Phlebology OnlineFirst, published on August 6, 2015 as doi:10.

1177/0268355515599692

Original Article
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ClariveinÕ mechano-chemical ablation an

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interim analysis of a randomized DOI: 10.1177/0268355515599692
phl.sagepub.com
controlled trial dose-finding study

YL Lam1,2, Irwin M Toonder1 and Cees HA Wittens1,3

Abstract
Objectives: The ClariVeinÕ system is an endovenous technique that uses mechano-chemical ablation to treat incom-
petent truncal veins. This study was conducted to identify the ideal Polidocanol dosage and form for mechano-chemical
ablation in order to occlude the great saphenous vein. When adhering to safe dosage levels, sclerosants with higher
concentrations potentially limit the extent of treatment. It has been demonstrated that this problem may be overcome
by using Polidocanol as a microfoam. This paper was established on findings of a preliminary analysis.
Material and methods: The initial study was a single-blinded multicenter randomized controlled trial where patients
are allocated to three treatment arms. Group 1 consisted of mechano-chemical ablation þ2% Polidocanol liquid, group 2:
mechano-chemical ablation þ3% Polidocanol liquid and group 3: mechano-chemical ablation þ1% Polidocanol foam
Results: Eighty-seven, 34 males and 53 females (60.9%), mean age 55 years s.d. 16.0 (range 24–84), were enrolled in the
study. Treatment length was 30 cm (range 10–30) for 95.2% of the patients. Mean operating time was 16 minutes (range
5–70). The mean saphenofemoral junction diameter (7.7 mm) was similar in all three groups. At 6 weeks post-treatment
duplex ultrasound showed that 25 out of 25 ¼ 100%, 27 out of 28 ¼ 96.4% and 13 out of 23 ¼ 56.5% were occluded in
the mechano-chemical ablation þ 2% Polidocanol liquid, mechano-chemical ablation þ 3% Polidocanol liquid and
mechano-chemical ablation þ 1% Polidocanol microfoam respectively (p < 0.001). However, stricter scrutiny showed
that the anatomical success rate defined as occlusion of at least 85% of the treated length to be 88.0%, 85.7% and 30.4%
respectively (p < 0.001).
Conclusion: Mechano-chemical ablation using ClariVeinÕ combined with 1% Polidocanol microfoam is significantly less
effective and should not be considered as a treatment option of incompetent truncal veins. Further investigation to
determine the ideal Polidocanol liquid dosage with mechano-chemical ablation is advocated and is being conducted
accordingly.

Keywords
Varicose veins, ClariVein, mechanochemical ablation, foam, mechano-chemical ablation, great saphenous vein

contemporary endovenous thermal ablation meth-

Introduction
During the late 1990s various thermo-ablation
techniques have been introduced to treat saphenous
vein incompetence on the basis of endovenous laser
therapy (EVLT) and radio frequency ablation
(RFA).1 Numerous papers have been published report-
ing on ELVT and RFA. These studies reported better
outcomes, compared to classical stripping, in terms of
fewer complications, post procedural pain and return to
daily activities, with comparative rates of reflux
abolishment.2–5 Traditionally, classical surgical strip-
ping requires epidural or general anesthesia. However
with the introduction of tumescent anesthesia, surgical
stripping has become less invasive comparable to
ods.6,7 Although tumescent anesthesia allows proced-
ures to be less invasive, the desire to avoid multiple
skin pricks as well as potential risks of tumescent infu-
sion has been expressed.8 Minimal invasive obliteration
1
Department of Vascular Surgery, Maastricht University Medical Centre,
The Netherlands
2
Department of Dermatology, Maastricht University Medical Centre, The
Netherlands
3
Department of Vascular Surgery, Universitätsklinikum Aachen, Germany
Corresponding author:
YL Lam, European Venous Centre, Maastricht University Medical Center
P. Debyelaan 25, PO BOX 5800, 6202AZ Maastricht, The Netherlands.
Email: yeelai_1@hotmail.com

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2 Phlebology 0(0)
of saphenous veins without the need of tumescent anes-
thesia by ultrasound-guided foam sclerotherapy
(UGFS) is effective with short-term occlusion rates of
83%–93%. However long-term follow-up shows that
this drops to 62% with this technique requiring mul-
tiple sessions in order to achieve effective venous occlu-
sion.9–11 At the present day the use of minimal invasive
methods is gaining popularity in Europe, but disparities
of national guidance for treatment of varicose veins and
reimbursement systems are limiting the actual use of
new treatments.
In 2010, mechano-chemical ablation (MOCA) was
introduced, with the ClariVeinÕ system. This endove-
nous technique uses a combination of mechanical abra-
sion and chemical sclerosants components to assure
ablation of the incompetent truncal veins without the
use of tumescent anesthesia. Reported primary closure
rates range from 87% to 96.7% demonstrating its
potential as a novel treatment.12,13 The mechanical
component, a rotating wire, causes vein spasm and
damages the vein endothelium. Simultaneously the
sclerosant is infused to chemically enhance damage to
the vein wall resulting in its occlusion.14 Recently inves-
tigators reported a complete loss of the endothelial
layer, damage to the medial layer and fibrosis of the
treated vein.15
Protocol background
Currently there are a few widely accepted sclerosing
agents in the market. In the United States, detergent
solutions such as sodium tetradecyl sulphate (STS)
received FDA approval in 1946 whereas Polidocanol
(POL) (AethoxysklerolÕ , KreusslerPharma,
Wiesbaden, Germany) received approval in 2010.
Since STS is not registered for use in the Netherlands
our study was designed to assess MOCA with POL in
adherence to the manufacturer’s specifications of a
maximum dose of 2 mg POL per kg body weight per
day. It was decided to compare between MOCA þ 2%
and MOCA þ 3% POL liquid with a fixed dosage rate
per centimeter. It has been described that 1.5% POL
liquid may give inferior results.13 However, higher con-
centrations limit the dosage allowance and therefore
may limit the treatment length. It has been postulated
that this limitation may be overcome by using POL as a
microfoam (MF).16 Catheter-directed sclerotherapy
(CDS) is not new and has been developed since mid
1990s providing an increase of safety and efficacy of
UGFS. Parsi and Devereux reported a complete occlu-
sion rate of 75%, 73.9% at one year using 2% POL MF
(1:4 ratio), respectively, while Ascuitto and Williamson
showed 67%, 70%, 86% complete occlusion of the
treated vein at one year follow-up 3% POL MF (1:4
ratio), respectively.17–21 This led to the hypothesis that
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POL MF in combination with the ClariVeinÕ system
may allow us to treat larger treatment lengths and/or
multiple superficial veins in one session if the effective-
ness and safety remains the same. First we must state
that the use of foam is not within the instructions for
use of the ClariVeinÕ device. In vitro bench tests were
performed to determine the feasibility of MF delivery
through the catheter before undertaking the study.
In vitro it was seen that MF could be infused through
the device making it plausible to expect results similar
to previous CDS. This research falls under the scope of
the Medical Research Involving Human Subjects Act
(WMO in Dutch), is subjected to the Agreement of
Medical treatment (WGBO in Dutch) and to the per-
sonal data protection act (Wbp in Dutch). The trial
design, all three treatment arms, especially the MF
treatment, underwent comprehensive review by the
competent authority and the independent medical
research ethics committee since our research included
the use of a medical device and medicinal product.
Coleridge Smith reported in his review that 3% POL
MF is no more effective than 1% POL MF.22 The great
saphenous vein (GSV) in vasospasm becomes a low-
volume vessel. For this reason, a third arm was added
to the trial, to investigate the closure rate using 5 mL
1% POL MF in combination with MOCA for the treat-
ment of a 30 cm of the GSV created according to
European guidelines.23 A maximum of 10 mL 1%
POL foam is regarded as safe, according to the
European consensus on sclerotherapy, because larger
foam volumes showed a higher incidence of transient
complications.24,25 But a higher volume can be used in
combination of treating more veins such as small
saphenous vein (SSV) or the contralateral GSV and
SSV.
This paper was established on the basis of prelimin-
ary results, particularly focusing on the third arm
involving MOCA with 1% POL MF.
Material and methods
Prior to undertaking the study ethical approval was
obtained by the independent medical ethics committee
of the University Hospital Maastricht and Maastricht
University (project number: 11-2-064). The study was
overseen by an independent data safety monitoring
committee that periodically reviewed the study con-
duct, progress and participant safety.
The initial study is a single-blinded multicenter
randomized controlled trial with 600 patients allocated
in three treatment arms of 200 patients each. Group 1
consisted of MOCA þ 2% POL liquid, group 2
MOCA þ 3% POL liquid and group 3 MOCA þ MF.
Participants were recruited from five hospitals in the
Netherlands, the Maastricht UMC þ , Rode Kruis
Lam et al.
Ziekenhuis, Onze Lieve Vrouwe Gasthuis, Maasstad
Ziekenhuis and BovenIJ Ziekenhuis.
Inclusion criterion was primary truncal incompe-
tence of the GSV. The incompetence was defined as
retrograde flow lasting > 0.5 second measured in an
upright position with duplex ultrasound (DUS) exam-
ination. Patients were excluded from the study on the
basis of age < 18 years, a history of previous surgery for
ipsilateral GSV incompetence, GSV diam-
eter > 12.0 mm, obstruction of the deep venous
system, extreme obesity that is defined as BMI > 40,
C5-C6 in the CEAP classification, allergy or contraindi-
cation to POL, gravida or a life expectancy of less than
6 months.
The physician assessed referred patients for symp-
tomatic superficial venous incompetence where eligible
patients were informed about the study. Once written
informed consent had been obtained, the patients were
enrolled. Computerized block randomization, stratified
by center, allocated the patient for one of the three
treatment arms. To check the reliability of preoperative
DUS vein mapping all measurements such as diameter,
tributaries and reflux times throughout the incompetent
GSV segment, over a length of at least 30 cm, were
reproduced on the day of treatment.
Patients who were randomized to MF were treated
according to the standardized dose-finding study proto-
col. All physicians were trained at their local hospital
by the coordinating investigator till they passed the
learning curve. Prior to MF, the treated area was
disinfected, and sterile drapery was applied with the
patient supine. The GSV would be accessed at knee
level below the 30-cm incompetent segment, with ultra-
sound-guided positioning of the ClariVeinÕ catheter
through a 5-French introducer sheath with the ball
tip of the wire up at 2 cm distal to the apex of the
saphenofemoral junction (SFJ). Once the motor
handle unit is assembled onto the rotating wire cath-
eter, it is activated at a setting of 3500 r/min held sta-
tionary for 3 seconds prior to withdrawal at a steady
pullback rate of 1 cm per 6 seconds, causing mechanical
damage without sclerosant infusion for a length of
30 cm. The next step was to resheath the ball-tip and
return the catheter to the initial point, repositioning it
at 2 cm from the SFJ apex. The treating physician
would then create the MF with 1 mL 1% POL, using
the Tessari method in a 5-mL luerlock syringe with a
liquid/air ratio of 1:4.26 The syringe was then mounted
onto the motor handle unit without delay and the foam
was infused through the catheter, while simultaneously
pulling back the catheter at a rate of 5 cm/s without
wire rotation under ultrasound guidance. The deep
venous system was checked for its patency after infu-
sion and vein spasm and MF delivery was monitored by
DUS. MOCA þ 2% and MOCA þ 3% POL was
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3
performed according to the protocol as described in
earlier published literature.14 Aftercare consisted of
wearing a class 2 thigh stocking continuously for
48 hours, followed by 2 weeks during daytime.
Moreover the patient was advised to remain mobile
without extreme exertion.
Follow up was carried out at 6 weeks postoperative
in an outpatient setting. During this visit clinical assess-
ment was evaluated using the venous clinical severity
score (VCSS) and CEAP classification. Serious and
non-serious adverse events were also recorded. DUS
was carried out to evaluate the treated GSV.
Statistical analysis
The primary endpoint, anatomical success was defined
as an occlusion of at least 85% of the treated GSV, was
scored at 6 weeks visit. For the primary analysis a dif-
ference of 7.5% in the occlusion rate is considered clin-
ically significant. Using a power of 80%, an a ¼ 0.05
and two-sided testing, we calculated a sample size of
188 patients per group. To allow for lost-to-follow-up
200 patients per group are included. For statistical
significance the 2 test was used to compare the ana-
tomical success rate between the randomized treat-
ments at 6 weeks follow-up time point. Secondary
analysis evaluated differences in VCSS, among the
treatment groups over mentioned time point with the
non-parametric Kruksal Wallis Test. Next to this for
un-paired settings also a one-way ANOVA test was
used. A p < 0.050 was considered to indicate statistical
significance. All data were analyzed with SPSS-pc, ver-
sion 23.
Results
Between August 2012 and March 2013, up to eighty-
seven patients were enrolled for the study. The mean
age was 55 years (range 24–84), 34 males and 53 females
(60.9%). Enrolled were C1 to C5 patients according to
the CEAP classification with a mean SFJ diameter in all
three groups of 7.7 mm (NS between groups) and a
mean VCSS baseline 6.0 (NS between groups). Four
patients were not treated and left the study since they
had a preference for EVLT. Five patients had diameters
larger than 12 mm and one C5 patient should not have
been included in the trial. One patient did not attend
the 6 weeks visit and was lost to follow-up. Table 1
presents the results obtained from all three treatment
arms in the dose-finding study.
Treatment length was 30 cm for 95.2% (range 10–30)
patients. Mean operating time was 16 minutes (range 5–
70) and was similar between all groups (NS) (Table 1).
At 6 weeks follow-up 25/25 ¼ 100%, 27/28 ¼ 96.4%
and 13/23 ¼ 56.5% were occluded in the MOCA þ 2%
4 Phlebology 0(0)

Table 1. Baseline characteristics, occlusion rates and anatomical success.

Polidocanol treatment group

1% 2% 3% Total

SFJ diameter in mma Mean 7.8593 7.4667 7.7143 7.6886

Std. Deviation 2.69719 2.09340 3.28653 2.73524
VCSS Baselineb Mean 6.7 5.5 6.0 6.0
Std. Deviation 3.5 1.8 2.5 2.7
VCSS 6 weeks follow-upc Mean 3.4 3.2 2.4 3.0 d
Std. Deviation 2.7 2.4 1.8 2.4
Treatment duration (in min)e Mean 19 15 15 16
Std. Deviation 12 13 10 11
Occlusionf N 13 25 27 65
% within Polidocanol treatment group 56.5% 100.0% 96.4% 85.5 %
Anatomical successg N 7 22 24 53
% within Polidocanol treatment group 30.4% 88.0% 85.7% 69.7%
Anatomical failure N 16 3 4 23
% within Polidocanol treatment group 69.6% 12.0% 14.3% 30.3%
Total N 23 25 28 76
Total % 100.0% 100.0% 100.0% 100.0%
SFJ: saphenofemoral junction; VCSS: venous clinical severity score.
a
SFJ diameter between groups: NS (p ¼ 0.878).
b
VCSS baseline between groups: NS (p ¼ 0.513).
c
VCSS 6 weeks follow-up between groups: NS (p ¼ 0.252).
d
Total mean VCSS change: significant (p < 0.001).
e
Treatment duration between groups: NS (p ¼ 0.071).
f
Occlusion rate (p < 0.001).
g
Anatomical success was defined as an occlusion of at least 85% of the treated segment (p < 0.001).

POL liquid, MOCA þ 3% POL liquid and
MOCA þ MF group, respectively (p < 0.001). The
mean change in the VCSS score from baseline was –
3.0 (p < 0.001), but this result was similar between the
groups (p ¼ 0.355). At 6 weeks post-treatment DUS
showed for MOCA þ 2% POL liquid, MOCA þ 3%
POL liquid and group 3 MF an anatomical succes
rate, defined as an occlusion of at least 85% of the
treated segment, of 88.0%, 85.7%, 30.4%, respectively
(p < 0.001) (Table 1).
No serious adverse events such as pulmonary embol-
ism or deep vein thrombosis occurred. The total inci-
dence of thrombophlebitis was 11.3%.
Discussion
This study was conducted to identify the ideal POL
dosage and form for the MOCA in order to occlude
the GSV. Potentially the lowest effective dosage in com-
bination with the MOCA could extend treatment
lengths and/or multiple incompetent superficial veins
whilst adhering to POL dosage safety constrictions.
Various authors employ different definitions of success
and occlusion rates.2,9,27,28 In this paper it was decided
that the best method to adopt for this was defining 85%
occlusion of the treated segment for the definition of
anatomical success. No consensus on reporting on ana-
tomical occlusion is found in the literature therefore
both ways of scoring occlusion rates has been used.
We postulate that obliteration percentage of the treated
segment is a good way to report on occlusion since less
occlusion might be prone to recanalization and may
cause early recurrence. However our method was
time-consuming and did not seem very practical for
daily use. The most interesting finding was the distinct
number of failures in the MOCA þ MF group that we
did not expect since the published literature on CDS
has proven to be efficacious; however, the KAVS
(Catheter-Assisted Venous Sclerotherapy, Richter &
Rothe AG Co., Leipzig, Germany), Cavafix Certo 355
(FA Braun, Melsungen, Germany), Beacon Tip Royal
Flush Plus high-flow catheter (Cook) used in trials for
CDS have significantly different larger lumen diameter
sizes and lengths than the ClariVeinÕ .17–19,21 This
forced an interim analysis of the efficacy of
MOCA þ MF before continuing the study. Although
the total group of treated patients is small, a strong
significant difference of the anatomical success and

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Lam et al.
the clinical relevance outcome was found (p < 0.001)
between MOCA þ MF and the other two treatment
arms. The data safety monitoring committee
recommended to discontinue MOCA þ MF due to con-
siderable less effectiveness. Re-evaluation of the ori-
ginal study protocol meant that primary and
secondary endpoints could be maintained and statis-
tical analysis determined that no revisions were neces-
sary for the remaining study arms. The dose-finding
study continues with the remaining two treatment
arms where 200 patients are allocated in each group.
There are certain possibilities to explain the poor
closure rate with MOCA þ MF. The first most plaus-
ible explanation is that the original catheter design was
never meant to cater for the delivery of sclerosant as an
MF. There is noticeably more pressure necessary
during foam infusion through the catheter when com-
pared to a liquid sclerosant. The lumen size of the cath-
eter is restricting easy infusion; 25 G (0.46 mm) or
larger needles are recommended for UGFS as to
avoid affecting the MF quality.29 The outer diameter
of the ClariVeinÕ catheter is 2.67 French, (0.89 mm)
and the central lumen of the infusion channel
0.77 mm, which contains the abrasion wire of 0.36 mm
diameter leaving an actual channel of only 0.41 mm.
Secondly, in our protocol, the simultaneous
mechano-chemical treatment was separated, as the
mechanical component was a separate step preceding
the chemical component. First mechanical ablation was
applied preceding the actual introduction of foam.
Potentially this would result in endothelial lesions,
with cell debris, lipids and proteins released from
lysed cell membranes would not only disallowing for
normal MF interaction with the vein wall but also
deactivate the active sclerosant.30,31 Normally MF is
introduced at the puncture site, displacing blood,
while inducing a vasospasm and travels towards the
SFJ. Because it is common for mechanical ablation
itself to cause a vasospasm we decided to introduce
the foam using the ClariVeinÕ catheter as a MF carrier
being displaced from proximal to distal which proved
to be challenging after a pullback with only the mech-
anical ablation. The repositioning of the catheter tip is
therefore somewhat cumbersome but was always
possible.
Third, the protocol employs the Tessari technique
for the creation of MF. The concentration of POL in
MF state is a widely debated subject. A concentration
of 1% up to 3% POL MF is indicated according to the
European guidelines for diameters between 4 mm and
8 mm in incompetent saphenous veins.29 In our study
1% POL and a ratio of 1:4 is used since there is no
difference in efficacy between 1% POL and 3%
POL MF.29,32,33 Furthermore, MF made with a low-
concentration sclerosant has a shorter half-life of
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5
115–157 seconds.34 A conflicting foam half-life and
slow pullback rate made it impossible to infuse the
MF sclerosant simultaneously with the mechanical
ablation necessitating it to be done in two steps.
Additionally, the poor results may be related to the
used dosage of 5 mL 1% POL (1:4 ratio), which is
lower than the published amounts in UGFS stu-
dies.35,36 Since Hamel-Desnos concluded that compres-
sion regime has no effect on the successful outcome of
the foam treatment, failure is unlikely to be caused by
not wearing the compression stockings during night-
time or our short post-procedure compression hosiery
regime.37
Patel recently reported the significant longevity
increase of foam half-life by using silicon free syr-
inges.38 Although the specific use of silicon-free syr-
inges is recommended, this aspect may have been
overlooked, as each center was allowed to use products
at its own discretion. The possibility of silicon elements
in the ClariVeinÕ product itself was excluded because
ClariVeinÕ manufacturers’ technical department claims
that there is no silicon used in the catheter, three-way
stopcock and the included 5-mL syringe.
Finally, despite the discouraging results and the
problems encountered with the combination of POL
foam and the ClariVeinÕ catheter, based on our current
experience, in an attempt to overcome the encountered
problems, further investigation will be carried out to
explore the feasibility of MF sclerosant combined
with mechanical ablation.
Conclusion
MOCA using ClariVeinÕ combined with 1% POL MF
is significantly less effective and should not be con-
sidered as a treatment option for incompetent truncal
veins. Further investigation to determine the ideal POL
liquid dosage with MOCA is advocated and is being
conducted accordingly.
Ethical approval
Ethical approval was obtained by the independent medical
ethics committee of the University Hospital Maastricht and
Maastricht University (project number: 11-2-064).
Acknowledgements
We gratefully acknowledge the assistance provided to us by
the following persons listed in alphabetical order: Mrs
Kramer, Mr Nieman, Dr Schreve, Dr de Smet, Mrs
Terlouw and Dr Vahl.
Conflict of interest statement
The authors declared the following potential conflicts of inter-
est with respect to the research, authorship, and/or publica-
tion of this article: YL Lam has been paid a consulting fee by
6 Phlebology 0(0)
Vascular Insights LLC and is on their speakers’ panel. The
other authors have no commercial, proprietary, or financial
interest in any products or companies described in this article.
Funding
The authors disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: This study was supported by an unrestricted grant by
Vascular Insights LLC. The sponsor had no involvement in
the study design; data collection, analysis and interpretation
of data; in the writing of the report; and in the decision to
submit the article for publication.
Author contributions:
Conception and design: YL, IT, CW; Analysis and interpret-
ation: YL, IT, CW; Data collection: YL; Writing the article:
YL; Critical revision of the article: IT, CW; Final approval of
the article: YL, IT, CW; Statistical analysis: YL; Obtained
funding: CW; Overall responsibility: YL, IT, CW.
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