1

Original communication

N-butyl cyanoacrylate in the

treatment of venous insufficiency:
The effect of embolisation with
ablative polymerisation
Eyüp Serhat Çalık1, Ümit Arslan1, Fırat Ayaz2, Mehmet Tort1, Ziya Yıldız1, Volkan Aksu3,
Oruç Alper Onk4, Hüsnü Kamil Limandal1, Evren Ekingen5, Özgür Dağ1, Mehmet Ali Kaygın1,
and Bilgehan Erkut1

1
Erzurum Training and Research Hospital, Erzurum, Turkey
2
Diyarbakır Gazi Yaşargil Training and Research Hospital, Turkey
3
Ardahan State Hospital, Turkey
4
Erzincan University Medical Faculty, Turkey
5
Batman Region State Hospital, Turkey

Summary: Background: The primary objective of this multicentre prospective observational study was to evaluate the early results of a new
non-thermal embolisation method using N-butyl cyanoacrylate in venous insufficiency. Patients and methods: A total of 181 patients with a
varicose vein diagnosis were treated with the VariClose: Vein Sealing Systems at four different centres. The protocol included physical and col-
our Doppler ultrasonography examination, venous clinical severity score and quality of life assessment before and after the procedure on days
1 and 7 and at months 1, 3 and 6. Clinical recovery was evaluated by comparing the venous clinical severity score and the quality of life assess-
ment before and after the procedure. Results: In total, 215 embolisation procedures were successfully completed on 181 patients (110 female)
with a mean age of 37.6 ± 13.2 years (range 18 – 72 years). The 215 procedures consisted of 25 bilateral applications on 206 great saphenous
veins and 9 small saphenous veins. The average pre-interventional diameter of great saphenous veins was 6.5 ± 1.4 mm (4.3 – 14 mm), and the
mean diameter of small saphenous veins was 5.2 ± 1.3 mm (3.8 – 8.6 mm). The average length of the sealed vein segments was 31.6 ± 6.1 cm
(23 – 70 cm), and the average N-butyl cyanoacrylate usage for the patient was 0.9 ml (0.7 – 2.1 ml). The procedural occlusion rate was 100 %.
Post-operative pain was observed in 11 patients (6.1 %), and thrombophlebitis was observed in 1 patient (0.5 %). No total recanalisation was
observed. Five (2.7 %) partial recanalisations were observed at the 6 month follow-up. The 6 month total occlusion rate was 97.2 %. Conclusions:
This new tumescent-free non-thermal embolisation method can be applied safely with high success rates.

Key words: Chronic venous insufficiency, varicose veins, treatment, embolisation, cyanoacrylate

Introduction needs in surgical treatments led to a search for alternative

treatment methods [3, 4]. In recent years, thermal ablation
Chronic venous insufficiency (CVI) and varicose veins (VV) methods, such as radiofrequency (RFA) and endovenous
are common chronic medical problems that have a signifi- laser (EVLA), have become popular [5] and have been ac-
cant effect on quality of life. Symptoms of CVI that affect cepted as safe and effective treatment methods for great
daily activities include pain, swelling, heaviness, fatigue, saphenous vein (GSV) insufficiency [6]. A quick healing
restlessness in the legs, burning, itching, and cosmetic prob- time and high occlusion rates are the most advantageous
lems. More serious complications such as spontaneous var- features of these two methods [7, 8]. Despite these advan-
ix rupture and bleeding, superficial thrombophlebitis, deep tages, thermal ablation has several disadvantages, such as
vein thrombosis (DVT) and ulcers can also occur [1]. It is re- the necessity of tumescent anaesthesia, rupture of the vein
ported that CVI occurs at a rate of 25 – 33 % in women and wall with EVLA, post-operative pain, bruising and paraes-
19 – 20 % in men, with an annual incidence of 2.6 % in wom- thesia [9, 10]. Liquid or foam sclerotherapy are chemical
en and 1.9 % in men [2]. ablation methods with low costs and versatile applicability.
Surgical intervention is the technique that has been High recurrence rates, re-intervention potential, post-pro-
used classically for the management of CVI and varicosi- cedural thrombophlebitis, inflammation, pain, pigmenta-
ties. High recurrence rates, complications and cosmetic tion, headache, defect of vision, DVT, pulmonary embo-

Vasa (2016), 45 (3), 1 – 6 © 2016 Hogrefe

DOI 10.1024/0301-1526/a000xxx
2 E. S. Çalık et al.: The Treatment of venous insufficiency

lism (PE), and stroke related to paradox embolism are Patient history and physical examination with colour
potential disadvantages of sclerotherapy [11]. Doppler ultrasonography (CDUS) comprised the primary
N-butyl cyanoacrylate (NBCA) glue has been used for evaluation. The severity of insufficiency in GSVs or SSVs
many years in Europe for the embolisation of vascular le- was determined, vein diameter was measured, and map-
sions, such as arterio-venous malformations (AVM), pelvic ping and determination of reflux sources in the affected
congestion syndrome and varicocele. It has been used in veins were performed during the CDUS examination. The
the treatment of devascularisation of cerebral AVMs in the current venous insufficiency symptoms were assessed
USA since 2000 [12]. The safety and efficiency of using based on the venous clinical severity score (VCSS), where-
NBCA in the treatment of GSV insufficiency seems prom- as the clinical findings were assessed based on the clinical,
ising based on early results from several recent studies aetiological, anatomical and pathophysiological classifica-
[13 – 16]. We have used another NBCA-based system that is tion for chronic venous disorders (CEAP) [17, 18]. The
less viscous and has a different composition. In this multi- quality of life (QOL) assessment, including general pain
centre cohort study, we present the early results of the use and associated physical, social, and psychological param-
of endovenous ablation with the NBCA system for the eters, was performed using the Chronic Venous Insuffi-
treatment of CVI. ciency Quality of Life Questionnaire (CIVIQ ), version 2
[19]. VCSS, CEAP classifications and CIVIQ values were
determined and recorded at baseline and at each follow-
up visit by the same local investigator for all patients.
Patients and methods
In this study, 181 patients (110 female) with a mean age of Procedure technique
37.6 ± 13.2 years (range 18 – 72 years) were included. The
average body mass index was 24.2 kg / m2 (18.1 – 41.8 kg / m2. GSV or SSV embolisations were performed with Vari-
102 (56 %) patients presented with a family history of ve- Close®, which contains a 7F introducer set, a 0.035” guide-
nous disease, 73 (40 %) patients were smokers, 17 (9 %) wire, two or more of 1 ml VariClose NBCA, a 2-ml syringe,
patients had hypertension, 14 (7.5 %) patients a pathologic a 5F long introducer sheath, and a VariClose delivery sys-
lipid profile, 11 (6 %) were obese, 8 (4.5 %) had diabetes tem (VDS) consisting of a 4F delivery catheter, a dispens-
mellitus, 3 (2 %) patients chronic obstructive pulmonary ing gun and an adaptor. The VDS is designed to deliver
disease and 2 (1 %) patients overt coronary artery disease. 0.3 cc NBCA in 5 s for 10 cm of vein. Holding the trigger
The patients were treated in four different centres in for 5 s provides 0.3 cc of NBCA. A pulling back rate of
Turkey (Erzurum, Diyarbakır, Ardahan and Erzincan) with 2 cm/sec relates to 0.03 cc of NBCA applied to each cm of
the NBCA-based system “VariClose®: Vein Sealing Sys- the vein. VariClose® is a specially developed formulation of
tems (Biolas, Ankara, Turkey). Written consent was re- NBCA that creates rapid polymerisation upon interaction
ceived from all patients who had symptomatic GSV or with the endothelium. The NBCA was developed specifi-
small saphenous vein (SSV) incompetence, along with per- cally for long vein segment sealing. It has lower viscosity
mission from the local ethics board from April, 2014 to with reinforced adhesive properties. Therefore, it leads to
September, 2014. Inclusion and exclusion criteria are list- fast polymerisation, and the difference in the method used
ed in Table 1. results from this property of VariClose®.

Table 1. Inclusion and exclusion criteria.

Inclusion criteria 
 Patients between the ages of 18-75 with symptomatic varicose veins, CEAP classification between C2-C5, GSV insufficiency 0.5 sec, and who
were over-determined by CDUS, could come to follow up examinations and were mentally healthy to approve the operation. 

Exclusion criteria 
 Saphenous vein duplication or accessory saphenous vein with venous insufficiency 
Advanced tortuous GSV  
Saphenous vein under 3 mm and over 15-mm diameter   
DVT history 
Active thrombophlebitis in deep or superficial veins 
Arterial insufficiency history or ankle-brachial index under 0.9 
Significant femoral or popliteal vein insufficiency 
History of intervention (surgical, thermal or chemical ablation) with saphenous vein
to be treated 
Hypersensitivity to the NBCA or reaction history with the past surgeries 
Cancer  
Life expectancy under two years 

CEAP: clinical, aetiological, anatomical and pathophysiological classification, GSV: great saphenous vein, CDUS: colour Doppler ultrasonogra-
phy, DVT: deep vein thrombosis, NBCA: N-butyl cyanoacrylate

© 2016 Hogrefe Vasa (2016), 45 (3), 1 – 6

E. S. Çalık et al.: The Treatment of venous insufficiency 3

The GSV was accessed percutaneously with a 7F sheath Results

under ultrasound guidance at the level of the knee or an-
kle. For SSV treatment, access was performed at the outer
malleoli level. A 0.035” guidewire was inserted through Overall, 215 embolisation procedures were successfully
the short sheath of the introducer kit and was advanced completed. Procedures were performed by 8 different spe-
into the saphenofemoral junction (SFJ) or saphenopo- cialists in the 4 different clinics. The 215 procedures con-
pliteal junction (SPJ). The tip of the guidewire at the junc- sisted of 25 bilateral applications on 206 GSVs and 9 SSVs.
tion was confirmed using ultrasonography (USG). A 5F The average pre-interventional diameter of the GSVs
long introducer was advanced over the wire to the junc- was 6.5 ± 1.4 mm (4.3 – 14 mm). The mean diameter of the
tion. After the tip of the catheter was confirmed to be at the SSVs was 5.2 ± 1.3 mm (3.8 – 8.6 mm). The average length of
beginning of the junction by USG, a long introducer sheath the sealed vein segments was 31.6 ± 6.1 cm (23 – 70 cm).
was pulled back 6 cm distal to the junction. The access For all patients with GSV insufficiency, the segment above
sheath was removed due to the fast pull back procedure. A the knee was occluded. In 18 patients, the segment below
delivery catheter was inserted into the long introducer the knee was also occluded, and, in three patients, the en-
sheath and then advanced through and secured using a tire GSV was treated. The SSVs were completely occluded
spin lock mechanism. The tip of the delivery catheter was in 9 patients. The average NBCA usage for the patients
confirmed to be 3 cm distal to the SFJ or SPJ by USG. was 0.9 ml (0.7 – 2.1 ml), and the average procedure time
The VDS was prepared using the gun, adapter and in- was 5.4 ± 2.5 min (3 – 14 min). Mini phlebectomy was per-
jector after filling the injector with 2 cc NBCA. The VDS formed on 3 legs with very large varicosities during the op-
was attached to the delivery catheter using a spin lock erations, and adjunctive foam sclerotherapy was performed
mechanism. SFJ or SPJ compression by USG and closure of on 5 legs with large varicosities during the follow- up with a
the junction was confirmed. Before injecting NBCA into slight deviation in the protocol.
the vein lumen, the catheter was primed by pulling the
trigger for 1 s. After priming, the trigger was pulled again
and pressed for 5 s. While the trigger was being pulled, the Complications
delivery catheter was pulled back 2 cm per second. The
pullback rate was observed using the markers over the long Adverse events were minor after treatment with VariClose®.
introducer sheath. After injecting NBCA for the first 10 cm The most noteworthy adverse events were post-operative
in 5 s, the trigger was pulled and pressed for 5 s again. Si- pain and thrombophlebitis. Post-operative pain was ob-
multaneously, after the first 10 cm of NBCA injection, served in 11 patients (6.1 %) at entry or at the SFJ level during
pressure was applied over the GSV or the SSV by USG the first two days (1 to 4 days). Thrombophlebitis was ob-
probe (transducer) at the pull-back rate of 2 cm / s, while served in one patient (0.5 %) on the second day. Non-steroi-
the compression over the SFJ continued. This injection / re- dal anti-inflammatory medication was administered for 3
traction process was repeated until the whole vein seg- days; when erythema increased along the trace of the treat-
ment was sealed. After the whole vein segment was inject- ed GSV, antibiotics were added for 7 days, and the patient
ed with NBCA, pressure was applied with a towel over the fully recovered after 14 days. Mild stiffness and sensitivity
whole vein segment for 30 s. Then, venous closure was were observed in four patients (2.2 %) who fully recovered
confirmed by USG, and a small elastic bandage with ap- after an average of 5 days (range 3 to 8 days) of non-steroidal
proximately 20 – 30 mmHg pressure was applied to the anti-inflammatory treatment. Clot extension to the SFJ was
treated vein segment for one day. observed in 2 (1.1 %) patients on the second day by USG ex-
The protocol included a physical and CDUS examina- amination. The clot extensions had completely disappeared
tion and QOL assessment before and after the operation after six months. Serious complications such as paraesthe-
on days 1 and 7 and at months 1, 3, 6, 12 and 24. Follow-ups sia, DVT or PE and allergic reactions were not observed in
were completed on days 1 and 7 and at months 1, 3 and 6. any patients.
The success of the operation was defined as the total oc-
clusion of the treated vein segment, or in any segment
opening or recanalisation below 5 cm [20]. The evaluation Efficacy
of clinic recovery was performed by comparing VCSSs and
QOL assessments before and after the procedure. The 1-, 3- and 6-month follow-up visits were completed in
163 (90 %) patients. The average follow-up time was
7.5 months (range 6 – 11 months). Clinical, CDUS and QOL
Statistical methods evaluations of the patients were performed during the fol-
low-up visits. The procedural 1-day, 7-day and 1-month oc-
The results are presented as the mean ± standard devia- clusion rates were 100 %. No total recanalisation was ob-
tion. Comparisons between pre-operative and post-opera- served in any patients, and 5 (2.7 %) partial recanalisations
tive variables were conducted using independent t-tests were observed during the follow-up. Two of them were at
for continuous variables. A p-value of less than 0.05 was the SFJ level at 8- and 10-cm in length, at three months. The
accepted as statistically significant. other three recanalisations were in the middle of the thigh at

Vasa (2016), 45 (3), 1 – 6 © 2016 Hogrefe

4 E. S. Çalık et al.: The Treatment of venous insufficiency

6-, 4-, and 4-cm in length, at six months. Based on the life- [23 – 26]. Min et al. showed the occupation of tunica inti-
table analysis (ESM Figure 1), the 6 month total occlusion ma using an eosinophilic matrix and spindle cells and re-
rate was 97.2 %, and the 6 month success rate was 98.3 %. ported that the swine superficial epigastric vein remained
The patients with recanalisation were not clinically sympto- closed without any recanalisation 30 days after NBCA
matic. Importantly, recanalisations occurred around the an- injection [24]. In another study, Almeida et al. reported
eurysmal segments and junctions of large varicosities. 60-day results of histological changes such as wall thick-
ness and fibrosis [23].
Polymerisation is composed of three stages. These three
Clinical success stages, defined by Kailasnath and Chaloupka [27] in an ex-
plant pig carotid artery model, are as follows: 1) the fast pol-
All baseline and follow-up VCSS values were recorded and ymerisation stage with increasing tensile forces for approxi-
compared (ESM Figure 2). At the 6 month follow-up, VC- mately 10 s, 2) a second stage with stable tensile force for up
SSs declined from 4.9 ± 1.2 to 1.4 ± 0.8 (P < .0001). During to 1 min and 3) the final polymerisation stage with fast and
follow-up, patients free from leg oedema, pain and vari- logarithmic expansion of tensile force. Polymerisation time
cosities are shown at ESM Figure 3. may differ according to the NBCA type, formulation and in-
travascular salt and blood levels. Almeida et al. [13] stated in
their study of the first human use of NBCA in venous insuf-
Quality of life assessment ficiency that their intravascular injection of NBCA pulsed
pullback with manual compression using a USG probe
QOL measurements have provided valuable information method was based on these three stages of polymerisation.
about the success of treatment. Measurements in five Our method is based on the lower viscosity and the faster
categories were acquired before the procedure and at reaction and polymerisation time of this product of NBCA.
each follow-up visit. QOL scores demonstrated meaning- Following SFJ closure, which was confirmed by pressing
ful improvement during the follow-up (ESM 4). CIVIQ with a USG probe and placing a catheter 3 cm distal to the
scores improved significantly for all categories. There- SFJ, continuous NBCA delivery and pressure at a pullback
fore, the global CIVIQ score improved significantly from rate of 2 cm/sec was applicable. This continuous delivery
a baseline value of 42.9 ± 18.6 to 17.4 ± 3.8 at 6 months method and fast polymerisation enables us to administer
(P < 0.0001). NBCA to each cm of the vein (0.03 cc of NBCA per cm),
while significantly decreasing the procedure time. In this
manner, the rate of thrombophlebitis development is lower
because, due to the continuous technique, there is no empty
Discussion space filled without NBCA and no residual blood inside the
vessel. Although mild phlebitis occurred at rates of 15.8 %,
Chronic venous insufficiency and the resulting VV forma- 11.4 % and 20 % in previous reports of NBCA embolisation
tion significantly affects quality of life and causes serious for the treatment of CVI, the phlebitis rate in our study was
epidemiologic and socioeconomic complications. A high 0.5 % [14 – 16]. We attribute this result to the lower viscosity
incidence rate, frequent diagnosis, significant loss of the of NBCA, the enhanced adhesive properties of NBCA and
workforce and negative impacts on patients’ lives have the continuous pressing technique used in the present
increased the diversity of the search for treatment alter- study.
natives. The current treatment of VV has shifted from We were enlightened by the new tumescent-free abla-
classic surgery to minimally invasive methods. End- tion method of a recently published two-year study by
ovenous thermal ablation (EVTA) methods such as RFA Almeida et al. [14] with a 92 % closure rate, and of a re-
and EVLA have been proven to be safe and effective for cently published multi-centre study by Proebstle et al. [15]
years [6]. Intravascular NBCA has been used for over 20 in Europe with a 92.9 % closure rate. In a new comparative
years in AVM and varicosity treatment in different parts study by Morrison et al. [16], closure rates were 99 % for
of the human body [12, 21, 22]. Recently, histopathologi- cyanoacrylate embolisation compared with 96 % for RFA
cal changes in the vascular wall caused by NBCA have at three months. This prospective randomised trial showed
been shown in experimental studies using swine and rab- that NBCA was not inferior to radiofrequency ablation
bit models [23 – 26]. Immediately after intravenous injec- [16]. However, this new method requires further develop-
tion, NBCA causes instant blockage in vessels by stimu- ment and support through additional comprehensive stud-
lating a strong polymerisation reaction when it contacts ies. Therefore, our early results supported these studies
ionised anions and vessel proteins in the serum. The pol- and also showed that the new method can be applied safe-
ymerisation reaction causes damage to the vessel wall ly with high occlusion rates. On the other hand, Toonder
and induces an acute immunologic response. As a result, et al. [28] used NBCA in the perforating veins of the leg
the polymer degrades gradually, while sub-acute vasculi- using a similar method and showed that NBCA can also be
tis and chronic granulomatous foreign body reactions fol- applied safely in perforators.
low polymerisation. The progression of the polymer to fi- We also used NBCA embolisation in the treatment of
brotic tissues is complete within two to three months SSV insufficiency in 9 patients and in the treatment of the

© 2016 Hogrefe Vasa (2016), 45 (3), 1 – 6

E. S. Çalık et al.: The Treatment of venous insufficiency 5

entire GSV in 3 patients. Nerve injury may occur with inter- Conclusions
ventions below the knee segments. It is known that sural
nerve injury often occurs in open surgery of the SSV or sa-
phenous nerve injury often occurs in interventions on the We believe that our success rate was highly dependent on
GSV below the knee segment. This minimally invasive the polymerisation rate and viscosity. Therefore, our pro-
technique with USG guidance will prevent nerve injury as a cedure technique differs from previous methods. A con-
result of no multi-puncture with needles, no incision, no tinuous technique that offers fast application without leav-
stripping and no requirement for TA and thermal energy ing any open segments in the vein should be considered
compared with open surgery or EVTA. Nevertheless, the significant. Consequently, this new tumescent-free, non-
needle can cause nerve damage when treating below the thermal embolisation method can be applied safely with
knee segment using this method; however, we did not ob- high success rates. These results should be further sup-
serve nerve injury and paraesthesia in any patients. There- ported by our long-term results and new alternative stud-
fore, we suggest that this technique may be advantageous ies. Low procedure times, early recovery times and the im-
in the treatment of SSV insufficiency. mediate return to a daily routine without compression
The polymerisation time is a function of the contacting stockings are all significant advantages of this technique.
tissue type, the fluid characteristics and the amount of
product used. When applied under the proper conditions,
NBCA begins to polymerise after 1 – 2 s and completes the Funding
polymerisation process within approximately 5 s. Addi-
tionally, our study showed that because the NBCA poly- This study was funded by the FG Group, Ankara, Turkey.
mer has a faster polymerisation rate with low viscosity, the
operation time, post-operative thrombophlebitis and pain
decreased significantly. In the previously mentioned arti-
cles, the average procedure times were 21, 18.6 and 24 min Electronic Supplementary Material
[14 – 16]. Our study resulted in an average procedure time
of 5.4 min with a high total occlusion rate. The electronic supplementary material is available with the
Patients with post-operative pain and thrombophlebi- online version of the article at http: // dx.doi.org / 10.1024 /
tis had the following in common: high pre-procedural  0301-1526 / a000XXX.
CEAP classifications, high pre-procedural VCSSs, high
vein diameters and high aneurysmal segments in the ESM 1. Figure.
veins. We observed that with an adequate dosage of Survival free from recanalisation with the life-table
NBCA and more pressure over these aneurysmal seg- analysis.
ments it was possible to prevent the development of pain
and thrombophlebitis. Additionally, we observed that an- ESM 2. Figure.
eurysmal segments are potential causes of recanalisa- Comparison of venous clinical severity scores (VCSSs) for
tion. Therefore, both to reduce the adverse effects and to each patient at baseline and after six months.
increase the success of the treatment, the most impor-
tant factors are to apply an adequate dosage of NBCA ESM 3. Figure.
without missing any space and to apply sufficient pres- Patients free of symptoms at follow-up.
sure. In addition, one of the issues to be considered is to
apply a higher dosage of NBCA. Our results revealed ESM 4. Table.
mild stiffness and sensitivity in four patients. This was Chronic Venous Insufficiency Quality of Life Question-
the result of over dosage of NBCA caused by solidifica- naire (CIVIQ ) measures during follow-up.
tion of the polymer, and the patients recovered complete-
ly within an average of 5 days.
Although a vein diameter of up to 15 mm was included
in the study criteria, we tried not to select especially large- References
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