A Randomised Clinical Trial Comparing N-Butyl Cyanoacrylate,Radiofrequency Ablation and Endovenous Laser Ablation for the Treatmentof Superficial Venous Incompetence: Two Year Follow up Results

WHAT THIS PAPER ADDS
This is the first study to compare N-butyl cyanoacrylate (NBCA), radiofrequency ablation (RFA) and endovenous
laser ablation (EVLA) concurrently in terms of both early patient comfort and complications and late occlusion
rates, in the treatment of varicose veins. The findings will permit a new review of therapeutic options in varicose
vein treatment.

Objective: To compare early and two year results for N-butyl cyanoacrylate (NBCA), radiofrequency ablation
(RFA), and endovenous laser ablation (EVLA) in the treatment of varicose veins.
Methods: This was a randomised clinical trial. Five hundred and twenty five patients were blindly randomised into
NBCA, RFA, and EVLT groups (175 patients to each group; block randomisation using sealed envelopes). Four
hundred and fifty six patients were monitored for 2 years (ultrasound at 2 days, and 6, 12, and 24 months). The
primary endpoint was the saphenous vein occlusion rates, and the secondary endpoints were peri- and postprocedural pain, complications, and time to return to work. No simultaneous phlebectomies were performed.
Results: The numbers of patients lost to follow up were NBCA seven, RFA 26, and EVLA 36. Occlusion rates were
similar at 6, 12, and 24 months (6 months [NBCA 98.1%, RFA 94.1%, and EVLA 95.1%, p ¼ .14], 1 year [NBCA
94.7%, RFA 92.5%, and EVLA 94.2%, p ¼ .72], 2 years [NBCA 92.6%, RFA 90.9%, and EVLA 91.5%, p ¼ .89]).
Peri-procedural pain was significantly lower after NBCA (p < .001), but complication rates (DVT, bleeding, and
phlebitis) were similar. Time to return to work was shortest after NBCA (NBCA 1.04 days, RFA 1.56 days and
EVLA 1.31 days (p < .001) with 95% (NBCA), 50% (RFA) and 75% (EVLA) of patients returning to work on Day

Pre-procedural venous clinical severity scores (VCSSs) were the same in all groups. A decrease was
observed in VCSS values in all groups at 6 months, and this persisted at 1 and 2 years. However, VCSS scores
at 6 months and 2 years were significantly lower in the NBCA group (p < .001). Foam sclerotherapy was
subsequently applied to varicose tributaries in 18 patients from all groups.
Conclusion: No differences were observed in occlusion rates between the three modalities, but NBCA appeared
superior with respect to peri-procedural pain, return to work and decreased VCSS.
2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.
Article history: Received 9 October 2017, Accepted 24 May 2018, Available online 2 July 2018
Keywords: Endovenous laser ablation, N-butyl cyanoacrylate, Radiofrequency ablation, Varicose vein

INTRODUCTION
Chronic venous disorders are a public health problem that
have existed since the very earliest times and that represent
a significant socio-economic problem.1,2
Endovenous ablation techniques have become increasingly common and have taken the place of surgical treatment. Nonetheless, these methods are essentially based on
the principle of destruction of the vessel using thermal
energy. Very high energy is produced inside the vessel
during the procedure, and the vascular structure is thus
irreversibly damaged. Tumescent anaesthesia is mandatory
in order to prevent this thermal energy damaging surrounding tissues (to prevent damage to nerves, or vein
collapse around the laser/radiofrequency ablation [RFA]
fibre) and in order that the patient should not be subjected
to pain (or should at least experience less pain). However,
tumescent anaesthesia is uncomfortable for patients, who
may nevertheless experience pain in association with
repeated injections. Haematoma and ecchymosis associated
with the piercing of surrounding small vessels may sometimes also be observed.
Non-tumescent endovenous ablation techniques began
being developed in order to avoid these problems. One of

these methods involves gluing of the vessel using N-butyl
cyanoacrylate (NBCA). The first experimental and small scale
clinical studies began being published after 2011.3e6 The
early results of studies with larger patient numbers in
Europe then appeared.7e10 Ablation rates of more than 90%
were observed in the first year in all these studies. In early
period studies comparing cyanoacrylate with endovenous
laser ablation (EVLA) and RFA, the success rate of cyanoacrylate was better than those of EVLA and RFA, although
the difference was not statistically significant, while
cyanoacrylate was reported to have fewer side effects.11,12
However, the mid-term results for cyanoacrylate and EVLA
and RFA have not yet been compared. This prospective
study was therefore designed to compare NBCA, RFA, and
EVLA in terms of effectiveness and side effects.
MATERIALS AND METHODS
Patients
The study was approved by the Ethics Committee of the
Faculty of Medicine, Kahramanmaras Sutcu Imam University, Turkey. Endovenous ablation was applied to 525 patients with great saphenous vein (GSV) or small saphenous
vein (SSV) incompetence between November, 2014, and
June, 2015. Subjects undergoing duplex ultrasound (DUS)
during which incompetence of the GSV or SSV was identified were enrolled. Inclusion criteria consisted of a GSV
exceeding 5.5 mm in diameter and a SSV exceeding 4 mm in
diameter two cm below the saphenofemoral or saphenopopliteal junctions with the patient in standing position,

combined with reflux exceeding 0.5 s, according to the ESVS
guideline.1 Exclusions included 132 patients under the age
of 18 years, with obstruction in the deep venous system,
who had previously used another invasive treatment
method (thermal and chemical ablation, or surgery), with
cardiac and renal failure, who were immobile or who had
secondary varicose veins, hypercoagulability status, and
local or systemic infection. Patients were blindly assigned
into three groups (Fig. 1) using block randomisation with
sealed envelopes. Repeat DUS was performed by the surgeon immediately prior to the procedure. This assessment
was conducted with a Mindray model M7 USG device
(Shenzen, China). All patients were informed about the aims
of the study and gave consent to participate. They were
then transferred to the operating room.
The primary endpoint of this study consisted of the
ablation rate, while the secondary endpoints were incidence of complications, and patient satisfaction, including
such parameters as freedom from pain during and after the
procedure, complications observed, time of return to work
and change in VCSS scores.
Patients’ age, sex, weight, height, and VCSS scores were
recorded before the procedure. The pre-procedural Clinical,
Etiological, Anatomical and Pathophysiological (CEAP) classification of the extremity scheduled for the procedure was
also recorded. The diameter, length and depth beneath the
skin in the cannulation site of the vein receiving the procedure were recorded during the operation. The duration of
the procedure was also recorded. Patients were asked to
describe pain experienced during the procedure as none,

mild pain, moderate pain or severe pain, these levels being
expressed as 0, 1, 2, and 3, respectively.
Randomisation and blinding. The subjects were randomised
as outpatients scheduled to receive NBCA, EVLA, or RFA.
Patients were selected by means of sealed envelopes in the
examination room at least 24 h before surgery, and were
randomised at a ratio of 1:1:1. The treatment method was
explained to all patients, and written consent was obtained.
No stratification was performed for GSV or SSV.
Procedures. All procedures were performed in the operating room, with patients in a supine position and under
aseptic conditions. The saphenous vein was punctured
percutaneously with 21G needle guided by ultrasound.
Cannulation was performed at the lowest point of reflux. A
6F introducer sheath was then inserted. No simultaneous
phlebectomy was performed on any patient.
NBCA: Endovenous ablation was performed on all patients
using the VariClose Vein Sealing System (Biolas, FG Grup,
Turkey). A 0.035 inch 150 cm guidewire was passed
through the 6F introducer sheath to the saphenofemoral
junction (SFJ) or the saphenopopliteal junction (SPJ). Once
the presence of the guidewire in the SFJ or SPJ was confirmed
by DUS, a 5F catheter was advanced to the SFJ or SPJ over the
guidewire. Following confirmation of the position of the 5F
catheter at the beginning of the SFJ or SPJ, it was retracted
from it by 6 cm. This distance was used because the 4F delivery catheter tip protrudes from the 5F marker catheter by
3 cm. The 4F delivery catheter therefore had to be positioned
3 cm distal to the SFJ or SPJ. Once the position of the 4F
delivery catheter was confirmed, the NBCA injection
groundwork was complete. A gun and adaptor were connected to one another, and 2 mL from the 3 mL of the NBCA
was aspirated into the two mL injector. If more NBCA was
required, the remaining 1 mL was aspirated.
The procedure then commenced. Pressure over the SFJ
was applied using DUS, and the SFJ was identified as closed.
The delivery catheter was primed immediately before NBCA
was injected into the vein lumen. A one second trigger push
was administered for delivery catheter priming. Once
priming was complete, the trigger was held for a further 5 s,
and the delivery catheter was retracted at a speed of 2 cm/
second. The delivery catheter was then adjusted for the
injection of 0.03 mL of NBCA per cm. Continuous pressure
was applied over the target vein segment with the DUS
probe at the same time as the delivery catheter was
retracted, with no relaxation of pressure on the SFJ. The
catheter was retracted by 10 cm during this period by
pressing the trigger for 5 s. This procedure was performed
on a continuous basis until complete sealing of the target
vein segment was achieved. In the final stage, once NBCA
had been injected into the entire vein segment with pressure being applied as described, final pressure was applied
for 30 s to the entire target vein segment.
RFA: This was performed using a Closurefast catheter
(VNUS Medical Technologies, San Jose, CA, USA) in line with
the manufacturer’s instructions for use and as previously
described elsewhere.11 A tumescent anaesthesia mixture of
20 mL of 2% prilocaine, 500 mL of 0.9% isotonic solution
(4 C), 20 mL 8.4% sodium bicarbonate and 0.5 mg of
adrenalin was then prepared. Tumescent local anaesthesia
was delivered to the saphenous compartment surrounding
the vein. This procedure was applied in two cycles, to the
region of the saphenofemoral or saphenopopliteal junction.
EVLA: A 1470 nm wavelength 12 W radial laser source
(EVLAS Circular-2; FG Grup, Ankara, Turkey) and a single use
radial laser fibre were used. This was applied as described by
Bozkurt and Yilmaz.12 Tumescent anaesthesia was applied as
described above. Laser energy was applied in pulse mode
(0.2 s interval) with laser parameters being adjusted to the
vascular diameter and the depth beneath the skin of the
saphenous vein, with greater application to those parts close
to the SFJ (a mean 80e100 joules of energy was applied per
cm).
No simultaneous phlebectomy was performed on any
patient since this would compromise the reliability of the
study by leading to changes in procedure related pain levels.
Compression therapy was administered after the ablation
procedure. This consisted of an elastic compression bandage
with clip closure (MesKon, Istanbul, Turkey) for the first two
days followed by a Class I (18e21 mmHg at the ankle)
compression stocking for one month. Paracetamol 500 mg
was prescribed, and patients were advised to take this up to
four times a day if they experienced pain. No patient received
anticoagulant therapy before or after the procedure.
Follow up protocol
Patients were advised that they could return to work when
they felt well enough. They were asked to return for a
follow up visit 2 days after the procedure. Patients were
asked how frequently they used analgesics during this time.
DUS was performed. The presence of deep vein thrombosis
(DVT), phlebitis (including local swelling, redness and pain
in the treated area), ecchymosis, and bleeding from the
cannulation site were also monitored. Times to return to
work of patients who had not yet started work on the
second day were ascertained by telephone. Subjects were
also advised to return to hospital in the event of oedema,
rash, pain in the legs or shortness of breath.
Patients were also invited to follow up at 1, 6, 12, and 24
months. Clinical examinations were performed at 1, 6, 12,
and 24 months and DUS examinations at 6, 12, and 24
months. DUS was performed by a radiologist in a blinded
manner. The radiologist assessed whether or not incompetence was present in the saphenous vein (whether the vein
was thrombosed, fibrotic, or open), perforator veins or deep
veins. VCSS scores and DUS results at 6, 12, and 24 months
were recorded. Additional foam sclerotherapy was allowed
six months after the procedure.
Statistical analysis
Variables were expressed as mean values SD, median,
and range for numerical variables and as frequencies and

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