Phlebology Forum July - October 2012

forum J UL - SEP 2 0 1 2

Can foam sclerotherapy be used to safely treat bilateral varicose veins? page 7

Sclerotherapy in tumescent anesthesia of reticular veins and telangiectasias page 11

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Can foam sclerotherapy be used to safely treat bilateral varicose veins?

jul-sep ‘12

Dr. Nick Morrison

contents

From the Editor-in-Chief

5

Sclerotherapy in tumescent anesthesia of reticular veins and telangiectasias Contributing Editor/Reviewer: Claudine Hamel-Desnos, MD

Contributing Editor/Reviewer: Lorenzo Tessari, MD

7

Associate Editor: Sukirtharan Sinnathamby, MD, FACC, FSCAI, RVT

Associate Editor: Pauline Raymond-Martimbeau, MD, FACPh

11

Great saphenous varicose vein surgery without saphenofemoral junction disconnection

Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, doubleblind, randomised, placebo-controlled trial

Contributing Editor/Reviewer: Attilio Cavezzi, MD

Contributing Editor/Reviewer: Giovanni Mosti, MD

Associate Editor: Eric Mowatt-Larssen, MD, FACPh, RPhS

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Associate Editor: Mark Forrestal, MD, FACPh

Sleep Apnea and Risk of Deep Vein Thrombosis: A Nonrandomized, Pairmatched Cohort Study

The efficiency of pain control using a thigh pad under the elastic stocking in patients following venous stripping: results of a case-control study

Contributing Editor/Reviewer: AndrĂŠ Cornu-Thenard, MD, FACPh

Contributing Editor/Reviewer: Hugo Partsch, MD, FACPh

Associate Editor: Stephanie Dentoni, MD

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Associate Editor: Mitchel Goldman, MD, FACPh

26

19

disclosure of interests

Name

Role

Disclosure

Stephanie Dentoni, MD

Recruitment & Retention Cmte (C), Leadership Development

Nothing to Disclose

Mark Forrestal, MD, FACPh

ACP

CoolTouch: Stockholder

Mitchel P. Goldman, MD, FACPh

Merz: Grant/Research Support, Consultant, Speakers’ Bureau; Bioniche: Consultant; STD Pharmaceudicals: Consultant; BTG: Grant/ Research Support, Consultant; New Star Lasers: Stock and/or Shareholder; Lumens: Consultant, Stock and/or Shareholder

Jean-Jerome Guex, MD, FACPh

ACP BOD, Communications Standing Committee (C), International Affairs (C), Leadership Development Standing Committee, UIP 2013 Task Force, AMA HOD Task Force

Innotech International- Investigator; Pierre Fabre: Consultant; Sigvaris: Investigator; Vascular Insights, LLC: Scientific Advisory Board; ServierEutherapie: Speaker

Lowell Kabnick, MD, FACS, FACPh

ACP BOD, Education Standing Committee (C), UIP 2013 Task Force, Exhibitor Advisory (C), Phlebology Forum, Program Development, Leadership Development

Angiodynamics: Consultant, Scientific Advisory, Stockholder; Merz: Speaker; Vascular Insights LLC: Consultant, Scientific Advisory

Neil Khilnani, MD, FACPh

ACP

Sapheon: Consultant

Ted King, MD, FAAFP, FACPh

ACPF BOD

Angiodynamics: Investigator; BTG: Investigator; Merz: Speaker, Consultant

Mark Meissner, MD

ACP

Nothing to Disclose

Eric Mowatt-Larssen, MD

CME Committee

BTG: Consultant

Nick Morrison, MD, FACS, FACPh

ACP

BTG: Principal Site Investigator; VenX: Scientific Advisory Board; Medi: Speakers Bureau

Diana Neuhardt, RVT, RPhS

ACP BOD, Member Services Standing Committee, Education Standing Committee, Public Education (C), Recruitment & Retention, UIP 2013 Task Force, CME Committee, Distance Learning, Leadership Development

Nothing to Disclose

Pauline Raymond-Martimbeau, MD, FACPh

UIP 2013 Task Force

Nothing to Disclose

4

From the

Editor-in-Chief Dear Readers,

In Issue #5 reports from a variety of journals will be of great interest to the clinical phlebologist. The wisdom on treating both legs with foam sclerotherapy in the same session is discussed with interesting personal perspectives from the inventor of foam for sclerotherapy as it is currently formulated. A novel technique is presented of sclerotherapy for those difficult-to-resolve telangiectasias. Also strong arguments are made for more conservative treatment of varicose veins based on careful duplex examination prior to treatment. Data is presented and arguments made from a multicenter French group for the use of eccentric compression following saphenous vein surgery which can easily be applied to endovenous treatment as well. And finally two very interesting topics are presented regarding a novel treatment for non-healing venous ulcers as well as a relationship between sleep apnea and deep venous thrombosis is uncovered.

We hope there is something for every phlebologist in this issue of Phlebology Forum no matter what spectrum of venous disease one deals with regularly. As always if you have suggestions for topics please feel free to send them to us.

Nick Morrison, MD Editor-in-Chief Phlebology Forum

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Phlebology Takes its Place in the Sun Join us in Hollywood, Florida this November for the ACP Annual Congress

Join your colleagues from all over the nation for the latest in venous education. The ACP Annual Congress provides opportunities for CME credit—with basic, intermediate and advanced seminar tracks available.

Featuring two keynote addresses: Deep Vein Thrombosis and The Role of Ultrasound in Vein Care, this year’s curriculum will be more in-depth than ever before. Event exhibitors also will be showcasing the world’s most advanced products and services specific to phlebology.

TOP REASONS TO ATTEND THE ACP ANNUAL CONGRESS • Approximately 1,000 primary care providers, allied health and industry professionals attend the ACP Annual Congress to network and incorporate the latest research, technology and techniques in the treatment of venous disease • More than 120 clinically relevant sessions, built around basic, intermediate and advanced tracks are available for attendees to customize their experience • Choose from a diverse collection of topics, including Sclerotherapy, Venous Malformations, Compression, Duplex Ultrasound, Aesthetics, Ulcer/Wound Care and Practice Management • Collaborate with colleagues and respected faculty in hands-on, interactive workshops • Discover the latest products, technology and treatment options from the industry’s leading exhibitors • Network with your peers in a variety of social activities, including the annual Golf Outing, Opening Reception, Dinner & Social, and Silent Auction • Hosted at The Westin Diplomat Resort & Spa, located steps away from the Atlantic and Blue Wave Certified beaches, and just moments from the mature Banyan and Royal Palm trees of their championship golf course, 30,000 square foot signature spa or numerous local shopping and dining options.

FOR MORE INFORMATION, VISIT THE ACP CONGRESS WEBSITE AT WWW.ACPCONGRESS.ORG

510.346.6800 • www.acpcongress.org advancing vein care

Can foam sclerotherapy be used to safely treat bilateral varicose veins?

R H Bhogal, C E Moffat, P Coney and I K Nyamekye Worcester Royal Hospital – Vascular Surgery, Worcester, UK Contributing Editor/Reviewer: Lorenzo Tessari, MD Associate Editor: Sukirtharan Sinnathamby, MD, FACC, FSCAI, RVT

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Summary: The incidence of bilateral varicose veins in patients with varicose disease is between 26% and 49%, and prospective studies on a-one step surgical approach for both limbs showed equal efficacy in terms of pain, complications and return to work (with the advantage of a single hospitalisation, one anesthesia and one abstention from work).

UGFS (compared to the surgical treatment) allows the treatment of bilateral varices, without the need for anesthesia or hospitalisation, with an almost immediate return to their normal activities.

A recent systematic review has shown that short-term rates of venous occlusion after foam sclerotherapy, although variable, can reach 94%.

The variables on the volume of foam to be used and the number of treatments in the literature are somewhat conflicting, as the European guidelines define maximum limit per session as 10 ml, the recommendations from the Australasian College of Phlebology take this limit to 20 mL while in United Kingdom the majority of surgeons (NICE) use 12 ml per session.

A number of uncommon to rare complications may follow the UGFS such as deep venous thrombosis (DVT), transient visual disturbances, anaphylactic reactions, as well as less serious local complications such as superficial thrombophlebitis.

These adverse phenomena and the very rare reported cases of ischemic deficits could be partially due to large volumes of foam, hence a tendency to reduce the volume of foam for sclerotherapy treatment has developed.

This trend of using small volumes of foam has resulted in indications of procedures on one limb for patients with bilateral varicose veins.

Limiting the treatment volumes to 8-10 ml for session means, for patients with bilateral varicose veins, the need to undergo multiple treatment procedures with a higher burden on social services. This led the authors to compare the results and early complications following bilateral or unilateral UGFS in patients with bilateral varicose veins.

Between August 2005 and December 2007 one hundred and twelve patients had undergone bilateral UGFS for varicose veins. Patients were asked to choose the treatment - bilateral or unilateral - and patients were also offered the alternative of conventional surgery. Sixty-one patients chose the bilateral treatment in one time (122 limbs) and 51 unilateral treatment regimen. All treatments were performed in the clinic using aduplex scanner Sonosite Titan™.

The foam was made with the Tessari method using STS and Air in the ratio 1/4, and sclerosant foam was injected with elevated limbs with increasing quantities to fill all the varicosities of the leg to be treated (The patients underwent regular movements of the ankle after each injection). The volumes in each session were as follows:

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17.5ml in bilateral treatment, and 10 ml in the unilateral treatment. The total volumes of foam used to treat both limbs separately were, however, higher (22.3 ml) than those used for the treatment of the two limbs in the same session (17.5 ml).

Results: The percentage of occlusion of the trunk after a single treatment was 81% for bilateral and 70% for unilateral procedure. The systemic complications were: (after bilateral treatment) 1 patient with migraine scotoma and one with nausea, erythema and hypotension (defined as anaphylaxis). There were no systemic complications in unilateral treatments. Local complications were similar in the two groups: 17% in the bilateral group and 16.6% in the unilateral group.

The percentage of occlusion of the trunk after a single treatment was 81% for bilateral and 70% for unilateral procedure.

COMMENT: The article is well written from the point of view of both methodological and analytical approach.

Some observations can be highlighted based on strategic choices and objectives which I personally consider differently from the authors.

I do not practice (in agreement with the recent European guidelines) the immediate movement of the ankle after each injection, as this manoeuvre reduces the contact between drug and endothelium.

The Anglo-Saxon phlebology school, most of whom are of surgical extraction, has always had as its primary purpose the radical treatment of varicose pathology; that is to say the total destruction of varicose veins with both the surgical treatment (most) or by means of sclerotherapy (school of G.Fegan).

This is evident in some passages of the article (“was injected with limbs elevated with increasing quantities to fill all the varicosities of the leg to be treated “).

The comparison that the authors make with the bilateral surgical treatment is definitely in favour of ‘UGSF that eludes the hospital stay and the use of the operating room’.“UGFS (compared to surgery) allows the treatment of varicose veins bilaterally, without need for anesthesia, hospitalization, with an almost immediate return to your

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normal activities. “

The authors also followed the volume use which has been proposed by different schools of thought and also aim at resolving all varicose problem in one step only (“By limiting treatment volumes of 8-10 ml per session means for the patients with bilateral varicose veins, to undergo multiple procedures for treatment with a higher load on social services” ). Hence they lean towards high doses of foam in a single bilateral treatment comforted by the fact that the two types of treatment are equal with respect to results (indeed best in contemporary treatment of the two limbs) and complications. “The percentage of occlusion of the trunk after a single treatment was 81% for bilateral and 70% for the procedures unilateral interspersed”.

The criticism that can be raised for this article is about the essence and knowledge about sclerotherapy, which cannot substitute surgery. Furthermore it is well known that treating just the escape points and the upper incompetent tracts, the lower diseased veins tend to disappear and /or recover.

It is not properly the aim of sclerotherapy to “run” and if a treatment strategy is based on shorter time of hospitalization, the lack of use of the operating room, and the lower burden on the health care system, then this is in fact the philosophy of conservative hemodynamic treatment for the superficial venous system. Through conservative therapy you may address the treatment of escape points with the use of targeted surgery or sclerotherapy, taking advantage of deferred treatments (2-3 months interval) so as to allow the varices to recover their functionality. Thereafter it will be possible to re-evaluate the limb to proceed to a further treatment with the most appropriate method.

At the end of the day, as opposed to a “demolition” phlebology, based on short protocols for mono-or bilateral varices, it is possible to switch to conservative phlebology for treatment of the superficial venous system, which was so clearly appreciated by my teacher Glauco Bassi. This approach allows the functional recovery of much of the venous network, though it is clear that this approach requires a different mindset from the phlebologist and treatment times over a longer period of time. Therefore a new relationship with the health care system or with the reimbursement agencies should be taken in consideration; an opposite mentality to the one which searches a quick closure of the medical chart and case, hence of the medical provision.

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Sclerotherapy in tumescent anesthesia of reticular veins and telangiectasias Author: Ramelet AA Department of Dermatology, Inselspital, Bern, Switzerland. aar@ramelet-dr.ch Dermatol Surg. 2012 May;38(5):748-51. doi: 10.1111/j.1524-4725.2011.02287.x. Epub 2012 Jan 23.

Contributing Editor/Reviewer: Claudine Hamel-Desnos, MD Associate Editor: Pauline Raymond-Martimbeau, MD, FACPh

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SUMMARY AND COMMENTS CONCERNING THE PAPER “START” In a preliminary report, the author describes a new technique for treating C1 veins that are refractory to conventional sclerotherapy: the “START ” treatment (Sclerotherapy in Tumescent Anesthesia of Reticular veins and Telangiectasias). The procedure, tested on more than 300 patients over six years, consists of performing sclerotherapy using 0.25% or 0.5% polidocanol (POL) foam, accompanied by tumescence of the area concerned just before or just after the sclerosing injections.

In a single session, the sclerosing treatment performed was judged to be very effective and long-lasting (reduction or disappearance of the vessels over several years). The addition of lidocaine and epinephrine in Ringer’s solution, for the tumescence, did not seem to alter the efficacy of the sclerotherapy when compared with the use of Ringer alone.

Side effects such as pigmentation, matting, and cutaneous necrosis seemed to have occurred slightly more frequently in comparison to their occurrence after conventional sclerotherapy. This led the author to use a concentration of 0.25% rather than 0.5% POL and not to advise this procedure as a first resort. Reinforcement of the sclerosing action can be explained by the endoluminal blood emptying obtained thanks to the intra-tissular compression exercised by the tumescence fluid; consequently, contact between the sclerosing agent and the venous endothelium will be improved.

The encouraging results noted should be an incentive for the performance of other clinical studies in order to determine the real place for this procedure.

Comments The empirical interest of tumescence is known for such treatments of varices as surgery, thermal ablation, isolated sclerotherapy, or sclerotherapy associated with thermal or surgical treatment.

The effect sought is an anesthetic action and/or a reduction in the vein caliber using an endovenous blood emptying that is particularly useful for chemical or thermal ablation of large-diameter veins, since a significant volume of blood adversely affects the efficacy of the sclerosing agent or the thermal energy.

The use of the tumescence for the sclerosing treatment of C1 veins was not described, but this is now a fait accompli, thanks to this paper. Despite narrow veins (less than 1 mm for telangiectasias) and a blood emptying that is easily obtained and visible during conventional sclerotherapy, tumescence would appear to reinforce the efficacy of the sclerosing agent even with these indications.

An increase in side effects, however, such as pigmentation, matting, and cutaneous necrosis has been observed.

This caused the author to reduce the concentration of POL from 0.5% to 0.25% for the sclerosing foam, in order to obtain a reduction in undesirable side effects.

POL could possibly be used even at a concentration of 0.12%; in our personal experience, this is the concentration

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that we currently use for treating telangiectasias with sclerosing foam. As for C2 veins, when performing foam sclerotherapy accompanying thermal ablation of the saphenous vein under tumescence, we reduce the concentrations of the sclerosing agent to half the amount we use normally. We also limit the volumes and the injection points, and we even often postpone the sclerotherapy itself.

In fact, even though the pathophysiological explanation is not completely clear, there are frequent inflammatory reactions in this context.

The author also advises not using the START protocol as the first resort on C1 veins, but rather reserving this procedure for C1 veins that

The author also advises not using the START protocol as the first resort on C1 veins, but rather reserving this procedure for refractory C1 veins...

are refractory to conventional sclerotherapy.

He rightly recalls that before C1 veins can be described as “refractory�, a clinical and Duplex-scan reassessment must be performed, so as to detect any feeding vein and reflux that may not have been detected in previous examinations.

Correct use of the Duplex-scan is a key element for success in sclerotherapy, even for telangiectasias.

In conclusion, this interesting preliminary study deserves to be followed up with prospective clinical studies, randomized if possible, that could target C1 as well as C2 veins. Such studies would thus make it possible, in the case of sclerotherapy, to establish indications of tumescence, methods of usage, and the advantages and disadvantages of the procedure.

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intellectual capital

/// UIP 2013 Call for Abstracts

World Meeting of the International Union of Phlebology /// September 8–13, 2013

Call For Abstracts The Scientific Committee of the International Union of Phlebology invites you to submit an abstract for consideration at the 2013 World Congress of the International Union of Phlebology, September 8–13, 2013 in Boston, MA. Please submit an abstract on any of the following topics:

+ BASIC SCIENCE + CCSVI + CHRONIC VENOUS INSUFFICIENCY AND VENOUS ULCERATION + COMPRESSION THERAPY + DEEP VENOUS THROMBOSIS + EPIDEMIOLOGY + LYMPHADEMA + MISCELLANEOUS

+ PELVIC VENOUS DISEASE - REFLUX & OBSTRUCTION + PHLEBOLOGIC NURSING + SUPERFICIAL VENOUS DISEASE » Venous Ablation » Sclerotherapy » Miscellaneous + VENOTONIC DRUGS + VENOUS DIAGNOSTICS + VENOUS MALFORMATIONS

Deadline for Submission is April 15, 2013 Abstracts must be submitted online and are limited to 250 words.

For additional details and to submit an oral or poster abstract for presentation at UIP 2013, please visit http://ww4.aievolution.com/acp1301/

510.346.6800 | www.uip2013.org | www.phlebology.org

Great saphenous varicose vein surgery without saphenofemoral junction disconnection P. Zamboni, S. Gianesini, E. Menegatti, G. Tacconi, A. Palazzo and A. Liboni British Journal of Surgery 2010; 97: 820–825 Contributing Editor/Reviewer: Attilio Cavezzi, MD Associate Editor: Eric Mowatt-Larssen, MD, FACPh, RPhS

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SUMMARY This case-control study compared two groups of varicose patients (100 patients per group) who had great saphenous vein (GSV) incompetence. According to colour-duplex ultrasound (CDU) pre-operative investigation, all cases presented with a typical condition (about 2/3 of the varicose patients in our experience) of GSV reflux and re-entry points located in one or more tributaries (not in GSV trunk). The reflux-elimination test (compression of incompetent tributaries just below their connection with saphenous trunk to see if GSV reflux is eliminated) was used to discriminate the re-entry points locations; and the terminal valve (TV) competence/incompetence was assessed placing the colour/Doppler sample on the common femoral vein side of the sapheno-femoral junction (SFJ).

Patients in group 1 had an incompetent TV at SFJ, whereas those in group 2 had a competent TV (i.e. no reflux from common femoral vein through TV). The two groups had no relevant differences as to CEAP, age, gender, disease duration.

All patients were treated by means of 1st step of CHIVA 2, which consists of hook phlebectomy of the varicose tributaries in their proximal tract and flush ligation + disconnection at the level of the connection between GSV trunk and the uppermost refluxing tributary emerging from GSV. SFJ treatment (high ligation) and/orGSV trunk treatment was not performed in any case.

At 1-month clinical and CDU follow-up, the results were good and comparable in the two groups, whereas at 1 year follow-up results started to have a clear trend in favour of group 2. Finally after 3 years, an independent assessor and the patients themselves judged the outcomes largely better in group 2 (limbs with TV competence). The CDUbased overall recurrence rate of GSV reflux was 14% in group 2, while in group 1 the recurrence rate was 82%. These differences were all statistically significant.

COMMENTARY In these years of fibres and foam, it is always nice to read about varicose vein surgery, even nicer is to read about CDU investigation as a fundamental tool to tailor a proper treatment for varicose patients. Unfortunately reimbursement-based medicine leads phlebologists to neglect the value of pre-operative CDU assessment and of tailored, more conservative treatments.

Conversely there is a lack of evidence on how CDU may positively influence the long-term outcomes and the cost/benefit ratio of whichever varicose vein therapy is used.

Anyway this article has the greatest merit to stress the importance of the saphenous TV in varicose vein disease.

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In fact several authors (Somjen, Abu-Own, Pieri) have focused on this issue since 20 years ago1.

Furthermore Cappelli demonstrated that TV competence corresponds to a mid-thigh GSV calibre below 5-6 mm in the vast majority of the cases, while GSV calibre over 7 mm is clearly associated with TV incompetence2. Yet this is the first sound demonstration about the achievement of adequate mid-term outcomes without any ablation/stripping of GSV trunk, in the presence of a competent TV .

The results shown by Zamboni’s article are consistent with those obtained by Escribano et al at a similar follow-up3.

...the phlebology community has probably found a definitive confirmation of the importance of GSV TV..

What phlebectomy + primary incompetent tributary disconnection achieves in the vast majority of the cases, after one-to-six months, is the abolition of GSV trunk reflux and the GSV calibre reduction, due to the abolition of the re-entry veins (abolition of the varicose network and thus reduction of compliance) and the subsequent favourable hemodynamic changes. Invariably, and unfortunately, this is a transient finding, as GSV calibre/ reflux tend to return to the antecedent morphologic/hemodynamic condition after a few months or very few years.

The current trend towards a more conservative treatment is based on CDU investigation, hence mini-invasive/less expensive treatments (such as phlebectomy and foam sclerotherapy) should be regarded as an interesting option if the decision process is based on cost/benefit ratio.

Through this article the phlebology community has probably found a definitive confirmation of the importance of GSV TV (hence of GSV calibre accordingly ..) in terms of prognosis for those who leave the GSV in situ (ablated or not).

Unfortunately this is not a randomized controlled trial, yet the evidence we may draw from this clinical series is of high enough quality to let us re-think the way we approach GSV treatment nowadays. In fact some 50% of our

1 Coleridge-Smith P, Labropoulos N, Partsch H, Myers K,Nicolaides A, Cavezzi A. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs – UIP consensus document. Part I. Basic principles. Eur J Vasc Endovasc Surg 2006; 31: 83–92.

2 Cappelli M, Molino Lova R, Ermini S, Zamboni P. Hemodynamics of the sapheno-femoral junction. Patterns of reflux and their clinical implications.

Int Angiol 2004; 23:25–28 3 Escribano JM, Juan J, Bofill R, Maeso J, Rodrıguez-Mori A, Matas M. Durability of reflux-elimination by a minimally invasive CHIVA procedure on patients with varicose veins. A 3-year prospective case study. Eur J Vasc Endovasc Surg 2003; 25: 159–163

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patients may have a competent TV1,2, which could lead to a saphenous-sparing treatment in many cases.

At later stages of saphenous disease, TV incompetence (and larger GSV calibre) will be invariably more frequent and possibly a more “aggressive� treatment is a due option, notwithstanding a few studies proved that conservative treatments may achieve interesting results also in these advanced cases4.

In fact we have limited data on long-term outcomes of GSV chemical or thermal ablation, while stripping seems to result in suboptimal results, especially in non-expert hands. It is of notice also that nearly the totality of the past (and present?) trials on GSV ablative therapy do not take in consideration pre-operative TV hemodynamics. This fact spoils the possibility to differentiate and understand more comprehensively mid-long-term outcomes as to one possible cause of recurrence5.

As a matter of fact the authors are to be congratulated for their effort to illuminate a bit our decisional process when treating GSV. Hopefully new, long-term and randomised clinical trials, based on a thorough prepostoperative CDU investigation, will define the criteria for the proper indications of varicose vein treatment.

4 Carandina S, Mari C, De Palma M, Marcellino MG, Cisno C, Legnaro A et al. Varicose vein stripping vs haemodynamic correction (CHIVA): a long term randomised trial. Eur J Vasc Endovasc Surg 2008; 35: 230–237 5 De Maeseneer M., Cavezzi A , Etiology and pathophysiology of varicose vein recurrence at the saphenofemoral or saphenopopliteal junction: an update. Veins and Lymphatics DOI:10.4081/vl.2012.e4 http://www.pagepressjournals.org/index.php/vl/article/view/vl.2012.e4 . Last access Sept 2nd, 2012

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Spray-applied cell therapy with human

allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, doubleblind, randomised, placebocontrolled trial

Robert S Kirsner, William A Marston, Robert J Snyder, Tommy D Lee, D Innes Cargill, Herbert B Slade The Lancet. Published online August 3, 2012 (http://dx.doi.org/10.1016/S0140-6736(12)60644-8) Contributing Editor/Reviewer: Giovanni Mosti, MD Associate Editor: Mark Forrestal, MD, FACPh

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SUMMARY Phase 2, multicentre, randomised, placebo-controlled trial including 205 out patients from 28 centres in the USA and Canada affected by hard-to-heal venous leg ulcers and randomly divided into 4 groups. Three groups were treated with different concentration and dosing frequencies of HP802-247 a novel spray-applied cell therapy containing growth-arrested allogeneic neonatal keratinocytes and fibroblasts; the fourth group with the vehicle alone (control group). Aim: to investigate HP802-247 for benefit and harm when applied to chronic venous leg ulcers.

Due to some drop out, results include 188 patients: 45 patients were assigned to 5·0×106 cells per mL every 7 days, 44 to 5·0×106 cells per mL every 14 days, 43 to 0·5 ×106 cells per mL every 7 days, 46 to 0·5 ×106 cells per mL every 14 days, and 50 to vehicle alone. The primary outcome analysis showed significantly greater mean reduction in wound area associated with active treatment compared with vehicle (p=0·0446), with the dose of 0·5 ×106 cells/mL every 14 days showing the largest improvement compared with vehicle (15·98%, 95% CI 5·56–26·41, p=0·0028). Adverse events were much the same across all groups, with only new skin ulcers and cellulitis occurring in more than 5% of patients.

In conclusion venous leg ulcers can be successfully treated with a spray formulation of allogeneic neonatal keratinocytes and fibroblasts at an optimum dose of 0·5×106 cells per mL every 14 days.

COMMENT This well-designed phase 2 trial is an important contribution to the attempts to improve the healing rate in patients with hard-to-heal venous ulcers. The enrollment was correct, inclusion and exclusion criteria well defined, the treatment protocol well explained and effective; statistical analysis extremely complete. The results show the effectiveness of the treatment compared to the control group with a higher effectiveness for the group with the lower cells concentration and the higher time interval in application; anyway the difference between the three treatment groups was small. The discussion is well focused on the results, clear and exhaustive.

Nevertheless the authors treated venous ulcers “which measured between 2 cm2 and 12 cm2 in area without exposed tendon, muscle, or bone”. It is well know that the longer the ulcer duration the longer the healing time1; in this trial wound duration ranged from 6 to 104 weeks but only 28% ranged from 1 to 2 years. No information on previous treatment was provided especially with regard to compression therapy. All the main factors potentially delaying healing were correctly excluded during patients’ enrollment. All this data can raise the doubt if these were really hard-to heal ulcers or if good compression treatment could have healed the great majority of them.

Compression treatment is still the best therapeutical option for pure venous ulcer treatment and this is especially true if all the factors potentially preventing healing are excluded. Unfortunately almost all the trials on compression treatments of venous ulcer have a huge flaw represented by the lack of compression pressure measurement that represents the dosage of this treatment and is the only determinant of compression effectiveness. Almost all these studies, including this one, just refer to “experienced personnel” who applied compression. As was clearly shown

1 Margolis DJ, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol. 1999 Aug;135(8):920-6.

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by Keller2 ”experienced personnel” is meaningless since, in her study, 77% of bandages applied with an inadequate pressure range were applied by “nurses with more than 10 years of working experience”. So, many experienced bandage applicators are very experienced in applying a poor, ineffective bandage. As a consequence the actual effectiveness of good compression is certainly underestimated. Nevertheless the usefulness of compression in ulcer treatment is widely accepted and the level of evidence is graded 1A3.

The effectiveness of compression must be always considered in evaluating every trial suggesting new treatment for venous ulcer treatment as compression certainly is the most cost-effective treatment and, furthermore, it must be included with all other treatment modalities that will, obviously, increase the costs. It must be also considered that when compression is adequately applied in venous ulcer treatment, with achievement of the target pressure4, 5, the healing rate is extremely high, certainly much higher than that reported in Cochrane review6 also considering poorly applied compression devices.

It is of considerable interest that in the Milic study4 that included patients with larger and older ulcers and with previous DVT, all of which are known to worsen the healing time expectation (36% of cases), the unique treatment with compression produced a healing rate that was about the same as in this trial and in the Mosti study5 including patients

As a consequence

with the same clinical characteristics as in this trial, the healing rate achieved by compression alone was even higher.

In this trial no information on cost-effectiveness of the

the actual

treatment was provided. The result shows that the best

effectiveness

the longest time interval of application. It is conceivable that

of good

But analysing the Kaplan-Meier survival curves the healing time

compression

mL every 14 days) while “differences between vehicle and other

outcome was achieved with the lower cell concentration and the global cost of this treatment will not be extremely high. was 21 days shorter with the best treatment (0·5 ×106 cells per active groups were not significant”.

is certainly underestimated.

It would be really interesting to know if, in terms of costeffectiveness, treatment is worthwhile to shorten the healing time only by 20 days.

2 Keller A, Müller ML, Calow T, Kern IK, Schumann H. Bandage pressure measurement and training: simple interventions to improve efficacy in compression bandaging. Int Wound J. 2009 Oct;6(5):324-30.

3 Partsch H, ed. Evidence based compression therapy. Vasa. 2003;32 (63 Suppl)1-39.

4 Milic DJ, Zivic SS, Bogdanovic DC, Jovanovic MM, Jankovic RJ, Milosevic ZD, Stamenkovic DM, Trenkic MS.The influence of different sub-bandage pressure values on venous leg ulcers healing when treated with compression therapy. J Vasc Surg. 2010 Mar;51(3):655-61.

5 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.

6 O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers (Review). The Cochrane Library 2009, Issue 1.

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Finally it is not easy to understand the number of adverse events: 194 in a case series of 188 patients. Even if many of them were maybe not treatment-related (nervous system disorder, psychiatric disorder, respiratory disorder, vascular disorder, vomiting) there was a not negligible number of cellulitis and new ulcers whose appearance is certainly unusual when good compression is used in patients with venous insufficiency.

In conclusion all therapeutic strategies improving the healing rate of hard-to-heal ulcers are welcome and every research effort is extremely useful in this field. But every new treatment should be beneficial in really hard-to-heal ulcers, meaning, in my opinion, ulcers that are larger and of longer duration “despite correct pre-trial treatment�, or those ulcers associated with comorbidities of different pathophysiology; i.e., arterial, mixed, inflammatory, immunologic ulcers.

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Sleep Apnea and Risk of Deep Vein Thrombosis: A Nonrandomized, Pair-matched Cohort Study Kun-Ta Chou, MD et al.

Contributing Editor/Reviewer: AndrĂŠ Cornu-Thenard, MD, FACPh Associate Editor: Stephanie Dentoni, MD

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Summary of the paper After having described the precise meaning of sleep apnea (SA), in 90% of cases resulting from repetitive collapse of the upper airway (obstructive sleep apnea - OSA) the authors give us the reasons why they did this study, the huge work to get the population, the great results and some important remarks.

In some papers patients with SA have been reported to be associated with increased prevalence of deep vein thrombosis (DVT). However the material and method was criticized: too small sample size and lack of control. The aim of their study was to explore the relationship of sleep apnea and the subsequent development of DVT using a nationwide, population-based database.

The method they used was to identify a study cohort consisting of newly diagnosed sleep apnea cases in the National Health Insurance Research Database.

A control cohort without sleep apnea, matched for age, sex, co-morbidities, major operation, and so on, was selected for comparison. The 2 cohorts were followed-up, and the occurrence of DVT by registry of DVT diagnosis was observed.

The results indicate that of the 10,185 sampled patients, 40 cases developed DVT during a mean follow-up period of 3.6 years, including 30 (0.53%) from the SA cohort and 10 (0.22%) from the control group. Subjects with SA experienced a 3.113-fold increase in incident DVT, which was independent of age, sex, and co-morbidities. KaplanMeier analysis also revealed the tendency of SA patients toward DVT development. The risk of DVT was even higher in SA cases requiring continuous positive airway pressure treatment.

In conclusion, SA may be an independent risk factor for DVT.

Comments by AndrĂŠ Cornu-Thenard MD Positive point of view

Authors in their study identified SA as an independent risk factor for future development of DVT using a largescale nationwide database, which supports the concept that SA may contribute to the formation or progression of thrombosis in venous circulation. It is a real improvement. In fact they have used a very large sample. The only way to get these patients and a prospective control was to work with a Health Insurance and their research database.

They studied more than 20 signs like demographic data, age, pregnancy, diabetes, hypertension, continuous positive airway pressure, etc. which is a major work.

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Negative point of view

On the other hand the relationship with DVT has been previously studied by other authors. The two prospective observational studies had concluded that a possible link of OSA and DVT existed. However the sample size was too small or the control group was missing. But to forget them is not logical, so perhaps it could be a good idea to continue this kind of personal studies and to put them together in one work.

The relationship between SA and arterial thrombotic events such as coronary artery diseases and cerebrovascular accidents is known. Now we know that SA is an independent risk factor for DVT.

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The efficiency of pain control using a thigh pad under the elastic stocking in patients following venous stripping: results of a case-control study.

Benigni JP, Allaert FA, Desoutter P, CohenSolal G, Stalnikiewicz X. Perspect Vasc Surg Endovasc Ther. 2011 Dec;23(4):238-43.

Contributing Editor/Reviewer: Hugo Partsch MD, FACPh Associate Editor: Mitchel Goldman, MD, FACPh

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In this case control study 3 centres recruited a total of 53 patients undergoing stripping of the great saphenous vein. All patients received one compression stocking (thigh length, 15-20 mmHg at ankle level) for the night and applied a second stocking over it during day time. In 36 patients a newly designed wedge-shaped rubber foam pad was put under these stockings along the stripping canal, 17 got no pad (control group). For the duration of one week daily pain intensity was assessed using a visual analogue scale. On day 1, pain was 40.8 ± 20.8 in the control group and 27.4 ± 24.2 in the pad group (P = .05). On day 7, pain was 15.3 ± 13.4 in the control group and 3.7 ± 5.5 in the pad group (P < .0001) . Measuring the area under the timeintensity curve over 7 days a global mean pain score was calculated, which was reduced by 49% in the pad-group compared to the control-group.

Comment:

Fig. 1: MRI cross- section at mid thigh level in the standing position in a patient before GSV surgery wearing a compression stocking under which Benigni’s pad is fixed by tapes (left) .(Pressure under the pad: 66 mmHg.) The tissue deformation by the pad is clearly visible, the arrow points to the collapsed GSV. (Examination performed together with A. Mosti in the ESAOTE labs, Genova).

This study demonstrating significant pain reduction after stripping of the great saphenous vein (GSV) by using eccentric compression is in excellent agreement with a previous report by M. Lugli and co-workers showing a comparable pain-relieving effect after laser abolition1.In this latter randomized trial the authors applied tapes in a cross-wise fashion over their cotton- wool pads, thereby increasing the local pressure and preventing a dislocation of the device during walking. 100 patients were treated with stockings and pads, 100 with stockings alone.

According to the law of Laplace the compression pressure exerted on an extremity is directly proportional to the stretch of the material and indirectly proportional to the radius of the extremity. By applying a roll to the leg the local radius will decrease and the local pressure will increase (“eccentric compression”). The increase of pressure depends also on the compressibility of the padding material which is very low for the pads used by Benigni and colleagues.

Using special blood pressure cuffs, transparent for Duplex- ultrasound, we were able to demonstrate that the median pressure needed to occlude the GSV at mid-thigh level in the standing position is around 70 mmHg, which can be reduced to 50 mmHg when water-filled pads are applied under the compression cuff2 . Cross sectional MRI of the thigh performed in the standing position showed a collapse of the GSV under the same wedge-like pad as used by Benigni and co-workers applied under a compression stocking (Fig 1). The local pressure

1 Lugli M, Cogo A, Guerzoni S, Petti A, Maleti O. Effects of eccentric compression by a crossed-tape technique after endovenous laser ablation of the great saphenous vein: a randomized study. Phlebology. 2009 Aug;24(4):151-6.

2 Partsch B, Partsch H. Which pressure do we need to compress the great saphenous vein on the thigh? Dermatol Surg. 2008 Dec;34(12):1726-8.

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under the pad was 66 mmHg 3.

Strong compression after stripping is not only able to reduce pain but also hematoma formation. Comparing bandages and stockings after GSV stripping we found the best results with respect to the reduction of pain and hematoma when eccentric compression pads were taped to the skin of the thigh and a compression stocking was worn on top4.

Even more important than the subjective feeling of pain which is only a problem in the first days after surgery are potential long term consequences:

Postoperative hematoma in the strip track is a source for revascularisation5 6 so that a reduction of bleeding might have important implications also concerning recurrence of varicose veins. It is unknown if hematomas occasionally seen after laser ablation as well could have a similar potential.

Benigni`s study is one of several trials showing undoubtedly a beneficial effect of sufficient compression concerning the reduction of adverse events, namely of pain. However, studies showing a positive effect of proper compression on the objective outcome after varicose vein abolition, e.g. regarding recurrence, are still sparse7.

3 Partsch H, Mosti G. Thigh compression. Phlebology. 2008;23(6):252-8.

4 Mosti G, Mattaliano V, Arleo S, Partsch H. Thigh compression after great saphenous surgery is more effective with high pressure.Int Angiol. 2009 Aug;28(4): 274-80.

5 Munasinghe A, Smith C, Kianifard B, Price BA, Holdstock JM, Whiteley MS. Strip-track revascularization after stripping of the great saphenous vein. Br J Surg. 2007;94:840-3 6 Mitchel G, Rosser S, Edwards PR, Dimitri S, de Cossart L. Vascularisation of the haematoma tract following long saphenous vein stripping: a new cause of recurrent varicose veins. Phlebology 2003;18:48 7 Travers JP, Makin GS. Reduction of varicose vein recurrence by use of postoperative compression stockings. Phlebology. 1994;9:104-9

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