What’s New in Phlebology?
Wednesday, March 09, 2011
America Finally Gets Polidocanol
For the first time since 1946, the US Food and Drug
Administration (FDA) has approved a second detergent sclerosant for
the treatment of lower extremity veins. Polidocanol (POL), sold
worldwide under a number of proprietary names, has been widely used
in the US despite lack of FDA approval. Fortunately for American
physicians, FDA approval for a commercial preparation of POL
(Asclera®; Merz Aesthetics) in 1.0% and 0.5%
concentrations specifically for the treatment of reticular veins
and telangiectasia was granted in 2010. Approval followed an
FDA-monitored study in which POL proved to be as efficacious and
less complication prone when compared with sodium sotradecol
sulfate (STS) in this application.1
STS, which is considered to be two to three times more potent,
is the only other sclerosant specifically approved for the
treatment of lower extremity venous disease. Critics suggest that,
had the concentrations of both agents been equivalent, they would
have fared equally well. Long considered to be an almost ideal
sclerosant, POL exhibits three extremely desirable
- Its anesthetic effects make it extremely comfortable to
- Although tissue necrosis can occur when POL is injected into
arteries or arterioles, it has the lowest incidence of
extravasation necrosis (0.0001%) following inadvertent perivascular
injections of any potent sclerosant2
- It is the first sclerosant to undergo rigorous testing before
clinical use in the US
Sclerotherapy and Sclerosants
Although the term sclerotherapy was coined in
1936,3 the technique of injecting caustic solutions
into varicose veins began in 1851 when Pravaz4
used the newly developed hypodermic syringe to inject ferric
chloride into lower extremity varicosities. Since then, at least 25
sclerosants have been used for the treatment of varicose veins and
half a dozen for the treatment of
telangiectasia.5 Most of the more potent
sclerosants were abandoned when unpredictable and horrific
complications, including fatalities, occurred.
There is no "perfect sclerosant", ie complication-free and 100%
effective (Table 1) - they all represent a compromise
between efficacy and toxicity. Any modality with the ability to
induce vascular thrombosis followed by scarring is capable of
producing a wide range of complications. Mild sclerosant use is
associated with complications such as pigmentation, bruising,
neovascularization (matting) and treatment failure.
More potent sclerosants can produce life-threatening thrombotic
phenomena (superficial and deep thrombophlebitis) and pulmonary
emboli, as well as intra-arterial and extravasation tissue
necrosis, anaphylaxis and neurologic phenomena. Good results
following sclerotherapy rely as much on the experience and skill of
the phlebologist as they do on the predictability and
benefit-to-risk ratio of any particular sclerosant (see Figures
POL in Europe
Synthesized in 1936 and still used as a topical, local and
epidural anesthetic,6 the surprising ability of POL
to sclerose blood vessels without significantly damaging
surrounding tissues led to its use as a sclerosant in the 1960s. By
1967, it was registered in Germany as Aethyoxysclerol®,
and is at this time the only sclerosant approved for use in that
country. Between 1987 and 2005, 210,000,000 ml was sold, enough to
treat approximately 35-40 million patients (Kreussler, GMBH,
Detergent sclerosants can be agitated and foamed, a process
which makes them two to three times more potent than liquids of
equivalent concentrations. In this form, lower volumes and
concentrations can be used, theoretically decreasing both tissue
toxicity and allergenicity. Sclerosants in this form are
particularly useful for treating large refluxing
Foam can lodge in the ocular and cerebral circulation when it
passes through a patent foramen ovale (present in approximately 27%
of the population), occasionally producing migrainoid visual
disturbances, amaurosis and strokes. Refinements in the composition
of foam and duplex-guided injection techniques have substantially
reduced the risks of using these agents, as reported in two recent
Phase III clinical trials currently underway may secure FDA
approval for the first commercially prepared foamed version of POL
(Varisolve® microfoam) for the treatment of varicose
veins.10 The American College of Phlebology (ACP) is
developing an American consensus (white paper) to evaluate the use
of foams in this country (Nick Morrison, MD, past president of the
ACP, personal communication).
POL in America: Seniority vs Science
Increasingly stringent FDA requirements that have increased the
cost and complexity of introducing new sclerosants, coupled with
the relatively small prospect for significant profits (it is
reputed to have cost $5 million to introduce POL), have prolonged
the use of older, far more destructive agents. The inability of
American phlebologists to acquire modern sclerosants has created a
market both for extemporaneous sclerosant preparations of
unpredictable potency and toxicity and for the importation of
American phlebologists faced a bureaucratic conundrum in which
the acceptability of using certain types of sclerosants was
unrelated to their risks. As usual, when the law and hippocratic
dictates collide, common sense supervenes. Many American
phlebologists have been using POL for at least 20 years. Certain
malpractice insurance carriers have provided explicit waivers to
cover its use. It has also widely been used in training programs
all over the US.11
Sclerosant Types - Advantages and Disadvantages
Sclerosants are arbitrarily classified into three groups -
detergent, osmotic and chemical - on the basis of the mechanisms
they use to destroy vascular tissue. Each type has specific
advantages and disadvantages in specific clinical
During the 1920s and 1930s, detergent sclerosants, which were
easier to control, more predictable and less toxic than older
agents, became available. First-generation detergents (sodium
morrhuate and ethanolamine oleate) have been largely supplanted by
STS and POL, which are equally efficacious and far less
complication-prone. By changing concentration or form (liquid or
foam), they can be used to treat vessels of all sizes and types.
Concentrated detergents can occasionally produce serious allergies
and unintended destruction of non-targeted vascular tissue.
Both STS and POL have a very low (and approximately equal)
incidence of allergic complications, which is noticeably increased
when using higher concentrations and volumes. Neither STS nor POL
should be used for patients with multiple allergies or asthma.
Although STS is reputed to cause more hemosiderotic
hyperpigmentation, this effect is probably related to its strength
and not its structure. The real drawback to using STS is the
occurrence of painful extravasation tissue necrosis at
concentrations ≥1% when used to treat varicose veins. POL use
suffers from the rare possibility of cardiotoxicity (as do all
local anesthetics) when large volumes of both high and low
concentrations are used.13
Osmotic Sclerosants - Hypertonic Saline
Weak and extremely uncomfortable to use (ie, it causes cramping
and burning), hypertonic saline (HS) exerts its effects only a
short distance from the injection site. It is a very crude
sclerosant, destroying all cells indiscriminately within the
osmotic gradient. It will produce volume-dependent massive necrosis
in the absence of meticulous technique. Scarring and slow-healing
ulcers following its use are a leading cause of malpractice actions
against phlebologists in the US. Its only advantage is absolute
freedom from allergies, useful when treating polyallergic patients
who should not receive any type of detergent sclerosant.
Exaggerated concerns regarding the frequency of allergies following
the use of detergents has prolonged the use of this decidedly
inferior sclerosant. There is every reason to believe that HS will
largely be replaced by POL.
Chemical Irritants - Glycerin
A total of 72% glycerin combined with xylocaine and epinephrine
is legal to use and particularly suitable for fragile
telangiectasia. Viscous and slightly uncomfortable to use, it is
inexpensive and non-allergenic. Because of its comparative
weakness, it is thought to produce less pigmentation and, even more
rarely, tissue necrosis. Safe to use in low volumes (<10 ml),
higher volumes may be associated with hypoglycemia and hematuria.
It should be used carefully in patients who are diabetic.
Sclerosants - Comparative Potency
Easy to measure in vitro14,15 but
a great deal more difficult in vivo, personal
experience suggests that a great deal of "potency" is related to
patient-to-patient variability and the type of vein being treated.
STS is considered to be two to three times more potent than POL; HS
is roughly equivalent to 0.5-0.75% POL; and 72% glycerin has the
equivalent potency of approximately 0.25-0.5% POL .
POL: Impact on American Phlebological Practices
The approval of POL will hopefully result in:
- An end to the routine use of HS to treat most small vessels,
resulting in greater comfort and compliance, while virtually
eliminating technique errors as a cause of tissue necrosis.
- A reduction in the use of imprecisely formulated extemporaneous
concoctions of POL.
- The elimination of dinosaurs, such as sodium morrhuate and
ethanolamine oleate, which should be taken off formulary. The
approval of detergent foam preparations will eliminate any need for
these dangerous agents.16
What Else is New?
Although FDA approval of an excellent sclerosant is the most
dramatic news, the practice of phlebology involves many other
treatment modalities in which slow but useful advances are also
occurring. The APC (American College of Phlebology;
www.phlebology.org) and the American Venous Forum (AVF;
www.veinforum.org)17 are busy both refining older
methods of treating venous disease and introducing new ones.
For the treatment of varicose veins, endovenous lasers and
radiofrequency devices are proving effective and complementary to
injection treatments. For telangiectasia involving the lower
extremities, sclerotherapy is still the gold standard, although
sophisticated electrocoagulative devices (eg, VeinWave®)
are proving useful for the treatment of tiny, difficult to
cannulate telangiectasia. Topical antiangiogenic agents coupled
with lasers have been used for port wine stains.18
2010 was a great year for phlebology and it's going to get
better and bigger. Organizations like the ACP and AVF will
unquestionably give American phlebologists more clout when it comes
to dealing with the government. Cost-effective phlebologic
procedures with low risks and minimum downtime will unquestionably
please our governmental overseers; phlebology should therefore
Figure 1. (a) Intradermal injection of 0.4cc of 1% STS
produced a small ulcer. (b) An injection of an equal volume of 3%
POL (a roughly equivalent potency) did not.
Figure 2. In this case, 0.25% of POL produced this ulcer.
The retromalleolar area is particularly susceptible to this
complication, probably on the basis of arteriolar-venous
Figure 3. Allergies are a rare complication following
the use of polidocanol. This patient developed respiratory stridor,
periorbital edema and severe pruritis following the use of 1 ml of
1% polidocanol. The author has encountered three cases in 33 years
of practice. Epinephrine and Benadryl® were an effective
Figure 4. Hypertonic saline is famous for producing
extravasation ulcers. In this case, more hypertonic saline was
added to "dilute" extravasated sclerosant. This could have been
avoided with proper syringe labeling.
Figure 5. Syringe labels indicate the concentration of
Figure 6 (a-f). POL can be used (off-label) in a number of
applications. Comfort and significant margins of safety permit the
safe treatment of veins located at sites other than the lower
- Rabe E, Schliephake D, Otto J. Sclerotherapy of telangiectases
and reticular veins: a double-blind, randomized, comparative
clinical trial of polidocanol, sodium tetradecyl sulphate and
isotonic saline (EASI
study). Phlebology 2010;25:124-131.
- Nouri K. Complications in dermatologic surgery. St Louis:
- Small Vessel Sclerotherapy: An Overview. In: Advances
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- Beigeleisen HI. Varicose veins, related diseases and
sclerotherapy: A guide for practitioners. Montreal, Canada: Eden
- Goldman MP. Sclerotherapy: Treatment of varicose and
telangeictatic leg veins. Edited by Klein EA, Menczer BS. St Louis,
MO: Mosby, 1994.
- Sclerotherapy; Procedures in Cosmetic Dermatology Series;
Volume: Leg Veins. 2nd Edn. Edited by Murad Alam, Sirunya Silapunt.
Saunders Elsevier, 2011.
- Rabe E, Pannier-Fischer F, Gerlach H, et al.
Guidelines for sclerotherapy of varicose veins (ICD 10: 183.0,
183.1, 183.2, and 183.9). Dermatol
- Palm M, Guiha I, Goldman MP. Foam sclerotherapy for reticular
veins and varicose veins of the legs: a retrospective review of
outcomes and adverse effects. Dermatol Surg
- Peterson, JD, Goldman MP. An investigation into the influence
of various gasses and concentrations of sclerosants on foam
stability. Dermaol Surg 2011;37:12-18.
- Epstein AB. Phase III clinical trials of varisolve planned for
Q1 2010. Vein Magazine 2010;3(1):30.
- Vein diagnosis & treatment: a comprehensive approach.
Edited by Weiss RA, Fried CF, Weiss MA, New York, NY: Mc Graw-Hill
- Duffy DM. Sclerosants: a comparative review. Dermatol
- Sylvoz N, Villier C, Blaise S, et al. Polidocanol
induced cardio- toxicity. A case report and review of the
literature. J Des Maladies
- Mol W, Furukawa H, Sasaki S, et al. Evaluation of
the sclero- therapeutic efficacy of ethanol, polidocanol, and
OK-432 using an in vitro model. Dermatol
- Kobayashi S, Crooks S, Eckmann DM. Dose and time dependent
liquid sclerosant effects on endothelial cell
death. Dermatol Surg 2006;32:1444-1452.
- Duffy D. The EASI Study: implications for American
phlebologist. J Dermatol Surg
2011, in press.
- van den Bos RR, Milleret R, Neumann M, Nijsten T. Steam
ablation of saphenous varicose veins: a promising new endovenous
thermal therapy. EVF Abstracts. Eleventh Meeting of the European
Venous Forum: Antwerp, Belgium, 24-26 June
2010. Phlebology 2010;25:296-311.
- Wangcun J, Sun V, Tran N, et al. Long-term blood
vessel removal with combined laser and topical rapamycin
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