forum

Can foam sClerotherapy

be used to safely treat bilateral variCose veins?

page 7

sClerotherapy in tumesCent

anesthesia of retiCular

veins and telangieCtasias

page 11

J u l - s e p 2 0 1 2

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From the Editor-in-Chief

dr. nick morrison 5

Sleep Apnea and Risk of Deep Vein Thrombosis: A Nonrandomized, Pair-matched Cohort Study

Contributing editor/reviewer: andré Cornu-thenard, md, faCph

associate editor: stephanie dentoni, md 23

Sclerotherapy in tumescent anesthesia of reticular veins and telangiectasias

Contributing editor/reviewer: Claudine hamel-desnos, md

associate editor: pauline raymond-martimbeau, md, faCph 11

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

Contributing editor/reviewer: lorenzo tessari, md

associate editor: sukirtharan sinnathamby, md, faCC, fsCai, rvt 7

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: hugo partsch, md, faCph

associate editor: mitchel goldman, md, faCph 26

Great saphenous varicose vein surgery without saphenofemoral junction disconnection

Contributing editor/reviewer: attilio Cavezzi, md

associate editor: eric mowatt-larssen, md, faCph, rphs 15

Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trialContributing editor/reviewer: giovanni mosti, md

associate editor: mark forrestal, md, faCph 19

co

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nts

jul-

se

p ‘1

2

4

disclosureof 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; servier-eutherapie: 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

5

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

510.346.6800 • www.acpcongress.org

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

advancing vein care

Phlebology Takes its Place in the SunJoin 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.

• 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.

TOP REASONS TO ATTEND THE ACP ANNUAL CONGRESS

7

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

8

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:

9

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.

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

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

10

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.

11

Sclerotherapy in tumescent anesthesia of reticular veins and telangiectasiasAuthor: 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

12

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

13

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

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.

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...

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

intellectual capital/// UIP 2013 Call for Abstracts

Call For AbstractsThe 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:

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

+ 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

15

Great saphenous varicose vein surgery without saphenofemoral junction disconnectionP. 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

16

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 Cdu-

based 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.

17

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.

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

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

18

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 pre-

postoperative 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

19

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

20

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.

21

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

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

treatment was provided. the result shows that the best

outcome was achieved with the lower cell concentration and

the longest time interval of application. it is conceivable that

the global cost of this treatment will not be extremely high.

but analysing the Kaplan-meier survival curves the healing time

was 21 days shorter with the best treatment (0·5 ×106 cells per

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

active groups were not significant”.

it would be really interesting to know if, in terms of cost-

effectiveness, 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.

As a

consequence

the actual

effectiveness

of good

compression

is certainly

underestimated.

22

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.

23

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

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

Associate Editor: Stephanie Dentoni, MD

24

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. Kaplan-

meier 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 ANDRé 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 large-

scale 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.

25

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.

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, Cohen-

Solal 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

26

27

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 time-

intensity 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:

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.

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).

28

under the pad was 66 mmhg3.

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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