Phlebology Forum January-February 2016

JANUARY - FEBRUARY 2016

SUCCESSFUL SEGMENTAL THERMAL ABLATION OF VARICOSE SAPHENOUS VEINS IN A PATIENT WITH CONFIRMED VASCULAR EHLERS-DANLOS SYNDROME PAGE 7

TREATMENT OPTIONS FOR VENOUS LEG ULCERS PAGE 10

This is not an actual patient.

Varicose vein foam therapy takes a leap forward The first and only FDA-approved foam for GSV system incompetence Varithena® (polidocanol injectable foam) is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins and visible varicosities of the great saphenous vein (GSV) system above and below the knee. Varithena® improves the symptoms of superficial venous incompetence and the appearance of visible varicosities.

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The use of Varithena® is contraindicated in patients with known allergy to polidocanol and those with acute thromboembolic disease.

Severe allergic reactions have been reported following administration of liquid polidocanol, including anaphylactic reactions, some of them fatal. Observe patients for at least 10 minutes following injection and be prepared to treat anaphylaxis appropriately.

Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene.

Patients with underlying arterial disease may be at increased risk for tissue ischemia. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

Varithena® can cause venous thrombosis. Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within 3 months) major surgery, prolonged hospitalization, or pregnancy are at increased risk for developing thrombosis.

The most common adverse events observed were pain/discomfort in extremity, retained coagulum, injection site hematoma or pain, common femoral vein thrombus extension, superficial thrombophlebitis, and deep vein thrombosis.

Physicians administering Varithena® must be experienced with venous procedures, possess a detailed working knowledge of the use of the duplex ultrasound in venous disease and be trained in the administration of Varithena®.

See Full Prescribing Information for Varithena®.

Find out more at VarithenaProfessional.com © 2015 Biocompatibles, Inc., a BTG International group company All rights reserved US-VAR-2014-0993b(1) 10/15 Varithena is a registered trademark and Varithena Solutions Center is a trademark of Provensis Ltd, a BTG International group company BTG and the BTG roundel logo are registered trademarks of BTG International Ltd

Varithena® (polidocanol injectable foam), for intravenous use Initial U.S. Approval: 2013 Brief Summary of Prescribing Information. For complete Prescribing Information, consult official package insert.

INDICATIONS AND USAGE Varithena® (polidocanol injectable foam) is indicated for the treatment of incompetent great saphenous veins, accessory saphenous veins and visible varicosities of the great saphenous vein (GSV) system above and below the knee. Varithena® improves the symptoms of superficial venous incompetence and the appearance of visible varicosities.

In Varithena®-treated patients, 80% of pain events in the treated extremity resolved within 1 week.

DOSAGE AND ADMINISTRATION Varithena® is intended for intravenous injection using ultrasound guidance, administered via a single cannula into the lumen of the target incompetent trunk veins or by direct injection into varicosities.

Proximal symptomatic venous thrombi occurred in <1% of patients treated with Varithena®. Approximately half (49%) of patients with thrombi received treatment with anticoagulants.

Physicians administering Varithena® must be experienced with venous procedures, possess a detailed working knowledge of the use of the duplex ultrasound in venous disease, and be trained in the administration of Varithena®.

CONTRAINDICATIONS The use of Varithena® is contraindicated in patients with: • known allergy to polidocanol [see Warnings and Precautions] • acute thromboembolic disease WARNINGS AND PRECAUTIONS Anaphylaxis Severe allergic reactions have been reported following administration of liquid polidocanol, including anaphylactic reactions, some of them fatal. Observe patients for at least 10 minutes following injection and be prepared to treat anaphylaxis appropriately.

Tissue Ischemia and Necrosis Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene. Patients with underlying arterial disease, such as marked peripheral arteriosclerosis or thromboangiitis obliterans (Buerger’s Disease) may be at increased risk for tissue ischemia. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

Venous Thrombosis Varithena® can cause venous thrombosis [see Adverse Reactions]. Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within 3 months) major surgery, prolonged hospitalization, or pregnancy are at increased risk for developing thrombosis.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of Varithena® cannot be directly compared to rates in the clinical trials of other drugs or procedures and may not reflect the rates observed in practice.

A total of 1333 patients in 12 clinical trials were evaluated for safety when treated with Varithena® at dose concentrations of 0.125%, 0.5%, 1.0% or 2.0%, including 437 patients treated with Varithena® in placebo-controlled clinical trials.

Adverse reactions occurring in 3% more patients receiving Varithena® 1% than receiving placebo are shown in Table 1.

Table 1: Treatment-emergent adverse reactions (3% more on Varithena® 1% than on placebo) through Week 8 (n=588) Adverse Reaction Pain in extremity Infusion site thrombosis b Contusion/injection site hematoma Limb discomfort Tenderness/injection site pain Venous thrombosis limbc Thrombophlebitis superficial Deep vein thrombosis

Placebo (N=151) 14 (9.3) 0 9 (6.0) 5 (3.3) 5 (3.3) 0 2 (1.3) 0

Varithena® 1.0% (N=149) 25 (16.8) 24 (16.1) 23 (15.4) 18 (12.1) 16 (10.7) 12 (8.1) 8 (5.4) 7 (4.7)

Pooleda Varithena® (N=437) 65 (14.9) 46 (10.5) 38 (8.7) 32 (7.3) 30 (6.9) 24 (5.5) 40 (9.2) 10 (2.3)

a Includes Varithena® 0.125%, 0.5%, 1.0%, and 2.0% from the placebo-controlled trials. b Retained coagulum. c Common femoral vein thrombus extension (non-occlusive thrombi starting in the superficial vein and extending into the common femoral vein).

In the 1333 patients treated with Varithena®, the following venous thrombus adverse events occurred: common femoral vein thrombus extension (2.9%), proximal deep vein thrombosis (DVT) (1.7%), distal DVT (1.1%), isolated gastrocnemius and soleal vein thrombosis (1.4%).

Since Varithena® induces thrombosis in the treated superficial veins, D-dimer is commonly elevated post-treatment and is not useful diagnostically to assess patients for venous thrombus following treatment with Varithena®.

Neurologic adverse events (cerebrovascular accident, migraines) have been reported in patients following administration of physician compounded foam sclerosants. None of the 1333 patients in the Varithena® trials experienced clinically important neurological or visual adverse events suggestive of cerebral gas embolism. The incidence of neurologic and visual adverse events within 1 day of treatment in the placebo-controlled studies was 2.7% in the pooled Varithena® group and 4.0% in the placebo groups.

Skin discoloration adverse events were reported in 1.1% of the pooled Varithena® group and 0.7% of the placebo group in the placebo-controlled studies.

DRUG INTERACTIONS No specific drug interaction studies have been performed. There are no known drug interactions with Varithena®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies of Varithena® in pregnant women. Do not use Varithena® during pregnancy.

Labor and Delivery The effects of Varithena® on labor and delivery in pregnant women are unknown.

Nursing Mothers It is not known whether polidocanol, the active pharmaceutical ingredient in Varithena®, 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 Varithena® to a nursing woman.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Geriatric Use Of the 1333 subjects in clinical studies treated with Varithena®, 9.1% (n=121) were ≥65 years of age. No clinically important differences in safety or efficacy were observed between older and younger patients in all studies.

OVERDOSAGE There are no known cases of overdosage with Varithena®. In clinical studies, total volumes of up to 60 mL of Varithena® per treatment session have been administered.

Manufactured for Provensis Ltd by: Biocompatibles UK Ltd Chapman House, Weydon Lane, Farnham, UK, GU9 8QL. Distributed by: Biocompatibles, Inc. 115 Hurley Road, Building 3, Oxford, CT 06478 Provensis Ltd, Biocompatibles UK Ltd, and Biocompatibles, Inc. are BTG International group companies Varithena is a registered trademark of Provensis Ltd. BTG and the BTG roundel logo are registered trademarks of BTG International Ltd

From the Editor-in-Chief Sherry Scovell, MD

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Contributing Editor/Reviewer: Dermot Moore, MD Associate Editor: Sherry Scovell, MD

Treatment Options for Venous Leg Ulcers: Effectiveness of Vascular Surgery, Bioengineered Tissue, and Electrical Stimulation Contributing Editor/Reviewer: Giovanni Mosti, MD Associate Editor: Mark Forrestal, MD, FACPh

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january â&#x20AC;&#x2DC;16

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Endovenous management of venous leg ulcers Contributing Editor/Reviewer: Stephen F. Daugherty, MD, FACS, RVT, RPhS Associate Editor: Eric Mowatt-Larssen MD, FACPh, RPhS

Frequency of Malignant Neoplasms in 257 Chronic Leg Ulcers Contributing Editor/Reviewer: Tania Phillips, MD Associate Editor: Mitchel Goldman, MD, FACPh

contents

Successful segmental thermal ablation of varicose saphenous veins in a patient with confirmed vascular Ehlers-Danlos syndrome

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disclosure of interests

Name

ACP Role

Date Submitted

Disclosure

Stephanie Dentoni, MD

Recruitment & Retention(Chair), Leadership Development

9/8/13

Nothing to Disclose

Mark Forrestal, MD, FACPh

ACP BOD(President-Elect) Advocacy(Chair), Nominating, Finance, Exhibitor Advisory, Phlebology Forum,

9/8/13

Cooltouch Lasers: Speaker, Trainer

Mitchel Goldman, MD, FACPh

Phlebology Forum

9/8/13

Merz Aesthetics/Kreussler: Consultant/Research; New Star Lasers: Consultant

Lowell Kabnick, MD, FACS, FACPh

Phlebology Forum

9/8/13

Angiodynamics: Consultant, Shareholder, Patent; Veniti, Scientific Advisory Board; BTG: Consultant

Neil Khilnani, MD, FACPh

ACP BOD(Secretary), Member Engagement(Chair), CME Standing, CME, CME Workgorup 1,

9/8/13

Sapheon: Data Safety Board Member

Mark Meissner, MD

ACP BOD, Eductation, CME, Fellowship Training(Chair)

9/8/13

Nothing to Disclose

Nick Morrison, MD, FACS, FACPh

ACP Foundation (Chair), ACP Ethics and Industrial Advisory Committees, Phlebology Forum

2/24/14

medi: Educational Grant; Merz: Consultant/Speakers Bureau; Sapheon: Principle Investigator; VeinX: Scientific Advisory Board

Eric Mowatt-Larssen, MD

ACP Leadership Development CME Workgroup 2 & 3

6/25/12

BTG International, Inc.: Consultant

Diana Neuhardt, RVT, RPhS

ACP BOD, Member Engagement, Education, VeinLine, Phlebology Forum, Leadership Development, Public Education(Chair), CME-Workgroup 2

6/15/12

Nothing to Disclose

Pauline RaymondMartimbeau, MD, FACPh

ACP Foundation BOD

9/8/13

Nothing to Disclose

Sherry Scovell, MD

Phlebology Forum (Editor-In-Chief)

7/31/15

Nothing to Disclose

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From the

Editor-in-Chief Dear Readers As we begin 2016, we want to welcome you back for another year of Phlebology Forum!

I would be remiss if I didnâ&#x20AC;&#x2122;t thank Nick Morrison for all of his incredible work since the inception of Phlebology Forum and wish him great success as the President of the International Union of Phlebology. I look forward to being able to continue his tradition of working closely with all of the associate editors to bring you exceptional reviews of the latest literature on subjects pertinent to your practice of Phlebology. We will be identifying a specific topic for each edition and focus on delivering several reviews dealing with multiple facets of that topic.

This issue will mainly focus on venous leg ulcerations, including endovenous management of patients with leg ulcers, the effectiveness of alternate treatment options for patients with ulcers, and the risk of malignancy in chronic leg ulcers. We also include an article on ablation in a patient with Ehlers-Danlos syndrome for interest. We hope that you enjoy this selection of articles and the excellent reviews that accompany them.

Wishing everyone a happy, healthy 2016 from all of us at Phlebology Forum!

Sherry Scovell, MD Editor-in-Chief Phlebology Forum

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Successful segmental thermal ablation of varicose saphenous veins in a patient with confirmed vascular Ehlers-Danlos syndrome Authors: Frank M , Says J , Denarié N , Sapoval M , Messas E .

Phlebology. 2015 Apr 28.

Contributing Editor/Reviewer: Dermot Moore, MD Associate Editor: Sherry Scovell MD

ABSTRACT This is a case report from France describing elective treatment of bilateral symptomatic varicose veins in a 43-year-old woman with previously diagnosed vascular Ehlers-Danlos Syndrome (vEDS).

The varicose veins were causing pain and swelling despite compression and analgesics, with a Vein Clinical Severity Score (VCSS) of 12/30. The chosen treatment modality was radiofrequency thermal ablation (RFA) with local anaesthesia for truncal incompetence, rather than surgical stripping, and subsequently using foam sclerotherapy for the varices. There was a minor dissection of a thigh saphenous trunk during the procedure, which was managed successfully by a more distal

Generally, surgical removal of varicose veins in vEDS would be a risk-filled adventure...

puncture and RF ablation. The patient spent two days in hospital. The three treated truncal segments remained occluded at one year follow up. The VCSS fell to 6 and sclerotherapy continues in the outpatient clinic after a nine month pause.

COMMENTARY Ehlers-Danlos syndrome includes a range of clinical conditions involving inheritance of defective collagen. Collagen stabilises all connective tissue and if it is deficient, disorders of joints, bones, muscles, skin and eyes and blood vessels will occur. One rare form of the disorder, known as vascular Ehlers-Danlos Syndrome, involves mutation of the COL3A1 gene.1 In the vascular syndrome, the most deadly form of EDS, weakness of intra abdominal viscera and blood vessels leads to rupture and bleeding catastrophes. It is reported that 25% of sufferers will have a major life threatening illness by the age of 20 years, 80% by 40 years and that the median life span is only 48 years.2 Most patients suffer from chronic pain syndromes due to joint, muscle and back problems. Many, as alluded to in the discussion are resistant to local anaesthetic

1

A Parapia, Carolyn Jackson. British Journal of Haematology 05/2008; 141(1): 32-5. Ehlers-Danlos syndrome - A historical review

2

Pepin M, Schwarze U, Sup N Engl J Med. 2000 Mar 9;342(10):673-80. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

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Against this background, this woman was in her early forties, wearing compression and taking pain killers for her varicose vein symptoms of pain and swelling. There was no description of any lower limb skin changes or ulceration, and VCSS was only 12 where the maximum score is 30. The article discusses in detail the vEDS condition, the venous issues are well documented and the multidisciplinary discussions about treatment, and the contraindications to surgery (including the risks of non-healing wounds, risk of postoperative arteriovenous fistulae and bleeding) are well aired. Resistance to local anaesthetic is also mentioned.

Generally, surgical removal of varicose veins in vEDS would be a risk-filled adventure due to friability of blood vessels and bleeding.3 Whether there is justification for any interventional treatment in this setting is debatable, especially since in this individual there was no indication of impending skin or leg ulcer problems. A postoperative VCSS of 6 (after only partial treatment of the incompetent trunks) suggests that perhaps not all of the original symptoms were due to venous incompetence; certainly, lower limb pain unresponsive to compression socks in a patient with vEDS could also be attributed to a musculoskeletal origin. It is not clear what part of the VCSS improved after treatment and whether she continued wearing compression socks.

The importance of this case report is because it brings awareness of a rare condition forward for discussion; however, the fact that one patient with known and symptomatic vEDS had a benign outcome after RFA for varicose veins should not be used to encourage phlebologists that it is wise to use invasive treatment in treating this group of people with a very dangerous underlying disease.

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Whiteley MS, Holdstock JM Phlebology. 2015 Aug;30(7):489-91 Endovenous surgery for recurrent varicose veins with a one-year follow up in a patient with Ehlers Danlos syndrome type IV

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Treatment Options for Venous Leg Ulcers: Effectiveness of Vascular Surgery, Bioengineered Tissue, and Electrical Stimulation Author: Thakral G. et al Adv Skin Wound Care. 2015 Apr;28(4):164-72.

Contributing Editor/Reviewer: Giovanni Mosti, MD Associate Editor: Mark Forrestal, MD, FACPh

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ABSTRACT Treatment Options for Venous Leg Ulcers: Effectiveness of Vascular Surgery, Bioengineered Tissue, and Electrical Stimulation by Thakral G et al. is an excellent review of treatment options for venous leg ulcers (VLU). I think it deserves a careful reading by all care-givers involved in the VLU treatment. The paragraph where compromised muscle pump function is underlined as a possible cause of VLU, even with a normal venous system, is particularly interesting as the population in western countries is becoming older and older. This type of ulcer starts to be very common in old and poorly mobile patients who are stationary most of their time. I have one minor and

It is very clear that the effectiveness

two major comments.

of compression

COMMENTARY

therapy depends

Minor Comment

on pressure and

Regarding pathophysiology, major importance is given to the fibrin cuffs hypothesis; according to this theory, â&#x20AC;&#x153;fibrinogen polymerizes to form a pericapillary fibrin cuff that prevents exchange of oxygen and nutrients leading to cell death and ulcerationâ&#x20AC;?.

stiffness exerted by compression materials.

Nevertheless, this theory is more than questioned as no one has shown that the fibrin cuff presents a true barrier to gas diffusion.1,2,3 The third hypothesis for venous ulcer formation considering the possible white cell trapping in the leg venous capillary4 is not reported.

Major Comment Compression therapy, according to the authors, represents the standard treatment for VLU. Unfortunately Thakral and co-authors, as well as many other authors referring to compression

1

Kobrin KL, Thompson PJ, van de Scheur M, Kwak TH, Kim S, Falanga V. Evaluation of dermal pericapillary fibrin cuffs in venous ulceration using confocal microscopy. Wound Repair Regen. 2008 Jul-Aug;16(4):503-6.

2

Van de Scheur M, Falanga V. Pericapillary fibrin cuffs in venous disease. A reappraisal. Dermatol Surg. 1997 Oct;23(10):955-9.

3

Falanga V, Kirsner R, Katz MH, Gould E, Eaglstein WH, McFalls S. Pericapillary fibrin cuffs in venous ulceration. Persistence with treatment and during ulcer healing. J Dermatol Surg Oncol.

4

Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J (Clin Res Ed). 1988 Jun 18;296:1726-7.

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therapy, do not report that compression therapy includes a wide range of treatment, a wide range of compression devices and, most of all, a wide range of compression pressure. In this and many other reviews, every “compression therapy” is always considered “the same” without any other definition or distinction.

Nevertheless, it is very clear that the effectiveness of compression therapy depends on pressure and stiffness5 exerted by compression materials. Certainly, pressure range and stiffness provided by different compression devices (elastic stockings, inelastic bandages or Velcro straps) are not the same. The main flaw of almost all studies reporting compression therapy is that the compression pressure is never measured, and this fact makes the reported outcomes at least doubtful.

The authors report “Compression therapy is the criterion standard treatment for VLUs.13-15 A review of 16 studies that applied multilayered high compression for VLUs showed healing rates of 34% to 79% (average, 60.9%) at 12 weeks. As a result, many ulcers remain unhealed.16,17” Unfortunately, none of the reported studies measured the pressure; thus a “high level of compression” is only supposed. Furthermore when applying bandages, the expertise of caregivers is extremely important to achieve the target pressure, but once again, if pressure is not measured, even expert personnel may not exert the desired pressure when applying compression bandages as results from many studies.6 7 8 9 Elastic stockings, in the papers the authors consider, exert an average pressure of 20 to 30 mm Hg; obviously the SSI10 is lower than 10, in the elastic range. This means that in the standing position, the compression pressure of elastic stockings rises just very slightly to 30-35 mm Hg. This standing pressure is not enough to overcome the intravenous pressure at ankle level (in the range of 70-80 mm Hg) and, as a consequence, elastic stockings are unable to narrow or occlude the veins lumen which is mandatory to exert a hemodynamic effect.11 5

Partsch H. The use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. Eur J Vasc Endovasc Surg.

2005;30:415-21.

6

Reynolds S. The impact of a bandage training programme JWC. 8:55-60;1999

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Satpathy A, Hayes S, Dodds SR. Is compression bandaging accurate. The routine use of interface pressure measurement in compression bandaging of venous leg ulcers. Phlebology 2006; 21: 36-40

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Zarchi K, Jemec GBE. Delivery of Compression Therapy for Venous Leg Ulcers. JAMA Dermatol. 2014;150(7):730-736.

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Keller A, Muller ML, Calow T, Kern IK, Schumann H. Bandage pressure measurement and training: simple interventions to improve efficacy in compression bandaging. Int Wound J 2009; 6:324–330

10 Partsch H. The static stiffness index: a simple method to assess the elastic property of compression material in vivo. Dermatol. Surg.2005; 31 625-30 11

Partsch B, Mayer W, Partsch H. Improvement of ambulatory venous hypertension by narrowing of the femoral vein in congenital absence of venous valves. Phlebology 1992;7:101-4.

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Actually inelastic bandages showed to be more effective than elastic material and even more than elastic stockings in increasing venous pumping function and in reducing venous reflux, thus reducing ambulatory venous pressure 12 13 14 15 Inelastic bandages are effective also when exerting a low pressure and do not lose their effectiveness over time despite of their pressure loss.16 17 Due to their effectiveness in counteracting the impaired venous hemodynamic in patients with VLU, inelastic bandages, when properly applied to exert a strong “measured” supine pressure of 50 mm Hg rising to more than 65 mm Hg in standing position, are extremely effective in achieving ulcer healing in 12 weeks with an healing rate close to 100% much higher than that reported by the authors.18 In conclusion, speaking about compression therapy or reporting on the results of compression therapy, generically, without any other specification (which material was used, which pressure and stiffness were exerted, which expertise of bandage wrappers) as standard therapy with which other treatment outcomes are compared must be critically considered. The statement “Although compression therapy may be the criterion standard in the treatment of VLUs, the results are less than ideal. The rate of healing is low, and the rate of recurrence is high” largely underestimates the outcomes of a properly applied compression therapy with high pressure and high stiffness which is the only one effective in VLU treatment.

Lastly, a few words must be spent regarding almost all the review papers and, therefore, also this review. Clinical trials, in order to correctly compare homogeneous groups of patients, have strict inclusion criteria and a very long exclusion criteria list. So it is very common that only very small ulcers are included, often less than 10 cm2 (just for an example look at the very well known ESCHAR study19, and exclusion criteria include arterial involvement, even minimal, diabetes mellitus, infection, steroid or immunosuppressive treatment, rheumatic, hematological, neoplastic disease, etc. In brief, almost all studies enroll patients with small venous ulcers and

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Partsch H. Do we still need compression bandages? Haemodynamic effects of compression stockings and bandages. Phlebology 2006; 21:132-138.

13

Mosti G, Partsch H. Measuring venous pumping function by strain-gauge plethysmography. Int Angiol. 2010;29(5):421-5.

14 Mosti G, Mattaliano V, Partsch H. Inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. Phlebology. 2008;23(6):287-94.

15

Mosti G, Partsch H. Duplex scanning to evaluate the effect of compression on venous reflux. Int Angiol. 2010 Oct;29(5):416-20.

16 Mosti G, Partsch H. Is low compression pressure able to improve venous pumping function in patients with venous insufficiency? Phlebology. 2010 Jun;25(3):145-50.

17

Mosti G, Partsch H. Inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. J Vasc Surg 2010;52(4):925-31.

18 Mosti G, Crespi A, Mattaliano V. Comparison Between a New, Two-component Compression System With Zinc Paste Bandages for Leg Ulcer Healing: A Prospective, Multicenter, Randomized, Controlled Trial Monitoring Sub-bandage Pressures. Wounds 23, 5:126-134; 2011.

19 Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004;363:1854-9.

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exclude patients with large and/or infected wounds and co-morbidities that make such cases difficult to treat and heal: a highly selected sample unlikely to be found in routine clinical practice.

In addition, the randomization scheme sometimes is not correctly described, a blinded outcome assessment is questionable, and the sample size is often not powered for statistical significance.

In these conditions, it is difficult to find a statistically significant difference between different treatments.

This is particularly true for complex treatment, like bioengineered tissue and/or electrical stimulation, which could be extremely effective when treating hard-to-heal ulcers.

Unfortunately, nobody knows as patients with these types of ulcers are typically not enrolled in clinical trials.

The importance and effectiveness of these complex treatments are minimized when they are used in small, uncomplicated, not infected VLU which can easily heal just by properly applying the compression therapy.

This is the reason why, when complex treatments are compared to standard treatment in these easy-to-heal ulcers, there is no statistical difference and the conclusion is that “there is little evidence to support the use of adjunctive therapies to heal VLUs at this time.”

In fact, the lack of effectiveness in the conditions considered in these clinical trials incorrectly becomes universally true and is then extrapolated to more complex conditions (large and deep ulcers, with comorbidities) which are hard-to-heal and could benefit from complex treatments.

Actually the above reported statement should be changed in ““there is little evidence to support the use of adjunctive therapies to heal very small and uncomplicated VLUs without any comorbidity at this time.”

The “fault”, if a “fault” exists, of this amazing way to perform clinical trials is not certainly attributable to the authors, but they could better underline the limits of the trials they considered.

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Endovenous management

of venous leg ulcers Author: Seshadri Raju, Orla K. Kirk, Tamekia L. Jones Journal of Vascular Surgery: Venous and Lymphatic Disorders, Volume 1, Issue 2, Pages 165-172 Contributing Editor/Reviewer: Stephen F. Daugherty, MD, FACS, RVT, RPhS Associate Editor: Eric Mowatt-Larssen MD, FACPh, RPhS

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ABSTRACT Compression therapy has been standard management for venous leg ulcers (VLU) for thousands of years. Treatment of saphenous vein reflux has been viewed until recently as a means to reduce the rate of ulcer recurrence, but not to shorten ulcer healing time. This series of 192 consecutive limbs treated with endovenous techniques for VLU after failed conservative treatment at one center from July, 2000 through September, 2011 is analyzed.

Thirty limbs were treated with endovenous saphenous LASER ablation alone, 89 were treated with iliac vein stenting, and 69 were treated with both technologies. Residual deep vein reflux was not treated. Compression was continued if it was in use prior to the intervention, but compression was not added for those who previously had not been using compression. Thirty-eight percent of patients did not use elastic compression. Local care consisted of cleansing and an absorbent, nonadherent dressing

One of the most important findings is the frequency of iliac vein obstruction in VLU patients.

without aggressive debridement or topical chemicals or antibiotics.

Endovenous saphenous ablation was performed in limbs with a refluxing saphenous vein 5 mm or greater in diameter and no clinical indication of iliac vein obstruction such as limb swelling or severe diffuse limb pain. Combined saphenous vein ablation and iliac vein stenting were performed if the refluxing saphenous vein diameter was <5 mm and if symptoms of iliac vein obstruction were dominant in the presence of intravascular ultrasound (IVUS) findings of obstruction. Iliac vein stenting alone was performed for iliac vein obstruction in the absence of saphenous vein reflux.

By 14 weeks after treatment, 81% of the ulcers up to 1 inch in diameter healed, but only 15% of the larger ulcers healed. By 23 weeks, only 23% of the larger ulcers healed. Healing time was not observed to be affected by post-thrombotic etiology, presence of uncorrected deep vein reflux, demographics, or compression stocking use. There were 47 unhealed ulcers or recurrences (24%) and 5 of those involved stent occlusions or stenosis. At 5 years, 87% of the non-thrombotic limbs and 66% of the post-thrombotic limbs remained healed. Long term ulcer healing was

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inferior in limbs with a reflux segment score of 3 or more, but 66% of the post-thrombotic patients with a score of 3 or more remained healed.

The recommended algorithm to treat VLU is to treat the saphenous reflux in a saphenous vein 5 mm or larger in diameter. If no significant saphenous reflux is identified, IVUS examination and stenting of iliac vein stenosis, if found, is recommended. If a refluxing saphenous vein is less than 5 mm in diameter, combined saphenous vein ablation and IVUS with iliac vein stenting (if iliac vein stenosis is identified) are recommended for consideration. An adjunctive therapy suggested is local ablation of a refluxing perforating vein beneath an ulcer bed in a non-thrombotic limb.

COMMENTARY This is an important report which should stimulate a paradigm change in the way we evaluate and treat patients with VLU. One of the most important findings is the frequency of iliac vein obstruction in VLU patients. The authors treated 158 of 192 patients with iliac vein stents with or without saphenous ablation. Some may argue that the criteria for iliac vein stenting are too liberal (>50% cross-sectional area stenosis by IVUS or the finding of â&#x20AC;&#x153;balloon waistingâ&#x20AC;?), but the median cross-sectional area stenosis by IVUS was 70%.

The authors utilize venography and IVUS to evaluate VLU patients who have signs suggesting iliac vein obstruction. While CT or MR venography may be highly specific for significant iliac vein stenosis, they are insensitive and highly dependent upon technique and interpretive skill. Transabdominal color duplex ultrasound (CDU) is very dependent upon technologist skill and effort, but it is much more sensitive in our experience because the anatomic findings may be correlated with hemodynamic changes at the lesion or abnormal flow in collateral veins before and after treadmill exercise. IVUS provides excellent anatomic measurements, but it remains unsettled as to what represents a hemodynamically significant stenosis. Our experience is that iliac vein lesions which are found by CDU to be hemodynamically significant almost always are associated with a >50% diameter stenosis by IVUS which usually is considerably worse than a 50% crosssectional area stenosis. Dr. Raju utilizes balloon-waisting to identify lesions missed by IVUS and we occasionally note such a lesion.

Raju argues for identification of obstruction and reflux in the VLU patient with failed conservative treatment and for treatment of the causes of venous hypertension rather than

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prolonged aggressive local ulcer care with multiple debridements and expensive wound care programs. His data support treatment of small ulcers though results with large ulcers are less impressive.

This report reviews consecutive patients treated after failed conservative therapy of an unspecified duration and there is no control group of patients continuing conservative care.

Additionally, the criteria for stenting are anatomic and are not fully accepted. Dr. Raju notes that â&#x20AC;&#x153;rigorous comparative trialsâ&#x20AC;? are needed to establish validity of variant findings. The most interesting of these is the apparent failure of elastic compression to affect healing time. I urge those who read this report not to abandon compression and perhaps consider the use of inelastic compression as an alternative.

I believe that the evidence is sufficient to encourage early identification and treatment of iliac vein obstruction and/or saphenous vein reflux in VLU patients. Randomized controlled clinical trials need to be performed to better delineate the best technologies to identify clinically significant iliac vein stenosis and the role of compression after endovenous treatment in ulcer healing time and prevention of recurrent VLU. Earlier ulcer healing and avoidance of protracted, expensive wound care may reduce costs of care and should reduce the costs of disability and travel costs associated with lengthy courses of VLU care.

All physicians who treat VLU should read the entire report carefully. Dr. Raju and colleagues have made important observations which should be understood and further evaluated.

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Frequency of Malignant Neoplasms in 257 Chronic

Leg Ulcers Author: Misciali C , Dika E, Fanti PA et al Dermatol Surg 2013; 39; 849-854 Contributing Editor/Reviewer: Tania Phillips, MD Associate Editor: Mitchel Goldman, MD, FACPh

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ABSTRACT This was an observational study of 257 chronic leg ulcers seen during a 3-year period at the University of Bologna. All patients admitted to the wound unit with ulcers were biopsied. Ten patients were found to have ulcers of neoplastic origin. The majority of these (9) were basal cell carcinomas. One patient had an ulcerated porocarcinoma (sweat gland carcinoma.) Mean duration of leg ulcers before a diagnosis of skin cancer was made was 3.3 years(range 6 moths to 10 years) Most of the malignant ulcers were larger than 5cm². Clinically the ulcers appear to show granulation with frequent bleeding and little or no response to conventional medical treatments.

Overall, approximately 4% of the total number of patients in the series had ulcerated skin cancers. This study illustrates the importance of routine screening of chronic leg ulcers for underlying malignancy, particularly those that are of long-standing duration and not responding to conventional treatment.

It...seems very reasonable to consider a wound biopsy in a chronic ulcer which is not responding to standard care.

COMMENTARY It is important to consider the possibility of underlying malignancy in chronic wounds that fail to heal. In 1828, Marjolin first described malignant changes in ulcerated chronic burn scars.

Since then, there have been reports of malignant changes in chronic wounds of various etiologies, including radiotherapy sites, osteomyelitis, pressure ulcers and more rarely, venous ulcers. Traditionally squamous cell carcinomas have been reported in venous ulcers. In 1991, we published a small series of seven basal cell carcinomas (BCC) presenting as non-healing venous leg ulcers1. All the ulcers appeared clinically benign, with apparently healthy granulation tissue at the base and none of the classic signs of BCC. In our clinic the overall incidence of BCC in leg ulcers was high, (9%). Another publication documented histologic evidence of multifocal BCC development in skin adjacent to venous ulcers2. The authors suggested that chronic

1

Phillips TJ, Salman S, Rogers GS Non healing leg ulcer; a manifestation of basal cell carcinoma Journal of the American Academy of Dermatology 1991; 25: 47-49].

2

Black MM Walkden VM Basal cell carcinomatous changes on the lower leg, a possible association with venous stasis Histopathology 1983; 7: 219-227

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venous insufficiency can induce epidermal hyperplasia which might lead to frank basal cell carcinomatous changes. It has been suggested that vascular insufficiency may be associated with altered local immunity and over-expression of proto-oncogenes3. In 2012 a prospective crosssectional study was performed to determine the frequency of skin cancers associated with chronic leg ulcers that had failed to heal despite 3 months or more of appropriate treatment4.

144 patients had at least 2 6mm skin punch biopsies performed, one at the wound edge, and one in the wound bed, in the most clinically suspicious areas. This group of patients was found to have an overall skin cancer frequency of 10.4%: nine squamous cell, 5 basal cell carcinomas, 1 melanoma, and 1 leiomyosarcoma. Fifty-three percent of the ulcers had persisted for at least 3 years. In this study wound area or duration was not significantly associated with skin cancer.

However, older patient age, abnormal excessive granulation tissue at the wound edges, high clinical suspicion of cancer, and number of biopsies were significantly associated with skin cancer.

In these 2 recently published prospective studies skin cancer rates in non-healing, chronic leg ulcers were high. It is possible that previously published retrospective reviews may be have underestimated the risk of skin cancers in chronic leg ulcers.

It, therefore, seems very reasonable to consider a wound biopsy in a chronic ulcer which is not responding to standard care. Some physicians may hesitate to perform biopsies of wounds due to concerns about possible infection or wound enlargement. However, we have found that wound biopsy sites in chronic wounds heal rapidly and do not result in delayed overall healing of the wound. We do not suture the biopsy site and use an absorbable gelatin sponge or alginate dressing for hemostasis.

There is no consensus about when a wound should be biopsied to exclude malignancy. Some researchers recommend early biopsy of wounds within 2 weeks of non-healing. Other guidelines recommend biopsy between 6 weeks â&#x20AC;&#x201C; 3 months5. Based upon my personal experience I would recommend routine biopsy of chronic wounds that have not healed or shown any signs of improvement despite 3 months of good wound care, including well-applied compression bandaging. Wounds that have hyperkeratotic borders, heaped up granulation tissue, or a nodular appearance are biopsied immediately. Misciali et al recommend biopsy specimens both from the 3

Oahes N Phillips TJ Park H. Expression of c fos and h ras proto-oncogenes is induced in human chronic wounds, Dermatologic Surgery 1998; 24: 1354-8

4

Senet P, Combemale P, Debure C et al Malignancy and Chronic Ulcers Arch Dermatolol 2012;148: 704-708

5

Bennet et al and Robson MC et al, Guidelines for the treatment of venous ulcers. Wound repair regeneration 2006; 14: 649-662

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border and the bed of the ulcer. While this is usually adequate, sometimes it may be necessary to perform multiple punch biopsies, or even a wedge biopsy to ascertain the diagnosis. If the wound is large or the index of suspicion is high sampling error can always be a problem. I have followed several patients who had multiple biopsies performed which were negative for skin cancer but eventually turned out to have positive pathology on the 4th or 5th biopsy. Wounds in an unusual location, or on a background of photodamaged skin, are also biopsied early. One should always consider malignancy in any leg ulcer that fails to heal.

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