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CLINICAL RESEARCH STUDIES
From the American Venous Forum
The European multicenter cohort study on
cyanoacrylate embolization of refluxing great
saphenous veins
Thomas Michael Proebstle, MD,
a
Jens Alm, MD,
b
Sameh Dimitri, MD,
c
Lars Rasmussen, MD,
d
Mark Whiteley, MS, FRCS (Gen),
e
James Lawson, MD,
f
Daniel Cher, MD,
g
and
Alun Davies, MA, DM, FRCS, FEBVS,
h
Mainz and Hamburg, Germany; Chester, Guildford, and London,
United Kingdom; Naestved, Denmark; Alkmaar, The Netherlands; and Palo Alto, Calif
Objective: Cyanoacrylate (CA) embolization of refluxing great
saphenous veins (GSVs) has been previously described. The
outcomes from a multicenter study are still lacking.
Methods: A prospective multicenter study was conducted in
seven centers in four European countries to abolish GSV
reflux by endovenous CA embolization. Neither tumescent
anesthesia nor postinterventional compression stockings were
used. Varicose tributaries remained untreated until at least
3 months after the index treatment. Clinical examination,
quality of life assessment, and duplex ultrasound evaluation
were performed at 2 days and after 1, 3, 6, and 12 months.
Results: In 70 patients, of whom 68 (97.1%) were available for
12-month follow-up, 70 GSVs were treated. Two-day follow-
up showed one proximal and one distal partial recanalization.
Three additional proximal recanalizations were observed at
3-month (n [ 2) and 6-month (n [ 1) follow-up. Cumulative
12-month survival free from recanalization was 92.9% (95%
confidence interval, 87.0%-99.1%). Mean (standard deviation)
Venous Clinical Severity Score improved from 4.3 % 2.3 at
baseline to 1.1 % 1.3 at 12 months. Aberdeen Varicose Vein
Questionnaire score showed an improvement from 16.3 at
baseline to 6.7 at 12 months (P < .0001). Side effects were
generally mild; a phlebitic reaction occurred in eight cases
(11.4%) with a median duration of 6.5 days (range, 2-
12 days). Pain without a phlebitic reaction was observed in
five patients (8.6%) for a median duration of 1 day (range, 0 -
12 days). No serious adverse event occurred. Paresthesia was
not observed.
Conclusions: Endovenous CA embolization of refluxing GSVs
is safe and effective without the use of tumescent anesthesia or
compression stockings. (J Vasc Surg: Venous and Lym Dis
2015;3:2-7.)
Endovenous thermal ablation (EVTA) by radiofre-
quencyorlaserisasafeand effective treatment of
refluxing great saphenous veins (GSVs) and has replaced
traditional high ligation and stripping in official recom-
mendations of various leading Vascular Societies in the
United States
1
and the United K ingdom.
2
Whereas
EVTA certainly is a successful treatment modality with
limited downtime,
3-5
it requires the use of perivenous
tumescent anesthesia and can still cause a variety of
side effects like postoperative pain, bruising, and sensory
nerve damage.
6,7
As an alternative treatment without
the use of tumescent local anesthesia, foam sclerother-
apy has also been engaged for treatment of refluxing
saphenous veins, but anatomic 1-year success rates
have been report ed dis appoi ntingly low on the order
of 70%.
8
From the Department of Dermatology, University Medical Center, Mainz
a
;
the Dermatologikum Hamburg, Hamburg
b
; the Countess of Chester
Hospital, Chester
c
; The Danish Vein Centers, Naestved
d
; The Whiteley
Clinic, Guildford
e
; the Centrum Oosterwal, Alkmaar
f
; Wild Iris Consul-
ting LLC, Palo Alto
g
; and the Imperial College London, London.
h
This study was funded by Sapheon, Inc (Morrisville, NC).
This trial (NCT01570101) was registered in March 2012 (before enroll-
ment began) on ClinicalTrials.gov.
Author conflict of interest: All authors except D.C. received research sup-
port associated with the reported study. D.C. is a consultant to Sapheon.
In addition, T.P. and J.A. are consultants to the sponsor. T.P. and S.D.
are stock owners of the sponsor.
Presented in part at the Twenty-fifth Annual Meeting of the American
Venous Forum, Phoeni x, Ariz, February 27-March 2, 2013; the XVII
World Meeting of the International Union of Ph lebology (UIP), Boston,
Mass, September 8-13, 2013, where it received th e UIP Gold Award; and
the Twenty-sixth Annual Meeting of the American Venous Forum, New
Orleans, La, February 19-21, 2014.
Reprint requests: Thomas Michael Proebstle, MD, Department of Derma-
tology, University Medical Center Mainz, Langenbeckstr 1, 55131
Mainz, Germany (e-mail: thomas.proebstle@web.de).
The editors an d reviewers of this art icle have no relev ant financial rela-
tionships to disclose per the Journal policy that requires reviewers to
decline review of any manuscript for which they may have a conflict
of int e rest .
2213-333X
Copyright Ó 2015 The Authors. Published by Elsevi er Inc. on behalf of the
Society for Vascular Surgery. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc -nd/3.0/).
http://dx.doi.org/10.1016/j.jvsv.2014.09.001
2
An embolizing treatment of refluxing GSVs using a
specific cyanoacrylate (CA) adhesive has recently been
described, and 2-year follow-up of first-in-man use has
just been reported.
9
Endovenously delivered CA immedi-
ately occludes the vessel. It elicits a granulomatous foreign
body reaction and a concomitant inflammatory vein wall
reaction, leading to subsequent fibrotic degradation.
9
CA
as a well-understood substance
10-14
already in use in other
medical devices is potentially advantageous for abolition of
saphenous vein reflux because (1) it does not require the
use of tumescent anesthesia; (2) by chemically bonding
vein walls to each other, it obviates the need for postinter-
ventional compression stockings; and (3) it precludes the
risk of treatment-related sensory nerve damage.
This paper describes the 1-year-results of the prospec-
tive European multicenter cohort study that was initiated
in December 2011, shortly after approval by European reg-
ulatory authorities (CE mark) and subsequent commercial-
ization of endovenous use of CA adhesive.
METHODS
Study design. This prospective, multicenter clinical
study on endovenous CA embolization of refluxing GSVs
(NCT01570101) was performed in seven specialized vein
centers in four European countries. Each site obtained local
ethics committee approval before initiation, and all partici-
pants signed an ethics committee-approved, study-specific
informed consent form before participation. Consecutive
patients were included if they had symptomatic GSV
incompetence with or without visible varicosities confirmed
by duplex ultrasound imaging and a Clinical, Etiologic,
Anatomic, and Pathologic (CEAP) stage of C2, C3, or C4.
Additional inclusion and exclusion criteria were used as
listed in Table I. Before treatment, patients underwent
clinical examination, including CEAP classification and
Venous Clinical Severity Score (VCSS) and duplex ultra-
sound examination of the vein system; in addition, patients
completed the EQ-5D quality of life survey
15
and the
Aberdeen Varicose Vein Questionnaire (AVVQ).
16
Pa-
tients returned to the clinic at 48 hours and at 1, 3, 6, and
12 months. At each clinic visit, patients underwent physical
examination, CEAP classification, VCSS, and assessment of
potential adverse events and duplex ultrasound examina-
tion of the target limb. All physical examinations and
duplex ultrasound examinations were performed by the
local investigator or by staff under his supervision. Patients
also completed EQ-5D and AVVQ. Reintervention and
adjunctive vein treatment for potentially remaining tribu-
taries at the target limb were disallowed until after the 3-
month visit was complete.
Procedure technique. Endovenous embolization of
the GSV with the proprietary Sapheon VenaSeal (Sapheon
Inc, Morrisville, NC) CA adhesive and delivery system was
performed as described previously.
17
In brief, the delivery
system consists of a 7F introducer sheath/dilator, a 5F
delivery catheter, a 3-mL syringe, and a dispenser gun. The
5F delivery catheter has a hydrophobic coating to prevent
adhesion to delivered CA as well as air-filled microchannels
to enhance sonographic visibility. Each pull of the trigger
delivers 0.09 mL of CA. Sapheon CA is a custom formu-
lation of CA, having properties of rapid polymerization
when it is exposed to an aqueous environment, high vis-
cosity, and plasticizers to enhance flexibility in its final
polymerized state. The GSV is accessed at the distal point
of reflux percutaneously with a micropuncture introducer
kit (Cook, Bloomington, Ind), followed by insertion of a
0.035-inch J guidewire (Cook). With use of ultrasound
control, a 7F introducer sheath/dilator is advanced to the
saphenofemoral junction (SFJ) and positioned approxi-
mately 5 cm caudal to the SFJ. The distance of 5 cm was
Table I. Eligibility criteria
Inclusion criteria
Age $18 years and #70 years
Symptomatic primary GSV incompetence diagnosed by clinical symptoms, with or without visible varicosities, and confirmed by duplex
ultrasound imaging
GSV on standing preprocedure Doppler ultrasound examination $3 mm and #10 mm (maximum diameter)
CEAP classification of C2, C3, or C4
Ability to walk unassisted
Ability to attend follow-up visits
Ability to understand the requirements of the study and to provide written informed consent
Exclusion criteria
Life expectancy <1 year
Regular pain medication
Anticoagulation including heparin or coumadin
Previous deep venous thrombosis
Previous superficial thrombophlebitis in GSV
Previous venous treatment on target limb
Known hypercoagulable disorder
Conditions that prevent routine vein treatment, like acute disease, immobilization or inability to ambulate, and pregnancy
Tortuous GSV that will limit catheter placement in the opinion of the investigator ($2 primary access sites are not allowed)
Incompetent ipsilateral small saphenous vein or anterior accessory GSV
Known sensitivity to the CA adhesive
Participation in another clinical study involving an investigational agent or treatment within 30 days of enrollment
CA, Cyanoacrylate; CEAP, Clinical, Etiologic, Anatomic, and Pathologic classification; GSV, great saphenous vein.
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS
Volume 3, Number 1
Proebstle et al 3
chosen both to give space for ultrasound compression be-
tween the delivery catheter and the SFJ and to allow slight
glue propagation toward the SFJ after injections. The 3-
mL syringe containing CA extracted from its shipping
vial is attached to the delivery catheter. The catheter is
primed with the dispenser gun to fill all but the final 3 cm
of catheter tubing. The primed delivery catheter is inserted
into the introducer sheath and secured with a spin-lock
mechanism. Then 5 cm of the catheter tip is exposed
distal to the sheath tip and positioned 5 cm from the SFJ.
After leg elevation of about 15 degrees, CA delivery con-
sists of an initial double CA injection spaced 1 cm apart,
followed by a 3-cm pullback and 3-minute localized
compression directly over the injected vein segment.
Repeated injections of CA followed by pullbacks of 3 cm
and 30-second localized compressions of delivered CA
then take place until the entire targeted vein segment is
treated. The catheter is removed and compression applied
to the catheter entry site until hemostasis is achieved. A
single small bandage is applied, and venous occlusion is
confirmed by duplex ultrasound. Patients were discharged
and instructed to resume normal activities, avoiding
strenuous activities for 1 day.
Statistical evaluation. As CA embolization is a novel
embolization technique in the field of venous disease, the
study’s primary end point was the proportion of patients
with complete occlusion of the target vein at 6-month
duplex ultrasound evaluation. Whereas closure of the
target vein promotes improved clinical symptoms in almost
all patients, some cases have improvement already with
only partial closure. For this reason, direct assessment of
vein closure was chosen to be more informative compared
with clinical scores with respect to a more accurate measure
of the device’sefficacy.
Complete occlusion was defined as no segments of
patency longer than 10 cm.
18
As a secondary analysis of
the complete occlusion rate, the proportion of patients
with freedom from >10 cm of recanalization was tabulated
by life-table methods and plotted with Kaplan-Meier anal-
ysis. The study’s secondary end point was the rate of all
adverse events. Changes from baseline in VCSS, AVVQ,
and the general quality of life tool EQ-5D were evaluated
by repeated measures analysis of variance. P values < .05
were considered statistically significant. Calculations were
performed with SAS (version 9.0; Cary, NC) or R.
19
RESULTS
Between December 2011 and July 2012, 70 patients
were enrolled. Participating centers in the order of authors
included 20, 15, 11, 10, 7, 4, and 3 patients, respectively.
Fifty-five patients (78.6%) were women; mean (range) age
and body mass index were 48.4 years (22-72 years) and
25.6 (18.9-43.4), respectively. Mean GSV diameter at
the SFJ was 7.8 6 2.1 mm (range, 6.6-14.0 mm). General
risk factors included a family history of venous disease (n ¼
21), cigarette smoking (n ¼ 9), hypertension (n ¼ 5),
abnormal blood lipids (n ¼ 4), obesity (n ¼ 4), and dia-
betes mellitus (n ¼ 3).
Anatomic results. All enrolled patients received a
technically successful study procedure. Thirty-four pa-
tients (49%) underwent treatment of the left GSV. Forty
patients (57%) had no ultrasound-detectable tributaries in
the treatment zone; 23 (33%) had one or two tributaries,
and seven (10%) had more than two tributaries. Four pa-
tients (6%) had perforating veins in the treatment zone. All
tributaries or perforators were left untreated for at least
3 months after study treatment. Mean treated vein length
was 37.6 cm (range, 7-72 cm). Average net treatment time
measured from catheter in to catheter out was 18.6 mi-
nutes (range, 8-74 minutes). Immediately after the pro-
cedure, all but one patient had complete closure of the
target GSV. This single case still showed flow in the
proximal 20 cm of the GSV fed through a large tributary
entering at the distal point of flow. To achieve full
occlusion, foam sclerotherapy was injected immediately,
resembling a protocol deviation. At 48 hours, this GSV was
fully occluded and remained so during 12 months of
follow-up.
Sixty-eight patients (97.1%) were available for the 12-
month visit. During 12 months of follow-up, a total of
five patients were detected with partial recanalization,
defined as patency in the treated segment by duplex ultra-
sound examination of more than 10 cm. Two of these pa-
tients had recanalization observed at 48 hours of follow-up,
two at 3 months, and one at 6 months. All but one case
showed patency originating at the SFJ; this case, which
had recanalization at the distal 20 cm of the CA-
embolized GSV segment, was noticed at 2-day follow-up.
The proximal part of the GSV in this case, however,
remained occluded until 12-month follow-up. The other
case with recanalization at 48 hours presented with a prox-
imal open GSV segment of 25 cm in length but was
observed closed at 1-month follow-up and recanalized
again after 3 months. The distal segment of the GSV, how-
ever, remained occluded until 12-month follow-up.
Fig 1. Survival free from recanalization of the target vein.
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS
4 Proebstle et al January 2015
At 3 months of follow-up, two additional cases were
observed with a proximal GSV recanalization of 12 and
25 cm, respectively, both with a durable GSV occlusion
distally. The last recanalization at 6-month follow-up pre-
sented as a microchannel recanalization of the proximal
20 cm of the GSV. Noteworthy, none of the patients
with recanalization appeared to become clinically symp-
tomatic, and all recanalizations had junctions with large
tributaries. By life-table methods, the 12-month complete
occlusion rate was 92.9% (95% confidence interval,
87.0-99.1%) (Fig 1).
Clinical improvement. Patients showed significant
improvement of venous symptoms after GSV embolization.
VCSS improved from a mean of 4.3 at baseline to 1.1 at
12 months (Fig 2); changes in VCSS from baseline were
statistically significant for all follow-up intervals (P <
.0001). There was no statistically significant difference
between patients showing sustained occlusion of the once
embolized GSV and those who experienced a partial
recanalization during follow-up.
Remarkably, as indicated by VCSS subdomain scores,
the proportion of patients whose target limbs were free
from visible varicosities increased from 1.4% at baseline to
41.4% at 3 months of follow-up. Even more pronounced
in the same period, the proportion of patients free from
edema and pain increased from 41.4% and 32.9% at base-
line to 90.0% and 82.1%, respectively. The improvements
were largely preserved during 12-month follow-up (Fig 3).
Similarly, quality of life scores showed significant
improvement (Table II). EQ-5D, which was modestly
depressed at baseline, improved at all follow-up visits to
near-maximum levels (P ¼ .0009). AVVQ score also
improved significantly from a baseline value of 16.3 to
6.7 at 12 months (P < .0001).
Side effects. Adverse events were mild and self-
limited. Eight patients (11.4%) had a postprocedure phle-
bitic reaction along the treated vein or its tributaries
defined as reddening of the overlying skin and pain on
palpation. The median onset of symptoms was observed
6 days (range, 3-11 days) after the procedure; the median
duration was 6.5 days (range, 2-12 days). Pain without
phlebitic reaction was noticed in five patients (8.6%) for a
median duration of 1 day (range, 0-12 days), starting at a
median of 0 days (range, 0-3 days) after the procedure.
Specific treatment of phlebitic reactions was under the
discretion of the treating physician, but only two patients
under this condition received nonsteroidal anti-
inflammatory drugs for 2 and 15 days, respectively. No
serious adverse event occurred, and moreover, paresthesia
was not observed.
One patient (1.4%) developed a localized infection at
the access point, and one (1.4%) had minor access point
bruising. Finally, one patient (1.4%) had diagnosed prostate
cancer 6 months after study treatment, which was deemed
not related to the study treatment. One patient (1.4%)
had glue extension measuring 6 mm beyond the SFJ recog-
nized immediately after the procedure and still present at 1-
year follow-up. Low-molecular-weight heparin was given
for 2 weeks with spontaneous resolution. Thrombus exten-
sions into the deep vein system were not observed.
DISCUSSION
EVTA is currently the “gold standard” for treatment of
GSV reflux and is recommended as first-line therapy in the
United States
1
and the United Kingdom.
2
Whereas EVTA
produces high venous occlusion rates with limited down-
time,
3-5
it requires at least perivenous tumescent anes-
thesia, which can cause postoperative pain, bruising, and
other complications, such as sensory nerve damage,
6,7
even if the last risk is difficult to differentiate from heat
damage during endothermal treatment. Ultrasound-
guided foam sclerotherapy is also widely used because of
its low cost and high versatility, but success rates for
Fig 2. Change in Venous Clinical Severity Score (VCSS) by time
since treatment.
0
20
40
60
80
100
036912
Freedom from symptom (%)
Months after treatment
Pain
Edema
Varicosities
Fig 3. Proportion of patients free from varicosities, edema, and
pain at baseline and during study follow-up.
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS
Volume 3, Number 1
Proebstle et al 5
treatment of the GSV are as low as 75%,
8
with frequently
needed repetitive treatment sessions. Sclerotherapy is also
marred by postprocedure inflammation and staining, visual
disturbances,
20,21
and, rarely, stroke related to paradoxical
air embolism.
22-24
All of these treatments also require post-
operative graduated compression stockings to support
closure of the treated vein, compliance with which is well
known to be frequently poor, particularly in countries
with a predominantly sunny climate. Obviously, in our
study, CA embolization treatment of refluxing GSVs does
not necessarily require the use of graduated compression
stockings. However, in this study, what benefit compres-
sion stockings could add under special circumstances like
CA embolization of huge-diameter veins has not been
formally evaluated. Unfortunately, we cannot say whether
their use might have prevented some treatment failures.
Shortly after completion of the feasibility study on first-
in-man use of CA for GSV embolization,
9,17
this European
prospective multicenter cohort study was set up to obtain
anatomic and clinical data from seven centers in four
different countries, all with previous expertise in endother-
mal treatments of GSV reflux. The CA delivery system re-
quires skill sets familiar to those who perform thermal vein
ablation. The proprietary formulation used in the current
clinical study was designed to have high viscosity, rapid
polymerization, and a rubber-like elasticity once polymer-
ized. The polymerized adhesive chemically bonds to the
apposed intimal walls of the vein, effectively embolizing
the vein by immediate closure. This, in general, is followed
by a subacute inflammatory tissue response, a typical
foreign body reaction, leading to a fibrotic transformation
and degradation of glue and vein wall over time.
The closure rate reported herein was similar to that
observed in a prior feasibility trial
9,17
and mirrors the effi-
cacy of thermal techniques.
4,5
Per protocol, no adjunctive
therapy like foam sclerotherapy or phlebectomy was per-
formed until after the 3-month follow-up visit. Many com-
parable thermal clinical trials have allowed adjunctive
therapy even at the time of study treatment
7
or shortly
thereafter, theoretically increasing overall ef ficacy of study
treatment. Remarkably, in the current study, we observed
that all five cases of recanalization were somehow con-
nected to untreated tributaries with high blood flow or
even reflux. Identification and potential treatment of those
large-diameter tributaries during the initial procedural visit
would likely have increased the efficacy of CA embolization
of GSVs during routine treatments. Noteworthy, in this
study, the anatomic results of CA embolization were
achieved without the use of tumescent local anesthesia or
graduated compression stockings. Even if not addressed
in the current study, C5 and C6 patients should also be
treatable by CA embolization as long as the principles of
sterile administration of the glue are respected in venous ul-
cer patients. As expected, paralleling anatomic success of
CA embolization, clinical outcomes measured by VCSS
as well as patient-rated disease-specific (AVVQ) and
generic quality of life measurements (EQ-5D) showed
marked improvement. Improvements were both statisti-
cally significant and durable over the total follow-up time
of 12 months. On the other hand, adverse events were
generally mild and self-limited. Remarkably, unlike with
thermal ablation or classic surgery, paresthesia was not
recorded as a side effect of CA embolization in this study.
A phlebitic reaction in the treatment zone and in untreated
varicosities was the most common event in eight legs
(11.4%); however, only two patients used nonsteroidal
anti-inflammatory drugs to ameliorate it. Pain as an adverse
event was noted in five more patients, of whom four
required the use of analgesics. The rate of this kind of
adverse event was in the range of thermal ablation of the
GSV.
5
In the prior study of CA for varicose vein emboliza-
tion,
8
21% of treated legs showed thrombus extension, sug-
gesting a risk of inadvertent glue embolization to the
pulmonary arteries. Even if it is clinically without meaning
and spontaneous resolution occurred without specific treat-
ment, these observations of extensions to the deep vein sys-
tem might have been a matter of concern to some
physicians. In the current study, with adjusted instructions
for use increasing the distance to the SFJ for placement of
the first shot of CA, only one subject had a thrombus
extension of 6 mm into the common femoral vein, suggest-
ing that in conjunction with careful ultrasound monitoring
during the first delivery of CA, glue embolization proxi-
mally can be reliably avoided. Treatment was 2 weeks
with low-molecular-weight heparin; the thrombus exten-
sion resolved thereafter without any clinical sequelae.
CONCLUSIONS
In this prospective multicenter study on endovenous
CA embolization of refluxing GSVs, CA proved safe and
efficient, without the use of perivenous tumescent anes-
thesia and without postprocedure compression stockings.
Table II. Subject-rated scores by study visit
Visit EQ-5D index EQ-5D change from baseline AVVQ AVVQ change from baseline
Baseline 84.8 (15.7) d 16.25 (7.99) d
Month 1 96.9 (7.1) 12.0 (15.9) 9.76 (7.62) 6.49 (8.16)
Month 3 96.8 (7.7) 12.0 (16.5) 7.62 (6.34) 8.63 (7.50)
Month 6 96.6 (7.7) 11.7 (17.3) 6.28 (5.83) 9.97 (8.36)
Month 12 94.5 (11.4) 9.5 (17.6) 6.67 (6.40) 9.64 (8.99)
AVVQ, Aberdeen Varicose Vein Questionnaire.
All values shown are mean (standard deviation).
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS
6 Proebstle et al January 2015
However, further work is required to compare CA against
endothermal ablation in randomized controlled trials.
AUTHOR CONTRIBUTIONS
Conception and design: TP, AD
Analysis and interpretation: TP, AD
Data collection: TP, JA, SD, LR, MW, JL, DC, AD
Writing the article: TP, AD, DC
Critical revision of the article: TP, JA, SD, LR, MW, JL,
DC, AD
Final approval of the article: TP, JA, SD, LR, MW, JL, DC,
AD
Statistical analysis: TP, AD, DC
Obtained funding: TP, JA, SD, LR, MW, JL, DC, AD
Overall responsibility: TP
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Submitted Jul 25, 2014; accepted Sep 8, 2014.
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS
Volume 3, Number 1
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