Introduction
The management of chronic venous disease and varicose veins has been developed in
recent years by introducing the minimally invasive endovenous thermal techniques to
eliminate the pathological reflux in the saphenous vein. Endovenous thermal ablation
(EVTA) has become the first line treatment as it allows to avoid general anesthesia,
enables faster recovery and return to daily activities, as well as improves patient
health-related quality of life (HLQoL), compared with traditional open surgery. [1]
However, thermal techniques require tumescent infiltration for local anesthesia and
to protect the surrounding tissue from thermal injury. Although the tumescent infiltration
is generally well tolerated, it may be the cause of discomfort, especially in patients
with the fear of injections. Furthermore, the use of EVTA has a potential risk of
thermal damage of superficial nerves and it requires to wear stocking for at least
1 week after the procedure to reduce pain and improve physical function.
Non-thermal non-tumescent techniques (NTNT) were introduced as an alternative to EVTA
to occlude incompetent superficial veins of lower limbs without the need for tumescent
infiltration. They have a potential benefit for acceptability by patients and also
for decrease risk of nerve injure. A few novel NTNT have emerged recently. The most
common are catheter-directed cyanoacrylate adhesive closure (CAC) and mechanochemical
ablation. In the paper an overview of the currently available data regarding the NTNT
method efficacy and safety is presented.
Catheter directed Cyanoacrylate Adhesive Closure (CAC)
CAC involves intravascular injection of cyanoacrylate (CA) which rapidly solidifies
in the polymerization reaction and produces an inflammatory reaction of the vein wall
to the foreign body and finally the vein fibrosis, causing permanent vein occlusion.
Several CAC systems for treatment of superficial veins incompetence are available
but currently three products are most commonly used: VenaSeal (Medtronic, Santa Rosa,
Ca, USA), Variclose (BiolasInc., Ankara, Turkey) and VenaBlock (Invamed, Ankara, Turkey).
The main difference between these devices relates to the CA formulation [2].
VenaSeal uses n-butyl-2-cyanoacrylate which has the highest viscosity and the longest
polymerization time. It begins to polymerize approximately 5 seconds after the contact
with the blood and it takes up to three minutes to complete the polymerization. It
has a soft and flexible texture after polymerization. The high viscosity prevents
the CA from entering the non-target veins.
VenaBlock also uses n-butyl-2-cyanoacrylate with also high viscosity, although at
least 60 times less than VenaSeal. It has a very short polymerization time and is
relatively firm after polymerization.
VariClose uses n-butyl-5-cyanoacrylate with the lowest viscosity but the fastest polymerization
time, what reduces the possibility of CA migration. It has a hard texture after polymerization.
These products also rely on various application techniques. With VenaSeal device,
catheter tip is positioned 5 cm distally to the sapheno-femoral junction (SFJ) and
CA is delivered using segmental pullback, while with VariClose and VenaBlock devices,
the catheter tip is 3 cm distally to SFJ and CA is applied during the continuous pullback.
There is no evidence-based data regarding the maximum dose of CA per treatment session.
Australasian College of Phlebology recommends an upper limit of 10 ml [2].
Effectiveness
Several studies have shown that CAC is effective with cumulative occlusion rates comparable
to those for EVTA in the early and midterm observations. [3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
In the first-in-men prospective study by Almeida et al., a 36-month occlusion rate
was 94.7 % in 29 out of 38 patients with great saphenous vein (GSV) incompetence and
a vein diameter of 3–12 mm. [3] A subsequent multicenter European trial (eSCOPE) presented by Proebstle et al. enrolling
70 subjects with GSV incompetence and a vein diameter of 6.6–14 mm showed a 12-month
occlusion rate of 92.9 %. [9] In systematic review and meta-analysis reporting CAC outcomes in 954 patients, the
complete closure rate at 6 months ranged from 89.5 % to 99.1 % and the pooled anatomic
success was 94.8 % (95 % CI, 92.0 %–97.6 %). The 12-month complete closure rate ranged
from 78.9 % to 95.5 % and the pooled anatomic success was 89.0 % (95 % CI, 84.2–93.9 %)
[10].
The WAVES study was the first to demonstrate the efficacy of CAC for GSV, small saphenous
veins (SSV) and/or accessory saphenous veins (AASV) up to 20 mm in diameter. All veins
were completely occluded at 1-month follow-up [7], although according to Chan at al. analysis of 108 GSV with a diameter of 2.3–11.4 mm,
the mean GSV diameter > 6.6 mm appeared to be a significant predictor for recanalization
(p < 0.016). The 12-month occlusion rate in GSV < 6.6 mm was 90 %, while in GSV > 6.6 mm,
58.6 % (p = .002). [5] The GSV diameter showed also a significant inversely proportional relationship with
the glue extension length and veins > 7 mm had a significantly longer remnant stump
length than smaller veins (p < .001). [11]
The feasibility of CAC in treatment of incompetent perforating veins was presented
by Toonder et al. The 3-month occlusion rate was 76 %, without any serious complications.
[12]
Comparison with thermal ablation
A few RCTs compared CAC with EVTA. [4]
[6]
[8]
In RCT by Çalık et al. including 400 patients with GSV incompetence, CAC was compared
with endovenous laser ablation (EVLA) and at 12-month follow-up the occlusion rate
was 96.6 % and 94.1 %, respectively. [4] The VeClose multicenter RCT, involving 10 centers in USA and 222 patients with GSV
reflux in veins up to 12 mm in diameter has shown that CAC was noninferior to radiofrequency
ablation (RFA), because the 36-month occlusion rate for CAC was 94.4 % and for RFA,
91.9 %. [8]
Another RCT compared CAC with EVLA and RFA in 525 patients and found 24-month occlusion
rates of 94.7 %, 90.9 % and 91.5 % after CAC, RFA and EVLA, respectively. [6]
A systematic review and meta-analysis by Hassanin et al. has also shown that there
was no significant difference in outcomes, when CAC was compared with EVLA and RFA
(RR, 1.02; 95 % CI, 0.94–1.11). [13]
Clinical and quality of life assessment
All studies on CAC, reporting the Venous Clinical Severity Score (VCSS) found a significant
or clinically relevant reduction in these scores after treatment, compared with the
baseline value [3]
[9]
[10], with no statistical difference between EVTA techniques and CAC in comparative studies,
[4]
[8]
[13] with an exception of RCT by Eroglu et al., where VCSS scores were significantly
lower in the CAC group than in EVTA groups at 6-month and 2-year follow- up (p < 0.001).
[6]
The HLQoL, measured by Aberdeen Varicose Vein Questionnaire (AVVQ), EQ-D5 quality
of life survey and Chronic Venous Insufficiency Quality of Life Questionnaire (CVIQ),
improved significantly after CAC in all studies. No statistical difference between
EVTA techniques and CAC was found in any comparative studies. [4]
[6]
[8]
[9]
[10]
[13] Both clinical and HLQoL assessment reminded improved at all follow-up intervals
in all studies reporting these patient-reported outcomes.
According to Morrison et al., 84.7 % of patients from CAC group were very satisfied
with the treatment, compared to 78.4 % patients after RFA (p >.05), and according
to Gibson, 98 % were satisfied with CAC procedure. [7]
[8]
Procedural duration
The average procedural duration of CAC, analyzed by Proebstle et al. was 18.6 minutes
[9] and in the direct comparative study, it was significantly shorter than the duration
of EVLA procedures (13 ± 3.4 vs 31.7 ± 8.8 min, p < 0.001). [4]
Pain and recovery
Çalık et al. noticed that procedural pain was significantly less in the CAC group
compared to EVLA (p < 0.001). [4] Morrison et al. found no difference in pain when compared to RFA (2.2 vs 2.4, on
a 10-point scale; P = 0 0.11). [8] Eroglu demonstrated that CAC was significantly less painful than EVLA and RFA (p < 0.001),
but found no difference between groups in term of pain in the post-operative period.
[6]
The recovery time and time to return to daily activities were significantly shorter
after CAC group than after EVTA. [4]
[6]
The great advantage of CAC is that there is no need for compression therapy after
the procedure. [2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Adverse events
Adverse events were reported in all studies of CAC, although their type and rate varied.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
The most common reported adverse event was a local inflammatory reaction of the skin
and subcutaneous area overlying the treated vein, reported at a rate of 11.4 % in
the study by Almeida et al. and 20 % in a study by Morrison et al. [3]
[8] Usually it’s not specified if it is a truth phlebitis or an immune skin reaction
resembling phlebitis, related to a local hypersensitivity reaction to the CA implantation.
In most studies it is grouped together and includes hypersensitivity, granulomatous-
type phlebitis and typical phlebitis.
There have been no clinical reports of anaphylactic reactions and only a few reports
concerning allergic reactions have been published. [2] According to systematic review a rate of hypersensitivity reaction to the CA is
7 %. [10] Gibson et al. reported the appearance of hypersensitivity in 6 % of patients. [14] The reaction was mild in 4.2 % of patients, moderate in 1.3 % and severe in 0.3 %.
In most cases the hypersensitivity reaction is transient, benign and self-limiting,
although it sometimes requires treatment, which includes the combination of nonsteroidal
anti-inflammatory drugs and oral antihistamines and in severe cases, systemic immunosupperssant
such as oral or intravenous steroids.
A granulomatous-type phlebitis reaction may develop in the mid -term and long term
follow up after the CAC. It commonly remains asymptomatic, but may progress to suppuration,
necrosis and ulceration. [2] Despite the large number of cases performed worldwide, only a few late granulomatous
reactions have been reported, some of them with considerable morbidity. [15]
Immediate and delayed hypersensitivity reaction with granulomas formation have been
reported to be the most significant concerns of clinicians. Further registration and
adequate follow-up after CAC are required. In case of patients with systemic autoimmune
disorders, Australasian College of Phlebology recommend EVTA instead of CAC, which
should be offered only if no other safe treatment options are available, and with
pre and post treatment steroid administration. [2]
Phlebitic reaction has been reported by Proebstle et al. in 11.4 % with a median duration
of 6.5 days. [9] In the Waves study phlebitis in the treatment area or in tributaries occurred in
20 % of patients but completely resolved in all but one, in a month. [7]
Other complications included deep venous thrombosis (0 %–3.5 %) [10] and CA protrusion into the SFJ, found by Proebstle et al. in 1.4 % and by Chan et
al. in 1.8 % of patients, that resolved within a week after subcutaneous low-molecular-weight
heparin injections. [5]
[9] Earlier studies reported higher rates of CA extension, up to even 21 % at the 48-hour
follow-up. [3] It was likely due to the catheter being positioned 3 cm from SFJ. With current technique
modifications involving an increase of the distance to 5 cm, the incidences of CA
protrusion are less common. Pulmonary embolism following CAC has not been published.
Hyperpigmentation had a reported incidence of 1.6 %–3.5 %, and appeared more often
after the treatment of veins coursing close to the skin surface. Other adverse events
included access site infection or cellulitis (1.4 %-3 %), hematoma (1.4 %–1.6 %),
nerve injury or paresthesia (0 %-2 %). [2]
[9]
[10] Proebstle noticed that 8.6 % of patients had pain over treated vein without phlebitis.
[9]
Compared to EVTA, induration, ecchymosis and paresthesia were found statistically
significant less in the CAC group (p < 0.001), but there was no significant difference
in appearance of deep venous thrombosis (DVT) and hyperpigmentation. [4]
Morrison et al. and Hassanin et al. found that only ecchymosis at day 3 was significantly
more often after CAC than after EVTA (p < 0.01) with no difference identified with
regard to rates of paresthesia, phlebitis and skin pigmentation between groups. Adverse
events were generally mild and well tolerated. [6]
[8]
[13]
Mechanochemical Ablation
Mechanochemical ablation is another NTNT technique commonly used in daily practice.
It uses a dual mechanism of action that combines mechanical injury to the venous endothelium
with simultaneous chemical endovenous ablation by delivery and dispersion of injected
sclerosing agent. Because no heat is generated during the therapy, there is no need
of tumescent anesthesia application.
At least two devices have been recently introduced for the treatment of superficial
venous incompetence: Clarivein (Vascular Insights, Quincy, Mass, USA) and Flebogrif
(Balton, Poland).
Mechanochemical Ablation with Clarivein (MOCA) mechanically damages the venous endothelium
by the tip of the catheter’s rotating wire, while simultaneous catheter- guided infusion
of the sclerosant agent. Usually the sclerosants, such as the sodium-tetradecyl-sulphate
(STS) or polidocanol (POL), are used in a liquid form, what limits the total dose
that can be applied during the procedure. Since the introduction of MOCA several procedural
changes have been introduced. The latest recommendation from the manufacturer includes
a minimum of 3 seconds of rotating time under the SFJ to create vasospasm and the
retreatment is advised if the proximal 10 cm is not occluded after the first run.
The different concentrations and the forms of the sclerosant have also been tested
in terms of the effectiveness. In RCT by Lam et al. liquid POL (2 % and 3 %) has been
compared with 1 % POL microfoam and according to the results, the foam was significantly
less effective than 2 % or 3 % liquid POL (p <.001) for treatment of GSV incompetence.
[16]
Effectiveness
The effectiveness of MOCA for ablating saphenous trunks have been shown in several
studies. [10]
[17]
[18]
[19]
[20]
A systematic review and meta-analysis by Vos et al. including seven studies, reported
outcomes in 691 patients found that complete closure rate ranged from 87.1 % to 98.1 %
at 6 months and 87.7 % to 95.2 %. at 12 months. The pooled anatomic success was 94.7 %
(95 % CI, 93.3 %-98 %) and 94.1 % (95 % CI, 91.5–96.8 %, at 6- and 12-months, respectively.
Anatomic success at 2-year follow-up ranged from 89.5 % to 95.0 %. To date, only one
study has reported the 3-year follow-up results and the occlusion rate was 86.5 %.
[10]
Comparison with EVTA
In the LAMA trial including 150 patients with GSV, SSV or AASV incompetence, MOCA
was compared with EVLA and the complete occlusion of the treated vein was found in
77 % of patients in MOCA group at 1-year follow-up, what was significantly lower than
in EVLA group (p = .020), in which the complete occlusion was noticed in 91 % of patients.
[19]
The comparison of MOCA with RFA was presented in the multicenter MARADONNA trial,
which included 209 patients with GSV incompetence. The 1- and 2-year anatomic success
rate after MOCA was 83.5 % and 80 %, respectively, what was significantly lower than
after RFA (p = .025 and 0.066), where the complete occlusion was found in 94.2 % and
88.3 % of patients, respectively. The anatomic failure was mainly caused by partial
recanalization. Analyzing the clinical success, no significant differences were found
between groups. [20] Another RCT similarly revealed significantly worse results after MOCA, with the
complete occlusion rate at 1 year of 82 %, compared to 100 % after EVLA and RFA (p = .009).
In this study a strong association between recanalization and the preoperative GSV
diameter was found. A mean GSV diameter of 8.6 mm was significantly more often associated
with proximal recanalization at one year, compared to a mean GSV diameter of 6.5 mm
(p = 0⋅007). [18]
In systematic review and meta-analysis of comparative studies comparing NTNT techniques
with EVTA, including 178 patients treated with MOCA, 281 with RFA and 385 with EVLA,
no difference in success between groups during immediate, 6-month, 12-month and > 12-month
follow-up periods was observed (RR0.96; 95 % CI, 0.89–1.03). [13] Considering complete and proximal occlusions (> 5 cm proximally occluded vein, with
> 5 cm open distally), another multicenter RCT also didn’t find the significant difference
between MOCA and RFA at 6- month follow up (MOCA vs RFA: 87 % vs 93 %, p = .483).
[17]
Clinical and quality of life assessment
All MOCA studies reporting VCSS noticed a significant or clinically relevant reduction
in these scores after treatment, compared to baseline. There was no significant difference
in the improvement of VCSS between MOCA and EVTA patients in the mid-term and long-term
results [10]
[17]
[19], although MARADONNA trial has showed significantly lower VCSS at after MOCA than
after RFA at 30-day follow-up (p = 0.001). [20]
The HLQoL measured by AVVQ, SF-36 improved significantly after MOCA procedure. No
statistical differences were observed between MOCA and EVTA groups. [10]
[13]
[17]
[18]
[19]
[20]
Pain and recovery
Maximum and median pain during the procedure was significantly lower in the MOCA group
then in RFA group with both VAS (15 vs 34; p = .003 and 10 vs 19.5; p = .003) and
Number Scale (3 vs 4 p = .002 and 2 vs 3 p = .004). [17] Pain scores during the first 14 days were significantly lower after MOCA than after
RFA (p = .01). [20] In systematic review by Hassanin et al. postprocedural pain compared by a visual
analogue scale was also lower in those undergoing MOCA than RFA, with a mean difference
of –9.83 (95 % CI, –19.4 to –0.25). A significantly lower median pain scores were
found in the MOCA group compared with RFA and EVLA, respectively (1 vs 5 vs 6; p < .01).
[13]
One RCT, the LAMA trial by Mohamed et al. did not confirm such results, because they
found no difference in pain score during MOCA and EVLA (15 vs 22; p = .210). The intergroup
comparison showed a nonsignificant trend of lower pain scores in the MOCA group most
days, except for day 3 where there was a significant difference between groups. [19]
An RCT by Vähäaho also found no difference in VAS pain score during the procedure
in MOCA, EVLA and RFA group (p = .118), however the procedures were performed under
the sedatives and patients treated with MOCA received significantly less propofol
than patients who received EVTA (p < .001). The amount of painkillers taken did not
differ between the groups. [18]
Median time to work and to normal activity also did not differ significantly between
MOCA and EVTA patients. [17]
[18]
[19]
Adverse events
The most common adverse events after MOCA are induration (12 %–18 %), superficial
venous thrombosis (2 %–13 %), hematoma (1 %–11 %), DVT (0 %-1 %) and hyperpigmentation
(5 %). No nerve injuries, skin injuries and infections have been reported. [10]
Comparing the incidence of adverse events, most studies reported no significant differences
between MOCA and EVTA, both in major (DVT) and minor (phlebitis, ecchymosis, paresthesia
and skin pigmentation) adverse events [13]
[17], although in MARADONNA trial the incidence of ankle edema was significantly lower
after MOCA than after RFA, with similar incidence at baseline (p = 0.002). [20] An RCT by Vähäaho et al. found no sensory disturbances after MOCA, compared to
8 % of patients after EVTA with such adverse event (p = .090). [18]
Flebogrif
Flebogrif is another mechanochemical ablation device used for ablation of the incompetent
saphenous vein. It mechanically scarifies the vein wall by a specially designed endovenous
catheter, at the end of which sharp hooks are deployed, which damage the endothelium.
During the continuous withdrawing the catheter, the chemical ablation is performed
by simultaneously injecting a foam sclerosant. Up to now the available evidence is
very limited. A first study has shown promising results with the complete occlusion
rate of 92 % after 2 years. [21]
Other non-thermal and non-tumescent Techniques
The V-Block Occlusion System
Another new NTNT method of treatment the incompetent saphenous vein is the V-Block
occlusion system, which uses self-expandable vein occluder inserted below the SFJ
to eliminate the possibility of forwarding passage of clot and sclerosant to the deep
veins and dual procedure syringe system. During the foam sclerotherapy, the blood
is simultaneously evacuated from vein. The analysis of 51 patients has shown the complete
occlusion rate of 98 % at 7 day and 77.8 % at 3 years, without device-related complications.
[22]
Coil Embolization and Foam Sclerotherapy
The combination of coil embolization and foam sclerotherapy of GSV has also been alternative
described in the literature as a novel and effective NTNT treatment for varicose veins
with good short-term results. [23]
There is currently no high-quality evidence to support the use of physical embolic
agents, such as coils, to treat axial venous reflux, therefore the International Union
of Phlebology, the Australasian College of Phlebology, the Australia and New Zealand
Society for Vascular Surgery, the American Venous Forum, the American Vein and Lymphatic
Society, and the Interventional Radiology Society of Australia recommend against the
use of such approaches for the treatment of saphenous incompetence outside of the
clinical trial settings (Grade 2C against). [24]
Further research is needed to confirm the validity of these new methods.
Summary
NTNT represent the next generation of endovenous therapy. The currently available
evidence demonstrated high clinical and anatomical success rates for novel techniques,
comparable to those previously reported for thermal ablation.
The main advantage over established treatment modalities for saphenous vein incompetence
is no need for tumescent anesthesia, what leads to reduce the procedure time and increase
comfort of patients during and after the procedure with less hematoma and ecchymosis
formation. Furthermore, no thermal energy is used with a related risk of nerve injury,
therefore these NTNT may be a valuable alternative, in particular if ablation of the
more distal part of the below-knee GSV or the SSV is considered. Additionally, the
use of CAC obviates to wear the postprocedural compression stockings what is an important
advantage for the compliance of the patients.
The safety of these NTNT is also well documented, although precautions should be taken
in case of CAC due to the possibility of late hypersensitivity reaction and granuloma
formation.
The novel non-tumescent non-thermal are a valuable alternative to well- established
thermal techniques, however further studies with long-term results are needed, also
with regard to safety aspects.
