Choosing the Best Treatment Approach for Axial Vein Reflux: Thermal versus Nonthermal Approaches

Abstract

Chronic venous insufficiency is a common and treatable medical condition which has a high morbidity if left untreated, progressing to lower extremity edema, skin changes of lipodermatosclerosis, and venous ulceration. Treatment options have significantly expanded over the last several decades, shifting away from the traditional surgical approach to more minimally invasive procedures such as endoluminal venous laser ablation or radiofrequency ablation. Even more recently, several techniques using nonthermal methods to ablate varicose veins have been developed, which offer the advantage of not requiring labor-intensive and painful tumescent anesthesia to protect the surrounding tissues. These techniques include mechanochemical ablation, cyanoacrylate closure, or polidocanol microfoam injection and can be offered to a wider range of patients without the need for sedation while offering similar closure rates and improved postprocedure symptom profile. Furthermore, certain patient characteristics which might preclude or complicate the use of thermal ablation methods might not pose a problem with nonthermal nontumescent methods.

Chronic venous insufficiency due to axial vein reflux affects more than 30 million American adults and results in significant morbidity as well as a healthcare expenditure of close to 1 billion dollars annually. ¹ Aside from the cosmetic problems caused by large varicose veins, patients might also suffer from fatigue, pain, restlessness, and heavy sensation in their legs, and if left untreated, venous insufficiency can progress to leg swelling, pigmentation, ulceration, and bleeding. ² Historically, axial reflux of the great saphenous vein (GSV) or small saphenous vein (SSV) was treated with surgical ligation and stripping via large incision, an effective yet invasive procedure with high morbidity. However, within the past 30 years, endovenous methods have largely replaced these more invasive procedures, with surgery now typically reserved for refractory or challenging cases or for patients who desire a more “definitive,” “one-step” treatment approach. ¹ Endovenous methods do not require general anesthesia and have previously been shown to be as effective as surgery, more cost-effective, and associated with significantly less perioperative morbidity, ^{2 3} including pain, ecchymosis/hematoma, scarring, and nerve damage. Additionally, improved quality-of-life scores and improved cosmetic results have also been noted with endovenous methods compared with surgical stripping. ⁴ Guidelines imposed in 2013 by the National Institute of Clinical Excellence (NICE) recommend thermal endovenous ablation as first-line treatment for patients with confirmed varicose veins due to reflux. ⁵

Endovenous methods can be broadly characterized into two main categories, thermal/tumescent and nonthermal/nontumescent, with the traditional endovenous methods, endoluminal venous laser ablation (EVLA) and radiofrequency ablation (RFA), falling under the former category. These methods require the subcutaneous injection of large volumes of lidocaine and saline, also known as tumescent anesthesia, to protect the surrounding structures from possible damage, including skin burns, nerve damage, pain, and arteriovenous fistula formation due to the endoluminal heating effects during ablation. ⁶ Tumescent anesthesia is time consuming to administer; carries its own risks of ecchymosis, hematoma, and postprocedure pain ⁷ ; and is limited by a whole body lidocaine dose limit of 35 to 45 mg/kg. ⁸ Therefore, newer, nonthermal methods have recently been gaining favor as they do not require tumescent anesthesia. These methods—namely, mechanical occlusion chemically assisted (MOCA; (ClariVein; Vascular Insights, Madison, CT), cyanoacrylate closure (CAC; VenaSeal; Medtronic, Minneapolis, MN), and polidocanol endovenous microfoam (Varithena, Provensis Ltd)—have been shown to produce similar rates of venous occlusion with decreased postprocedure pain.

Given the newer treatment methods for symptomatic varicose veins, it is important to select the right method for each patient. Patient factors such as vein size, vein depth, severity of venous ulcer disease, and adherence to compression therapy can all affect treatment outcomes. Additional technical factors such as vein tortuosity and operator skill need to be considered as well.

Thermal Tumescent

Radiofrequency Ablation

One of the traditional endovenous methods for varicose vein ablation, RFA has been validated by numerous studies to be as effective as surgical ligation and stripping with fewer postprocedure complications. ⁹ RFA devices generate thermal energy by inducing a rapidly alternating current through an electrode, heating the venous endothelium to 120°C by direct contact, resulting in tissue damage, scarring, and subsequent vein closure. ⁹ The procedure can be performed with minimal anesthesia often limited to oral anxiolytic medications. Briefly, after marking the dilated veins, a 6-Fr sheath is inserted into the GSV and an RFA catheter is advanced until it reaches approximately 2 cm caudal to the saphenofemoral junction (SFJ). Tumescent anesthesia consisting of a solution of lidocaine, sodium bicarbonate, and epinephrine is administered throughout the soft tissues of the saphenous compartment with a 21-G needle to decrease risk of thermal injury to nearby structures. While applying external pressure on the GSV, RFA is performed in overlapping segments along the length of the GSV while the patient is in Trendelenburg position. Postprocedure, the lower extremity is wrapped with an elastic bandage for 48 hours after which the patient is instructed to wear compression socks for 2 to 4 weeks.

Sevil et al studied 100 patients who underwent RFA ablation of the GSV and compared clinical outcomes pre- and postprocedure, namely, the VCSS (venous clinical severity score) and CEAP ( c linical manifestation, e tiologic factors, a natomic distribution, and p athophysiologic dysfunction) classification scores. They found VCSS to be significantly decreased after treatment ( p  < 0.001) and that the mean CEAP score went from C2 pretreatment to C0 posttreatment. ⁹ Only minor complications were noted with an overall frequency of 5% or less, with the most common being bleeding, ecchymosis/hematoma, thrombophlebitis, and paresthesias, and one case of deep-vein thrombosis (DVT). Three-year closure rate determined by van den Bos et al via meta-analysis of 119 studies was demonstrated to be at 84% for RFA. ¹⁰

Endovenous Laser Ablation

EVLA induces thrombosis and vessel closure by heating both the vessel endothelium and the blood resulting in tissue damage and fibrosis. ¹¹ It can be performed via a 5-Fr sheath after the introduction of approximately 500 mL of tumescent solution. Varying laser wire diameters are available to choose from based on the vein diameter. Laser ablation can then be performed at 15 W energy retracting the device slowly along the length of the vein. ¹¹ The laser can produce temperatures of up to 140°C. ¹² Patients are instructed to wear compression stockings postprocedure for 2 to 4 weeks.

Occlusion rates of 75 to 97% have been reported ^{13 14} with EVLA. Minor complications include pain, bruising, and paresthesias which reportedly occurred at rates of 21, 15, and 4%, respectively. ¹⁵ In one retrospective study, skin pigmentation occurred at a rate of 6.9%. ¹⁶ One of the most significant complications that may occur with EVLA is endothermal heat-induced thrombosis (EHIT), by which clot related to EVLA treatment in a superficial vein is propagated into a deep vein resulting in DVT and possible pulmonary embolism. AlGhofili et al examined rates of EHIT post-EVLA in 65 treated limbs, with a rate of EHIT in 5.3% of patients. ¹¹ Of note, EHIT was more common in their study in patients with a higher maximum proximal GSV diameter and in those with a competent SFJ, which permits antegrade flow to the deep veins. Additional literature has reported rates of DVT and EHIT of 1.7 and 1.4%, respectively. ¹⁷

EVLA has additionally been demonstrated to be effective in larger and more tortuous saphenous veins. A retrospective review of 44 patients who underwent EVLA with a mean GSV diameter of 16.95 mm demonstrated 1-month closure rates of 97.7 and 100% at 6 and 12 months, respectively. ¹⁶ Fourteen percent of patients required multiple puncture sites during the procedure due to tortuosity and one patient required a second treatment before the 6-month period. No major complications were reported and there was statistically significant improvement in postoperative VCSS and CIVIQ-2 scores.

Nonthermal Nontumescent

Mechanical Occlusion Chemically Assisted

The premise of MOCA combines chemical sclerosis with mechanical damage to the endothelium, resulting in venous ablation. The ClariVein system (Merit Medical, South Jordan, UT) combines a rotating catheter tip at 3,500 rpm which results in mechanical agitation of the vessel wall as well as dispersion of an injection of 1.5 to 2.0% sodium tetradecyl sulfate (STS) through the catheter tip to achieve chemical sclerosis. ¹² This procedure can be performed without sedation using local anesthesia at the insertion site and through a 4- or 5-Fr sheath. The ClariVein sheath and wire are introduced into the vessel percutaneously and advanced approximately 2 cm from the SFJ for GSV treatment or to the fascial curve near the saphenopopliteal junction (SPJ) for SSV treatment, the catheter sheath is retracted to expose the wire tip, and the motor is turned on while the catheter and wire are pulled down the vein at a rate of 1 to 2 mm per second. Pull-back is performed under continuous ultrasound monitoring to visualize spasm and collapse of the vein, indicating appropriate administration of sclerosant, while striving to not exceed the safe dosage limit ⁴ ( Fig. 1 presents a schematic of the ClariVein system). Postprocedure care requires a compression bandage applied from the foot to the groin for 24 hours, followed by continuous thigh-high compression stockings at 15 to 20 mm Hg for the next 48 hours, after which the compression stockings need to be worn only during daytime for the next 10 days.

Fig. 1.

Clarivein schematic ( https://clarivein.com/ ).

An early clinical trial performed by Elias and Raines ¹⁸ treated 30 GSVs in 29 patients with an average VCSS score of 4.5 and CEAP classification ranging from 2 to 4. Average GSV diameter was 8.1 mm. Average patient follow-up was 260 days with ultrasound evaluation demonstrating a primary closure rate of 96.7%. No adverse events were reported outside of minor local ecchymosis. A later trial by Witte et al ¹⁹ treated 85 patients (104 limbs) over the course of 1 year with a technical success rate of 99%. No major complications were noted with minor complications such a hyperpigmentation, hematoma/bruising, induration, superficial thrombophlebitis, and prolonged pain all occurring in less than 14.3% of patients. The average time for patients to resume their normal daily activities and return to work was 1 day. The authors did note, however, that after 36 months of follow-up, recanalization was seen in approximately 15% of treated vein segments, although this is a well-documented phenomenon in varicose vein disease overall. Similar rates of technical and clinical success as well as similar low complication rates were noted by Tang et al, ⁴ although this group used MOCA to successfully treat SSV lesions in addition to the GSV, with a closure rate of 100% at 8 weeks. Additionally, Tang et al reported a mean immediate postprocedure pain score of 0.8 on a scale from 0 to 10, with a range of 0 to 3, demonstrating that MOCA can be a very well-tolerated method for varicose vein ablation.

Cyanoacrylate Closure

Cyanoacrylate is an adhesive substance which rapidly polymerizes and solidifies in the intravascular compartment upon interaction with an anionic medium (blood) resulting in immediate occlusion of the vein as well as inciting an inflammatory response and granulomatous foreign body reaction, leading to fibrosis of the venous wall. ^{20 21} The VenaSeal system (Medtronic, Minneapolis, MN) requires a 7-Fr introducer sheath through which a 5-Fr delivery catheter is advanced approximately 5.0 cm distal to the SFJ or SPJ. The saphenous vein is compressed by the ultrasound probe approximately 2.0 cm distal to the delivery catheter tip and the cyanoacrylate glue is injected in fixed 0.1-mL aliquots by the handheld dispensing gun at 1 cm apart followed by 3 minutes of compression with the opposite hand. ⁷ This is then followed by repeat injection every 3 cm apart with 30 seconds of compression along the length of the desired treatment segment. Fig. 2 presents a schematic of the VenaSeal system.

Fig. 2.

VenaSeal schematic ( https://www.medtronic.com/us-en/healthcare-professionals/products/cardiovascular/superficial-vein/venaseal-closure-system.html ).

The initial safety and efficacy study by Almeida et al treated 38 patients with a 92.1% 12-month occlusion rate. ²¹ No serious adverse events were reported, although 21% of patients were found to have thread-like thrombus extension across the SFJ which did not necessitate treatment with blood thinners. Some minor adverse effects were noted in approximately 21% of patients, which included phlebitis consisting of local pain and erythema, low-grade fever, and hyperpigmentation. The 3-year follow-up study by the same group demonstrated a 36-month closure rate of 94.7% with no long-term adverse events and resolution of the thread-like thrombus noted in the immediate postoperative period. ²² A multicenter prospective trial encompassing 70 GSVs treated at seven European centers demonstrated 92.9% occlusion at 12 months with 11.4% of patients experiencing localized phlebitis, 8.6% experiencing postprocedure pain without evidence of phlebitis, and 1.4% experiencing localized infection at skin-entry site. ²⁰

Polidocanol Endovenous Microfoam

Ultrasound-guided foam sclerotherapy (UGFS) has been in use as a treatment for varicose veins since the early 1990s, with the rationale being that the greater volume of the foam sclerosant is better able to contact the vessel walls and produce more efficacious fibrosis and occlusion than liquid-form sclerosant, especially in large vessels. ²³ However, due to the use of room air as a foaming agent, rare case reports of significant adverse events such as stroke, TIA, and seizure have been reported. Varithena polidocanol endovenous microfoam is an O ₂ /CO ₂ mixture containing less than 0.8% of nitrogen gas, significantly decreasing the risk of gas embolism–associated adverse events. This foam sclerosant displaces blood from the vessel lumen and attaches to lipids on the endothelial cell membranes, denaturing them and resulting in thrombosis and vessel occlusion. Each 1% Varithena canister generates approximately 45 mL of useable foam which can be injected through a micropuncture set or a 16- to 22-gauge IV, preferably 4 to 5 cm in length. Approximately 5 mL or less of foam volume is recommended at each injection site for a total limit of 15 mL per session. It is currently approved only for GSV treatment.

Todd et al reported a 73% closure rate at 1 year, ²³ decreased from 89% at 5 weeks during the VANISH-2 trial, although the authors do note that treatment failure on duplex ultrasound as defined by recanalization does not necessarily correlate with symptom recurrence and conversely, sonographic success does not indicate complete symptomatic resolution. Clinically significant symptom improvement was noted and no major adverse events related to the procedure were seen. The VANISH-2 trial led by King et al confirmed the safety and efficacy of polidocanol endovenous microfoam compared with placebo treatment, with statistically significant VVSymQ score improvement from baseline to 8 weeks postprocedure in the treatment group compared with placebo group. ²⁴ The most common adverse events were mild, such as pain in treated extremity (21.1%), superficial thrombophlebitis (10.5%), and injection-site hematoma (8%); 3.3% of patients experienced postprocedure DVT.

Comparison of Thermal versus Nonthermal Techniques in the Literature

Multiple clinical trials, retrospective studies, and meta-analyses have been performed comparing the various thermal and nonthermal ablative methods among each other to demonstrate noninferiority of nonthermal methods, as well as determine which method overall might have the highest rates of success and more favorable complication profile.

A large meta-analysis of 64 randomized control trials, clinical trials, and prospective and retrospective case series by van den Bos et al comparing EVLA, RFA, UGFS, and surgical stripping found that EVLA and RFA achieved higher rates of anatomic success than UGFS and stripping, and that EVLA even significantly outperformed RFA in terms of obliteration of incompetent veins. ¹⁰ A prospective study comparing two methods of EVLA (one with a 1,470-nm radial fiber [EVLA-R] and one with a 1,470-nm jacket-tip fiber [EVLA-J]) to segmental RFA (sRFA) demonstrated 1-year GSV occlusion rates of 95% in the EVLA-J group compared with 93% in the EVLA-R and sRFA groups. ¹⁷ EHIT was noted in 4.4% of EVLA-J and sRFA patients and 2.2% of EVLA-R patients. No other major adverse events were noted. EVLA-R-treated patients experienced greater symptom improvement and less postprocedure pain than the other two groups; however, at 1 year, there was similar clinical symptom reduction across the three modalities.

A meta-analysis of literature comparing cyanoacrylate closure to EVLA or RFA, including the VeClose trial, demonstrated no significant difference in 12- and 24-month occlusion rates between CA and RFA groups as well as no statistically significant difference in closure rates between CA and EVLA. ²⁵ Additionally, there was no statistically significant difference in clinical symptom and quality-of-life improvement scores between CA and EVLA and CA and RFA. CA had a lower ecchymosis rate than RFA, and several trials reported higher rates of phlebitis in CA patients, although this difference was not significant. No statistically significant difference in rates of phlebitis and ecchymosis were noted between CA and EVLA.

In evaluating Clarivein versus Venefit RF, Lane et al found lower pain scores on average with Clarivein compared with RFA, ²⁶ with similar rates of clinical and technical success and safety outcomes.

A meta-analysis of studies comparing various thermal and nonthermal methods undertaken by Hassanin et al found no statistically significant difference in successful ablation rates between thermal and nonthermal techniques at the study endpoints. ²⁷ There was, however, a statistically significant difference in postprocedural pain scores, favoring nonthermal techniques, as well as decreased rates of ecchymosis and hematoma. No difference was found among techniques for rates of phlebitis, paresthesia, or skin pigmentation. No significant difference in the rates of DVT was noted. Degree of quality-of-life scores postprocedure was similar across all techniques.

Conclusion

Thermal, tumescent venous ablation methods have a relatively long-standing use in the treatment of varicose veins, backed by numerous studies demonstrating improved postprocedure pain and similar success rates to traditional surgical venous ligation and stripping. However, due to the necessary use of tumescent anesthesia to prevent thermal damage to adjacent structures, these procedures can still produce a significant amount of pain and discomfort to the patient, and require higher operator technical skill to deliver the tumescent solution. Patients with very superficial varicosities, advanced lipodermatosclerosis, or those with large overlying venous ulcers may be poor candidates for thermal ablation techniques given the high risk of superficial thermal injury and difficulty administering the tumescent solution. Patients with significant venous ulcers may also be less adherence to compression therapy postprocedure, which is necessary to help with reabsorption of the tumescent fluid. Additionally, thermal ablation techniques rely on apposition of the heat-damaged endothelial-lined vessel walls, which may not be achieved in large-diameter varicosities based on the technical skill of the provider administering tumescent anesthesia, the by-product of which collapses the vein walls to promote occlusion. Table 1 compares the indications and benefits of thermal tumescent and nonthermal nontumescent ablation therapies .

Table 1. Comparison of indications and benefits of thermal tumescent versus nonthermal nontumescent ablation therapies.

Thermal tumescent	Nonthermal nontumescent
Big veins >10–12 mm	Smaller veins
Good long-term data	Can go to malleolus
Potential for nerve injury	Advanced disease patients—can treat C5–C6 disease: tumescent hard to place
Patient discomfort due to tumescent	Shorter follow-up but equal
	Nerve/skin injury—no issues
	Decreased procedural pain and time

For these reason, more novel methods of endovenous ablation that do not rely on thermal energy for venous occlusion, such as mechanochemical ablation, low-nitrogen foam sclerosant, and cyanoacrylate glue, may be more appropriate for the clinically and technically challenging axial vein reflux patient. These nonthermal methods have been shown to offer similar rates of technical success and similar degrees of improvement in clinical outcome and postprocedure quality of life as thermal methods, with reduced postprocedure pain and minor complications such as ecchymosis and hematoma.