (2019) reported an RCT that compared MOCA with endovenous thermal ablation (EVLA or RFA).^19, Liquid sclerosant at a concentration of 1.5% was used. Out of 132 patients enrolled, 7 patients were later excluded and 117 (88.6%) attended the 1-year follow-up evaluation. Occlusion of the great saphenous vein was observed in 45 of 55 (82%) of the MOCA group compared to 100% of the EVLA and RFA groups (p=0.002). Another randomized trial (Lam et al [2016]) reported interim results of a dose-finding study, finding greater closure with use of polidocanol 2% or 3% (liquid) than with polidocanol 1%.^27,Therefore, it is uncertain whether the concentration of sclerosant in the study by Vahaaho et al (2019) was optimal (see Table 5).

Three percent policocanol was tested in the Mechanochemical endovenous Ablation to RADiOfrequeNcy Ablation (MARADONA) non-inferiority trial reported by Holewijn et al (2019).^28, Athough the study was powered for 400 participants, only 213 patients were randomized before reimbursement for the procedure was suspended. Pain scores in the 14 days after the procedure were slightly lower, but hyperpigmentation was higher. Anatomic failures were significantly greater in the MOCA group at 1 year and approached significance at 2-years; with the note that the study was underpowered for anatomic failures because of the early stoppage of the study. At 1 and 2-years, clinical and quality of life outcomes were similar in the two groups.

A fourth RCT reported by Mohamed et al (2020) is the ongoing Randomised Clinical Trial Comparing Endovenous Laser Ablation and Mechanochemical Ablation (ClariVein) in the Management of Superficial Venous Insufficiency (LAMA).^29, Patients (n=150) were randomized to MOCA with 1.5% sodium tetradecyl sulfate or to EVLA. Anatomic success (occlusion) rates were lower in the MOCA group 77% compared to the EVLA group (91%) with no significant difference between the 2 treatments in intraprocedural pain scores. In contrast to the difference in anatomical occlusion rates, clinical severity and quality of life scores were not significantly different between the groups at 1 year follow-up. Follow-up is continuing to evaluate durability of the treatments.

Table 3. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Booton et al (2016),25, Lane et al (2017)26,				170 patients with varicose veins	MOCA	RFA
Vahaaho et al (2019) 19,				132 patients with varicose veins	MOCA with 1.5% polidocanol	Thermal ablation (EVLA or RFA)
Holewijn et al (2019)28, (MARADONA)	E.U.	4	2012- 2015	213 patients with GSV incompetence and CEAP C2 - C5	MOCA wit 2 mL of 3% polidocanol for the first 10 to 15 cm and 1.5% polidocanol for the remainder	RFA
Mohamed et al (2020)29, LAMA	U.K.	1	2015-2018	150 patients with symptomatic superficial venous incompetence CEAP grades 2 to 6	MOCA (n=75) with 1.5% sodium tetradecyl sulfate	EVLA (n=75)

EVLA: endovenous laser ablation; CEAP: clinical etiologic anatomic pathological; GSV: Great saphenous vein; LAMA: A Randomised Clinical Trial Comparing Endovenous Laser Ablation and Mechanochemical Ablation (ClariVein) in the Management of Superficial Venous Insufficiency;
MOCA: mechanochemical ablation; RCT: randomized controlled trial; RFA: radiofrequency ablation.

Table 4. Summary of Key RCT Results

Study	Pain	Post-procedure Occlusion Rate	Occlusion Rate at Follow-up	Clinical Severity	Clinical Severity at Follow-up		Quality of Life
Booton (2016),25, Lane (2017)26,	During Procedure -VAS		6 mo occlusion rates
N			71%		71%
MOCA	10 mm
RFA	19.5 mm
p-value	0.003	NS	NS	NS	NS		NS
Vahaaho (2019)19,			1 yr		1 yr
N			117 (88.6%)		117 (88.6%)
MOCA			45 of 55 (82%)
EVLA or RFA			100%
p-Value			0.002
Holewijn et al (2019)28, MARADONA	For 14 days after the procedure median (range)	30 day failure rate	1 yr recanalization rate	2 yr recanalization rate	1 yr VCSS	2 yr VCSS	AVVQ improved
N			153 (72%)	157 (73%)	153 (72%)	157 (73%)
MOCA	0.2 (0.0-0.8)	5 (4.9%)	15 (16.5%)	21 (20%)	1.8	1.0	88%
RFA	0.5 (0.2-1.3)	1 (1%)	5 (5.8%)	12 (11.7%)	1.7	1.0	89%
p-Value	0.01	0.10	0.025	0.066	0.695	0.882	0.90
Mohamed et al (2020)29, LAMA	Median (IQR)		Occlusion at 1 yr		VCSS		AVVQ Median (IQR)
N			138 (92%)
MOCA	15 (9-29)		53/69 (77%)				2.0 (0.0–5.3)
EVLA	22 (9–44)		63/69 (91%)				2.0 (0.0–4.8)
p-Value	0.21		0.020		NS		NS

AVVQ: Aberdeen varicose vein questionnaire; EVLA: endovenous laser ablation; IQR: intraquartile range; LAMA: A Randomised Clinical Trial Comparing Endovenous Laser Ablation and Mechanochemical Ablation (ClariVein) in the Management of Superficial Venous Insufficiency
MARADONA: Mechanochemical endovenous Ablation to RADiOfrequeNcy Ablation; MOCA: mechanochemical ablation; NS: not significant; RCT: randomized controlled trial; RFA: radiofrequency ablation; VAS: visual analog scale.; VCSS: venous clinical severity score

Table 5. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Bootun et al (2016);25, Lane et al (2017)26,				1.Primary outcome was pain during the procedure	1. Outcomes only out to 6 mo, which is insufficient to assess durability
Vahaaho et al (2019)19,	4. Strict inclusion criteria that may not be representative of intended use.	3. The concentration of sclerosant (1.5% polidocanol) may not have been optimal.			1. Outcomes only out to 1 yr, which is insufficient to assess durability
Holewijn et al (2019)28, (MARADONA)	4. Patients with bilateral reflux were excluded due to dosing limits of polidocanol
Mohamed et al (2020) LAMA29,					1. Outcomes out to 1 yr, follow-up is continuing

LAMA: A Randomised Clinical Trial Comparing Endovenous Laser Ablation and Mechanochemical Ablation (ClariVein) in the Management of Superficial Venous Insufficiency; MARADONA: Mechanochemical endovenous Ablation to RADiOfrequeNcy Ablation
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective  Reportingc	Follow-Upd	Powere	Statisticalf
Bootun et al (2016);25, Lane et al (2017)26,		1. Patients not blinded to treatment (assessors of duplex ultrasound were blinded)		1. There was high loss to follow-up (76% follow-up at 1 mo and 71% follow-up at 6 mo)
Vahaaho et al (2019)19,		1, 2, 3. Patients, surgeons, and assessors were not blinded to treatment
Holewijn et al (2019)28, (MARADONA)		1, 2, 3. Patients, surgeons, and assessors were not blinded to treatment			3. Underpowered for anatomic success due to early termination of recruitment	4. Results of non-inferiority analysis were not reported
Mohamed et al (2020) LAMA29,		1, 2, 3. Patients, surgeons, and assessors were not blinded to treatment				2. 14 day pain scores were not analyzed by repeated measures ANOVA

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

A prospective cohort study that had 5 year follow-up was reported by Thierens et al (2019).^30, Study inclusion criteria are described in Table 7. Anatomic and clinical follow-ups were performed at 4 weeks, 6 months, and 1, 3, and 5 years after the procedure (Table 8). With slightly less than half of the participants remaining in the study through 5 years, 79% had freedom from anatomic failure and clinical measures had worsened. Nearly 15% of the recanalizations occurred in the first year, which the authors considered to be due to technical issues when the procedure was initially introduced. For example, there has been an increase in the concentration of sclerosant over time. It should be noted, however, that the more recent MARADONA trial from the same group of investigators using 3% polidocanol (described above) also saw a rate of recanalization of 16.5% in the first year and 20% in the second year.^28, Without a control condition, it cannot be determined whether the loss of clinical improvement in this cohort study is due to recanalization or the usual progression of venous disease over time.

Table 7. Summary of Prospective Cohort Study Characteristics

Study	Country	Participants	Treatment Delivery	Follow-Up
Thierens et al, (2019)30,	Netherlands	C2 to C5 varicose veins, GSV diameter of 3 to 12 mm and primary GSV insufficiency determined by duplex ultrasound examination	MOCA with 2% polidocanol as sclerosant	5 yr

GSV: Great saphenous vein; MOCA: mechanochemical ablation

Table 8. Summary of Prospective Cohort Study Results

Outcome Measure	Baseline	1 yr	3 yr	5 yr
Thierens et al, (2019)30,	n=94	90	71	58
Freedom from anatomic failure (SE)		85.6% (0.033)	80.1% (0.039)	78.7% (0.041)
AVVQ score	8.9	2.3	5.6	6.3
VCSS score	4.0	1.0	1.0	2.0
Clinical improvement		80%	74%	65%

AVVQ: Aberdeen varicose vein questionnaire; MOCA: mechanochemical ablation; VAS: visual analog scale.; VCSS: venous clinical severity score; SE: standard error

Subsection Summary: Mechanochemical Ablation

MOCA is a combination of liquid sclerotherapy and mechanical abrasion of the lumen. The evidence on MOCA includes 4 RCTs that compared MOCA to thermal ablation with 6 mo to 2 yr results, a prospective cohort with follow-up out to 5 years, and retrospective case series. Results to date have been mixed regarding a reduction in intraprocedural pain, which is a proposed benefit of MOCA compared to thermal ablation procedures. Occlusion rates at 6 mo to 2 years in the RCTs indicate lower anatomic success rates compared to thermal ablation, but a difference in clinical outcomes at these early time points has not been observed. Experience with other endoluminal ablation procedures suggests that lower anatomic success in the short term is associated with recanalization and clinical recurrence between 2 to 5 years. The possibility of later clinical recurrence is supported by a prospective cohort study with 5-year follow-up following treatment with MOCA. However, there have been improvements in technique since the cohort study was begun, and clinical progression is frequently observed with venous disease. Because of these limitations of the single arm studies, longer follow-up in the more recently conducted RCTs is needed to establish the efficacy and durability of this procedure compared with the criterion standard of thermal ablation.

Treatment of Saphenous Veins: Cyanoacrylate Adhesive

The VenaSeal pivotal study (VeClose), a multicenter noninferiority trial with 222 patients, compared VenaSeal with RFA for the treatment of venous reflux.^31,32, The pivotal registration study for the VeClose study and follow-up through 36 months have been published. These reports are summarized in Tables 9 and 10. The primary endpoint (the proportion of patients with complete closure of the target GSV at 3 months measured by ultrasound) was noninferior to RFA, with a 99% closure rate for VenaSeal compared with 96% for RFA. The secondary endpoint (intraoperative pain) was similar for both groups (2.2 on a 10-point scale for VenaSeal vs 2.4 for RFA, p=0.11). Ecchymosis at day 3 was significantly lower in the cyanoacrylate group; 67.6% of patients treated with cyanoacrylate had no ecchymosis compared with 48.2% of patients following RFA (p<0.01). Scores on the AVVQ and Venous Clinical Severity Score improved to a similar extent in both groups. The mean time to return to work in a prospective cohort of 50 patients reported by Gibson and Ferris (2017) was 0.2 days.^33,

For the CAC and RFA groups, the complete occlusion rates were 97.2% and 97.0%. Freedom from recanalization was also similar between the two groups (p=0.08).^34, Twenty-four month results were reported by Gibson et al (2018), which included 171 patients (87 from CAC and 84 from RFA).^35,Thirty-six month results were reported by Morrison et al (2019), with follow-up on 146 (66%) patients (72 from CAC and 74 from RFA).^36, Loss to follow-up was similar in the two groups. The complete closure rates for CAC and RFA were 94.4% and 91.9% (p=0.005 for non-inferiority), respectively. Recanalization-free survival through 36 months was not statistically different for the 2 groups. No significant device- or procedure-related adverse events were reported for either group.

VariClose CAC was compared with RFA and EVLA by Eroglu and Yasim (2018) in an RCT with 525 patients (Table 9).^37, Periprocedural outcomes showed a shorter intervention time, less pain, and shorter return to work with CAC compared to endovenous thermal ablation (see Table 10). There was no significant difference in occlusion rates between the three treatments at 6, 12, and 24 month follow-up.

Table 9. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions2
					Active	Comparator
FDA SSED (2015);31, Morrison et al (2015, 2017, 2019);32,38,36,  Gibson et al (2018);33,[VeClose trial]	US	10	2013- 2014	Age ≥21 and ≤ 70 years with symptomatic1 GSV reflux and CEAP C2- C4b GSV diameter while standing of 3-12 mm	108 VenaSeal CAC	114 RFA
Eroglu and Yasim (2018)37,	Asia	1	NR	525 patients ≥ 18 years with inncompetence of the GSV (>5.5 mm in diameter) or SSV (>4 mm in diameter) and reflux >0.5 sec.	175 VariClose CAC	125 RFA and 125 EVLA

CAC: cyanoacrylate ; CEAP: Clinical Etiology Anatomy Pathophysiology; EVLA: endovenous laser ablation; FDA: Food and Drug Administration; GSV: great saphenous vein; NR: not reported; RCT: randomized controlled trial; RFA: radiofrequency ablation; SSV: small saphenous vein; SSED; Summary of Safety and Effectiveness Data;

¹ One or more of the following symptoms related to the target vein: aching, throbbing, heaviness, fatigue, pruritus, night cramps, restlessness, generalized pain or discomfort, swelling.
² Protocol mandated use of compression stockings for 7 days post-procedure

Eroglu and Yasim (2018)37,	Duration of Procedure min (sd)	Average Periprocedural Pain1	2 or More Analgesics Used Daily n (%)	1 Day to Return to Work n (%)	2 Days to Return to Work n (%)	3 or More Days to Return to Work n (%)
N	503	503	456	456	456	456
VariClose	15.3 (2.6)	1 (mild)	105 (62.5)	161 (95.8)	7 (4.2)	0 (0)
RFA	27.3 (7.7)	2 (moderate)	98 (65.8)	75 (50.3)	53 (35.6)	21 (14.1)
EVLA	35.0 (5.2)	2 (moderate)	105 (75.5)	105 (75.5)	24 (17.3)	10 (7.2)
p-Value	<0.001		0.1472	<0.0012

Study	Vein Closure1 n (%)	Vein Closure 12 months n (%)	Vein Closure 24 months n (%)	Vein Closure 36 months n (%)or VCSS	Device Related Event n (%)
FDA SSED (2015);31, Morrison et al (2015, 2017, 2019);32,38,36,Gibson et al (2018);33,[VeClose trial]	3 months
N	222	189	171	146	222
VenaSeal	107 (99.1%)2	92 (96.7%)	82/86 (95.3%)	68/72 (94.4%)	31 (27%)
RFA	109 (95.6%)2	91 (96.8%)	79/84 (94.0%)	68/74 (91.9%)	7 (6%)
Eroglu and Yasim (2018)37,	6 months			VCSS at 24 months
N		503	456	456
VariClose	98.1%	94.1%	95.1%	2.7
RFA	94.7%	92.5%	94.2%	3.7
EVLA	92.6%	90.9%	91.5%	3.5
p-Value	NS	NS	NS	<0.001

¹Complete closure defined as Doppler ultrasound showing vein closure along entire treated vein segment with no discrete segments of patency exceeding 5 cm. Central laboratory confirmation.
² Used prespecified data imputation method (Last Observation Carried Forward)

Table 12. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Morrison (2015), 32,Morrison (2017),38,Gibson (2018)35,Morrison (2019)36, [VeClose trial]					1.Follow-up scheduled to continue to 60 months
Eroglu and Yasim (2018)37,		2. This specific cyanoacrylate product is not currently available in the US

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingd	Follow-Upe	Powerd	Statisticalf
Morrison (2015), 32,Morrison (2017),38, Gibson (2018)35,Morrison (2019)36, [VeClose trial]		1, 2, 3. The outcome was assessed by the treating physician and patients were not blinded		1. >20% loss to follow-up		3.variable reporting of CI and p values
Eroglu and Yasim (2018)37,		1, 2, 3. Patients were notified of the group assignment a day before the procedure		6. Not intent-to-treat analysis and unequal loss to follow-up. 21 patients did not receive the allocated intervention, 19 of whom were in the control groups

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Cyanoacrylate Adhesive

Evidence assessing CAC for the treatment of varicose veins and venous insufficiency includes a multicenter noninferiority trial with follow-up through 36 months, an RCT with follow-up through 24 months, and a prospective cohort with 30 month follow-up. The short-term efficacy of VenaSeal CAC has been shown to be noninferior to RFA at up to 36-month follow-up. At 24 and 36 months the study had greater than 20% loss to follow-up, but loss to follow-up was similar in the two groups at the long-term follow-up and is not expected to influence the comparative results. A second RCT (n=525) with the same active CAC ingredient (N-butyl cyanoacrylate) that is currently available outside of the U.S. found no significant differences in vein closure between CAC and thermal ablation controls at 24-month follow-up. The CAC procedure and return to work were shorter and pain scores were lower compared to thermal ablation; the subjective pain scores may have been influenced by differing expectations in this study. A prospective cohort reported high closure rates at 30 months. Overall, results indicate that outcomes from CAC are at least as good as thermal ablation techniques, the current standard of care.

Treatment of Saphenous Veins: Cryoablation

Klem et al (2009) reported on a randomized trial that found endovenous cryoablation (n=249) to be inferior to conventional stripping (n=245) for treating patients with symptomatic varicose veins.^34, Forty-four percent of patients had residual GSV remaining with cryoablation while 15% had residual vein remaining with conventional stripping. AVVQ scores also showed better results for conventional stripping (score, 11.7) than cryoablation (score, 8.0). There were no differences between groups in 36-Item Short-Form Health Survey summary scores or neural damage (12% in both groups).

Disselhoff et al (2008, 2011) reported on 2- and 5-year outcomes from a randomized trial that compared cryoablation with endovenous laser ablation.^41,42, Included were 120 patients with symptomatic uncomplicated varicose veins (CEAP class C2) with saphenofemoral incompetence and GSV reflux. At 10 days after treatment, endovenous laser ablation provided better results than cryoablation with respect to pain scores over the first 10 days (2.9 vs 4.4), resumption of normal activity (75% vs 45%), and induration (15% vs 52%), all respectively. At 2-year follow-up, freedom from recurrent incompetence was observed in 77% of patients after endovenous laser ablation and in 66% of patients after cryoablation (p=NS). At 5 years, 36.7% of patients were lost to follow-up; freedom from incompetence and neovascularization were found in 62% of patients treated with endovenous laser ablation and in 51% of patients treated with cryoablation (p=NS). Neovascularization was more common after cryoablation, but incompetent tributaries were more common after endovenous laser ablation. There were no significant differences between groups in the Venous Clinical Severity Score or AVVQ scores at either the two or five-month follow-ups for endovenous laser ablation.

Subsection Summary: Cryoablation

Two RCTs have suggested that cryotherapy is ineffective for treating varicose veins compared with available alternatives.

Tributary Varicosities
Clinical Context and Therapy Purpose

The purpose of ablation (stab avulsion, sclerotherapy, or phlebectomy) of tributary veins in patients who have varicose tributary veins is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the use of ablation (stab avulsion, sclerotherapy, or phlebectomy) of tributary veins improve the net health outcome in individuals who have varicose tributary veins?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who have varicose tributary veins.

Interventions

The therapy being considered is ablation (stab avulsion, sclerotherapy, or phlebectomy) of tributary veins.

Transilluminated powered phlebectomy is an alternative to stab avulsion and hook phlebectomy. This procedure uses two instruments: an illuminator, which also provides irrigation, and a resector, which has an oscillating tip and suction pump. Following removal of the saphenous vein, the illuminator is introduced via a small incision in the skin and tumescence solution (anesthetic and epinephrine) is infiltrated along the course of varicosity. The resector is then inserted under the skin from the opposite direction, and the oscillating tip is placed directly beneath the illuminated veins to fragment and loosen the veins from the supporting tissue. Irrigation from the illuminator is used to clear the vein fragments and blood through aspiration and additional drainage holes. The illuminator and resector tips may then be repositioned, thereby reducing the number of incisions needed when compared with stab avulsion or hook phlebectomy. It has been proposed that transilluminated powered phlebectomy might decrease surgical time, decrease complications such as bruising and lead to a faster recovery than established procedures.

Comparators

The following therapy is currently being used to treat varicose tributary veins: conservative therapy.

Outcomes

The general outcomes of interest are reductions in symptoms and morbid events, change in disease status, and improvements in quality of life. Follow-up at 6- and 12-months is of interest for ablation (stab avulsion, sclerotherapy, or phlebectomy) of tributary veins to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Early studies established ligation and stripping as the criterion standard for treating saphenofemoral incompetence based on improved long-term recurrence rates, with sclerotherapy used primarily as an adjunct to treat varicose tributaries. A Cochrane review by Tisi et al (2006), based primarily on RCTs from the 1980s, concluded that: "The evidence supports the current place of sclerotherapy in modern clinical practice, which is usually limited to treatment of recurrent varicose veins following surgery and thread veins."^43,Sclerotherapy and phlebectomy are considered appropriate in the absence of reflux of the saphenous system (eg, post- or adjunctive treatment to other procedures such as surgery).^44, El-Sheikha et al (2014) reported on a small randomized trial of concomitant or sequential (if needed) phlebectomy following endovenous laser ablation for varicose veins.^45,Quality of life and clinical severity scores were similar between the groups by 1 year, with 16 (67%) of 24 patients in the sequential phlebectomy group receiving a secondary intervention.

The bulk of the literature discussing the role of ultrasound guidance refers to sclerotherapy of the saphenous vein, as opposed to the varicose tributaries. For example, Yamaki et al (2012) reported on a prospective RCT that compared visual foam sclerotherapy plus ultrasound-guided foam sclerotherapy of the GSV with visual foam sclerotherapy for varicose tributary veins.^46, Fifty-one limbs in 48 patients were treated with ultrasound-guided foam sclerotherapy plus visual foam sclerotherapy of the varicose tributaries, and 52 limbs in 49 patients were treated with foam sclerotherapy alone. At 6-month follow-up, complete occlusion was found in 23 (45.1%) limbs treated with ultrasound plus visually guided foam sclerotherapy and in 22 (42.3%) limbs treated with visual sclerotherapy alone. Reflux was absent in 30 (58.8%) limbs treated with ultrasound plus visual guidance and in 37 (71.2%) treated with visual guidance alone (p=NS). The authors noted that, for the treatment of tributary veins in clinical practice, most patients receive a direct injection of foam without ultrasound guidance.

A small proportion of patients may present with tributary varicosities in the absence of saphenous reflux. For example, as reported by Michaels et al (2006), of 1009 patients recruited for an RCT, 64 patients had minor varicose veins without reflux, 34 of whom agreed to be randomized to sclerotherapy or conservative treatment.^47, At baseline, 92% had symptoms of heaviness, 69% had cosmetic concerns, 53% reported itching, and 30% reported relief of symptoms using compression hosiery. At 1-year follow-up, there was an improvement in clinicians-assessment of the anatomic extent of varicose veins, with 85% of patients in the sclerotherapy group showing improvement compared with 29% of patients in the conservative therapy group. Symptoms of aching were milder or eliminated in 69% of the sclerotherapy group and 28% of the group treated with conservative therapy.

Transilluminated Powered Phlebectomy

A meta-analysis by Luebke and Brunkwall (2008) included 5 studies that compared TIPP with conventional surgery.^48, Results showed a significant advantage of TIPP over the conventional treatment for the number of incisions, mean cosmetic score, and duration of the procedure. However, TIPP also increased the incidence of hematoma and resulted in worse mean pain scores. Included in the meta-analysis was an RCT by Chetter et al (2006) that compared TIPP (n=29) with a multiple stab incision procedure (n=33).^49, A single surgeon performed all but two of the procedures, and there was no difference in operating time. Patients treated with TIPP had an average of 5 incisions, compared with 20 for the multiple stab procedure. However, the blinded evaluation revealed that bruising or discoloration was higher for the TIPP group at one and six weeks postsurgery. At 6 weeks after surgery, patients in the TIPP group showed no reductions in pain (-2 points on the Burford Pain Scale), while patients in the multiple stab incision group had a significant reduction in pain scores compared with presurgical baseline (-20 points). Six weeks postsurgery, quality of life measures had improved in the multiple stab incision group but not in the TIPP group. Thus, although TIPP required fewer surgical incisions, in this single-center study, it was associated with longer recovery due to more extensive bruising, prolonged pain, and reduced early postoperative quality of life.

Section Summary: Tributary Varicosities

The evidence on the use of stab avulsion, sclerotherapy, and phlebectomy includes RCTs and systematic reviews of RCTs. The literature has indicated that sclerotherapy is effective for the treatment of tributary veins following occlusion of the saphenofemoral or saphenopopliteal junction and saphenous veins. No studies have been identified comparing RFA or laser ablation of tributary veins with standard procedures (microphlebectomy and/or sclerotherapy). TIPP is effective at removing varicosities; outcomes are comparable with available alternatives such as stab avulsion and hook phlebectomy. However, there is limited evidence that TIPP is associated with more pain, bruising, discoloration, and a longer recovery, and the current literature does not show an advantage of TIPP over conventional treatment.

Perforator Reflux
Clinical Context and Therapy Purpose

Perforator veins cross through the fascia and connect the deep and superficial venous systems. Incompetent perforating veins were originally treated with an open surgical procedure, called the Linton procedure, which involved a long medial calf incision to expose all posterior, medial, and paramedial perforators. While this procedure was associated with healing of ulcers, it was largely abandoned due to a high incidence of wound complications. The Linton procedure was subsequently modified by using a series of perpendicular skin flaps instead of a longitudinal skin flap to provide access to incompetent perforator veins in the lower part of the leg. The modified Linton procedure may occasionally be used to close incompetent perforator veins that cannot be reached by less invasive procedures.

The question addressed in this policy is: Does the use of ablation of perforator veins reduce venous insufficiency in individuals who have perforator vein reflux?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals who have perforator vein reflux.

Interventions

The therapy being considered is ablation with subfascial endoscopic perforator surgery (SEPS) of perforator veins. SEPS is a less invasive surgical procedure for the treatment of incompetent perforators and has been reported since the mid-1980s. Guided by Duplex ultrasound scanning, small incisions are made in the skin, and the perforating veins are clipped or divided by endoscopic scissors. The surgery can be performed as an outpatient procedure. Endovenous ablation of incompetent perforator veins with sclerotherapy and radiofrequency ablation has also been reported.

Comparators

The following is currently being used to treat perforator vein reflux: conservative therapy or treatment of saphenous veins alone.

Outcomes

The general outcomes of interest are reductions in symptoms and morbid events, change in disease status, and improvements in quality of life. These may be assessed by VAS, AVVQ, and VCSS, along with ulcer healing and recurrence.

Follow-up at two years is of interest for ablation (eg, SEPS) of perforator veins to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

A systematic literature review by O'Donnell (2008) indicated there was a lack of evidence on the role of incompetent perforator vein surgery performed in conjunction with superficial saphenous vein surgery.^5, These conclusions were based on 4 RCTs published since 2000 that compared superficial vein surgery with conservative therapy for advanced chronic venous insufficiency (CEAP classes C5-C6). The four trials included two level I (large subject population) and two level II (small subject population) studies. Two trials combined surgical treatment of the incompetent perforator veins with concurrent or prior treatment of the superficial saphenous veins; the other two treated the GSV alone. The 2 randomized studies (2004, 2007) in which the GSV alone was treated (including the ESCHAR trial) showed a significant reduction in ulcer recurrence compared with conservative therapy.^50,51,

Treatment of the GSV alone has been reported to improve perforator function. For example, Blomgren et al (2005) showed that reversal of perforator vein incompetence (28 [41%] of 68 previously incompetent perforators) was more common than new perforator vein incompetence (41 [22%] of 183 previously competent perforators) following superficial vein surgery.^52,O'Donnell (2008) discussed additional (lower quality) evidence to suggest deep venous valvular involvement rather than incompetent perforators in venous insufficiency. ^5, Thus, although incompetence of perforator veins is frequently cited as an important etiologic factor in the pathogenesis of venous ulcer, current evidence does not support the routine ligation or ablation of perforator veins.

Subfascial Endoscopic Perforator Surgery

A Cochrane review by Lin et al (2019) evaluated the efficacy of SEPS for the treatment of venous ulcers^53,. They identified 4 RCTs, 2 compared SEPS plus compression with compression alone (n=208), one compared SEPS with the Linton procedure (n=39), and one compared SEPS plus saphenous vein surgery with saphenous vein surgery alone (n=75). Results are shown in Table 14. The authors concluded that:

• Compared with compression alone, there was low certainty evidence that SEPS may increase the rate of ulcer healing compared to compression alone, but it was uncertain whether SEPS reduced the rate of ulcer recurrence.
• Compared with the Linton procedure, it was uncertain whether there was a difference in ulcer healing, and very uncertain whether there was a difference in ulcer recurrence. Based on very low certainty evidence, the Linton procedure was possibly associated more adverse events.
• Compared to saphenous vein surgery alone, it was uncertain whether there was a difference in ulcer healing or the risk of ulcer recurrence. It was uncertain whether SEPS led to an increase in adverse events (very low certainty due to imprecision and risk of reporting bias)

Comparator	Ulcer Healing	Ulcer Recurrence	Adverse Events
Compression alone N	196	208
Risk ratio (95% CI)	1.17 (1.03 to 1.33)	0.85 (0.26 to 2.76)
Linton Procedure N	39	39	39
Risk ratio (95% CI)	0.95 (0.83 to 1.09)	0.47 (0.10 to 2.30)	0.04 (0.00 to 0.60)
Saphenous Vein Surgery	22	75	75
Risk ratio (95% CI)	0.96 (0.64 to 1.43)	1.03 (0.15 to 6.91)	2.05 (0.86 to 4.90)

¹ If the M-A includes a quantitative synthesis then include numbers analyzed, measures of effect (absolute or relative) with CI and measure of heterogeneity. If the M-A includes only a qualitative synthesis then include the ranges of N and effects.

Section Summary: Perforator Reflux

The literature has shown that the routine ligation and ablation of incompetent perforator veins is not necessary for treating varicose veins and venous insufficiency concurrent with superficial vein procedures. However, when combined superficial vein procedures and compression therapy have failed to improve symptoms (ie, ulcers), treatment of perforator vein reflux may be as beneficial as any alternative (eg, deep vein valve replacement). Comparative studies are needed to determine the most effective method of ligating and ablating incompetent perforator veins. There is some low quality evidence that SEPS is as effective as the Linton procedure with a reduction in adverse events. Although only one case series has been identified showing an improvement in health outcomes, endovenous ablation with specialized laser or RFA probes has been shown to effectively ablate incompetent perforator veins with a potential decrease in morbidity compared with surgical interventions.

Summary of Evidence
Saphenous Veins

For individuals who have varicose veins/venous insufficiency and saphenous vein reflux who receive endovenous thermal ablation (radiofrequency or laser), the evidence includes RCTs and systematic reviews of controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. There are a number of large RCTs and systematic reviews of RCTs assessing endovenous thermal ablation of the saphenous veins. Comparison with the standard of ligation and stripping at 2- to 5-year follow-up has supported the use of both endovenous laser ablation and RFA. Evidence has suggested that ligation and stripping lead to more neovascularization, while thermal ablation leads to more recanalization, resulting in similar clinical outcomes for endovenous thermal ablation and surgery. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have varicose veins/venous insufficiency and saphenous vein reflux who receive microfoam sclerotherapy, the evidence includes RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and TRM. For physician-compounded sclerotherapy, there is high variability in success rates and some reports of serious adverse events. By comparison, rates of occlusion with the microfoam sclerotherapy (polidocanol 1%) approved by the FDA are similar to those reported for endovenous laser ablation or stripping. Results of a noninferiority trial of physician-compounded sclerotherapy have indicated that once occluded, recurrence rates at two years are similar to those of ligation and stripping. Together, this evidence indicates that the more consistent occlusion with the microfoam sclerotherapy preparation will lead to recurrence rates similar to ligation and stripping in the longer term. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Based on the available evidence, clinical input obtained in 2015, and clinical practice guidelines, the use of endovenous RFA, endovenous laser ablation, and microfoam sclerotherapy are considered to improve outcomes when used in the saphenous veins. For treatment of saphenous tributaries at the same time or following treatment of the saphenous vein, stab avulsion, hook phlebectomy, sclerotherapy, or transilluminated powered phlebectomy improve outcomes.

For individuals who have varicose veins/venous insufficiency and saphenous vein reflux who receive MOCA, the evidence includes 4 RCTs with 6 mo to 2 yr results that compared MOCA to thermal ablation, a prospective cohort with follow-up out to 5 years, and retrospective case series. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and TRM. MOCA is a combination of liquid sclerotherapy with mechanical abrasion. A potential advantage of this procedure compared with thermal ablation is that MOCA does not require tumescent anesthesia and may result in less pain during the procedure. Results to date have been mixed regarding a reduction in intraprocedural pain compared to thermal ablation procedures. Occlusion rates at 6 mo to 2 year from RCTs indicate lower anatomic success rates compared to thermal ablation, but a difference in clinical outcomes at these early time points has not been observed. Experience with other endoluminal ablation procedures suggests that lower anatomic success in the short term is associated with recanalization and clinical recurrence between 2 to 5 years. The possibility of later clinical recurrence is supported by a prospective cohort study with 5-year follow-up following treatment with MOCA. However, there have been improvements in technique since the cohort study was begun, and clinical progression is frequently observed with venous disease. Because of these limitations of the single arm studies, longer follow-up in the more recently conducted RCTs is needed to establish the efficacy and durability of this procedure compared with the criterion standard of thermal ablation. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have varicose veins/venous insufficiency and saphenous vein reflux who receive CAC, the evidence includes two RCTs and a prospective cohort. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and TRM. Evidence includes a multicenter noninferiority trial with follow-up through 36 months, an RCT with follow-up through 24 months, and a prospective cohort with 30-month follow-up. The short-term efficacy of VenaSeal CAC has been shown to be noninferior to RFA at up to 36 months. At 24 and 36 months the study had greater than 20% loss to follow-up, but loss to follow-up was similar in the 2 groups at the long-term follow-up and is not expected to influence the comparative results. A second RCT (n=525) with the same active CAC ingredient (N-butyl cyanoacrylate) that is currently available outside of the U.S. found no significant differences in vein closure between CAC and thermal ablation controls at 24-month follow-up. The CAC procedure and return to work were shorter and pain scores were lower compared to thermal ablation, although the subjective pain scores may have been influenced by differing expectations in this study. A prospective cohort reported high closure rates at 30 months. Overall, results indicate that outcomes from CAC are at least as good as thermal ablation techniques, the current standard of care. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have varicose veins/venous insufficiency and saphenous vein reflux who receive cryoablation, the evidence includes RCTs and multicenter series. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and TRM. Results from a recent RCT of cryoablation have indicated that this therapy is inferior to conventional stripping. Studies showing a benefit on health outcomes are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Varicose Tributary Veins

For individuals who have varicose tributary veins who receive ablation (stab avulsion, sclerotherapy, or phlebectomy) of tributary veins, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. The literature has shown that sclerotherapy is effective for treating tributary veins following occlusion of the saphenofemoral or saphenopopliteal junction and saphenous veins. No studies have been identified comparing RFA or laser ablation of tributary veins with standard procedures (microphlebectomy and/or sclerotherapy). TIPP is effective at removing varicosities; outcomes are comparable to available alternatives such as stab avulsion and hook phlebectomy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Perforator Veins

For individuals who have perforator vein reflux who receive ablation (eg, subfascial endoscopic perforator surgery) of perforator veins, the evidence includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. The literature has indicated that the routine ligation or ablation of incompetent perforator veins is not necessary for the treatment of varicose veins/venous insufficiency at the time of superficial vein procedures. However, when combined superficial vein procedures and compression therapy have failed to improve symptoms (ie, ulcers), treatment of perforator vein reflux may be as beneficial as an alternative (eg, deep vein valve replacement). Comparative studies are needed to determine the most effective method of ligating or ablating incompetent perforator veins. Subfascial endoscopic perforator surgery is possibly as effective as the Linton procedure with a reduction in adverse events. Although only one case series has been identified showing an improvement in health outcomes, endovenous ablation with specialized laser or radiofrequency probes has been shown to effectively ablate incompetent perforator veins with a potential decrease in morbidity compared with surgical interventions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 physician specialty societies while this policy was under review in 2015. There was no agreement on the need to treat varicose tributaries to improve functional outcomes in the absence of saphenous vein disease. Input was also mixed on the use of mechanochemical ablation and cyanoacrylate adhesive.

Practice Guidelines and Position Statements
Society for Vascular Surgery and American Venous Forum

The Society for Vascular Surgery and the American Venous Forum (2011) published joint clinical practice guidelines.^55, Table 15 provides the recommendations.

Table 15. Guidelines on Management of Varicose Veins and Associated Chronic Venous Diseases

Recommendation	Gradea	SOR	QOE
Compression therapy for venous ulcerations and varicose veins
Compression therapy is recommended as the primary treatment to aid healing of venous ulceration	1B	Strong	Moderate
To decrease the recurrence of venous ulcers, ablation of the incompetent superficial veins in addition to compression therapy is recommended	1A	Strong	High
Use of compression therapy for patients with symptomatic varicose veins is recommended	2C	Weak	Low
Compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation is not recommended	1B	Strong	Moderate
Treatment of the incompetent great saphenous vein
Endovenous thermal ablation (radiofrequency or laser) is recommended over chemical ablation with foam or high ligation and stripping due to reduced convalescence and less pain and morbidity. Cryostripping is a technique that is new in the United States, and it has not been fully evaluated.	1B	Strong	Moderate
Varicose tributaries
Phlebectomy or sclerotherapy are recommended to treat varicose tributaries	1B	Strong	Moderate
Transilluminated powered phlebectomy using lower oscillation speeds and extended tumescence is an alternative to traditional phlebectomy	2C	Weak	Low
Perforating vein incompetence
Selective treatment of perforating vein incompetence in patients with simple varicose veins is not recommended	1B	Strong	Moderate
Treatment of pathologic perforating veins (outward flow of ≥500 ms duration, with a diameter of ≥3.5 mm) located underneath healed or active ulcers (CEAP class C5-C6) is recommended	2B	Weak	Moderate

QOE: quality of evidence; SOR: strength of recommendation.
^a Grading: strong = 1 or weak = 2, based on a level of evidence that is either high quality = A, moderate quality = B, or low quality = C.

Society of Interventional Radiography et al.

In 2010, the Society of Interventional Radiography, along with Cardiovascular Interventional Radiological Society of Europe, American College of Phlebology, and Canadian Interventional Radiology Association, published consensus quality improvement guidelines for the treatment of lower extremity superficial venous insufficiency using endovenous thermal ablation.^56,

In a joint statement, American Venous Forum and Society of Interventional Radiography (2007) recommended reporting standards for endovenous ablation for the treatment of venous insufficiency.^57, They recommended that reporting in clinical studies should include the symptoms of venous disease, history of the disease and prior treatment, the presence of major comorbidities, and any exclusion criteria. It was noted that potential candidates for endovenous ablation might include patients with reflux in an incompetent great saphenous vein or smaller saphenous vein or a major tributary branch of the great or smaller saphenous veins such as the anterior thigh circumflex vein, posterior thigh circumflex vein, or anterior accessory great saphenous vein. The presence of reflux in these veins is important to document using duplex ultrasound imaging, and the ultrasound criteria used to define reflux should be indicated. It was also stated that, in current practice, most vascular laboratories consider the presence of venous flow reversal for greater than 0.5 to 1.0 second with proximal compression, Valsalva maneuver, or distal compression and release to represent pathologic reflux.

American Vein and Lymphatic Society

In 2015, the American Vein and Lymphatic Society (AVL, previously named the American College of Phlebology) published guidelines on the treatment of superficial vein disease.^58,

AVL gave a Grade 1 recommendation based on high quality evidence that compression is an effective method for the management of symptoms, but when patients have a correctable source of reflux definitive treatment should be offered unless contraindicated. AVL recommends against a requirement for compression therapy when a definitive treatment is available. AVL gave a strong recommendation based on moderate quality evidence that endovenous thermal ablation is the preferred treatment for saphenous and accessory saphenous vein incompetence, and gave a weak recommendation based on moderate quality evidence that mechanochemical ablation may also be used to treat venous reflux.

In 2017, AVL published guidelines on the treatment of refluxing accessory saphenous veins.^35, The College gave a Grade 1 recommendation based on level C evidence that patients with symptomatic incompetence of the accessory saphenous veins be treated with endovenous thermal ablation or sclerotherapy to reduce symptomatology. The guidelines noted that although accessory saphenous veins may drain into the great saphenous vein before it drains into the common femoral vein, they can also empty directly into the common femoral vein.

National Institute for Health and Care Excellence

In 2013, the U.K.s National Institute for Health and Care Excellence (NICE) updated its guidance on ultrasound-guided foam sclerotherapy for varicose veins.^59, NICE stated that:

"1.1 Current evidence on the efficacy of ultrasound-guided foam sclerotherapy for varicose veins is adequate. The evidence on safety is adequate, and provided that patients are warned of the small but significant risks of foam embolization (see section 1.2), this procedure may be used with normal arrangements for clinical governance, consent and audit.

1.2 During the consent process, clinicians should inform patients that there are reports of temporary chest tightness, dry cough, headaches and visual disturbance, and rare but significant complications including myocardial infarction, seizures, transient ischaemic attacks and stroke."

NICE (2016) revised its guidance on endovenous mechanochemical ablation, concluding that "Current evidence on the safety and efficacy of endovenous mechanochemical ablation for varicose veins appears adequate to support the use of this procedure...."^55,

NICE (2013) published guidance on the diagnosis and management of varicose veins in the leg.^60, The NICE (2015) published a technology assessment on the clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation, and surgery for varicose veins.^57, Five-year trial results are currently being evaluated.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 16.

Table 16. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03392753	Randomised Controlled Trial of Mechanochemical Ablation Versus Cyanoacrylate Adhesive for the Treatment of Varicose Veins	180	Dec 2020
NCT03722134	Mechanochemical Ablation vs Thermal Ablation in Patients With Great Saphenous Vein Insufficiency	132	Dec 2020
NTR4613a	Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial)	160	Apr 2020
NCT01936168	Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary great saphenous vein incompetence (MARADONA)	213	Dec 2020
NCT03835559	Randomized Controlled Trial Comparing the Clinical Outcomes After Cyanoacrylate Closure and Surgical Stripping for Incompetent Saphenous Veins	146	Feb 2021
NCT02627846	A Randomised Clinical Trial Comparing Endovenous Laser Ablation and Mechanochemical Ablation (ClariVein) in the Management of Superficial Venous Insufficiency (LAMA)	140	Aug 2025

NCT: national clinical trial. NTR: Netherlands Trial Registry.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Treatment of Varicose Veins/Venous Insufficiency
Surgical Treatment of Varicose Veins of the Lower Extremities
Accessory Saphenous Vein Reflux, Treatment of
Echosclerotherapy
Endoluminal Ablation of Varicose Veins, Radiofrequency or Laser
Endovenous Laser Therapy
Endovenous Radiofrequency Ablation
EVLT (Endovenous Laser Therapy)
Injection of Sclerosing Solution to Varicose Veins
Greater Saphenous Vein Ligation and Stripping
Great Saphenous Vein Ligation and Stripping
Laser, Endovenous Therapy
Lesser Saphenous Vein Ligation and Stripping
Linton Procedure
Perforator Vein Ligation
Phlebectomy, Transilluminated Powered
PhotoDerm
Photothermal Sclerosis
Radiofrequency Ablation, Endovenous
RFSFlex
Saphenous Vein Ligation and Stripping
Saphenofemoral Junction Ligation and Division
Saphenopopliteal Junction Ligation and Division
Sclerotherapy, Varicose Veins of the Lower Extremities
SEPS (Subfascial Endoscopic Perforator Surgery)
Small Saphenous Vein Ligation and Stripping
Spider Veins
Subfascial Endoscopic Perforator Surgery (SEPS)
Telangiectasia
Transilluminated Powered Phlebectomy
TriVex System
Ultrasound-Guided Sclerotherapy
Varicose Veins of the Lower Extremities
VNUS Closure System
VNUS RFS
ClariVein
Endovenous Mechanochemical Ablation
Mechanochemical Ablation
MOCA
Varithena
Varisolve
Microfoam Sclerotherapy
VenaSeal Closure System
Cyanoacrylate Adhesive Agent

References:
1. O'Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev. Jan 21 2009; (1): CD000265. PMID 19160178

2. O'Meara S, Cullum N, Nelson EA, et al. Compression for venous leg ulcers. Cochrane Database Syst Rev. Nov 14 2012; 11: CD000265. PMID 23152202

3. Shingler S, Robertson L, Boghossian S, et al. Compression stockings for the initial treatment of varicose veins in patients without venous ulceration. Cochrane Database Syst Rev. Nov 09 2011; (11): CD008819. PMID 22071857

4. Howard DP, Howard A, Kothari A, et al. The role of superficial venous surgery in the management of venous ulcers: a systematic review. Eur J Vasc Endovasc Surg. Oct 2008; 36(4): 458-65. PMID 18675558

5. O'Donnell TF. The present status of surgery of the superficial venous system in the management of venous ulcer and the evidence for the role of perforator interruption. J Vasc Surg. Oct 2008; 48(4): 1044-52. PMID 18992425

6. Jones L, Braithwaite BD, Selwyn D, et al. Neovascularisation is the principal cause of varicose vein recurrence: results of a randomised trial of stripping the long saphenous vein. Eur J Vasc Endovasc Surg. Nov 1996; 12(4): 442-5. PMID 8980434

7. Rutgers PH, Kitslaar PJ. Randomized trial of stripping versus high ligation combined with sclerotherapy in the treatment of the incompetent greater saphenous vein. Am J Surg. Oct 1994; 168(4): 311-5. PMID 7943585

8. Nesbitt C, Bedenis R, Bhattacharya V, et al. Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus open surgery for great saphenous vein varices. Cochrane Database Syst Rev. Jul 30 2014; (7): CD005624. PMID 25075589

9. Paravastu SC, Horne M, Dodd PD. Endovenous ablation therapy (laser or radiofrequency) or foam sclerotherapy versus conventional surgical repair for short saphenous varicose veins. Cochrane Database Syst Rev. Nov 29 2016; 11: CD010878. PMID 27898181

10. Brittenden J, Cotton SC, Elders A, et al. A randomized trial comparing treatments for varicose veins. N Engl J Med. Sep 25 2014; 371(13): 1218-27. PMID 25251616

11. Rass K, Frings N, Glowacki P, et al. Comparable effectiveness of endovenous laser ablation and high ligation with stripping of the great saphenous vein: two-year results of a randomized clinical trial (RELACS study). Arch Dermatol. Jan 2012; 148(1): 49-58. PMID 21931012

12. Rass K, Frings N, Glowacki P, et al. Same Site Recurrence is More Frequent After Endovenous Laser Ablation Compared with High Ligation and Stripping of the Great Saphenous Vein: 5 year Results of a Randomized Clinical Trial (RELACS Study). Eur J Vasc Endovasc Surg. Nov 2015; 50(5): 648-56. PMID 26319476

13. Christenson JT, Gueddi S, Gemayel G, et al. Prospective randomized trial comparing endovenous laser ablation and surgery for treatment of primary great saphenous varicose veins with a 2-year follow-up. J Vasc Surg. Nov 2010; 52(5): 1234-41. PMID 20801608

14. Biemans AA, Kockaert M, Akkersdijk GP, et al. Comparing endovenous laser ablation, foam sclerotherapy, and conventional surgery for great saphenous varicose veins. J Vasc Surg. Sep 2013; 58(3): 727-34.e1. PMID 23769603

15. van der Velden SK, Biemans AA, De Maeseneer MG, et al. Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins. Br J Surg. Sep 2015; 102(10): 1184-94. PMID 26132315

16. Wallace T, El-Sheikha J, Nandhra S, et al. Long-term outcomes of endovenous laser ablation and conventional surgery for great saphenous varicose veins. Br J Surg. Dec 2018; 105(13): 1759-1767. PMID 30132797

17. Theivacumar NS, Darwood RJ, Gough MJ. Endovenous laser ablation (EVLA) of the anterior accessory great saphenous vein (AAGSV): abolition of sapheno-femoral reflux with preservation of the great saphenous vein. Eur J Vasc Endovasc Surg. Apr 2009; 37(4): 477-81. PMID 19201621

18. Hamann SAS, Giang J, De Maeseneer MGR, et al. Editor's Choice - Five Year Results of Great Saphenous Vein Treatment: A Meta-analysis. Eur J Vasc Endovasc Surg. Dec 2017; 54(6): 760-770. PMID 29033337

19. Vahaaho S, Mahmoud O, Halmesmaki K, et al. Randomized clinical trial of mechanochemical and endovenous thermal ablation of great saphenous varicose veins. Br J Surg. Apr 2019; 106(5): 548-554. PMID 30908611

20. Shadid N, Ceulen R, Nelemans P, et al. Randomized clinical trial of ultrasound-guided foam sclerotherapy versus surgery for the incompetent great saphenous vein. Br J Surg. Aug 2012; 99(8): 1062-70. PMID 22627969

21. Lam YL, Lawson JA, Toonder IM, et al. Eight-year follow-up of a randomized clinical trial comparing ultrasound-guided foam sclerotherapy with surgical stripping of the great saphenous vein. Br J Surg. May 2018; 105(6): 692-698. PMID 29652081

22. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Summary Review: 205098 Varithena. 2013; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205098Orig1s000SumR.pdf. Accessed March 27, 2020.

23. Todd KL, Wright DI, Gibson K, et al. The VANISH-2 study: a randomized, blinded, multicenter study to evaluate the efficacy and safety of polidocanol endovenous microfoam 0.5% and 1.0% compared with placebo for the treatment of saphenofemoral junction incompetence. Phlebology. Oct 2014; 29(9): 608-18. PMID 23864535

24. Vasquez M, Gasparis AP. 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. Phlebology. May 2017; 32(4): 272-281. PMID 26957489

25. Bootun R, Lane TR, Dharmarajah B, et al. Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: The Multicentre Venefit versus ClariVein(R) for varicose veins trial. Phlebology. Feb 2016; 31(1): 61-5. PMID 25193822

26. Lane T, Bootun R, Dharmarajah B, et al. A multi-centre randomised controlled trial comparing radiofrequency and mechanical occlusion chemically assisted ablation of varicose veins - Final results of the Venefit versus Clarivein for varicose veins trial. Phlebology. Mar 2017; 32(2): 89-98. PMID 27221810

27. Lam YL, Toonder IM, Wittens CH. Clarivein(R) mechano-chemical ablation an interim analysis of a randomized controlled trial dose-finding study. Phlebology. Apr 2016; 31(3): 170-6. PMID 26249150

28. Holewijn S, van Eekeren RRJP, Vahl A, et al. Two-year results of a multicenter randomized controlled trial comparing Mechanochemical endovenous Ablation to RADiOfrequeNcy Ablation in the treatment of primary great saphenous vein incompetence (MARADONA trial). J Vasc Surg Venous Lymphat Disord. May 2019; 7(3): 364-374. PMID 31000063

29. Mohamed AH, Leung C, Wallace T, et al. A Randomized Controlled Trial of Endovenous Laser Ablation Versus Mechanochemical Ablation With ClariVein in the Management of Superficial Venous Incompetence (LAMA Trial). Ann Surg. Jan 21 2020. PMID 31977509

30. Thierens N, Holewijn S, Vissers WH, et al. Five-year outcomes of mechano-chemical ablation of primary great saphenous vein incompetence. Phlebology. May 2020; 35(4): 255-261. PMID 31291849

31. U.S. Food and Drug Administration. VenaSeal Closure System. PMA P140018. 2015; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140018. Accessed March 27, 2020.

32. Morrison N, Gibson K, McEnroe S, et al. Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (VeClose). J Vasc Surg. Apr 2015; 61(4): 985-94. PMID 25650040

33. Gibson K, Ferris B. Cyanoacrylate closure of incompetent great, small and accessory saphenous veins without the use of post-procedure compression: Initial outcomes of a post-market evaluation of the VenaSeal System (the WAVES Study). Vascular. Apr 2017; 25(2): 149-156. PMID 27206470

34. Klem TM, Schnater JM, Schutte PR, et al. A randomized trial of cryo stripping versus conventional stripping of the great saphenous vein. J Vasc Surg. Feb 2009; 49(2): 403-9. PMID 19028042

35. Gibson K, Khilnani N, Schul M, et al. American College of Phlebology Guidelines - Treatment of refluxing accessory saphenous veins. Phlebology. Aug 2017; 32(7): 448-452. PMID 27738242

36. Morrison N, Kolluri R, Vasquez M, et al. Comparison of cyanoacrylate closure and radiofrequency ablation for the treatment of incompetent great saphenous veins: 36-Month outcomes of the VeClose randomized controlled trial. Phlebology. Jul 2019; 34(6): 380-390. PMID 30403154

37. Eroglu E, Yasim A. A Randomised Clinical Trial Comparing N-Butyl Cyanoacrylate, Radiofrequency Ablation and Endovenous Laser Ablation for the Treatment of Superficial Venous Incompetence: Two Year Follow up Results. Eur J Vasc Endovasc Surg. Oct 2018; 56(4): 553-560. PMID 30042039

38. Morrison N, Gibson K, Vasquez M, et al. VeClose trial 12-month outcomes of cyanoacrylate closure versus radiofrequency ablation for incompetent great saphenous veins. J Vasc Surg Venous Lymphat Disord. May 2017; 5(3): 321-330. PMID 28411697

39. Eroglu E, Yasim A, Ari M, et al. Mid-term results in the treatment of varicose veins with N-butyl cyanoacrylate. Phlebology. Dec 2017; 32(10): 665-669. PMID 28669248

40. Zierau UT. Sealing veins with the VenaSeal Sapheon Closure System: results for 795 treated truncal veins after 1000 days. Vasomed. 2015;27:124-127.

41. Disselhoff BC, der Kinderen DJ, Kelder JC, et al. Randomized clinical trial comparing endovenous laser with cryostripping for great saphenous varicose veins. Br J Surg. Oct 2008; 95(10): 1232-8. PMID 18763255

42. Disselhoff BC, der Kinderen DJ, Kelder JC, et al. Five-year results of a randomized clinical trial comparing endovenous laser ablation with cryostripping for great saphenous varicose veins. Br J Surg. Aug 2011; 98(8): 1107-11. PMID 21633948

43. Tisi PV, Beverley C, Rees A. Injection sclerotherapy for varicose veins. Cochrane Database Syst Rev. Oct 18 2006; (4): CD001732. PMID 17054141

44. Leopardi D, Hoggan BL, Fitridge RA, et al. Systematic review of treatments for varicose veins. Ann Vasc Surg. Mar 2009; 23(2): 264-76. PMID 19059756

45. El-Sheikha J, Nandhra S, Carradice D, et al. Clinical outcomes and quality of life 5 years after a randomized trial of concomitant or sequential phlebectomy following endovenous laser ablation for varicose veins. Br J Surg. Aug 2014; 101(9): 1093-7. PMID 24916467

46. Yamaki T, Hamahata A, Soejima K, et al. Prospective randomised comparative study of visual foam sclerotherapy alone or in combination with ultrasound-guided foam sclerotherapy for treatment of superficial venous insufficiency: preliminary report. Eur J Vasc Endovasc Surg. Mar 2012; 43(3): 343-7. PMID 22230599

47. Michaels JA, Campbell WB, Brazier JE, et al. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial). Health Technol Assess. Apr 2006; 10(13): 1-196, iii-iv. PMID 16707070

48. Luebke T, Brunkwall J. Meta-analysis of transilluminated powered phlebectomy for superficial varicosities. J Cardiovasc Surg (Torino). Dec 2008; 49(6): 757-64. PMID 19043390

49. Chetter IC, Mylankal KJ, Hughes H, et al. Randomized clinical trial comparing multiple stab incision phlebectomy and transilluminated powered phlebectomy for varicose veins. Br J Surg. Feb 2006; 93(2): 169-74. PMID 16432820

50. Tenbrook JA, Iafrati MD, O'donnell TF, et al. Systematic review of outcomes after surgical management of venous disease incorporating subfascial endoscopic perforator surgery. J Vasc Surg. Mar 2004; 39(3): 583-9. PMID 14981453

51. van Gent WB, Catarinella FS, Lam YL, et al. Conservative versus surgical treatment of venous leg ulcers: 10-year follow up of a randomized, multicenter trial. Phlebology. Mar 2015; 30(1 Suppl): 35-41. PMID 25729066

52. Blomgren L, Johansson G, Dahlberg-Akerman A, et al. Changes in superficial and perforating vein reflux after varicose vein surgery. J Vasc Surg. Aug 2005; 42(2): 315-20. PMID 16102633

53. Lin ZC, Loveland PM, Johnston RV, et al. Subfascial endoscopic perforator surgery (SEPS) for treating venous leg ulcers. Cochrane Database Syst Rev. Mar 03 2019; 3: CD012164. PMID 30827037

54. Luebke T, Brunkwall J. Meta-analysis of subfascial endoscopic perforator vein surgery (SEPS) for chronic venous insufficiency. Phlebology. Feb 2009; 24(1): 8-16. PMID 19155335

55. National Institute for Health and Care Excellence (NICE). Endovenous mechanochemical ablation for varicose veins [IPG557]. 2016; https://www.nice.org.uk/guidance/ipg557. Accessed March 27, 2020.

56. Khilnani NM, Grassi CJ, Kundu S, et al. Multi-society consensus quality improvement guidelines for the treatment of lower-extremity superficial venous insufficiency with endovenous thermal ablation from the Society of Interventional Radiology, Cardiovascular Interventional Radiological Society of Europe, American College of Phlebology and Canadian Interventional Radiology Association. J Vasc Interv Radiol. Jan 2010; 21(1): 14-31. PMID 20123189

57. Brittenden J, Cotton SC, Elders A, et al. Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the Comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial. Health Technol Assess. Apr 2015; 19(27): 1-342. PMID 25858333

58. American College of Phlebology. Superficial venous disease. 2015; https://www.myavls.org/assets/pdf/VaricoseVeinGuidelines3.9.15.pdf. Accessed March 29, 2020

59. National Institute for Health and Care Excellence (NICE). Ultrasound-guided foam sclerotherapy for varicose veins [IPG440] 2013; https://www.nice.org.uk/guidance/ipg440. Accessed March 27, 2020.

60. National Institute for Health and Care Excellence (NICE). Varicose veins: diagnosis and management [CG168]. 2013; https://www.nice.org.uk/guidance/cg168. Accessed March 27, 2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

01520
36465
36466
36468
36470
36471
36473
36474
36475
36476
36478
36479
36482
36483
37500
37700
37718
37722
37735
37760
37761
37765
37766
37780
37785
37799
96999
0524T

S2202