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Surgery and Cosmetics

David M Duffy, MD, FAAD

What’s New in Phlebology?

David Duffy

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 characteristics:

  • Its anesthetic effects make it extremely comfortable to use
  • 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 Pravaz 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 1-6). 

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, personal communication). 

Foamed POL

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 veins.

Foam Disadvantages

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 American studies.8,9

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 European sclerosants.

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 applications.12

Detergent Sclerosants

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:

  1. 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.
  2. A reduction in the use of imprecisely formulated extemporaneous concoctions of POL.
  3. 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

Conclusions

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 flourish.

 (a)

(b)

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 shunting.

 

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 treatment.

 

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 hypertonic saline.

(a)

(b)

(c)

(d)

 (e)

(f)

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 extremities.

References

  1. 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.
  2. Nouri K. Complications in dermatologic surgery. St Louis: Mosby/Elsevier, 2008.
  3. Small Vessel Sclerotherapy: An Overview. In: Advances in Dermatology, Volume 3. Edited by David M Duffy; 1987.
  4. Beigeleisen HI. Varicose veins, related diseases and sclerotherapy: A guide for practitioners. Montreal, Canada: Eden Press, 1984.
  5. Goldman MP. Sclerotherapy: Treatment of varicose and telangeictatic leg veins. Edited by Klein EA, Menczer BS. St Louis, MO: Mosby, 1994.
  6. Sclerotherapy; Procedures in Cosmetic Dermatology Series; Volume: Leg Veins. 2nd Edn. Edited by Murad Alam, Sirunya Silapunt. Saunders Elsevier, 2011.
  7. 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 Surg 2004;30:687-693.
  8. 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  2010;36:1026-1033.
  9. 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.
  10. Epstein AB. Phase III clinical trials of varisolve planned for Q1 2010. Vein Magazine  2010;3(1):30.
  11. Vein diagnosis & treatment: a comprehensive approach. Edited by Weiss RA, Fried CF, Weiss MA, New York, NY: Mc Graw-Hill Inc; 2001.
  12. Duffy DM. Sclerosants: a comparative review. Dermatol Surg 2010:36:1010-1025.
  13. Sylvoz N, Villier C, Blaise S, et al. Polidocanol induced cardio- toxicity. A case report and review of the literature. J Des Maladies Vascularies 2009;33:234.
  14. 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 Surg 2007;33:1452-1459.
  15. Kobayashi S, Crooks S, Eckmann DM. Dose and time dependent liquid sclerosant effects on endothelial cell death. Dermatol Surg 2006;32:1444-1452.
  16. Duffy D. The EASI Study: implications for American phlebologist.  Dermatol Surg  2011, in press.
  17. 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.
  18. Wangcun J, Sun V, Tran N, et al. Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: Implications for effective port wine stain treatment. Lasers in Surgery and Medicine 2010;42:105-112.

 

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