Insufficiency of the superficial venous system can be treated conservatively by compression and venoactive drugs, as well as by ablative invasive treatment options, including open surgery and endovenous treatments. Currently, endovenous treatments are the recommended first-line treatment for CVD, according to the latest guidelines [1,2]. While thermal techniques, such as endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), remain standard, they carry risks, including nerve injury and pain due to tumescent anesthesia. NTNT techniques have emerged to address these limitations.

This paper reviews the most commonly used NTNT techniques, evaluating their safety profiles, effectiveness, and long term outcomes.

Cyanoacrylate adhesive closure (CAC) uses an adhesive agent to directly close the vein, providing a streamlined process and mitigating the risks associated with thermal ablation. Trials on CAC have shown both short- and long-term efficacy, with high closure rates [3-6]. Recently, however, serious adverse events (AEs) associated with CAC have raised concerns. An analysis of three major databases—the Total Product Life Cycle (TPLC) database from the US Food and Drug Administration (FDA), the Database of Adverse Event Notifications (DAEN) from the Australian Therapeutic Goods Administration (TGA), and the Yellow Card database from the UK Medicines and Healthcare Products Regulatory Agency (MHRA)—noted 14 fatalities, 7 strokes, 211 thromboembolic events, 482 immune reactions, and 9 other reportable AEs. This prompted caution around CAC usage. Nevertheless, Elias et al. [7] argued that without knowing the total number of CAC procedures performed, these statistics may exaggerate the true incidence of such events. A comparative study involving 803 patients and 1,096 procedures showed minimal incidence of thrombotic complications: endovenous heat-induced thrombosis (EHIT) occurred in 1.9% of cases and endovenous glue-induced thrombosis (EGIT) in 1.3% (p=0.57). Deep vein thrombosis rates were 0.1% in the radiofrequency ablation (RFA) group and 0.3% in the CAC group (p=0.81) [8]. CAC has been associated with distinct adverse effects, including foreign body reactions and allergic responses to the glue. A 2023 systematic review identified 55 cases of glue-related adverse reactions [9]. These risks can be reduced by excluding patients with a history of allergies to specific CAC formulations. Currently, the Spectrum program using the VenaSeal system (Medtronic, Minneapolis, MN, USA) is underway, encompassing two randomized controlled trials (RCTs) comparing VenaSeal with surgical stripping (SS) and endothermal ablation (ETA) and a single-arm study focused on venous leg ulcers. The program’s primary endpoints include the Venous Treatment Satisfaction Questionnaire (VenousTSQ) and the elimination of truncal reflux, which includes valuable insights into patient satisfaction and clinical efficacy [10].

Mechenochemical ablation (MOCA) utilizes mechanical injury combined with sclerosant infusion, with reduced anesthesia requirements. MOCA is another non-tumescent alternative that works by a combination of mechanical injury (the vein wall is touched by a catheter tip) and liquid sclerotherapy. Currently there are two types of MOCA is available in Korea: Clarivein (Merit Medical, South Jordan, Utah, USA) and Flebogrif (Balton, Warsaw, Poland). ClariVein device abrades the intima with the tip of a catheter’s rotating wire. The liquid form of STS or POL are used most often, which limits the total dose that can be applied MOCA using the ClariVein device, reintervention was performed in 5 out of 75 limbs [11]. Recent study published in 2024 included 109 patients (115 limbs) and the anatomical success rate defined as complete occlusion was 60.5% in over 8 years of follow-up [12]. Flebogrif device causes vein wall damage through a catheter with sharp hooks at the tip, while chemical ablation is performed simultaneously by injecting a foam sclerosant. The MOCA technique by Flebogrif shows, a closure success of up to 93.2% (95% CI, 90.3%–96.1%) at 1 year, according to the information comes from a systematic review and meta-analysis of MOCA [13]. At three years, a success rate of up to 92% was achieved [14]. In a comparative retrospective study of treatment of the small saphenous vein with MOCA with ClariVein catheter versus surgical ligation and stripping of saphenopopliteal junction published in 2022, involving 118 limbs at 10 month follow-up, the recurrence rate was similar (7.5% [4/53] for MOCA vs 5.7% [3/52] for the surgical stripping) [15]. However, it seems noteworthy that there were no neurological adverse events in the MOCA group while 3.4% of neurological adverse events in the surgical stripping group. Though this technology is well tolerated and effective, well-designed studies with a higher number in follow-up are required to define the definitive role of these devices.

Foam sclerotherapy is historically used treatment modality and the physician formulated foam is advanced further to pre-manufactured foams incuding Polidocanol Endovenous Microfoam (PEM: Varithena, Boston Scientiric, Marlborough, Massachusetts, US) or Varixio (Vascular Barcelona Devices, S.L., Barcelona, Spain). Injectable foam causes direct endothelial damage, especially effective in veins with complex anatomy and offer several advantages over physician-compounded (physician-made) foam for treating varicose veins: pre-manufactured foams produce foam with a standardized ratio and bubble size, leading to more stable, uniform foam. This is difficult to achieve consistently with physician-made foam, which can vary in quality depending on technique and experience. These pre-manufactured foams are designed to be more stable than manually compounded foam, which tends to break down more quickly. Stable foam allows for more effective treatment as it can maintain contact with the vein wall for longer, improving sclerosis of the vein. The standardized formulation and longer stability reduce the risk of complications, such as embolization, associated with the variable quality of physician-made foam. Pre-manufactured foams simplify the procedure, reducing the need for manual preparation and potentially saving time for physicians. The automated nature of Varixio, in particular, provides an added level of convenience and consistency. Varithena has regulatory approval (such as FDA approval in the U.S.) as a commercial product specifically designed for sclerotherapy, ensuring it meets rigorous safety and efficacy standards. Physician-made foam does not have the same level of oversight or uniformity. These factors can contribute to better outcomes, less variability in results, and potentially lower recurrence rates compared to physician-compounded foam. The vacuum-assisted sclerotherapy catheter (Velex, I-VASC, Milan, Italy) is currently undergoing post-market trials. A six-month follow-up reported outcomes in 22 patients, with complete occlusion observed in 11 of them [16].

Ultrasound-guided high-intensity focused Ultrasound (HIFU) technology is an effective non-invasive technique for precisely destroying deep target tissues. Its therapeutic principle is to concentrate energy at a focus using a concave HIFU probe, thereby producing a range of effects, including thermal, mechanical, and cavitation effects, that lead to precise tissue necrosis and vascular fibrosis [17].

Thermal ablation techniques, such as endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), have consistently demonstrated long-term occlusion rates exceeding 90% in various studies. In comparison, NTNT methods, particularly CAC, have shown comparable occlusion rates in the short to medium term, with rates nearing 94% at 12 months [18]. Notably, MOCA has been associated with slightly higher recanalization rates, ranging from 10% to 20% within the first year [19]. However, a systematic review of eight RCTs comparing MOCA to RFA reported similar recanalization rates at the two-year mark [20]. Another systematic review, published in 2021, assessed the effectiveness, safety, and cost-efficiency of NTNT techniques, specifically MOCA and CAC, by analyzing 19 primary studies reported in 25 publications [21]. This review found that NTNT methods were equally effective in achieving clinical improvement and enhancing quality of life compared to thermal ablation. CAC demonstrated similar anatomical closure outcomes to thermal ablation, whereas MOCA showed slightly poorer results in anatomical closure rates. In patients with venous ulcers, MOCA yielded comparable anatomical outcomes to RFA and EVLA but achieved higher ulcer healing rates with similar healing times and recurrence rates [22]. A study by Shaprynskyi et al. [23] (2023) evaluated the treatment of chronic venous disease with superficial venous reflux in 228 patients across C2-C6 stages. The study compared various methods, including EVLA, RFA, MOCA, CAC, and ultrasound-guided foam sclerotherapy. EVLA emerged as the most effective approach, providing superior long-term results [23].

One of the primary advantages of NTNT techniques is the absence of thermal injury, thereby eliminating risks such as nerve damage or skin burns, which, although rare, remain significant complications of thermal ablation. Moreover, NTNT methods do not require tumescent anesthesia, leading to reduced patient discomfort during the procedure. However, CAC has been linked to adverse reactions, including hypersensitivity and local inflammation. In contrast, thermal ablation, while generally safe, is associated with a higher incidence of transient paresthesia and ecchymosis. According to a systematic review, the complication profiles of NTNT procedures are generally minor [21]. While the nature of adverse events varies from those seen in EVLA or RFA, most reported complications are mild, transient, and resolve without major interference in patients’ lives. It is worth noting, however, that many studies on complication data were not sufficiently powered to detect statistically significant differences between treatment groups.

The cost-effectiveness of NTNT techniques remains a topic of debate [24]. Thermal ablation tends to have lower procedural costs due to the widespread availability of equipment and expertise. However, NTNT methods, such as CAC, eliminate the need for anesthesia and extensive post-procedure care, potentially reducing indirect costs. A market simulation analysis examining out-of-pocket expenses favored NTNT procedures over thermal ablation. This study highlighted that to maximize patient satisfaction, factors beyond anatomical success rates—such as patient comfort and recovery experience—should also be considered [25].

Patient selection is a critical factor in determining the success of NTNT techniques for varicose vein treatment. Specific patient characteristics such as vein anatomy, comorbidities, and prior allergies play a significant role in guiding the choice of the most suitable treatment modality. For vein anatomy, factors like vein diameter, tortuosity, and the extent of saphenous vein reflux should be carefully evaluated. CAC is generally more suitable for straight and larger veins, while MOCA may be better for tortuous veins due to the flexibility of its catheter system [26]. Comorbidities also influence the choice of NTNT techniques. Patients with bleeding disorders may benefit from NTNT methods as they avoid the risks associated with tumescent anesthesia. Similarly, NTNT techniques are often preferred in patients with anatomical considerations, such as proximity to heat-sensitive structures, where thermal ablation techniques could pose a higher risk [27]. Allergy history is another crucial factor. Patients should be screened for allergies to cyanoacrylate glue, sclerosants used in MOCA, or other device components to prevent adverse reactions [9]. Elderly or frail individuals who may not tolerate tumescent anesthesia or invasive procedures can benefit from these minimally invasive options. Patients with cosmetic concerns or those seeking faster recovery times may also favor NTNT methods [28].

NTNT endovenous ablation using cyanoacrylate appear to be safe and effective form of therapy yet long term data regarding the safety and efficacy of the CAC as endovenous ablation technique are yet to come up. Further randomized studies comparing CAC with thermal ablation techniques are needed. Also, direct comparison between the two available CAC endovenous devices i.e., Variclose and VenaSeal need to come up before recommending one over another. MOCA and HIFU require further long-term data to validate their efficacy and safety compared to established techniques. For MOCA, standardization of procedural protocols and additional RCTs are essential to address variability in outcomes and solidify its role in clinical practice. HIFU, as a non-invasive option, holds promise but requires more cost-effective solutions and robust comparative studies to enhance its feasibility and adoption. Advances in device technology and head-to-head trials against thermal and other NTNT techniques will be pivotal in determining their place in the treatment algorithm for varicose veins.

NTNT techniques for varicose veins show promising outcomes with favorable complication and recurrence rates in selected patient populations. NTNT technology is promising in terms of patients’ satisfaction and lower risk of nerve associated complication. However, additional longitudinal studies are needed to optimize patient selection between the thermal and NTNT techniques.

The author declares no conflicts interest.