Transcript Endovenous Laser Ablation and the Risk of Perivenous Thermal Injury

POLIDOCANOL VS STS
FOR SPIDER VEINS
Steven E. Zimmet, MD RPVI RVT FACPh
Disclosures/COI


No COI
Off-label use
Lipid bilayer with membrane proteins
• Lipid bilayers are the basic structures that make up cell membranes.
• Membrane phospholipids are amphiphilic and contain a hydrophilic polar head group and a
hydrophobic tail group.
Mechanism of Action
Detergent sclerosants produce endothelial damage via
interference with cell surface lipids
 Strong detergents, such as STS, produce maceration of the
endothelium within 1 second of exposure.
 The intercellular ‘cement’ is disrupted
 Detergent destructive action on endothelial cells is enhanced
when they act as aggregates rather than monomers.

Bioactive Aggregates
Critical Micellar Concentration



Concentration
dependent
CMC of STS to be
0.075% in normal
saline and 0.200% in
water1
CMC of POL to be
0.002% in both
normal saline and
water1
Thus, the concentration of the sclerosing solution in the vessel is
an important factor regarding endothelial destruction and activity



STS and POL are clinically used to induce endovascular fibrosis and vessel
occlusion.
They achieve this by lysing the endothelial lining of target vessels. These agents
are surface active (surfactant) molecules that interfere with cell membranes.
The ionic charge of the surfactant molecule can influence the effect on plasma
proteins and the protein contents of cell membranes. STS, an anionic detergent,
denatures the tertiary complex of most proteins and in particular the clinically
relevant clotting factors. By contrast, POL has no effect on proteins due to its nonionic structure. These agents therefore exhibit remarkable differences in their
interaction with lipid membranes, target cells and circulating proteins with
potential implications in a range of clinical applications
Cell lysis reached almost 100 % with STS at
0.3 % and with POL at 0.6 %.
 Both sclerosants induced endothelial cell (EC)
apoptosis at sub-lytic concentrations through a
caspase-dependant pathway. Both agents
induced EC oncosis.

Cooley-Andrade et al. Apoptosis. 2016 Jul;21(7):836-45.
The lytic effect of sclerosants is not limited to EC.
 Our group demonstrated lysis of erythrocytes, leukocytes, and
platelets at concentrations specific to cell types
 Both sclerosants induced leukocyte apoptosis at sublytic
concentrations. STS activated both extrinsic and intrinsic
pathways of apoptosis, while POL stimulated the intrinsic
pathway of apoptosis only. Both agents induced oncosis. Based
on these results, STS appears to have a greater effect than
POL.

Cooley-Andrade et al. Eur J Vasc Endovasc Surg. 2016 Jun;51(6):846-56
Histological Study





40 patients after spider vein (0.8-1.0 mm diameter) treatment
Punch biopsies obtained 15 minutes after treatment
H&E stains
Pre- and post-tx photos compared by authors regarding amount of
intraluminal thrombus and hyperpigmentation
Histological findings
Level 1: endothelial cell destruction
 Level 2: subintimal disruption
 Level 3: fibrin replacement of vessel wall
 Level 4: disruption of vessel wall

Bush et al. Evaluation of sodium tetradecyl sulfate and polidocanol as sclerosants for legtelangiectasia
based on histological evaluation with clinical correlation. Accepted for publication in Phlebology
Histological Study
Histological Study




Based on the histological determinations in this study,
STS 0.15% and POL 0.31% appear to be equivalent in
cellular alterations.
The clinical effects after treatment with these two
sclerosants are also similar with minimal staining and
mild intraluminal thrombosis.
Using concentrations less than the STS 0.15% or POL
0.31% is not as effective in producing the desired level
of cellular damage.
Using concentrations above these levels may produce
thrombosis of vessel with resultant inflammatory
changes and hyperpigmentation.
Sodium Tetradecyl Sulfate (STS)









Anionic surfactant
Nonmutagenic when tested in a mouse lymphoma assay, but no long-term animal carcinogenicity
studies have been performed
FDA-approved 1946
Commercially available preparations as1% or 3% solutions
Indicated in the treatment of small uncomplicated varicose veins of the lower extremities that show
simple dilation with competent valves
Sotradecol should be given to a pregnant woman only if clearly needed and the benefits outweigh the
risks
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when Sotradecol is administered to a nursing woman.
Maximum single treatment should not exceed 10 mL.
Can be readily made into foam (physician-compounded)
Polidocanol (POL)








Non-ionic detergent, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an
apolar hydrophobic (polyethylene oxide) chain.
FDA-approved 2010
Asclera (polidocanol) indicated to treat uncomplicated spider veins (varicose veins ≤1 mm in diameter)
and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. It has
not been studied in larger varicose veins > 3 mm in diameter.
Maximum 10 mL/session
Severe allergic reactions have been reported following polidocanol use, including anaphylactic
reactions, some of them fatal.
Severe reactions are more frequent with use of larger volumes (> 3 mL). The dose of polidocanol
should therefore be minimized. Be prepared to treat anaphylaxis appropriately.
It is not known whether polidocanol is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants, avoid
administering to a nursing woman.
Can readily made into foam (physician-compounded), commericially available as Varithena (GSV)
Clinical Pharmacology

Mechanism of Action
 Damages
endothelium
 Dense network of platelets, cellular debris and fibrin occludes the vein

Pharmacodynamics
 Concentration

and volume-dependent
Pharmacokinetics
 The
mean plasma half life (4 subjects) who received 4.5 to 18.0 mg
polidocanol was 1.5 hours. These are far greater mg dosages than would
be reached in a typical clinical setting.
 Maximum recommended volume per treatment session of 10 mL.

Polidocanol has been shown to have an embryocidal effect in rabbits
when given in doses approximately equal (on the basis of body
surface area) to the human dose. This effect may have been
secondary to maternal toxicity. There are no adequate and wellcontrolled studies in pregnant women. Asclera should not be used
during pregnancy.




STS & POL are deactivated by blood proteins1,2
Conner et al3 found detergent sclerosants are also deactivated by
circulating blood cells. This deactivating effect is above and beyond
the neutralizing effects of plasma proteins and contributes to the
overall neutralizing effect of blood.
At high enough concentrations, surfactants solubilise cell membranes
resulting in cell lysis.
In Vitro study: endothelial cell lysis at STS .25% and POL 0.4%2
Watkns. European Journal of Vascular & Endovascular Surgery 2011;41(4):521-525.
Parsi et al. Eur J Vasc Endovasc Surg (2008) 36, 216e223.



Samples of whole blood, platelet-rich plasma, and isolated leukocytes
were incubated with various concentrations of STS or POL and added to
human umbilical vein endothelial cells
Detergent sclerosant activity was decreased in WB when compared with
plasma and saline controls
Detergent sclerosants are consumed and deactivated by circulating
blood cells. This deactivating effect is above and beyond the neutralizing
effects of plasma proteins and contributes to the overall neutralizing
effect of blood.
Connor et al. Eur J Vasc Endovasc Surg (2015) 49, 426e431
Liquid Detergent Sclerosants
& Endothelial Cell Death



Cell cultures of bovine aortic endothelial cells
Continuous exposure to varying concentrations of Pol (0.003-1.5%) and
STS (0.005-0.5%)
Fluorescence imaging every 2-6 seconds for up to 60 minutes to assess:
Intracellular calcium
 Nitric oxide
 Cell death

Kobayashi et. al. Derm Surg 2006;32(12):1444-52.
Liquid Detergent Sclerosants
& Endothelial Cell Death

Time to response for all markers was inversely related to sclerosant
concentration
STS 0.5%
 STS 0.1%
 STS 0.02%
 STS 0.005%


15 seconds to cell death
3.5 minutes to cell death
15 minutes to cell death
no cell death
Appeared to be sequential activation of
Calcium-dependent pathways
 Nitric oxide production
 Followed by rapid progression to cell death

French POL Study


12 physicians- Data on 1,605 patients included in the French registry
were reviewed with a maximum followup of 60 months, covering
3,357 patient years.
Most of the sessions were performed with sclerosants in foamed
formulation (n = 4,403); the rest (n = 2,041) was performed with
liquid sclerosants.
French Study
Australian POL study





98 physicians, 16804 limbs,
results at 2 years
65 Investigators utilized
polidocanol and compared it to
their previous use of other
sclerosants
0.5-1.0% for spider veins
85% felt POL superior to STS
90% felt fewer complications
Conrad et al. Derm Surg 1995;25:334-6.
Goldman RCT






129 pts w/o related underlying reflux
Spider veins, reticular veins, varicose veins
Spiders: .25% STS or .5% POL
3 Independent blinded photo reviewers at 4 and 16 wks
Both groups average 70% improvement
Similar side effect rate
EASI Study

Double blind, randomized prospective study
 Spider
veins (n=160)
0.5% Pol
 1% STS
 placebo

 Reticular
veins (n=156)
 1%
Pol
 1% STS
 placebo
Rabe et al. Phlebology. 2010 Jun;25(3):124-31s
Treatment Success Rates

Treatment Success*

Rated by blinded panel

Defined as grade 4 0r 5 (good
or complete success)

No difference between Pol and
STS
*Treatment success was rated on a 5-point scale:
1 = worse than before
2 = same as before
3 = moderate improvement
4 = good improvement
5 = complete treatment success
Patient Satisfaction
Patients Satisfied/Very Satisfied
100%
80%
60%
Patient Satisfaction rated on 1-5
scale
(% reflects patients satisfied or Asclera (0.5% or 1%)
STS (1%)
very87%
satisfied)
84%
®
Placebo (0.9% isotonic saline)
64%
63%
40%
20%
14%
16%
0%
12 weeks
26 weeks
P<0.0001 for all comparisons
Complications
80%
70%
60%
50%
STS
POL
40%
30%
20%
10%
0%
Pigmentation
Necrosis
Matting
Actually,
Too POL
highconcentration
a concentration
(0.5/1.0 %) also too high
of STS (1%)
Complications
80%
70%
60%
50%
Used too high a concentration of STS
STS
POL
40%
30%
20%
10%
0%
Pigmentation
Necrosis
Matting
Rabe et al. Phlebology. 2010 Jun;25(3):124-31
Spider vein: HS vs POL

Non-randomized study in 113 consecutive patients
HS
POL .5 %
POL 1 %
Pigmentation
10.8%
20%
30.7%
Matting
13 %
10%
33%
POL concentration probably too high
Weiss and Weiss. Derm Surg 1990, 16(9):800-4.
Liquid vs Foam



Spider veins: Higher incidence pigmentation,
ulceration1
French POL Study2: “We recommend the use of liquid
polidocanol for treatment of spider, reticular, and
small varicose veins”
Liquid treatment of choice in C1 patients3
1.
2.
3.
Kern et al. Derm Surg. 2004 Mar;30(3):367-72
Guex et al. Derm Surg 2010;36:S2:993-1002.
Rabe et al. European guidelines. Phlebology,
Sclerosant: Liquid vs Foam



RCT: 75 pts (69 women) served as their own control
Reticular or post-op varices
1 session: POL liquid or foam
 Concentration
adjusted based on vein size
 [Foam] 50% lower than liquid
Eur J Vasc Endovasc Surg. 2006 Jan;31(1):101-7.
Sclerosant Concentration
The key is to deliver a minimum sclerosant volume &
concentration to irreversibly damage the endothelium &
cause complete sclerosis, without collateral damage.
Spider Veins
Reticular Veins
Varicose Veins
HS
11.7 – 23.4%
n/a
n/a
D/
S
FS (25%/10%)
n/a
n/a
G
72%
n/a
n/a
Pol
.25-.5%
.5 - 1%
1 - 3%
STS .1 - .2%
.2 - .5%
.33 – 3%
Cost of FDA-Approved Agents
Sotradecol
Cost/mL
Asclera
Cost/mL
1%
$57
.5%
$10
3%
$63
1%
$11
.15%
$3.13
.25%
$3.33
Compounded Sclerosants


1% Polidocanol concentrations ranged 1-3%, and
impurities found1
STS 3% concentrations ranged 2.59%-3.39% and
carbitol present in samples from all three sources
(0.33%-4.18%)2
Weiss et al. Dermatol Surg. 2011 Jun;37(6):812-5.
Goldman. Dermatol Surg. 2004 Dec;30(12 Pt 1):1454-6.
Compounding: Ask Yourself




Is an FDA-approved version available?
Do you inform your patients you’re using a compounded version as a
substitute for an FDA-approved medication?
Why are you using a compounded product when an FDA-approved
version exists?
If compounded drug determined to be the cause of a negative,
preventable outcome, the physician may be liable for selecting the
compounded drug
Think New England Compounding Center