PracticalDermatology

The following is the final in a 3-part series on the history and contemporary use of sclerotherapy. Read parts one and two or download the full 3-part series in PDF format online at PracticalDermatology.com.

1989 was not a particularly opportune time for an American dermatologist / phlebologist (we’ll call him Dr. A), to write an enthusiastic article describing his use and satisfaction with polidocanol (POL), an agent which would remain illegal to use for another 21 years. The FDA had essentially paralyzed Dr. A with fear when they investigated his use of this “illegal” drug. In a state of panic, he asked an experienced phlebologist (Dr. B) to mollify the FDA by providing him with a character reference. When Dr. B was interviewed by an FDA investigator, after being assured that he was not being investigated, he naively confessed that he considered polidocanol the treatment of choice for small vessels, confessing that he used it himself on a daily basis. This turned out to be a big mistake. About a year later, a series of increasingly threatening letters began to arrive at his office. The FDA advised him that it intended to impose draconian sanctions unless he signed an agreement to stop using or advocating the use of this agent. Logic didn’t seem to help. A careful review of the world literature, which confirmed the safety, patient comfort, and freedom from extravasation necrosis (I’ve injected 0.5cc of 3% polidocanol mid-dermally into my arm without developing tissue necrosis), as well as its widespread employment internationally (enough has been sold to treat several million people) was dispatched to the FDA. They replied with a form letter. A Washington, DC attorney, who routinely handled FDA cases, was retained. He was depressingly pessimistic about the prospects of wringing any concessions from the FDA.

A few weeks later, providentially, two events occurred that dramatically changed the trajectory, frequency, and menace of subsequent interactions. The first involved a letter from a phlebologist in Minnesota describing to Dr. B the death of a patient some 15 minutes after the employment of a 0.5cc test dose of 0.5% sodium Sotradecol sulfate (STS). At that time, this was the only sclerosant specifically approved for the treatment of lower extremity venous disease, although other highly toxic sclerosants could be legally employed. The patient who died was a healthy woman with no risk factors other than a reported allergy to diazepam. Tryptase studies, which at that time were considered experimental, rose precipitously to a level consistent with the occurrence of anaphylaxis. Even more providentially, one of Dr. B’s patients, the fiancé of a well-known television talk show host who, after reading the letter that described the circumstances of the fatality, arranged with her fiancé to have Dr. B share an appearance on his show with an FDA representative in a kind of point counterpoint colloquium. After receiving this information, Dr. B’s attorney informed him that the FDA had decided to terminate the investigation.

Hippocratic dissonance: The circumstances of the time

Robert Weiss summarized the moral ambiguities vis-a-vis the use of approved and non-approved sclerosants in the United States. In his 2001 text he noted, “Paradoxically, routine use of what are widely regarded as safer, more efficacious agents has become the usual standard of care today, despite the fact they have not been approved for this purpose by the FDA…POL, intensely studied and in many ways more advantageous than other sclerosants, is taught and recommended at a number of major universities and in nearly every medical textbook…Malpractice carriers provided explicit waivers to cover its use.”

In one survey carried out in 1990, physicians using POL outnumbered those who used sodium sotradecol sulfate, hypertonic saline, or the extraordinarily toxic sodium morrhuate by a considerable margin. The notion that the legality of using certain types of sclerosants was essentially unrelated to the risks they presented would have made Hippocrates curse. In all fairness, the FDA faces a zero sum game. If they approve a drug and things go wrong, there will be no end of investigations, breast-beating, finger pointing, scapegoating, and head rolling. Conversely, if they didn’t approve a useful drug, which was widely and legally employed in counties with respectable scientific infrastructures, they face the same circumstances. Fortunately, for all concerned, by 2010, polidocanol was finally approved and was comfortably ensconced under the name Asclera.

Insights from the phlebologic community

The opinions of “The ad hoc” advisors, who were kind enough to contribute their ideas and experiences solicited in a detailed survey (mentioned above), reflect an unexpected degree of unanimity. Their ranks included general and vascular surgeons, dermatologists, and practitioners from different countries, cultures, training backgrounds, and treatment approaches.

An attempt was also made to balance the opinions of acknowledged phlebological experts whose CVs resemble the Guttenberg Bible, with front line phlebologists, surgeons, and non-surgeons. A brief synopsis of their observations is reported here.

Where did you receive your training?

Only one of the respondents received training in a formal program. All of them gratefully identified their mentors and role models whose names, unfortunately, I do not have space to include.

What were the most important advances in phlebology?

Advances in sclerotherapy included “Safe and effective detergent solutions,” and FDA approval for polidocanol. Foam sclerotherapy was considered to be a major advance as were endoluminal therapies, specifically EVLT (endovenous laser therapy), and radiofrequency ablation. For the treatment of telangiectasia, the usefulness of compression and a clearer understanding of the relationship of telangiectasia to reticular veins and venous hypertension were cited as major advances. None of the respondents regarded the use of lasers for lower extremity telangiectasia and reticular veins to be worthy of comment.

Surgical advances included refinements in vein ligation and stripping and better surgical techniques “Except in the US, where surgery is fading.” Propagation of ambulatory phlebectomy by an eminent Swiss dermatologist, R. Muller, and the substitution of tumescent anesthesia for general anesthesia for its employment were also cited.

Innovations and refinements

Good quality, accessible venous duplex scanning was considered to be, “By far the most important advance.” “Magnetic resonance venography”, “Thrombolysis for ilieofemoral DVTs”, and “The recognition of iliac obstructions”, are cited. Good quality, graduated, compression stockings, low molecular weight heparin, and novel anticoagulants were also part of the list.

Will phlebology become a bona fide subspecialty? What practitioners should be included?

Members of the European Union are “establishing a register of phlebologists to achieve this goal.” “Phlebology will gain acceptance as a bonafide subspecialty because of work by phlebologic organizations.” “Phlebologists should be recruited from any physicians interested in venous and lymphatic diseases who have completed appropriate training, including diagnostic ultrasound,” regardless of their primary specialty.

Practicing phlebological physicians “Are already a part of an existing sub-specialty, and must be given ‘grandfathered’ sub specialty phlebology status. Newcomers to phlebology have to go through an accredited training scheme.”

What are your concerns?

“Cost and profit.”The many great advances in phlebology are being counterbalanced on the downside by the pursuit of money, especially in the west.” “We are developing more and more expensive venous treatments which other countries cannot afford.” “Vested interest exists in each country for and against each sub specialty.” “Dishonest phlebologists are going toward fraudulent misrepresentation that endovenous ablation will cure telangiectasia.” “It will achieve the status of a recognized sub specialty once we work through all the unnecessary endovenous procedures being performed.”

Phlebologic monopolies, are they real?

“Depends on individual countries.” “Invasive radiologists see this as a profitable opportunity; they have the most 3-D duplex knowledge.” “The interventional cardiologists and radiologists want to take over the world and all of medicine.” “Great technicians, but they know nothing about venous disease so they may gather the revenue for the procedures, but a long-term phlebologist is needed.” “Fight between interventional radiologists, vascular surgeons, and hucksters.” “Now the surgeons are learning endovenous treatments, I think it may swing back to surgeons filling this phlebology role.”

Phlebological organizations, how do you rate them?

ACP, AVF, and UIP are rated different ways. “UIP, the most importantly globally, ACP, the most clinical members, AVF, is the most academic.” “The American board of venous and lymphatic medicine is the only organization in the world that provides anything near a comprehensive certification process in venous disease.” “ACP is truly inclusive, great educational opportunities, has fostered investment in the field by healthcare professionals and industry.” “AVF, principle academic venous society, numerous important contributions such as the CEAP classification, guideline and consensus documents, and an emphasis on evidence based medicine.” “French Society of Phlebology, the mother of all others, still the only society having sponsored / published clinical trials.” “ACP biggest, most energetic.” “There are some, made for truly developing phlebology, and some that are made just to promote some individuals.”

Future trends

“We’re still pretty far away from understanding the genetic and pathogenetic basis of the most common forms of varicose syndromes.” “Many of the clinical contradictions and controversies will be laid to rest as the mechanisms underlying their occurrence are understood at the molecular level.” Replies include “Molecular scientists and geneticists, and basic researchers were predicted to be the people, who in the future, will lead the evolution of phlebology”, “It will not be frontline phlebologists”. “Only textbooks and electronic formats like iBook’s will be used.”, “Tissue manipulation, and genetic engineering” are cited as important issues. “Enhanced visualization, less invasive saphenous vein closure techniques”, and “Control and even prevention with medication” are predicted. “Diagnostic tools beyond duplex ultrasound”and“More endovenous thermal devices, sclerotherapy, and possibly glue, which may even replace RF and internal laser devices”. “Stripping will no longer be a standard”. Further predictions include “Sonography will develop toward 3-dimensional scanning”, “DVT treatment may become more invasive, “and “Compression will change toward new devices with more indication related design.” “Stenting and stents with valves for PTS (post thrombotic syndrome) along with the accelerated development of some pharmacologic treatment and or prevention” will eventuate. Thermals and glue will come and go, “The use of glue may increase, however, it is effective, but still too expensive”. “The expansion of sclerotherapy into for a wide range of cosmetic concerns may represent a new era and application for this versatile technique.” “The development of procedures that do not require anesthesia” holds promise for the simplification and accessibility of phlebological procedures.

Novel future treatment modalities

“FALOS, Laser assisted foam sclerotherapy combines a holmium laser with sclerotherapy. Laser energy is concentrated in the media and not on adventitia or on tunica intima…perivascular damage is zero.” Photochemical cross linking of main wall collagen in which riboflavin and blue light are used for formation of new covalent links among collagen fiber in the vein wall. This provokes shrinkage of the vein without endothelial damage.

Conclusion

Current phlebological practices can be viewed as the latest links in a 3,500-year old chain of theoretical and therapeutic advances, mishaps, discoveries, technologies and innovations. The addition of each new link cannot occur without the knowledge and experience embedded in the preceding link. The first links were forged by ancient empiricists. The last, will be hammered out worldwide in the laboratories of geneticists, molecular biologists, pharmacologic, and biomaterials researchers. It is also quite possible that ethical issues, and political and legal concerns will result in a few kinks in the newest links. n

This series is adapted from a chapter originally written by Dr. Duffy at the request of friend and colleague Stuart Maddin, MD, who long considered to be the godfather of Canadian dermatology. He was until his recent death a Professor Emeritus at the University of British Columbia. He unfortunately passed away before the book could be published.

Dedications and acknowledgements

This treatise is dedicated to John Bergan, whose willingness to share his expertise with interested specialists regardless of their backgrounds motivated an entire generation of phlebologists, and to Stuart Maddin whose extraordinary contributions to medical advances in a number of fields has provided guidance for over five decades. Sincere thanks must be given to A. Frullini, Mitchel Goldman, Jean-Jerome Guex, Nick Morrison, Milos Pavolvic, Eberhard Rabe, Neil Sadick, Margaret and Robert Weiss, and Steven Zimmet, whose wisdom has enriched this publication. I must personally acknowledge the debt I have to Donald Alderman at Yale who instructed me in sclerotherapy in 1978. Recognition for their discoveries and the clarity of their publications are also in order for H.I. Biegeleisen, Andre Davy, C.M. Hamel-Desnos, Craig Feid, Larry Fields, William Foley, Arnost and Helene Froneck, Mihael Georgiev, David Green, W.P. De Groot, Mary Lupo, Pauline Raymond-Martimbeau and A.N. Nicolaides. Certain individuals have provided me with enthusiastic encouragement; they include Jay Barnett, Gene Bodian, Anton Butie, Al and Jean Carruthers, William Coleman, Mitch Goldman, Neil Sadick, Margaret Weiss, Robert Weiss and the late Larry Tretbar. Some of my most inspirational colleagues are also no longer with us. They include the brilliant Sam Stegman, Ted Tromovich and Murray Zimmerman. Organizations which have been particularly supportive include The American Society for Dermatologic Surgery, and The American College of Phlebology, along with the unfortunately defunct American Society of Cosmetic Dermatology and Aesthetic Surgery. Last, but not least, Mitchel Goldman, Robert and Margaret Weiss, and Neil Sadick deserve credit for being the tireless phlebological apostles who have almost single handedly reanimated a longstanding moribund American interest in phlebology. Finally, this paper could never have been written without the patience and extraordinary efforts of Peggy Goodwin, my industrious and invaluable helpmate.

Apologies are also in order for the omission of the names and accomplishments of many individuals and organizations in the United States and abroad, who have steadfastly advanced the development of phlebology worldwide, both currently, and in times past.

David M. Duffy, MD is Clinical Professor of Medicine (Dermatology), University of Southern California.

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