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EDITORIALGuidelines in chronic venous disease: providing clinicians with betterdecision-making tools. Directives sur l’insuffisance veineuse chronique :fournir aux cliniciens de meilleurs outils de décisionA. J. Comerota, USA

THEMED ARTICLESUpdating guidelines in chronic venous disease: what is needed?C. Allegra, Italy

Chronic venous disease guidelines and terminology:sharing a common languageM. R. Perrin, France, and B. Eklöf, Sweden

Prevalence and socioeconomic data in chronic venous disease:how useful are they in planning appropriate management?D. J. Milic, Serbia

Treatment of chronic venous disease: pathophysiological underpinningsR. D. Malgor, N. Labropoulos, USA

Classifications, severity scorings, and chronic venous disease guidelinesM. Kurtoglu, M. Aksoy, Turkey

Current status of patient-reported outcomes and chronicvenous disease guidelinesA. Mansilha, Portugal

Rating the quality of evidence and the strength of recommendations:the new GRADE system in venous diseaseG. Le Gal, Z. Alavi, France

European and American guidelines on primary chronic venous disease:what’s new?J.-L. Gillet, France

A S e r v i e r p u b l i c a t i o n

MedicographiaVol 33, No. 3, 2011

108Chronic venous disease

guidelines anddaily clinical practice

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CONTROVERSIAL QUESTIONAre chronic venous disease guidelines adapted to daily practice?K. A. Aal, Egypt - H. S. Caldevilla, Argentina - R. Costa-Val, Brazil -H. S. Yuwono, Indonesia - H. N. T. H. Le, Vietnam - S. M. Kulisic,Croatia - A. Puskás, Romania - K. Roztocil, Czech Republic -M. Salah, Saudi Arabia - I. S. Escotto, Mexico - J.-F. Uhl, France -I. A. Zolotukhin, Russia

DAFLON 500 MGThe place of Daflon 500 mg in recent guidelines on the management ofchronic venous diseaseF. Pitsch, France

INTERVIEWAre we any better at identifying the risk factors for chronic venousdisease progression?M. Flour, Belgium

FOCUSIdentifying and accessing patients with chronic venous disease:the large-scale VCP International StudyE. Rabe, Germany

UPDATEPain in chronic venous disease: perspectives for researchN. Danziger, France

A TOUCH OF FRANCETheory and practice: European Renaissance medicineS. Daynes-Diallo, France

Écouen: from château to museum, or Beauty is in the detailS. Deprouw, France

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Guidelines in CVD: providing clinicians with better decision-making tools – Comerota MEDICOGRAPHIA, Vol 33, No. 3, 2011 231

Chronic venous disease (CVD) is the most prevalent vascular disorder indeveloped countries1,2 and it may be the single most common chronicdisease overall. Therefore, standard descriptors of the disease—its loca-tion, presentation, etiology, pathophysiology, impact on patients, re-

sponse to therapy, and cost—are crucial, if not mandatory. Reporting standardsand guidelines for the above measures organize patient evaluation and treatment,standardize nomenclature, and offer tools to evaluate the severity, natural history,and response to treatment of the disease. Unfortunately, the reporting of outcomesof therapy for venous disease has lagged behind other disease categories.3 Dur-ing the past several years, there has been growing interest in the development ofguidelines for venous anatomy (nomenclature),4 the description of patient presen-tation,5 the severity of venous disease,6-8 and the outcome measures followingtherapy.9,10

Use of guidelines for disease description and measurement of treatment outcomesis the first step in the process of implementing evidence-based care. Evidence-based medicine has been defined as “the conscientious, explicit, and judicioususe of the current best evidence in making decisions about the care of individualpatients.”11

This article highlights areas of standardized nomenclature, patient presentation,severity of venous disease, and standardized and validated outcome measuresfollowing therapy. It is hoped that all physicians will incorporate these guidelinesinto their clinical care of patients with CVD.

Need for standard definitionsFor many years, the description of patients with venous disease and measurementof outcomes were subjective and arbitrary. Ambiguity in clinical descriptors led toconfusion and misunderstanding. Standardized nomenclature is the first step todeveloping clear, objective documentation and communication regarding patients,disease status, and outcome measures.

� Anatomic nomenclatureGuidelines for venous disease must begin with a standard nomenclature regard-ing the anatomy of the venous system. Until 2002, the veins of the lower extrem-ity were often incorrectly characterized, and physicians used numerous eponymsto refer to specific veins. Caggiati et al4 made an important contribution to the fieldwhen they proposed a standard international nomenclature for the veins of the low-

Anthony J. COMEROTAMD, FACS, FACCUniversity of MichiganMichigan; Jobst Vascular CenterThe Toledo HospitalToledo, Ohio, USA

Address for correspondence:Anthony J. Comerota, MD, FACS,Jobst Vascular Center,2109 Hughes Dr Suite 400,Toledo, OH 43606, USA (e-mail:[email protected])

Medicographia. 2011;33:231-237.

www.medicographia.com

Guidelines in chronicvenous disease: providing

clinicians with betterdecision-making tools

by A. J . Comerota , USA

EDITORIALFor many years, the descrip-

tionof patientswith venous diseaseand measurement of outcomeswere subjective and arbitrary. Am-biguity in clinical descriptors ledto confusion and misunderstand-ing. Standardized nomenclature isthe first step in developing clear,objective documentation and com-munication regarding patients, dis-ease status, and outcome meas-ures. Guidelines for venous diseasemust beginwith a standard nomen-clature regarding the anatomy ofthe venous system.”

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er extremity. Examples of their contribution include precisedefinitions of perforating veins, which penetrate the muscu-lar fascia to connect superficial veins to deep veins, andcommunicating veins, which connect veins within the samecompartment.

A major misnomer that existed for decades was the term“superficial femoral vein,” referring to the major deep vein ofthe thigh that connects the popliteal vein to the commonfemoral vein. That vein is now appropriately termed the femoralvein. Noninvasive imaging has led to our increased under-standing of the saphenous subcompartment and saphe-nous fascia. Standardization of the terms “great saphenousvein” and “small saphenous vein” has added greater clarityto the superficial venous nomenclature.

The saphenofemoral junction, previously a major point of con-tention, is now called the confluence of the superficial inguinalveins, which refers to that segment of the great saphenousvein extending from the inferior epigastric vein to its junctionwith the common femoral vein.

International nomenclature has discarded eponyms and re-named veins appropriately, according to proper anatomicterms, eg, by replacing the name “vein of Giacomini” with “in-tersaphenous vein.”

This international nomenclature consensus statement4 is animportant reference that allows us to ensure that a standard-ized nomenclature is incorporated into all our communicationregarding patient care, clinical studies, and reports of patientoutcomes.

Standardizing investigationsTools are necessary to build strong and enduring structures.With few exceptions, the better the tools available, the morerapidly the job is done and the more enduring the product.Investigative tools have been developed to describe, char-acterize, and monitor the outcome of venous disease. Per-haps the most important metric is patients’ view of how the

disease has affected their life. Just as no single tool can builda large and durable building, no single tool fully meets theinvestigative needs in CVD.

It is appropriate to identify what is needed and then to choosethe appropriate instrument. Instruments can be broadly cat-egorized into discriminative and evaluative instruments. Adiscriminative instrument is one that clearly describes thepatient (current status of venous disease) and is capable ofidentifying differences between patients, whereas evaluativeinstruments are designed to detect changes over time, eitherdeterioration due to disease or improvement with treatment.12

Perhaps the best discriminative instrument available is theCEAP (Clinical-Etiological-Anatomical-Pathophysiological)classification. The CEAP classification describes the clinicalseverity of a patient’s venous disease, its etiology, its anatom-ic location, and the patient’s underlying pathophysiology.5 Pa-tients presenting with venous disease should be classified ac-cording to the CEAP classification.

One potential weakness of current discriminative instrumentsis our inability to identify and quantify venous obstruction. Sincenoninvasive evaluation of venous disease is now standardfor most patients, we know that imaging methods under-state the magnitude of venous luminal obstruction (short ofshowing venous occlusion), with the possible exception ofintravascular ultrasound. Noninvasive physiological testingusing maximal venous outflow techniques are notoriously in-sensitive at detecting venous obstruction13; much more workis required to identify a noninvasive method to more clearlydelineate this element of venous pathophysiology.

Other deficiencies include our inadequate understanding ofthe effects of venous disease on the microcirculation and whymicrocirculatory dysfunction occurs in some patients and notin others. This likely explains why there are different clinicalvenous categories of CVD in patients with similar venous he-modynamics.14 It becomes evident that until we develop di-agnostic techniques to assess these important end points,classification systems that include pathophysiology as partof their description will remain potentially inaccurate if not mis-leading.

A number of good evaluative instruments exist that can mon-itor changes in patients’ status over time and are responsiveto disease progression or therapeutic intervention. Each in-strument should be carefully studied to ensure that it is valid(capable of quantifying what it is intended to measure), reli-able (produces consistent results when used repeatedly onstable subjects), and responsive (capable of detecting clini-cally important changes).12 Two of the better evaluative instru-ments are the Venous Clinical Severity Score (VCSS)6,15 andthe Villalta scale.7,16 Other evaluative instruments focus on pa-tients’ quality of life, arguably the most important outcome of

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SELECTED ABBREVIATIONS AND ACRONYMS

CEAP Clinical-Etiological-Anatomical-Pathophysio-logical

CIVIQ-20 ChronIc Venous dIsease quality of lifeQuestionnaire [20]

CVD chronic venous diseaseSF-36 Short Form 36 [health survey]VCSS Venous Clinical Severity ScoreVDS Venous Disability ScoreVEINES-QOL VEnous INsufficiency Epidemiological and

economic Study–Quality Of LifeVSDS Venous Segmental Disease Score

all. Examples include the SF-36 (Short Form 36 [health sur-vey]),17,18 VEINES-QOL (VEnous INsufficiency Epidemiologicaland economic Study–Quality Of Life),11 CIVIQ-20 (ChronIcVenous dIsease quality of life Questionnaire [20]),19 and Ab-erdeen questionnaires.20

Adjuncts to the VCSS are the Venous Segmental DiseaseScore (VSDS) and the Venous Disability Score (VDS).21 TheVSDS is designed to anatomically localize venous diseaseand describe whether the identified segment has reflux or isobstructed. Points have been arbitrarily assigned for eachsegment. The VSDS has not yet been validated, and it is like-ly that further modification will be required after appropriateprospective clinical studies are performed.

The VDS is a 4-point scale (4 categories) of disability rangingfrom 0 (asymptomatic) to 3 (unable to carry out usual activ-ities, even with compression and/or limb elevation). Like theVSDS, the VDS requires validation. However, in light of itsbroad categories and their limited number, the VDS is likelyto be insensitive as an evaluative instrument and more ap-propriately used as a descriptive measure.

Guidelines and the treatment of CVDObjective outcome measures and guidelines for the manage-ment of patients with venous disease are more important nowthan ever and will assume even greater importance in thefuture. Management of patients with CVD is rapidly evolvingfrom open surgical procedures to endovascular techniques.In patients with the most complex forms of CVD, hybrid pro-cedures that include both open and endovascular compo-nents are being performed.22 To assess whether a particulartreatment is appropriate, reliable, standardized, and objective,evaluation instruments are required. These should be prospec-tively applied to all patients; that is, prior to treatment, patientsshould be objectively classified according to the CEAP classi-fication and a validated quality-of-life instrument and a goodevaluative instrument should be used. Following treatmentat appropriate time intervals, evaluative and quality-of-life

measures should be repeated. These objective measurescan then be assessed and integrated into a cost analysis todetermine the true value of a treatment for specific patientgroups.

Handbook of Venous Disorders: Guidelines ofthe American Venous ForumAn excellent source of guidelines for the clinician to follow isthe 3rd edition of the Handbook of Venous Disorders: Guide-lines of the American Venous Forum, edited by Peter Glovi-czki, MD.23 This is perhaps the best single volume of guide-lines for the management of venous disease available today.The handbook, comprised of 65 chapters divided into sevensections, contains the latest information on epidemiology, ba-sic science, and investigation of venous and lymphatic dis-eases, as well as modern venous imaging techniques. Bothacute and chronic venous diseases are covered, and the in-creasing enthusiasm for minimally invasive and endovenoustechnology is appropriately addressed.

Perhaps the most important and enduring aspect of this vol-ume is the addition to each chapter of evidence-based clin-ical guidelines regarding the evaluation and management ofvenous disease. Evidence scores are given to assist the read-er in assessing the strength of the evidence and the grade ofrecommendation. In the final chapter, the volume culminateswith a list of all the evidence-based guidelines of the Ameri-can Venous Forum.

SummaryThe important topics inMedicographia No.108 are addressedin a timely manner by an international collection of experts fo-cusing on areas of venous disease in which they have a spe-cial interest and have made major contributions. The spe-cific topics are important for all of us to recognize, as they willhave practical implications for the care of patients with CVDas wemove forward. I recommend this issue ofMedicographiato each of you and I am sure you will find it as valuable as Ihave. �

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References1. Task Force on Chronic Venous Disorders of the Leg. The management of chron-

ic venous disorders of the leg: an evidence-based report of an international taskforce. Phlebology. 1999;14(suppl 1):1-126.

2. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venousinsufficiency. Angiology. 2001;52(suppl 1):S5-S15.

3. Rutherford RB. Vascular surgery—comparing outcomes. J Vasc Surg. 1996;23:5-17.

4. Caggiati A, Bergan JJ, Gloviczki P, Jantet G, Wendell-Smith CP, Partsch H.Nomenclature of the veins of the lower limbs: an international interdisciplinaryconsensus statement. J Vasc Surg. 2002;36:416-422.

5. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification forchronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-1252.

6. Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH,Moneta GL. Venous severity scoring: An adjunct to venous outcome assess-ment. J Vasc Surg. 2000;31:1307-1312.

7. Villalta S, Bagatella P, Piccioli A, Lensing AW, Prins M, Prandoni P. Assessmentof validity and reproducibility of a clinical scale for the post-thrombotic syn-

drome. Haemostasis. 1994;24:158a. Abstract.8. Gillet JL, Perrin MR, Allaert FA. Clinical presentation and venous severity scor-

ing of patients with extended deep axial venous reflux. J Vasc Surg. 2006;44:588-594.

9. Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-relat-ed quality of life after deep venous thrombosis. Arch Intern Med. 2002;162:1144-1148.

10. Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related qualityof life during the 2 years following deep vein thrombosis. J Thromb Haemost.2008;6:1105-1112.

11. Kahn SR, Lamping DL, Ducruet T, et al. VEINES-QOL/Sym questionnaire wasa reliable and valid disease-specific quality of life measure for deep venous throm-bosis. J Clin Epidemiol. 2006;59:1049-1056.

12. Guyatt G, Walter S, Norman G. Measuring change over time: assessing the use-fulness of evaluative instruments. J Chronic Dis. 1987;40:171-178.

13. Comerota AJ, Katz ML, Grossi RJ, et al. The comparative value of noninva-sive testing for diagnosis and surveillance of deep vein thrombosis. J Vasc Surg.1988;7:40-49.

14. Welkie JF, Comerota AJ, Katz ML, Aldridge SC, Kerr RP, White JV. Hemody-namic deterioration in chronic venous disease. J Vasc Surg. 1992;16:733-740.

15. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the ve-nous clinical severity score. J Vasc Surg. 2002;36:889-895.

16. Kahn SR. Measurement properties of the Villalta scale to define and classify theseverity of the post-thrombotic syndrome. J Thromb Haemost. 2009;7:884-888.

17. Ware JE Jr. The SF-36 Physical and Mental Health Summary Scales: A Ma-nual for Users of Version 1. 2nd ed. Boston: The Health Institute, New EnglandMedical Center; 2001.

18. Garratt AM, Ruta DA, Abdalla MI, Russell IT. Responsiveness of the SF-36 anda condition-specific measure of health for patients with varicose veins.Qual LifeRes. 1996;5:223-234.

19. Launois R, Mansilha A, Jantet G. International psychometric validation of the

chronic venous disease quality of life questionnaire (CIVIQ-20). Eur J Vasc En-dovasc Surg. 2010;40:783-789.

20. Garratt AM, Macdonald LM, Ruta DA, Russell IT, Buckingham JK, KrukowskiZH. Towards measurement of outcome for patients with varicose veins. QualHealth Care. 1993;2:5-10.

21. Rutherford RB, Padberg FR, Comerota AJ, Kistner RL, Meissner MH, MonetaGL. Venous Outcomes Assessment. In: Gloviczki P, Yao JS, eds. Handbookof Venous Disorders. 2nd ed. London, UK: Hodder Arnold; 2001:497-508.

22. Comerota AJ, Grewal NK, Thakur S, Assi Z. Endovenectomy of the commonfemoral vein and intraoperative iliac vein recanalization for chronic iliofemoralvenous occlusion. J Vasc Surg. 2010;52:243-247.

23. Gloviczki P, ed. Handbook of Venous Disorders. 3rd ed. London, UK: OxfordUniversity Press; 2009.

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Keywords: guidelines; chronic venous disease; decision-making

L’insuffisance veineuse chronique (IVC) est l’affection vasculaire la plus fré-quente dans les pays développés1,2, et pourrait constituer la pathologiechronique individuelle la plus fréquemment rencontrée. Par conséquent,les descriptions standard de la maladie, qui comprennent la localisation, le

tableau clinique, l’étiologie, la physiopathologie, l’impact sur les patients, la réponseau traitement et les coûts, sont essentielles, si ce n’est obligatoire. Les normes et lesdirectives de notification des paramètres précédents organisent l’évaluation et letraitement des patients, standardisent la nomenclature et offrent des outils d’éva-luation de la sévérité et de l’histoire naturelle de la maladie, ainsi que de la réponseau traitement. Malheureusement, l’expression des résultats thérapeutiques dansl’insuffisance veineuse est restée en retrait par rapport aux autres domaines pa-thologiques3. Au cours de ces dernières années, un intérêt croissant est né pour ledéveloppement de directives sur l’anatomie veineuse (nomenclature)4, la descrip-tion du tableau clinique5, la sévérité de l’insuffisance veineuse6-8, et la mesure desrésultats thérapeutiques9,10.

L’utilisation de directives pour la description de la maladie et la mesure des résultatsthérapeutiques est le premier pas dans le processus de mise en œuvre des soinsfactuels. La médecine factuelle est définie comme « l’utilisation consciencieuse,explicite et judicieuse des meilleures preuves actuelles dans la prise de décisionpour les soins prodigués aux patients11. » Cet article présente certains aspects d’unenomenclature standardisée, du tableau clinique, de la sévérité de l’insuffisance vei-neuse et des mesures standardisées et validées des résultats thérapeutiques. Il fautespérer que tous les médecins tiendront compte de ces directives dans les soinsqu’ils prodigueront à leurs patients atteints d’IVC.

Nécessité de définitions standardDepuis de nombreuses années, la description des symptômes de l’insuffisanceveineuse et la mesure des résultats thérapeutiques étaient subjectives et arbitraires.L’ambiguïté des descriptions cliniques a conduit à la confusion et à l’incompréhen-sion. Une nomenclature standardisée constitue la première étape pour développerune documentation et une communication claires et objectives sur les patients, lestade de la maladie et les critères d’évaluation.

� Nomenclature anatomiqueLes directives sur l’insuffisance veineuse doivent débuter par une nomenclaturestandard concernant l’anatomie du système veineux. Jusqu’en 2002, les veines desmembres inférieurs ont été souvent caractérisées de manière incorrecte, et les mé-

Directives sur l’IVC : fournir aux cliniciens de meilleurs outils de décision – Comerota MEDICOGRAPHIA, Vol 33, No. 3, 2011 235

Directives sur l’insuffisanceveineuse chronique : fourniraux cliniciens de meilleurs

outils de décision

par A. J . Comerota , États-Unis

ÉDITORIALLa description des symp-

tômes de l’insuffisance veineusechronique (IVC) et la mesure desrésultats thérapeutiques ont long-temps été subjectives et arbitraires.L’ambiguïté des descriptions cli-niques a conduit à la confusion etaux méprises. Une nomenclaturestandardisée,en particulier concer-nant l’anatomie du système vei-neux, constitue le préalable à unedocumentation et communicationclaires et objectives sur les pa-tients, le stade de la maladie et lescritères d’évaluation, et donc auxdirectives pour l’IVC »

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decins ont utilisé de nombreuses appellations éponymes pourdésigner certaines veines spécifiques. Caggiati et al.4 ont ap-porté une contribution importante à ce domaine en propo-sant une nomenclature internationale standard pour les veinesdes membres inférieurs. Citons par exemple dans cette contri-bution des définitions précises des veines perforantes, quipénètrent les aponévroses musculaires pour connecter lesveines superficielles aux veines profondes, et les veines com-municantes, qui connectent les veines appartenant au mêmecompartiment.

L’un des principaux termes impropres utilisés depuis des dé-cennies concernait la « veine fémorale superficielle », qui fai-sait référence à la principale veine profonde de la cuisse quiconnecte la veine poplitée à la veine fémorale commune. Cetteveine porte désormais l’appellation appropriée de veine fé-morale. L’imagerie non invasive a permis d’améliorer notreconnaissance du sous-compartiment saphène et de l’aponé-vrose saphène. La standardisation des termes « veine grandesaphène » et « veine petite saphène » a apporté une plusgrande clarté à la nomenclature des veines superficielles.

La jonction saphéno-fémorale, un point litigieux important au-paravant, est désormais dénommée « confluence des veinesinguinales superficielles », faisant ainsi référence au fait qu’unsegment de la veine grande saphène s’étend de la veine épi-gastrique inférieure jusqu’à sa jonction avec la veine fémoralecommune.

La nomenclature internationale a éliminé les éponymes et arenommé les veines de façon appropriée, en leur donnant destermes anatomiques propres, par exemple en remplaçant lenom de « veine de Giacomini » par « veine intersaphène ».

Cette déclaration de consensus concernant une nomencla-ture internationale4 est une référence importante qui nous per-met d’assurer qu’une nomenclature standardisée sera utili-sée dans toutes nos communications concernant les soinsaux patients, les études cliniques et les notifications de résul-tats thérapeutiques.

Standardiser les investigationsDes outils sont nécessaires pour élaborer des structures forteset durables. À quelques exceptions près, plus les outils sontefficaces, plus le travail est fait rapidement et plus le produitest durable.

Des outils d’investigation ont été développés pour décrire, ca-ractériser et contrôler l’évolution de l’insuffisance veineuse.L’une des mesures peut-être la plus importante est l’opiniondes patients concernant la manière dont leur maladie a affectéleur vie. Exactement de la même manière qu’un seul outil nepermet pas de construire un édifice important et durable, demême aucun outil isolé ne pourra répondre aux besoins d’in-vestigation dans l’IVC.

Il convient d’identifier ce qui est nécessaire, puis de choisirl’instrument approprié. Les instruments peuvent être clas-sés globalement en instruments de distinction et d’évalua-tion. Un instrument de distinction permettra de décrire clai-rement le patient (stade actuel de l’insuffisance veineuse) etd’identifier les différences entre les patients, tandis qu’un ins-trument d’évaluation sera conçu pour détecter des change-ments au cours du temps, ou une détérioration due à la ma-ladie ou une amélioration apportée par le traitement12.

La classification CEAP (clinique – étiologique – anatomique –physiopathologique) peut être considérée comme le meilleurinstrument de discrimination disponible. La classification CEAPdécrit la sévérité clinique de l’insuffisance veineuse, son étio-logie, sa localisation anatomique et les processus physiopa-thologiques sous-jacents chez le patient 5. Tous les patientsprésentant une insuffisance veineuse devraient être classésavec la classification CEAP.

L’une des faiblesses potentielles des instruments actuels dedistinction est notre incapacité à identifier et quantifier l’obs-truction veineuse. Dans la mesure où l’évaluation non invasivede l’insuffisance veineuse est désormais la norme pour laplupart des patients, nous savons que les méthodes d’ima-gerie minimisent l’ampleur de l’obstruction luminale veineuse(réduction de l’importance de l’occlusion veineuse), à l’ex-ception éventuelle de l’échographie intravasculaire. Il estégalement établi que les épreuves physiologiques invasivesutilisant les techniques de débit veineux maximal ne sont passensibles à la détection de l’obstruction veineuse13 ; beau-coup d’efforts doivent encore être accomplis pour identifierune méthode non invasive permettant de définir clairementcet élément de la physiopathologie veineuse.

Les autres inconvénients comprennent notre mauvaise com-préhension des effets de l’insuffisance veineuse sur la micro-circulation, et les raisons de la survenue d’un dysfonction-nement microcirculatoire chez certains patients et non chezd’autres. Cela explique vraisemblablement pourquoi il existedifférentes catégories cliniques d’IVC chez des patients pré-sentant des caractéristiques hémodynamiques veineusessimilaires14. Il est certain que, jusqu’à ce que nous dévelop-pions des techniques diagnostiques permettant d’évaluer cescritères importants, les systèmes de classification incluant laphysiopathologie dans leur description resteront potentielle-ment inexacts, si ce n’est trompeurs.

Un certain nombre d’instruments d’évaluation satisfaisantspermettent actuellement de surveiller l’évolution de l’état despatients avec le temps, et sont sensibles à une progressionde la maladie ou à une intervention thérapeutique. Chaqueinstrument doit être étudié avec attention pour s’assurer desa validité (capacité de quantifier ce qu’il est supposé mesu-rer), fiable (produisant des résultats constants lorsqu’il estutilisé de façon répétée chez des sujets stables) et sensible

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(en mesure de détecter des changements cliniquement im-portants)12. Deux des meilleurs instruments d’évaluation sontle score de sévérité clinique de l’insuffisance veineuse (Ve-nous Clinical Severity Score, VCSS)6,15 et l’échelle de Villalta7,16.D’autres instruments d’évaluation portent sur la qualité de viedu patient, qui peut être considérée comme le paramètre leplus important, par exemple : le questionnaire de santé SF-36(Short Form 36)17,18, le questionnaire de l’étude épidémiolo-gique et économique sur l’insuffisance veineuse – qualitéde vie (VEnous INsufficiency Epidemiological and economicStudy–Quality Of Life, VEINES-QOL)11, le questionnaire dequalité de vie dans l’insuffisance veineuse chronique (ChronIcVenous dIsease quality of life Questionnaire, CIVIQ-20 [20])19,et le questionnaire d’Aberdeen20.

Deux outils supplémentaires complètent le VCSS, le scoresegmentaire de l’insuffisance veineuse (Venous SegmentalDisease Score, VSDS) et le score d’incapacité veineuse (Ve-nous Disability Score, VDS)21. Le VSDS est conçu pour lo-caliser anatomiquement l’insuffisance veineuse et décrire si lesegment identifié présente un reflux ou une obstruction. Despoints ont été arbitrairement assignés à chaque segment. LeVSDS n’a pas encore été validé, et il est probable que cer-taines modifications seront nécessaires après la réalisationdes études cliniques prospectives appropriées.

Le VDS est une échelle en 4 points (4 catégories) pour l’éva-luation de l’incapacité, comprise entre 0 (asymptomatique)et 3 (incapable d’effectuer les activités usuelles, même avecune compression et/ou une élévation des membres). Commele VSDS, le VDS nécessite une validation. Cependant, comptetenu de ses larges catégories et de leur nombre limité, le VDSne sera probablement pas assez sensible comme instrumentd’évaluation, et sera utilisé de façon plus appropriée commemesure descriptive.

Directives et traitement de l’IVCDes mesures objectives des résultats thérapeutiques et desdirectives pour la prise en charge des patients atteints d’in-suffisance veineuse sont aujourd’hui plus importantes quejamais, et le seront encore davantage à l’avenir. La prise encharge des patients atteints d’IVC évolue rapidement desprocédures chirurgicales ouvertes vers les techniques endo-vasculaires. Chez les patients souffrant de formes plus com-plexes d’IVC, des procédures hybrides comprenant des com-posantes ouvertes et endovasculaires sont actuellementréalisées22. Afin d’évaluer si un traitement particulier est ap-proprié, fiable, standardisé et objectif, des instruments d’éva-luation sont nécessaires. Ils devront être appliqués de façon

prospective à tous les patients ; cela signifie qu’avant le trai-tement les patients devront être classés de manière objec-tive selon la classification CEAP, et qu’un instrument de qua-lité de vie validé et un instrument d’évaluation satisfaisantdevront être utilisés. Après le traitement, à intervalles déter-minés, les mesures d’évaluation et de qualité de vie devrontêtre répétées. Ces mesures objectives pourront ensuite êtreévaluées et intégrées dans une analyse coût-efficacité afin dedéterminer la valeur réelle d’un traitement dans des groupesde patients spécifiques.

Manuel des troubles veineux : directives duforum américain sur l’insuffisance veineuseUne excellente source de directives pour le clinicien se trouvedans la troisième édition du Manuel des troubles veineux : Di-rectives du Forum Américain sur l’insuffisance veineuse (Hand-book of Venous Disorders: Guidelines of the American Ve-nous Forum), de Peter Gloviczki, MD23. Il s’agit peut-être dumeilleur ouvrage sur les directives relatives à la prise en chargede l’insuffisance veineuse disponible aujourd’hui. Le manuel,composé de 65 chapitres divisés en sept parties, contientles informations les plus récentes sur l’épidémiologie, les don-nées scientifiques fondamentales et l’investigation des mala-dies veineuses et lymphatiques, et sur les techniques d’ima-gerie veineuse modernes. Les maladies veineuses aiguës etchroniques y sont traitées, et le livre rend compte de l’enthou-siasme croissant suscité par les techniques mini-invasiveset endoveineuses.

L’aspect le plus important et pérenne de ce manuel pourraitêtre l’ajout à chaque chapitre des directives cliniques fac-tuelles concernant l’évaluation et la prise en charge de l’in-suffisance veineuse. Les scores de preuves sont fournis pouraider le lecteur à évaluer le niveau de la preuve et la classede recommandation. Dans son dernier chapitre, le livre pré-sente une liste de l’ensemble des directives factuelles del’American Venous Forum.

RésuméLes sujets importants abordés dans le nº 108 deMedicogra-phia sont traités à point nommé par un groupe internationald’experts spécialisés dans le domaine de l’insuffisance vei-neuse, et auquel ils ont apporté des contributions majeures.Les sujets spécifiques sont particulièrement importants, car ilsnous font comprendre qu’ils auront des applications pratiquesdans les soins des patients atteints d’IVC à l’avenir. Je recom-mande fortement à chacun d’entre vous la lecture de ce nu-méro de Medicographia, et je suis persuadé qu’il susciterapour vous autant d’intérêt qu’il en a fait naître chez moi. �

É D I T O R I A L

Directives sur l’IVC : fournir aux cliniciens de meilleurs outils de décision – Comerota MEDICOGRAPHIA, Vol 33, No. 3, 2011 237

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Updating guidelines in chronic venous disease: what is needed? – Allegra238

C hronic venous disease (CVD) is a highly prevalent disorder among pop-ulations of Western countries and one with which both general prac-titioners and specialists have to deal. A lack of precision in the de-

scription of CVD, which induces pain, discomfort, and significant deleteriousalterations to the quality of life of affected patients, and in the reporting ofstudy results had led to conflicting conclusions and to a poor understandingof the management of this venous pathology. The rectification of these fail-ings was the spur for the current efforts of the medical community to betterdefine the field of CVD, to clarify the anatomical and clinical terminology andnomenclature, to standardize investigations, and to introduce new therapeu-tic approaches, which will be highlighted in this article. In addition, to thesemajor prerequisites for developing venous disease guidelines, it has been ac-knowledged that adequate prevalence data are needed to better grasp themagnitude of the problem, together with knowledge of the underlying mech-anisms of the manifestations of venous disease in order to develop appropri-ate therapies. For the production of a set of guidelines, a universal consen-sus on the assessment tools needed to measure treatment-induced changesusing either physician-generated tools or patient questionnaires is manda-tory, but some of these tools remain to be validated. Last but not least, anoptimal grading system that is easily understood by all clinicians is the maintool required, so that any guidelines proposed are accepted by the medicalcommunity.

Medicographia. 2011;33:238-244 (see French abstract on page 244)

Because the venous system is in many respects more complex than the arte-rial system, chronic venous disease (CVD) is common in Western populations.Both specialists and general practitioners have to deal with this disease, and

there is a need for practical support regarding CVD management in daily practice.The most recent guidelines have considered the many possible treatments of CVD,including venoactive drugs such as Daflon 500 mg. First, it must be stressed thatno consensus on guidelines is possible without the sharing of a common interna-tional scientific language for the investigation and management of CVD.

What is also important for building guidelines is to have reliable prevalence datathat can serve as a valuable basis for the planning of appropriate actions to deal withproblems, and by repeating an epidemiological survey within a defined geograph-ical area to allow the assessment of the effect of treatment changes. Better knowl-

Claudio ALLEGRA, MDServizio di AngiologiaOspedale San GiovanniRome, ITALY

Address for correspondence:Claudio Allegra, MD, OspedaleSan Giovanni, Servizio di Angiologia,Via S. Giovanni Laterano 155,00184 Rome, Italy(e-mail: [email protected])


Updating guidelinesin chronic venous disease:

what is needed?

by C. Al legra , I ta ly

C H R O N I C V E N O U S D I S E A S E G U I D E L I N E S

A N D D A I L Y C L I N I C A L P R A C T I C E

The setting up of the CEAPclassification and its adjuncts wasa great leap forward in the man-agement of CVD. The CEAP classi-fication can be used by physiciansto keep records of diagnostic in-formation, while the adjuncts toCEAP (VCSS, VSDS, and VDS) arescoring schemes that are quan-tifiable and include elements thatchange in response to treatment.These instruments may be usedto evaluate any stage of CVD inpatients, although they are im-perfect in the early stages.”

‘‘

edge of the underlying mechanisms of CVD will create thebasis for correctly targeted treatment and, in a certain way,will improve the recommendations in guidelines. In addition,validated assessment tools to measure changes to treatmentand their proper use would improve the management of CVD.A rigorous system for rating the quality of evidence and grad-ing the strength of a recommendation has to be used in orderto offer proper recommendations to the clinical communitythat are easy to understand, transparent, and pragmatic. Thisis challenging.

All the above aspects are of the utmost importance for guide-lines to be adopted and will be reviewed in the present article.

Terminology, classifications, and severity scoringof CVDA great leap forward, a consensus on the use of commonvenous anatomical terminology1-3 for a standardized classifi-cation system—CEAP (Clinical-Etiological-Anatomical-Patho-physiological)—and on the use of duplex ultrasound inves-tigation to assess the anatomy of superficial and perforatingveins by ultrasound imaging4 and its derivatives has now beenuniversally adopted, which has facilitated and improved com-munication on and served as a foundation for the accuratereporting of the severity of CVD.3,5,6

Because the CEAP classification is descriptive, with staticcomponents that do not change in response to treatment,it cannot be used for venous severity scoring. As a result, aVenous Severity Scoring System (VSSS) has been proposedby the American Venous Forum (AVF) Ad Hoc Committee on

Outcomes, which consists of three scores: the Venous Clin-ical Severity Score (VCSS) that includes 10 hallmarks of ve-nous disease that are likely to show the greatest change inresponse to therapy and are scored on a scale of severitygraded 0-3; the Venous Segmental Disease Score (VSDS),which uses the anatomical and pathophysiological classifi-cations of the CEAP system to generate a grade based onvenous reflux or obstruction; and the Venous Disability Score(VDS), which assesses the ability to work with or without a“support device.”7

VCSS, one of the components of the VSSS, has been stud-ied and shown to be valid, in that its score increases in a lin-ear fashion with CEAP clinical class, and VCSS is reliable, asdemonstrated in tests of intraobserver variability.8 A changein the score of this instrument could therefore be used as anoutcome measure to assess treatment. Unfortunately, the re-sponsiveness of VCSS has not been adequately evaluated;therefore, it cannot as yet be used to calculate sample sizesfor clinical trials.

Updated definitions of terms related to CVD by the Vein-TermTransatlantic Interdisciplinary Consensus Group of interna-tional experts have decreased problems of interpretation andimproved communication and reporting in the investigationandmanagement of CVD.9 The consensus document includes33 broadly used venous terms relating to the management ofCVD of the lower extremities, which were agreed to have vari-able applicability and interpretation in reports in venous litera-ture. The terms selected for inclusion in the VEIN-Term con-sensus document are stratified into three different groups:clinical, physiological, and descriptive. It is worth noting that13 terms had not to our knowledge been previously defined invenous literature. They are: the acronym PREVAIT (PREsenceof Varices (residual or recurrent) After InTervention), axial reflux,venous occlusion, venous obstruction, venous compression,recanalization, iliac vein obstruction syndrome, venous abla-tion, perforating vein interruption, perforating vein ligation, per-forating vein ablation, miniphlebectomy, and sclerotherapy.

Some commonly used terms, such as chronic venous dis-orders, chronic venous disease, and chronic venous insuffi-ciency, were clarified for the first time and given disease stagelimits. For instance, a consensus was reached for the term“chronic venous insufficiency,” which covers patients from C3to C6 of the CEAP classification; some doctors had until thenused it to describe C4 to C6 patients, while others had usedit for all patients, whatever their stage of CVD. The frequent-ly encountered term “venous symptoms,” which had a veryvague definition, has now been given the description: “Com-plaints related to venous disease, which may include tingling,aching, burning, pain, muscle cramps, swelling, sensations ofthrobbing or heaviness, itching skin, restless legs, leg tired-ness, and/or fatigue. Although not pathognomonic, thesemay be suggestive of CVD, particularly if they are exacerbat-

C H R O N I C V E N O U S D I S E A S E G U I D E L I N E S A N D D A I L Y C L I N I C A L P R A C T I C E

Updating guidelines in chronic venous disease: what is needed? – Allegra MEDICOGRAPHIA, Vol 33, No. 3, 2011 239


ACCP American College of Chest PhysiciansAVF American Venous ForumAVVQ Aberdeen Varicose Veins QuestionnaireCEAP Clinical-Etiological-Anatomical-Pathophysio-

logicalCIVIQ ChronIc Venous dIsease quality of life QuestionnaireCVD chronic venous diseaseGRADE Grading of Recommendations Assessment,

Development and EvaluationMOS SF-36 Medical Outcome Study health survey Short

Form 36PREVAIT PREsence of Varices (residual or recurrent) After

InTerventionQOL quality of lifeRCT randomized controlled trialVCSS Venous Clinical Severity ScoreVDS Venous Disability ScoreVEINES VEnous INsufficiency Epidemiological and

economic StudyVSDS Venous Segmental Disease ScoreVSSS Venous Severity Scoring System



ed by heat or worsen during the course of the day, and are re-lieved by leg rest and/or elevation.” The VEIN-Term consen-sus document is intended to clarify venous terminology. It isto be hoped that it will result in a more precise use of venousterms in English-language articles and guidelines on CVD inthe future. Nevertheless, one challenge still remains, and thatis to translate the English definitions as accurately as pos-sible into other languages for national documents. This is noteasy, although it has already been done for CEAP classifica-tion and anatomic nomenclature. Lastly, VEIN-Term has notcovered all the imprecise terms in phlebology, and furtherrefinements are needed to complete this work.

Prevalence dataCVD is a common condition with a major socioeconomic im-pact due to its high prevalence. The cost of CVD includes itsinvestigation, its treatment, and the loss of working days of theafflicted patients.10 Mild forms of venous disease, such asreticular veins and telangiectasias, are present in 80%-85%of the population, while varicose veins are present in 40% ofmen and 60% of women and ankle edema in 7% of men and16% of women.11 Venous ulceration occurs in 0.3% of thepopulation on an annual basis and approximately 1% of thepopulation in Western countries has either an active or healedvenous ulcer.10-12 The prevalence of CVD increases with age.Age can be considered a “dose-related risk factor,”10,11 butvaricose veins are not restricted to adults: 27% of the schoolchildren between the ages of 10 and 16 years old in the Bo-chum study (from 11 German secondary schools)13 present-ed with varicose disease. From a French survey in 199914 ofrepresentative samples of the adult population aged 15 andover, it appeared that almost half this population suffered fromlower-limb venous complaints and that 43% of them wereuntreated.

The proportion of patients presenting with chronic venoussymptoms increases in a linear fashion with increasing clini-cal scale of the CEAP classification.6 Quality-of-life (QOL) stud-ies have shown that CVD is associated with increased pain,reduced physical function and mobility, and increased feelingsof depression and social isolation,15 and QOL assessment isdirectly associated with the severity of venous disease.16 Pa-tients who have or have had venous ulcers report a QOL sim-ilar to patients suffering from congestive heart failure.17

� Why are prevalence data important?Epidemiological studies are used to assess the prevalence(occurrence) of diseases or disorders within populations in or-der to establish the magnitude of a certain problem. Usuallycross-sectional studies have been used to assess the num-ber of patients with a certain disease within the health-caresystem. Large random samples have been used to assesspopulations and have the advantage of including people whoself-treat. Prevalence data from such studies serve as a valu-able basis for the planning of appropriate action(s) to deal

with a problem, in this case venous leg ulcers. By repeatinga prevalence study within a defined geographical area, wehave a unique opportunity to assess the effect of treatmentchanges.18

There are many pitfalls in performing a prevalence study ofvenous leg ulcers that can introduce a risk of misinterpreta-tion of the true prevalence. For prevalence data to be reliable,the study has to be large enough. By calculating the 95%confidence interval, certainty is possible when examining asmaller population. Validation of all or a randomly selectedsample of the reported patients is mandatory to determinethe number of false positives and to establish the diagnosis,which is usually done nowadays by performing a duplex scaninvestigation in combination with a clinical examination.19 With-out objective validation, there is a high risk of overestimatingthe prevalence of CVD.

The use of only the “C” of CEAP, as is usually done in preva-lence studies, presents weaknesses because of the difficul-ty in distinguishing between C1 and C2 patients, as shownby the wide variation in disease prevalence in epidemiolog-ical studies from one paper to another20; it is not clearly stat-ed in the CEAP classification whether the edema of C3 pa-tients is a permanent edema (ie, a preliminary stage leadingto skin changes and CVD complications) or if it is a reversibleedema that occurs at the end of the day and disappears af-ter rest.20-22 Despite corona phlebectatica (corona) being aclinical sign associated with CVD, it is not yet included in theCEAP classification. Corona is defined by fan-shaped intra-dermal telangiectasias in the medial and sometimes lateralportions of the ankle and foot. It has been shown that co-rona strongly correlates with the clinical severity and hemo-dynamic disturbances of the disease.23 The inclusion of co-rona in the C3 class would probably improve the reliability ofthe clinical classes of CEAP.

Pathophysiology of CVDUnderstanding the pathophysiology of a disease state is ba-sic to effective treatment. Results from studies that demon-strate treatment efficacy lead to guideline recommendations.CVD is defined as: “morphological and functional abnormal-ities of the venous system of long duration manifested eitherby symptoms and/or signs indicating the need for investi-gation and/or care.”9 It is caused by venous valvular incom-petence with or without associated venous outflow obstruc-tion, which may affect the superficial venous system, the deepvenous system, or both. Venous dysfunction may result fromeither a congenital or an acquired disorder. CVD is the con-sequence of venous hypertension.

Chronic venous hypertension leads to disturbances of themicrocirculation, which is responsible for exchange with in-terstitial tissues. This results in a local inflammatory reaction,which is associated with an increase in capillary permeability



and fragility. The lymphatic system can compensate for theincrease in fluid outflow into the surrounding tissues in theearly stages of the disease.24,25 However, if CVD persists orworsens, edema develops because the lymphatic system be-comes overloaded and can no longer handle the drainage ofexcess fluid. Studies of the mechanism of tissue injury at thedifferent stages of CVD show how changes in venous pres-sure and hemodynamic forces (particularly fluid shear stress,the force exerted on venous walls that is predominantly linkedto blood speed) lead to cellular and biochemical disorders.

Leukocytes, due to their ability to respond to physical stimu-lation, are now known to play a key role in the resultant tissueinjury that leads to the development of CVD symptoms, vari-cose veins, edema, and ulcers.26 Recent data suggest thatvalve damage may be acquired rather than congenital andmay be caused by inflammatory factors, notably leukocyte ac-tivation triggered by venous hypertension. Immunohistochem-ical studies using monoclonal antibodies have demonstrat-ed monocyte/macrophage infiltration into the valve leafletsand venous walls of patients with varicose veins, and leuko-cyte infiltration was found to be greater on proximal surfacesof venous valves. A key event in CVD is valve failure, whichleads to increased venous hypertension, maintains a viciouscircle of inflammatory events, and causes eventual venouscomplications.27

Assessment tools in CVDBoth general practitioners and specialist doctors have to dealwith CVD. The treatments of this pathology are usually eval-uated on the basis of clinical outcomes, but such evaluationdoes not take into account patients’ perception of the dis-ease and the impact of treatment on their QOL, which is sig-nificantly altered by the disease. Specific tools capable of as-sessing the full spectrum of CVD, its signs and symptoms,impact on QOL, and treatment effects are key to the efficientmanagement of the disease.

Assessment tools in CVD can be categorized into two class-es (those for symptoms and those for CVD-related signs) andare summarized below20:

� Regarding symptom assessmentThe first step should be to ascribe symptoms to CVD, sincethey are not pathognomonic. The scoring system by P. Car-pentier is a patient-administered diagnostic tool combining 4criteria worth 1 mark each, which allows leg symptoms to beascribed to CVD if the threshold level is equal to or greaterthan 3. The VEINES-Sym (VEnous INsufficiency Epidemio-logical and economic Study), developed by D. L. Lamping,is a 10-item self-administered questionnaire that includesquestions on the frequency of 9 symptoms encountered inCVD, while the 11-item Phleboscore® of P. Blanchemaison,which includes questions about the frequency of symptoms,helps predict the risk of developing CVD.

Of the various instruments that are available to physicians tomeasure symptoms such as pain, the most widely validatedis the 10-cm visual analogue scale. This type of scale providespatients with an easy and rapid means to express the inten-sity of their pain and has numerous applications, including inCVD. Other types of scale, such as numerical rating scales, areusually graded from 0 to 4, 0 to 5, or 0 to 10. These scalesallow the measurement of pain both during the medical visitand retrospectively, and are also used in the evaluation of treat-ment in CVD.

Besides physician-guided tools, there is an increasing needfor patients’ impressions of treatment outcomes and conse-quently a need for patient-reported outcome tools. The toolsused to assess patient-reported outcomes consist mainly ofQOL scales that may be either generic or disease-specific.Of the specific QOL scales, the following are noteworthy: the13-item Aberdeen Varicose Veins Questionnaire (AVVQ), theCharing Cross Venous Ulceration Questionnaire, the VEINESquestionnaire, and the 20-item ChronIc Venous dIsease qual-ity of life Questionnaire (CIVIQ-20) and its recently shortenedversion, CIVIQ-14. CIVIQ has been used extensively, as re-ported in numerous studies some of which included largesamples of patients.28

All four specific questionnaires above were used in conjunc-tion with the 36-item Medical Outcome Study health surveyShort Form (MOS SF-36), a generic health-related QOL in-strument whose validity, reproducibility, and responsivenessto changes over time have been well demonstrated.

� Regarding assessment of signsAs mentioned in the section, “Terminology, classificationsand severity scoring of CVD,” above, the setting up of theCEAP classification and its adjuncts was a great leap for-ward in the management of CVD. The CEAP classification canbe used by physicians to keep records of diagnostic informa-tion, while the adjuncts to CEAP (VCSS, VSDS, and VDS) arescoring schemes that are quantifiable and include elementsthat change in response to treatment. These instruments maybe used to evaluate any stage of CVD in patients, althoughthey are imperfect in the early stages.29 Besides these “glob-al” assessment tools, signs such as varicose veins, edema,and venous ulcers can be specifically assessed. Vein diame-ter can be measured on duplex scan investigation. Leg ede-ma can be assessed by measuring either leg circumference(tape, Leg-o-Meter®) or volume (water displacement volu-metry, optoelectronic methods, computed tomography [CT]scanning, magnetic resonance imaging [MRI], or dual x-rayabsorptiometry).20

Numerous techniques are available for the assessment ofvenous ulcers, ranging from the simple use of tracings tomore sophisticated methods requiring the use of cameras,videos, and computers.30 The parameters most frequently

used to measure a wound are the length of the principalaxes (length and width of the wound), the projected surfacearea, and the perimeter.30

Invasive therapyNew minimally invasive techniques for the treatment of pri-mary and secondary varicose veins, such as radio frequencyablation and Endolaser™, have existed for some years. Boththese techniques are designed to eliminate the larger and/orlesser saphenous veins, collateral varices, or recurrent vari-cosity. With either treatment of the greater saphenous vein,the tributary veins at the femoral saphenous junction arespared, leaving a long saphenous stump. Currently, two ofthe most frequently cited causes of restripping are inade-quate sectioning of saphenous vein tributaries at the saphe-nous junction and leaving too long a saphenous stump. De-spite this, it would seem that the 5-year results using thesetechniques are at least similar to and in fact often better thanthose of traditional stripping.31-35

Another great addition to these techniques is foam sclero-therapy, which gives the same excellent results at remarkablylow cost.36,37 A comparative consensus conference is need-ed to clarify the specific indications and the long-term effec-tiveness and complications of each of these different meth-ods, so that we are able to better inform patients and helpthem choose the most appropriate treatment for them.

Methods of determining the strength and qualityof the recommendationsGuideline developers have used a bewildering variety of sys-tems to rate the quality of the evidence underlying their rec-ommendations. Some are facile, some confused, and otherssophisticated but complex. The recent documents that re-ported recommendations in CVD used several systems.

The one used by Cochrane’s group consists of applying a ran-dom effects statistical model as used in meta-analyses to aselection of randomized controlled trials (RCTs). Selection ofRCTs is done by classifying trials as level A (low risk of bias),level B (moderate risk of bias), or level C (high risk of bias). Atotal of 10 Cochrane reviews have been published in CVDsince 2000.38

In European guidelines on CVD management, studies wereclassified as: grade A (at least two RCTs with large samplesizes, meta-analyses combining homogeneous results), gradeB (RCTs with small sample sizes, single RCT), or grade C(other controlled trials, nonrandomized controlled trials).38 Thiswas the case in an important document on the “Managementof Chronic Venous Disorders of the Lower Limbs: GuidelinesAccording to Scientific Evidence,” prepared by an internation-al consensus group under the auspices of the leading soci-eties for venous disease.39 Another recent document, “Anti-thrombotic Therapy for Venous Thromboembolic Disease,”

from the American College of Chest Physicians (ACCP) 8thconsensus conference, has recently been published to helpphysicians care for patients with venous disease.40

These recent ACCP guidelines have made specific changeswith recommendations and suggestions linked to objectivegrades. The so-called “Grading of Recommendations As-sessment, Development and Evaluation” (GRADE) method ofdetermining the strength and quality of the recommendationsdeserves mention. The strength of the recommendation (1:“We recommend,” or 2: “We suggest”) is no longer based, aswas the case only a few years ago, solely on the type andquality of available studies. It is a true judgement of the over-all value of the balance between the benefits and risks in-curred by following this recommendation, a judgement based

not only on the expected health benefits, treatment-relatedrisks, and patients’ values and preferences, but also on eco-nomic considerations and the allocation of resources. In thelater document, recommendations are accompanied by anumber which refers to the strength of the recommendation(“1” for a strong and “2” for a weak recommendation), and aletter, which refers to the quality of evidence supporting therecommendation (“A” for “high quality,” which is consistentevidence from randomized trials; “B” for “moderate quality,”which is evidence from nonrandomized trials or inconsistentevidence from randomized trials; and “C” for “low quality,”which is suggestive evidence from nonrandomized trials, ob-servational reports, or expert opinion).

The advantages of GRADE over other systems are summa-rized by the developers themselves41 in Table I. This new ap-proach provides a system for rating the quality of evidenceand the strength of recommendations that is explicit, com-



� Developed by a widely representative group of internationalguideline developers

� Clear separation between quality of evidence and strengthof recommendations

� Explicit evaluation of the importance of outcomes of alterna-tive management strategies

� Explicit, comprehensive criteria for downgrading and upgrad-ing quality of evidence ratings

� Transparent process of moving from evidence to recommen-dations

� Explicit acknowledgment of values and preferences

� Clear, pragmatic interpretation of strong versus weak recom-mendations for clinicians, patients, and policy makers

� Useful for systematic reviews and health technology assess-ments, as well as guidelines

Table I. Advantages of GRADE over other systems.Abbreviation: GRADE, Grading of Recommendations Assessment, Developmentand Evaluation.Reproduced from reference 41: Guyatt et al. BMJ. 2008;336;924-926. © 2008,BMJ Publishing Group Ltd.

prehensive, transparent, and pragmatic. That is why it is wide-ly used in North America: 25 organizations have alreadyadopted it, and it is increasingly being adopted by other or-ganizations worldwide.

The task of building international guidelines is challenging,particularly in the venous field. This is because of the largespectrum of disease manifestations and either the lack ofvalidated methods or the weak consensus for methods that

have been adopted for assessing symptoms, signs, and QOL,not to mention the resource constraints that vary consider-ably from region to region. Even if much still remains to bedone to get the high-quality scientific studies needed to sup-port the development of guidelines, we are at a point wherea lot of progress in standardization, classification, fundamen-tal research, and assessment methods has been made in ashort time. Let us hope that we can continue to advance inthe same way. �



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13. International Task Force. The management of chronic venous disorders of theleg: an evidence-based report of an international task force. Epidemiology.Phlebology. 1999;14(suppl 1):23.

14. Levy E, Los F, Chevalier H, Levy P. The 1999 French venous disease surgery:epidemiology, management, and patient profiles. Angiology. 2001;52:195-199.

15. van Korlaar I, Vossen C, Rosendaal F, et al. Quality of life in venous disease.Thromb Haemost. 2003;90:27-35.

16. Kaplan RM, Criqui MH, Denenberg JO, et al. Quality of life in patients with chron-ic venous disease:SanDiegopopulationstudy. JVasc Surg.2003;37:1047-1053.

17. Andreozzi GM, Cordova RM, Scomparin A, et al. Quality of life in chronic venousinsufficiency. An Italian pilot study of the Triveneto Region. Int Angiol. 2005;24:272-277.

18. Forssgren A, Fransson I, Nelzén O. Leg ulcer point prevalence can be decreasedby broad-scale intervention: a follow-up cross-sectional study of a defined ge-ographical population. Acta Derm Venereol. 2008;88:252-256.

19. Nelzén O. Prevalence of venous leg ulcer: the importance of the data collectionmethod. Phlebolymphology. 2008;15:143-150.

20. Jawien A. Unmet needs in the assessment of symptoms and signs related tochronic venous disease. Application to Daflon 500 mg. Phlebolymphology. 2009;16:331-339.

21. Allegra C, Carlizza A. Oedema in chronic venous insufficiency: physiopathologyand investigation. Phlebology. 2000;15:122-125.

22. Allegra C. Patients with chronic venous disease–related symptoms without signs:

prevalence and hypotheses. Medicographia. 2006;28:123-127.23. Uhl JF, Cornu-Thénard A, Carpentier PH, et al. Clinical and hemodynamic sig-

nificance of corona phlebectatica in chronic venous disorders. J Vasc Surg.2005;42:1163-1168.

24. Allegra C, Bartolo M Jr, Cariot B, Cassiani D. 6th World Congress for Microcir-culation. Munich, Germany, August 25-30, 1996. Abstracts. Effectiveness ofDaflon 500 mg on microlymphatics in chronics venous insufficiency. Int J Mi-crocirc Clin Exp.1996;16(suppl 1):1-308.

25. Bartolo M Jr, Carioti B, Cassiani D, Allegra C. 18th European Conference onMicrocirculation. Rome, Italy, 4-8 September 1994. Abstracts. Lymphatic cap-illaries pressure in human skin of patients with chronic venous insufficiency.Int J Microcirc Clin Exp.1994;14(suppl 1):1-262.

26. Lyseng-Williamson A, Perry CM. Micronised purified flavonoid fraction. A reviewof its use in chronic venous insufficiency, venous ulcers and haemorrhoids.Drugs. 2003;63:71-100.

27. Bergan JJ, Schmid-Schönbein G, Coleridge-Smith P, Nicolaides A, Boisseau M,Eklof B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

28. Launois R, Mansilha A, Jantet G. International psychometric validation of theChronic Venous Disease quality of life Questionnaire (CIVIQ-20). Eur J VascEndovasc Surg. 2010;40:783-789.

29. Perrin M, Dedieu F, Jessent V, Blanc MP. Evaluation of the new severity scoringsystem in chronic venous disease of the lower limbs: an observational studyconducted by French angiologists. Phlebolymphology. 2006;13:6-16.

30. Humbert P, Meaune S, Gharbi T. Wound healing assessment. Phlebolympho-logy. 2004;47:312-319.

31. Perrin MR, Guex JJ, Ruckley CV, et al. Recurrent varices after surgery (REVAS),a consensus document. REVAS group. Cardiovasc Surg. 2000;8:233-245.

32. Perrin M. Lower limb varicose veins endoluminal treatment by endovenous laserand radiofrequency. A literature analysis at March 1st 2004 [in French]. Phlé-bologie. 2004;57:125-133.

33. Nicolini P; Closure Group. Treatment of primary varicose veins by endovenousobliteration with the VNUS closure system: results of a prospective multicenterstudy. Eur J Vasc Endovasc Surg. 2005;29:433-439.

34. Hinchiffe RJ, Ubhi J, Beech A, Ellison J, Braithwaite BD. A prospective ran-domised controlled trial of VNUS closure versus surgery for the treatment of re-current long saphenous varicose veins. Eur J Vasc Endovasc Surg. 2006;31:212-218.

35. Merchant RF, DePalma RG, Kabnick LS. Endovascular obliteration of saphe-nous reflux: a multicenter study. J Vasc Surg. 2002;35:1190-1196.

36. Coleridge Smith P. Echo-guided sclerotherapy: the future? Phlebol Digest.2006;19:4-6.

37. Breu FX, Guggenbichler S. European Consensus Meeting on Foam Sclero-therapy, April, 4-6, 2003, Tegernsee, Germany. Dermatol Surg. 2004;30:709-717.

38. Nicolaides A. Venoactive medications and the place of Daflon 500 mg in re-cent guidelines on the management of chronic venous disease. Phlebolym-phology. 2009;16:340-346.

39. Nicolaides A, Allegra C, Bergan J, et al. Management of chronic venous dis-orders of the lower limbs. Guidelines according to scientific evidence. Int An-giol. 2008;27:1-59.

40. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; Amer-ican College of Chest Physicians. Antithrombotic therapy for venous thrombo-embolic disease: American College of Chest Physicians Evidence-Based Clin-ical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S.

41. Guyatt GH, Oxman AD, Kunz R, et al. GRADE: an emerging consensus onrating quality of evidence and strength of recommendations. BMJ. 2008;336;924-926.



MISE À JOUR DES RECOMMANDATIONS DANSLA MALADIE VEINEUSE CHRONIQUE : DE QUOI AVONS-NOUS BESOIN ?

La maladie veineuse chronique (MVC) est un trouble très fréquent dans la population occidentale, que doivent trai-ter à la fois les généralistes et les spécialistes. Un manque de précision dans la description de la MVC (qui entraînedouleur, gêne et altérations significatives de la qualité de vie des patients), et dans les résultats des études, a conduità des conclusions contradictoires et à compréhension limitée de la prise en charge de la pathologie veineuse. Dansle but de rectifier ces manques, la communauté médicale s’efforce actuellement de mieux définir le domaine de laMVC, de clarifier la terminologie et la nomenclature anatomique et clinique, de standardiser les examens et d’intro-duire de nouvelles approches thérapeutiques, qui seront présentées dans cet article. En plus, à ces prérequis impor-tants pour l’élaboration de recommandations sur la maladie veineuse, s’ajoute la nécessité de données de prévalenceadéquates pour mieux appréhender l’amplitude du problème, tout en reconnaissant les mécanismes sous-tendantles manifestations de la maladie veineuse afin de développer des traitements appropriés. Afin d’établir des recom-mandations, il faut obligatoirement un accord général sur des outils d’évaluation pouvant mesurer les changementsinduits par le traitement en utilisant soit des outils de médecin soit des questionnaires de patients, encore à valider.Enfin et surtout, le principal outil nécessaire est un système optimal de cotation facilement compréhensible par tousles cliniciens afin que la communauté médicale accepte toutes les recommandations proposées.

Keywords: guidelines; chronic venous disease; update

CVD guidelines and terminology: sharing a common language – Perrin and Eklöf MEDICOGRAPHIA, Vol 33, No. 3, 2011 245

O ne of the important lessons from the biblical story of the Tower of Ba-bel is that a common language allows men to achieve extraordinarythings. For all those involved in the management of chronic venous

disease (CVD), the American Venous Forum (AVF) has created a “common lan-guage” in the classification of CVD, the CEAP (Clinical-Etiological-Anatomi-cal-Pathophysiological) classification. The need for an accurate classificationsystem is fundamental to understanding the clinical disease processes and tointerinstitutional communication about the disease. The CEAP classificationsystem was established in 1994 and was followed by REVAS (REcurrence af-ter VAricose vein Surgery), created in Paris in 1998, and the Venous ClinicalSeverity Score (VCSS), in 2000. Several consensus documents from the UnionInternationale de Phlébologie (UIP) led to the revision of the CEAP classifica-tion system in 2004. The latest update of terminology for CVD was the VEIN-TERM consensus document published in the Journal of Vascular Surgery in2009. All these efforts have led to the creation of a common language in CVD,which is essential for the establishment of clinical practice guidelines.


Hidden within the main story of the Tower of Babel (Figure 1, page 246) fromthe Bible lies an interesting and valuable lesson: that with a common lan-guage, men can achieve extraordinary things. Without a common language,

not only would this project have been impossible (as it later transpires), but it alsowould have been unimaginable. In creating the CEAP (Clinical-Etiological-Anatom-ical-Pathophysiological) classification as a “common language” for chronic venousdisorders, the American Venous Forum (AVF) has laid the foundations for future pro-gress in chronic venous disease (CVD).

The need for an accurate classification system in venous disease is fundamental tothe understanding of the clinical disease processes and to interinstitutional commu-nication about the separate entities. The imprecise diagnoses that were the normin venous disease in the past have been replaced by accurate imaging studies,since the introduction of noninvasive ultrasound scans in the 1980s.

Once presented with the ability to make accurate diagnoses of the causes and mech-anisms of chronic disease in individual segments of the lower extremity veins, it be-came necessary to devise a classification system capable of organizing the data ina meaningful way.

Address for correspondence:Prof Bo Eklöf, Batteritorget 8,SE-252 70 Helsingborg, Sweden(e-mail: [email protected])


Chronic venous diseaseguidelines and terminology:sharing a common language

by M. R . Perr in , France ,and B. Ek löf, Sweden



The imprecise diagnoses thatwere the norm in venous diseasein the past have been replaced byaccurate imaging studies, sincethe introduction of noninvasive ul-trasound scans in the 1980s. Oncepresented with the ability to makeaccurate diagnoses of the causesand mechanisms of chronic dis-ease in individual segments of thelower extremity veins, it becamenecessary to devise a classifica-tion system capable of organizingthe data in a meaningful way.”

‘‘

Michel R. PERRIN, MDChassieu, FRANCE

Bo EKLÖF, MD, PhDUniversity of LundLund, SWEDEN

In 1994, the AVF convened a subcommittee of world expertsin CVD to address this challenge. Recognizing that a mod-ern classification of CVD must now embrace more than justthe clinical state of the patient, this committee created theCEAP classification, which provides a system whereby themultiple variations of CVD can be communicated in a clinical-ly and scientifically meaningful manner, allowing analysis andcomparison of treatment modalities for like conditions.1

Because identical clinical presentations of CVD spring fromdifferent etiologies, and the distribution of specific patholog-ical processes have different implications for treatment andlong-term prognosis, the CEAP classification organizes theseelements into the methodology. In the CEAP system, the“C”-linical state is complemented by the “E”-tiological basisfor the disease in each case, and this is described in termsof the “A”-natomical distribution of the “P”-athophysiologicalprocess throughout the axial venous drainage system, fromthe calf to the diaphragm. This organization of informationhas been successfully promulgated around the world by theinternational body that devised it. Its widespread accept-ance has become fundamental to interinstitutional commu-nication and to describing chronic venous disorders.

Development of the CEAP classificationThe CEAP classification provides a framework around whichthe clinical manifestations found in CVD are paired with keypathological elements of causation and physiological mech-anisms in specific anatomical locations of the lower extremity.Specifically, for each clinical condition it distinguishes:� Primary, secondary, and congenital causes of the problem;

� Reflux from obstructive pathophysiology;� And identifies the precise anatomical seg-ments affected by reflux or obstruction using18 named segments of the lower extremityvenous tree.

In this way, clinical manifestations can be cou-pled with the precise pathological entity. Us-ing this, the natural history of the pathologicalprocesses and the effects of management al-ternatives for like clinical states can be identi-fied and studied. The classification describesthe status of the disease process at a pointin time; these details can change over timewith the introduction of interval treatments andwith the natural history of the disease pro-cess. By CEAP examination at regular inter-vals, the longitudinal changes that occur overtime or after interventions can be documented.

This classification addressed the considera-tions imposed by modern diagnostic andtreatment capabilities. It was incorporatedinto the updated Reporting Standards for Ve-

nous Disease in 1995 and became known as the CEAP clas-sification. Its acceptance was engendered around the worldby venous authorities in America, Asia, Australia, and Europe,and the classification has now been published in at least 11languages (Chinese, English, French, German, Greek, Italian,Japanese, Polish, Portuguese, Spanish, and Swedish). Theworldwide dissemination addresses the need for a universalclassification that enables accurate communication betweeninstitutions and countries about the details of CVD and theresults of different forms of treatment. The CEAP classifica-tion was originally intended as a preliminary document; it wasmeant to be amended in light of future experience with usage.Since this time, several evaluations of the clinical categoriesand of the appended scoring systems based upon CEAP havebeen published, which have both validated and appraised theircontent.

In 1998, at an international consensus meeting in Paris, Perrinet al established a classification for recurrent varicose veins(REcurrent Varices After Surgery [REVAS]).2 Two years later in


MEDICOGRAPHIA, Vol 33, No. 3, 2011 CVD guidelines and terminology: sharing a common language – Perrin and Eklöf246


AVF American Venous ForumCEAP Clinical-Etiological-Anatomical-PathophysiologicalCVD chronic venous diseaseLDS lipodermatosclerosisREVAS REcurrent Varices After SurgeryUIP Union Internationale de Phlébologie [International

Union of Phlebology]

Figure 1. The Tower of Babel by Pieter Bruegel the Elder (1563).The biblical story of the Tower of Babel illustrates why a common language is so important and whathappens when people fail to understand each other. Oil on oak panel (114 × 155 cm). KunsthistorischesMuseum Wien, Vienna, Austria. © Kunsthistorisches Museum Wien.

2000, Rutherford et al and the Ad Hoc Outcomes Committeeof the AVF published an upgraded version of the original ve-nous severity scoring system.3 Uhl et al established a Euro-pean Venous Registry based on CEAP and reported stud-ies on intraobserver and interobserver variability that showedsignificant discrepancies in the clinical classification of CEAP,which prompted the improvement of definitions of clinicalclasses C0 to C6.4 Further changes regarding definitions andrefinements of the clinical classification, the “C” in CEAP, weresuggested soon after at the Union Internationale de Phlé-bologie [International Union of Phlebology] (UIP) internationalconsensus meeting in Rome in 2001,5 which not only con-

tributed to CEAP, but ultimately formed the basis for its mod-ification. At the same meeting, Caggiati et al published a con-sensus document on nomenclature of the veins of the lowerlimbs, which was updated a couple of years later.6,7

After a decade (in 2004), a new international subcommitteeof the American Venous Forum decided to review the validityand usefulness of CEAP and to make revisions if needed. Thisnew version affirmed and retained the fundamental struc-ture of the CEAP categories, but included additions to clas-sification, such as specific definitions of terms, clarification ofdetails within the “C” class, and improvements in the methodof recording of findings to render classification more completein its long form, and more user-friendly in its short form.8

Terminology and new definitionsThe CEAP classification deals with all forms of CVD. The term“chronic venous disorder” includes the full spectrum of mor-phologic and functional abnormalities of the venous system,from telangiectasias to venous ulcers. Some of these, suchas telangiectasias, are highly prevalent in the healthy adultpopulation, and in many cases use of the term “disease” isnot appropriate. The term “chronic venous insufficiency” im-plies a functional abnormality of the venous system, and isusually reserved for more advanced disease, including ede-ma (C3), skin changes (C4), and venous ulcers (C5-C6).

It was agreed to maintain the present overall structure of theCEAP classification, but to add more precise definitions. Thefollowing recommended definitions apply to the clinical (“C”)class of CEAP:

� Atrophie blanche (white atrophy)Localized, often circular whitish and atrophic skin areas sur-rounded by dilated capillaries and sometimes hyperpigmen-tation. Sign of severe CVD, and not to be confused with healedulcer scars. Scars of healed ulceration may also exhibit at-rophic skin with pigmentary changes, but are distinguishableby history of ulceration and appearance from atrophie blanche,and are excluded from this definition (Figure 2).

� Corona phlebectaticaFan-shaped pattern of numerous small intradermal veins onmedial or lateral aspects of ankle and foot. Commonly thoughtto be an early sign of advanced venous disease. Synonymsinclude malleolar flare and ankle flare (Figure 3).

� EczemaAn erythematous dermatitis that may progress to blistering,weeping, or scaling eruption of skin of the leg. Most often lo-cated near varicose veins, but may be located anywhere onthe leg. Usually seen in uncontrolled CVD, but may reflect sen-sitization to local therapy.

� EdemaPerceptible increase in volume of fluid in skin and subcuta-neous tissue, which is characteristically indented with pres-sure. Venous edema usually occurs in the ankle region, butmay extend to the leg and foot (Figure 4, page 248).

� LipodermatosclerosisLipodermatosclerosis (LDS) is a localized chronic inflamma-tion and fibrosis of the skin and subcutaneous tissues of thelower leg, sometimes associated with scarring or contractureof the Achilles tendon. LDS is sometimes preceded by dif-fuse inflammatory edema of the skin, which may be painfuland which often is referred to as hypodermitis. Lymphangitis,erysipelas, or cellulitis must be differentiated from LDS by theircharacteristically different local signs and systemic features.LDS is a sign of severe CVD (Figure 5, page 248).



Figure 2. Atrophie blanche (C4b).

Figure 3. Corona phlebectatica.

� PigmentationBrownish darkening of skin, resulting from extravasated blood.Usually occurs in the ankle region, but may extend to the legand foot (Figure 6).

� Reticular veinDilated bluish subdermal vein, usually 1 mm to less than 3 mmin diameter. Usually tortuous. Excludes normal visible veinsin persons with thin, transparent skin. Synonyms include blueveins, subdermal varices, and venulectasias.

� TelangiectasiaConfluence of dilated intradermal venules less than 1 mm incaliber. Synonyms include spider veins, hyphen webs, andthread veins (Figure 7).

� Varicose veinSubcutaneous dilated vein 3 mm in di-ameter or larger, measured in uprightposition, may involve saphenous veins,saphenous tributaries, or nonsaphenoussuperficial leg veins.

Varicose veins are usually tortuous, buttubular saphenous veins with demon-strated reflux may be classified as vari-cose veins. Synonyms include varix,varices, and varicosities (Figure 8).

� Venous ulcerFull-thickness defect of skin, most fre-quently in the ankle region, that fails toheal spontaneously and is sustained byCVD (Figure 9).



Figure 5. Lipodermatosclerosis (+ atrophieblanche) (C4b).

Figure 7. Telangiectasias (C1).

Figure 4. Edema (C3). Figure 6. Pigmentation (C4a).Courtesy of Albert-Adrien Ramelet (Bern, Switzerland).

Figure 8. Varicose veins (C2). Figure 9. Active venous ulcer (C6).



Table I. VEIN-TERM definitions/Clinical venous terms.2,3,5,8-13

VEIN-TERM UPDATE9

Chronic venous disorders: this term includes the full spec-trum of morphological and functional abnormalities of thevenous system.

Chronic venous disease: morphological and functionalabnormalities of the venous system of long durationmanifested either by symptoms and/or signs indicatingthe need for investigation and/or care.

Chronic venous insufficiency (C3*-C6): a term reserved foradvanced chronic venous disorders, which is applied tofunctional abnormalities of the venous system producingedema,* skin changes, or venous ulcers. [C3*: moderateor severe edema, as stratified by Rutherford et al3]

Venous symptoms*: complaints related to venous disease,which may include tingling, aching, burning, pain, musclecramps, swelling, sensations of throbbing or heaviness,itching skin, restless legs, and leg tiredness and/or fa-tigue. Although not pathognomonic, these may be sug-gestive of chronic venous disease, particularly if they areexacerbated by heat or dependency in the day’s course,and relieved with leg rest and/or elevation.

Venous signs: visible manifestations of venous disorders,which include dilated veins (telangiectasiae, reticularveins, varicose veins), leg edema, skin changes, and ul-cers, as included in the CEAP classification.8

Recurrent varices: reappearance of varicose veins in anarea previously treated successfully.

Residual varices: varicose veins remaining after treatment.

New acronym PREVAIT: this acronym stands for:PREsence of Varices (residual or recurrent) After opera-tIve Treatment)

Postthrombotic syndrome: chronic venous symptomsand/or signs secondary to deep vein thrombosis.

Pelvic congestion syndrome: chronic symptoms, which mayinclude pelvic pain, perineal heaviness, urgency of micturi-tion, and postcoital pain, caused by ovarian and/or pelvicvein reflux and/or obstruction, and which may be associ-ated with vulvar, perineal, and/or lower extremity varices.

Varicocele: presence of scrotal varicose veins.

Venous aneurysm: localized saccular or fusiform dilatationof a venous segment with a caliber at least 50% greaterthan the normal trunk.

PREVIOUS DEFINITIONS

Chronic venous disorders: include all clinical abnormalities(symptoms or signs) resulting from disease of the lowerlimb veins and progressing chronically.8

Chronic venous disease: is defined as an abnormallyfunctioning venous system caused by venous valvularincompetence with or without associated venous outflowobstruction, which may affect the superficial venous sys-tem, the deep venous system, or both.10

Chronic venous insufficiency: implies a functional abnormal-ity of the venous system, and is usually reserved for moreadvanced disease, including edema (C3), skin changes(C4), or venous ulcers (C5-C6).8

Venous symptoms: may be associated with telangiectasic,reticular, or varicose veins and include lower extremityaching, pain, and skin irritation.10

Venous signs: described in the “C” of the CEAPclassification.5,10

Recurrent varices: the presence of varicose veins in a lowerlimb previously operated on for varices (with or without ad-juvant therapies).2

Persisting or residual varices: original varicosities that maypersist so that the failure of treatment is apparent from

an early stage after surgery.11

No previous definition

Postthrombotic syndrome: the term may be used if thepatient has experienced an objectively documented priorepisode of deep vein thrombosis.10

Pelvic congestion syndrome: characterized by chronicpelvic pain in the setting of pelvic venous varicosities.The syndrome has been shown to be the result of en-gorgement of the pelvis due to gross dilatation and in-competence of one or both the ovarian veins.12

No venous literature definition

Venous aneurysm: the diameter above which a vein is considered to be aneurysmal is debated: it is generally accept-ed that its diameter must be twice that of the normal vein.Aneurysms are classified into saccular and fusiform.13

*In the original article, the definition is followed by the sentence: “Existing venous signs and/or (noninvasive) laboratory evidence are crucial in as-sociating these symptoms with chronic venous disorder,” which conflicts with the acknowledged existence of the clinical CEAP category C0s EnAn Pn, corresponding to patients complaining of leg symptoms, but presenting with no visible signs and without detectable pathophysiologicalabnormalities identifiable by routine investigations. This is why we removed this paragraph from the present brochure.



Table II. VEIN-TERM definitions/Physiological venous terms.9,13-20

VEIN-TERM UPDATE9

Venous valvular incompetence: venous valve dysfunctionresulting in retrograde venous flow of abnormal duration.

Venous reflux: retrograde venous flow of abnormal durationin any venous segment.

Primary: caused by idiopathic venous valve dysfunction.

Secondary: caused by thrombosis, trauma, or mechan-ical, thermal, or chemical etiologies.

Congenital: caused by the absence or abnormal de-velopment of venous valves.

Axial reflux: uninterrupted retrograde venous flow from thegroin to the calf.

Superficial: confined to the superficial venous system.

Deep: confined to the deep venous system.

Combined: involving any combination of the threevenous systems (superficial, deep, perforating)

Segmental reflux: localized retrograde flow in venous seg-ments of any of the three venous systems (superficial,deep, perforating) in any combination in the thigh and/orthe calf, but NOT in continuity from the groin to calf.

Perforator incompetence: perforating veins with outwardflow of abnormal duration.

Neovascularization: presence of multiple new, small tortu-ous veins in anatomic proximity to a previous venousintervention.

Venous occlusion: total obliteration of the venous lumen.

Venous obstruction: partial or total blockage of venous flow.

Venous compression: narrowing or occlusion of the venouslumen as a result of extraluminal pressure.

Recanalization: development of a new lumen in a previouslyobstructed vein.

Iliac vein obstruction syndrome: venous symptoms andsigns caused by narrowing or occlusion of the commonor external iliac vein

May-Thurner syndrome: venous symptoms and signscaused by obstruction of the left common iliac vein dueto external compression at its crossing posterior to theright common iliac artery.


Venous valvular incompetence: abnormal functioning ofthe veins of the lower extremities is recognized clinicallyas venous dysfunction.14

Venous reflux: reversal of flow in a segment of vein follow-ing its dilatation and/or anatomical or functional incom-petence of its valves.15

Primary valve dysfunction: absence of completeclosure of the valves.15

Secondary valve dysfunction: valves irreversiblydamaged by the thrombotic process.15

Congenital valve dysfunction: atrophy or absenceof valve.15

No previous definition

Superficial: reflux in the entire great saphenous vein to belowthe knee.16

Deep: superficial femoral vein and popliteal vein or thedeep femoral vein and popliteal vein when those are con-nected.17

No precise previous definition


Perforator incompetence: retrograde (outward) outflowflow lasting greater than 0.3 s or longer than antegradeflow during the relaxation phase after release of manualcompression.18

Neovascularization: recurrence of varices after vein tran-section restored by growth of new vessels in the sur-rounding tissue and vein wall.19



Venous compression: compression by external structures.20



May-Thurner syndrome: Compression of the left commoniliac vein by vascular bone entrapment. The anterior sur-face entrapment is the common iliac artery, the posterioris formed by vertebral column.13

Need for updated CVD terminologyDespite the revision of the CEAP classification and the up-dated nomenclature of the venous anatomy of the leg, manyterms need a better definition to create a common scientificlanguage for the investigation and management of CVD. In Oc-tober 2007 onboard M/S Trollfjord, we organized the ArcticFjords Conference and workshops on CVD. During this voy-age, an interdisciplinary faculty of experts under the auspicesof the European Venous Forum, the AVF, the UIP, the Interna-tional Union of Angiology, the American College of Phlebolo-gy, and the Society for Vascular Surgery met in order to pro-vide recommendations for fundamental venous terminology.The group met again in February 2008 at the of AVF meetingin Charleston, South Carolina, to finalize the document that wasendorsed by the organizations and published in the Journalof Vascular Surgery as the VEIN-TERM consensus document.The venous terms defined in this document are presented un-

der three headings: clinical, physiological, and descriptive,alongside the previous literature definitions when available.Some may not have been used in any previous publication.Most of the terms previously defined in CEAP documents andprior venous nomenclature refinements were excluded.9

The aim of Table I (page 249),2,3,5,8-13 Table II,9,13-20 and Ta-ble III 9,21-23 is to summarize the venous terms relating to themanagement of chronic venous disorders of the lower ex-tremities that are widely used and recognized to vary in appli-cability and interpretation in reports in the venous literature.The venous terms newly defined in the VEIN-TERM consen-sus document are compared with those in previous literaturedefinitions. The definitions presented in VEIN-TERM testify toa continued effort to create a common language upon whichwe can build clinical practice guidelines (presented by PeterGloviczki in his editorial).9 �



Table III. VEIN-TERM definitions/Descriptive venous terms.9,21-23

Abbreviation: GSV, great saphenous vein.

VEIN-TERM UPDATE9

High ligation and division: ligation and division of the greatsaphenous vein (GSV) at its confluence with the common

femoral vein, including interruption of all upper GSVtributaries.

Stripping: removal of a long vein segment, usually most ofthe GSV or the small saphenous vein by means of a device.

Venous ablation: removal or destruction of a vein bymechanical, thermal, or chemical means.

Perforating vein interruption: disconnection of a perforatingvein by mechanical, chemical, or thermal means.

Perforating vein ligation: interruption of a perforating veinby mechanical means.

Perforating vein ablation: disconnection or destruction of aperforating vein by mechanical, chemical, or thermal means.

Miniphlebectomy: removal of a vein segment through asmall skin incision.

Sclerotherapy: obliteration of a vein by introduction of achemical (liquid or foam).

Endophlebectomy: removal of postthrombotic residue fromthe venous lumen.


High ligation and division: ligation and division of the longsaphenous vein and its tributaries at the saphenofemoraljunction.21

Stripping: removal of the saphenous vein.22







Endophlebectomy: surgical disobliteration of chronicallyobstructed venous segment.23

References1. Bergan JJ, Eklof B, Kistner RL, et al. Classification and grading of chronic ve-

nous disease in the lower limbs. A consensus statement. Ad Hoc Committee,American Venous Forum. J Cardiovasc Surg (Torino). 1997;38:437-441.

2. Perrin MR, Guex JJ, Ruckley CV, et al; REVAS Group. Recurrent varices aftersurgery (REVAS), a consensus document. Cardiovasc Surg. 2000;8:233-245.

3. Rutherford RB, Padberg FT, Comerota AJ, Kistner RL, Meissner MH, MonetaGL. Venous severity scoring: an adjustment to venous outcome assessment.

J Vasc Surg. 2000,31:1307-1312.4. Uhl JF, Cornu-Thénard A, Carpentier PH, Schadek M, Parpex P, Chleir F. Re-

producibility of the “C” classes of the CEAP classification. J Phlebology. 2001;1:39-48.

5. Allegra C, Antignani PL, Bergan JJ, et al. The “C” of CEAP: suggested defini-tions and refinements: an International Union of Phlebology conference of ex-perts. J Vasc Surg. 2003;37:129-131.



TERMINOLOGIE ET RECOMMANDATIONS DANS LA MALADIE VEINEUSE CHRONIQUE :PARTAGER UN LANGAGE COMMUN

Un des enseignements que nous pouvons tirer de l’allégorie biblique de la Tour de Babel est qu’un langage com-mun permet aux hommes de réaliser des choses extraordinaires. À l’intention de tous ceux impliqués dans la priseen charge de la maladie veineuse chronique (MVC), l’American Venous Forum a créé un « langage commun » per-mettant la classification de la MVC, la classification CEAP (Clinique – Étiologique – Anatomique – Physiopatholo-gique). Il est essentiel de disposer d’une classification précise pour appréhender en détail les aspects cliniques dela MVC et pour communiquer au plan international sur le sujet. La classification CEAP a été établie en 1994 et aété suivie par la classification REVAS (REcurrence After VAricose vein Surgery) élaborée à Paris en 1998 et par lescore de sévérité clinique (VCSS : Venous Clinical Severity Score), en 2000. Plusieurs documents de consensus del’Union Internationale de Phlébologie ont conduit à la révision de la classification CEAP en 2004. La dernière mise àjour de la terminologie pour la MVC est le document de consensus VEIN-TERM publié dans le Journal of VascularSurgery en 2009. Tous ces efforts ont conduit à la création d’un langage commun dans la MVC, ce qui est essentielpour l’établissement de recommandations en pratique clinique.

Keywords: chronic venous disease; definition; terminology

6. Caggiati A, Bergan JJ, Gloviczki P, Jantet G, Wendell-Smith CP, Partsch H.Nomenclature of the veins of the lower limbs: an international interdisciplinaryconsensus statement. J Vasc Surg. 2002;36:416-422.

7. Caggiati A, Bergan JJ, Gloviczki P, Eklöf B, Allegra C, Partsch H. Nomenclatureof the veins of the lower limb: Extensions, refinements, and clinical application.J Vasc Surg. 2005;41:719-724.

8. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification forchronic venous disorders: Consensus statement. J Vasc Surg. 2004;40:1248-1252.

9. Eklöf B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminologyof chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary con-sensus document. J Vasc Surg. 2009:49:498-501.

10. Porter IP, Moneta GM; International Consensus Committee on Chronic VenousDisease. Reporting standards in venous disease: an update. J Vasc Surg. 1995;21:635-645.

11. Tibbs DJ. Superficial vein incompetence: further considerations. In: Tibbs DJ,ed. Varicose Veins and Related Disorders. 1st ed. London, UK: Butterworth-Heinemann; 1992:112.

12. Richardson G. Pelvic congestion syndrome: diagnosis and treatment. In: Ber-gan JJ, ed. The Vein Book. 1st ed. London, UK: Elsevier; 2007:315-322.

13. Anatomy and pathology of the limb veins. In: Ramelet AA, Perrin M, Kern P,Bounameaux H, eds. Phlebology. 5th ed. Issy-les-Moulineaux, France: Else-vier Masson; 2008:41-48.

14. Bergan JJ, Pascarella L. Venous anatomy, physiology, and pathophysiology.In: Bergan JJ, ed. The Vein Book. 1st ed. London, UK: Elsevier; 2007:39-45.

15. Pathophysiology of chronic venous disease. In: Ramelet AA, Perrin M, Kern P,Bounameaux H, eds. Phlebology. 5th ed. Issy-les-Moulineaux, France: ElsevierMasson; 2008:61-62.

16. Danielsson G, Eklöf B, Grandinetti A, Lurie F, Kistner RL. Deep axial reflux, animportant contributor to skin changes or ulcer in chronic venous disease. J VascSurg. 2003;38:1336-1341.

17. Puggioni A, Lurie F, Kistner RT, Eklöf B. How often is deep venous reflux elim-inated after saphenous vein ablation? J Vasc Surg. 2003;38:517-521.

18. Gloviczki P, Lewis BD, Lindsey JR, McKusick MA. Preoperative evaluation ofchronic venous insufficiency. In: Gloviczki P, Bergan JJ, eds. Atlas of Endo-scopic Perforator Vein Surgery. London, UK: Springer Verlag; 1998:81-91.

19. Glass GM. Neovascularization in recurrence of the varicose great saphenousvein following transection. Phlebology. 1987;2:81-89.

20. Becker F. Dictionary of Vascular Medicine Terms. Paris, France: Elsevier; 2006.21. Browse NL, Burnand KG, Thomas ML, eds. Diseases of the Veins: Pathology,

Diagnosis and Treatment. London, UK: Edward Arnold; 1995:408.22. Bergan JJ, Kistner RL, eds. Atlas of Venous Surgery. Philadelphia: WB Saunders;

1992:68.23. Puggioni A, Kistner RL, Eklöf B, Lurie F. Surgical disobliteration of postthrom-

botic deep veins—endophlebectomy—is feasible. J Vasc Surg. 2004;39:1048-1052.

Prevalence and socioeconomic data in chronic venous disease – Milic MEDICOGRAPHIA, Vol 33, No. 3, 2011 253

T he exact prevalence of chronic venous disease (CVD) remains difficultto determine because of variations in study population, selection crite-ria, and disease definition between different studies. The prevalence of

CVD, as reported in studies, ranges from 2%-56% in men and from 1%-60%in women. Despite the fact that it has a huge impact on health-care budgetsand patients’ quality of life, it is still an underestimated condition. CVD is morecommon with increasing age, and in recently published studies there were nosignificant sex differences. Family history, obesity, prolonged standing, anddiet have been proposed as risk factors, but further studies are needed toclarify the influence of potential risk factors on the development of CVD. Thefinancial burden on the health-care system is enormous, with recent estimatesplacing the cost of CVD treatment at $3 billion per year in the United States,or up to 2% of the total health-care budget of all Western countries. Existingevidence highlights the need for good quality longitudinal and cross-section-al studies measuring the incidence and prevalence of CVD. These studiesmay help to reduce the magnitude of the problem of CVD by raising aware-ness among public and health-care authorities, and health-care profession-als. Furthermore, prevalence and socioeconomic data may serve as a valu-able basis for the planning of appropriate steps to deal with CVD and for theeducation and hire of skilled personnel.


C hronic venous disease (CVD) of the lower extremities is one of the mostwidespread diseases in the populations of Western European countries andthe USA. Data from undeveloped countries are scarce, and the true mag-

nitude of the problem is not known. Unfortunately, even in developed Western Eu-ropean countries and the USA, where the problem of CVD is well recognized, theprevalence of CVD is still underestimated by both patients and health-care profes-sionals. This underestimation comes from the fact that chronic venous insufficiency(CVI) is not a lethal condition and that the consequences of this chronic disorderare often overlooked. However, the impact of CVD on patients’ quality of life (QOL)and health-care budgets, especially in the more severe stages, is considerably high.The most common manifestations of CVD are dilated cutaneous veins, such astelangiectasias, reticular veins, and varicose veins. The term “chronic venous insuf-ficiency” describes a condition that affects the venous system of the lower extrem-ities with venous hypertension, causing various pathologies including pain, swelling,edema, skin changes, and ulcerations.

Dragan J. MILIC, MD, PhDClinic for Vascular SurgeryClinical Center NisNis Medical SchoolUniversity of NisNis, SERBIA

Address for correspondence:Dr Dragan J. Milic, BulevarNemanjica 72A/25, 18 000 Nis,Serbia (e-mail:[email protected]/[email protected])


by D. J . Mi l ic , Serbia



The balance of evidence sup-ports the finding that the preva-lence of venous disease increaseswith increasing age. The magni-tude of risk appears to differ de-pending on the classification crite-ria, and estimates vary in publishedstudies. The prevalence of vari-cose veins in men aged 30 to 40years old is about 3%, while in theage group over 70 years old, it in-creases up to about 40%. Similarresults were also found in women.”

‘‘ Prevalence and socioeconomicdata in chronic venous disease:how useful are they in planning

appropriate management?


MEDICOGRAPHIA, Vol 33, No. 3, 2011 Prevalence and socioeconomic data in chronic venous disease – Milic254

Published studiesData from available epidemiological literature published dur-ing the last 30 years are very difficult to compare due to thefact that different evaluation criteria of CVD were used. Law-rence1 confirms that the prevalence of varicose veins dependson the definition of this disease because dilated veins rang-ing from telangiectasias to massive varicosities come underthe general category of varicose veins. In order to standard-ize the evaluation of severity of venous disease in 1994, a newclassification system was suggested by the American VenousForum. The CEAP (Clinical-Etiological-Anatomical-Pathophys-iological) classification system includes not only the clinicalsymptoms of CVD, but also considers the etiology, anatom-ic distribution, and the pathogenic mechanisms and pro-duces a score based on the severity of the disease.2 Theclinical signs in the affected leg are categorized into sevenclasses designated C0 to C6. CVD encompasses the fullspectrum of signs and symptoms associated with classesC0 to C6, whereas the term “chronic venous insufficiency”is generally restricted to disease of greater severity, such asedema, trophic skin changes (such as pigmentation and lipo-dermatosclerosis), and ulceration.3

CVD is extremely common, although the prevalence estimatesin the literature vary because of differences in the methods ofevaluation, criteria for definition, and the geographic regionsanalyzed.4 In order to establish the magnitude of the prob-lem, epidemiological studies are used to assess the preva-lence of diseases or disorders within a population. Cross-sec-tional studies have usually been used to assess the numberof patients with a certain disease within a health-care system.Large random samples have been used to assess popula-tions and have the advantage of including people who self-treat. Prevalence data from such studies are a valuable ba-sis for the planning of appropriate actions to deal with theproblem. By repeating a prevalence study within a definedgeographical area, we have an opportunity to assess the ef-fect of treatment changes, which is important.5 Unfortunately,

published epidemiological studies often misuse prevalencedata by mixing overall prevalence figures with point preva-lence data, giving an inaccurately wide range that leads toincorrect interpretations of prevalence data between coun-tries and studies. Therefore, in order to provide the most reli-able data and to generate accurate comparisons, it is essen-tial to analyze the methods used in various epidemiologicalstudies. However, we still have many pitfalls that can lead toinaccurate conclusions and interpretations6 (Table I).

Prevalence data are often harvested from cross-sectionalstudies or large population samples. The former investigatea defined cohort, generally all patients receiving treatmentfrom health-care professionals within a relatively short timeframe, usually one to three months. The latter usually consistof randomly selected people in a certain age range who havenot necessarily been in previous contact with the health-care system. The benefit of population samples is that peo-ple who self-treat are included, unlike cross-sectional stud-ies.6 The drawback of a population sample is that usually notall age groups are represented.5

To facilitate recruitment, it is important to avoid approachingcarers and patients with lengthy questionnaires. Such formstake time to fill in and introduce a risk of dropout becauseof lack of time of the carer, patient, or both. A cross-section-al study involves selection bias since only patients treatedwithin the health-care system will be included. Such a studywill give an indication of the workload for health-care pro-fessionals, but there are, in addition, people who treat the dis-ease on their own. A population sample overcomes this byincluding all people within the selected sample. The biggestproblem of population sample studies is that they need to befairly large (more than 10 000 people) in order to detect enough


CEAP Clinical-Etiological-Anatomical-Pathophysiological

CIVIQ ChronIc Venous dIsease Questionnaire

CVD chronic venous disease

CVI chronic venous insufficiency

DALY disability-adjusted life year

GIS global index score

QALY quality-adjusted life year

QOL quality of life

RELIEF Reflux assEssment and quaLity of lIfe improvEmentwith micronized Flavonoids [study]

YLD years lived with disability

YLL years of life lost

Pitfall Effect on results of the study

Population sample Not all age groups arerepresented

Cross-sectional studies Patients who self-treat arenot included

Follow-up studies May affect patient recruitmentnegatively

Different evaluation criteria Possible high drop-out rateof CVD

Too small a sample Uncertain prevalence estimate

Selection bias Prevalence not representativefor the general population

Low response rate Risk of underestimation ofprevalence

Extensive primary Noncomparable resultsquestionnaire

Table I. Pitfalls in performing prevalence studies and their effectson the results.Abbreviation: CVD, chronic venous disease.



patients with the disease so that a reliable prevalence esti-mate can be made. These studies are expensive, time con-suming, and difficult to perform.6

Prevalence of chronic venous insufficiencyThe prevalence of varicose veins reported in studies rangesfrom 2%-56% in men and from 1%-60% in women3 (Table II).Seven general population surveys have been conducted todate,7-13 and only a few studies have measured the incidenceof varicose veins. The Framingham Study was a longitudinalstudy that followed up men and women living in Framingham,USA, over a 16-year period from 1966.14 Every second yearover this period, subjects were examined for varicose veins,defined as “the presence of distended and tortuous veins,clearly visible on the lower limbs with the subject standing.”Over the 16-year period, 396 out of the 1720 men and 629out of the 2012 women who were free from venous diseasein 1966 developed varicose veins. On average, the two-yearincidence rate of varicose veins was 39.4 per 1000 for men

and 51.9 per 1000 for women. However, further studies arerequired to determine the incidence and progression of ve-nous disease in the general population. One such study isthe Edinburgh Vein Follow-Up Study. Subjects examined atbaseline in 1994-1996 are currently undergoing a follow-upexamination to determine the incidence and natural historyof CVD as well as to establish the risk factors relating to pro-gression.

A cross-sectional study of a random sample of 1566 subjects18 to 64 years of age from the general population in Edin-burgh, Scotland,12 found that telangiectasias and reticularveins were each present in approximately 80% of men and85% of women. Varicose veins were present in 40% of menand 16% of women, whereas ankle edema was present in7% of men and 16% of women.12 In this study, duplex ultra-sound found reflux in 9.4% of men and 6.6% of women and

after age adjustment, reflux rose significantly with age (21.2%in men >50 years old, and 12.0% in women >50 years old).15

Interestingly, it appears that certain treatments can reducevenous reflux. Jantet16 in the RELIEF (Reflux assEssment andquaLity of lIfe improvEment with micronized Flavonoids) studyfound that venous reflux was absent in 57% of patients di-agnosed as suffering from CVI belonging to CEAP classes C0to C4. Moreover, during treatment with micronized purifiedflavonoid fraction, all symptoms showed a decrease in bothgroups of patients (with and without venous reflux).16

The balance of evidence supports the finding that the preva-lence of venousdisease increaseswith increasing age.7-9,11,13,17-20

The magnitude of risk appears to differ depending on the clas-sification criteria, and estimates vary in published studies. Theprevalence of varicose veins in men aged 30 to 40 years oldis about 3%, while in the age group over 70 years old, it in-creases up to about 40%.11,13 Similar results were also foundin women: a prevalence of 20% at the age of 30 to 40 yearsold increases gradually with age and by 70 years of age, itexceeds 50%.12 The prevalence of trunk varices rose from11.5% in persons aged 18 to 24 years old to 55.7% in thepopulation between 55 to 64 years of age.12 The occurrenceof skin changes in CVI depends on the patient’s age as well.In the Tecumseh Health Study,7 the prevalence of skin changesin women aged 30 to 39 years old was 1.8%, whereas inpatients aged over 70 years old a prevalence of 20.7% wasreported.

The San Valentino Vascular Screening Project found a preva-lence of 7% for varicose veins and 0.86% for “symptomatic”CVI among the 30 000 subjects evaluated by clinical as-sessment and duplex ultrasound.21 As in previous studies,CVI was more common with increasing age, but there wasno significant sex difference.

Active or healed venous leg ulcers occur in approximately 1%of the general population.12,22 Although not restricted to theelderly, the prevalence of CVD, especially leg ulcers, increas-es with age.22,23 It has been estimated that 2.5 million peo-ple have CVI in the United States, and of those, 20% developvenous ulcers.24 The overall prognosis of venous ulcers is poorwith delayed healing and recurrent ulceration.25 More than50% of venous ulcers require prolonged therapy lasting morethan 1 year.26

Most studies have shown that CVI is more prevalent amongwomen, although in a recent study, the difference betweensexes was small.4 Selection bias may be a problem in someof these studies, as more women than men may be aware oftheir varicose veins or consider them to be a problem and,thus, may be more likely to participate in such studies. More-over, many of the results from these studies have not been ad-justed for age, a factor that may contribute to the observedgender differences.3 In the Framingham Study,14 the annual

First Studyauthor Year Country sample size Men Women

Mekky 1969 Egypt 467 – 5.8Mekky 1969 England 504 – 32.1Coon 1973 USA 6389 12.9 25.9Abramson 1981 Israel 4802 10.4 29.5Maffei 1986 Brazil 1755 37.9 50.9Franks 1992 England 1338 17.4 31.6Komsuoglu 1994 Turkey 850 34.5 38.3Sisto 1995 Finland 8000 6.8 24.6Evans 1999 Scotland 1566 39.7 32.2Criqui 2003 USA 2211 15 27.7

Table II. Prevalence of varicose veins (%) by sex in studies fromdifferent countries.After reference 3: Robertson et al. Phlebology. 2008;23:103-111. © 2008, TheRoyal Society of Medicine Press.


MEDICOGRAPHIA, Vol 33, No. 3, 2011 Prevalence and socioeconomic data in chronic venous disease – Milic256

incidence of varicose veins was 2.6% among women and1.9% among men, and in contrast to the Edinburgh VeinStudy, the prevalence of varicose veins was higher in men.12

In the San Diego Population Study, CVD was more prevalentin populations of European origin than in blacks or Asians.13

Geographic differences in the prevalence of varicose veinssuggest a correlation with race. In particular, the prevalenceof CVD has been found to be higher in more developed, in-dustrialized countries than in underdeveloped regions. Mekkyet al observed that the prevalence of varicose veins in Englishwomen was more than five times as great as that in Egyptianwomen.27

Risk factors for CVD include heredity, age, female sex, obe-sity (especially in women), pregnancy, prolonged standing,and greater height.10,28-30

Socioeconomic burden of chronic venousinsufficiencyThe high prevalence of CVI, cost of investigation and treat-ment, and loss of working days mean that CVD has a consid-erable socioeconomic impact. The problem is compound-ed by the fact that CVI is progressive and has a propensityto recur.31 In France, 2.24 billion Euros are spent for the treat-ment of CVI, of which 41% was for drugs, 34% for hospitalcare, and 13% for medical fees. In France in 1991, there were200 000 hospitalizations for CVI (50%were for varicose veins),which was the eighth most common cause of hospitalization.The cost of treatment represented 2.6% of the total health-care budget for that year.32 In Germany, in-patient direct costswere 250 million Euros, out-patient costs were 234 millionEuros, and drug costs were 207 million Euros.33

In Sweden, the average weekly cost of treating venous legulcers in 2002 was 101 Euros, with an estimated annual costof 73 million Euros.34 Indirect costs of venous disease in termsof working days lost were the most important cost factor in1990 in Germany, amounting to 270 million Euros.33 In theUSA, venous ulcers cause the loss of 2 million workdays peryear,35 while in France 6.4 million workdays were lost in 1991due to venous disease.32 The socioeconomic impact of ve-nous ulceration is dramatic, resulting in an impaired ability toengage in social and occupational activities, a reduction inpatients’ QOL, and the imposition of financial constraints. Ina population study in the United Kingdom, the median dura-tion of ulceration was nine months, but 20% of ulcers had nothealed within two years, and ulcer recurrence meant that 66%of patients had episodes of ulceration lasting longer than fiveyears.25 Published data show that venous ulcers may causethe early retirement of a substantial portion, up to 12.5%, ofworkers with this condition.36

A useful tool to determine the burden of CVI in populationis to calculate health expectancies, which are population in-dicators that estimate the average time (in years) that a per-

son could expect to live in a defined state of health. Healthgaps measure the difference between actual population healthand some specified norm or goal. The principle characteris-tic defining a health gap measure is the population norm (age)chosen to define the period before which death or disabilityis considered premature. Methods for defining health statesand for eliciting health state valuations, as well as incorpora-tion of other social values also affect the calculation and in-terpretation of health gaps, as for health expectancies. Thebest known of the health gap measures is the disability-ad-justed life year (DALY), developed for use in burden of diseasestudies by Murray and Lopez.37 The DALY combines a meas-urement of premature mortality and disability and express-es years of life lost to premature death together with yearslived with disability of specified severity and duration. OneDALY is thus one lost year of healthy life. This indicator is theaggregate of years of life lost (YLL) and years lived with dis-ability (YLD) at a population level, and reflects the burden ofdisease in a population: DALY = YLL + YLD.

An even more useful tool for assessing the importance of CVIis the quality-adjusted life year (QALY), a measure of diseaseburden that includes both the quality and the quantity of lifelived. It can be used to assess the value for money of a med-ical intervention. Unfortunately, to date, there are no studiesthat have assessed DALYs and QALYs in patients with CVI.

Quality of life in patients with chronic venousinsufficiencyCVI has a huge impact on patients’ QOL.38,39 Clinical assess-ment of CVD severity may be carried out using different re-ported outcome tools: physician reported outcomes (VDS[Venous Disability Score], VCSS [Venous Clinical SeverityScore]) and patient reported outcomes, such as QOL scales(generic: SF-12 and SF-36 [Short Form 12 and 36]; or specif-ic: VEINES [VEnous INsufficiency Epidemiological and eco-nomic Study], AVVQ [Aberdeen Varicose Veins Questionnaire],CIVIQ [ChronIc Venous dIsease Questionnaire], SQOR-V [Spe-cific Quality Of life Response–Venous]). In the study publishedby Jantet, patients with venous reflux had lower CIVIQ scoresthan patients without reflux, reflecting a poorer QOL (62.2 ver-sus 66.7; P=0.0001).16 This was observed not only for theglobal index scores (GIS), but for all aspects of the CIVIQ(psychological, pain, physical, and social). The subgroup withboth short and long saphenous vein involvement had signif-icantly lower QOL scores, and hence poorer QOLs, thanthe subgroups of patients with isolated reflux of the shortsaphenous vein or of the long saphenous vein only (GIS =59.3 versus 64.1 and 64.7, respectively; P=0.0001). It is alsointeresting to observe from this study that only 21.8% of allpatients with CVI were treated for this condition.

The CIVIQ questionnaire is a specific instrument for assess-ing the impact of venous disease on patients’ QOL. This scaleconsists of 20 items that assess physical limitation (4 items),



physical pain (4 items), social relationships (3 items), and psy-chological limitations (9 items). The CIVIQ questionnaire usesa Likert response scale, in which each item is scored from 0to 5. A score per item (a value of 1-5) or a global score (a val-ue of 0-100) can then be calculated. These questionnaireshave been successfully used in previous studies.38,40

ConclusionThe exact prevalence of CVD remains difficult to determinebecause of variations in study population, selection criteria,and disease definition between different studies. The preva-lence of varicose veins, as reported in studies, ranges from2%-56% in men and from 1%-60% in women. Evidence sug-gests that the prevalence of venous disease increases withage. Varicose veins appear to be more prevalent in women,but pregnancy and the fact that women report the presenceof varicose veins more often than men may play a role in thisvariation. Family history, obesity, prolonged standing, and diethave been proposed as risk factors, but further studies areneeded to clarify the influence of potential risk factors on thedevelopment of CVI. Existing evidence highlights the need

for good quality longitudinal studies measuring the incidenceand prevalence of CVD. Varicose veins and CVI are often ig-nored as an important public health issue even though evi-dence from research indicates that venous disease affectsa significant proportion of the population, causes consider-able morbidity, and adversely impacts the QOL of those af-fected. All of these factors have an influence on health-carebudgets and public spending.

Future prevalence and socioeconomic studies may help toreduce the magnitude of the problem of CVI. This type of CVIassessment could raise awareness among the public, health-care authorities, and health-care professionals. In turn, thiscould mean that patients in the early stages of CVI receiveadequate treatment preventing the development of more se-vere stages of CVI. Furthermore, prevalence and socioeco-nomic data may serve as a valuable basis for the planning ofappropriate actions to deal with CVD and for the educationand hire of skilled personnel. By repeating an epidemiologicalsurvey within a defined geographical area, these studies makeit possible to assess the effects of treatment protocols. �

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29. Fowkes FG, Lee AJ, Evans CJ, Allan PL, Bradbury AW, Ruckley CV. Lifestylerisk factors for lower limb venous reflux in the general population: EdinburghVein Study. Int J Epidemiol. 2001;30:846-852.

30. Chiesa R, Marone EM, Limoni C, Volonte M, Schaefer E, Petrini O. Demograph-ic factors and their relationship with the presence of CVI signs in Italy: the 24cities cohort study. Eur J Vasc Endovasc Surg. 2005;30:674-680.

31. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous dis-orders of the lower limbs: guidelines according to scientific evidence. Int An-giol. 2008;27:1-59.

32. Lafuma A, Fagnani F, Peltier-Pujol F, Rauss A. Venous disease in France: an un-recognized public health problem [in French]. J Mal Vasc. 1994;19:185-189.

33. Dinkel R. Venous disorders, a cost intensive disease. Phlebology. 1997;26:164-168.

34. Tennvall GR, Andersson K, Bjellerup M, Hjelmgren J, Oien R. Treatment of ve-nous leg ulcers can be better and cheaper. Annual costs calculation basedon an inquiry study. Lakartidningen. 2004;101:1506-1510,1512-1513.

35. McGuckin M, Waterman R, Brooks J, Cherry G, Porten L, Hurley S, KersteinMD. Validation of venous leg ulcer guidelines in the United States and UnitedKingdom. Am J Surg. 2002;183:132-137.

36. Da Silva A, Navarro MF, Batalheiro J. The importance of chronic venous in-sufficiency: various preliminary data on its medico-social consequences. Phle-bologie. 1992;45:439-443.

37. The global burden of disease: a comprehensive assessment of mortality anddisability from diseases, injuries and risk factors in 1990 and projected to 2020.In: Murray CJL, Lopez, AD, eds. Global Burden of Disease and Injury Series,

Vol. 1. Cambridge, Mass: Harvard University Press; 1996.38. Guex JJ, Myon E, Didier L, Nguyen Le C, Taieb C. Chronic venous disease:

health status of a population and care impact on this health status throughquality of life questionnaires. Int Angiol. 2005;24:258-264.

39. Guex JJ, Zimmet SE, Boussetta S, Nguyen Le C, Taieb C. Construction andvalidation of a patient reported outcome dedicated to chronic venous disor-der: SQOR-V (Specific Quality of Life and Outcome Response-Venous). J MalVasc. 2007;32:135-137.

40. Guex JJ, Enrici E, Boussetta S, Avril L, Lis C, Taieb C. Correlations betweenankle circumference, symptoms, and quality of life demonstrate the clinical rel-evance of minimal leg swelling reduction: results of a study in 1,036 Argen-tinean patients. Dermatol Surg. 2008;34:1666-1668.

PRÉVALENCE ET DONNÉES SOCIO-ÉCONOMIQUES DANS LA MALADIE VEINEUSE CHRONIQUE :QUELLE EST LEUR UTILITÉ POUR UNE PRISE EN CHARGE APPROPRIÉE ?

La prévalence exacte de la maladie veineuse chronique (MVC) reste difficile à déterminer à cause de la variation despopulations des études, des critères de sélection et de la définition de la maladie entre les différentes études. La pré-valence de la MVC, rapportée dans les études, varie de 2 % à 56 % chez les hommes et de 1 % à 60 % chez lesfemmes. Cette pathologie reste encore sous-estimée malgré son impact énorme sur les dépenses de santé et sur laqualité de vie des patients. La MVC augmente avec l’âge et d’après des études récemment publiées, il n’y avait au-cune différence significative entre les sexes. Les antécédents familiaux, l’obésité, la station debout prolongée etle régime alimentaire sont des facteurs de risque, mais d’autres études sont nécessaires pour évaluer l’influencedes facteurs de risque potentiels sur le développement de la MVC. Le poids financier sur le système de santé esténorme, de récentes estimations plaçant le coût du traitement de la MVC à 3 milliards de $ par an aux États-Unis,ou à plus de 2 % du budget total de la santé dans tous les pays occidentaux. L’état actuel des connaissances sou-ligne le besoin d’études croisées et longitudinales de bonne qualité permettant de mesurer l’incidence et la pré-valence de la MVC. Ces études pourraient permettre de réduire l’ampleur du problème de la MVC en éveillant laconscience du public, des autorités et des professionnels de santé. De plus, la prévalence et les données socio-économiques pourraient servir de base précieuse à la mise en œuvre d’étapes appropriées pour la prise en chargede la MVC et pour éduquer et recruter du personnel qualifié.

Keywords: chronic venous insufficiency; prevalence; socioeconomic data; chronic venous disease

258 Prevalence and socioeconomic data in chronic venous disease – MilicMEDICOGRAPHIA, Vol 33, No. 3, 2011


Treatment of CVD: pathophysiological underpinnings – Malgor and Labropoulos MEDICOGRAPHIA, Vol 33, No. 3, 2011 259

C hronic venous disease (CVD) causes a significant negative socioeco-nomic impact in society. Its indolent course confers a high toleranceuntil treatment is pursued. The initial phase of the disease is often neg-

lected by most patients and many seek treatment when the disease is ad-vanced. The most common pathology is reflux in the superficial veins, whileisolated deep vein reflux is uncommon. Obstruction alone is rare, but is fre-quently found in combination with reflux, a scenario that has the worst prog-nosis. Several modalities of treatment are available, from medication usingvenoactive drugs through to open and endovenous interventions. A compre-hensive understanding of the causative mechanisms involved in the devel-opment of CVD is mandatory for choosing the most appropriate and tailoredtreatment for each patient. This review focuses on the pathophysiological un-derpinnings involved in the treatment of CVD.


Primary and secondary venous disease

C hronic venous disease (CVD) is a worldwide affliction affecting a great por-tion of the world’s population.1 Despite its widespread prevalence, there areseveral reasons why CVD treatment is delayed and why it attracts little at-

tention for major research funding: it has an indolent course; clinical presentationis late, with skin changes; and there is no risk of loss of limbs or mortality. There areseveral factors involved in the pathophysiology of CVD. In recent years, the in-flammatory pathway in CVD, on which certain medications act, has become betterknown.2,3 Inflammatory processes, such as leukocyte migration, plasma-granulo-cyte activation, and increased metalloproteinase activity, all cause degradation ofthe valve leaflets.4,5 Another factor involved in the pathophysiology of the CVD is calfpump function. The calf pump increases blood flow velocity and maintains fluidbalance.6 Patients with dysfunctional calf pumps are more prone to develop skinchanges and more severe venous ulcer disease.7

CVD is classified into two types: primary and secondary. Essentially, primary venousdisease is caused by venous reflux and affects two-third of limbs with CVD. Initial-ly, increased venous pressure causes smooth muscle relaxation, endothelial dam-age, and extracellular matrix degradation.1,4 Subsequently, the vein wall becomesweak and eventually dilated.4 Superficial vein reflux, in the great saphenous vein (GSV)and small saphenous vein (SSV), is the most common type of reflux, occurring in80% of cases, followed by reflux in perforator veins (PVs) and deep veins. Isolated

Address for correspondence:Dr Nicos Labropoulos, Professorof Surgery and Radiology, Director,Vascular Laboratory, Department ofSurgery, HSC T19 Rm90, StonyBrook University Medical Center,Stony Brook, NY 11794-8191, USA(e-mail: [email protected])


Treatment of chronic venousdisease: pathophysiological

underpinnings

by R. D. Malgorand N. Labropoulos , USA



The identification and loca-tion of reflux can be accurately as-sessed with duplex ultrasound, sothe vascular laboratory should bethe first stop for a workup to ob-tain a noninvasive, comprehensive,and dynamic assessment of thesuperficial, perforator, and deepveins. It is recommended that notonly patients with chronic venousinsufficiency, but those with telan-giectasias and varicose veins un-dergo duplex ultrasound exami-nation of the superficial, deep, and(selectively) perforator veins.”

‘‘

�

Nicos LABROPOULOS,BSc (Med), PhD, DIC, RVT

Rafael D. MALGOR, MD

Division of Vascular SurgeryStony Brook Medical CenterStony Brook, New YorkUSA


MEDICOGRAPHIA, Vol 33, No. 3, 2011 Treatment of CVD: pathophysiological underpinnings – Malgor and Labropoulos260

involvement of deep veins is rare.8 Likely deep vein reflux isnoted when longstanding superficial vein reflux affects the ve-nous junctions (Figure 1) and the PVs in turn render the deepveins incompetent. Often, isolated primary deep vein reflux isfound in the common femoral vein, followed by the femoraland popliteal vein. Deep vein reflux can be found in associ-ation with superficial vein reflux in up to 40% of cases.9-11

PV reflux is another component of CVD commonly relatedto superficial vein reflux.12 Two mechanisms have been pro-

posed to explain how PV valves become incompetent. Thefirst mechanism is an ascending extension of superficial veinreflux causing progressive vein dilation and reflux that prop-agates proximally rendering the perforator vein dilated and in-competent. The second mechanism is a descending prop-agation where re-entry PVs drain reflux blood into the deepveins. Over a long period of time, the high flow volume in thePVs causes dilatation and reflux in these veins.12,13 PV refluxmost often originates in the GSV system and may render thedeep veins incompetent.12 In cases of deep vein reflux second-ary to PV reflux, frequently only a short segment is affected.

Secondary venous disease is less common than primary CVDand is caused by either a thrombotic event or arteriovenousfistula (AVF). Trauma has been mentioned as a cause of sec-ondary CVD, but this occurs through deep venous throm-bosis (DVT) of an AVF that can occur after trauma. Increasingvenous pressure secondary to AVF formation creates localvenous hypertension causing endothelium damage, vein wallweakening, and dilation faster but similar to that observed inprimary CVD.2,14

DVT is the most common cause of secondary CVD. Manyrisk factors are involved in the development of DVTs, such aspregnancy, operations, immobilization, malignancy, trauma,and obesity. In addition, patients who have a hypercoagula-tion disorder (ie, mutation of coagulation factors, active pro-tein C resistance, protein S and antithrombin III deficiency) arelikely to develop DVT. Reflux, obstruction, and a combinationof reflux and obstruction are the three possible patterns pres-ent in secondary CVD. The worst prognosis is when reflux and


AVF arteriovenous fistulaCEAP Clinical-Etiological-Anatomical-PathophysiologicalCT computed tomographyCVD chronic venous diseaseCVI chronic venous insufficiencyDVT deep vein thrombosisESCHAR Effect of Surgery and Compression on Healing And

Recurrence [study]EVLT endovenous laser therapyGSV great saphenous veinMR magnetic resonancePTFE polytetrafluoroethylenePTS postthrombotic syndromePV perforator veinRFA radiofrequency ablationSFJ saphenofemoral junctionSPJ saphenopopliteal junctionSSV small saphenous veinSVS Steam Vein Sclerosis™ [system]

Figure 1. Examples of reflux withultrasound imaging from a femalepatient who presented with vari-cose veins and swelling in the

right lower extremity.(A) Reflux in the saphenofemoral junc-

tion. The common femoral vein andgreater saphenous vein (GSV) tributariesin the groin were normal. (B) The GSVat the knee is mildly dilated. The mild

dilatation in the center of the image andthe reflux pattern (blue color in eachvalve cusp) during the release of the

compression indicate the presence of avalve. (C) The GSV in the lower calf hasa small diameter, but a high velocity, veryprolonged retrograde flow. (D) Varicose

tributaries of the GSV from the lowerthigh to the calf. This particular segmentis actually one vein, although there ap-pears to be many due to the tortuosityof the tributary. The patient underwent

endovenous thermal ablation of theGSV from the upper calf to a point 2 cmfrom the saphenofemoral junction andphlebectomies of the tributaries. The

remaining GSV was treated with foamsclerotherapy.

Abbreviation: GSV, great saphenous vein.



obstruction are present in the same limb, rendering the limbprone to skin changes, such as discoloration, and to venousulcers. Ipsilateral recurrent DVT, iliofemoral thrombosis, andpersistent intensity of signs and symptoms in the first monthafter the episode of DVT are important predictors for devel-oping postthrombotic syndrome (PTS).15-17

Partial recanalization (Figure 2) is seen more frequently thantotal recanalization or complete occlusion of veins after anepisode of thrombosis.18 The location of reflux and obstruc-tion also plays a role in the development of PTS, which is de-fined as a group of signs and symptoms comprising heavi-ness, edema, itching, and eventually skin damage includingvenous ulcers.18 Lastly, in a minority of cases, congenital ve-nous malformations are to blame for CVD. Agenesis, hypo-plasia, and the absence of valves in a short or long segmentof superficial or deep veins are the most common findings.19

Although the clinical course of CVD is indolent, over time itcauses a negative impact on health and quality of life. In orderto create a standardized method to describe patients withCVD, a classification based on clinical (“C”—telangiectasias toskin damage), etiological (“E”—primary, secondary, or congen-ital), anatomical (“A”—superficial, deep, or perforators), andpathophysiological (“P”—reflux, obstruction, or both) findingshas been created, which is known by the acronym CEAP:Clinical-Etiological-Anatomical-Pathophysiological. The ma-jority of patients are at an initial stage of the disease (C1-C2)and have telangiectasias and varicose veins. Chronic venousinsufficiency (CVI) occurs when patients present with edemaor skin damage (discoloration or venous ulcers).

TreatmentTreatment modalities for CVD, for which there are many,should be tailored to the specifics of each patient based onpathophysiological findings. Patients should then be strati-fied according to disease severity, and nonoperative and in-vasive treatments used alone or in combination. All patientswith CVD should be referred to specialists for general and fo-cused history taking and physical examination. Many optionsfor venous disease workup are available, including direct andindirect noninvasive methods and other imaging studies, suchas computed tomography (CT)/CT venograms, magnetic res-onance (MR) imaging/MR venograms, and contrast venogra-phy (ascending and descending).

The identification and location of reflux can be accurately as-sessed with duplex ultrasound, so the vascular laboratoryshould be the first stop for a workup to obtain a noninvasive,comprehensive, and dynamic assessment of the superficial,perforator, and deep veins. It is recommended that not onlypatients with CVI, but those with telangiectasias and vari-cose veins undergo duplex ultrasound examination of thesuperficial, deep, and (selectively) perforator veins to evalu-ate valvular incompetence prior to initial treatment of CVD.Laboratory workup for screening of patients with positive fa-milial histories of hypercoagulation states or venous ulcersshould be individually tailored.

Recently, the role of CT venograms and MR venograms forthe identification of iliofemoral and caval obstructions in pa-tients with skin damage has been investigated. A positive re-sult showing significant stenosis or obstruction can change

Figure 2. Chronic obstructionwith partial recanalization andreflux in a 58-year-old femalepatient with previous caval,iliofemoral, and popliteal veinthrombosis.She had significant thigh and calfswelling bilaterally. (A) Chronic throm-bosis of the common femoral vein.Echogenic material is seen in the lu-men and there is a lack of compress-ibility. (B) Irregular flow channels areseen in the lumen. Flow is detectedin collateral veins on either side ofthe thrombosed segment. (C) Thefemoral vein is partially recanalizedand has reflux. Chronic thrombus isseen mostly towards the far wall. (D)Reflux in a perforator vein in the lowercalf. The vein is dilated with a diame-ter of 5 mm. Reflux was found in theposterior tibial vein, and the calf pos-terior accessory tributary. The greatsaphenous vein was normal at thislevel, but chronically thrombosed atthe saphenofemoral junction. The pa-tient was treated conservatively withcompression.



the treatment approach and therapy and potentially reducethe recurrence of the venous disease. However, the routineindication of noninvasive and invasive treatments with intra-vascular ultrasound assessment of iliofemoral and caval ob-structive disease is not yet recommended for routine use.

� Medication (venoactive drugs)Many different categories of medication have been used for thetreatment of CVD: alpfa-benzopyrones (coumarin), gamma-benzopyrones (ie, purified flavonoids), saponins (escin andruscus extract), plant extracts (ie, ginkgo biloba), and synthet-ic products (ie, benzaron).20 The use of medication for vari-cose veins is based on the targeting of inflammatory path-ways involved in the development of CVD. The best results ofall the medication regimens are achieved in early cases ofCVD where no significant structural changes of the vein walland valves have occurred. However, certain venoactive drugshave been used successfully in patients with more advanceddisease (with edema and venous ulcers). A meta-analysis of 5prospective, randomized trials in 723 patients demonstratedencouraging results with the adjuvant use of Daflon 500 mg,reporting a 32% improvement in venous ulcer healing rates.21

In an experimental study in rats, purified flavonoid (Daflon500 mg) was found to decrease the levels of granulocyte andmacrophage infiltration in the valves preventing valve dam-age and delaying the development of reflux.22 Another classof flavonoids, the oxerutins, are also utilized for their anti-in-flammatory properties. Low cost, widespread availability, andrare side effects are advantages of treating CVD with medica-tion. The only contraindication to the use of venoactive drugsis allergy to one of the components of the formula, but thisis rare.

� Compression therapy, structured exercise,and wound careCompression therapy has long been considered the first-linetreatment for all symptomatic patients with CVD (C1-C6) wherevenoactive drugs are unavailable (USA, for example). The ra-tionale for using compression hosiery is to increase venousblood flow velocity, thus improving venous reflux, and also toassist the calf muscle pump, therefore reducing leg edema.23,24

The local inflammatory response also decreases with a reduc-tion in cytokine production and the shift of local cutaneousfluid from the interstitial space to the lymphatic system.25,26

There are several advantages of compression therapy. First, allpatients are eligible for use except for those with severe pe-ripheral arterial insufficiency (ankle-brachial index [ABI] <0.5).Second, patients with CVI (C3-C6), especially those with ve-nous stasis ulcers, benefit significantly from therapy with goodlevels of ulcer healing and they remain ulcer-free for a reason-able length of time. In a prospective, multicenter randomizedstudy that examined 200 limbs with venous ulcers that wererandomized for compression or surgical treatment, the ulcerhealing rate was similar in both groups (53%).27 A larger pros-

pective, randomized trial of 500 patients, the ESCHAR (Effectof Surgery and Compression on Healing And Recurrence)trial, demonstrated that compression therapy is as effectiveas surgery plus compression therapy for ulcer healing, butrecurrence rates were higher when compression was usedalone.28 A document detailing multiple modalities of com-pression therapy (ie, simple component, two- or four-com-ponent, elastic, nonelastic) was produced by the CochraneCollaborative Group. The results of the Cochrane systematicreview show that elastic multicomponent systems, ie, con-taining an elastic bandage, appear more effective than thosethat have inelastic components.29 Regardless of the high ef-ficacy of the different compression garments and techniquesin ulcer healing and preventing ulcer recurrence, the mostchallenging aspect of treatment remains the lack of compli-ance: four in five patients are noncompliant.30

Exercises to strengthen the calf muscle pump and intermit-tent pneumatic devices have proven beneficial as an adju-vant therapy in patients with CVD. Calf muscle pump con-ditioning can lead to a subsequent improvement in venousblood return.31 A randomized controlled trial in 31 patients withskin damage or ulcers who were divided into two groups (astructured exercise group [n=18] and controls [n=13]) showedthat the calf pump function did improve venous blood return,but the quality of life and severity scores of the groups weresimilar.32 However, this study only provides short-term resultswith a 6-month follow-up. Large trials with mid- and long-termfollow-ups are warranted to gauge the actual impact of calfpump function on quality of life, venous ulcer healing, and ul-cer recurrence. Compression therapy should not be viewed asa definitive therapy, but rather as a valuable adjuvant tool thatcan be utilized in all symptomatic patients with CVD to hinderthe progress and prevent the recurrence of venous ulcers.

Venous ulcers are responsible for lost work productivity andhigh health-care costs.33,34 Patients with skin damage whodevelop ulcers must be evaluated and treated in specializedwound care centers by a multidisciplinary team.35 The initialtreatment of venous ulcers targets the underlying cause ofCVD (venous obstruction, reflux, or a combination of obstruc-tion and reflux).28 In addition, infected areas require treat-ment with appropriate antibiotic regimens (guided by culturebiopsies) and debridement, which is performed in operatingrooms.36 There has been progress in the field of ulcer de-bridement recently. A new technique for the debridement ofvenous ulcers, low-frequency ultrasound, has been devel-oped, but for the moment limited experience and low-qual-ity evidence mean the routine use of this technique is notrecommended.37

� SclerotherapyVenous injection of sclerosing agents has gained popularitydue to the minimal material, low cost, and short learning curverequired. Currently, two types of sclerotherapy are available:



liquid and foam (Figure 3). Whatever formulation is utilizedfor the ablation of the GSV or SSV, ultrasound guidance ismandatory in order to gauge the amount of foam necessaryto obliterate the segment of interest and, more importantly,to control the extent of sclerotherapy.

The advantages of foam over liquid are better control duringinjection, less volume required to fill the target vessel, greatercircumferential contact area between the treatment and en-dothelial cells, and a longer sclerosing time due to a slowerabsorption compared to the liquid preparation. A multicen-ter randomized controlled trial of 95 patients showed that apolidocanol foam preparation wastwice as effective at achieving andmaintaining venous occlusion overa 2-year follow-up as the liquid ver-sion.38 Furthermore, other studieshave demonstrated that more dilutesolutions, such as 1% polidocanol,are as effective as stronger solutionsof 3% in obliterating GSV <8 mm.39

The drawback of the technique isthe possible inadvertent passage ofsclerosing agent into the deep veins,which is not completely preventedeither with ligation or compression ofthe saphenofemoral junction (SFJ)with the ultrasound probe during theintervention.40 Fortunately, complica-tions of sclerotherapy are rare be-cause they can be serious41: lung and brain emboli have beenreported.41,42 Long-term results from large multicenter, ran-domized controlled trials are still warranted to assess thedurability of treatment and to define potential predictive fac-tors to prevent adverse outcomes.

� Stripping, stab phlebectomy, and ablation proceduresThe treatment of superficial venous reflux has evolved greatlyover the past three decades. The old standard of care, liga-tion of the SFJ or saphenopopliteal junction (SPJ) with or with-out stripping of the GSV or SSV, has been replaced by radio-frequency ablation (RFA) or endovenous laser therapy (EVLT).The stripping of the GSV consisted of dissection and isolationof the SFJ and the distal segment of the GSV or SSV at theend point of reflux with insertion of a metallic or plastic wirethrough the isolated segment with subsequent stripping ofthe vein. The disadvantages of the technique included therisk of wound infection, postoperative pain, longer recoverytime, and a significant inflammatory response in the SFJ orSPJ leading to neovascularization and the recurrence of thevaricose veins.43 Modifications to the traditional stripping withinvagination technique and the use of tumescence have re-duced complications of this technique and have made it anoutpatient procedure.44

EVLT and RFA are ultrasound-guided, catheter-based tech-niques that obliterate the lumen of the GSV and SSV andoccasionally perforator veins via a totally endovascular ap-proach. First, diluted local anesthetic in saline solution is in-jected abundantly prior to the venous ablation in the subcu-taneous tissue around the GSV, SSV, or accessory veins tocreate a fluid barrier between the vein and the skin and to re-duce the size of the vein lumen. The purpose of the tumes-cent local anesthesia is to prevent skin damage (such asthermal injury or discoloration), to increase the effectivenessof the procedure (via vein wall compression), and to provideintra- and postoperative analgesia.

The RFA or EVLT catheter is then inserted into the vein andpositioned up to 2 cm away from the SFJ or SPJ in order toavoid thermal injury or extension of the thrombus into the com-mon femoral or popliteal vein. Different wavelengths of laser(ie, 810-1470 nm) and two different types of energy trans-mission (ie, pulsed or continuous) are commercially availablein the USA.

Endovenous interventions have some advantages over veinstripping as an ambulatory-based intervention with same-daydischarge. These include the feasibility of performing the inter-vention under local anesthesia with light sedation and a fasterreturn to work. Modified stripping techniques with ultrasoundguidance and local perivenous anesthesia without ligation ofthe junction and its triburies may have similar results.44-47 Sev-eral trials have reported similar efficacies with GSV and SSVablation and the resolution of symptoms using either EVLT orRFA.48-50 Complications of endovenous ablation include skinburns and the propagation of the thrombus into the deepveins causing DVT and pulmonary embolism. Venous throm-boembolic events have also been reported with ligation andstripping.51 Recent studies have demonstrated that thermalablation procedures and surgical techniques have similar out-comes in abolishing reflux and improving quality of life.52

Figure 3. Nonsaphenous vein reflux.(A) Prolonged reflux in the left ovarian vein in a patient who presented with pelvic congestion syndrome andvaricose veins in the groin medial to the saphenofemoral junction extending down to posteromedial thigh. Thepatient was treated with selective catheterization of the left ovarian vein. Foam sclerotherapy was used for thedistal tributaries in the pelvis and the ovarian vein was coiled with long coils. The varicosities in the thigh wereremoved with phlebectomy and those in the inner groin with foam sclerotherapy. (B) Prolonged reflux in the veinof the popliteal fossa in a patient who presented with varicosities in the posterior and later calf. The small saphe-nous vein was intact. Phlebectomies were performed with adjunct foam sclerotherapy.



Two other innovative alternatives to vein ablation are the Clari-Vein™ (Vascular Insights,Madison,Connecticut) and the SteamVein Sclerosis (SVS) system™ (Guttman Medical ServicesGmbH, Geretsried, Germany). The former consists of a per-cutaneous 0.035" infusion catheter that contains a rotatingwire operated and activated from a DC battery-powered hand-held device. The pharmacomechanical effects cause endo-thelial damage, intense vasospasm, and eventually throm-bosis of the lumen. The SVS™ system delivers water vaporthrough a heating catheter that does not require a wire in-side the vein causing thermoablation comparable to that ofRFA or EVLT. Like EVLT or RFA, ultrasound guidance is need-ed for both ClariVein™ and SVS™, but tumescent local anes-thesia is only required for the SVS™ system. The initial re-sults of Clarivein™53 and SVS™54 for venous ablation arepromising, but further research is still needed.

In light of the fact that the varicosities of tributaries and acces-sory veins are far more prevalent than those of saphenoustrunks, these veins can be treated alone or in combinationwith the saphenous veins.55 Treatment of varicose veins canbe easily accomplished with stab phlebectomies (Figure 4).

A microincision is carried out near the varicose vein wall topermit the insertion of an angle-tipped instrument used tofish and remove the varicosity. It may be a definitive treatmentfor patients who have isolated varicose veins with superficialor deep vein reflux (CEAP C2) or an adjunct therapy, frequent-ly performed on the same day as venous stripping or abla-tion. Patients with segmental GSV reflux or an incompetentGSV with a normal or mildly dilated caliber and varicose veins

may also be treated with stab phlebectomies alone.44,56 In astudy of 303 limbs, the incompetent GSV was not removed,but only the varicose veins linked to the zones of reflux. Inthis series, 78% of the patients reported an improvement insymptoms or no symptoms at 4-year follow-up.57

The role of PV treatment has been controversial. Although thenumber and size of incompetent PVs increases with CVDseverity, evidence for treating most of these veins is lackingwith the exception of a few cases.13,28,58,59 The role of superfi-cial venous reflux on the development of deep venous incom-petence has been investigated. Since isolated deep venousreflux is rare, the concept of volume overload in the super-ficial venous system causing valve dysfunction in the perfo-rator and deep veins has been reported.11 Treatment of su-perficial vein reflux has been shown to correct valve functionin deep veins.9,10 Patients with skin damage or secondary CVDhave worse results because of chronic inflammatory changes,severe valve dysfunction, and vein wall dilation.

� Open and endovascular venous reconstructionVenous reconstructions are frequently indicated in sympto-matic patients with secondary CVD who have significant ve-nous stenosis, obstruction, or a residual thrombus (Figure 5).Before the endovenous era all patients with ilio-femoral andcaval obstruction were treated with open procedures includ-ing bypass graft, spiral vein interposition graft, and venoplasty.

Initially, an arteriovenous fistula (AVF) is frequently associatedwith venous bypass construction aimed at reducing venousstasis and therefore increasing the patency of the repair. The

Figure 4. Reflux in the lowerthigh great saphenous vein and

a knee tributary.(A) Reflux in the great saphenous vein(GSV) and a tributary at the knee lev-el. High velocity prolonged retrogradeflow was seen in both veins, but wasworst in the tributary (waveform trac-ings not shown). (B) The GSV at thislevel is dilated (8.7 mm). A valve leaflet

is seen at the 9 o’clock position.(C) Cross-sectional view of the GSVand tributary 1 cm below the conflu-

ence of the tributary and GSV. The GSVis normal and the tributary is dilated.(D) At this level, reflux is seen in the

tributary while the GSV is normal. Thispatient was treated with phlebectomies

and the GSV was spared. After theprocedure, GSV diameter was reduced

in size and there was no reflux.Abbreviation: GSV, great

saphenous vein.



shortcoming of AVFs is that the venous hypertension gener-ated causes vein wall dilation, valve destruction, and venousreflux if the AVF is not monitored and ligated in a timely fash-ion. A series of 44 patients with nonmalignant venous ob-struction who underwent different types of reconstructions(ie, spiral vein, bypass, venoplasty, Palma procedure) report-ed an overall primary and secondary patency at 3-years of54% and 62%, respectively.60 Lower primary and secondarypatency rates were found for iliofemoral and iliocaval bypass-es when analyzed separately, only 38% and 54% at 2-yearfollow-up, respectively, likely because the majority of repairswere done using extended polytetrafluoroethylene (PTFE)grafts.60

Endovenous treatment of common femoral and iliocaval ob-struction comprise angioplasty and stenting. The big advan-tage of percutaneous treatment compared with transperitonealor retroperitoneal approaches under general anesthesia isthe lower morbidity and mortality. In a series of 982 chron-ic nonmalignant obstructive lesions of the common femoraland iliocaval veins that were stented, complete relief of painand swelling occurred in 62% and 32% of cases, respec-tively, and ulcer healing in 58% of the patients at 5-year fol-low-up.61

Treatment of venous reflux, obstruction, or a combination ofreflux and obstruction in the femoropopliteal venous segmentremains challenging. Reduced blood flow and caliber of theveins, associated with an aggressive pattern of the disease,are some of the reasons responsible for the significant failurerate and poorer patency.

Several open surgical valve reconstruction techniques havebeen proposed to correct venous reflux and obstruction.The main procedures described are internal and external(transcommissural) valvuloplasty, axillary vein transfer, veintransplantation, and valve transplant.62-64 Surgical expertise,postprocedural care, and referral to a high-volume special-ized center for these specific procedures are essential.

Briefly, with an internal valvuloplasty, the incompetent valveis exposed and the leaflets are approximated suturing theintercomissural space with subsequent closure of the veno-tomy.65 The external (transcommissural) valvuloplasty is per-formed without doing a venotomy with interrupted suturesplaced externally transfixing the venous wall to approximatethe intercomissural space.66 The advantage of the transcom-missural repair is the possibility of treating long segments ina shorter operating time. Valve transfer is often carried outwhile dissecting, dividing, and resecting a segment of veinthat serves as a graft (ie, axillary vein) for replacement of a dis-eased venous segment in a lower extremity.67 Neovalve cre-ation is now feasible with a technique developed by Maletiand colleagues.68 In this technique, an endophlebectomy ofthe venous segment is performed with dissection of the in-tima layer creating a flap that is positioned as a mono- orbicuspid valve with subsequent venorraphy in a transversefashion.68

The use of an external sleeve of Dacron or PTFE wrappedaround the incompetent valve has been advocated by someauthors in order to narrow and approximate the valve leafletsor as an adjunct after a vein transfer to prevent future vein

Figure 5. Pathology in tributariesin a patient with a normal greatsaphenous vein.(A) The saphenofemoral junction is nor-mal during the Valsalva maneuver. Thegreater saphenous vein (GSV) has anormal diameter and refluxing tributariesare seen. (B) The anterior accessorysaphenous vein had reflux from the upperthigh to the calf. The segment seen isfrom the midthigh, where the vein is out-side its canal. It is dilated, tortuous, andhas prolonged reflux. (C) The accessoryvein was in continuity with varicose trib-utaries extending from the lower anterior-medial thigh to the posterior-lateral calf.(D) A short segment of the accessoryvein had acute and chronic thrombosis.The bright areas from the 3 to 5 o’clockposition and the near wall are chronicthrombus, while the dark area is freshthrombus. The patient had localizedinflammation and tenderness over thisarea. Because of the thrombosis, theaccessory vein was partially strippedand the tributaries were treated withphlebectomies.Abbreviation: GSV, great saphenous vein.



wall dilation.69 Satisfactory results have been reported usingall techniques, although limited experiences in a few spe-cialized centers are available for comparison in the US andEurope.

ConclusionCVD is a multifaceted entity responsible for significant neg-ative socioeconomic impact. Treatment of the CVD requires

a complete understanding of the pathophysiological under-pinnings of the disease in order to offer the most appropriatetreatment tailored to the disease specifics of each patient.Combinations of different types of treatment may be neces-sary in the majority of the patients. Given that over 25% of pa-tients with CVD have skin damage, treatment at earlier stagesmay be important to slow down the progression and to re-duce the prevalence of skin damage from CVD. �

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35. Wakefield TW, Henke PK. The Sixth Pacific Vascular Symposium: the venousulcer summit. Arterioscler Thromb Vasc Biol. 2010;30:2337-2338.

36. Williams D, Enoch S, Miller D, Harris K, Price P, Harding KG. Effect of sharpdebridement using curette on recalcitrant nonhealing venous leg ulcers: a con-currently controlled, prospective cohort study.Wound Repair Regen. 2005;13:131-137.

37. Cullum NA, Al-Kurdi D, Bell-Syer SE. Therapeutic ultrasound for venous leg ul-cers. Cochrane Database Syst Rev. 2010;(6):CD001180.

38. Ouvry P, Allaert FA, Desnos P, Hamel-Desnos C. Efficacy of polidocanol foamversus liquid in sclerotherapy of the great saphenous vein: a multicentre ran-domised controlled trial with a 2-year follow-up. Eur J Vasc Endovasc Surg.2008;36:366-370.

39. Hamel-Desnos C, Ouvry P, Benigni JP, et al. Comparison of 1% and 3% polido-canol foam in ultrasound guided sclerotherapy of the great saphenous vein:a randomised, double-blind trial with 2 year-follow-up. “The 3/1 Study”. Eur JVasc Endovasc Surg. 2007;34:723-729; discussion 730.

40. Ceulen RP, Jagtman EA, Sommer A, Teule GJ, Schurink GW, Kemerink GJ.Blocking the saphenofemoral junction during ultrasound-guided foam scle-rotherapy—assessment of a presumed safety-measure procedure. Eur J VascEndovasc Surg. 2010;40:772-776.

41. Gillet JL, Guedes JM, Guex JJ, et al. Side-effects and complications of foamsclerotherapy of the great and small saphenous veins: a controlled multicen-tre prospective study including 1,025 patients. Phlebology. 2009;24:131-138.

42. Bush RG, Derrick M, Manjoney D. Major neurological events following foamsclerotherapy. Phlebology. 2008;23:189-192.

43. Jiang P, van Rij AM, Christie R, Hill G, Solomon C, Thomson I. Recurrent vari-cose veins: patterns of reflux and clinical severity. Cardiovasc Surg. 1999;7:332-339.



44. Pittaluga P, Chastanet S, Guex JJ. Great saphenous vein stripping with preser-vation of sapheno-femoral confluence: hemodynamic and clinical results. J VascSurg. 2008;47:1300-1304; discussion 1304-1305.

45. Bush RG, Hammond KA. Tumescent anesthetic technique for long saphenousstripping. J Am Coll Surg. 1999;189:626-628.

46. Scheltinga MR, Wijburg ER, Keulers BJ, de Kroon KE. Conventional versus in-vaginated stripping of the great saphenous vein: a randomized, double-blind,controlled clinical trial. World J Surg. 2007;31:2236-2242.

47. Proebstle TM, Paepcke U, Weisel G, Gass S, Weber L. High ligation and strip-ping of the long saphenous vein using the tumescent technique for local anes-thesia. Dermatol Surg. 1998;24:149-153.

48. Gale SS, Lee JN, Walsh ME, Wojnarowski DL, Comerota AJ. A randomized,controlled trial of endovenous thermal ablation using the 810-nm wavelengthlaser and the ClosurePLUS radiofrequency ablation methods for superficial ve-nous insufficiency of the great saphenous vein. J Vasc Surg. 2010;52:645-650.

49. Puggioni A, Kalra M, Carmo M, Mozes G, Gloviczki P. Endovenous laser thera-py and radiofrequency ablation of the great saphenous vein: analysis of earlyefficacy and complications. J Vasc Surg. 2005;42:488-493.

50. Goode SD, Chowdhury A, Crockett M, et al. Laser and radiofrequency abla-tion study (LARA study): a randomised study comparing radiofrequency ab-lation and endovenous laser ablation (810 nm). Eur J Vasc Endovasc Surg.2010;40:246-253.

51. van Rij AM, Chai J, Hill GB, Christie RA. Incidence of deep vein thrombosis aftervaricose vein surgery. Br J Surg. 2004;91:1582-1585.

52. Christenson JT, Gueddi S, Gemayel G, Bounameaux H. Prospective random-ized trial comparing endovenous laser ablation and surgery for treatment ofprimary great saphenous varicose veins with a 2-year follow-up. J Vasc Surg.2010;52:1234-1241.

53. Elias S. The ClariVein catheter trial: final results and recommendations. Pre-sented at the 22nd Annual Meeting of the American Venous Forum; February,2010; Amelia Island, Fla.

54. van den Bos RR, Milleret R, Neumann M, Nijsten T. Proof-of-principle study ofsteam ablation as novel thermal therapy for saphenous varicose veins. J VascSurg. 2011;53:181-186.

55. Labropoulos N, Kokkosis AA, Spentzouris G, Gasparis AP, Tassiopoulos AK.The distribution and significance of varicosities in the saphenous trunks. J VascSurg. 2010;51:96-103.

56. Labropoulos N, Leon L, Engelhorn CA, et al. Sapheno-femoral junction refluxin patients with a normal saphenous trunk. Eur J Vasc Endovasc Surg. 2004;28:595-599.

57. Pittaluga P, Chastanet S, Rea B, Barbe R. Midterm results of the surgical treat-ment of varices by phlebectomy with conservation of a refluxing saphenous vein.J Vasc Surg. 2009;50:107-118.

58. Nelzén O, Fransson I; Swedish SEPS Study Group. Early results from a random-ized trial of saphenous surgery with or without subfascial endoscopic perfora-tor surgery in patients with a venous ulcer. Br J Surg. 2010 Dec 24. Epub aheadof print.

59. Kalra M, Gloviczki P. Subfascial endoscopic perforator vein surgery: who ben-efits? Semin Vasc Surg. 2002;15:39-49.

60. Jost CJ, Gloviczki P, Cherry KJ Jr, et al. Surgical reconstruction of iliofemoralveins and the inferior vena cava for nonmalignant occlusive disease. J VascSurg. 2001;33:320-327; discussion 327-328.

61. Neglen P, Hollis KC, Olivier J, Raju S. Stenting of the venous outflow in chronicvenous disease: long-term stent-related outcome, clinical, and hemodynamicresult. J Vasc Surg. 2007;46:979-990.

62. Meissner MH, Eklof B, Smith PC, et al. Secondary chronic venous disorders.J Vasc Surg. 2007;46(suppl S):68S-83S.

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TRAITEMENT DE LA MALADIE VEINEUSE CHRONIQUE : BASES PHYSIOPATHOLOGIQUES

L’impact socio-économique de la maladie veineuse chronique (MVC) est significativement négatif dans la société.Peu douloureuse, elle est bien tolérée jusqu’à la mise en route du traitement. La plupart des patients négligent sou-vent la phase initiale de la maladie et sont demandeurs d’un traitement lorsque la maladie est évoluée. Le refluxveineux superficiel est la pathologie la plus courante, contrairement au reflux veineux profond isolé. L’obstruction iso-lée est rare mais fréquemment retrouvée en association avec un reflux, scénario au plus mauvais pronostic. Il existeplusieurs modalités de traitement, des phlébotoniques aux interventions endoveineuses ou à ciel ouvert. Il faut unecompréhension complète des mécanismes impliqués dans le développement de la MVC pour choisir le traitementle plus approprié et personnalisé pour chaque patient. Cet article traite des bases physiopathologiques impliquéesdans le traitement de la MVC.

Keywords: chronic venous disease; treatment; pathophysiology

Ğ

ğ

ğMEDICOGRAPHIA, Vol 33, No. 3, 2011 Classifications, severity scorings, and chronic venous disease guidelines – Kurtoglu and Aksoy268

C hronic venous disease (CVD) continues to impose a significant burdenon both patients and physicians since the way to manage it most ef-fectively still remains elusive. A great deal of research has revealed

that the long-term outcomes of highly distinct treatment methods, includinginvasive and completely noninvasive techniques, yield comparable resultsoverall. The rationales behind these techniques are very different from eachother, which raises a concern about the validity of the methods that are usedto calculate the severity of CVD before and after treatment. One of the majorobstacles to collecting consistent CVD management data is that CVD sever-ity can be evaluated in many different ways. While a patient’s quality of lifeis perhaps the most important measurement, physician-centered parame-ters exist and they are primarily based on the pathophysiology of the disease.Furthermore, the variability in the perception of the disease among differentgroups of patients presents another challenge in drawing conclusions fromvarious studies. These scoring systems need to be dynamic, since CVDman-agement comprises the treatment of clinical issues that evolve over a longperiod of time. Realization of these pitfalls has resulted in a number of mod-ifications to previously established scoring systems. However, even today,the modified versions individually fail to indicate the overall severity of the dis-ease. Thus, there is still the need to generate a universally acceptable scor-ing system in CVD that combines the most significant parameters of the cur-rent investigation methods.


R ecently, management of chronic venous disease (CVD) has embraced newmethods of treatment. In the 20th century, the only treatment for CVD was var-ious methods of surgery with some forms of conservative therapy, ie, stock-

ings. Although all of these methods were claimed to be effective, the long-termoutcomes as well as the efficacy of these treatments have never been compared toeach other. Until recently, it was assumed that surgery was more efficacious thanconservative approaches, and therefore the latter form of treatment was saved forpatients who were not eligible for surgery.

The move towards surgical management of CVD has generated newer forms ofmethods, such as ASVAL (incompetent sAphenouS Vein preservAtion with phLe-bectomy [Ablation Sélective des Varices sous Anesthésie Locale]) and CHIVA (Con-servative ambulatory HemodynamIc management of VAricose veins [Cure conser-

Address for correspondence:Prof Murat Aksoy, Departmentof General Surgery, Istanbul TipFakultesi Capa, Istanbul,34390 Turkey(e-mail: [email protected])


Classifications, severityscorings, and chronic

venous disease guidelines

by M. Kurtoglu and M. Aksoy, Turkey



In summary, it is clear thatone investigational method doesnot suffice to evaluate the man-agement of CVD. Both physician-and patient-centered methodsneed to be utilized to generatesatisfactory conclusions. However,using all these methods togetherproduces complex results that arecumbersome to interpret and com-municate. Thus, we need to revisitour understanding of the etio-pathogenesis of CVD to guide usin designing evaluation methodsthat focus on pathologic factors.”

‘‘

Murat AKSOY, PhD

Peripheral Vascular Surgery UnitDepartment of General SurgeryIstanbul Medical FacultyIstanbul University, IstanbulTURKEY

Mehmet KURTOGLU, MD

ğ


Classifications, severity scorings, and chronic venous disease guidelines – Kurtoglu and Aksoy MEDICOGRAPHIA, Vol 33, No. 3, 2011 269

vatrice et Hémodynamique de l’Insuffisance Veineuse en Am-bulatoire]). However, postoperative analysis of these meth-ods by Doppler ultrasonography has revealed that all of thesurgical approaches were comparable. This finding is inter-esting since the methodologies of these surgical approacheswere distinct from each other: CHIVA is based on correctingdescending venous reflux, while ASVAL is based on the as-cending negative pressure steal phenomenon. Despite thesedifferences, the early anatomical, clinical, and hemodynam-ic results of these methods were surprisingly similar.1,2

In addition to surgical methods, newer approaches using ra-diofrequency, lasers, and sclerotherapy to ablate veins havefurther expanded the range of methods to manage CVD.These newer approaches are reported to be at least as ef-fective as conventional surgical methods.3-5 It appears thatmethods that are grossly different from each other claim tohave similar outcomes. The question then becomes: “Howshould we define the effectiveness or success of CVD man-agement?” From the patient’s point of view, success and sat-isfaction is usually based on improving quality of life, whilephysicians would also focus on resolving the anatomical andhemodynamical pathologies of CVD. Another measure of ef-fectiveness comes from an economic standpoint: cost-effec-tiveness of management. Lastly, it should not be forgottenthat the severity of recurrence has its own role in defining theefficacy and success of a treatment method.

What current instruments can assess the efficacyof CVD treatment?Since all methods of CVDmanagement claim to be efficacious,we need to elaborate on what kind of assessment tools canbe used to evaluate the efficacy of CVD management. Thefollowing section will focus on defining these tools as well astheir validity in assessing the efficacy of CVD management.

These tools can be summarized as anatomical (color duplex),hemodynamical (venous pressures), clinical (CEAP [Clinical-Etiological-Anatomical-Pathophysiological] and VSS [VenousSeverity Score]), and functional (quality of life).

� Anatomical investigationThe clinical outcome of venous disease is related to the ex-tent of venous insufficiency involvement.6 In consequence,anatomical assessment is an outstanding way of evaluatingthe disease. Anatomical assessment of CVD is mainly basedon color duplex imaging of veins. This instrument-based ap-proach generates both morphological and functional resultsto evaluate CVD management. There is a widely acceptedterminology used in this method, which is based on the ob-struction and reflux of superficial, perforating, and deep veins.Therefore, color duplex imaging allows both quantitative andqualitative assessment of the severity of pathology in theseveins. The diameter of the incompetent vein can be measuredby duplex imaging. However, diameter alone is not a valid

method of assessment. This measurement may be of valuein cases where an increase is detected during follow-up be-cause it may be indicative of a recently developed connectionbetween the greater saphenous vein and pelvic sources of re-flux. Measurement of diameter is recommended at the junc-tion and along the great saphenous vein if there is reflux. Al-though a definitive cutoff for all vein segments has not beenagreed, venous reflux is considered to be retrograde flow inthe reverse direction to physiological flow if it lasts for morethan 0.5 s.7,8 Finally, diameter is not a marker for indication, butmay help in deciding the type of intervention required, such assclerotherapy, laser, or radiofrequency ablation.

� Clinical investigationClinical investigations are based on the assessment of visiblepathologies that result from CVD, such as edema, varicoseveins, and ulcers. The clinical evaluation of these pathologiesis further supplemented by color duplex imaging of veins. Inthe course of CVD management, these visible pathologiescan be partially or completely resolved, and clinical investi-gations score the level of this improvement. However, it isimportant to note that these investigations are not sufficient-ly dynamic to assess the durability of wellness.


ASVAL incompetent sAphenouS Vein preservAtion withphLebectomy [Ablation Sélective des Varicessous Anesthésie Locale]

AVVQ Aberdeen Varicose Veins Questionnaire

CEAP Clinical-Etiological-Anatomical-Pathophysiological

CHIVA Conservative ambulatory HemodynamIc managementof VAricose veins [Cure conservatrice et Hémody-namique de l’Insuffisance Veineuse en Ambulatoire]



CVI chronic venous insufficiency

CXVUQ Charing X [cross] Venous Ulceration Questionnaire

EQ-5D EuroQol 5 Dimension [mobility, self-care, usual activ-ities, pain/discomfort, anxiety/depression healthsurvey]

NHP Nottingham Health Profile

RELIEF Reflux assEssment and quaLity of lIfe improvEmentwith micronized Flavonoids

SF-12 Short Form 12 [-item health survey]

SF-36 Short Form 36 [-item health survey]

SQOR-V Specific Quality Of life Response–Venous

VCSS Venous Clinical Severity Score

VDS Venous Disability Score

VEINES VEnous INsufficiency Epidemiological and economicStudy

VSDS Venous Segmental Disease Score

VSS Venous Severity Score

ğ


MEDICOGRAPHIA, Vol 33, No. 3, 2011 Classifications, severity scorings, and chronic venous disease guidelines – Kurtoglu and Aksoy270

There are two main clinical investigation methods: CEAPand VSS. The CEAP classification was first developed in the1990s.9,10 The original classification was modified in 2004,since at the time it was not adequately dynamic nor did itadequately correlate with symptoms. This modification al-lowed better communication between physicians, which ledto improved assessment of CVD management efficacy. How-ever, even the modified version continued to be physician-cen-tered and hence did not always correlate with patient symp-toms. These investigations are not necessarily responsive toimprovements following treatment.

Upon realization of the pitfalls of CEAP, the American VenousForum developed the VSS, which was designed to supple-ment CEAP scoring and to provide a method for serial as-sessment. VSS is mainly used for longitudinal follow-up of apatient’s condition during and following treatment. The scor-ing system has three components10:

� Venous Disability Score (VDS)This method is an extension of CEAP that evaluates the levelof work-based disability. Based on the ability to work with orwithout support, disability is scored from 0 to 3. The total re-sult will show the disability associated with venous disease.

� Venous Segmental Disease Score (VSDS)This score is based on anatomical and pathophysiologicalcomponents of CEAP, obstruction and reflux. This part requiresassessment with Doppler ultrasonography or phlebography.

� Venous Clinical Severity Score (VCSS)This is a dynamic form of CEAP evaluation that has been de-signed to include 9 hallmarks of the most severe complica-tions of CVD. These include skin changes, inflammation, in-duration, and ulcers. Each hallmark is scored on a severityscale ranging from 0 to 3. VCSS is an easy-to-apply, stand-alone scoring system. This part of the VSS has been stud-ied expansively and is frequently used for longitudinal sur-veillance of venous disease.

� Physiological investigationThese are hemodynamic investigations that are usually per-formed for academic purposes. This method uses plethys-mography, which monitors the change in ambulatory venouspressures following treatment of CVD. The patterns of venousflow in different vein segments are also evaluated by either du-plex scan or phlebography.

� Functional investigationThese are generic and disease-specific assessments of qual-ity of life. The generic assessments are SF-36 (Short Form 36[-item health survey]), SF-12 (Short Form 12 [-item health sur-vey]), EQ-5D (EuroQol 5 Dimension [mobility, self-care, usualactivities, pain/discomfort, anxiety/depression health survey]),while the disease specific ones are AVVQ (Aberdeen Varicose

Veins Questionnaire), SQOR-V (Specific Quality Of life Re-sponse–Venous), CIVIQ-2 (ChronIc Venous dIsease Question-naire 2), and VEINES (VEnous INsufficiency Epidemiologicaland economic Study). Generic methods are geared towardevaluating the subjective assessment of quality of life, whilethe disease-related surveys examine specific elements as-sociated with a particular disease process. Since the latterones are more specific in their scope, they have becomemore popular in evaluating CVD management.

� Generic instruments– SF-36The SF-36 is a valid assessment of quality of life. The scoringsystem is based on two types of health aspect: physical healthand mental health.11 The former is assessed via the patient’slevel of functioning, whilst the latter is assessed via an indi-cator of well-being. These two types include eight domains:assessment of physical and social functioning, role limitationsdue to physical and emotional problems, mental health, pain,vitality, and health perception. The SF-36 is a good way of as-sessing changes in quality of life in CVD. It has beenwidely usedin studies concerning patients affected with venous disorders.

– Nottingham Health ProfileThe Nottingham Health Profile (NHP) is intended for primaryhealth care to provide a brief indication of a patient’s perceivedemotional, social, and physical health problems.12 It consistsof two parts. Part I contains 38 yes/no items in 6 domains:pain, physical mobility, emotional reaction, energy, social iso-lation, and sleep. Part II contains 7 general yes/no questionsconcerning daily-living problems. It can be applicable to oth-er diseases as well as to CVD.

� Disease-specific instruments– CIVIQThis method contains questions to assess the physical, psy-chological, social, and pain aspects of CVD. The first versionof this questionnaire included different numbers of questionsin each category.13 The second version, CIVIQ 2, provides aglobal score covering all aspects of the questionnaire andweighs the categories equally. Both versions of the ques-tionnaire are reported to be valid quality-of-life measurements.The RELIEF (Reflux assEssment and quaLity of lIfe improvE-ment with micronized Flavonoids) study,13 which was con-ducted in 23 countries worldwide and included the partici-pation of more than 10 000 patients suffering from chronicvenous insufficiency (CVI), validated CIVIQ, the first quality-of-life scale specific to chronic venous insufficiency, and as-sessed changes in the quality of life of patients suffering fromCVI, with or without venous reflux, treated with micronized pu-rified flavonoid fraction.

– VEINESCompared with CIVIQ, this method focuses more on symp-toms than the psychological and social aspects of the dis-

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ease. The VEINES questionnaire consists of 25 items that es-timate the effect of disease on quality of life, and the VEINESsymptom questionnaire consists of 10 items that measuresymptoms.14

– Aberdeen Varicose Vein QuestionnaireAVVQ addresses multiple aspects of varicose disease, includ-ing physical symptoms, social issues, as well as the cosmet-ic manifestations of treatment outcome. The overall evalua-tion consists of a score with a range of 0 to 100.15

– Charing Cross Venous Ulceration QuestionnaireThe CXVUQ was developed to provide a valid quality-of-lifemeasurement of venous ulcers. This method may be com-bined with the SF-36 to generate valuable information on theprogression of ulcers and their treatment. This questionnairehas been mainly designed for patients with venous ulcers.16

– Cost-effectiveness investigationThis type of investigation is independent of patient- or physi-cian-centered assessments and plays an important role inselecting effective treatment, although it is currently under-utilized. As the use of new technologies in CVD managementbecomes more widespread, their current high costs are ex-pected to decrease, which may affect physicians’ decisionon what appropriate treatment of CVD they choose. It is im-portant to include early economic impact measures in thisinvestigation, such as time away from work following treat-ment as well as possible costs due to recurrences. Theseeconomic aspects of CVD are currently underemphasizedand require more attention.

DiscussionThe main dilemma in evaluating these investigative methodsis whether patient- or physician-centered evaluation meth-ods are superior. In other words, should we rely on indicatorsfrom the perspective of the physician or the patient? Perhapsmore importantly, can we develop methods to satisfy both?

It is important to note that venous diseases are individual-based pathologies, such that patient satisfaction becomesa hallmark of effective treatment. However, evaluation of pa-tient satisfaction can contain obvious subjective measures,which generate an obstacle to standardizing the method ofreporting CVD management outcomes.17

It is obvious that investigations that are patient-centered needto remain a critical part of evaluating CVD management out-comes. However, there is a high degree of variation in theway that patients assess the effect of CVD on their quality oflife.18 Ethnic, educational, and work-related issues play animportant role in how patients perceive CVD-related symp-toms.14 A further complication of this issue is the observationthat CVD pain can manifest itself in various forms dependingon the underlying pathogenesis of the disease.

It is evident that combining methods geared toward patientsand physicians would generate more satisfactory results.12

However, combining methods would likely compromise ef-fective communication of results, since the methodologieswould be cumbersome and somewhat complicated. How-ever, it is our opinion that the combination of CEAP and VCSSyields the most complete evaluation of CVD treatment meth-ods without compromising effective communication betweenvarious centers.

The prevalence of venous disease is approaching 30%, asreported in various studies worldwide.19 However, the effec-tiveness of the treatment of CVD is still unsatisfactory, de-spite the recent development of various techniques to pro-vide alternatives to conventional surgery. As a matter of fact,these new techniques have raised further questions, sinceearly, short-period, ie, 3 weeks, posttreatment follow-up hasdemonstrated no differences in patient satisfaction comparedwith either surgery or with other new techniques.20,21 Thus withthis equivalence, cost-effectiveness becomes an importantfactor, since these new technologies cost more than surgicalmethods. Balancing this, we cannot exclude the fact thatthese newer technologies provide better comfort in the ear-ly posttreatment period and shorter delays in returning towork.22 As a result, patients and therefore physicians con-tinue to want to utilize these techniques, which may reducetheir cost in the near future. These arguments provide a ba-sis for why more dynamic treatment evaluation methods areneeded since in addition to early outcomes in CVD manage-ment, long-term effects and recurrences need to be factoredin to draw better balanced conclusions from studies.

Different surgical approaches as well as new technology-based techniques are designed to ablate superficial venoussystem and to resolve obstructions in the deep venous sys-tem. However, a fundamental difference between surgical andnewer approaches is that the former focuses on preventingsaphenofemoral junction reflux with high ligation, while thelatter minimally invasive techniques ablate the vein at least2.5 cm below the junction in order to prevent potential com-plications of the common femoral vein, including deep veinthrombosis. Interestingly, as mentioned above, these thera-peutic methods are reported to result in similar outcomes,20,21

which raises the question of whether reflux of the sapheno-femoral junction plays a significant role in progression of ve-nous disease.

Anatomical investigations, ie, Doppler ultrasound, indicate theseverity of venous disease based on the investigation of thepathway of the saphenous trunk and saphenofemoral junc-tion reflux. If reversing the reflux appears to play no role in theoutcome of CVD management, are anatomical investigationmethods biased? On the other hand, in the deep venous sys-tem, resolving postthrombotic obstructions improves patientsymptoms, since recanalization via stents without prevent-

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MEDICOGRAPHIA, Vol 33, No. 3, 2011 Classifications, severity scorings, and chronic venous disease guidelines – Kurtoglu and Aksoy272

ing reflux has been shown to resolve symptoms of CVD.23,24

Yet again, there is another perspective: CVD primarily due toreflux is treated by obviating this pathology via reconstructionof the valves.25,26 These contradictions in the use of CVD man-agement techniques and their results reveal the lack of un-derstanding of how venous disease progresses and showthat evaluation techniques that mainly rely on anatomical in-vestigations, such as CEAP, may give biased results.

In summary, it is clear that one investigational method doesnot suffice to evaluate the management of CVD. Both physi-cian- and patient-centered methods need to be utilized togenerate satisfactory conclusions. However, using all thesemethods together produces complex results that are cumber-some to interpret and communicate. Thus, we need to revisitour understanding of the etiopathogenesis of CVD to guideus in designing evaluation methods that focus on pathologicfactors that play a significant role in the progression of venousdisease. All reports indicate that current treatment of patholo-gies that are thought to underlie CVD does not prevent recur-

rence of the disease. Furthermore, every recurrence appearsto demonstrate distinct clinical and anatomical features ineach patient: generalization of CVD treatment outcome maybe challenging in an individual-based disease. Moreover, sinceCVD is a life-long progressive disease, all investigation meth-ods should be adequately dynamic to work in parallel with theprogression of management.

ConclusionCurrently, there are several investigational methods availablethat provide somewhat limited, but nevertheless adequate,information regarding the management outcomes of CVD.We believe that the reason for developing significantly dis-tinct investigation methods is the diversity of ways in whichCVD manifests in each individual and therefore methods likeCEAP and VCSS, which are dynamic and patient- and physi-cian-centered, appear to provide sufficient data to evaluatethe efficacy of CVD management. A better understanding ofthe etiopathogenesis of CVD will facilitate further modifica-tion of investigational methods. �

References1. Maeso J, Juan J, Escribano J, et al. Comparison of clinical outcome of strip-ping and CHIVA for treatment of varicose veins in the lower extremities. AnnVasc Surg. 2001;15:661-665.

2. Carandina S, Mari C, De Palma M, et al. Varicose vein stripping vs haemody-namic correction (CHIVA): a long term randomised trial. Eur J Vasc EndovascSurg. 2008;35:230-237.

3. Agus GB, Mancini S, Magi G. The first 1000 cases of Italian Endovenous-laserWorking Group (IEWG). Rationale, and long-term outcomes for the 1999-2003period. Int Angiol. 2006;25:209-215.

4. Nael R, Rathbun S. Treatment of varicose veins. Curr Treat Options CardiovascMed. 2009;11:91-103.

5. Almeida JI, Kaufman J, Göckeritz O, et al. Radiofrequency endovenous Clo-sureFAST versus laser ablation for the treatment of great saphenous reflux: amulticenter, single-blinded, randomized study (RECOVERY study). J Vasc In-terv Radiol. 2009;20:752-759.

6. Gillet JL, Perrin MR, Allaert FA. Clinical presentation and venous severity scor-ing of patients with extended deep axial venous reflux. J Vasc Surg. 2006;44:588-594.

7. Sarin S, Sommerville K, Farrah J, Scurr JH, Coleridge Smith PD. Duplex ul-trasonography for assessment of venous valvular function of the lower limb.Br J Surg. 1994;81:1591-1595.

8. Labropoulos N, Tiongson J, Pryor L, et al. Definition of venous reflux in lower-extremity veins. J Vasc Surg. 2003;38:793-798.

9. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum InternationalAd Hoc Committee for Revision of the CEAP Classification. Revision of the CEAPclassification for chronic venous disorders: consensus statement. J Vasc Surg.2004;40:1248-1252.

10. Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH, Mon-eta GL. Venous severity scoring: An adjunct to venous outcome assessment.J Vasc Surg. 2000;31:1307-1312.

11. Davies AH, Rudarakanchaana N. Quality of life and outcome assessment inpatients with varicose veins. In: Davies AH, Lees TA, Lane IF, eds. Venous Di-sease Simplified. Shropshire, England: TFM Publishing Ltd; 2006.

12. Vasquez MA, Munschauer CE. Venous clinical severity score and quality of lifeassessment tools: application to vein practice. Phlebology. 2008;23:259-275.

13. Jantet G. RELIEF study: first consolidated European data. Reflux assEssmentand quaLity of lIfe improvement with micronized Flavonoids. Angiology. 2000;51:31-37.

14. Kurz X, Lamping DL, Kahn SR, et al; VEINES Study Group. Do varicose veinsaffect quality of life? Results of an international population-based study. J VascSurg. 2001;34:641-648.

15. Klem TM, Sybrandy JE, Wittens CH. Measurement of health-related quality oflife with the Dutch translated Aberdeen Varicose Vein Questionnaire before andafter treatment. Eur J Vasc Endovasc Surg. 2009;37:470-476.

16. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of lifein patients with venous ulcers. J Vasc Surg. 2000;31:642-649.

17. Chassany O, Le-Jeunne P, Duracinsky M, Schwalm MS, Mathieu M. Discrep-ancies between patient-reported outcomes and clinician-reported outcomesin chronic venous disease, irritable bowel syndrome, and peripheral arterial oc-clusive disease. Value Health. 2006;9:39-46.

18. Dunic I, Medenica L, Bobic B, Djurkovic-Djakovic O. Patients’ reported qual-ity of life in chronic venous disease in an outpatient service in Belgrade, Ser-bia. Eur J Dermatol. 2009;19:616-620.

19. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venousstasis syndrome and venous ulcer: a 25-year population-based study. J VascSurg. 2001;33:1022-1027.

20. Rasmussen LH, Bjoern L, Lawaetz M, Blemings A, Lawaetz B, Eklof B. Ran-domized trial comparing endovenous laser ablation of the great saphenous veinwith high ligation and stripping in patients with varicose veins: short-term re-sults. J Vasc Surg. 2007;46:308-315.

21. Kalteis M, Berger I, Messie-Werndl S, et al. High ligation combined with strip-ping and endovenous laser ablation of the great saphenous vein: early resultsof a randomized controlled study. J Vasc Surg. 2008;47:822-829.

22. Subramonia S, Lees T. Radiofrequency ablation vs conventional surgery forvaricose veins—a comparison of treatment costs in a randomised trial. Eur JVasc Endovasc Surg. 2010;39:104-111.

23. Neglén P. Chronic deep venous obstruction: definition, prevalence, diagnosis,management. Phlebology. 2008;23:149-157.

24. Kölbel T, Lindh M, Akesson M, Wassèlius J, Gottsäter A, Ivancev K. Chroniciliac vein occlusion: midterm results of endovascular recanalization. J Endo-vasc Ther. 2009;16:483-491.

25. Raju S, Neglén P, Doolittle J, Meydrech EF. Axillary vein transfer in trabeculatedpostthrombotic veins. J Vasc Surg. 1999;29:1050-1062.

26. Lugli M, Guerzoni S, Garofalo M, Smedile G, Maleti O. Neovalve construction indeep venous incompetence. J Vasc Surg. 2009;49:156-162.

Keywords: chronic venous disease; guidelines; scoring systems; classifications

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CLASSIFICATIONS, COTATION DE SÉVÉRITÉ ET RECOMMANDATIONSDANS LA MALADIE VEINEUSE CHRONIQUE

La maladie veineuse chronique (MVC) représente toujours une charge significative pour les patients et les médecinspuisque la façon la plus efficace de la prendre en charge reste difficile à déterminer. De nombreuses recherchesont montré que les résultats à long terme de méthodes de traitement très différentes, y compris des techniquesinvasives ou non invasives, étaient globalement identiques. Les argumentaires de ces techniques sont très différentsles uns des autres, ce qui pose la question de la validité des méthodes utilisées pour calculer la sévérité de la MVCavant et après traitement. Le fait que cette sévérité puisse être évaluée de différentes façons est un des principauxobstacles au recueil de données pertinentes sur la prise en charge de la MVC. La qualité de vie du patient est pro-bablement le critère le plus important mais il existe des paramètres centrés sur le médecin et basés principalementsur la physiopathologie de la maladie. De plus, la variabilité de la perception de la maladie dans les différents groupesde patients est une autre difficulté pour tirer des conclusions des diverses études. Ces systèmes de cotation doiventêtre dynamiques puisque la prise en charge de la MVC prend en compte le traitement des problèmes cliniques quiapparaissent sur une longue période. La compréhension de ces obstacles a entraîné de nombreuses modificationsdes systèmes de cotation précédents. Cependant, même aujourd’hui, les versions modifiées prises séparément neparviennent pas à indiquer la sévérité de la maladie dans sa totalité. Il faut donc créer un système de cotation uni-versel dans la MVC qui réunirait les critères les plus importants de toutes les méthodes d’investigation actuelles.

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Current status of PROs and chronic venous disease guidelines – Mansilha274

C hronic venous disease (CVD) is highly prevalent in the Western worldand is associated with significant costs. Outcome studies promoteunderstanding of the disease and the results of treatment. The use of

patient-reported outcomes (PROs) by patients suffering from CVD is thoughtto be an important step forward in the assessment of patients’ perspective ofthe disease, quality-of-life (QOL) questionnaires being the best adapted in-struments. Despite some limitations in the evidence available, there are eightcriteria that provide an explicit framework for selecting PROs. Eight simplequestions can help choose PROs, each question being linked to a specificcriterion: appropriateness, reliability, validity, responsiveness, precision, inter-pretability, acceptability, and feasibility. Concerning the evaluation of patients’QOL, two types of questionnaires can be used: generic and disease-specific.Generic instruments are designed to be applicable across a wide range ofpopulations and treatments and are able to capture information on a broadrange of aspects of health status and disease consequences. On the otherhand, specific QOL instruments have been developed to provide patients’perception of a specific disease, health problem, or intervention. In the latestguidelines published in the area of venous disease, it is clear that PRO assess-ment is already a priority, CIVIQ (ChronIc Venous dIsease Questionnaire) be-ing the most recent and validated specific questionnaire with psychometriccriteria.


T oday, contemporary medicine places great value on patients’ perspectiveof disease—how they are concerned by it and experience it—and patients’respective health condition. With this in mind, there is a growing interest in

patient-reported outcomes (PROs), which nowadays are considered key outcomes.1

“Patient-reported outcome” is a term used for instruments that measure perceivedhealth outcomes or end points assessed by patient reports, implemented by self-administered questionnaires, and completed by patients themselves or by interview-ers.2 These instruments can cover several aspects, such as preferences about carereceived, health behaviors, and outcomes of care (subjective symptoms, patient sat-isfaction, and health-related quality of life [QOL]).3-5

It is widely recognized that traditional outcomes (clinical and laboratory measures)need to be complemented by measures that focus on patients’ concerns in orderto evaluate interventions and identify more appropriate forms of health care.6 In this

Armando MANSILHAMD, PhD, FEBVSFaculty of Medicine of PortoUniversity, Hospital São JoãoPorto, PORTUGAL

Address for correspondence:Prof Armando Mansilha, Rua JúlioDinis, nº 826, 5º, 4050-322 Porto,Portugal (e-mail:[email protected])


Current status ofpatient-reported outcomes

and chronic venousdisease guidelines

by A. Mansi lha , Por tugal



It is widely recognized thattraditional outcomes (clinical andlaboratory measures) need to becomplemented by measures thatfocus on patients’ concerns in or-der to evaluate interventions andidentify more appropriate forms ofhealth care. In this regard, patient-reported outcomes are uniqueand complementary indicators oftraditional outcomes, providingadditional information about dis-ease and treatment efficacy.”

‘‘

regard, PROs are unique and complementary indicators oftraditional outcomes, providing additional information aboutdisease and treatment efficacy.4

Types and application of PROsAn enormous range of instruments in the form of question-naires, interviews, and rating and assessment forms werecreated with the objective of evaluating states of health andillness from a patient’s perspective.7 Maybe because no ex-clusive and rigid classification exists, several authors haveproposed dividing these instruments into seven major types(Table I).7

With regard to their application, PROs can be applied in dif-ferent fields, particularly generic and disease-specific QOLquestionnaires. However, the majority have been developedfor clinical trials and economic evaluation to assess the health-care needs of populations and to assist health-care profes-sionals in the treatment of individual patients.

� Clinical trials and cost-utility studiesThe number of trials and cost-utility studies that include PROmeasures is progressively increasing. Nowadays, the major-ity of studies include determinations of health status or QOL,unless these outcomes are not relevant to the study.7 PROmeasures have been used as primary outcomes (eg, in theevaluation of a drug’s treatment effect on QOL) in random-ized controlled trials or in nonrandomized research designs,despite their more complex interpretation.7

In a different way, when investigators need to obtain an over-all evidence value for a health-care intervention that allowscomparisons with other interventions, in the same treatmentarea or across areas, outcomes in the form of utilities are re-quired. The most widely known form of a summary value forthe purpose of comparing treatments is the quality-adjust-ed life year (QALY).7

� Assessing health-care needs of populationsApart from conventional data such as mortality and morbidityrates, there are other measures that may also indicate health-care needs. Among them, PRO measures provide a feasible

and valid measure of health status, particularly if such assess-ments are based on questionnaires with proven acceptabil-ity. There is growing evidence reinforcing the idea that poorscores on health-status measures may be associated with el-evated rates of subsequent health service use and mortality.7

Health authorities and those responsible for purchasing orproviding health care are increasingly expected to base theirdecisions about health-care resource allocation on evidence,and PROmeasures add invaluable material to existing sources

of health status information, helping these decision-makers.7

Even though the value of patients’ input is acknowledged,there is some resistance to including PROs as one of the keysources of information among health-care decision-makersowing to issues related to the measurement and interpreta-tion of patients’ perspective.8

� Individual patient carePROs offer an important aid to physicians in patient care. Self-completed questionnaires, with proven reliability and validity,offer quick and consistent evidence of a patient’s view abouthis health that complements the clinical data of physicians.7

Using PROs, health-care professionals can screen health prob-lems that would otherwise not be apparent and can moni-tor the progression of disease as perceived by the patientand the outcomes of any treatment.7 Nevertheless, it is nec-essary to consider that in the context of clinical care, an indi-vidual score is less precise than the one obtained for a groupof patients.7 As a consequence, the applicability of PROs inindividual patient care is more difficult.7


Current status of PROs and chronic venous disease guidelines – Mansilha MEDICOGRAPHIA, Vol 33, No. 3, 2011 275




FLP Functional Limitations Profile

PRO patient-reported outcome

QOL quality of life

SF-36 Short Form 36-item [health survey]

SIP Sickness Impact Profile

WHO World Health Organization

Type of PRO Examples of this type of PRO

Generic Medical Outcomes Study 36-Item ShortForm health survey, Functional Limita-tions Profile

Disease-specific Asthma Quality of Life Questionnaire,Arthritis Impact Measurement Scales

Population-, site-, Child Health and Illness Profile-Childor region-specific Edition, Oxford Hip Score, Shoulder

Disability Questionnaire

Dimension-specific Beck Depression Inventory, McGill PainQuestionnaire

Summary items Question about limiting, long-standing ill-ness in the General Household Survey

Individualized McMaster Toronto Arthritis Patient Pref-erence Disability Questionnaire,Schedule for the Evaluation of Individ-ual Quality of Life

Utility measures EuroQol 5D, Health Utility Index

Table I. The seven major types of PROs and examples of eachtype.Abbreviations: PRO, patient-reported outcome.



Choosing a PRODespite clear limitations in the evidence available, there areeight criteria that provide an explicit framework for selectingPROs. Eight simple questions can be formulated in order tohelp choose PROs, each question being linked to a specificcriterion (Table II).7,9

Chronic venous deseaseIn Western countries, chronic venous disease (CVD) has ahigh prevalence and morbidity. Recent data indicate that theprevalence of varicose veins is estimated to be 25% to 33%in women and 10% to 20% in men.10 The prevalence of moresevere stages of CVD, such as edema and skin changes (hy-perpigmentation and eczema), varies from 3% to 11% of thepopulation,10 and it is estimated that the assessment andtreatment of patients with varicose veins and leg ulcers con-sume 2% to 3% of the health budget of Western countries.11

For instance, the costs of dressing a leg ulcer in the UK Na-tional Health Service reaches £6000 to £20 000 per year.12

As a result of the complexity and chronicity of venous dis-ease, the application of PROs to patients suffering from CVDis thought to be an important step forward in the assessmentof patients’ perspective of disease, QOL questionnaires be-

ing the most adapted instruments.1 The use of QOL ques-tionnaires in patients suffering from CVD can provide impor-tant information regarding disease burden in patients thatwould otherwise be unobtainable.1,13

Quality of lifeQOL is a broad ranging concept that has been changing overthe years and, depending on the perspective, different defi-nitions of QOL are acceptable. In 1947, the World Health Or-ganization (WHO) defined QOL as a “state of complete phys-ical, mental, and social well-being and not merely the absenceof disease or infirmity,” while, in 1984, Calman wrote: “Qualityof life measures the difference, or the gap, at a particular pe-riod of time, between the hopes and expectations of the in-dividual and that individual’s experiences.” Although no sin-gle definition or theory can be considered more correct thananother, it is clear that the WHO provides the most coherentand comprehensive definition. In 1998, the WHO updated itsdefinition of QOL to: “Individuals’ perception of their positionin life in the context of the culture and value systems in whichthey live and in relation to their goals, expectations, stan-dards and concerns. It is a broad ranging concept affected ina complex way by the person’s physical health, psycholog-ical state, level of independence, social relationships, person-

PRO Question to askselection criterion Comment on criterion when choosing a PRO

Appropriateness This criterion requires that investigators consider as directly as Is the content of the instrument appro-possible how well the content of an instrument corresponds priate to the questions which theto the intended purpose of their specific trial.7 clinical trial is intended to address

Reliability Reliability is related to the reproducibility and internal consistency Does the instrument produce resultsof an instrument. It assesses the extent to which the instrument that are reproducible and internallyis free from random error and can be considered as the amount consistent?of a score that is signal rather than noise.

Validity The validity of a measure is an assessment of the extent to which Does the instrument measure whatit measures what it purports to measure.7 it claims to measure?

Responsiveness It is essential for a health status questionnaire to detect important Does the instrument detect changeschanges over time within individuals, which might reflect over time that matter to patients?therapeutic effects. Responsiveness could be defined as theability of an instrument to detect important clinical changes.

Precision Precision refers to the number of distinctions that an instrument How precise are the scores of themakes. It is related to the capacity to make numerous distinctions. instrument?

Interpretability Interpretability is concerned with how meaningful the scores of How interpretable are the scores ofan instrument are. an instrument?

Acceptability This criterion requires that an instrument is acceptable to patients Is the instrument acceptable to patients?

Feasibility Feasibility is related to the impact of different PRO measures upon Is the instrument easy to administerstaff and researchers in collecting and processing information. and process?The time and resources required to collect, process, and analyzea PRO measure.

Table II. PRO selection criteria and questions to ask when choosing a PRO. Based on reference 7.Abbreviations: PRO, patient-reported outcome.



al beliefs and their relationship to salient features of their en-vironment.” This definition is the one most commonly used.14

Regarding clinical trials and health-care interventions, QOLis considered an important outcome that provides an over-all assessment of the effect of both the disease and treat-ment on the patient.15 More simply, QOL has been defined as:“the extent to which our hopes and ambitions are matchedby experience,” while improving patients’ QOL through med-ical care has been defined as: “narrow[ing] the gap betweena patient’s hopes and expectations and what actually hap-pens.”16 Concerning the evaluation of patients’ QOL, two typesof questionnaires can be used: generic and disease-specificQOL questionnaires.

Generic quality-of-life questionnairesGeneric instruments are designed to be applicable across abroad range of populations and treatments and to be ableto capture information on a wide range of aspects of healthstatus and disease consequences.7 Due to their broad rangeof content and more general applicability, these instrumentshave been used more frequently than disease-specific in-struments to assess health status of nonhospital samples inthe general population.7

Regarding generic QOL questionnaires, those most used andmentioned in international literature are: the Medical Out-comes Study Short Form 36-item (SF-36) health survey, Not-tingham Health Profile (NHP), Functional Limitations Profile(FLP), Sickness Impact Profile (SIP), and EuroQol Instrument(EQ-5D).17 For example, SF-36 was designed to be used inclinical practice and research, health policy evaluations, andgeneral population surveys. This questionnaire has 36 itemsthat measure health status in eight categories.18,19 Anotherexample is FLP, which is the English version of SIP, whichwas developed in the United States. It consists of 136 itemsgrouped into 12 categories.7

� AdvantagesRegarding the advantages and drawbacks of the differenttypes of questionnaires, what will be mentioned are suppo-sitions rather than firm statements, and the generalizationsare difficult to substantiate because there is little evidenceavailable, particularly from direct comparisons of their use.7

The main advantage of generic instruments is that they canbe used for a broad range of health problems, allowing com-parisons between different treatments and their respectiveeffectiveness. With a generic QOL questionnaire, it is possibleto calculate “normative values,” which give scores for patientswith distinct health problems and allow comparisons to bemade.7 Another advantage of the generic QOL questionnaireis its broad scope, so they may be of value in detecting theunexpected positive or negative effects of an intervention.7

Finally, even though they cover a wide range of different cat-egories, they are relatively economic and reduce patients’burden.7

� DrawbacksBy including items that cover a broad range of aspectsabout health status, generic instruments lose some level ofdetail in terms of a particular disease’s relevance.7

Disease-specific quality-of-life questionnairesSpecific QOL instruments have been developed to providepatients’ perception of a specific disease, health problem, orintervention.7,17 An example is the Asthma Quality of Life Ques-tionnaire that contains 32 questions in four different catego-ries20 or the Arthritis Impact Measurement Scale, a self-ad-ministered questionnaire for use in rheumatic diseases, whichcovers 45 items in nine categories.7 Both instruments clearlyhave a specific range of applications in each disease, respec-tively.7 In relation to CVD, some specific instruments exist: theChronIc Venous dIsease Questionnaire (CIVIQ),21 the VEnousINsufficiency Epidemiological and economic Study (VEINES),22

the Aberdeen Varicose Vein Questionnaire (AVVQ),23 and theCharing Cross Venous Ulceration Questionnaire (CXVUQ).24

� AdvantagesThe content of specific QOL questionnaires is relevant for aparticular disease, as all items of the instrument were devel-oped specifically to assess a specific health problem.7 Theseinstruments are more likely to detect important changes thatoccur over time in a particular disease.7 Another importantadvantage is that with specific QOL questionnaires, accept-ability and conclusion rates are usually higher compared withgeneric instruments. This occurs because specific instrumentsare clearly relevant to a patient’s problem.7

� DrawbacksGenerally, it is not possible to use a disease-specific instru-ment in samples of patients that do not have a specific con-dition or disease because logically it is not possible to ask aperson about a problem or condition that he/she does nothave. In the same way, disease-specific instruments do not al-low easy comparison between outcomes of different treat-ments for patients with different health problems. This situ-ation is a problem when certain data from a general sampleof healthy individuals must be compared with the health sta-tus scores of a study or when comparative judgments on therelative effectiveness of different treatments in different dis-eases are required in order to propose resource allocation.7

Another problem of disease-specific instruments is that theymay not capture certain data associated with a disease ora treatment when these have not been anticipated. An in-strument with a broader scope may be more effective in de-tecting unexpected effects.7

CIVIQIn CVD, there are several reasons, mostly linked to diseasecharacteristics, which justify the creation and developmentof a specific questionnaire to assess patients’ QOL. Among

them, we could highlight that CVD has a high and growingprevalence, as one in two adults complains about symp-toms and/or signs of the disease,10 CVD has a considerablesocioeconomic impact representing around 1% to 3% of thetotal health-care budget of countries with developed health-care systems,25 and CVD’s negative impact on patients’ dai-ly life is usually underestimated by physicians due to its in-dolent clinical course and the absence of a relation betweensymptoms and signs.21 Taking into account these previouslymentioned reasons and knowing that disease-specific instru-ments are usually more sensitive in key categories of QOLthan generic scales, it was crucial to develop a specific QOLquestionnaire for widespread use in CVD.

The CIVIQ questionnaire was developed and validated (rel-evance, acceptability, reliability, construct validity, and sensi-tivity) by a French group in 1996.21 Later in 2000, it was trans-lated, adapted to the cultural habits of 18 countries, and thenrevalidated in different languages to give high significant va-lidity and reproducibility (P<0.0001).26 The CIVIQ question-naire is a 20-item self-reported instrument that includes fourcategories of questions: physical (4 items), psychological (9items), social (3 items), and pain (4 items). Its score rangesfrom 0, the worst score, to 100, the best.

As the number of publications including the CIVIQ question-naire has increased, it has become possible to confirm that itis extremely reliable, easy to use, and shows an excellent abil-ity to detect changes of state among CVD patients.27 For allthese reasons, the CIVIQ questionnaire represents a step for-ward in the assessment of patients’ QOL in CVD.

PROs and current guidelines in venous diseaseIn the latest guidelines published in venous disease, it is ev-ident that PRO assessment is already a priority and thatseveral instruments are mentioned. In the third edition of theHandbook of Venous Disorders: Guidelines of the AmericanVenous Forum, there are 2 chapters dedicated to PROs inwhich the CIVIQ questionnaire is mentioned (chapter 62, “Out-come assessment in acute venous disease,” and chapter 63,“Outcome assessment in chronic venous disease.”). Chap-ter 61 details how the CIVIQ questionnaire has been success-fully validated in several groups of patients, including thosewith severe postthrombotic syndrome. In chapter 62, theCIVIQ questionnaire is referred to as one of the four venousdisease–specific instruments developed for evaluating CVDand one with excellent internal consistency and stability.

The latest guidelines of European Venous Forum, Manage-ment of Chronic Venous Disorders of the Lower Limbs: Gui-delines according to Scientific Evidence, also highlight PROs.

In the part on the assessment of efficacy of therapies, it statesthat QOL has been assessed by generic and disease-spe-cific measures in CVD patients. However, considering the factthat specific complaints of patients with CVD have not beenidentified by currently used generic QOL questionnaires, spe-cific questionnaires have been developed to assess the func-tional and psychological effects of venous disease. The uniquespecific QOL instrument mentioned is the CIVIQ questionnaire,which is referred to as the most recent, validated question-naire with psychometric criteria, including reliability, content,construct validity, and responsiveness.

ConclusionIn the last few years, the rapid expansion in the assessmentof outcomes from the patients’ perspective has resulted inhundreds of instruments.7 In this time, PROs have undergonean incredible evolution from being nearly “irrelevant” to be-ing a “priority” in population health assessment and are nowbeing applied in various contexts, particularly generic and dis-ease-specific QOL questionnaires.8 This marked improvementin the importance of PROs is related to their potential formonitoring disease progression and response to treatment,assessing quality of care provided, and providing importantinformation that is not properly expressed by the statisticalvalues of morbidity and mortality that physicians traditionallyuse. Furthermore, these data are assessed directly from thepatients’ perspective and are invaluable outcomes that com-plement more conventional data, such as clinical and labo-ratory measures.

In CVD, the use of QOL instruments has already proven tobe reliable and much appreciated by practitioners, especiallythe CIVIQ questionnaire, which is a disease-specific instru-ment that has been validated in different languages with highsignificant validity and reproducibility. Furthermore, this ques-tionnaire has been used successfully in different situations:in the RELIEF (Reflux assEssment and quaLity of lIfe improvE-ment with micronized Flavonoids) study, a worldwide studyperformed in CVD; the Vein Consult Program, an internation-al educational survey carried out under the auspices of theInternational Union of Phlebology (UIP [Union Internationalede Phlébologie]); and the study, “What do you know aboutyour veins?”, the first Portuguese study to evaluate the impactof CVD on the QOL of the Portuguese population.

All the cumulative experience with the CIVIQ questionnaire, inaddition to the knowledge that QOL is likely to be responsiveto clinical changes, leads us to conclude that PROs, especial-ly CIVIQ, could be widely used by the medical community toimprove patient health care by eliciting earlier diagnosis andtreatment, particularly in CVD. �





References1. Guex JJ, Myon E, Didier L, Nguyen LC, Taieb C. Chronic venous disease: Healthstatus of a population and care impact on this health status through quality oflife questionnaires. Int Angiol. 2005;24:258-264.

2. Valderas JM, Alonso J. Patient reported outcome measures: a model-basedclassification system for research and clinical practice. Qual Life Res. 2008;17:1125-1135.

3. Fung CH, Hays RD. Prospects and challenges in using patient-reported out-comes in clinical practice. Qual Life Res. 2008;17:1297-1302.

4. Wiklund I. Assessment of patient-reported outcomes in clinical trials: the exam-ple of health-related quality of life. Fundam Clin Pharmacol. 2004;18:351-363.

5. Willke RJ, Burke LB, Erickson P. Measuring treatment impact: a review of pa-tient-reported outcomes and other efficacy endpoints in approved productlabels. Control Clin Trials. 2004;25:535-552.

6. Slevin ML, Terry Y, Hallett N, et al. BACUP-the first two year: evaluation of anational cancer information service. BMJ. 1988;297:669-672.

7. Fitzpatrick R, Davey C, Buxton MJ, Jones DR. Evaluating patient-based out-come measures for use in clinical trials. Health Technol Assess. 1998;2:i-iv,1-74.

8. Snyder C, Brundage M. Integrating patient-reported outcomes in healthcarepolicy, research and practice. Expert Rev Pharmacoecon Outcomes Res. 2010;10:351-353.

9. Valderas JM, Ferrer M, Alonso J. Health-related quality of life instruments andother patient-reported outcomes. Med Clin (Barc). 2005;125(suppl 1):56-60.

10. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous dis-orders of the lower limbs: guidelines according to scientific evidence. Int Angiol.2008;27:1-59.

11. Gohel MS, Davies AH. Pharmacological agents in the treatment of venous dis-ease: an update of the available evidence. Curr Vasc Pharmacol. 2009;7:303-308.

12. Coleridge-Smith P. Drug treatment of varicose veins, venous edema, and ul-cers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of theAmerican Venous Forum. 3rd ed. London, UK: Hodder Arnold; 2009;31:359-365.

13. Kahn SR, M'lan CE, Lamping DL, Kurz X, Bérard A, Abenhaim LA. Relation-ship between clinical classification of chronic venous disease and patient-re-ported quality of life: results from an international cohort study. J Vasc Surg.2004;39:823-828.

14. World Health Organization. WHOQOL Measuring Quality of Life. Geneva,

Switzerland: WHO; 1997. WHO/MSA/MNH/PSF/97.4.15. Doward LC, Mckenna SP. Defining patient-reported outcomes. Value Health.

2004;7(suppl 1):S4-S8.16. Ruta DA, Garratt AM, Leng M, Russell IT, MacDonald LM. A new approach to

the measurement of quality of life. The Patient-Generated Index. Med Care.1994;32:1109-1126.

17. Coons SJ, Rao S, Keininger DL, Hays RD. A comparative review of genericquality-of-life instruments. Pharmacoeconomics. 2000;17:13-35.

18. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.Med Care. 1992;30:473-483.

19. Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A.Comparison of methods for the scoring and statistical analysis of SF-36 healthprofile and summary measures: summary of results from the Medical OutcomesStudy. Med Care. 1995;33(4 suppl):AS264-AS279.

20. Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescentswith allergic rhinoconjunctivitis: development and testing of a questionnaire forclinical trials. J Allergy Clin Immunol. 1994;93:413-423.

21. Launois R, Reboul-Marty J, Henry B. Construction and validation of a qualityof life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual LifeRes. 1996;5:539-554.

22. Lamping DL, Schroter S, Kurz X, Kahn SR, Abenhaim L. Evaluating outcomesin chronic venous disorders of the leg: development of a scientifically rigorous,patient-reported measure of symptoms and quality of life. J Vasc Surg. 2003;37:410-419.

23. Garratt AM, Macdonald LM, Ruta DA, Russell IT, Buckingham JK, KrukowskiZH. Towards measurement of outcome for patients with varicose veins. QualHealth Care. 1993;2:5-10.

24. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of lifein patients with venous ulcers. J Vasc Surg. 2000;31:642-649.

25. Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR,Eklof B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

26. Jantet G. RELIEF study: first consolidated European data. Reflux assEss-ment and quaLity of lIfe improvement with micronized Flavonoids. Angiology.2000;51:31-37.

27. Launois R, Mansilha A, Jantet G. International psychometric validation of thechronic venous disease quality of life questionnaire (CIVIQ-20). Eur J Vasc En-dovasc Surg. 2010;40:783-789.

ÉTAT ACTUEL DES RÉSULTATS RAPPORTÉS PAR LES PATIENTSET DES RECOMMANDATIONS SUR LA MALADIE VEINEUSE CHRONIQUE

La maladie veineuse chronique (MVC) est hautement prévalente dans les pays occidentaux et est associée à descoûts significatifs. Les études d’impact insistent sur la compréhension de la maladie et les résultats du traitement.L’utilisation des résultats rapportés par les patients (RRP) atteints de MVC a permis de faire un important pas enavant dans l’évaluation de la perspective de sa maladie par le patient, les questionnaires de qualité de vie (QDV) étantles instruments les mieux adaptés. Malgré des limites concernant les preuves disponibles, huit critères fournissentun cadre explicite pour sélectionner les RRP. Huit questions simples peuvent aider à choisir les RRP, chaque ques-tion étant reliée à un critère spécifique : opportunité, fiabilité, validité, réactivité, précision, capacité d’interprétation,acceptabilité et faisabilité. En ce qui concerne l’évaluation de la QDV des patients, deux types de questionnairespeuvent être utilisés : les questionnaires génériques et ceux spécifiques à la maladie. Les instruments génériquessont conçus pour être utilisés pour toutes sortes de population et de traitements et peuvent collecter de l’informa-tion sur l’état de santé et les conséquences de la maladie. Par ailleurs, des instruments spécifiques de la QDV ont étédéveloppés pour donner aux patients la mesure d’une maladie spécifique, d’un problème de santé ou d’un traite-ment. Dans les dernières recommandations publiées sur la maladie veineuse, il est clair que l’évaluation des RRP estdéjà une priorité, le questionnaire CIVIQ (ChronIc Venous dIsease Questionnaire) étant le questionnaire spécifiquevalidé le plus récent doté de critères psychométriques.

Keywords: patient-reported outcomes; PROs; CIVIQ; quality of life; chronic venous disease; disease-specificquestionnaires

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Rating the new GRADE system in venous disease – Le Gal and Alavi280

T he Grades of Recommendation Assessment, Development and Eval-uation (GRADE) system was developed in 2004 as an attempt to pro-vide systematic and explicit methods of building guidelines for clinicians.

The system was adopted by the American College of Chest Physicians (ACCP)in the latest edition of the ACCP Evidence-Based Clinical Practice Guidelineson Antithrombotic and Thrombolytic Therapy. The ACCP grades its recom-mendations both in terms of the strength of recommendation (1 = strong; 2 =weak) and of the quality of evidence (A = high; B = intermediate; and C = low).Although the numbers and letters used in the grading system remain un-changed compared with previous editions, there have been significant changesin the underlying definitions and criteria leading to these grading recommen-dations over the latest few editions of these guidelines. In particular, themethodological quality of available studies is no longer the only determinantof the quality of evidence, while the strength of a recommendation is no longeronly based on the quality of evidence, but also on the balance between ben-efit and harm, on values and preferences, and on cost. Guideline users needto be aware of the way grades of recommendations are obtained in order tofully understand and take advantage of guidelines for their patients’ care.


T reatment decisions involve finding the balance between benefits on the onehand and risks, burdens, and inherent costs on the other. In order for cli-nicians to integrate guideline recommendations with their own clinical judg-

ment and fully exploit them in daily clinical practice, they need to understand thefoundation for these recommendations and to know how much confidence theycan place in them.

Many guidelines are published by medical societies, public health agencies, or journalsaround the world. Unfortunately, they often use different ways of rating the qualityof evidence and of grading the strength of recommendations. As a result, clinicians,patients, managers of health-care systems, and policy makers face challenges inunderstanding the messages that grading systems are trying to convey when theyneed to compare alternative strategies and diagnostic tests and weigh up their ben-efits and downsides. A lot of effort has been spent coming up with the much antic-ipated criteria and approaches for an optimal worldwide grading system, reflectinggreater awareness of the variability in patients’ values and preferences. In additionto minimizing bias and aiding interpretation, following a systematic approach to grad-

�

Grégoire LE GAL, MD, PhD

Zarrin ALAVI, MSc

Université Européenne deBretagne; Université de BrestINSERM CIC 05-02 IFR148CHU de la Cavale BlancheDépartement de médecineinterne et de pneumologieBrest, FRANCE

Address for correspondence:Prof Grégoire Le Gal, Centred’investigation clinique CHRU de laCavale Blanche, Boulevard TanguyPrigent, 29609 Brest Cedex, France(e-mail: [email protected])


Rating the quality of evidenceand the strength of recom-

mendations: the new GRADEsystem in venous disease

by G. Le Gal and Z. Alav i , France



The most dramatic change isthat the strength of recommenda-tion is no longer based, as was thecase only a few years ago, solelyon the type and quality of avail-able studies. Back in 1989, pan-elists would first rate the level ofevidence from “large trials withclear-cut results and low risk oferror” to “case series only,” andthe grade of recommendation de-pended on the level of evidence,with no other parameter takeninto account.”

‘‘

ing the strength of recommendations enhances the useful-ness of clinical guidelines. The Grades of RecommendationAssessment, Development and Evaluation (GRADE) systemwas developed in 2004 as an attempt to provide systematicand explicit methods of making judgements.1

The American College of Chest Physicians (ACCP) Evidence-Based Practice Guidelines on Antithrombotic and Thrombo-lytic Therapy is “bedtime reading work” for physicians involvedin the management of patients with venous disease. In its lat-est edition released in 2008, the ACCP committee of method-ologists and guideline developers adopted a grading sys-tem based on the GRADE approach. The criteria, displayedin Table I, have been placed in an order that approximatestheir relative significance.2 The ACCP team in charge of thetask agreed on these criteria for defining a grading systemthat would be consistent with the latest developments inthe field.

In this paper, we will focus on the GRADE approach to rec-ommendations and on how the GRADE system categorizesthe quality of evidence and strength of recommendations,and explore the implications of these grading categories forpatients, clinicians, and policy makers.

What makes a good grading system?For an optimal grading system, decisions regarding quality ofevidence should be separate from those regarding strengthof recommendations. Not all grading systems succeed in do-ing this. For instance, early systems of grading methodolog-ical quality relied primarily on the basic study design (ie, ran-domized control trials [RCTs] or observational studies). Studydesign was used by these early grading systems as an es-sential component for determining our level of confidence inestimates of beneficial and adverse treatment effects.

Over the past few years, there has been increased awarenessof a number of other factors that require consideration in or-der for us to be confident in the estimation of benefits, risks,burden, and costs.

What differentiates GRADE from previous gradingsystems?Compared with previous/other grading systems, the GRADEworking group wanted a system that used explicit definitionsof strength of recommendation and of quality of evidence.Their system takes into account various factors that can af-fect the quality of evidence, not only the study design andquality, but also study limitations, imprecision, and possibleconfounding. It assesses the relative importance of outcomes,clarifies the judgement on benefit and harm by providing anexplicit definition for trade-offs between benefit and harm,and includes judgement on whether the incremental healthbenefits are worth the costs. Finally, it provides a clear inter-pretation of the recommendation.

Quality of evidence in the GRADE system“Quality of evidence” reflects the extent to which the confi-dence in an estimate of an effect is adequate in supportinga recommendation. To achieve transparency and simplicity,the GRADE system classifies the quality of evidence at oneof four levels: high, moderate, low, and very low.

As with early systems for grading the quality of evidence,GRADE initially focuses on study design. In this way, RCTswithout limitations constitute high-quality evidence, observa-tional studies without special strengths or with important lim-itations constitute low-quality evidence, while any other study(case series) constitutes very low–quality evidence.

� Negative factors affecting quality of evidenceThere are, however, negative factors that affect the quality ofevidence that can downgrade the quality of observationalstudies as well as RCTs:

a) Study limitationsIf studies have major limitations that may bias their estimatesof the treatment effect, confidence in the evidence decreases.Such limitations include a lack of allocation concealment, alack of blinding, a significant number of patients lost to fol-low-up, failure in the intention-to-treat analysis, failure to re-port outcomes, and early ending of a study due to benefit.


Rating the new GRADE system in venous disease – Le Gal and Alavi MEDICOGRAPHIA, Vol 33, No. 3, 2011 281


ACCP American College of Chest PhysiciansGRADE Grades of Recommendation Assessment,

Development and EvaluationRCT randomized controlled trialVTE venous thromboembolism

Criteria Description

1 Separation of grades of recommendations fromquality of evidence

2 Simplicity and transparency for clinician consumer

3 Sufficient (but not too many) categories

4 Explicitness of methodology for guideline developers

5 Simplicity for guideline developers

6 Consistent with general trends in grading systems

7 Explicit approach to different levels of evidence fordifferent outcomes

Table I. Criteria for an optimal grading system, according to theACCP Task Force.Abbreviations: ACCP, American College of Chest Physicians.Modified from reference 2: Guyatt et al. Chest. 2006;129:174-181. © 2006,American College of Chest Physicians.



b) Inconsistency of resultsHeterogeneity or variability in results across studies suggeststrue differences in underlying treatment effect. This variabilitymay come from differences in populations, interventions (larg-er effects with higher drug doses), or outcomes (decreasingtreatment effect with time). The quality of evidence diminish-es when there is heterogeneity of results, but investigators failto identify a credible explanation.

c) Indirectness of evidenceTwo types of indirectness of evidence addressed by the guide-line developers are:- When considering the use of one of two active drugs. Inthe absence of a randomized comparison of the drugs, ran-domized trials may compare one drug with placebo and theother with placebo. This leads to a comparison of the mag-nitude of effect of both drugs, therefore, the evidence is ofa lower quality than it would have been had there been a di-rect head-to-head comparison of the drugs.- When there are discrepancies between the population, inter-vention, intervention comparator, or outcome of interest andthose included in the applicable studies.

d) ImprecisionThe quality of evidence is reduced in cases where studiesuse relatively few patients or have few events, leading to wideconfidence intervals.

e) Publication biasNot reporting studies, especially those that show no effect,downgrades the quality of evidence. A prototypical situationwould be when published evidence is limited to a small num-ber of trials, all of which are financed by industry.

� Positive factors affecting quality of evidenceConversely, there are also some factors that might increasequality of evidence.

a) Even though observational studies usually result in a lowquality of evidence, strong observational studies can method-ologically provide large or very large and consistent estimatesof the magnitude of a treatment effect. This gives good con-fidence in the results, in particular when there is no majorplausible confounder. The larger the magnitude of effect, thestronger the evidence becomes.

b) If all the plausible confounders tend to reduce the estima-tion of the effect, the confidence in the evidence increases.

c) Finally, the existence of a dose-response gradient also in-creases confidence in the authenticity of the effect.

The GRADE system has four levels of quality of evidence: A =high; B = moderate; C = low; and D = very low. A “high qual-ity of evidence” means that further research is unlikely to

change our confidence in the estimate of effect. A “moderatequality of evidence” means that further higher-quality researchmay have an impact on our confidence in the estimate of ef-fect or to change this estimate. A “low quality of evidence”is used when further higher-quality research is likely to havean important impact on our confidence in the estimate of ef-fect, or to change the estimate. Finally, the evidence is grad-ed “very low” when any estimate of effect is highly uncertain.

Strength of a recommendation in the GRADE systemThe “strength of recommendation” reflects the extent to whichwe can be confident that the desirable effects of adhering toan intervention outweigh its undesirable effects. There aretwo grades of recommendations: strong (1) and weak (2). Astrong recommendation means that benefits clearly out-weigh risks, while a weak recommendation means that onecan’t be sure that benefits outweigh risks.

The strength of a recommendation is no longer exclusivelybased on the quality of evidence. It is also determined by 2:

a) The balance between desirable and undesirable effectsThis takes into account the incidence rate of the target event,the importance of the event that treatment prevents, themagnitude of treatment effect, the precision of estimates oftreatment effect, and the risks associated with therapy.

b) Burdens of therapy

c) CostsA judgement may be made on whether the net benefits areworth the incremental cost.

d) Patients’ varying values and preferencesStrong and weak recommendations may be interpreted asfollows. If the recommendation is strong, benefits clearly out-weigh risks, or vice versa, and apply to most patients in mostcircumstances. The use of a decision aid tool is not needed,and the patient only needs to be informed. In the case of aweak recommendation, the best action may differ and oth-er alternatives may be equally reasonable. In this case, de-cision aid tools may be useful, and the physician needs tomake sure that the choice is in accordance with the patient’svalues. While almost all patients would make the same choicefor strong recommendations, the choice may significantly varyfor a weak recommendation.

Rating evidence and recommendations invenous diseaseThe GRADE system has been implemented in the 8th edi-tion of the ACCP Evidence-Based Clinical Practice Guidelineson Antithrombotic and Thrombolytic Therapy. There are twolevels of strength of recommendation (1 = strong, “We rec-ommend”; and 2 = weak, “We suggest”), and three levels ofquality of evidence (A = high; B = moderate; and C = low).


Rating the new GRADE system in venous disease – Le Gal and Alavi MEDICOGRAPHIA, Vol 33, No. 3, 2011 283

Therefore, six different grades may be used to grade a recom-mendation (Table II).3 The reader needs to understand the im-portant changes made in the way the final recommendationsare obtained. The most dramatic change is that the strengthof recommendation is no longer based, as was the case onlya few years ago, solely on the type and quality of availablestudies. Back in 1989,4 panelists would first rate the level ofevidence from “large trials with clear-cut results and low riskof error” to “case series only,” and the grade of recommen-dation depended on the level of evidence, with no other pa-rameter taken into account. Interestingly, until the 6th editionin 2001, the quality of evidence rating preceded the strengthof recommendation rating in the grading system (from A1 toC2), and the assessment of quality of evidence was mainlybased on study design, the highest level being limited to RCTsand meta-analyses of RCTs.

In 2001, for first time,5 the primacy of the judgement on theclarity of the risk-benefit trade-off of an intervention over themethodological quality of a study alone became clear. Thegrade of recommendation (1 or 2) was therefore placed be-fore the quality of evidence (A, B, or C). Moreover, high-quali-ty studies could lead to weak recommendations because ofuncertainty over precise estimates of benefit, harm, or costsand small effect sizes. Conversely, in 2004, it became possibleto make a grade 1 recommendation even in the absence ofRCTs with no important limitations. If experts judged that anextrapolation made from available RCTs was secure or thatdata from observational studies were overwhelmingly com-pelling, the quality of evidence was marked “C+”, which couldlead to a grade 1 recommendation.6 The 2004 edition was thefirst to be named, “Evidence-Based Practice Guidelines,” and

the four steps of evidence-based medicine were followed foreach recommendation: clear identification of the clinical prob-lem; literature retrieval; literature appraisal; and application ofthe findings acknowledging factors other than evidence.

In 2008, quality of evidence became “only one” of the determi-nants of the strength of recommendation, along with beneficialhealth outcomes, decreased burden of treatment, variabilityin patients’ preferences, and resource use. The recommen-dation is a true judgement on the overall value of the balancebetween the benefits and risks incurred by following this rec-ommendation, a judgement based not only on the expectedbenefits in terms of health, treatment-related risks, and pa-tient values and preferences, but also on economic consid-erations and the allocation of resources.

Limitations and misunderstandingsThe GRADE system certainly represents a major improvementin clinical guideline methodology. It provides the clinician withrecommendations based not only on the methodological qual-ity of available studies, but also on other important criteria (seeabove). However, one could consider that recommendationsbased on the GRADE system are more demanding for thereader. In fact, it is crucial for guideline users to carefully readand understand the way recommendations are made. Aboveall, to fully appraise a recommendation, they need to read notonly the final summary sentence, but the whole text giving theexplicit criteria leading to the recommendation.

For example, the latest edition of the ACCP guidelines is oftenquoted as strongly recommending long-term treatment in pa-tients who experience a first unprovoked deep vein throm-

Table II. ACCP grades for recommendations.Abbreviations: ACCP, American College of Chest Physicians; RCT, randomized controlled trial.Modified from reference 3: Guyatt et al. Chest. 2008;133:123S-131S. © 2008, American College of Chest Physicians.

Grade

1A

1B

1C

2A

2B

2C

Benefit vs risk

Benefits clearly outweighrisks, or vice versa;recommendation canapply to most patientsin most circumstances.

Benefits balanced withrisks; best action maydiffer depending oncircumstances orpatient/society values.

Benefits balanced withrisks; other alternativesmay be equally reasonable.

Quality of evidence

RCTs with no important limitations, or exceptionally strong evidence from observationalstudies. Further research is unlikely to change our confidence in the estimate of effect.

RCTs with important limitations or strong evidence from observational studies.Further higher-quality research may have an important impact.

At least one critical outcome from RCTs with serious flaws, observational studies,case series, or indirect evidence. Further higher-quality research is likely to havean important impact.

RCTs with no important limitations, or exceptionally strong evidence from observationalstudies. Further research is unlikely to change our confidence in the estimate of effect.

RCTs with important limitations or strong evidence from observational studies.Further higher-quality research may have an important impact.

At least one critical outcome from RCTs with serious flaws, observational studies,case series, or indirect evidence. Further higher-quality research is likely to have animportant impact.

bosis or pulmonary embolism. However, the exact recom-mendation reads: “For patients with a first unprovoked VTE[venous thromboembolism], and in whom risk factors forbleeding are absent and for whom good anticoagulant mon-itoring is achievable, we recommend long-term treatment(Grade 1A).” In terms of values and preferences, this recom-mendation attaches a relatively high value to the preventionof recurrent VTE and a lower value to the burden of long-termanticoagulant therapy. This is obviously very different to thequick summary and reveals the thinking behind how deci-sions are made.7

Moreover, GRADE authors insist that recommendations ap-ply to specific settings, groups of patients, and economiccontexts. There may be significant variations across coun-tries or hospitals that may influence the decision of whetherto adhere to a recommendation. Costs, for example, as wellas the way costs influence clinical decisions, differ widely be-tween countries. Most of all, no recommendation can takeinto account all individual clinical circumstances. The ACCPguideline authors warn that any grade other than a grade 1A

recommendation indicates that the authors acknowledgethat other interpretations of evidence and other clinical poli-cies may be appropriate. Furthermore, they suggest that evengrade 1A recommendations may not apply to all patients andcircumstances, either because of resource constraints orbecause of patients’ atypical values and preferences. Final-ly, physicians must use their judgement and consider localand individual circumstances along with their patients’ valuesand preferences to achieve the best-tailored decisions.

ConclusionClinical decision-making is not simple. Guidelines help clini-cians and patients facing complex choices to choose in-formed options, to improve quality of care, and to make thebest use of limited resources. The GRADE system provides astandardized and explicit way of compiling recommendations,of which physicians must be aware in order to fully make themost of guidelines in the care of their patients. �

Acknowledgements: the author would like to thank Mrs Alavi for heruseful assistance.



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6. Guyatt G, Schunemann HJ, Cook D, Jaeschke R, Pauker S. Applying thegrades of recommendation for antithrombotic and thrombolytic therapy: theSeventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest.2004;126:179S-187S.

7. Kearon C, Kahn SR, Agnelli G, Goldhaber SZ, Raskob GE, Comerota AJ. Anti-thrombotic therapy for venous thromboembolic disease: American College ofChest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008;133:454S-545S.

COTER LA QUALITÉ DE LA PREUVE ET LA FORCE DES RECOMMANDATIONS :LE NOUVEAU SYSTÈME GRADE DANS LA MALADIE VEINEUSE

Le système GRADE (Grades of Recommendation Assessment, Development and Evaluation) a été développé en2004 dans le but de fournir des méthodes systématiques et explicites pour établir des recommandations pour lesmédecins. Le système a été adopté par l’ACCP (American College of Chest Physicians) dans la dernière édition desRecommandations pratiques cliniques basées sur des preuves au sujet du traitement antithrombotique et throm-bolytique (Evidence-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy) de l’ACCP.L’ACCP classe ses recommandations à la fois en termes de force de recommandation (1 = fort ; 2 = faible) et de qua-lité de preuve (A = fort ; B = intermédiaire ; et C = faible). Bien que les chiffres et les lettres utilisés dans le systèmede classification restent inchangés par rapport aux éditions précédentes, les changements ont été significatifs dansles définitions et les critères sous-jacents, conduisant à ces nouvelles recommandations de classification. En par-ticulier, la qualité méthodologique des études disponibles n’est plus seulement basée sur la qualité de la preuve,mais aussi sur l’équilibre bénéfice/risque, sur les avantages et les préférences et sur le coût. Les utilisateurs des re-commandations doivent être avertis de la façon dont elles sont obtenues afin de les comprendre parfaitement etde les utiliser au mieux pour traiter leurs patients.

Keywords: evidence-based medicine; review; recommendations

European and American guidelines on primary chronic venous disease: what’s new? – Gillet MEDICOGRAPHIA, Vol 33, No. 3, 2011 285

P rimary chronic venous disease (CVD) is defined as morphological andfunctional abnormalities of the venous system of long duration, mani-fested by symptoms, signs, or both. CVD is extremely common in most

countries and has a considerable socioeconomic impact in Western countries.Venoactive drugs (VADs) are a heterogenic group of drugs of vegetal or syn-thetic origin. The objective of this article is to highlight the role and impact ofVADs in the management of primary CVD according to recent European andAmerican guidelines. Following analysis of the recent guidelines on primaryCVD and their recommendations regarding the place of VADs in the manage-ment of primary CVD, three VADs were given the highest level of recommen-dation. Calcium dobesilate, micronized purified flavonoid fraction (MPFF),and hydroxyethylrutoside (ie, oxerutins) were assigned a Grade A recommen-dation, the highest level of recommendation by the International ConsensusStatement (Siena, 2005) and the Consensus Statement led by Nicolaides in2008, with regard to CVD-related symptoms. The guidelines detailed evi-dence of the efficacy of several VADs in CVD-related edema, and the efficacyof MPFF as an adjunct to standard treatment in the healing of venous ulcers.The use of MPFF and pentoxifylline in combination with compression in long-standing or large venous ulcers was recommended and assigned Grade 1Bin the latest edition of the Handbook of Venous Disorders (2009). Sugges-tions regarding expected improvements in future guideline documents arealso presented.


P rimary chronic venous disease (CVD) is defined as morphological and function-al abnormalities of the venous system of long duration, manifested by symp-toms, signs, or both. Symptoms related to CVD are diverse1: tingling, aching,

burning, pain, muscle cramp, sensation of swelling, sensation of throbbing or heav-iness, itching skin, restless legs, leg tiredness, and fatigue. They are not pathog-nomonic, but may be suggestive of CVD if they get worse as the day progressesor are exacerbated by heat, and relieved with leg rest and elevation.1

Clinical signs include telangiectasias, reticular and varicose veins, edema, skinchanges, and venous ulcers. They are categorized into seven classes designatedC0-C6 according to the CEAP (Clinical-Etiological-Anatomical-Pathophysiological)classification (Table I, page 286).2 Each clinical class is characterized by a subscriptletter indicating the presence of symptoms (S, symptomatic) or absence of symp-

Jean-Luc GILLET, MDVascular MedicinePhlebologyFRANCE

Address for correspondence:Dr Jean-Luc Gillet,Vascular Medicine,51 bis Avenue Professeur Tixier,38300 Bourgoin-Jallieu, France(e-mail: [email protected])


European and Americanguidelines on primary

chronic venous disease:what’s new?

by J . -L . Gi l let , France



Several well-conducted con-trolled trials versus placebo orstockings have shown the efficacyof oral venoactive drugs…. An up-date of the guidelines for testingdrugs for chronic venous diseaseis needed to enable the pharma-ceutical industry to invest the re-sources required to perform largeand definitive clinical trials, with aview to improving the recommen-dations. Recommendations areuseful to clinicians and organiza-tions involved in decision-makingin this important field.”

‘‘

toms (A, asymptomatic). All classes of CVD can be associat-ed with symptoms. Epidemiological studies have shown thatCVD is extremely common in most countries and has a con-siderable socioeconomic impact in Western countries. Insome studies, the majority of the adult population showedsome degree of CVD. In the Edinburgh Vein Study,3 morethan 80% of people aged 8 to 64 years had mild hyphen-web or reticular varices, while a study carried out in 24 Italiancities4 showed that only 3% of subjects examined were freeof visible signs of CVD. In the San Diego Population Study,5

featuring 2211 people, visible disease was present in 84% ofwomen and 57% of men.

Reported prevalences of the clinical manifestations of CVDvary widely. The prevalence of edema and skin changes,such as hyperpigmentation and eczema, due to CVD variesfrom 3% to 11% of the population. In Western countries, itis estimated that 1% of the population will develop one ormore episode(s) of leg ulcer.

The economic cost of CVD is thought to be very high. It hasbeen estimated that the cost of managing CVD represents1%-3% of the total health-care budget in Western coun-tries,6-9 with treatment costs amounting to approximatelyUS $3 billion annually in the USA.10 In addition, venous leg ul-cers cause the loss of some 2 million working days per yearin the USA.10

Venoactive drugsVenoactive drugs (VADs) are a heterogenic group of drugsof vegetal or synthetic origin. They can be classified in 4 ma-jor categories (Table II): benzopyrones; saponins; other plantextracts; and synthetics drugs.11

� Main categories of VADs� BenzopyronesThere are two classes of VAD in this category: alpha-benzo-pyrones and gamma-benzopyrones. Coumarin is the mostnotable alpha-benzopyrone. Gamma-benzopyrones, whichare also known as flavonoids, include diosmin, micronizedpurified flavonoid fraction (MPFF), and rutosides, such asrutin, troxerutin, and hydroxyethylrutosides (HRs).� SaponinsThis category includes horse chestnut seed extract (HCSE)and Ruscus extracts.� Other plant extractsAll these plant extracts, such as extracts of Ginkgo biloba,Centella asiatica, and Hamamelis, contain flavonoids, suchas anthocyans and proanthocyanidins, together with otheractive substances.� Synthetic drugsThe principal synthetic drugs are calcium dobesilate, nafta-zone, and benzarone.

� Mode of action of VADsVADs have multiple effects on the venous system.11 Themode of action varies depending on the drug. They attenu-ate macrocirculatory changes in the venous wall and ve-nous valves that cause hemodynamic disturbances leadingto venous hypertension and attenuate microcirculatory effectsof venous hypertension that lead to venous microangiopathy.They also have effects, eg, anti-inflammatory, on venous tone,venous wall, venous valves, capillary leakage, the lymphaticnetwork, and hemorrheologic parameters.

Recently, attention has focused on the roles of oxidative stressand inflammation in causing adverse changes in the vein walland venous valves, which lead to subsequent skin changes.12

Some VADs have free-radical scavenging actions and caninterfere with inflammatory cascades, notably in the case ofMPFF by inhibiting leukocyte-endothelial interactions.13 An-


MEDICOGRAPHIA, Vol 33, No. 3, 2011 European and American guidelines on primary chronic venous disease: what’s new? – Gillet286


CEAP Clinical-Etiological-Anatomical-PathophysiologicalCIVIQ ChronIc Venous dIsease QuestionnaireCONSORT CONSOlidated standards of Reporting TrialsCVD chronic venous diseaseGRADE Grades of Recommendation Assessment,

Development and EvaluationHCSE horse chestnut seed extractHR hydroxyethylrutosideMPFF micronized purified flavonoid fractionQOL quality of lifeRCT randomized controlled trialSF-12 Short Form 12-item [health survey]SF-36 Short Form 36-item [health survey]VAD venoactive drug

CEAPclassification Clinical description

C0 No visible or palpable signs of venous diseaseC1 Telangiectasias or reticular veinsC2 Varicose veins; distinguished from reticular

veins by a diameter of 3 mm or moreC3 EdemaC4 Changes in skin and subcutaneous tissue

secondary to CVD, divided into 2 sub-classes to better define the differing severityof venous disease:C4a: pigmentation or eczemaC4b: lipodermatosclerosis or atrophieblanche

C5 Healed venous ulcerC6 Active venous ulcer

Table I. Clinical descriptions of the revised CEAP classification.Abbreviations: CEAP, Clinical-Etiological-Anatomical-Pathophysiological; CVD,chronic venous disease.Modified from reference 2: Eklöf et al; American Venous Forum InternationalAd Hoc Committee for Revision of the CEAP Classification. J Vasc Surg. 2004;40:1248-1252. © 2004, The Society for Vascular Surgery.

imal studies suggest that these actions of VADs can protectthe vein wall and valves from deleterious changes, with thepotential for slowing or preventing the progression of pri-mary CVD.14

� Recent guidelines on VADsNumerous randomized, controlled, double-blind studies havedemonstrated the improvement of CVD-related symptomsby VADs, and the antiedema effect of VADs has also beenobjectively demonstrated in double-blind trials. The main in-dications for VADs are symptoms related to CVD and edemain patients at any stage of CVD. VADs may also have a role inthe treatment of leg ulcers. A meta-analysis of MPFF, from thebenzopyrone category of VADs, confirmed its value as an ad-junct to standard treatment for healing leg ulcers.15

This article will assess the role and impact of VADs in themanagement of primary CVD in light of the recent Europeanand American guidelines. Two guidelines have been publishedrecently discussing the therapeutic efficacy of VADs on CVD-related symptoms and venous edema.11,16,17 The latest editionof the Handbook of Venous Disorders: Guidelines of the Ame-rican Venous Forum18 includes a chapter on drug treatment ofvaricose veins, venous edema, and ulcers. Elsewhere, Perrinand Ramelet19 have proposed their own recommendationsfor the use of VADs, based on the principle of the GRADE(Grades of Recommendation Assessment, Development andEvaluation) system.

� Therapeutic efficacy of VADs and impact on guidelinesA Cochrane review of VADs by Martinez et al (2005) exam-ined the efficacy of such drugs in detail.20 Clinical trials of arange of different VADs were analyzed. Studies of HCSE wereexcluded because they were covered in a separate Cochranereview (see below).21 The authors identified 110 randomized,placebo-controlled trials, 44 of which were included in the fi-nal analysis. Studies were classified level A (low risk of bias),level B (moderate risk of bias), or level C (high risk of bias). Awide range of outcome variables, including objective signsand subjective symptoms, were analyzed using a random ef-fects statistical model. For every outcome variable except ve-nous ulcer, the analyses showed significant treatment bene-fits for VADs compared with placebo when analyzed as eithera dichotomous or a continuous variable, or both in some cas-es. The analyses showed that VADs had significant treatmentbenefits compared with placebo with regard to pain, cramps,heaviness, and sensations of swelling and paresthesia, de-spite a lack of homogeneity between trials.19 The only non-significant effects were for venous ulcer, itching assessed asa continuous variable, and paresthesias assessed as a con-tinuous variable. For edema (relative risk [RR], 0.72; 95% con-fidence interval [CI], 0.65-0.81), trophic disorders (RR, 0.88;95%CI, 0.83-0.94), and restless legs (RR, 0.84; 95%CI, 0.74-0.95), the analyses showed a significant benefit with VAD treat-ment, with no evidence of heterogeneity among the studies.This was in contrast to most of the analyses, which showedevidence of heterogeneity.19



Table II. Classifi-cation of themain venoactivedrugs.Modified fromreference 11: Nico-laides et al. Int Angiol.2008;27:1-59.© 2008, EdizioniMinerva Medica.

Group

Benzopyrones

Alpha-benzopyrones

Gamma-benzopyrones(flavonoids)

Saponins

Other plant extracts

Synthetic products

Substance

Coumarin

Diosmin

Micronised purified flavonoidfraction (MPFF)

Rutin and rutosides

O-(β-hydroxyethyl)-rutosides

Escin

Ruscus extract

Anthocyans

Proanthocyanidins (oligomers)

Extracts of ginkgo, heptaminol,and troxerutin

Calcium dobesilate

Benzarone

Naftazone

Origin

Melinot (Melilotus officinalis)Woodruff (Asperula odorata)

Ciprus sp (Sophora japonica)

Rutaceae aurantiae

Sophora japonica

Eucalyptus spFagopyrum esculentum

Horse chestnut (Aesculushippocastanum)

Butcher’s broom (Ruscus aculeatus)

Bilberry (Vaccinium myrtillus)Grape pips (Vitis vinifera)

Maritime pine (Pinus maritima)

Ginkgo biloba

Synthetic

Synthetic

Synthetic

� The Cochrane review of horse chestnut seed extract 21

Randomized clinical trials (RCTs) of HCSE, whose main activecomponent is the triterpenic saponin iscin, were the subjectof a Cochrane review published by Pittler and Ernst in 2006.Twenty-nine studies were identified, 17 of which were includ-ed in the review. The authors concluded that HCSE was ef-ficacious compared with placebo and of similar efficacy tocompression therapy in the short-term treatment of CVD. Ad-verse effects were generally mild and infrequent, so the over-all risk/benefit ratio for HCSE was favorable. On the basis ofpublications, including Cochrane reviews, VADs as a wholehave been assigned a weak recommendation (Grade 2B) forimproving symptoms and edema associated with CVD in thelatest edition of the Handbook of Venous Disorders.18

International consensusThe International Consensus Statement in 200516 representsthe outcome of the International Medical Consensus Meet-ing on Venoactive Drugs in the Management of Chronic Ve-nous Disease, held during the 13th Conference of the Euro-pean Society for Clinical Hemorheology in Siena, Italy, from26-29 June, 2005.

A group of 14 experts, from countries in which VADs wereavailable and with experience of their clinical use, analyzeda total of 83 studies. Three grades of recommendation wereconsidered, based on the following levels of evidence: grade A(several RCTs with large sample sizes, meta-analysis of ho-mogenous results); grade B (RCTs with small sample sizes,or a single RCT); and grade C (other controlled trials, non-randomized controlled trials, and observational studies). Out-comes included only symptoms at any stage of CVD.

As a result of the analysis, calcium dobesilate, MPFF, and HRwere all assigned the highest level (Grade A) recommenda-tion, while HCSE and Ruscus extracts were assigned Grade B(Table III).

� Management of CVD of the lower limbsA consensus statement on the management of chronic ve-nous disorders of the lower limbs was prepared in 200811 un-der the auspices of several learned societies, including theAmerican Venous Forum, the American College of Phlebology,and the European Venous Forum. A set of guidelines arisingfrom the consensus statement covers most aspects of themanagement of CVD, including investigations, treatment, andmanagement strategy.

With respect to VADs, the guidelines largely summarized andendorsed the positive findings of the recent Cochrane re-views20,21 and the grades of recommendation of the Interna-tional Consensus Statement of Siena.16 These guidelines usedthe same grading system as the Siena Consensus, exceptfor meta-analyses, which were considered to have a grade Blevel of evidence. Outcomes this time included not only symp-toms, but also edema and venous ulcer healing.

Table IV summarizes VAD effects on symptoms, edema, andskin changes by category of drug. Grade A status was as-signed to three VADs: calcium dobesilate, MPFF, and HR, butonly symptoms were considered. Generally, no reservationswere voiced regarding the safety of VADs, except for a cou-ple of specific cases: coumarin-rutin and benzarone (hepa-totoxicity) and calcium dobesilate (some cases of transcientagranulocytosis were reported from 1992 to 2005).11

Guidelines and VADs for venous edemaAlthough edema is a nonspecific sign, it is one of the mostfrequent and typical symptoms and signs in CVD. All othercauses of edema should be excluded to confirm its venousorigin. CVD-related edema is described as sporadic, unilater-al or bilateral, and limited to the legs, which may also involveproximal parts of the lower extremities. It is enhanced by pro-longed orthostatic posture, and improved by leg elevation.22

Several well-conducted controlled trials versus placebo orstockings11,16 have shown the efficacy of oral VADs such asMPFF, rutosides, HCSE, calcium dobesilate, proanthocyani-dines, and coumarin-rutin. In these trials, the evaluation of anti-edematous efficacy was based on objective measures, suchas measurement of leg circumference, strain-gauge plethys-mography, and water displacement. Results of meta-analy-ses, including the Cochrane reviews,20,21 have confirmed theantiedematous efficacy of VADs.

The guidelines highlighted the evidence of efficacy of severalVADs (calcium dobesilate, MPFF, rutosides, HCSE, proantho-cyanidines, and coumarin + rutin) in CVD-related edema, and



Number ofinfluential studies

Compound Recommendation RCTs Meta-analyses

Calcium dobesilate Grade A 3 2

MPFF Grade A 4 1

Hydroxyethylrutosides Grade A 5 1

HCSE (escin) Grade B 1 2

Ruscus extracts Grade B 2 1

Diosmin (synthetic) Grade C 1

Troxerutin Grade C 2

Ginkgo biloba Grade C 2

Proanthocyanidines Grade C 2

Troxerutin + coumarin Grade C 1

Centella asiatica Grade C 1

Naftazone Grade C 1

Table III. Grades of recommendation of the International Consen-sus Statement. Based on data from reference 11.Abbreviations: HCSE, horse chestnut seed extract; MPFF, micronized purifiedflavonoid fraction; RCT, randomized clinical trial.

the efficacy of MPFF as an adjunct to standard treatment inthe healing of venous ulcers (although only symptoms havebeen considered in the assignation of a grade of recommen-dation) (Table IV).11

Guidelines and VADs for venous leg ulcersAcceleration of venous leg ulcer healing (stage C6 of theCEAP classification) has been demonstrated in a double-blindstudy using MPFF in combination with compression.23 Thisresult was confirmed in 2005 by a meta-analysis of five trialsin which MPFF was used as an adjunct to standard compres-sion treatment in 723 class C6 patients.15 HCSE and HRs werenot superior to compression in advanced chronic venous in-sufficiency24 or in the prevention of venous ulcer recurrence.25

The latest edition (3rd edition) of the Handbook of Venous Di-sorders18 includes a chapter on drug treatment of varicoseveins, venous edema, and ulcers. The method of determin-ing the strength and quality of recommendations in this doc-ument was based on GRADE.26 GRADE recommendationsconsist of a number (“1” for a “strong” or “we recommend”recommendation, and “2” for a “weak” or “we suggest” rec-ommendation) and a letter, which refers to the “quality ofevidence” supporting the recommendation. There are threegrades: “A” for high-quality evidence; “B” for moderate-qual-ity evidence; and “C” for low-quality evidence. The GRADEsystem is based on the distinction between the strength ofa recommendation and the quality of the evidence on whichit is based, although in practice the separation is not absoluteand the quality of evidence is an important determinant of thestrength of a GRADE recommendation.

The use of MPFF in combination with compression in long-standing or large venous ulcers was recommended and as-signed a grade 1B. The evidence for the addition of MPFF isbased on the meta-analysis of 5 trials with MPFF as an ad-junct to standard compression treatment in 723 patients men-tioned above.15 At 6 months, complete ulcer healing had oc-curred in 61% of MPFF patients and in 48% of control patients(RR reduction for persistent ulceration, 32%; 95% CI, 3% to70%; P=0.03). Subgroup analyses suggested that the ben-efits of MPFF were greatest in ulcers �5 cm2 and in ulcersof >6 months’ duration.

Pentoxifylline, a drug indicated for the management of pe-ripheral arterial disease, has also been used in the manage-ment of venous ulcers. Its use in combination with compres-sion in long-standing or large venous ulcers has a grade 1Brecommendation.

� Tentative recommendations for VADsBuilding on recent reviews and meta-analyses and taking intoaccount additional evidence that was either not available ornot included in them, Perrin and Ramelet have proposed ten-tative recommendations for the use of VADs based on theprinciples of the GRADE system.19 They stress that these rec-ommendations reflect their own opinions and judgements,and have not been endorsed by learned societies or other or-ganizations to date.

These recommendations are summarized in Table V (page290).19 A grade 1B was assigned to MPFF and rutosides forthe relief of symptoms associated with CVD in C0s to C6s pa-



Positive results on the Trials andCompound following indications* RCTs Recommendation** meta-analyses**

Calcium dobesilate Cramps, restless legs, 4 Grade A 2sensation of swelling,edema

MPFF Pain, cramps, heaviness, 5 Grade A 1sensation of swelling,trophic changes,venous leg ulcer

Hydroxyethylrutosides Itching, edema 10 Grade A 4

Escin, HCSE Pain, edema - Grade B 3

Ruscus extracts Pain, edema 2 Grade B 1

Synthetic diosmin - - Grade C 1

Troxerutin - 1 Grade C 1

Ginkgo biloba - - Grade C -

Proanthocyanidines Pain 3 Grade C 1

Troxerutin-coumarin - 1 Grade C -

Naftazone - - Grade C 1

* Homogeneity of results with relative risk (RR) <1.** Only symptoms have been considered.

Table IV. Summaryof VAD effects onsymptoms, edema,and skin changes bycategory of drugs.Abbreviations: HCSE,horse chestnut seedextract; MPFF, micronizedpurified flavonoid fraction;RCT, randomized con-trolled trial.Modified from reference11: Nicolaides et al. IntAngiol. 2008;27:1-59.© 2008, Edizioni MinervaMedica.

tients with CVD-related edema. A grade 1B recommendationwas also given for the use of MPFF as an adjunct to compres-sive and local therapy for healing large or long-standing ve-nous ulcers.18

Future challenges17,19

� Assessing the efficacy of treatmentAn update of the guidelines for testing drugs for CVD27 is need-ed to enable the pharmaceutical industry to invest the re-sources required to perform large and definitive clinical trials,with a view to improving the recommendations. Recommen-dations are useful to clinicians and organizations involved indecision-making in this important field. Such guidelines could:� Reiterate the basic principles that should prevail when re-porting (and setting up) a clinical trial, using the CONSORT(CONSOlidated standards of Reporting Trials) statement. Thisstatement is designed to help authors and investigators filereports using a published checklist and flow diagram,28 avail-able on the Web site: www.consort-statement.org.� Describe patients comprehensively at study selection usingthe advanced CEAP classification. This implies that not onlythe “C” (Clinical) of CEAP should be completed, but alsoitems “E” (Etiological), “A” (Anatomical), and “P” (Pathophys-iological), together with mandatory duplex color, with or with-out plethysmography (a level 2 investigation, according toEklöf et al),2 and in certain cases, invasive (level 3) investiga-tions; the addition of new descriptors for the “E”, “A”, and“P” items when no venous abnormality is identified may beuseful when describing patients with leg complaints, but novisible or detectable signs of CVD.2

� Promote the use of validated tools to assess symptoms,29

edema,30 and venous leg ulcer.31

� Reach a consensus on the standard use of dressings, com-pression therapy, and local antiseptics in venous leg ulcer.

In addition, there is a need for consensus on the following endpoints:� Symptoms: how great does the decrease on the visual ana-logue scale have to be in order to consider there is clinicalimprovement?� Edema: how great does the reduction in ankle volume haveto be in order to consider it as clinically relevant?� Varicose veins: which criteria should be used to considerwhether a drug treatment for varicose veins works?� Venous leg ulceration: when should we consider the ulcerto be healed?

� Adapted patient-reported outcome toolsEarly stages of CVD are difficult to assess objectively, par-ticularly in C0s patients, as symptoms are by definition sub-jective. The assessment of patients’ perception of their qual-ity of life (QOL) is desirable in such cases. Both generic andspecific QOL scales should be used: the generic SF-12 (ShortForm 12-item [health survey]) or SF-36 (Short Form 36-item[health survey]) are validated tools that could be adopted,while if a specific scale is required, the CIVIQ-20 (ChronIcVenous dIsease Questionnaire) QOL is a good choice. It hasbeen extensively validated,32 is the scale most often used inCVD, and has currently been validated in 13 languages.

ConclusionThe role of VADs in the prevention of the natural history of CVDprogression remains to be fully determined: are all VADs ableto protect CVD patients against the progression of the dis-ease to severe complications? The use of human-sized ex-perimental animals, such as pigs, might allow for better eval-uation of the key processes involved.33 Where grading isconcerned, the consensual adoption of a simple and univer-sally understood system of grading is desirable.26 �



References1. Eklöf B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminology

of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary con-sensus document. J Vasc Surg. 2009;49:498-501.

2. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum Internation-al Ad Hoc Committee for Revision of the CEAP Classification. Revision of the

CEAP classification for chronic venous disorders: consensus statement. J VascSurg. 2004;40:1248-1252.

3. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins andchronic venous insufficiency in men and women in the general population:Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.

Recommendation QualityIndication Venoactive drug for use of evidence Code

Relief of symptoms MPFF Strong Moderate 1Bassociated with CVD Rutosides Strong Moderate 1Bin C0s to C6s patients Calcium dobesilate Weak Moderate 2Bwith CVD-related edema

HCSE Weak Low 2C

Ruscus extracts Weak Low 2C

Healing of large or long-standing MPFF Strong Moderate 1Bvenous ulcers as an adjunct tocompression and local therapy

Table V. Summary oftentative recommen-dations, according toPerrin and Ramelet.Abbreviations: CVD,chronic venous disease;HCSE, horse chestnutseed extract; MPFF, mi-cronized purifiedflavonoid fraction.Modified from reference19: Perrin and Ramelet.Eur J Vasc EndovascSurg. 2011;41:117-125.© 2011, European Societyfor Vascular Surgery.



Keywords: chronic venous disease; venoactive drug; guidelines; grade of recommendation

RECOMMANDATIONS EUROPÉENNES ET AMÉRICAINESSUR LA MALADIE VEINEUSE CHRONIQUE PRIMAIRE : QUOI DE NEUF ?

La maladie veineuse chronique primaire (MVC) se définit par des anomalies morphologiques et fonctionnelles delongue durée touchant le système veineux, se manifestant par des symptômes, des signes ou les deux. La MVC estextrêmement courante dans la plupart des pays et son impact socio-économique est considérable dans les paysoccidentaux. Les médicaments veino-actifs (MVA) sont un groupe hétérogène de médicaments d’origine végétaleou synthétique. L’objectif de cet article est de souligner le rôle et l’impact des MVA dans la prise en charge de laMVC primaire selon les recommandations européennes et américaines récentes. En suivant les analyses des recom-mandations récentes sur la MVC primaire et leurs directives concernant la place des MVA dans la prise en chargede la MVC primaire, trois MVA ont obtenu le plus haut niveau de recommandation. Le dobésilate de calcium, la frac-tion flavonoïque purifiée micronisée (FFPM) et l’hydroxyéthylrutoside (c’est-à-dire les oxérutines) ont été classés enrecommandation de grade A, le plus haut niveau de recommandation du communiqué de Consensus International(International Consensus Statement) (Sienne, 2005) et du Communiqué de Consensus (Consensus Statement) di-rigé par Nicolaïdes en 2008, en ce qui concerne les symptômes liés à la MVC. Les recommandations ont détaillé lespreuves de l’efficacité de plusieurs MVA dans l’œdème lié à la MVC et l’efficacité de la FFPM comme additif autraitement standard dans la cicatrisation des ulcères veineux. L’utilisation de la FFPM et de la pentoxifylline asso-ciées à la compression dans les ulcères importants ou anciens a été recommandée et classée en grade 1B dans ladernière édition du Hanbook of Venous Disorders (2009). Nous présentons également des améliorations possiblesqui devraient être apportées aux futures recommandations.

4. Chiesa R, Marone EM, Limoni C, Volonté M, Schaefer E, Petrini O. Chronic ve-nous insufficiency in Italy: the 24-cities cohort study. Eur J Vasc Endovasc Surg.2005;30:422-429.

5. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethni-cally diverse population: the San Diego Population Study. Am J Epidemiol. 2003;158:448-456.

6. Lafuma A, Fagnani F, Peltier-Pujol F, Rauss A. Venous disease in France: an un-recognized public health problem [In French]. J Mal Vasc. 1994;19:185-189.

7. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ul-cers. Angiology. 1997;48:67-69.

8. Van den Oever R, Hepp B, Debbaut B, Simon I. Socio-economic impact ofchronic venous insufficiency. An underestimated public health problem. Int An-giol. 1998;17:161-167.


10. McGuckin M, Waterman R, Brooks J, et al. Validation of venous leg ulcer guide-lines in the United States and United Kingdom. Am J Surg. 2002;183:132-137.

11. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous dis-orders of the lower limbs: guidelines according to scientific evidence. Int An-giol. 2008;27:1-59.

12. Bergan JJ, Schmid-Schönbein GW, Coleridge Smith PD, Nicolaides AN, Bois-seau MR, Eklöf B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

13. Bergan J. Molecular mechanisms in chronic venous insufficiency. Ann VascSurg. 2007;21:260-266.

14. Bergan JJ, Pascarella L, Schmid-Schönbein GW. Pathogenesis of primarychronic venous disease: insights from animal models of venous hypertension.J Vasc Surg. 2008;47:183-192.

15. Coleridge Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of ad-junctive therapy with micronized purified flavonoid fraction. Eur J Vasc EndovascSurg. 2005;30:198-208.

16. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the manage-ment of chronic venous disease. An international consensus statement: cur-rent medical position, prospective views and final resolution. Clin HemorheolMicrocirc. 2005;33:309-319.

17. Nicolaides A. Venoactive medications and the place of Daflon 500 in recentguidelines on the management of chronic venous disease. Phlebolymphology.2009;16:340-346.

18. Coleridge Smith PD. Drug treatment of varicose veins, venous edema, and ul-cers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the Ame-rican Venous Forum. 3rd ed. London, UK. Hodder Arnold; 2009:359-365.

19. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venousdisease: rationale, results and unanswered questions. Eur J Vasc EndovascSurg. 2011;41:117-125.

20. Martinez MJ, Bonfill X, Moreno RM, Vargas E, Capellà D. Phlebotonics for venousinsufficiency. Cochrane Database Syst Rev. 2005;(3):CD003229.

21. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficien-cy. Cochrane Database Syst Rev. 2006;9(1):CD003230.

22. Priollet P. Venous edema of the lower limbs. Phlebolymphology. 2006;13:183-187.

23. Guilhou JJ, Dereure O, Marzin L, et al. Efficacy of Daflon 500 mg in venous legulcer healing: a double-blind, randomised, controlled versus placebo trial in 107patients. Angiology. 1997;48:77-85.

24. Ottilinger B, Greeske K. Rational therapy of chronic venous insufficiency: chancesand limits of the therapeutic use of horse-chestnut seed extracts. BMC Car-diovasc Disord. 2001;1:5.

25. Wright DDI, Franks PJ, Blair SD, Backhouse CM, Moffatt C, McCollum CN.Oxerutins in the prevention of recurrence in chronic venous ulceration: ran-domised, controlled trial. Br J Surg. 1991;78:1269-1270.

26. Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. GRADE: goingfrom evidence to recommendations. BMJ. 2008;336:1049-1051.

27. Vansheidt W, Heidrich H, Jünger M, Rabe E. Guidelines for testing drugs forchronic venous insufficiency. Vasa. 2000;29:274-278.

28. Moher D, Hopewell S, Schulz KS, et al. CONSORT 2010 explanation and elab-oration: updated guidelines for reporting parallel group randomised trials. BMJ.2010;340:c869.

29. Vasquez MA, Munschauer CE. Venous clinical severity score and quality-of-lifeassessment tools: application to vein practice. Phlebology. 2008;23:259-275.

30. Perrin M, Guex JJ. Edema and leg volume: methods of assessment. Angiology.2000;51:9-12.

31. Humbert P, Meaune S, Gharbi T. Wound healing assessment. Phlebolympho-logy. 2004;47:312-319.

32. Launois R, Reboul-Marty J, Henry B. Construction and validation of a qualityof life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual LifeRes. 1996;5:539-554.

33. Jones GT, Grant MW, Thomson IA, Hill BG, Van Rij A. Characterization of a por-cine model of chronic superficial varicose veins. J Vasc Surg. 2009;49:1554-1561.

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1. K. A. Aal, Egypt2. H. S. Caldevilla, Argentina3. R. Costa-Val, Brazil4. H. S. Yuwono, Indonesia

5. H. N. T. H. Le, Vietnam6. S. M. Kulisic, Croatia

7. A. Puskás, Romania

8. K. Roztocil, Czech Republic

9. M. Salah, Saudi Arabia

10. I. S. Escotto, Mexico

11. J.-F. Uhl, France12. I. A. Zolotukhin, Russia

Are chronic venous disease guidelines adapted to daily practice? MEDICOGRAPHIA, Vol 33, No. 3, 2011 293

C O N T R O V E R S I A L Q U E S T I O N

Are chronic venousdisease guidelines adapted

to daily practice?

THE QUESTION

CVD guidelines are based onwell-designed studies thatuse control groups, have

multiple planned follow-up visits,and are performed by skilled per-sonnel in dedicated facilities. How-ever, studies are not perfect andlimitations exist: exclusion be-cause of old age, inability or un-willingness to comply with moni-toring, and contraindications. So,do CVD guidelines reflect whatgoes on in real life and are theyapplicable and useful in all casesof CVD patient management? Ourexperts give their views.


MEDICOGRAPHIA, Vol 33, No. 3, 2011 Are chronic venous disease guidelines adapted to daily practice?294

B efore answering this question we must first identify ourneeds. These begin with a comprehensive study thatwould provide a simple classification of all the signs and

symptoms of chronic venous insufficiency. Using evidence-based studies, it would identify and standardize the most ap-propriate investigation(s) and treatment(s) for each diseasestage. It would also be readily applicable in daily practice andsufficiently malleable to incorporate the latest data.

The recent guidelines largely satisfy this wish list. They rep-resent a huge amount of work by international experts. Theyincorporate recent medical and surgical treatments, such asradiofrequency ablation, laser ablation, and foam sclerother-apy, and compare their results with conventional techniques.

But supposing we wished to use the recent Clinical-Etiolog-ical-Anatomical-Pathophysiological (CEAP) classification todescribe a typical case, how would the classification presentit? For example, for a patient with painful swelling of the leg,varicose veins, lipodermatosclerosis, and active ulceration,who had a duplex scan on May 17, 2004, showing axial re-flux of the great saphenous vein above and below the knee,incompetent calf perforators, and axial reflux in the femoraland popliteal veins, with no signs of postthrombotic obstruc-tion, we would need to write: C6,S , Ep, As,p,d , Pr in basic CEAPcode, and C2,3,4b,6,S , Ep, As,p,d , Pr2,3,18,13,14 (2004-05-17, L II) inadvanced CEAP code! These formulae are comprehensivein terms of provision of a detailed patient description for re-search purposes, but too complicated to be applied in rou-

tine practice, as shown by the fact that they were used in only23% of studies in a recent Cochrane review. Some phlebol-ogists also question their relevance to routine practice. Thenew guidelines have clearly shown that vasoactive drugs andcompression are the cornerstones of treatment. Fitting andapplying elastic hosiery can be problematic, however, in par-ticular in the elderly, the obese, and those with painful ulcers.Cost and frequent renewal are other drawbacks.

In France, vasoactive drugs are recommended in sympto-matic patients for a maximum duration of 3 months, exceptif symptoms recur on treatment withdrawal. This recommen-dation is driven by financial considerations in that vasoac-tive drugs are widely prescribed in France, where they rep-resent a major drain on the health insurance system, doublethat in Germany, sevenfold that in Spain, and twentyfold thatin Belgium.

However, many questions remained unanswered, such as therecommended treatment duration and the management ofhepatic and gastric side effects. Some manufacturers claimthat long-term treatment makes their drugs more effectiveagainst hemorrhoids, but do not mention similar effects forchronic venous disease or varicose veins. The same appliesto the treatment of lipodermatosclerosis (many patients com-plain of disfigurement after postthrombotic disease). Othertopics on which we need more information are ulcer recur-rence rates and evidence-based trials on methods of pre-vention.

Each new set of guidelines should make a point of recom-mending what further studies will be required in order toanswer outstanding questions. Meanwhile, we recommendimplementing the guidelines worldwide by contacting localsocieties and organizing frequent workshops (if possible, withresearch committees collecting data), which will allow im-proved prediction of ulcer healing, decreased health-carecosts, and better quality of life. �

Khaled Abdel AAL, MDChairman of the Department ofVascular and Endovascular SurgeryNational Institute of DiabetesCairo, EGYPT(e-mail: [email protected])

1. K. A. Aal, Egypt

I f guidelines are understood to be the systematic develop-ment of recommendations to help doctors and patientstake the best possible decisions in specific clinical circum-

stances, guidelines have a number of potential benefits, butalso disadvantages.

Benefits� Improved outcome� Increased standardization of medical procedures� Rejection of old, cost-ineffective treatments� Scientific validation of diagnostic tests, treatments,and results� Justification for reimbursement� Protection of health-care professionals frommalpractice suits.

Disadvantages� Disincentive to come up with local solutions� Absence of legal protection for doctors not following theguidelines1

� Poor reproducibility of clinical trial settings in daily prac-tice, due to:– Multiple comorbidity– Advanced age– Polypharmacy– Lack of social support– Incorrect information from patients about their diseasesand treatments– Patients’ difficulty in perceiving symptoms and recognizingtheir importance, eg, “Doctor, are you sure I need to have somany tests and complex treatments because of my ulcer andswollen leg?”– Frequent history of treatment nonadherence.2,3

Practicing doctors treating chronic venous disease have tocontend with the fact that even with the correct diagnosisand most appropriate treatments, the guidelines are insuffi-cient in themselves to guarantee improvement and controlof the disease, in particular in the cases of recurrent varicoseveins and postthrombotic syndrome. Payment and cost is-sues are the most frequently cited obstacles to guideline im-plementation, as much in venous disease as elsewhere. Stent-ing is impossible if nobody can afford it. If in a local institution

there is no provision for the reimbursement of endovascularprocedures, for instance, then there is no possibility of appro-priate training and guideline implementation.

Venous disease tends to be cared for by a variety of special-ists with different skills. Some may not trust their own abilityto implement the guideline recommendations. For example,practice is likely to be biased, independently of the guidelines,by those who happen to specialize only in sclerotherapy or insurgery. Some guideline recommendations may be difficult toimplement because of the intrinsic nature of the changes inpractice required. Some evidence-based strategies may ap-pear unconventional to certain practitioners, requiring theacquisition of new skills or equipment, and possibly systemchanges that are expensive or difficult to implement.4

Many doctors consider that guidelines restrict their autonomyand flexibility, and depersonalize the doctor-patient relation-ship. Such doctors prefer to think of the individual patient infront of them, who is often very different from the “typical” pa-tient in the clinical trials that generated the guidelines. Draw-ing on their own accumulated experience, these doctors of-ten see a tenuous resemblance between “their” patients andthose featured in the trials. They are therefore unsure that fol-lowing the guidelines will necessarily improve their results.

Yet despite these impediments to their use, there is no doubtthat, as in other areas, guidelines represent the way aheadin venous disease in terms of patient care, clinical efficacy,health-care costs, and quality of life. Indeed, we need moreand better trials to increase the proportion of asymptomaticpatients (currently <40%), so that doctors and their patientsbecome confident about what to do. The future in chronicvenous disease research lies in elucidating the genetics andepigenetics involved in the transmission, onset, and evolu-tion of the disease. In a few years’ time, the guidelines maywell be incorporating the benefits of a personalized health-care approach made possible by “omic” insights (from ge-nomics, epigenomics, proteomics, and the like) that predictthe natural history of the disease in individual patients togeth-er with their response to specific treatments.5 �

References1. Constantino-Casas P, Viniegra-Osorio A, Médigo-Micete C, del Pilar Torres-Arreola

L, Valenzuela-Flores A. [The potential of clinical practice guidelines to improvethe quality of care (in Spanish)]. Rev Med Inst Mex Seguro Soc. 2009;47:103-108.

2. Fried M, Quigley EM, Hunt RH, et al. Is an evidence-based approach to creat-ing guidelines always the right one? Nat Clin Pract Gastroenterol Hepatol. 2008;5:60-61.

3. Baiardini I, Braido F, Bonini M, Combalati E, Canónica GW. Why do doctors andpatients not follow guidelines? Curr Opin Allergy Clin Immunol. 2009;9:228-233.

4. Carey M, Buchan H, Sanson-Fisher R. The cycle of change: implementing best-evidence clinical practice. Int J Qual Health Care. 2009;21:37-43.

5. Xu LH, Zheng H, Sedmak DD, Sadée W. The reemerging concept of personal-ized health care. Personalized Med. 2008;5:457-469.



Hector Santiago CALDEVILLA, MDDirector, Department of SurgeryVicente Lopez “Prof. Dr. Bernardo Houssay”City Hospital, University of Buenos AiresFaculty of Medicine, Buenos AiresARGENTINA(e-mail: [email protected]))

2. H. S. Caldevilla, Argentina



T he latest guidelines published in journals such as Inter-national Angiology1 and Chest,2 and in the Handbookof Venous Disorders3 edited by Gloviczki, feature a new

approach to the analysis of clinical trial data, classifying theminto three levels of evidence (1, 2, and 3) and three gradingtreatment recommendations (A, B, and C), according to theirimpact on the prognosis and quality of life of patients withchronic venous disease (CVD).

Compression therapy is evaluated and classified by evidencegrades A to C, depending on indication. It emerges as a well-established recommendation to be used at all stages of CVD.However, it is important to point out that it is often best com-bined with other treatments, in particular venotropic drugs andvarious surgical and minimally invasive techniques. Venotrop-ics are a recommended treatment, although the indicationsfor specific agents differ between the European and Ameri-can guidelines.

Certain venotropics, in particular micronized purified flavonoidfraction (diosmin 450 mg plus hesperidin 50 mg [Daflon® 500mg]), have well-established effects on symptoms such as pain,cramps, itching, leg heaviness, and restless legs. The Amer-ican Venous Forum, responsible for the American guidelines,gives venotropics a 2A level recommendation in long-termulcer therapy. The European guidelines, published in Inter-national Angiology on behalf of the International Union of An-giology, International Union of Phlebology, and European Ve-nous Forum, recommend various venotropics for the signsand symptoms of CVD, including ulcers, with micronized pu-rified flavonoid fraction being the only drug carrying a gradeA recommendation for almost all signs and symptoms, except

edema. The Handbook of Venous Disorders also awards mi-cronized purified flavonoid fraction and pentoxifylline grade2A recommendations for use in venous ulceration.

The discrepancies in venotropic indications are probably driv-en by the different experience with these drugs, which is con-siderably more extensive in Europe than in North America.In addition, the huge variety of apparently similar drugs withmultiple differences in physicochemical properties representsa considerable obstacle to serious clinical and scientific analy-sis of their actions.

In Brazil, venotropics are commonly prescribed for almost allstages of CVD, including ulcers. There are evidence-basednational guidelines for this purpose, designed to be appliedin daily practice, enabling practitioners to offer their patientsa better-grounded therapeutic choice. They recommend com-pression, venotropics, and surgery, often in combination, es-pecially for the more severe stages of the disease. Indeed,much of the scientific activity undertaken by the Brazilian An-giology and Vascular Surgery Society (SBACV) consists of de-veloping such guidelines within an overarching guideline proj-ect coordinated by the Brazilian Medical Association, designedto provide a scientific foundation to clinical practice in a rangeof areas, including CVD. There are already rumors that theBrazilian Health System will be taking the SBACV guidelinesinto account in its control of therapeutic procedures. In otherwords, the Society’s recommendations may soon becomethe foundation for the official regulation of CVD managementby the world’s largest public health-care system. There can beno clearer indication of the importance of these scientific andinstitutional initiatives involving this challenging disease. �

References1. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous dis-

orders of the lower limbs: guidelines according to scientific evidence. Int Angiol.2008;27:1-59.

2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; Amer-ican College of Chest Physicians. Antithrombotic therapy for venous thrombo-embolic disease: American College of Chest Physicians Evidence-Based Prac-tice Guidelines (8th edition). Chest. 2008;133:454S-545S.

3. American Venous Forum. In: Gloviczki P, ed. Handbook of Venous Disorders:Guidelines of the American Venous Forum. London, UK: Hodder Arnold; 2009.

Ricardo COSTA-VAL, MD, PhDVice-Scientific DirectorBrazilian Society of Angiologyand Vascular SurgerySão Paolo, BRAZIL(e-mail: [email protected])

3. R. Costa-Val, Brazil



P hlebology has benefited from the general advance invascular diagnostics and therapeutics achieved in thesecond half of the twentieth century. The lessons of

multiple multicenter trials have been encapsulated in clinicalguidelines that should accelerate the pace of clinical researchby raising and standardizing the level of care worldwide, en-abling new lessons to be learned more quickly, which canthen be ploughed back into the recommendations to pro-duce ever better informed and relevant updates.

Guidelines play a key socioeconomic role by standardizingbest practice, ensuring that all patients with similar diseasecan expect to receive approximately similar treatment, andbe reimbursed accordingly. They also encourage communi-cation and cooperation between specialists, not only in thepreparatory stages of elaborating the guidelines themselves,but also in encouraging their uptake by others, whether injournal articles, scientific meetings, or simply hospital caseconferences and journal clubs. Guidelines provide a com-mon descriptive language and a point of reference that al-low specialists to compare like with like, rather than swap an-ecdotal, unextrapolative experiences, as tended to be thecase in the past. In other words, guidelines are essential toscientific progress.

In chronic venous disease, as in any other area, guidelinesneed to follow a number of obvious quality criteria if they areto be fit for purpose: they must be robust, in other wordsbased on the evidence contained in randomized controlledtrials published in quality journals; they must be nonpartisan,representing a consensus view of best practice; and, perhapsmost importantly, they should be updated at regular inter-vals, ideally by a data collection program incorporated with-in the guidelines themselves. An important word of warning,however: guidelines must always be applicable to routine clin-ical practice. They cannot be feasible only in an academic

or clinical trial setting. If so, they remain sterile and fail as driv-ers of progress. This, unfortunately, has been the fate of manyguidelines. Time management issues, staffing levels, sociocul-tural setting, economic and organizational environment1—allneed to be taken into account if guidelines are to fulfill theirpurpose.

Guidelines that are not informed by such considerations riskaccusations of irrelevance, gathering dust on academia’sshelves. Some accusations go further, referring to potentiallimitations and possible patient harm. Patients on bed restfor more than 3 days at the Hasan Sadikin General Hospital(Bandung, Indonesia) did not benefit from antiplatelet agents:cases of deep vein thrombosis were confined almost entirelyto gynecological patients with cancer.2

Elastic compression stockings are a mandatory precautionfor reducing the risk of postthrombotic syndrome.3 However,they find less favor among Indonesians than among inhab-itants of more temperate climates. The stockings are difficultto wear in hot and sweaty conditions. This is an instance of anorthern recommendation falling foul of a southern geograph-ic location.

For more detailed information on this topic, we interviewednine doctors treating chronic venous disease in four Bandunghospitals. Almost none ever follow the elastic compressionstocking guideline. Only two sometimes implemented theguideline. This decision appeared to alienate all the doctorsfrom the other recommendations in the guideline, with theresult that they did not understand why they should follow anysuch guideline or feel obliged to do so. Instead, they managetheir patients according to the relevant textbook and main-tain that this produces acceptable results. In this instance,it could be concluded that despite all the arguments in fa-vor of guidelines, there is little evidence of management fail-ing without them. �

References1. Groll R. Implementation of evidence and guidelines in clinical practice: a new

field of research. Int J Qual Health Care. 2000;12:455-456.2. Prasetyo E. Deep vein thrombosis: Is malignancy the most dominant risk?

Bandung, Indonesia: School of Medicine, Pajajaran University; 2007.3. Kolbach DN, Sandbrink MW, Hamulyak K, Neumann HA, Prins MH. Non-phar-

maceutical measures for prevention of post-thrombotic syndrome. CochraneDatabase Syst Rev. 2004;(1):CD004174.

Hendro Sudjono YUWONO, MD, PhDHasan Sadikin General HospitalJalan Pasteur 38, Bandung 40161INDONESIA(e-mail: [email protected])

4. H. S. Yuwono, Indonesia



T he most recent guidelines for managing chronic ve-nous disease (CVD), published in 2009 by the Interna-tional Union of Angiology, represent a dramatic change

in understanding and practice for Vietnam. Their major ad-vantage is that they are grounded in robust scientific andclinical evidence that can be readily extrapolated into dailypractice.

The most obvious use of the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification is in differenti-ating between different types of patients. Of the many CVDclassifications available, the CEAP is the most useful be-cause it is based on the signs and symptoms characteristicof each stage of the disease course, from onset to ulceration.It provides practitioners and patients with a clear vision of thepathology and its natural history. Unsurprisingly, it has beenrapidly adopted by Vietnamese specialists, who have incor-porated it into most of the recent epidemiological studies con-ducted in this region. CVD is caused by primary abnormal-ities of the vein wall and valves or secondary abnormalitiesresulting from deep vein thrombosis. These lead to reflux, ob-struction, or both. In my many years of clinical practice, I haveseen no case of a congenital malformation resulting in CVD.

CVD was once considered a disease with symptoms, but nosigns, especially in the early stages, making it especially dif-ficult to evaluate. Duplex ultrasound has since introduced arange of objective parameters and is the investigative tech-nique most favored by Vietnamese specialists.

As well as providing an aid to diagnosis, the guidelines rep-resent the first comprehensive review of CVD management.They provide an evidence-based evaluation of all CVD treat-ments. In particular, they discuss the mode of action and effi-cacy of venoactive drugs, concluding that most fail to meetthe requisite criteria and that some should even be withdrawn.Only diosmin, for which there is objective evidence of effi-cacy and a relevant mode of action, is recommended for allstages of CVD, from incipient disease to ulceration. The guide-lines thus provide specialists with an excellent diagnostic andtherapeutic framework for their clinical practice.

An understanding of its pathology at the microcirculatory levelexplains why CVD is a progressive condition and hence re-quires venoactive treatment. Although surgery may be indi-cated in particular patients, venoactive drug therapy is essen-tial in arresting changes in the venous microcirculation—apoint still not fully appreciated by some members of the Viet-namese medical community. At teaching hospital level, how-ever, diosmin + hesperidin is our first-line therapy in daily CVDpractice, although we depart somewhat from the guidelinesin tailoring the dosage to the patient’s weight. At the sametime as raising awareness among our fellow practitioners, weare also attempting to highlight the profile of CVD among thegeneral public, since this is essential if we are to improveunderstanding, diagnosis, and treatment of the disease. �

Hiep Nu Thi Hoa LE, MD, PhDProfessor, Vascular Surgery DepartmentMedical University Hospital ofHo Chi Minh City, Ho Chi MinhVIETNAM(e-mail: [email protected])

5. H. N. T. H. Le, Vietnam

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C hronic venous disease (CVD) guidelines were devel-oped to help physicians cope with a formidable spec-trum of signs, symptoms, and therapeutic approach-

es. Each fresh revision has brought the guidelines that muchcloser to grass roots practice, to the extent that the currentchallenge for the phlebological community may no longerbe, “How do we improve the guidelines?”, but, “How do weensure that clinicians implement the guidelines in their dailypractice?”.

Practical implementation of the guidelines requires a widelyaccepted classification system. The consolidation of severalformer systems into the Clinical-Etiological-Anatomical-Patho-physiological (CEAP) classification of CVD, revised in 2004, hasachieved acceptance in all important international guide-lines. It was a big step towards greater accuracy and con-sistency in diagnosis and better management. However, inCroatia, we have so far failed to convince all our colleaguesto adopt the CEAP classification as the basis of the guide-lines.

Reasons for this failure include:� a clear lack of trained phlebologists to promote the guide-lines;� the impossibility of implementing all requisite treatment op-tions within a single institution; and� medical insurance restrictions that exclude CVD as a pub-lic health problem, meaning that the patients concerned arenot the official responsibility of any institution or group and aretherefore not treated according to international CVD guidelines.

In this setting of low CVD awareness and with our appointmentas Croatia’s national reference center pending, our depart-ment has decided to issue some basic therapy recommen-

dations and supervise their implementation, before producingcomplete national guidelines based on the CEAP classification.

The following recommendations constitute our first draft:1. Compression therapy controls most symptoms of acuteand chronic venous disease, slows disease progression, andprevents deep vein thrombosis (DVT) in bedridden patients.2. Sclerotherapy is suitable for the treatment of smaller vari-cose veins, reticular veins, and telangiectasiae. It should beavoided in large veins, in the vicinity of small and great saphe-nous veins, and in perforators, owing to the risk of deep veinthrombosis. It is not an etiological treatment for varicose veinsand cannot prevent the emergence of new varicose veins.3. Surgical options include phlebectomy, stripping, perforatorligation (if it enhances function), paratibial fasciotomy, and ul-cer grafting.4.Medication comprises drugs with synthetic or naturally oc-curring active ingredients that act on capillary permeabilityand/or venous tone to relieve chronic venous hypertension.5. Physical therapy consists of various massage and lymphat-ic drainage techniques that may temporarily relieve symp-toms, provided they are always combined with compression.6. Local dermatitis therapy is based on physiological skin care,antimicrobial and anti-inflammatory ointments, and cortico-steroids. Proper wound care includes debridement of necrot-ic and infected tissue, exudate control, wound protection,and pain relief. The choice of wound dressing depends onthe wound itself, surrounding skin characteristics, allergies,and availability.7. Prevention includes exercise, compression, and micronizedpurified flavonoid fraction therapy, all of which are significant-ly cost-effective.

We shall be following up these basic recommendations by:� formally educating clinicians in the implementation of theCEAP classification for all their CVD patients; and� providing continuing medical education courses on thepathophysiology of CVD and the advanced treatment optionsavailable.

A huge amount of work remains to be done in this field, es-pecially in Croatia. But it is the only solution for improving themanagement of CVD and patients’ quality of life. �

Sandra Marinovic KULISIC, MD, PhDPhlebology Unit, Department ofDermatology and VenereologyUniversity Hospital Centre Zagreband School of MedicineZagreb, CROATIA(e-mail: [email protected])

6. S. M. Kulisic, Croatia



C hronic venous disease (CVD) has a high prevalencein the general population and as such represents amajor socioeconomic burden. Quality of life in the lat-

er stages is distressing: patients with venous ulcers report aquality of life similar to that of patients in heart failure.

CVD is usually caused by primary abnormalities of the veinwall and valves and/or secondary abnormalities resulting fromprevious deep venous thrombosis (DVT), leading to reflux,obstruction, or both. Congenital malformation is a rare cause.

The good news is that major progress has been made in thelast few years in diagnosis, prevention, and treatment. Rec-ommendations are now available for the management andprevention of CVD in recently developed guidelines drawn upin the US and Europe. Physicians caring for patients with ve-nous disease have two important documents at their dispos-al: “Management of Chronic Venous Disorders of the LowerLimbs: Guidelines According to Scientific Evidence,” pub-lished in International Angiology in 2008;1 and “Antithrombot-ic Therapy for Venous Thromboembolic Disease,” from theAmerican College of Chest Physicians (ACCP) 8th Consen-sus Conference in 2008.2

So, do these guidelines reflect real life and are they applicableand useful in everyday CVD management?

Answers in the affirmative highlight the systematic approachadopted in the guidelines, with recommendations based onliterature evidence and on studies selected for their impec-cable design, rigorous criteria, and follow-up visits performedby skilled investigators working in dedicated facilities. Lev-

els of evidence range from 1 to 3, and recommendations aregraded A through C. Level 1 and Grade A refer to randomizedcontrolled trials reporting clear-cut results applicable to every-day practice. The guidelines also include meta-analyses, butthese need to be used with caution. Some meta-analysescontain studies that have been included without due care,ignore substantive issues and relevant variables, and use het-erogeneous findings or interpret results with bias.1

Answers in the negative point to the high proportion of CVDpatients excluded from clinical trials because of old age andan inability or unwillingness to comply with regular laboratorymonitoring during therapy. Such studies often fail to reflect thereality of a regular outpatient clinic, in rural conditions, or rou-tine general practice. Rarely is there a single test that canprovide all the information needed to make a clinical decisionand plan a management strategy. A number of patients arelikely to require more than one investigation.1 In addition, suchinvestigations may require expertise in ultrasonography/phle-bology/vascular medicine that is lacking in many Europeancountries. CVD awareness among general practitioners dif-fers from country to country, and does so even among special-ists, to the extent that the general situation is far from ideal.Studies also suggest that patient compliance with compres-sion therapy is also very low in daily practice. In other words,there is a clear discrepancy between guideline recommen-dations and their application.

Daily phlebological practice remains remote from guidelinerecommendations in many European countries, making dis-semination by field leaders of the essential information con-tained in these documents all the more crucial if we are toimprove the lot of patients with CVD. �


orders of the lower limbs: guidelines according to scientific evidence. Int Angiol.2008;27:1-59.


Attila Puskás, MD, PhDAssociate Professor, IInd MedicalClinic, Department of Thrombosisand Angiology, University HospitalTirgu Mures/MarosvásárhelyROMANIA(e-mail: [email protected])

7. A. Puskás, Romania

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C linical guidelines are generally designed with severalaims in mind: to educate, to improve managementstandards, to eliminate inappropriate care, and to re-

duce costs. Their impact on the ground varies and is rarelysatisfactory in all respects. Monitoring adherence to guide-lines often reveals surprising gaps between evidence-basedrecommendations and actual clinical management. Notableexamples have included the care of coronary artery diseaseand the treatment and prophylaxis of venous thromboem-bolism.1-3

A similar situation exists in the case of chronic venous disease(CVD). Analysis of venoactive drug prescribing by 2092 gen-eral practitioners and 432 vascular specialists in the CzechRepublic4 showed significant divergence from the conclu-sions propounded in internationally accepted guidelines.5,6

Over half the drugs prescribed were supported by zero evi-dence of benefit in randomized controlled clinical trials or byminimal evidence of efficacy from other sources. Drugs withthe strongest evidence of efficacy—diosmin-hesperidin (mi-cronized purified flavonoid fraction [MPFF]), calcium dobesi-late, hydroxyethylrutoside (oxerutins)—accounted for no morethan 10% of overall prescriptions.

There are several reasons for poor guideline adherence. First,practitioner familiarity with the guidelines is low. Publicationis insufficient in itself to produce awareness. Second, confi-dence in the guidelines is low. Adherence is significantly influ-enced by scientific evidence. Recommendations based on alarge number of randomized controlled studies attract greateradherence than those based on expert opinion.1 Other rea-sons are more subjective, eg, the impression of a nonindivid-

ualized approach to the patient or a suspicion that certain rec-ommendations pander to cost-control considerations. Therecan also be economic reasons for deviating from guidelines.Our own analysis highlighted the important role played inthis regard by the reimbursement policy of insurance insti-tutions. Thus, in the case of our study referred to above, pre-scriptions for cheaper drugs unsupported by evidence fromrandomized controlled trials were fully or partially reimbursed,in contrast with those for more expensive drugs whose usewas backed by scientific evidence. An additional reason forguideline noncompliance, although probably theoretical inthe context of CVD, is a fresh discovery—whether a new di-agnostic approach or a promising treatment—that has yetto be incorporated in the official text.

Guidelines are most successfully introduced when they areeasy to implement, not overly complex, and useful in daily clin-ical practice. Brief study of the official texts currently availableon the treatment of patients with CVD5 confirms their readyapplicability to routine clinical practice. All that it is requiredto circumvent the reasons for noncompliance outlined aboveis that these guidelines be regularly updated, integrated intocontinuing medical education programs, and broadcast byfield leaders at every opportunity—whether at internationalmeetings or at the grass roots departmental or practice lev-el—with every opportunity for feedback. �

References1. Leape LL, Weissman JS, Schneider ES, et al. Adherence to practice guide-

lines: the role of specialty society guidelines. Am Heart J. 2003;145:19-26.2. Caprini JS, Tapson VF, Hyers TM, et al. Treatment of venous thromboembolism:

adherence to guidelines and impact of physician knowledge, attitudes, and be-liefs. J Vasc Surg. 2005;42:726-733.

3. Vallano A, Arnau JM, Miralda GP, Peréz-Bartolí J. Use of venous thromboprophy-laxis and adherence to guideline recommendations: a cross-sectional study.Thrombosis J. 2004,2:3.

4. Zemkova M, Roztocil K, Vlcek J. Venofarmaka v lecbe posttrombotickeho syn-dromu. Lek Listy. 2004;27:21-25.

5. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous disor-ders of the lower limbs: guidelines according to scientific evidence. Int Angiol.2008;27:1-59.

6. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the managementof chronic venous disease. An international consensus statement: Current med-ical position, prospective views and final resolution. Clin Hemorheol Microcirc.2005;33:309-319.

Karel ROZTOCIL, MD, PhDInstitute for Clinical andExperimental MedicinePrague, CZECH REPUBLIC(e-mail: [email protected])

8. K. Roztocil, Czech Republic



C linical guidelines for chronic venous disease (CVD)are designed to help health-care professionals andtheir patients reach the investigational or treatment

decisions most appropriate to their particular clinical situa-tion. Typically they emanate from reputable bodies and rep-resent the consensus view of field leaders.

But this raises the question of their relevance to the everydaypractice of less eminent specialists and primary care physi-cians. Perhaps we can reach a better understanding of theissues involved if we approach the guidelines in terms of theirbenefits and risks or their pros and cons.

The CVD guidelines have undoubted benefits. They havehelped develop a minimum standard of care and eliminatedunnecessary or inappropriate procedures, whether in diagno-sis, treatment, or follow-up. Official bodies can use the guide-lines to monitor the quality of care provided, and third par-ties (eg, insurance companies) can use them to approve ordeny applications for specific procedures. Practice guidelinesalso act as excellent educational tools for trainees.1

On the other hand, this does not apply to all guidelines. Al-though most guidelines are based on well-designed studiesusing control groups and visits at preset intervals undertakenby skilled investigators working in dedicated facilities, someare produced by governments or payers to control spiralingcosts. As such, they may constitute responsible public pol-icy, but can attract the resentment of clinicians and patientsas an invasion of personal and professional autonomy.2

In addition, some experts consider the scientific quality of clin-ical trials published in certain fields, such as compression ther-apy, as grossly defective.3 Furthermore, while most clinicaltrials are well-designed, some are actually over-designed, inthe sense that they exclude all but the most “typical” patients.The atypical patients not catered for in such trials representa large fraction of the patients presenting in daily practice.4

A further consideration is that the studies undertaken in onecountry, and the guidelines that ensue, may require modifi-cation or adaptation before they can be applied in anothercountry. This can be due to differences in patient types, skintypes, thresholds of complaint, and many other factors.

Socioeconomic factors are not always helpful when imple-menting guideline protocols in investigations or treatment.Some practitioners also dislike the more detailed kinds ofguidelines that convey, in their view, a cookbook approach tothe practice of medicine, which inevitably downgrades thepractitioner’s role to that of a technician.

Recommendations that fail to take due account of the evi-dence can result in suboptimal, ineffective, or harmful practice.Guidelines that are inflexible can have an impact oppositeto that intended by leaving insufficient room for clinicians totailor care to a patient’s personal circumstances and med-ical history.2 For these reasons, it is always preferable to pro-mote guidelines as works in progress rather than as defini-tive statements, as snapshots in a continuously evolving stateof the art rather than as pronouncements carved in stone.Guidelines must always be open to ready and rapid amend-ment in line with advances in basic and clinical research. Manyspecialists view them less as mandatory or compulsory thanas compilations of advice and suggestion, grounded in thebest available clinical evidence, to be resorted to in specificsets of circumstances.2

In summary, clinical guidelines are excellent compendia ofevidence-based medicine and have the potential not only tobroaden patient access to optimal strategies, but also, at thesocioeconomic level, to improve the cost-effectiveness of CVDmanagement. However, practice guidelines can never sub-stitute for the clinical judgment of a qualified health-care pro-fessional. My view, on balance, is one of qualified endorse-ment: “Yes, the CVD guidelines continue to be applicable toour daily practice in most cases.” �

References1. Markman M. Clinical practice guidelines in oncology: pros and cons. J CancerRes Clin Oncol. 1996;122:381-382.

2. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: po-tential benefits, limitations, and harms of clinical guidelines. BMJ. 1999;318:527.

3. Rabe E, Partsch H, Jünger M, et al. Guidelines for clinical studies with compres-sion devices in patients with venous disorders of lower limbs. Eur J Vasc Endo-vasc Surg. 2008;35:494-500.

4. Comerota AJ. Treatment of chronic venous disease of lower extremities: what’snew in guidelines. Phlebolymphology. 2009;16:313-320.

Mahmoud SALAH, MBBCh, MSc,MD, FRCSI, FICS, FACSConsultant & Head of the Departmentof Vascular Surgery, Saudi GermanHospitals Group, JeddahSAUDI ARABIA(e-mail: [email protected]/[email protected])

9. M. Salah, Saudi Arabia



G uidelines for chronic venous disease (CVD) need tobe considered first in terms of their strengths and thenin terms of their weaknesses.

StrengthsThe most important CVD guidelines were drawn up by pan-els of experts. As such, they enshrine an international con-sensus endorsed by major medical societies and organiza-tions involved in the study and treatment of the disease. Theydraw upon the most relevant evidence-based studies pub-lished in the highest-rated international journals. In additionthey grade their recommendations using a system similar tothat already used in consecrated guidelines for the majorspecialties, all of which casts them in a robust scientific struc-ture.1,2 As with guidelines in any specialty, the aim is to raiseminimum standards among the various categories of health-care professionals dealing with CVD by reducing subjectivityin diagnosis, treatment, and follow-up. Their main objectiveis to standardize knowledge and issue best-practice recom-mendations applicable to routine use.

Most guidelines have adopted well-established clinical clas-sifications, for example the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) system that standardizes diseasepresentations on the comprehensive basis of the four com-ponents indicated in its title.3 Other systems, such as the Ve-nous Clinical Severity Score (VCSS), have been useful in hand-ling large patient populations in clinical trials and also inevaluating treatment outcomes with greater objectivity.4

The guidelines have also helped to elucidate the role and ef-ficacy of specific venoactive drugs in managing the symptomsevaluated in particular studies. In the case of edema, for in-stance, the venoactive drug most strongly recommended forpatients with C0 to C6 disease, including for primary venousulcer healing, is micronized purified flavonoid fraction (dios-min + hesperidin), which is supported by good-quality evi-dence compared with other venoactive drugs.1,2,5

WeaknessesThe range of possible clinical presentations in CVD is verywide. Many patients present with different stages of the dis-

ease in one or two lower limbs. Secondary CVD is more fre-quent in patients with postthrombotic syndrome, which rep-resents a diagnostic and therapeutic challenge. The majorguidelines have begun to issue recommendations on the di-agnosis of acute deep vein thrombosis, drawing attentionto the improved results that can be achieved with more in-vasive treatment. This can be expected to lower the frequen-cy of this form of secondary CVD.

The guidelines fail to provide a convincing pathophysiologi-cal explanation for CVD recurrence in patients who have un-dergone open surgery or endovascular vein ablation. Nor dothey supply clear guidance as to the optimal management ofthis stage of the disease.

Specialists continue to debate the place of hormone replace-ment therapy in menopausal patients with CVD.6 Guidelineupdates will need to incorporate conclusive recommenda-tions as to patient identification and optimal treatment in thisregard, given the rising incidence and prevalence of this com-bination in numerous populations.

Further study is also required of certain previously establishedrisk factors for CVD, in particular age, being overweight, andfemale sex, given reports of the increasing prevalence of ear-ly CVD in women and the general impact of rising obesitylevels in various young populations of both sexes.1,2

ConclusionCVD guidelines have fulfilled their brief of standardizing thediagnosis and management of most typical presentationsof the disease. They simply need tweaking with input frommethodologically stronger studies that address less typicaldisease presentations. �


orders of the lower limbs: guidelines according to scientific evidence. Int An-giol. 2008;27:1-59.


3. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification forchronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-1252.

4. Vasquez MA, Munschauer CE. Venous clinical severity score and quality-of-lifeassessment tools: application to vein practice. Phlebology. 2008;23:259-275.

5. Coleridge Smith PD. Drug treatment of varicose veins, venous oedema, and ul-cers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the Ame-rican Venous Forum. 3rd ed. London, UK: Hodder Arnold; 2009:359-365.

6. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’sHealth Initiative Investigators. Risks and benefits of estrogen plus progestin inhealthy postmenopausal women: principal results from the Women’s Health Ini-tiative randomized controlled trial. JAMA. 2002;288:321-333.

Ignacio S. ESCOTTO, MDAssistant Professor of AngiologyVascular and Endovascular SurgeryNational Medical Center of Mexico ISSSTEUniversidad Nacional Autónomade México, MEXICO(e-mail: [email protected])

10. I. S. Escotto, Mexico



C hronic venous disease (CVD) guidelines based oncarefully conducted therapeutic trials are very use-ful in clinical practice. They help us to make the best

treatment choices, but there are two main limitations to theirapplication in our daily practice: first, the limitations inherent inthe evaluation tools on which they rely (primarily the Clinical-Etiological-Anatomical-Pathophysiological [CEAP] scoring sys-tem); and, second, the failure of clinical trials to be universallyapplicable.

Our main reference points when we use the CVD guidelinesare the CEAP parameters: symptoms, clinical class, anatom-ical venous lesions, and their etiology (reflux or obstruction).Updated venous nomenclature has recently made it easierfor CVD specialists to speak a common language.

But from our daily practice we also know that, for any givenpatient, other parameters are of great importance: way oflife and occupation, number of hours during the day spentstanding or walking, limitation of ankle movement, static footdisorders, concomitant treatments (hormones, in particular),heredity, and progression of CVD.

Any of these factors can impair venous return and quality oflife. They are not usually taken into account in the evaluation

tools used either to classify patients or to compare treatments.As a consequence, we don’t find them among the guidelineparameters. It is also difficult to standardize venous investiga-tions. The quantification of reflux and reproducibility of “provo-cative” maneuvers are rarely easy.

As for the second limitation, trials often exclude patients onthe grounds of old age, contraindications to therapy, inabilityor unwillingness to comply with laboratory monitoring duringtherapy, and other criteria that apply to swathes of the routinepopulation we are called upon to treat.

Our real-life patients do not necessarily fit the ideal clinicaltrial subject’s profile in other respects. International guidelinesare always unlikely to provide an exact match to particularpatients rooted in their given sociocultural characteristics,country, occupation, and language. This constitutes a majorlimitation.

Moreover, new treatments are continually appearing. Rigor-ous evaluation takes several years, during which time freshtechniques will have appeared, with the result that clinical re-search is forever playing catch-up. The guidelines thereforerequire continuous updating, which makes them difficult toapply in everyday clinical practice.

We should keep in mind that CVD is a complex and progres-sive disease that is both multifactorial and multidimensional,as well as particularly fast-moving. For these reasons CVDguidelines should not be considered as a set of directly appli-cable rules, but as general guides to good practice providinga conceptual reference frame for the most common cases. Itis in the very nature of guidelines that they cannot fully takeinto account the inevitable specificities of individual patients.�

Jean-François UHL, MD, FacPhVascular surgeon, Vice-presidentof the French Society of PhlebologyUnité de Recherche et Développementen Imagerie et Anatomie EA 4465Université Paris 5 DescartesParis, FRANCE(e-mail: [email protected])

11. J.-F. Uhl, France



T he prevalence of chronic venous disease (CVD) is wide-spread. Epidemiologic data from industrialized coun-tries, where studies have essentially been centered,

indicate that the signs and symptoms of CVD can be found inup to 70%-80% of subjects in some populations, dependingon age, gender, ethnicity, etc.

Such a vast pool of potential patients could never be cateredfor effectively by vascular specialists alone. That is why mul-tidisciplinary competence is required, extending across nu-merous other specialties, including primary care. This cannotbe achieved without the publication and dissemination of con-temporary diagnostic and management standards. Hence,the need for guidelines that can be consulted by any health-care professional called upon to care for a patient with CVD.

The development of the Clinical-Etiological-Anatomical-Patho-physiological (CEAP) classification was the first step in stan-dardizing diagnosis. It proved highly successful and hasbecome accepted worldwide. The next step was the devel-opment of guidelines intended to reduce the improper andunnecessary use of various diagnostic and treatment methodsand to improve CVD care. We now have a number of com-prehensive CVD guidelines available to us,1-4 headed by thoseproposed in 2008 by the expert group of Nicolaides et al,3

encompassing all aspects of the disease. Three years havepassed since the publication of these guidelines, which hasgiven us the time to consider their relevance to our dailypractice.

There are two possible views that can be taken. The first isthat of the doctors who manage CVD patients on a daily basis(phlebologists, angiologists, etc). I believe that most of thesespecialists consider the guidelines as really useful tools for an-alyzing and systematizing their own approaches and improv-ing their management of CVD. However, the alternative viewis that shared by specialists for whom CVD is not central totheir practice, even though, epidemiologically, they see and

manage (at least in the initial stages) the majority of patients.These specialists are general surgeons, vascular surgeons,and general practitioners. As they are not usually involved inthe routine treatment of CVD, they don’t only need a tool foranalyzing and systematizing their management, but also clear,strong, and unequivocal recommendations as to how to re-spond to different clinical situations.

A good example of such a document would be the AmericanCollege of Chest Physicians’ guidelines.5 Despite the vague-ness and uncertainty of some of the recommendations theycontain, most are direct and authoritative, enabling the doctorto make appropriate decisions. CVD guidelines, on the otherhand, are less firm and clear-cut. They often fail to provide doc-tors with ready-made solutions for many clinical situations.3

Even in the case of pharmacological therapy, where a high lev-el of evidence exists for the efficacy of venoactive drugs, thecurrent guidelines state that they “may be indicated” or “maybe used.” It is probable that such advice, which fails to fullyendorse the scientific evidence, will not prevent doctors reach-ing the right decision, assuming they have expert knowledgein phlebology. But if not, if phlebology is not central to theirpractice, it may lead them to withhold necessary and usefulmedication.

Good randomized controlled trials and reliable meta-analy-ses of the main CVD treatments are few and far between.They are therefore more essential than ever if the currentguidelines are to gain in authority, weight, and decisiveness.What doctors need in their daily practice is not discussion, butstrict and simple instructions. Such practice-oriented guide-lines should also be regularly and promptly updated, withchanges continuously taking place in the fast-moving field ofphlebology. �

References1. Partsch H. Evidence based compression therapy. VASA. 2003;34(suppl 63):1-39.2. Agus GB, Allegra C, Antignani PL, et al. Guidelines for the diagnosis and ther-

apy of the vein and lymphatic disorders. Int Angiol. 2005;24:107-168.3. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous disor-

ders of the lower limbs: guidelines according to scientific evidence. Int Angiol.2008;27:1-59.

4. Guideline Subcommittee of the European Dermatology Forum. Guidelines fordiagnostics and treatment of venous leg ulcers. http://www.euroderm.org/content/guideline_on_venous_leg_ulcers.htm. Accessed March 8, 2011.


Igor ZOLOTUKHIN, MD, PhDRussian State Medical University1, Ostrovitjanova str117997 Moscow, RUSSIA(e-mail: [email protected])

12. I. Zolotukhin, Russia

MEDICOGRAPHIA, Vol 33, No. 3, 2011 The place of Daflon 500 mg in recent guidelines on the management of CVD – Pitsch306

C hronic venous disease (CVD) is a common condition representing aspectrum of disorders. Much effort has been spent creating a commonlanguage, which is essential for the establishment of clinical practice

guidelines. In addition to improved methods of defining CVD, there is now alsoincreased understanding of the pathological processes involved in its devel-opment. Lack of venous tone, abnormal capillary permeability, and overloadedlymphatic vessels have been put forward as the mechanisms involved in thedevelopment of CVD. The leukocyte-endothelium interaction and its asso-ciation with valvular damage is one of the earliest pathophysiological mech-anisms at work in the disease. This has focused attention on Daflon 500 mg,the only available molecule whose activity is known to modify such inflamma-tory events. Besides its ability to increase venous tone, regulate capillary fil-tration, and speed up lymphatic drainage, it has been shown to reduce theinteraction of leukocytes with the endothelium in acute venous hypertensionand inflammation, and it is used clinically to treat CVD. Daflon 500 mg hasbeen intensively investigated in well-designed clinical trials and is well toler-ated. Micronization of the particle size of its components to <2 ��m improvesits oral absorption and bioavailability compared with those of nonmicronizeddiosmins. These characteristics explain why Daflon 500 mg is listed among thevenoactive drugs in recent guidelines on the management of this disease.


C hronic venous disease (CVD) covers a full spectrum of venous conditions fromtelangiectasias to the ultimate complication of CVD, venous ulcers. Symp-toms are commonly associated with signs of CVD. Venous symptoms are

defined as tingling, aching, burning, pain, muscle cramps, swelling, sensations ofthrobbing or heaviness, itching skin, restless legs, and leg tiredness and/or fatigue,which may be exacerbated by heat or during the course of a day, and relieved byleg rest, elevation, or both.1 Venous signs are visible manifestations of CVD, whichinclude dilated veins (telangiectasias, reticular veins, varicose veins), leg edema, skinchanges, and ulcers, as described in the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification.2,3

This article addresses some of the newer guidelines on venoactive drugs (VADs) ingeneral, and Daflon 500 mg in particular, in the management of CVD to help clini-cians better manage patients with CVD of the lower extremity. Intentionally, only pri-mary CVD will be tackled in this review, putting postthrombotic venous disease aside.

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Françoise PITSCH, PharmDServier International Suresnes FRANCE

Address for correspondence:Françoise Pitsch, ServierInternational, 35, rue de Verdun,92284 Suresnes Cedex, France(e-mail: [email protected])


The place of Daflon 500 mgin recent guidelines

on the management ofchronic venous disease

by F. P i tsch, France

Among the many reasonsthat make guidelines useful, one isbecause they provide recommen-dations that are based on goodquality evidence. Another is be-cause they balance the desirableand undesirable effects of a treat-ment, not to mention the cost-ef-fectiveness of such treatment. Arobust strength of recommenda-tion for a treatment indicates thatclinicians can offer this treatmentto almost all their patients with lit-tle or no hesitation. This is the casefor Daflon 500 mg.”

‘‘

What are the indications of Daflon 500 mg?Daflon 500 mg, micronized purified flavonoid fraction (MPFF),consists of 90% diosmin and 10% other flavonoids (hesperi-din, diosmetin, linarin, and isorhoifolin). Prescribing informationmay differ between countries, but in general Daflon 500 mg,which is available in more than 100 countries, is indicated asa first-line treatment of symptoms associated with any stageof CVD, and in lower limb edema. In more advanced diseasestages, such as venous leg ulcer, Daflon 500 mg may be usedin conjunction with sclerotherapy, surgery, and/or compres-sion therapy, or as an alternative treatment when surgery isnot indicated or is unfeasible.4

Pathophysiology of primary CVD and targets forDaflon 500 mg treatmentBecause they provide a rational explanation for the clinicalbenefits of treatments, it is important to consider the patho-physiological mechanisms underlying any disease in guide-lines. Ambulatory venous hypertension is the hemodynam-ic pathology related to all symptoms and signs of CVD. Theunderlying components of venous hypertension are failure ofthe calf muscle pump, venous valvular incompetence, and lu-minal obstruction.5

After prolonged standing, venous pressure in the foot is ap-proximately 90 mm Hg in both a patient with incompetent ve-nous valves and a person with a normal leg. However, ambu-latory venous pressures in CVD patients remain high in thelower limbs during walking (more than 40 mm Hg), whereasnormally these pressures should fall to a lower level (to 30mm Hg). Due to valve incompetence, venous refill time on airplethysmography is shorter in CVD patients compared withhealthy individuals.5

When venous pressures in the leg are at higher-than-normallevels and remain elevated for prolonged periods, a progres-sive increase in skin damage may occur. Nicolaides report-ed that nearly all patients with exercising venous pressures of>90 mm Hg experienced venous ulceration.6 How the appar-ently simple concept of venous hypertension is responsible

for CVD lies in the complex cellular and molecular process-es set in motion by the abnormal venous hemodynamics itengenders.

What initiates inflammatory events in venous valves and wallshas not yet been uncovered. It is likely that venous hyperten-sion and subsequent stasis lead to vein distension, which inturn causes venous flow reversal and areas of low shear stress.Even in the absence of reflux, endothelial cells that are ex-posed to flow reversal become activated. Leukocytes, on theother hand, are activated by low shear stress.

When leukocytes are activated as a result of venous hyper-tension, they produce adhesion molecules, which bind to in-tracellular adhesion molecules (ICAMs) at the endothelial sur-face. This permits endothelial cell adhesion of leukocytes andinitiates their migration through the vessel wall into the ex-travascular tissues, leading to degranulation and the releaseof proteolytic enzymes (such as matrix metalloproteinases[MMPs], tissue inhibitors of MMPs [TIMPs], and transforminggrowth factor β1 [TGFβ1]).7,8 This type of leukocyte-endothe-lial interaction initiates and maintains inflammation.5

The consequences of inflammation in primary CVD:the remodeling of vein wall and valves� Vein wall and valvesMorphologic changes in venous valves occur with prolongedpressure-induced inflammation. Wall and valve remodelingand damage occur as a result of leukocyte infiltration into veinwall and valve leaflets, leading to wall fibrosis together withprogressive reflux.

The production of MMPs and a greater proportion of TIMPsleads to the accumulation of extracellular matrix material. Inaddition, increased production of TGFβ1 stimulates collagensynthesis and further increases in TIMP production. The cu-mulative result of these events results is the structural and hy-pertrophic changes in venous wall that typify patients withvaricose veins.9

� MicrocirculationAn early event that occurs in CVD is elevated endothelial per-meability, with the opening of leakage sites between endo-thelial cells. As a result of this enhanced microvascular per-meability, extravasation of water and water-soluble nutrientsleads to edema.10 With further permeability, the extravasa-tion of red blood cells leads to the hyperpigmentation of skinin lipodermatosclerosis.

� Lymphatic networkFluid transport through the lymphatic vasculature completesthe body’s circulatory loop. The lymphatic vessels maintaintissue homeostasis and compensate for capillary leakageby absorbing extravasated interstitial fluid.11 In the case ofintense capillary leakage, the lymphatic drainage capacity be-

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The place of Daflon 500 mg in recent guidelines on the management of CVD – Pitsch MEDICOGRAPHIA, Vol 33, No. 3, 2011 307


CEAP Clinical-Etiological-Anatomical-PathophysiologicalCVD chronic venous diseaseICAM intracellular adhesion moleculeMMP matrix metalloproteinaseMPFF micronized purified flavonoid fractionRCT randomized controlled trialRELIEF Reflux assEssment and quaLity of lIfe improvEment

with micronized FlavonoidsTGFβ1 transforming growth factor β1TIMP tissue inhibitor of matrix metalloproteinasesVAD venoactive drug

D A F L O N 5 0 0 M G

MEDICOGRAPHIA, Vol 33, No. 3, 2011 The place of Daflon 500 mg in recent guidelines on the management of CVD – Pitsch 308

comes insufficient to absorb the excess fluid and macromol-ecules produced. This leads to venous edema, which sparestoes, in contrast to lymphatic edema. The Kaposi-Stemmertest allows us to distinguish between the two types of ede-ma (Figure 1).

Mechanisms of action of Daflon 500 mgDaflon 500 mg belongs to the gamma-benzopyrone classof VADs, which are for the most part of plant origin, but alsoof synthetic origin, too, as illustrated in Table I.12 So, what arethe mechanisms at work in the treatment of CVD by Daflon500 mg?13

� Daflon 500 mg, like most VADs, increases venous tone,thereby reducing venous distensibility and stasis.� The beneficial effect of Daflon 500 mg in reducing abnor-mal capillary permeability has been extensively demonstrat-ed. This effect has also been witnessed in almost all VADs.� Lymphatic drainage improves with Daflon 500 mg. Onlytwo other VADs have a beneficial effect on lymphatic drainage.

Figure 1. The Kaposi-Stemmer test allows physicians to distin-guish between venous and lymphatic edema. Lymphatic edemaaffects the toes, while venous edema spares them.

Dosage Number ofGroup Substance Origin (mg) doses/day

Benzyopyrones

Alpha- Coumarin Melilot (Melilotus 90 combined 3benzopyrones officinalis) with

Woodruff (Asperula troxerutin (540)odorata)

Gamma- Diosmin Citrus sp (Sophora 300-600 1 or 2benzopyrones japonica)(flavonoids) Micronized purified Rutaceae aurantiae 1000 1 or 2

flavonoid fraction (MPFF)

Rutin and rutosides Sophora japonica 1000 1 or 2

0-(β-Hydroxyethyl)- Eucalyptus sprutosides (troxerutin, HR) Fagopyrum esculentum

Saponins Escin Horse chestnut Initially 120, 3(Aesculus then 60hippocastanum)

Ruscus extract Butcher’s broom 2 to 3 tablets 2 to 3(Ruscus aculeatus)

Other plant Anthocyans Bilberry (Vaccinium 116 2extracts myrtillus)

Proanthocyanidins Maritime pine (Pinus 100 to 300 1 to 3maritimus)

Grape pips (Vitis vinifera) 300 to 360 3

Extracts of ginkgo Ginkgo biloba 2 sachets (extracts of 2ginkgo, heptaminol, and troxerutin)

Synthetic Calcium dobesilate Synthetic 1000 to 1500 2 to 3products

Benzarone Synthetic 400 to 600 2 to 3

Naftazone Synthetic 30 1

Table I. Classi-fication of themain venoac-tive drugs. Abbreviations:CVD, chronicvenous disease;GRADE, Grades ofRecommendationAssessment,Development andEvaluation; HCSE,horse chestnutseed extract;MPFF, micronizedpurified flavonoidfraction.Modified fromreference 12: Ramelet et al. Phle-bology. 5th ed.Issy-les-Mouli-neaux, France: Elsevier MassonSAS; 2008. © 2008, ElsevierMasson SAS.

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� Only Daflon 500 mg has documented evidence of the abil-ity to attenuate the effects of various inflammatory cascademediators, particularly those involved in the leukocyte-en-dothelial interaction, which are important in the genesis of ve-nous hypertension and its clinical repercussions (Figure 2).14

� Venous toneThe beneficial effect of Daflon 500 mg on venous tone hasbeen studied in three double-blind, placebo-controlled trialsin patient populations with varying degrees of CVD, includingwomen with venous insufficiency related to postthromboticsyndrome,15 with venous insufficiency related to pregnancy,16

and without any venous pathology.17 Daflon 500 mg, at a doseof two tablets per day, had an immediate, positive effect onvenous tone, which started to improve 1 hour after adminis-tration in all three groups of women. In the trial in women with-out any venous pathology,17 Daflon 500 mg significantly im-proved venous distensibility for 4 hours after administrationcompared with placebo (P<0.05). When treatment was con-tinued for 1 week, the significant effect on venous distensibilitycompared with placebo was maintained for 24 hours (P<0.05).

In a study aimed at determining the effect of Daflon 500 mg in25 female volunteers aged 18-35 years with abnormal venouselasticity but without varicose veins,18 12 women received asingle dose of two tablets of Daflon 500 mg for 4 weeks,while 13 women in the control group received no treatment.Venous tone significantly improved in patients receiving Daflon500 mg (P<0.02) compared with baseline. In contrast, ve-nous elasticity did not change significantly versus baselinein patients in the control group.

� Capillary hyperpermeabilityWhen subjected to prolonged venous hypertension, capillar-ies become elongated and dilated and develop abnormal per-

meability. The increased permeability causes interstitial ede-ma. The beneficial effects of Daflon 500 mg on capillary hy-perpermeability have been demonstrated in two trials.19,20 In a6-week, placebo-controlled trial in 30 patients with idiopathiccyclic edema, Daflon 500 mg significantly improved capillary

hyperpermeability (as measured by labeledalbumin retention) compared with placebo(P<0.05).19 This was accompanied by amean weight loss of at least 1.5 kg and a de-creased sensation of swelling, indicating aconcomitant decrease in edema. In a 4-week study in patients with venous hyper-tension, Daflon 500 mg given either two orthree times daily significantly decreased thecapillary filtration rate versus baseline valuesin a dose-dependent manner (P<0.05).20

� Lymphatic drainageIn patients with advanced CVD, there is anincrease in intralymphatic pressure and di-ameter, and in permeability of the lymphat-ic capillaries, leading to the transendothelialdiffusion of fluids (Figure 3).21 Daflon 500 mgis thought to improve lymph flow by increas-ing both the frequency and amplitude ofcontraction of lymphatic capillaries, as well

as by increasing the number of functional capillaries. Thisreduces edema by facilitating the drainage of interstitial fluidinto the lymphatic system. In a 4-week study in 24 patientswith severe CVD but no active ulceration, Daflon 500 mg sig-nificantly decreased the diameter of lymphatic capillaries andthe intralymphatic pressure from baseline (P<0.001).22 In ad-dition, the number of functional lymphatic capillaries also sig-nificantly increased (P<0.001).

Figure 2. The vicious circle of venous hypertension/venous inflammation. Modified from reference 14: Ramelet. Phlebolymphology. 2009;16:321-330. © 2009, Les Labora-toires Servier.

Years after enrolment

Venous hypertension Venous dilation

Increased hypertension

Skin changes

Capillary leakage

Capillary hypertension

Valve and wall changes

Edema

UlcerINFLAMMATION

Risk factors for chronic venous disease

Altered blood flow and shear stress

Valve distortion and leakageValve reflux

Figure 3. Venous hypertension is transmitted to the microcircula-tion and prompts leukocyte adhesion to capillary endothelium. Thisinitiates an inflammatory reaction which dramatically increases cap-illary permeability. When transcapillary filtration exceeds lymphaticflow, interstitial edema occurs. Thanks to its vein-specific anti-in-flammatory action and its beneficial effect on lymphatic drainage,Daflon 500 mg improves capillary reabsorption of excess fluids anddecreases edema. © Impact Médecin.

D A F L O N 5 0 0 M G


� The leukocyte-endothelial interactionThe well-established role of leukocytes in the pathophysiol-ogy of CVD has focused attention on drugs able to blockleukocyte adhesion to the venous valves and wall and there-by stop venous inflammation very early in the disease process

(Figure 4).23 Daflon 500 mg has up to now been the only avail-able VAD with documented evidence of the ability to attenu-ate the effects of various mediators involved in the inflamma-tory cascade, particularly leukocyte-endothelial mediators. These are important in many aspects of the disease. For years,it had been accepted that CVD was related to a primary failureof venous valves affected by inflammation.5,24 This hypothesiswas challenged recently, and evidence now seems to favor thehypothesis that CVD is related to a preexisting weakness inthe vessel wall, which produces dilation that in turn causes

secondary valvular incompetence.25 However, guidelines nowmention that early pharmacological treatment directed to-wards preventing or inhibiting the inflammatory response atall stages of the disease may play a significant role in prevent-ing or slowing the development and recurrence of the signsand symptoms of CVD.13 Key findings with Daflon 500 mgcome from the rat fistula model of venous hypertension.24

In this model, venous hypertension caused by a femoral ar-terial-venous fistula resulted in the development of venous re-flux and an inflammatory reaction in venous valves. In animalstreated with Daflon 500 mg, there was a significant, dose-de-pendent reduction in reflux rate. Daflon 500 mg also inhibit-ed the expression of the endothelial cell adhesion moleculesP-selectin and ICAM-1, reduced leukocyte infiltration, and de-creased the level of apoptosis in valves in a dose-dependentmanner. These data suggest that in the rat model of venoushypertension, Daflon 500 mg delays the development of re-flux and suppresses damage to valve structures by decreas-ing the interaction between leukocytes and endothelial cells.The administration of Daflon 500 mg reduced the edema andthe fistula blood flow produced by the acute arterial-venousfistula. Daflon 500 mg also reduced granulocyte and macro-phage infiltration of valves.24

Evidence for the clinical efficacy of Daflon 500 mgThe clinical efficacy of Daflon 500 mg has been evaluated ina number of clinical trials. Many studies with rigorous designshave demonstrated that Daflon 500 mg improves symptomsand signs in patients with CVD.4

� Improvement of symptoms of CVDA review of the data show that Daflon 500 mg is effective fromthe earliest stages of CVD, including in patients with a C0Sclassification, and that symptom relief is achieved rapidly andin a sustained manner. The efficacy of Daflon 500 mg’s reliefof clinical symptoms has been evaluated in two placebo-controlled trials in which the following symptoms were con-sidered: functional discomfort, leg heaviness, pain, fatiguewhen standing, night cramps, paresthesia, burning sensation,itching, and sensation of edema in the evening.26,27

In the first trial of 40 patients with CVD, Daflon 500 mg wasassociated with a significantly greater improvement in manyof the symptoms of CVD compared with placebo with P val-ues for global scores of P<0.001.26 In a second placebo-con-trolled trial of 160 patients with CVD, Daflon 500 mg wasagain associated with a significant improvement in symptomscompared with placebo.27 For the symptoms of functionaldiscomfort, sensation of heaviness, nocturnal cramps, andsensation of swelling, these changes were significant after4 weeks of treatment. The effects of Daflon 500 mg on thesymptoms of CVD have also been compared with nonmi-cronized diosmin in a study of 88 patients.28 While statisti-cally significant improvements in all subjective symptoms

Figure 4A illustrates the rolling and adhesion of leukocytes at thesurface of the endothelium before their migration into tissues.Figure 4B shows firm adhesion of leukocytes to and migrationinto the venous endothelium. This is the starting point of an inflammatory reaction and cascade that causesvein wall and valve remodeling, thereby prolonging venous hypertension andeventually progression to complications. Thanks to its vein-specific anti-inflam-matory action, Daflon 500 mg prevents the inflammatory cascade in the venoussystem.After reference 23: Joris et al. Am J Pathol. 1983;113:341-358. 1983, © Ameri-can Journal of Pathology.

A

B

D A F L O N 5 0 0 M G


were noted in both treatment groups at the end of 2 months,Daflon 500 mg was more effective than diosmin for the ma-jority of response measures.

� Reduction of leg edemaIn the three trials assessing the efficacy of Daflon 500 mg forthe relief of CVD symptoms, measures of edema were alsotaken. All three trials demonstrated a significant correlation be-tween the improvements in the symptom score of sensationof swelling and a decrease in ankle circumference.26-28 Threefurther studies that used different methods to quantify leg ede-ma also demonstrated that Daflon 500 mg has beneficial ef-fects. In two placebo-controlled trials of patients with eithersymptoms or signs of CVD, the administration of Daflon500 mg resulted in significant reductions in ankle circumfer-ence compared with placebo.26,28

In a third study, edema was assessed using a volumeter in pa-tients with varicose veins. Administration of Daflon 500 mgwas associated with a significant decrease in volume of themore affected lower leg of 263 mL (8%) in all patients and392 mL (12%) in patients with varicose veins.29 In a Czechstudy in 213 patients with venous edema receiving two tabletsa day of Daflon 500 mg for 6 months, the ankle and calf cir-cumferences were significantly less than those at baseline—24.4 vs 25 cm (P<0.001) for ankle circumference; and 39.9vs 40.6 cm (P<0.001) for calf circumference.

The reduction in circumferences continued until month 6. Legvolume decreased by an average of 78 cm3 after 2-months’treatment with Daflon 500 mg and by 121 cm3 after 6 months.This was significant both times (P<0.001).30 Finally, edema,as measured by leg circumference, also decreased signifi-cantly compared with baseline in the RELIEF (Reflux as-sEssment and quaLity of lIfe improvEment with micronizedFlavonoids) study.31

� Leg ulcer healingA meta-analysis that pooled 723 patients with venous ulcerstreated with Daflon 500 mg confirmed that the rate of ve-nous ulcer healing is accelerated by adding Daflon 500 mg toconventional treatments.32 At 6 months, the chance of heal-ing an ulcer was 32% better in patients treated with adjunc-tive Daflon 500 mg than in those managed by conventionaltherapy alone (relative risk reduction, 32%; 95% confidenceinterval [CI], 3% to 70%; P=0.03). Subgroup analyses sug-gested that the benefits of Daflon 500 mg were greatest inulcers >5 cm2 and >6 months in age.

Summary of Daflon 500 mg in recent guidelines� Cochrane reviewsIn recent Cochrane reviews on VADs, randomized, double-blind, placebo-controlled trials were classified as being level A(low risk of bias), level B (moderate risk of bias), or level C (highrisk of bias).33,34 Significant and homogeneous results were

found for edema reduction, decrease in restless leg symp-toms, and improvement in trophic disorders for most VADscompared with placebo.33 However, for most analyses therewas evidence of heterogeneity. No test for heterogeneity wasapplied in the review of horse chestnut seed extract.34

In the subgroup analyses of individual VADs, Daflon 500 mgwas shown to have significant benefits versus placebo, basedon multiple studies, on several dichotomous and continuousoutcome variables, such as cramps, heaviness, edema, andskin changes, albeit with evidence of heterogeneity in mostcases.33

� Consensus guidelinesIn most European guidelines, studies are usually classified:grade A (at least two randomized controlled trials [RCTs] withlarge sample sizes, meta-analyses combining homogeneousresults), grade B (RCTs with small sample size, single RCT),or grade C (other controlled trials, nonrandomized controlledtrials).13

Two of these guidelines deal with VADs (Figure 5, page 312).The article of Ramelet et al, published in Clinical Hemorrheo-logy and Microcirculation, represents the proceedings of theInternational Medical Consensus Meeting on Venoactive Drugsin the Management of Symptoms of Chronic Venous Disease,held in Siena.35 Eighty-three publications on the efficacy ofVADs on venous symptoms were analyzed. The “Internation-al Guidelines on the Management of Chronic Venous Dis-ease,” published in International Angiology,13 used the samegrading system as that of the Siena experts except for meta-analyses, which were graded B. Outcomes included not onlysymptoms, but also edema and venous ulcer healing. Onehundred and twenty-eight publications on VADs were ana-lyzed in this document.

Based on the consistency of the respective evidence fromthese two recent guidelines on VADs,13,35 a grade A was as-signed to two VADs: MPFF (Daflon 500 mg) and hydroxyethyl-rutosides (ie, oxerutins) for the effects of these VADs on symp-toms, edema, and skin changes.

A new grading system for CVD guidelinesThe method of determining the strength and quality of therecommendations in American guidelines deserves mention.Recommendations are generally accompanied by a num-ber, which refers to the strength of the recommendation, anda letter, which refers to the quality of the evidence supportingthe recommendation. Recent guidelines for venous diseasehave used two levels to specify the strength of their recom-mendations depending mainly on the benefit/risk ratio: grade 1for strong and grade 2 for weak. They go on to indicate thatstatements accompanied by a grade 1 rating are “recommen-dations,” while statements accompanied by a grade 2 ratingare “suggestions.”36

The quality of evidence upon which the strength of the rec-ommendation is based ranges from “A” for high-quality ev-idence, which is consistent evidence from randomized tri-als, to “B” for moderate-quality evidence, which is evidencefrom nonrandomized trials or inconsistent evidence from ran-domized trials. Level “C” is low-quality evidence, which is sug-gestive evidence from nonrandomized trials, observationalreports, or expert opinion. Writing committees are increasing-ly aware of the costs of care and patient values and prefer-ences, as are physicians. These are also considered in thestrength of recommendations.

Two guidelines on venous diseases use this system (Figure 5):� one is a recent educational article on the pharmacologicaltreatment of primary CVD, dealing almost exclusively withVADs and their place in the management of such disease.25

� the second is the latest edition (3rd edition) of the Hand-book of Venous Disorders: Guidelines of the American Ve-nous Forum.37

The educational article proposed a strong recommendation,based on evidence of moderate quality, for the use of Daflon500 mg to treat CVD symptoms and edema. The recommen-dations of the article reflect the opinions and judgements ofthe authors, but have not been endorsed by learned soci-eties or other organizations (Table II).25

There is evidence from a meta-analysis of RCTs that Daflon500 mg may be effective in healing venous ulcers.32 In the ab-sence of important safety concerns, its use in this indicationwas given a strong recommendation in primary ulcers (1B).On the basis of the meta-analysis mentioned above,32 the au-

312 The place of Daflon 500 mg in recent guidelines on the management of CVD – Pitsch MEDICOGRAPHIA, Vol 33, No. 3, 2011

D A F L O N 5 0 0 M G

Venoactive Recommendation QualityIndication drug for use of evidence Code

Relief of symptoms associated Daflon 500mg (MPFF) Strong Moderate 1Bwith CVD in patients C0S to

Rutosides Strong Moderate 1BC6S and with CVD-related

Calcium dobesilate Weak Moderate 2Bedema

HCSE Weak Low 2C

Ruscus extracts Weak Low 2C

Healing of primary venous ulcer, as anadjunct to compressive and local Daflon 500mg (MPFF) Strong Moderate 1B therapy (Coleridge-Smith, 2009)

Table II. Summary of ten-tative recommendations,according to the GRADErecommendation system.

Abbreviations: CVD, chronic ve-nous disease; GRADE, Gradesof Recommendation Assess-

ment, Development and Evalua-tion; HCSE, horse chestnut

seed extract; MPFF, micronizedpurified flavonoid fraction.

Modified from reference 25:Perrin and Ramelet. Eur J Vasc

Endo-vasc Surg. 2011; 41:117-125. © 2011, European Society

for Vascular Surgery.

Figure 5.Summary ofrecent guide-lines of Daflon500 mg in themanagementof primarychronic ve-nous disease.European andUS guidelineshave givenDaflon 500mg a strongrecommen-dation in thetreatment of primarychronic ve-nous disease.

First editionVenoactive drugs in themanagement of chronicvenous disease: an in-ternational consensus

statementClin Hemorheol Microcirc.

2005;33:309-319.

First editionManagement of chronicvenous disorders of thelower limbs: guidelinesaccording to scientific

evidenceInt Angiol. 2008;27:1-60.

First editionPharmacological treat-ment of primary chronic

venous diseaseEur J Vasc Endovasc Surg.

2011;41:117-125.

Third EditionHandbook of VenousDisorders: Guidelines ofthe American Venous

ForumHodder Arnold: London, UK;

2009.

2005 2008 2011 2009

USAEurope

thor of the chapter devoted to “Drug Treatment of VaricoseVeins, Venous Edema, and Ulcers” of the latest edition (3rdedition) of the Handbook of Venous Disorders: Guidelines ofthe American Venous Forum assigned VADs a grade 2B forthe improvement of symptoms and edema associated withCVD. In the same chapter, only MPFF (Daflon 500 mg) wasquoted for the pharmacological treatment of venous ulcers.The use of Daflon 500 mg in combination with compressionin long-standing or large venous ulcers of primary etiologywas recommended (grade 1B).37

Among the many reasons that make guidelines useful, oneis because they provide recommendations that are based ongood quality evidence. Another is because they balance thedesirable and undesirable effects of a treatment, not to men-tion the cost-effectiveness of such treatment. A robust strengthof recommendation for a treatment indicates that clinicianscan offer this treatment to almost all their patients with littleor no hesitation. This is the case for Daflon 500 mg, which hasreceived a strong recommendation in national as well as ininternational guidelines.38 �

D A F L O N 5 0 0 M G


References1. Eklof B, Perrin M, Delis K, Rutherford R. Updated terminology of chronic ve-nous disorders: the Vein Term Transatlantic Interdisciplinary Consensus Doc-ument. J Vasc Surg. 2009;49:498-501.

2. Porter JM, Moneta GL. Reporting standards in venous disease: an update.J Vasc Surg. 1995;21:635-645.

3. Eklöf B, Rutherford RB, Bergan JJ, et al: Revision of the CEAP classificationfor chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248-1252.

4. Lyseng-Williamson A, Perry CM. Micronised purified flavonoid fraction. A reviewof its use in chronic venous insufficiency, venous ulcers and haemorrhoids.Drugs. 2003;63:71-100.

5. Bergan JJ, Schmid-Schönbein G, Coleridge-Smith P, Nicolaides A, BoisseauM, Eklof B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

6. Nicolaides AN, Hussien MK, Szendro G, et al. The relation of venous ulcera-tion with ambulatory venous pressure measurements. J Vasc Surg. 1993;17:414-419.

7. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge Smith PD. Leukocyteactivity in the microcirculation of the leg in patients with chronic venous dis-ease. J Vasc Surg. 1997;26:265-273.

8. Takase S, Schmid-Schönbein G, Bergan JJ. Leukocyte activation in patientswith venous insufficiency. J Vasc Surg. 1999;30:148-156.

9. Badier-Commander C, Couvelard A, Henin D, Verbeuren T, Michel JB, JacobMP. Smooth muscle cell modulation and cytokine overproduction in varicoseveins. An in situ study. J Pathol. 2001;193:398-407.

10. Nicolaides AN. Investigation of chronic venous insufficiency; a consensus state-ment. Circulation. 2000;102:e126-e163.

11. Priollet P. Venous edema of the lower limbs. Phlebolymphology. 2006;13:183-187.

12. Ramelet AA, Perrin M, Kern P, Bounameaux H, eds. Phlebology. 5th ed. Issy-les-Moulineaux, France: Elsevier Masson SAS; 2008.

13. Nicolaides A, Allegra C, Bergan J, et al. Management of chronic venous disor-ders of the lower limbs. Guidelines according to scientific evidence. Int Angiol.2008;27:1-59.

14. Ramelet AA. Management of chronic venous disease: the example of Daflon500 mg. Phlebolymphology. 2009;16:321-330.

15. Amiel M, Barbe R. Etude du délai et de la durée d’action de Daflon 500mg. JIM.1987;88:22-24.

16. Barbe R, Amiel M: Pharmacodynamic properties and therapeutic efficacy ofDaflon 500 mg. Phlebology. 1992;7(suppl 2):41-44.

17. Amiel M, Barbe R. Etude de l’activité pharmacodynamique de Daflon 500mg.Ann Cardiol Angéiol. 1998;47:185-188.

18. Ibegbuna V, Nicolaides AN, Sowade O, Leon M, Geroulakos G. Venous elas-ticity after treatment with Daflon 500 mg. Angiology. 1997;48:45-49.

19. Behar A, Lagrue G, Cohen-Boulakia F, et al. Study of capillary filtration by dou-ble labelling I131-albumin and Tc99m red cells. Application to the pharmaco-dynamic activity of Daflon 500 mg. Int Angiol. 1988;7(2 suppl):35-38.

20. Cesarone MR, Laurora G, De Sanctis MT, et al. Capillary filtration and ankleedema in patients with venous hypertension: effects of Daflon. Angiology. 1993;44:57-61.

21. Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an

overview. J Vasc Res. 1999;36(suppl 1):37-41.22. Allegra C, Bartolo M Jr, Carioti B, et al. Microlymphography: assessment of

Daflon 500 mg activity in patients with chronic venous insufficiency. Lympho-logy. 1997;31(suppl):12-16.

23. Joris I, Zand T, Nunnari JJ, Krolikowski FJ, Majno G. Studies on the pathogen-esis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in theaorta of hypercholesterolemic rats. Am J Pathol. 1983;113:341-358.

24. Bergan JJ, Pascarella L, Schmid-Schönbein G. Pathogenesis of primary chron-ic venous disease: insights from animal models of venous hypertension. J VascSurg. 2008;47:183-192.

25. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venousdisease: rationale, results and unanswered questions. Eur J Vasc EndovascSurg. 2011;41:117-125.

26. Chassignolle J-F, Amiel M, Lanfranchi G, et al: Activité thérapeutique de Daflon500 mg dans l’insuffisance veineuse fonctionnelle. J Int Med. 1987;99(suppl):32-37.

27. Gilly R, Pillion G, Frileux C. Evaluation of a new venoactive micronized flavonoidfraction (S 5682) in symptomatic disturbances of the venolymphatic circula-tion of the lower limb: a double-blind, placebo controlled study. Phlebology.1994;9:67-70.

28. Cospite M, Dominici A. Double blind study of the pharmacodynamic and clin-ical activities of 5682 SE in venous insufficiency. Advantages of the new mi-cronized form. Int Angiol. 1989;8(4 suppl):61-65.

29. Blume J, Langenbahn H, de Champvallins M. Quantification of oedema usingthe volometer technique: therapeutic application of Daflon 500 mg in chronicvenous insufficiency. Phlebology. 1992;(suppl 2):37-40.

30. Navratilova Z. Efficacy of a 6-month treatment with Daflon 500 mg in patientswith venous edema. Phlebolymphology. 2010;17:137-143.

31. Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study.Angiology. 2002;53:245-256.

32. Coleridge-Smith P, Lok C, Ramelet AA: Venous leg ulcer: a meta-analysis ofadjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc En-dovasc Surg. 2005;30:198-208.

33. Martinez MJ, Bonfill X, Moreno RM, Vargas E, Capellà D. Phlebotonics for ve-nous insufficiency. Cochrane Database Syst Rev. 2005;(3):CD003229.

34. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insuffi-ciency. Cochrane Database Syst Rev. 2006;(1):CD003230.

35. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the manage-ment of chronic venous disease. An international consensus statement: cur-rent medical position, prospective views and final resolution. Clin Hemorheol Mi-crocirc. 2005;33:309-319.

36. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommen-dations and quality of evidence in clinical guidelines: report from an AmericanCollege of Chest Physicians Task Force. Chest. 2006;129:174-181.

37. Coleridge Smith PD. Drug treatment of varicose veins, venous oedema, and ul-cers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the Ame-rican Venous Forum. 3rd ed. London, UK: Hodder Arnold; 2009:359-365.

38. Nicolaides A. Venoactive medications and the place of Daflon 500 mg in re-cent guidelines on the management of chronic venous disease. Phlebolym-phology. 2009;16:340-346.

Keywords: Daflon 500 mg; guidelines; management; chronic venous disease

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LA PLACE DE DAFLON 500 MG DANS LES RECOMMANDATIONS RÉCENTESSUR LA PRISE EN CHARGE DE LA MALADIE VEINEUSE CHRONIQUE

La maladie veineuse chronique (MVC) est une pathologie courante constituée d’un ensemble de troubles. De nom-breux efforts ont été faits pour créer un langage commun, essentiel pour établir des recommandations pratiquescliniques. En plus de l’amélioration des méthodes pour définir la MVC, la compréhension des processus patholo-giques impliqués dans son développement a aussi maintenant fait de grands progrès. La perte du tonus veineux,une perméabilité capillaire anormale et des vaisseaux lymphatiques surchargés ont été proposés comme méca-nismes impliqués dans le développement de la MVC. L’interaction leucocyte-endothélium et son association aux al-térations valvulaires est l’un des mécanismes physiopathologiques les plus précoces impliqué dans la maladie, ce quia attiré l’attention sur Daflon 500 mg, la seule molécule disponible dont l’activité est connue pour modifier de telsévénements inflammatoires. En plus de son aptitude à augmenter le tonus veineux, ajuster la filtration capillaire etaccélérer le drainage lymphatique, il réduit l’interaction des leucocytes avec l’endothélium dans l’inflammation etl’hypertension veineuse aiguë. Il est utilisé en pratique clinique pour traiter la MVC. Daflon 500 mg, bien toléré, a étélargement étudié dans des études cliniques bien conçues. La micronisation de la taille des particules de ses compo-sés à moins de 2 µm améliore sa biodisponibilité et son absorption orales par rapport à celles des diosmines nonmicronisées. C’est pourquoi, Daflon 500 mg est répertorié comme traitement veinoactif dans les recommandationsrécentes sur la prise en charge de cette maladie.

Are we any better at identifying the risk factors for CVD progression? – Flour MEDICOGRAPHIA, Vol 33, No. 3, 2011 315

T he natural history of chronic venous disease (CVD) is poorly understood.There have been too few longitudinal studies. In Northern and WesternEurope the prevalence of varicose veins without skin changes is 20%

compared to 3% for advanced CVD. Only 10% of the many individuals with C2varicose veins progress to ulceration. The risk factors for progression are cur-rently believed to comprise the usual combination of the environmental andthe genetic. More specifically, the Bonn Vein Study (2008) identified the mainculprits as age, hypertension, and obesity, to which other studies have addedprevious deep vein thrombosis, absence of etiologic intervention, a positivefamily history, reduced ankle range of motion, and impaired calf muscle pumpfunction. Both hemochromatosis and thrombophilia predispose to ulcera-tion, while twin studies incriminate the FOXC2 gene on chromosome 16. Fe-male gender barely qualifies. Yet despite an additional plethora of sophisticat-ed studies featuring cytokine arrays and gene polymorphisms, there remainsno test, or test battery, that identifies the individual patient with early CVD atrisk of ulceration. The evidence suggests that best-practice prophylaxis com-prises aggressive intervention early in the course of the disease combinedwhere possible with a structured exercise program to improve ankle rangeof motion and calf muscle pump function.


How strong is the evidence for risk factors in the progression ofchronic venous disease?

T he natural history of chronic venous disease (CVD) remains poorly under-stood. Longitudinal studies are few. Most information comes from cross-sec-tional studies. One third of 116 limbs in 90 patients with venous reflux showed

progression when re-examined a median 19 months later using the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification and/or duplex ultrasound(DU).1 A prospective study of superficial and deep venous reflux showed that mostpatients had clinically deteriorated after 7 years: limbs treated with a superficial ordeep procedure improved or remained stable, while those treated with elasticcompression deteriorated hemodynamically and clinically.2

The Bochum study explored the natural history of varicosities and calf pump functionfrom childhood to adulthood. Telangiectasias and reticular veins occurred early on,independently of reflux. Large varicosities appeared in older subjects, often preceded

I N T E R V I E W

Mieke FLOUR, MDDermatology DepartmentLeuven University HospitalBELGIUM

Address for correspondence:Dr Mieke Flour, DermatologyDepartment, University HospitalLeuven, Kapucijnenvoer 33,B-3000 Leuven, Belgium(e-mail: [email protected])


Are we any better atidentifying the risk factors

for chronic venousdisease progression?

Interv iew with M. F lour, Belg ium

Ongoing studies, includingthose using the genome wide as-sociation approach, look to iden-tify relevant patterns of single nu-cleotide polymorphisms to predictdisease states and evaluate genepatterns that relate to multiplephenotypes of complex diseases.Gender, age, ethnicity, and envi-ronment appear strong determi-nants of disease penetrance. Weneedsystematic population-basedsearches for chronic venous dis-ease susceptibility genes.”

‘‘

I N T E R V I E W

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Are we any better at identifying the risk factors for CVD progression? – Flour316

by saphenous reflux. The Bonn Vein Studies I & II, conductedin 3072 women and men, found a 2.0% annual incidence ofprogression to C3-C6 disease (Table I). Age, hypertension,and obesity were the main risk factors for C4-C6 disease.3

Factors for progression include the combination of reflux andobstruction, ipsilateral recurrent deep venous thrombosis(DVT), multisegmental involvement, and absence of etiolog-ic CVD therapy. Prospective evaluation of the normal con-tralateral limb in 73 patients undergoing unilateral varicosevein (VV) surgery showed that half experienced clinical deteri-oration and reflux within 5 years. Independent risk factorswere obesity, orthostatism, and noncompliance with the useof elastic stockings.4 However, we have no hemodynamicmethods for identifying which patients with primary CVD andC2-C4 disease are likely to develop ulcers, despite the diseaseprogressing to C4-C6 in up to 20% or more of the elderly.

Risk factors for ulcer recurrence include residual iliofemoralvein obstruction, residual deep incompetence (in particularaxial deep reflux), residual or recurrent superficial reflux, andpersistent venous hypertension. Correction of the underlyingpathology reduces the risk of recurrence.

We need large, long-term prospective studies with DU scan-ning of the anatomic distribution of reflux and obstruction, andserial quantification of reflux. A more sophisticated protocolfor longitudinal research is required, using studies of venoushemodynamics and the microcirculation. If we could identifythe predictors of progression from C2-C4 to active ulceration,we could plan their modification where feasible.

What are the clinical risk factors warranting earlyintervention in stage C2 CVD?

R isk factor studies have given inconsistent results due tomultiple methodological differences. Risk factors arecurrently thought to combine the environmental with the

genetic. Age, a major risk factor, is compounded by a posi-tive family history, although evidence for a mode of inheritanceis lacking. Twin studies in Germany point to the FOXC2 geneon chromosome 16.5

Obesity has been incriminated in women, but appears to beaggravating rather than causal. It precipitates severe CVD,perhaps from functional rather than anatomical insufficiency.Female gender is universally cited, but CVD is barely moreprevalent in women. Onset is earlier in women, at 30.8 years(36.8 years in men). Pregnancy (multiparity) is a universallyrecognized risk or aggravating factor, but not oral contracep-tion. Major geographic differences suggest strong environ-mental influences. Although smoking affects the vascularwall and impairs endothelial function and behavior, its statusas a risk factor is inconclusive. In the Framingham Study,women with VVs were more often obese, sedentary, older atmenopause, and had higher systolic blood pressure; in men,VVs coexisted with sedentary lifestyle and higher smokingrates, suggesting that increased physical activity and weightcontrol may prevent VVs in high-risk adults.

The Bonn Vein Study II reported the “sensation of swelling”as symptomatic of impending CVD.3 Signs such as coronaphlebectatica and other skin changes may warrant early in-tervention to prevent ulcer formation. Risk relates to the sever-ity of varicosity and increases after DVT. But it may also be in-creased in smokers, the obese, and those with reduced anklerange of motion (ROM) and calf pump power.

Clinical hardening of the vessel wall is associated with an in-crease in thick disorganized collagen bundles and elastic fiberfragmentation. Similar changes in the extracellular matrix arefound in the vein wall and skin of C2 patients. Follow-up DUafter aggressive treatment of superficial CVD supports thecase for early recognition and intervention by showing im-provement or complete reversal of deep venous insufficiencyin most patients. Less aggressive treatment improved refluxvalve closure time in only 28%.6

It will be difficult to perform the prospective longitudinal andcross-cultural studies that we need in order to measure the im-pact of these clinical factors on disease progression. An alter-native is to identify features unique to limbs with establishedulcers (C6) and compare them to limbs with C2-C4 disease.


CEAP Clinical-Etiological-Anatomical-PathophysiologicalCVD chronic venous diseaseDU duplex ultrasoundDVT deep vein thrombosisEMP endothelial microparticlesMMP matrix metalloproteinasesROM range of motionSNP single nucleotide polymorphismTM thrombomodulinTNF tumor necrosis factorVV varicose vein

C0 No visible or palpable signs of venous disease

C1 Spider veins or reticular veins

C2 Varicose veins

C3 Edema of venous origin

C4a Pigmentation and/or eczema

C4b Lipodermatosclerosis and/or atrophie blanche

C5 Healed venous ulcer

C6 Open venous ulcer

Table I. CEAP clinical classification of chronic venous disease.Abbreviation: CEAP, Clinical-Etiological-Anatomical-Pathophysiological.

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Do any gene polymorphisms or biomarkersidentify patients at high risk of ulceration?

In Northern and Western Europe the prevalence of VVs with-out skin changes is 20% compared to 3% for advancedCVD. Only 10% of the many individuals with C2 VVs proceed

to ulceration. Genetic factors may play an important causalrole in both mild and severe disease, but we need to estab-lish biobanks and bloodbanks for longitudinal analysis.

Gene polymorphism and biomarker data may identify patientsat high risk of ulceration:� Tumor necrosis factor α (TNF-α) gene polymorphism hasbeen associated with increased susceptibility to ulceration.However, others dispute that the A allele of the 308 G/A sin-gle nucleotide polymorphism (SNP) located in the promoterregion of the TNFA gene is a potential factor for ulcer suscep-tibility, arguing that this association is secondary and that theprimary association is probably with obesity.� Estrogen receptor-beta polymorphism, associated with im-paired healing in the elderly, predisposes to venous ulceration.� SNPs of the fibroblast growth factor receptor 2 gene aresignificantly more frequent in CVD patients with chronic non-healing wounds.� Hemochromatosis studies suggest a role for iron deposition,iron trafficking genes, transglutaminases, and C282Y poly-morphism of the hemochromatosis gene in ulceration. A sim-ple C282Y blood test was highly specific in predicting ulcerdevelopment (98%), while ulcer onset was almost 10 yearsearlier in patients carrying the H63D variant.7

� Thrombophilia: venous ulceration was 2 to 30 times moreprevalent in thrombophilia patients, even with no history or DUevidence of DVT, than in the general population.8

� Cytokine gene polymorphisms do not significantly influencevenous thrombosis risk, despite the close relationship betweenvenous thrombosis and inflammation.

Ongoing studies, including those using the genome-wide as-sociation approach, are looking to identify relevant patternsof SNPs to predict disease states and evaluate gene pat-terns that relate to multiple phenotypes of complex diseases.Gender, age, ethnicity, and environment appear strong deter-minants of disease penetrance. We need systematic popula-tion-based searches for CVD susceptibility genes.

Are there differences in skin type, metabolism,or race that increase the risk of ulceration?

Sociodemographic factors may influence CVD progres-sion. A West London study collected age, sex, andethnicity data on all leg ulcer patients over one year. Ul-

ceration was more frequent in whites than in South Asians(odds ratio, 4.43; P=0.0004), suggesting either a real differ-ence in prevalence or a South Asian reluctance to seek treat-ment.

The San Diego multiethnic cross-sectional study in 2211 sub-jects found superficial functional disease to be more commonin women, while deep functional disease was more commonin men. CVD was more common in non-Hispanic whites thanin Hispanics, African Americans, or East Asians.

Humoral or genetic factors responsible for progression to ul-cer formation are related to thrombosis and inflammation. Hy-perhomocysteinemia, a risk factor for venous thrombosis andCVD development and progression, is present in about 65%of patients with CVD. Mild to moderately elevated plasmahomocysteine was closely associated with increasing CVDseverity, confirming that various inherited and acquired fac-tors act in concert to raise individuals above the thromboticthreshold. Prevalence of the C677T methylene tetrahydro-folate reductase mutation was higher in complicated C4-C6disease (20%) than in uncomplicated C2-C3 disease (10%),and more patients overall (15%) were homozygous comparedwith an estimated 5% of the healthy white population.9

Genetic variations that affect chronic inflammation may differacross ethnic groups. Cytokine SNPs affect cytokine levelsand hence the inflammatory response.

Elevation of interleukin 6 is a well-documentedinflammatory marker, but does it predict CVDprogression?

Most people agree that markers such as interleukin6 (IL-6) are elevated in CVD. IL-6 is produced andreleased into the systemic circulation from many dif-

ferent cells. It is the only cytokine to stimulate synthesis ofall the acute-phase proteins involved in the inflammatory re-sponse. It is a universal marker, hence not specific to nor di-agnostic of CVD progression. We need a specific biomarkerfor increased ulcer risk.

A prospective cohort study of elderly community residentsshowed an association between sociogeographic segrega-tion and IL-6 levels. Ingredients of social disadvantage (age,African American ethnicity, high prescription drug consump-tion, body mass index >30, high alcohol consumption, andsmoking) were all strong predictors of IL-6 elevation.

Elevated plasma inflammatory mediator levels are also riskfactors for venous thrombosis. Several biomarkers reflectfunctional monocyte-macrophage activation and structuralendothelial lesions related to venous stasis and venous hy-pertension that predispose to CVD. Baseline production ofinflammatory markers is duly elevated in VV patients, and allcytokine levels sharply increase in response to venous occlu-sion produced by cuff inflation. However, a systematic reviewof studies of the association between inflammatory markersand venous thrombosis concluded that plasma C reactiveprotein levels do not predict venous thrombosis.10

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MEDICOGRAPHIA, Vol 33, No. 3, 2011 Are we any better at identifying the risk factors for CVD progression? – Flour318

Between August 1995 and June 1997, blood was collectedfrom 66 140 people in the second Norwegian Health (cohort)Study of Nord-Trondelag (HUNT2); 506 cases were registeredwith a first venous thrombosis. Levels of IL-1β, IL-6, IL-8, IL-10,IL-12p70, and TNF-α, measured at baseline, showed no re-lationship between an altered inflammatory profile and venousthrombosis. These results suggest that an altered inflamma-tory profile is more likely to be a result than a cause of ve-nous thrombosis, although a short-term impact with transient-ly elevated levels cannot be excluded.11

No biomarker that accurately reflects wound healing statusin individual patients, singly or in combination, has been iden-tified.

What information would a test of endothelialdysfunction provide, and what are the prospectsof one being developed in the near future?

R ecent studies of CVD etiology have focused on endo-thelial cell integrity and function. Current evidence fa-vors a multifactorial origin involving vein wall remodel-

ing and changes in the microcirculation and dermis. Venousendothelial dysfunction is almost certainly implicated in thewall dilatation and valve incompetence seen in primary CVD.Markers of endothelial cell dysfunction are predictive of vas-cular events. They reflect multiple micro- or macrovascular dis-orders and early vascular changes, predating clinical pathol-ogy by many months or even years. Elevation is associatedwith aging, endocrinopathy, arterial disease, connective tissuedisease, smoking, and exposure to air pollution, in additionto venous disease. Endothelial function testing has great po-tential in cardiovascular screening, but is not yet feasible inroutine assessment: no test is sufficiently sensitive and spe-cific for clinical use. Most studies are observational. We stilldon’t know how best to investigate the multifaceted aspectsof endothelial dysfunction.

Three types of test are available: vascular reactivity, systemicplasma markers, and histological immunostaining.

� Vascular reactivity testsVascular reactivity tests are the most widely used: they arenoninvasive, and they evaluate the peripheral macrocircula-tion (conduit arteries) or microcirculation (resistance arteriesand arterioles).

� Systemic plasma markersSystemic plasma markers of endothelial damage and repairplay a minor role in individual patient assessment:� Nitric oxide: plasma levels of this potent mediator of vas-cular relaxation may be modulated in CVD.� Humoral mediators of vasoconstriction and venous dilata-tion: endothelin 1 levels increase and rise disproportionatelyin response to venous stasis.

� Pro- and anti-inflammatory cytokines: chronic venous hy-pertension leading to endothelial cellular injury and activationpromotes inflammatory reaction and leukocyte recruitmentin venous valves, causing dysfunction, reflux, and upstreamvenous hypertension.� Adhesion molecules: despite reflecting early leukocyte-en-dothelium interaction, intercellular adhesion molecule 1 andE-selectin expression did not differ significantly between VVpatients and controls.� Hypoxia inducible factor 1α: Elevation of this marker ofleukocyte-endothelium interaction results from prolongedmechanical stretching and increased vein wall tension, sup-porting the hypothesis of VV hypoxia.� Soluble markers are mixtures of truly soluble moleculeswith membrane-bound forms, eg, endothelial microparticles(EMP). EMP-monocyte conjugates enhance transendothe-lial leukocyte migration in vitro and reflect several inflamma-tory diseases. But EMP elevation is not diagnostic for CVDprogression or inflammation.� Enzyme activity (matrix metalloproteinases [MMPs] and theirinhibitors) increases in both high and low venous pressureregions. The degree of extracellular matrix remodeling of thevenous wall and valve leaflets correlates with macroscopiclesion morphology and changes in the microcirculation anddermis. MMP-2 may induce venous relaxation or inhibit ve-nous contraction.� Plasma thrombomodulin (TM) is a marker of endothelial in-jury. Two cohort studies found no difference in the prevalenceof the three TM genotypes between thrombosis cases andcontrols. There was no difference in age-adjusted mean sol-uble TM values by genotype, nor any association betweenage-adjusted soluble TM or the TMA455V genotype and over-all venous thromboembolism or thrombosis.

� Histological immunostainingImmunostaining and real-time polymerase chain reaction (RT-PCR) analysis reveal VV intimal changes, such as focal intimaldiscontinuity and endothelial denudation. Vein wall changesmay precede valvular dysfunction. Total elastin content is low-er in VVs than in healthy veins.

We need more longitudinal studies to identify prognostic mark-ers of endothelial dysfunction. We must also identify the ge-netic and humoral mediators of endothelial dysfunction inlimbs with primary CVD and disease progression.

How reliable are ankle mobility, calf musclepump function, and patient activity in ratingCVD progression?

Both photoplethysmography and air plethysmographyshow end-of-day deterioration in calf pump function, sug-gesting that venous return deteriorates with prolonged

standing. Musculoskeletal changes affect calf pump hemody-namics, complicating differentiation between cause and effect.

Goniometry shows significantly reduced ankle ROM acrossall grades of CVD.12 ROM decreases with increasing clinicalseverity, impairing calf pump function, and sustaining ambula-tory venous hypertension. Gastrocnemius biopsies reveal mor-phologic changes suggesting that disuse, denervation, and is-chemia lead to muscle dysfunction. The resultant impact ongait and ambulation predisposes to venous ulceration. Overtwo-thirds of ulcer patients have an impaired calf pump. Useof air plethysmography and color Doppler to study the relation-ship between degree of venous insufficiency, calf pump dys-function, and venous ulceration showed significantly poorerpump function in legs with active ulcers than in those withhealed ulcers or no history of ulceration. CVD is a necessary

but limited cause of ulceration; calf pump dysfunction is asignificant contributor to the severity of venous ulceration.13

In addition to known risk factors (longer ulcer duration, largesurface area, ankle brachial pressure index <0.85), calf pumpdysfunction correlates with delayed ulcer healing even withadequate compression. A study in 189 patients identified thatcalf/ankle circumference ratio <1.3, a fixed ankle joint, andreduced ankle ROM were the only independent parametersassociated with nonhealing.14 Prospective controlled studiesshow that supervised exercise programs to improve calf pumpfunction, muscle strength, and endurance improve healingrates and decrease recurrence in C6 disease, with benefit be-ing maintained for at least 3 months.15 �

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References1. Labropoulos N, Leon L, Kwon S, et al. Study of the venous reflux progression.

J Vasc Surg. 2005;41:291-295.2. Lurie F, Makarova NP. Clinical dynamics of varicose disease in patients with high

degree of venous reflux during conservative treatment and after surgery: a 7-year follow-up. Int J Angiol. 1998;7:234-237.

3. Maurins U, Hoffmann BH, Losch C, Jockel KH, Rabe E, Pannier F. Distribu-tion and prevalence of reflux in the superficial and deep venous system in thegeneral population—results from the Bonn Vein Study, Germany. J Vasc Surg.2008;48:680-687.

4. Kostas TI, Ioannou CV, Drygiannakis I, et al. Chronic venous disease progres-sion and modification of predisposing factors. J Vasc Surg. 2010;51:900-907.

5. Ng MY, Andrew T, Spector TD, Jeffery S; Lymphoedema Consortium. Linkageto the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy,unselected sibling pairs. J Med Genet. 2005;42:235-239.

6. Ahmad I, Ahmad W, Dingui M. Prevention or reversal of deep venous insufficien-cy by aggressive treatment of superficial venous disease. Am J Surg. 2006;191:33-38.

7. Gemmati D, Federici F, Catozzi L, et al. DNA-array of gene variants in venous legulcers: detection of prognostic indicators. J Vasc Surg. 2009;50:1444-1451.

8. Mackenzie RK, Ludlam CA, Ruckley CV, Allan PL, Burns P, Bradbury AW.The prevalence of thrombophilia in patients with chronic venous leg ulcera-

tion. J Vasc Surg. 2002;35:718-722.9. Sam RC, Burns PJ, Hobbs SD, et al. The prevalence of hyperhomocysteine-

mia, methylene tetrahydrofolate reductase C677T mutation, and vitamin B12and folate deficiency in patients with chronic venous insufficiency. J Vasc Surg.2003;38:904-908.

10. Fox EA, Kahn SR. The relationship between inflammation and venous thrombo-sis. A systematic review of clinical studies. Thromb Haemost. 2005;94:362-365.

11. Christiansen SC, Naess IA, Cannegieter SC, Hammerstrom J, Rosendaal FR,Reitsma PH. Inflammatory cytokines as risk factors for a first venous throm-bosis: A prospective population-based study. PLoS Med. 2006;3:e334.

12. Padberg FT, Johnston MV, Sisto SA. Structured exercise improves calf musclepump function in chronic venous insufficiency: a randomized trial. J Vasc Surg.2004;39:79-87.

13. Milic DJ, Zivic SS, Bogdanovic DC, Karanovic ND, Golubovic ZV. Risk factorsrelated to the failure of venous leg ulcers to heal with compression treatment.J Vasc Surg. 2009;49:1242-1247.

14. Araki C, Back TL, Padberg FT, et al. Significance of calf muscle pump functionin venous ulceration. J Vasc Surg. 1994;20:872-879.

15. Davies JA, Bull RH, Farrelly IJ, Wakelin MJ. A home-based exercise programmeimproves ankle range of motion in long-term venous ulcer patients. Phlebo-logy. 2007;22:86-89.

Keywords: risk factors; identification; chronic venous disease

NOUS SOMMES-NOUS AMÉLIORÉS DANS L’IDENTIFICATION DESFACTEURS DE RISQUE DE PROGRESSION DE LA MALADIE VEINEUSE CHRONIQUE ?

L’histoire naturelle de la maladie veineuse chronique (MVC) est mal comprise. Les études longitudinales ont ététrop rares. Dans l’Europe du Nord et de l’Ouest, la prévalence des varices sans modifications cutanées est de 20 %comparée à 3 % pour la MVC avancée. En d’autres termes, seuls 10 % des nombreux sujets atteints de MVC pré-coce vont jusqu’à l’ulcère. Actuellement, les facteurs de risque de progression englobent l’association habituelleenvironnement et génétique. Plus spécifiquement, l’étude Bonn Vein (2008) a identifié les principaux coupables : âge,hypertension et obésité auxquels d’autres études ont ajouté des antécédents de thrombose veineuse profonde,l’absence de traitement étiologique, des antécédents familiaux positifs, une mobilité réduite de la cheville et une fonc-tion altérée de la pompe musculaire du mollet. L’hémochromatose et la thrombophilie prédisposent à l’ulcère, desétudes jumelles incriminant le gène FOXC2 sur le chromosome 16. Le sexe féminin y prédispose peu. Malgré plé-thore d’études sophistiquées sur les gammes de cytokines et les polymorphismes de gène, nous ne disposonstoujours pas de tests ou de batteries de tests identifiant individuellement un patient atteint précocement de MVC àrisque d’ulcère. En pratique, les arguments d’une meilleure prévention sont en faveur d’un traitement agressif tôtdans l’évolution de la maladie associé si possible à des exercices structurés pour améliorer la mobilité de la che-ville et la fonction de la pompe musculaire du mollet.

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Identifying and accessing patients with CVD: the VCP International Study – Rabe320

C hronic venous disease (CVD) is defined as morphological and func-tional abnormalities of the venous system of long duration, manifest-ed either by symptoms and signs indicating the need for investigations

and/or care. The impact of CVD in the general population is often underesti-mated and not well recognized by health systems. In recent studies and ac-cording to the CEAP (Clinical-Etiological-Anatomical-Pathophysiological)classification, the C0 and C1 classes together are prevalent in more than 60%of the population. Varicose veins (C2) are prevalent in more than 20%. Skinchanges, including venous ulcers, are present in less than 10% of the popu-lation. For many countries, no epidemiologic data exist. The worldwide VeinConsult Program aims to assess the prevalence of CVD and provide a pictureof the typical adult patient and the management of their disease, in varyinggeographical areas. This is the largest ever CVD detection program to be un-dertaken. The Vein Consult Program is being carried out under the auspicesof the International Union of Phlebology with the support of an unrestrictedgrant from Servier. More than 4500 selected general practitioners are par-ticipating, and it is estimated that they will screen approximately 95 000 pa-tients. In step 1 of the program, general practitioners screen patients whomthey are consulting for any medical reason. Step 2 is a follow-up consultationwith a venous specialist. Preliminary results from 69 866 screened patientsfrom 13 countries worldwide are available.


C hronic venous disease (CVD) is defined as morphological and functional ab-normalities of the venous system of long duration, manifested either by symp-toms and signs indicating the need for investigations and/or care.1 Typical

symptoms associated with CVD are heavy legs, leg pain, sensation of swelling, pinsand needles in the legs, and itching. Typical signs of chronic venous insufficiency(CVI) are varicose veins, edema, skin changes (like pigmentation and atrophy), and legulcers. CVD is graded according to the CEAP (Clinical-Etiological-Anatomical-Patho-physiological) classification, which provides an orderly framework for diagnosis.Clinical signs in the affected legs are categorized as one of seven classes rangingfrom C0-C6 (Table I), and the limbs of any clinical class may be classified symp-tomatic or asymptomatic.2 CVD is a progressive disease that can lead to disease-related complications like venous ulceration. It is a result of abnormally raised venouspressure caused by venous inflammation, which can cause the disease to progressfrom early symptoms to vessel wall deterioration and damaged venous valves, which

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Eberhard RABE, MD, PhDDepartment of DermatologyUniversity of BonnBonn, GERMANY

Address for correspondence:Prof. Dr. med. Eberhard Rabe,Department of Dermatology,University of Bonn, Sigmund FreudStr. 25, 53105 Bonn, Germany(e-mail:[email protected])


Identifying and accessingpatients with chronic venous

disease: the large-scaleVCP International Study

by E . Rabe, Germany

Some 4500 GPs from 20countries are involved in step 1of the Vein Consult Program. Thepreliminary results from a total of69 866 screened patients fromBrazil, France, Georgia, Hungary,Mexico, Pakistan, Romania, Rus-sia, Serbia, Singapore, Slovakia,Spain, and the United Arab Emi-rates are already available. Seven-teen percent of these patients con-sulted a GP especially for venousleg problems. Signs of C1-C6 werepresent in 59% of the population,while 17% had venous symptomswithout clinical signs of venousdisease (C0S).”

‘‘

in turn lead to the appearance of signs of CVD such as vari-cose veins, skin changes, and leg ulceration.3,4 CVD is also arisk factor for the development of thromboembolic complica-tions. Disease progress can be prevented by early detectionand intervention. The impact of CVD in the general populationis often underestimated and not well recognized by healthsystems. It is also often overlooked in primary care and car-diovascular care because of an underappreciation of its scaleand of the impact of the disease.5

Prevalence of chronic venous diseaseIn the last few decades, epidemiological CVD studies havebeen performed in many countries worldwide, mainly focus-

ing on varicose veins.6-13 The results have not been homoge-neous; different definitions of CVD, different age groups, anddifferent methods of investigation in these studies led to differ-ing results. In recent years, a few studies based on the CEAPclassification have been published.14-19 In the CEAP-basedepidemiological studies, the reported prevalence is similar formost items (Table II). Classes C0 and C1 together are preva-lent in more than 60% of the population. Varicose veins (C2)

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Identifying and accessing patients with CVD: the VCP International Study – Rabe MEDICOGRAPHIA, Vol 33, No. 3, 2011 321


CEAP Clinical-Etiological-Anatomical-PathophysiologicalCIVIQ ChronIc Venous dIsease QuestionnaireCVD chronic venous diseaseCVI chronic venous insufficiencyQOL quality of lifeUIP Union Internationale de Phlébologie [International

Union of Phlebology]

Class Definition

C0 No visible or palpable signs of venous disease

C1 Telangiectasias or reticular veins

C2 Varicose veins (distinguished from reticularveins by a diameter of >3 mm)

C3 Edema

C4 Skin changes secondary to chronic venous diseaseC4a: pigmentation or eczemaC4b: lipodermatosclerosis or atrophie blanche

C5 Healed venous ulcer

C6 Active venous ulcer

Table I. CEAP classification: clinical classes and definitions.Abbreviation: CEAP, Clinical-Etiological-Anatomical-Pathophysiological.

Male/female C0 C1 C2Reference, ratio Age Sample All M F All M F All M Fyear Country (%/%) (years) size (%) (%) (%) (%) (%) (%) (%) (%) (%)

Criqui,** USA 35.3/64.7 40-79 2211 19.0 33.6 11.0 51.6 43.6 55.9 23.3 15.0 27.7200318

Jawien,** Poland 16.0/84.0 16-97 40 095 51.5 16.5 21.8200319

Rabe,** Germany 43.9/56.1 18-79 3072 9.6 13.6 6.4 59.1 58.4 59.5 14.3 12.4 15.8200314

Carpentier,*** France 67.7/32.3 >18 409 48.7 23.7 46.3200415 (including C0+C1)

Chiesa,*** Italy 14.1/85.9 18-90 5187 22.7 36.0 20.6 64.8 33.4 69.9 29.4 29.3 29.4*200516,17 13.6 11.4 13.9°

C3 C4 C5 C6Reference, All M F All M F All M F All M Fyear (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)

Criqui,** 5.8 7.4 4.9**** 6.2 7.8 5.3200318 (including C4-C6)

Jawien,** 4.5 4.6 1.0 0.5200319

Rabe,** 13.4 11.6 14.9 2.9 3.1 2.7 0.6 0.6 0.6 0.1 0.1 0.1200314

Carpentier,*** 1.1 2.2 4.0 2.1 1.4 0.7 0.0 0.0200415

Chiesa,*** 13.6 11.4 13.9 3.4 5.2 3.1 8.6 11.6 8.1200516,17 (including C4a only) (including C4b-C6)

* nonsaphenous varicose veins; ° saphenous varicose veins; ** highest assigned clinical category; *** all clinical categories listed;**** edema in the whole population.

Table II (aboveand left).Prevalence ofCEAP classesC0-C6 in recentstudies in West-ern countries.Based on refer-ences 14 to 19.Abbreviation:CEAP, Clinical-Etio-logical-Anatomical-Pathophysiological.

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are prevalent in more than 20%, with a higher prevalence inwomen. Skin changes due to venous diseases, including ve-nous ulcers, are present in less than 10% of the populationwith no significant gender differences. Older age, family his-tory of varicose veins, female gender, and pregnancy are es-tablished risk factors for varicose veins; obesity is an impor-tant additional risk factor for CVI. Unfortunately, such data isonly available for a few countries, and the epidemiologic sit-uation in many regions of the world remains unclear.

Quality of life and burden of chronic venousdiseaseCVD can negatively affect patients’ quality of life (QOL), as it isa painful and disabling disease that can restrict physical func-tioning and mobility and that is associated with depressionand social isolation.4 In consequence, CVD can result in limi-tation to daily activities, decreased productivity at work, andpatients needing to take sick leave, as well as having a neg-ative effect on their self-esteem. Disease severity appearsto be a good indicator of QOL. The higher the CEAP clinicalclass, the poorer the disease-specific QOL, as demonstrat-ed by low scores for physical and social functioning in QOLquestionnaires.4

One such questionnaire, CIVIQ (ChronIc Venous dIsease Ques-tionnaire), is a 20-item questionnaire that provides a globalindex score and a profile in four different categories: pain, phys-ical, psychological, and social functioning. It is valid across arange of different languages and cultures.20 A shortened ver-sion, CIVIQ-14, has been used in the Vein Consult Program.

CVD represents a significant socioeconomic burden in termsof health-care costs due to its high prevalence, the costs ofinvestigation and treatment of complications, and lost work-ing days.3 The overall cost of venous disease in Germany was€2.18 billion in 2006.21 A recent evaluation in Germany re-vealed the mean total yearly cost of an ulcer patient to be al-most €10 000.22

International Union of PhlebologyThe International Union of Phlebology (Union Internationalede Phlébologie [UIP]), founded in 1959, is an association ofnational phlebology societies from Europe, North America,Latin America, Asia, Africa, Australia, and New Zealand. TheUIP represents 50 phlebology societies in 47 countries. TheUIP is governed by its Executive Committee consisting ofthe president, the president elect/the past president, 5 vicepresidents, a general secretary, an assistant general secre-tary, and a treasurer.

The aims of the UIP are:� to strengthen the links between societies or associations,either existing or to be created, which have a special interestin the study and the treatment of CVDs� to spread recommendations on the teaching of phlebolo-

gy, as well as the training and continuing medical educationof phlebologists� to promote consensus on all aspects of CVD� to encourage studies and research on disorders of venousorigin� to promote joint meetings or international congresses� to encourage the creation and activities of national societiesor associations and to encourage membership of the UIP.

The UIP’s three main areas of focus are science, education,and communication. The UIP encourages ongoing scientificresearch in phlebology to help answer some of themany ques-tions that still exist in venous disease. One of the importantgoals is to gain more information on venous epidemiologyand on the burden of disease worldwide. For this reason, theUIP is cooperating with Servier on the Vein Consult Program.

Vein Consult ProgramThe Vein Consult Program is an international educational ef-fort to raise awareness of CVD amongst physicians, patients,the scientific community, and health authorities. The world-wide screening program aims to assess the prevalence ofCVD and provide a picture of the typical adult patient and themanagement of their disease, in varying geographical areas.This is the largest ever CVD detection program to be under-taken, and it will help to evaluate how general practitioners(GPs) and venous specialists manage patients with CVD andto better understand at which stage of the disease special-ists take over from GPs in the management process. Theprogram aims to detect CVD early, with the goal of improvingthe process of management of this chronic disease. It will alsoassess the impact of CVD on the QOL of patients, health-care resources, and the economy.

The Vein Consult Program is being carried out under the aus-pices of the UIP with the support of an unrestricted grant fromServier. The program will be scientifically validated by the UIPvia its operational board members and scientific advisorycommittee. The research is being coordinated in participatingcountries by national societies that are affiliated to the UIP. Ineach country, a local research organization will be responsiblefor data entry and its validation. An international research or-ganization will then pool all national data and be responsiblefor statistical analysis of these data, under the supervision ofthe UIP’s scientific advisory committee.

The Vein Consult Program, which started in 2009, is an in-ternational observational, multicenter, descriptive survey ofCVD. More than 4500 selected GPs are participating, and itis estimated that they will screen approximately 95 000 pa-tients (Table III). In step 1 of the program, GPs screen patientswhom they are consulting for any medical reason (except anemergency) and assess their suitability for inclusion in theprogram. There are several criteria: the patient (male or fe-male) must be over 18 years old; they must be informed of

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Identifying and accessing patients with CVD: the VCP International Study – Rabe MEDICOGRAPHIA, Vol 33, No. 3, 2011 323

their involvement in a screening program and accept to takepart; they must be informed that they have the right to refuseto participate fully or partly; and they should not be consult-ing for an emergency or for an acute episode of an ongoingevent. Patients need to be enrolled consecutively within ashort period of time.

If the patient fits the criteria, participating GPs need to com-plete a standardized case report form assessing their patient’shistory, list any CVD risk factors, screen for CVD symptoms,and perform a routine leg examination. The patient is thenclassified according to the CEAP clinical classification. If thepatient shows signs of having any CVD symptoms and theGP considers them to be eligible to participate in step 2 of theprogram, the patient will next be asked to complete a short,self-administered, 14-item QOL questionnaire, CIVIQ-14. TheGP will then recommend a follow-up consultation with a ve-nous specialist.

Step 2 is the follow-up consultation with a venous specialist.In step 2 of the Vein Consult Program, 500 selected special-ists will potentially follow up 6500 patients. For each patient,the specialists will complete a 21-item questionnaire to es-tablish the patient’s history of CVD and CVD risk factors,

carry out a lower leg examination, and assess whether treat-ment is required. The results from this program will help tocharacterize the typical CVD patient and to establish a bet-ter understanding of the prevalence of this chronic diseasein the participating countries.

� Preliminary resultsSome 4500 GPs from 20 countries are involved in step1of theVein Consult Program. The preliminary results from a total of69866 screened patients from Brazil, France, Georgia, Hun-gary, Mexico, Pakistan, Romania, Russia, Serbia, Singapore,Slovakia, Spain, and the United Arab Emirates are alreadyavailable. Seventeen percent of these patients consulted aGP especially for venous leg problems. Signs of C1-C6 werepresent in 59% of the population, while 17% had venoussymptoms without clinical signs of venous disease (C0S).

The prevalence of CVD in its early stages, stages C1-C3, wassignificantly higher in women than in men, whereas in stagesC0S, C4, C5, and C6, there was no statistical significant dif-ference between the sexes. The mean number of symptomsincreased with increasing classification from stage C2-C5.Leg pain was significantly more prevalent in the higher clas-sification stages (C3-C6) in 18%-19%. The CIVIQ-14 score in-creased significantly with severity of CVD. Patients in the C4-C6 stages had a significantly worse QOL compared withthose in the C1-C2 stages. Patients with venous symptomshad a worse QOL in CIVIQ-14 than those without symptoms.

SummaryThe Vein Consult Program, a cooperative venture betweenthe International Union of Phlebology and Servier, is the largestever CVD detection program to be undertaken with 95 000patients from 20 countries. The program will help us to betterunderstand the prevalence and risk factors of CVD, the im-pact of CVD on the QOL of patients and health resources,and the burden of the disease on the patient and on the econ-omy. The Vein Consult Program will also help to increase theawareness of CVDs among health-care professionals and of-ficials, politicians, and insurance companies. This is vital if weare to prevent an upcoming increase in the prevalence of CVDin the general population caused by demographic changes(eg, an increasing elderly population) and by changes in life-style (eg, an increasing prevalence of obesity). The issue ofimproved awareness needs to be urgently addressed. �

No. ofProcedure Countries doctors

Step 1Screening of patients Brazil, Columbia, 4500 gen-for any medical reason France, Georgia, eral practi-within the framework Hungary, Indonesia, tionersof general practice Mexico, Pakistan,

Romania, Russia,Serbia, Singapore,Slovakia, Slovenia,Spain, Thailand, UnitedArab Emirates, Ukraine,Venezuela, Vietnam

Step 2Diagnosis confirmation Mexico, Romania, 500 spe-by selected specialists Russia, Spain cialists

Patient self-questionnaireExamination of quality Allof life + costs

Table III. Initial procedures in the Vein Consult Program.

References1. Eklöf B, Perrin M, Delis KT, Rutherford RB, Glovizki P. Updated terminology

of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinaryconsensus document. J Vasc Surg. 2009;49:498-501.

2. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum’s Interna-tional Ad Hoc Committee for Revision of the CEAP Classification. Revision of theCEAP classification for chronic venous venous disorders. A consensus state-ment. J Vasc Surg. 2004;40:1248-1252.

3. Nicolaides AN, Allegra C, Bergan JJ, et al. Management of chronic venous dis-orders of the lower limbs: guidelines according to scientific evidence. Int An-giol. 2008;27:1-59.

4. Bergan JJ, Schmid-Schönbein GW, Coleridge-Smith PD, Nicolaides AN, Bois-seau MR, Eklöf B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

5. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2005;111:2398-2409.

6. Beebe-DimmerJL,Pfeifer J, Engle JS, Schottenfeld D. The epidemiology of chron-ic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15:175-184.

7. Evans CJ, Fowkes FGR, Hajivassiliou CA, Harper DR, Ruckley C. Epidemiologyof varicose veins. A review. Int Angiol. 1994;13:263-270.

8. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins andchronic venous insufficiency in men and women in the general population:

F O C U S


Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.9. Fischer H. (Hrsg.), Venenleiden – Eine repräsentative Untersuchung in der Bun-

desrepublik Deutschland ( Tübinger Studie ). München: Urban und Schwarzen-berg; 1981.

10. Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venousinsufficiency. Angiology. 2001;52:S5-S15.

11. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venousstasis syndrome and venous ulcer: a 25-year population-based study. J VascSurg. 2001;33:1022-1027.

12. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Chronic venous insuffi-ciency: clinical and duplex correlations. The Edinburgh Vein Study of venous dis-orders in the general population. J Vasc Surg. 2002;36:520-525.

13. Widmer LK, Stählin HB, Nissen C, Da Silva A (Hrsg.). Venen-, Arterien-Krankheit-en, koronare Herzkrankheit bei Berufstätigen, Prospektiv-epidemiologischeUntersuchung Baseler Studie I-III 1959-1978. Bern Stuttgart Wien: Verlag HansHuber.

14. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der DeutschenGesellschaft für Phlebologie – epidemiologische Untersuchung zur Frage derHäufigkeit und Ausprägung von chronischen Venenkrankheiten in der städtis-chen und ländlichen Wohnbevölkerung. Phlebologie. 2003;32;1-14.

15. Carpentier PH, Maricq HR, Biro C, Poncot-Makinen CO, Franco A. Prevalence,risk factors and clinical patterns of chronic venous disorders of lower limbs:a population-based study in France. J Vasc Surg. 2004;40:650-659.

16. Chiesa R, Marone EM, Limoni C, Volonté M, Schaefer E, Petrini O. Demograph-ic factors and their relationship with the presence of CVI signs in Italy. The 24-cities cohort study. Eur J Vasc Endovasc Surg. 2005;30:674-680.

17. Chiesa R, Marone EM, Limoni C, Volonté M, Schaefer E, Petrini O. Chronic ve-nous insufficiency in Italy: The 24-cities-cohort study. Eur J Vasc Endovasc Surg.2005;30:422-429.

18. Criqui MH, Jamosmos JM, Fronek AT, et al. Chronic venous disease in an eth-nically diverse population. The San Diego Population Study. Am J Epidemiol.2003;158:448-456.

19. Jawien A, Grzela T, Ochwat A. Prevalence of chronic venous insufficiency in menand women in Poland: multicenter cross-sectional study in 40 095 patients.Phlebology. 2003;18:110-121.

20. Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study.Angiology. 2002;53:245-256.

21. Rabe E, Pannier F. Societal costs of chronic venous disease in CEAP C4, C5,C6 disease. Phlebology. 2010;25 suppl 1:64-67.

22. Purwins S, Herberger K, Debus ES, et al. Cost-of-illness of chronic leg ulcers inGermany. Int Wound J. 2010;7:97-102.

IDENTIFICATION ET CONSULTATION DES PATIENTS ATTEINTS DEMALADIE VEINEUSE CHRONIQUE : L’ÉTUDE INTERNATIONALE À GRANDE ÉCHELLE VCP

La maladie veineuse chronique (MVC) se définit par des anomalies morphologiques et fonctionnelles de longuedurée touchant le système veineux et se manifestant par des signes et des symptômes nécessitant des examenscomplémentaires et/ou des soins. L’impact de la MVC dans la population générale est souvent sous-estimé et malreconnu par les systèmes de santé. Dans les études récentes et selon la classification CEAP (Clinique [sévérité] Étio-logie-Anatomie-Physiopathologie), les classes C0 et C1 sont toutes les deux prévalentes dans plus de 60 % de lapopulation. Les varices (C2) sont prévalentes chez plus de 20 % de la population. Les modifications cutanées, ycompris les ulcères, se retrouvent dans moins de 10 % de la population. Il n’existe pas de données épidémiologiquespour de nombreux pays. Le Vein Consult Program mondial a pour but d’évaluer la prévalence de la MVC et fournitune image du patient adulte typique et de la prise en charge de sa maladie, dans différentes zones géographiques.C’est le plus vaste programme de détection de la MVC jamais entrepris. Le Vein Consult Program est mis en œuvresous les auspices de l’Union Internationale de Phlébologie avec le soutien de Servier. Plus de 4500 généralistessélectionnés y participent, et l’on estime qu’ils dépisteront environ 95 000 patients. À la première étape du pro-gramme, les généralistes trient les patients qui consultent pour n’importe quelle raison médicale. La deuxième étapeest une consultation de suivi avec un spécialiste veineux. Les premiers résultats du dépistage de 69 866 patients de13 pays sont disponibles.

Keywords: Vein Consult Program; chronic venous disease; CEAP; CIVIQ; epidemiology; International Union of Phlebology; UIP

Pain in chronic venous disease: perspectives for research – Danziger MEDICOGRAPHIA, Vol 33, No. 3, 2011 325

P ain is the complaint that most often leads to a diagnosis of venous dis-ease, and it has a significant impact on patients’ quality of life. For allthose involved with chronic venous disease (CVD), pain is difficult to

assess both because of its multidimensional nature and because of the lackof a close relationship between pain as a symptom and severity of venous dis-ease. Current hypotheses on the mechanisms of pain induction in CVD high-light its local inflammatory origin. A variety of inflammatory mediators are re-leased locally in the early stages of CVD, which activate unmyelinated C-fibersin the venous wall, leading to pain. In the last five years, there has been a ver-itable explosion in the number of indicators suggesting an inflammatory re-action in varicose veins. The precise mechanisms governing the interactionbetween venous nociceptors and mediators of inflammation, which may ac-count for the variability of pain experienced in venous disease, remain dif-ficult to explain.


T he quality of life of chronic venous disease (CVD) patients is greatly affectedby pain,1,2 the complaint that most often leads to diagnosis of venous dis-ease.3,4 For everyone involved in CVD, pain is difficult to measure. Often pain

of venous origin is found in association with other disagreeable sensations that donot belong in the range of nociceptive symptoms, eg, pruritus or a sensation ofcramp, heaviness, or tension in the legs.3 The intensity of pain can also fluctuate sub-stantially, from patient to patient or in the same patient with progression of the dis-ease over a period of time.

A causal relationship between CVD and pain of venous origin remains difficult toclarify, both clinically and experimentally. This difficulty could be attributed to theabsence of a close link between pain and the severity of CVD. Nevertheless, thefuture looks promising as the neurophysiological mechanisms of pain of venousorigin are now better understood,5 and several biochemical and cellular process-es involved in varicose vein remodeling have been explained.6-8

Venous innervation and the physiological properties of venousand perivenous nociceptorsVeins are innervated by sensory nerve fibers whose cell body is situated in the dor-sal root ganglia of the spinal cord.5 Sensory fibers are located along the venous walland subdivide into collateral branches. Some cross the tunica adventitia and termi-

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Nicolas DANZIGER, MD, PhDDepartment of ClinicalNeurophysiology and PainCenter, Groupe HospitalierPitié-SalpêtrièreParis, FRANCE

Address for correspondence:Nicolas Danziger, Faculté deMédecine Pitié-Salpêtrière, 91,boulevard de l'Hôpital,75013 Paris, France(e-mail: [email protected])


Pain in chronicvenous disease:

perspectives for research

by N. Danziger, France

The intensity of the sensationof pain increases exponentiallywith the intensity of the stimulusand completely disappears afterinjection of a local anesthetic in theisolated venous segment. Regard-less of the source of the pain stim-ulus, the stimulus-sensation curves(intensity of sensation of pain withincreasing intensity of appliedstimulus) are all the same. Theseintriguing results suggest that thedifferent stimuli activate the samevenous nociceptors.”

‘‘

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MEDICOGRAPHIA, Vol 33, No. 3, 2011 Pain in chronic venous disease: perspectives for research – Danziger326

nate in the venous wall between endothelial cells and smoothmuscle cells of the tunica media. Other collateral branchespenetrate the connective tissue of the perivenous spacewhere they branch further into unmyelinated free nerve end-ings in proximity to the microcirculation. These subendothe-lial and perivascular nerve endings are nociceptors: their solepurpose is the transmission of nociceptive afferent signalsgenerated both in the venous wall and in the perivenous con-nective tissue, respectively.

Recently, these types of nerve endings have been shown tobe present in the wall of human varicose veins.9 These noci-ceptors account for the stimuli that generate pain sensationsof venous origin. This type of pain can be induced by a varietyof different stimuli. Mechanical stimuli used include tractionexerted on a vein, venipuncture, or the presence of a catheter,while nonphysiological chemical stimuli used include the in-jection of a strongly acidic (pH <4) or alkalinic (pH >11) solu-tion, the injection of hyperosmolar saline or a glucose solu-tion, or the injection of “cold” isotonic saline (<20°C).10

Animal studies have shown that there are two types of af-ferent fibers that transmit nociceptive signals of venous ori-gin. Electrophysiological tracings of nerve fibers innervatingvenous wall have shown that there is a type Aδ myelinatedafferent nerve fiber and a type C unmyelinated afferent nervefiber.11 Aδ fibers, with their higher conduction velocities, areresponsible for the acute, sharp sensation of pain that is feltfirst. They respond to a weaker intensity of stimulus than C-fibers. C-fibers, which are deemed polymodal because theyrespond to an assortment of stimuli, are responsible for thesensation of longer-lasting, slow, dull pain.

Other sources of acute pain of venous origin include super-ficial venous inflammation or deep vein thrombosis, both ofwhich are often observed in clinical practice. Traditionally, theproperties of venous nociceptors have been elucidated ex-perimentally in humans by mechanically, thermally, or chem-ically stimulating an isolated venous segment and asking thesubject to grade the intensity of the sensation induced (Fi-gure 1).12 This pain model has shown that a variety of non-physiological endovenous stimuli, such as the application ofcold or heat, balloon dilation of the vein, electrical stimulus,and infusion of hyperosmolar saline, produce a painful sen-sation that starts at a particular threshold and whose qual-ity is the same whatever the method of stimulation used.

Furthermore, the intensity of the sensation of pain increas-es exponentially with the intensity of the stimulus and com-pletely disappears after injection of a local anesthetic in theisolated venous segment.5 Regardless of the source of thepain stimulus, the stimulus-sensation curves (intensity of sen-sation of pain with increasing intensity of applied stimulus) areall the same. These intriguing results suggest that the differentstimuli activate the same venous nociceptors, which meansthat most nociceptors located in the venous wall are poly-modal nociceptors.

These experiments have shown that venous dilation is un-likely to be an important factor in the sensation of venous pain.Mechanical venous balloon dilation has to increase the di-ameter of a vein by three times its normal value before painbegins to be experienced. If we add to this observation thefact that venous dilation is not normally perceived as painfulwhen induced by pharmacological methods such as the lo-cal application of adenosine,13 it appears that even major ve-nous dilation is not in itself a significant source of venous painin normal subjects. Moreover, arteriovenous fistulae createdfor the purpose of hemodialysis are painless, another strandof support for this conclusion.

Pain experienced and clinical severity ofvenous diseaseNumerous epidemiological studies have shown that the ex-istence, intensity, or both of lower limb symptoms associatedwith CVD do not correlate with the severity of clinically eval-uated venous disease. The quantitative evaluation of CVD isnormally based on the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification,14 a system for classifyingclinical signs in one of seven classes (C0 to C6) (Table I) ac-cording to their severity. In a population study of over 1500


CEAP Clinical-Etiological-Anatomical-PathophysiologicalCVD chronic venous diseasePAF platelet-activating factor

Inflow

Outflow

Occlusivepneumatic

cuffs

Isolatedvenous

segment

Figure 1. Experimental set-up to study pain evoked by stimula-tion of an isolated venous segment in man.A venous segment in the back of the hand located between two Teflon canulasis isolated from the rest of the circulation by two occlusive pneumatic cuffs.Local anesthesia of the skin around the isolated venous segment ensures thatsensations induced are specifically related to activation of venous afferent fibers,without the participation of cutaneous sensory fibers.Modified from reference 12: Danziger. Phlebolymphology. 2008;15:107-114.© 2008, Les Laboratoires Servier.

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subjects aged 18 to 64 years, the Edinburgh Vein Study, Brad-bury et al demonstrated a correlation between the presenceof truncular varices and three lower limb symptoms in women:pain, sensation of heaviness or tension, and pruritus.3 Eventhough the correlations were statistically significant, they wereinsufficient to determine a causal relationship with the dis-comfort or pain associated with confirmed venous disease.In fact, 45% of patients who complained of lower limb paincompatible with CVD did not have varicose veins, while about40% of women presenting with varicose veins in the clinicalexamination were asymptomatic. Moreover, in men, no sig-nificant correlation was found between pain and the exis-tence of truncular varices.

Regardless of the sex of the patient, no symptoms seemed tovary according to the severity of varicose veins. Several stud-ies of patients with advanced CVD (classes C4 to C6) haveshown that there is a relation between the degree of Dopplerscanning–identified venous reflux and the severity of venousclinical signs and symptoms. Nonetheless, this does notseem to be the case for early-stage CVD. The search for sucha correlation in the Edinburgh Vein Study, which focused pri-marily on patients presenting with early-stage venous dis-ease, proved disappointing.15 In the Edinburgh Vein Study,the correlation observed between pathologic superficial ve-nous reflux (duration greater than or equal to 0.5 seconds)and sensation of swelling, heaviness, or tension was low. Inaddition, this correlation was limited either solely to men (sen-sation of swelling) or solely to women (sensation of heavinessor tension). Strictly speaking, no significant correlation wasobserved between superficial venous reflux and pain.

A lack of correlation between the presence of venous symp-toms and pain was not only limited to superficial veins; thiswas also the case for deep veins, too. When venous symp-

toms were compared with deep venous reflux (popliteal vein),no correlation was found, irrespective of the patient’s sex.Equally, in a study of over 120 patients with mild to moder-ate CVD,16 no correlation was seen between pain intensityand clinical severity of venous disease based on the CEAPclassification.

Furthermore, Howlader and Smith reported no statistical re-lation between the pain score or heaviness score of a patient,evaluated on a 10-point visual analogue scale, and the clin-ical severity of venous disease, in a cohort study of 132 pa-tients.17 The median pain score was 2.8 in the group of pa-tients with class C2 venous disease, 4.5 in class C3, only 0.5in class C4 and 0 in patients with class C5 venous disease.No difference was noted in pain scores between patients pre-senting with superficial venous reflux and those presentingwith deep venous reflux. These results fully uphold the find-ings of a French survey on the frequency of clinical symptomsaccording to the duration of venous disease.4

The French survey illustrated a very significant decrease inthe frequency of functional signs of venous disease, in par-ticular pain, over time. So, for example, the frequency of thepainful heaviness sensation dropped from 71% in the groupwith symptoms of less than 5 years’ duration to 50% in thegroup whose symptoms were of 30 years’ duration or longer.These findings concur with the results of a Swiss epidemi-ological study that indicate the prevalence of varicose veinsincreases with age, while pain decreases with age.18

Inflammatory autoamplification and painmechanisms in venous diseasePresent-day hypotheses on how pain mechanisms act invenous disease focus on a local inflammatory origin, relatedto venous stasis. The processes that generate pain in venousdisease in the short term seem to be identical to those involvedin the process of varicose vein remodeling, defined as all ofthe qualitative and quantitative alterations in the cellular andmatrix components of the venous wall, in the longer term.19

Local hypoxia associated with capillary stasis is probably theorigin of these mechanisms. The partial pressure of oxygenhas been demonstrated to fall significantly in lower limb veinsin venous disease after 30 minutes in a standing position,8

and many studies have shown that capillary stasis–inducedhypoxia activates endothelial cells.7 This type of activation issignaled by the elevation of calcium concentrations in the cy-toplasm of endothelial cells,20 which upregulate phospholi-pase A2 activity.

21

Activation of phospholipase A2, in turn, leads to the synthe-sis and local release of proinflammatory mediators such asplatelet-activating factor (PAF), bradykinin, prostaglandins E2and D2, and leukotriene B4.

22,23 PAF seems to play a key role:it boosts the local release of histamine and serotonin; it caus-

Class Definition

C0 No visible or palpable signs of venous diseaseC1 Telangiectasias or reticular veinsC2 Varicose veins; distinguished from reticular veins by

a diameter of 3 mm or moreC3 EdemaC4 Changes in skin and subcutaneous tissue secondary

to CVD, divided into 2 subclasses to better definethe differing severity of venous disease:

C4a: pigmentation or eczemaC4b: lipodermatosclerosis or atrophie blanche

C5 Healed venous ulcerC6 Active venous ulcer

Table I. The CEAP classification.The essential aim of this classification is to assess quantitatively the stage ofchronic venous disease. The clinical classification is the one most widely usedand consists of 7 classes, which can be symptomatic (S) or asymptomatic (A).Abbreviation: CEAP, Clinical-Etiological-Anatomical-Pathophysiological; CVD,chronic venous disease.

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es abnormal adherence of neutrophils to the venous endo-thelium, prior to their infiltration through the venous wall itself;and, finally, it stimulates the synthesis of leukotriene B4 by ac-tivated neutrophils. In the last few years, the amount of evi-dence for the existence of this type of inflammatory reactionin patients with varicose veins has snowballed,24 and the bio-chemical changes identified point to endothelial cells and neu-trophils as the source of this local inflammation (Figure 2).8,25-29

There are a plethora of indicators of inflammation in venousdisease: the presence of neutrophils, monocytes, and acti-vated T lymphocytes; the accumulation of macrophages andmast cells; the expression of adhesion molecules on the sur-face of leukocytes and endothelial cells (eg, LFA-1, VLA-4,ELAM-1, ICAM-1, VCAM-1); and the synthesis of cytokines(eg, IL-1β, IL-6, TNF-α) and prothrombotic factors (eg, vonWillebrand factor) are all indicators of inflammation in venousdisease.14,30 Venous nociceptors can be activated by proin-flammatory mediators released locally as a result of hypoxia.The intravenous or perivenous application of one such me-diator, bradykinin, evoked a sensation of pain in healthy sub-jects, which unambiguously establishes the role of this neu-romediator in venous pain.31

Many studies have highlighted the vital role of nitric oxide re-lease by endothelial cells, smooth muscle cells in the wall ofthe vein, or both32 and the subsequent activation of cyclicguanosine monophosphate synthesis33 in the production ofpain by bradykinin. Local administration of prostaglandin E2potentiates this algogenic action of bradykinin.34 ProstaglandinE2, whose application by itself is painless, appears to sen-sitize venous nociceptors. This type of autoamplification re-

action cascade causes the release of an “inflammatory mix-ture,” which activates venous and perivenous nociceptors aswell as causing the extravasation of plasma leading to trans-mural and tissue edema. Over time, varicose vein remodel-ing occurs, and this is characterized by cellular and matrixchanges that compromise the structural integrity of the ve-nous wall and its elastic properties.19

A finding that substantiates this hypothesis comes from astudy by Howlader and Smith, which demonstrated that ni-tric oxide concentrations measured in blood collected in thesaphenous vein or in a vein in the dorsal aspect of the footwere significantly higher in patients with the most severe stageof venous disease.35 Likewise, certain studies have reportedhigher levels of markers of endothelial activation in experimen-tal venous hypertension in the most advanced stages of ve-nous disease.36

Given the importance of these inflammatory processes in painproduction as well as in varicose vein remodeling, a correla-tion between levels of inflammatory markers and the intensi-ty of pain in venous disease might be expected to exist. How-ever, this is not the case, in much the sameway that the clinicalestimation and evaluation of venous pain by venous Dopplerscanning proved negative.17 No significant correlation wasfound between levels of 12 inflammatory markers (measuredin a vein on the dorsal aspect of the foot) and pain intensityscore on a visual analogue scale in a population of 132 pa-tients with CVD ranging from class C2 to C5. The relationshipbetween the venous wall inflammatory cascade and pain as-sociated with venous disease seems difficult to demonstrateformally.

Figure 2. Photomicrographs of propidium iodide–positive cells along the upstream (elevated micropressure) and downstream (low mi-cropressure) segment of an occluded rat venule.Elevation of venular blood pressure during occlusion/reperfusion exacerbates inflammation and tissue injury. Bright-field images (far left) show occlusion of the venule,while the fluorescence images display propidium iodide–positive cells in the same two visual fields preocclusion, 60 minutes after occlusion, and after 60 minutes ofocclusion followed by 60 minutes of reperfusion (120-minute time point). The proportion of propidium iodide–positive cells is an indicator of parenchymal cell death.Modified from reference 25: Takase et al. Am J Physiol Heart Circ Physiol. 2002;282:H1387-H1394. © 2002, American Physiological Society.

Micropipette

Up

stre

amD

ow

nstr

eam

Flow direction

Pre 60 min 120 min

Pain and objective markers of venous disease� Pain, clinical severity, and inflammatory markersIf the intensity of pain of venous origin does not correlate withthe extent of truncular varices observed in clinical examina-tion, the severity of reflux measured with Doppler scanning,or levels of inflammatory markers measured in a lower limbvein, could hypoxia offer a possible explanation? It is entirelypossible that many painful hypoxia-related conditions may oc-cur transiently in patients, eg, after standing for a prolongedperiod, at the end of the day, or during certain periods of themenstrual cycle, if hypoxia is indeed a major factor that trig-gers pain of venous origin.

If venous and perivenous nociceptor-activating chemical cas-cades were to occur before significant remodeling of large ve-nous vessels arises, this might explain the frequency of func-tional signs, such as pain or heaviness in the legs, in patientswho do not have varicose veins and the lack of abnormal re-flux seen in a Doppler scan, as in the Edinburgh Vein Study.While the same essentially inflammatory biochemical and cel-lular processes are implicated in pain and varicose vein remod-eling, the time frame over which these pathological mecha-nisms occur is different.

Pain appears to be a short-term consequence of venous hy-poxia, while varicose vein remodeling seems to take placeat a much later stage of CVD. Because the occurrence ofpain does not appear to be closely related to objective pa-rameters of varicose vein remodeling, incompetent venousvalves, or inflammation, this suggests the primary site of ve-nous/perivenous nociceptor activation may not be the largevenous vessels. In light of this fact, the hypothesis of localactivation of nociceptors in the microcirculation, where con-tact between nerve endings, the arteriole, the vein, and thecapillary is probably much closer than at the macrovascularlevel, seems highly conceivable.

As a result, several studies looked at microcirculatory param-eters of venous disease.37,38 In addition, several studies usingan experimental model of acute venous occlusion in the ratshowed that an increase in microvascular pressure triggeredan inflammatory reaction characterized by infiltration of neu-trophils into the endothelium and adjacent tissues.27

Shear stress on the endothelium produced by blood flow isanother essential factor that promotes inflammation of thevenous wall.24 Shear stress can influence many intracellularbiochemical processes, such as protein G phosphorylation,activation of tyrosine kinases, free radical production, and thesynthesis of different nuclear transcription factors, via integrinsanchored in the endothelial cell membrane.39-41 Physiologi-cally normal shear stress produces a potent, local anti-inflam-matory effect, while a reduction or an increase in this forcebelow or above a given physiological threshold can lead tooverexpression of proinflammatory genes.24,30

� Explaining the disappearance of pain in advancedstages of CVDAlteration of innervation of the venous wall and the perive-nous tissue may explain the significant decrease in the fre-quency and intensity of pain in the most advanced stages ofvenous disease. This change in nerve fibers may reflect sen-sory peripheral neuropathy, perhaps related to ischemia sec-ondary to venous microangiopathy, and an increase in en-doneural pressure.42 The threshold of tactile, vibrational, andthermal sensation in the extremities in patients with CVD issignificantly higher than normal, suggesting the loss of sen-sory axons.43,44 This sensory threshold elevation was signif-icantly more distinct in class C5 than in class C2 disease.44 Areduction in the number of venous and perivenous nocicep-tors could well account for a lessening of pain in the mostadvanced stages of venous disease.

� Interindividual pain variability in venous diseaseThe range and intricacy of mechanisms involved in the patho-genesis of venous disease pain are a significant source ofinterindividual variability. Both the reactivity of the cellularcomponents involved (endothelial cells, neutrophils, and ve-nous and perivenous nociceptors) and the ways in which no-ciceptive stimuli are processed in the brain produce this vari-ability. At a cellular level, for example, experimental studies ofhuman umbilical cord venous endothelial cells have demon-strated that the quantity of different prostaglandins releasedas a result of hypoxia can differ by a factor of 10 depending onthe donor.7 By the same token, neutrophil reactivity to otherinflammatory signals varies with age and previous sensitization(“priming”). What’s more, the density of venous and perivenousinnervation as well as the presence of nociceptors in ion chan-nels, which allows the conversion of a chemical message intoa nerve impulse relaying nociceptive information, can alsovary considerably from one person to another.

Interindividual variability in the way the brain reacts to painstimuli will also play a part. The intensity of brain modulationof nociceptive signals resulting from the release of endoge-nous opioids, whose concentrations vary from subject to sub-ject due in part to genetic factors, is also likely to account forsome of the pain sensitivity in a given individual with regardto venous nociceptive stimuli. For instance, the genotype ofthe catechol-O-methyl-transferase enzyme, which determinesthe quantity of endogenous opioid released during a painstimulus, significantly affects pain sensitivity.45

However, all these variables are just relative obstacles in theelucidation of pain mechanisms in venous disease. In the ab-sence of a correlation between the state of large venous ves-sels and the degree of pain reported, perhaps we ought tobe examining the interaction between the mediators of in-flammation and venous nociceptors in more detail, with amind to developing a method of testing nociceptive functionin venous disease microcirculation. �

U P D A T E


U P D A T E


Keywords: pain; chronic venous disease; inflammation; nociceptors; C-fibers

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17. Howlader MH, Smith PD. Symptoms of chronic venous disease and associa-tion with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.

18. Widmer LK, Zemp E. Diagnosis and treatment of varicose veins. Deductionsfrom on a Basel prospective epidemiological study [in German]. Helv Chir Acta.1988;54:531-539.

19. Badier-Commandier C, Jacob MP, Michel JB. Le remodelage variqueux. Méde-cine Thérapeutique. 2000;6:718-723.

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24. Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR,Eklof B. Chronic venous disease. N Engl J Med. 2006;355:488-498.

25. Takase S, Lerond L, Bergan JJ, Schmid-Schönbein GW. Enhancement of reper-fusion injury by elevation of microvascular pressures. Am J Physiol Heart CircPhysiol. 2002;282:H1387-H1394.

26. Smith PD. Update on chronic-venous insufficiency-induced inflammatory pro-cesses. Angiology. 2001;52:S35-S42.

27. Takase S, Schmid-Schonbein GW, Bergan JJ. Leukocyte activation in patientswith venous insufficiency. J Vasc Surg. 1999;30:148-156.

28. Junger M, Steins A, Hahn M, Hafner HM. Microcirculatory dysfunction in chron-ic venous insufficiency (CVI). Microcirculation. 2000;7:S3-S12.

29. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge Smith PD. Leucocyteactivity in the microcirculation of the leg in patients with chronic venous dis-ease. J Vasc Surg. 1997;26:265-273.

30. Schmid-Schönbein GW. Inflammation and the pathophysiology of chronic ve-nous insufficiency. Phlebolymphology. 2003;39:95-99.

31. Kindgen-Milles D, Klement W, Arndt JO. The nociceptive systems of skin, par-avascular tissue and hand veins of humans and their sensitivity to bradykinin.Neurosci Lett. 1994;181:39-42.

32. Holthusen H, Arndt JO. Nitric oxide evokes pain at nociceptors of the paravas-cular tissue and veins in humans. J Physiol. 1995;487:253-258.

33. Holthusen H. Involvement of the NO/cyclic GMP pathway in bradykinin-evokedpain from veins in humans. Pain. 1997;69:87-92.

34. Kindgen-Milles DW. Effects of prostaglandin E2 on the intensity of bradykinin-evoked pain fromskinand veinsof humans. EurJ Pharmacol.1995;294:491-496.

35. Howlader MH, Smith PD. Increased plasma total nitric oxide among patientswith severe chronic venous disease. Int Angiol. 2002;21:180-186.

36. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge Smith PD. Leukocyteactivity in the microcirculation of the leg in patients with chronic venous disease.J Vasc Surg. 1997;26:265-273.

37. Howlader MH, Smith PD. Correlation of severity of chronic venous disease withcapillary morphology assessed by capillary microscopy. J Vasc Surg. 2006;43:563-569.

38. Virgini-Magalhaes CE, Porto CL, Fernandes FF, Dorigo DM, Bottino DA, Bous-kela E. Use of microcirculatory parameters to evaluate chronic venous insuf-ficiency. J Vasc Surg. 2006;43:1037-1044.

39. Resnick N, Yahav H, Khachigian LM, et al. Endothelial gene regulation by lam-inar shear stress. Adv Exp Med Biol. 1997;430:155-164.

40. Shyy JY, Li YS, Lin MC, et al. Multiple cis-elements mediate shear stress-in-duced gene expression. J Biomech. 1995;28:1451-1457.

41. Chen KD, Li YS, Kim M, et al. Mechanotransduction in response to shear stress.Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem. 1999;274:18393-18400.

42. Reinhardt F, Wetzel T, Vetten S, et al. Peripheral neuropathy in chronic venousinsufficiency. Muscle Nerve. 2000;23:883-887.

43. Shami SK, Shields DA, Farrah J, Scurr JH, Coleridge Smith PD. Peripheral nervefunction in chronic venous insufficiency. Eur J Vasc Surg. 1993;7:195-200.

44. Padberg FT Jr, Maniker AH, Carmel G, Pappas PJ, Silva MB Jr, Hobson RW II.Sensory impairment: a feature of chronic venous insufficiency. J Vasc Surg.1999;30:836-842.

45. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affectsmu-opioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240-1243.

U P D A T E


DOULEUR DANS LA MALADIE VEINEUSE CHRONIQUE (MVC) :PERSPECTIVES POUR LA RECHERCHE

La douleur est la plainte qui mène le plus souvent au diagnostic de maladie veineuse et elle influe significativementsur la qualité de vie des patients. Pour tous ceux qui se préoccupent de la MVC, la douleur est difficile à évaluer àla fois à cause de sa nature multidimensionnelle et à cause du manque de relation étroite entre la douleur en tantque symptôme et la sévérité de la maladie veineuse. Des hypothèses actuelles sur le mécanisme d’induction de ladouleur dans la MVC soulignent son origine locale inflammatoire. De nombreux médiateurs inflammatoires sont libé-rés localement aux stades précoces de la MVC, activent des fibres C démyélinisées dans la paroi veineuse, entraî-nant la douleur. Ces 5 dernières années, on a assisté à une véritable explosion du nombre d’indicateurs suggérantune réaction inflammatoire dans les varices. Il est toujours difficile d’expliquer les mécanismes précis à l’origine del’interaction entre les nocicepteurs veineux et les médiateurs de l’inflammation, qui pourraient contribuer à la varia-bilité de la douleur observée dans la maladie veineuse.

MEDICOGRAPHIA, Vol 33, No. 3, 2011 333

Écouen: from châteauto museum, or Beauty isin the detailS . Deprouw, France

Dish with intertwinedflowers (detail).

Iznik, Turkey, circa 1580.© RMN/René-Gabriel Ojéda.

A TOUCHOF FRANCE

U nder this heading, eachissue of Medicographiafeatures two cultural arti-

cles. The first one touches on thehistory of medicine, based arounda great figure from French history,while the second one addressesbroader aspects of France’s her-itage, such as history, art, litera-ture, and the description of mu-seum collections.

Theory and practice:European Renaissance

medicineS . Daynes-Dia l lo , France

Dissection scene fromDe ProprietaribusRerum, by Barthélemyl’Anglais (vellum). End15th century. BibliothèqueNationale, Paris.© Archives Charmet/TheBridgeman Art Library.

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Theory and practice: European Renaissance medicine – Daynes-Diallo334

Theory and practice:European Renaissance

medicine

A TO U C H O F F R A N C E

R enaissance medicine amalgamated the theory and practice of medicalknowledge inherited from Antiquity and the Middle Ages. Although itbuilt on much from the past, it also innovated—Renaissance medicine

was determined to shake off its Medieval trappings. In spite of the fact thatmedicine in the 16th century did not experience a renaissance comparable tothat seen in the arts—the medical revolution was still a century away—it couldnot fail to be caught up in the Humanist wave sweeping through Europe, andit made genuine progress as a result. While the Copernican revolution turnedMedieval cosmology on its head, the Reformation undermined Catholic dog-ma and questioned the relationship between God and Man, and technicaladvances—spearheaded by printing—led to an unprecedented transforma-tion in knowledge and practice, medicine swung between a form of Human-ism that was extremely deferent to the Ancient Greeks and Romans, but whicheventually opened the way for textual criticism, and an increasingly empiricalform of clinical practice in response to the century’s two main scourges: epi-demics and the arquebus—one natural, the other man-made. It was also in the16th century that medical fraternities organized themselves into institutionsand prepared the ground for modern medicine and the completion of the syn-thesis of theory and practice.


by S . Daynes-Dia l lo , France

Sophie DAYNES-DIALLOMusée du Louvre, Paris, FRANCE

A lthough Renaissance med-icine has not had the im-pact of Renaissance art,

there were nevertheless major ad-vances in the field of medicine atthis time, notably in a Humanistreassessment of the medical lega-cy from antiquity, a ratification ofmedical education at medical in-stitutions, and an explosion in thedissemination of medical knowl-edge. In addition, Renaissancemedicine developed the first treat-ments for firearm wounds and wel-comed the arrival in Europe of newremedies from far-flung shores.

Address for correspondence:Sophie Daynes-Diallo, Régisseurd’œuvres d’art, Département desAntiquités Égyptiennes, Musée duLouvre, 75058 Paris CEDEX 01,France(e-mail: [email protected])


A n Africa specialist with a university background in the arts, human sciences,and museology, Sophie Daynes-Diallo has found herself stumbling repeat-edly in the course of her career into the history of medicine. She first worked

at the Paris Health Service Museum (Musée de l’Assistance Publique–Hôpitauxde Paris) on the 1935-2005. Avicenna Hospital: a history without borders exhibi-tion, the catalogue for which she coproduced with Katia Kukawka. In 2006, afterpassing the Ministry of Culture’s competitive documentalist examination with dis-tinction, she was appointed to the National Museum of the Renaissance, where shecommissioned the exhibition Ars medicina: medicine and knowledge in the 16thcentury, held in the spring of 2008. In the fall of 2009, she moved to the Louvreto become a registrar in the Department of Egyptian Antiquities.

©Allrig

htsreserved

enaissance* medicine amalgamatedthe theory and practice of medicalknowledge inherited from Antiquityand the Middle Ages. In response tothe humanism of the age, its attitudeconstantly oscillated between atav-ism and innovation, which producedtangible progress and prepared the

ground for the blossoming of modern medicine that occurredin the 17th century.

The legacy of the pastThe medical world of the Renaissance inevitably bore thestamp of its Medieval counterpart. Medicine in this era wasa component of physica—the Latin echo of Aristotle’s ταφυσικα—incorporating the natural sciences, philosophy, andreligion. It perceived the world as a macrocosm reflected in

the humanmicrocosm, so that the laws governing the one alsogoverned the other. The ambition of Renaissance man wasto unveil and understand God’s creation across both spheres.Medical doctrine inherited the synthesis of three great intel-lectual traditions from the Middle Ages: the Arabic teachingsof Antiquity, Christian doctrine, and Middle Eastern cultureand science. The corpus of a Renaissance medical librarycomprised the works of Hippocrates (circa 460 – circa 370BC), Aulus Cornelius Celsus (circa 25 BC - circa 50 AD), Pe-danius Dioscorides (circa 40-90), and Galen (129-199/217),along with thoseof Avicenna (circa 980-1037), Averroes (1126-1198), and the teachings of the Salerno School of Medicinefrom its heyday between the 10th and 13th centuries.

Medical science was based on the doctrine of humors ex-pounded by Hippocrates and his “prophet” Galen. Being amicrocosm of the universe, the human body was naturallycomposed, like the universe itself, of the four “fundamentalelements” of earth, water, air, and fire. Each of these elementswas in turn characterized by four essential “qualities”: hot,dry, cold, and wet. In addition, the human body was bathedin four “fluids” or “humors,” characterized by two essential“qualities” and one “fundamental element”: blood—hot andwet—was associated with air; phlegm—cold and wet—withwater; yellow bile—hot and dry—with fire; and black bile—cold and dry—with earth. In normal circumstances, the hu-mors acted in harmony to produce a healthy, “temperate” in-dividual.

A T O U C H O F F R A N C E

Theory and practice: European Renaissance medicine – Daynes-Diallo MEDICOGRAPHIA, Vol 33, No. 3, 2011 335

Prosthetic hand designed by French surgeon Ambroise Paré(1510-1590), a specialist of battle medicine and royal surgeon tofour kings. From: Instrumenta Chyrurgiae et Icones Anathomicae,by Ambroise Paré, published 1564. © Wellcome Library.

The FourHumours,

from QuintaEssentia by

LeonhartThurneisser

zun Thurn(1531-95/6)published inLeipzig, 1574(engraving)

(b/w photo),GermanSchool,

(16th centu-ry)/privatecollection.© Archives

Charmet/Bridgeman Giraudon.

*Decorated initial from the Basel 1555 edition of Andreas Vesalius's DeHumani Corporis Fabrica published by Johannes Oporinus. Woodcut.© Wellcome Images.

Disharmony resulted in illness and disease. Thus an excessof all four humors, especially blood, gave rise to “plethora”(forming the doctrinal basis for bloodletting), while the relativeexcess of a single humor produced a state of “cacochymy.”The humors were complemented by three spirits animatingthe body: the “natural” spirit residing in the liver, the “vital”spirit in the heart, and the “animal” spirit inthe brain. The aim of Renaissance medicinewas to understand more about these humors,recognize their disharmony in patients, andcorrect them with a set of defined interven-tions and long-established remedies.

A medley of medical professionsand skillsThe three guilds of physicians, apothecaries,and surgeons formed the basis of the prac-tice of Renaissance medicine. Over the cen-tury, they gradually established themselvesinto separate institutions, but not withoutclashes and competition. In addition to thesethree professions at the top of the medicalhierarchy, headed by physicians, 16th cen-tury citizens could also access the servicesof a huge spectrum of artisans prepared, inthe absence of the three notables, to under-take medical interventions based essentially

on practical experience and folk wisdom. Although Renais-sance physicians came from a wide range of social origins,the possession of a university doctorate of medicine con-ferred a relatively exalted social status on its holder. Attach-ment to the university was associated with a number of priv-ileges, an oath, and obligations. In provincial cities without auniversity, organization into corporations or colleges ensuredthe integrity and protection of the physicians’ guild.

Nevertheless, the gulf in status between the ennobled seniorcourt physician and the provincial physician, or between theprivate physician of an important figure such as a prince,prelate, or minister and the town-council physician caring forpaupers, was huge. In general, however, physicians confinedtheir practice to an urban and well-to-do clientele.

Physicians dressed austerely, in black cassock and cloak,turned down cuffs and collar, and wide-brimmed hat. Aboveall they were men of letters who taught natural science andliterature in universities or at the Collèges de France. Theytended to be humanists and poets, and were far more adeptin doctoral discourse than in clinical practice or intervention,which they delegated to students, barber surgeons, or evenapothecaries.

In France, apothecaries joined with grocers to form the sec-ond of the six merchant guilds. Like physicians, they enjoyedimportant privileges in the Renaissance period, which alsocame with obligations and an oath very similar to that of the



Interior of a pharmacy (fresco), Italian School, 15th century/Castello di Issogne,Val d’Aosta, Italy. © Giraudon/Bridgeman Giraudon.

Dutch surgeon. 1569, oil on wood, 16×21 cm. TheodoreM. Davis Collection, Bequest of Theodore M. Davis, 1915,The Metropolitan Museum of Art, New York.Distributed by RMN/© The Metropolitan Museum of Art.

current Hippocratic oath. Pharmaceutical studies had beenorganized since the previous century into several years’ ap-prenticeship crowned by the presentation of a “masterpiece,”according to the term’s original meaning: a piece of work pro-duced by an apprentice aspiring to become a master crafts-man in his chosen guild. Apprenticeship was supplementedfrom the second half of the16th century onwards by the teach-ing of theory that foreshadowed that dis-pensed in modern schools of pharmacy.Apothecaries dressed similarly to physi-cians, whom they served by dispensingtheir prescriptions.

The professional world of surgery duringthe Renaissance was extremely complexand beset by conflict, the primary althoughnot exclusive source of which lay in thecontempt that had been shown for this“manual” discipline by physicians since theMiddle Ages: in the 13th century, at a timewhen medical science was still the privi-lege of churchmen, Canon 18 of the FourthLateran Council forbade the “sheddingof blood.” This amounted to the de factoexclusion of surgery from both church-men’s medical practice and the universitycurriculum. Thus secularized, surgery wasleft to surgeons, who taught it in schoolsthat varied in the nature of their relation-ships with the universities.

The second source of conflict in the worldof surgery lay in the huge disparities inknowledge and practice within the pro-fession, from the educatedmaster of sur-gery at the pinnacle of the profession tothe barber surgeon, who had learned hiscraft on the job and who was licensed topractice minor surgery, bloodletting, andthe dressing of wounds, at the bottom. Inthe struggle to obtain recognition for theirprofession, both groups had to fight offantagonism and encroachment from theuniversity-trained medical profession throughout the 16th cen-tury. Below both these groups—mainly in the countryside,but also in towns and villages—a whole range of practitionersserved the swathes of population denied access to a physi-cian or surgeon, whether for geographic or financial reasons.

Folk wisdom based on a combination of magic, religion, andtime-honored empiricism enabled everyone either to treatthemselves or to consult someone more experienced, high-er born, better educated, or better off who was prepared totreat a fellow human being out of charity or neighborliness.Thus, folk remedies, charitable acts by priests or members

of religious orders, and recommendations and cure-alls en-dorsed by ladies in the aristocracy or bourgeoisie were avail-able alongside healers, sorcerers, soothsayers, astrologists,and peddlers of potions. Together they formed a motley armyof charlatans purveying an illicit and generally peripatetic med-icine that was condemned by the university medical author-ities. In addition to this array of dubious practitioners, not

forgetting the constant and insistent re-course to faith (ranging from regular devo-tion to supplications to healer-saints, notto mention a whole gamut of processions,prayers, pilgrimages, and penances), thereexisted a number of artisans who plied aspecialist trade across the class divide:bonesetters, peripatetic barbers, litho-tomists (extractors of human kidney, blad-der, and gall stones), specialists in her-nias and cataracts, toothdrawers, andmidwives.

Regulated university medicaltrainingRenaissance universities comprised fourfaculties. Students had to pass throughthe first, the faculty of arts—where theystudied grammar, the humanities, rheto-ric, and philosophy—before they could ac-cede to any of the other three major fac-ulties (theology, medicine, and canon law).

From the 13th century onwards, the facul-ty of medicine was separate from the fac-ulty of arts. Access required the degree ofMaster of Arts, accompanied by a certifi-cate of baptism in Paris, but granted “re-gardless of nationality or religion” in Padua.

The university course consisted of threeconsecutive qualifications: baccalaureate,degree, and doctorate. The cycle was vari-able, but generally extended over some tenyears. Although in practice some provin-cial physicians only had a baccalaureate

or a simple certificate, in theory none were allowed to prac-tice medicine without having obtained a degree. A doctorate,on the other hand, opened the door to recognition within theprofession and to employment on the university teaching oradministrative staff.

Studies were conducted in Latin. They consisted essentiallyof reading and analyzing the texts from Antiquity, mixed in-creasingly with those of more contemporary authors. In theearly 16th century, theoretical teaching was structured aroundthe study of “natural things” (anatomy, physiology, botany),“non-natural things” (hygiene and diet), and “contra-natural



Anatomical manikin made of ivoryused by midwives. Germany, begin-ning of 17th century. Ecouen, Musée

National de la Renaissance.© RMN/René-Gabriel Ojéda.

things” (pathology and therapeutics). Theoretical learning wassupplemented by practical sessions in botany and anatomy.Paris, Montpellier, Padua, and Bologna were the major 16thcentury universities and were all originally founded in the Mid-dle Ages. These major centers of learning were not isolated,however. For example, France numbered over twenty facul-ties of medicine or medical study centers. Students liked totravel from one center to another to study and accumulatequalifications from each.

A number of private medical teaching establishments coex-isted with the faculties. In Paris, some colleges that taughtmedicine gradually merged with the university, such as theColleges of Tricquet and Cornouailles; similarly, in Montpellier,there was the College of the Twelve Physicians. There werealso schools of surgery (colleges of Saint Cosmo), which grad-ually became incorporated into universities. The Collège deFrance, set up in 1530 by François I, boasted a chair in med-icine from as early as 1542.

Universities were thus not the only institutions that taught med-icine. But in addition to teaching and conducting research,they had other prerogatives. For example, they were consult-ed on issues of general interest to the State, such as publichealth and hygiene. They also produced the majority of physi-cians employed by royalty. Universities were also given the dutyof overseeing apothecaries, barber surgeons (to a lesser ex-tent), and midwives.

A change of intellectual direction: medicalHumanismHumanism informed the entire Renaissance, most visibly inthe arts and sciences. Positioning Man and human values atthe center of thought, the new philosophy was character-ized by a return to the writings and practices of the AncientGreeks and Romans, deliberately breaking from the supposedlegacy of the Middle Ages. The change of intellectual direc-tion that took place initially in Italy between the late 14th andmid-15th centuries spread rapidly throughout Europe. Hu-manism took its name from the Latin humanitas,meaning the“humanities” or the study of Latin and Greek in the broadestsense: the idea was to follow the paths laid down by the An-cient Greeks and Romans in knowledge, ethics, philosophy,and politics.

The Humanism of the Renaissance was thus characterized bya desire to return to the writings and practices of the ancientsstripped of their Medieval dross: these writings had, after all,

been translated, annotated, and added to throughout the Mid-dle Ages. Humanists in all branches of knowledge thereforeembarked on the vast undertaking of rereading, reanalyzing,and republishing the texts of Antiquity that had been hand-ed down to them. In medicine, for example, the last quarter ofthe 15th century saw the republication of De re medica byAulus Cornelius Celsus, along with central works by Hippo-crates and Galen.



Botanicaldrawing fromthe GreatHerbal ofLeonhart Fuchs(1501-166): DeHistoria StirpiumCommentariiInsignes (1542).© Chelsea PhysicGarden, London,UK/The BridgemanArt Library.

Frontispiece ofDe Re Medica by

Aulus CorneliusCelsus (Rome,

≈1st century BC/1st century AD).

Published in Parisby Chrestien

Wechel, 1529.© BIU Santé—Biblio-thèque Inter-Universi-taire de Santé, Paris.

Consequently, the entire centurywitnessed a vast dissemination ofHumanist thought, aided and abet-ted by the development of printingin particular, but also by universityteaching and Humanist practice.Magnificent testimony to themove-ment comes in the form of manu-scripts and printed works specif-ically composed and published forthe great Humanist libraries found-ed by princes and prelates, kingsand emperors, and the religiousfoundations of which the universi-ties were a part. Two compendiaof Greek and Roman surgical writ-ings organized by the celebratedFlorentine physician Guido Guidi(aka Vidus Vidius [1508-1569]) forthe Humanist library of François I and illustrated by the Flo-rentine artist Francesco Salviati (1510-1563) are exemplaryin this regard. This sublime work, published in 1544, was acrystallization of the scientific and artistic excellence to whichHumanists aspired. Reproduction of its plates throughout the16th century to adorn multiple works on allied topics, suchas those by the French royal surgeon Ambroise Paré (circa1510-1590), provide a perfect illustration of the disseminationof the Humanist movement.

Emergence and celebration of anatomy asa disciplineThe Renaissance updated the practice of anatomy to Human-ist times. Anatomical dissection, a practice inherited from An-tiquity, had been officially conducted in Italy since the 13thcentury and in France since the 14th century. The papal bullissued by Boniface VIII in the 13th century had secured its ap-proval by the Church for the sole purposes of legal autopsyand university demonstration.

At the start of the 16th century, dissection was only used in uni-versity teaching to illustrate the writings of Antiquity. Its roleand status grew steadily throughout the century. It began to beperformed outside universities, for instance, in independentcolleges, at the Collège de France, in schools of surgery, byprivate individuals (students and barber surgeons), and also byartists. The practice was almost always illegal, but generallytolerated. The details of cadaver provenance remain murky.Andreas Vesalius (1514-1564) is believed to have fetched hissupplies from the multistorey gibbet of Montfaucon in what is

now the 10th arrondissement of Paris. Other objects of dis-section included animals, colleagues, and even friends (whocould thus be said to have bequeathed their bodies to sci-ence!). An additional source of bodies was pauper cadaversfrom hospices.

The most remarkable expression of the new anatomy was themasterpiece by Vesalius, De humani corporis fabrica libri sep-tem. Published in 1543, the same year as De revolutionibusorbium coelestium by Copernicus, it incarnated the urge toquestion the all-powerful work of Galen and its reverential ex-ponents, which had begun at the turn of the century with thefirst pre-Vesalian anatomists: members of the Padua School,the English Humanist Thomas Linacre (circa 1460-1524), andthe Paris School, one of whose graduates, Charles Estienne(1504-1564), produced (some time before 1539) De dissec-tione partium corporis humani. This work was very similar toFabrica, except that unlike Vesalius, Estienne did not engagea pupil of Titian to take care of the illustrations.

Such fastidiousness was emblematic of the Vesalian revolu-tion: at the same time as Vesalius was insisting on the neces-sity of the teaching of anatomy and the superiority of hands-on experience over medical scripture and its associatediconography, he was calling on one of the great art work-shops of his day for illustrations, regardless of the expense.After all, it was the workshops of Leonardo da Vinci, Verroc-chio, Michelangelo, and Dürer that had pioneered the studyof anatomy, in terms of representing the human body, in thevery early Renaissance. These studies originated mainly from



Dissection scene fromDe Proprietaribus Rerum, by

Barthélemy l’Anglais (vellum). End 15thcentury. Bibliothèque Nationale, Paris.

© Archives Charmet/The BridgemanArt Library.



Scenes ofmedical lifeduring theRenaissance.Frontispiece ofDer GantzenArtzenei, by Jo-hann Eichmann(Dryander)(1500-1560),published byChristianEgenolph,1542, Frankfurtam Main. En-gravings out-side frame—upper left: doc-tor examining apatient’s urine;upper right:bloodletting;main engraving,clockwise fromtop left: examin-ing a bedriddenpatient; selec-tion, picking,and preparationof medicalherbs; discus-sion amongdoctors; apothe-cary preparingmedicines.© BIU Santé—Bibliothèque Inter-Universitaire deSanté, Paris.

Leonardo’s workshop and were unknown to immediate con-temporaries. But their direct influence was displayed for all tosee in Fabrica, in an explosion of magnificent yet elegant de-tail that symbolized the quest for meaning by an entire epochobsessed with the human body.

Anatomy thus came into its own in the 16th century, as pic-torial representation, descriptive treatise, and clinical method.It was to retain its central status for centuries to come. In ad-dition, by encouraging the investigation and elucidation ofthe human body, the commitment to research and empiricalmethod that drove Vesalius and those who came after himput clinical intervention and hands-on experience back intothe heart of medical practice, thereby opening the door tothe surgeons.

Surgical progress: the impact of the arquebusSurgery in the 16th century was marked by the beginning ofa rise in the social status of surgeons and the normalizationof their profession. In addition to celebrated anatomists andsurgeon-physicians such as Vesalius, a number of barbersurgeons helped their specialty to recover its scientific sta-tus. Under the direct challenge of their century’s two mainscourges—epidemics and the first firearms—these surgeonsled a revolution in surgery that extended way beyond thebattlefield and the hospitals where they practiced.

Battlefield surgeons such as Paré, their most celebrated rep-resentative, were also responsible for the extensive dissemi-nation of surgical knowledge. In direct contrast to the illiteratecaricatures disdained by faculty physicians, they producedsurgery and anatomy manuals in vernacular language, whichwere often richly illustrated and went hand in hand with Hu-manists’ dissemination of knowledge in similar areas.

It was the battlefield that generated the major surgical ad-vances of the 16th century. Surgeons routinely joined armyunits, replacing the charlatans that had been used up to thattime. Their presence was a necessary response to the in-creasing violence of battle due to the development of short-range firearms—the arquebus, then the musket—and the nov-el wounds they produced.

Paré introduced new methods of treating multiple wounds,and a new approach to firearm wounds. Like the personalphysician to Henri III, Laurent Joubert (1529-1582), the Swisssurgeon Félix Würtz (dates uncertain), and Hans von Gersdorf(circa 1455-1529) in Strasbourg, he also had an interest in am-putations, prostheses, and orthopedic corrective techniques,making some striking contributions in these fields. He pub-lished his studies in a large number of works with illustrations

combining realism, clarity, sobriety, and a talent for dissemi-nating knowledge. The works are also a treasure trove of thesurgical arsenal of the time, only very rare items of which havecome down to us. They are particularly valuable for identify-ing contemporary surgical implements because these can bedifficult to tell apart from the tools used by butchers, hunts-men, and even gardeners.



Anatomy of human veins and arteries. FromDe Humani Corporis Fabrica, by Andreas Vesalius,

published by J. Oporinus in Basle, 1543. © Wellcome Library.

Surgical instruments. From La Méthode Curative des Playes, etFractures de la Teste Humaine, by Ambroise Paré, published in1561 by Jehan le Roer, Imprimeur du Royès Mathématiques, Paris.© Wellcome Library.

Ordinary medical practiceOn the ground, far from the lofty heights of major surgery andanatomical research, there existed during the Renaissance,as at any other time, ordinary medical practice comprising aset of medical interventions and remedies. Patients were at-tended in their homes by all levels of practitioner, whether bythe prestigious doctors of medicine, who once atthe bedside mutated into practicing physicians,or by the humbler physicians themselves, alongwith their assistants (apothecaries, barbers, andstudents). The consultation consisted of elicit-ing and interpreting signs and symptoms, issu-ing recommendations as to diet or hygiene, per-forming medical interventions, and writing anextemporaneous prescription for medication.

In addition to the patient interview, the consulta-tion used the following techniques to elicit signsand symptoms: inspection and interpretation ofthe pulse, urine, and feces, and in some casesblood; and assessment of the patient’s “heat”(temperature), appearance, and complaints.Once interpreted, the condition could be treat-ed with a variety of interventions: bleeding, en-ema, and cauterization, selected according tothe most propitious planetary movement or signof the zodiac.

The documentary evidence for the ordinary medical practicedescribed above is fairly extensive. In particular, it is backed byan impressive catalogue of iconography. It is also document-ed in brilliant detail in the remarkable diary of Jean Héroard(1551-1628), physician to Louis XIII, which is held at the Bi-bliothèque nationale de France.

Apothecaries and their therapeutic arsenalDesigned to restore humoral harmony, the therapeutic arse-nal available in the Renaissance was boosted by new ingre-dients from the Americas (such as tobacco or the hardwoodlignum vitae) and by increasing trade relationships with oth-er distant lands. The basis of apothecary practice neverthe-less remained the Antidotarium by Nicholas of Salerno (12thcentury), along with numerous pharmacopoeias, compendia,and recipes.

The remedies made up by apothecaries against physicians’prescriptions fell into three main classes, termed “alterative,”“evacuative,” and “specific.” Although almost all were of plantor animal origin, some preparations were mineral (ie, metalssuch as the antimony prized by Paracelsus [1493-1541],pearls and precious stones, marble, crystal, chalk, and vari-ous earths) and a few were of human origin (eg, milk, blood,bone, urine, excrement, and a mellified human mummy con-fection known, in a variety of spellings, asmumie). Distillationwas increasingly used to obtain active ingredients and led toadvances in medicinal chemistry. Panaceas were taken as in-fusions, decoctions, tinctures, syrups, pills, preserves, and

confections (the most fa-mous of which was thetheriac of Andromachus[1st century] or theriacaAndromachi). Alternative-ly, they were applied top-



Philippus Theophrastus Aureolus Bombast von Hohenheim,or Paracelsus (1493-1541). Swiss physician, pharmacist, botanist,alchemist, and astrologer. Oil on wood, 72×54 cm. Paris, LouvreMuseum. © RMN/Hervé Lewandowski.

Theriac jar, 1641, Italy.Science Museum, London.Theriac was a syrupy medi-cine originally prepared inAncient Greece in the 1stcentury AD as an antidotefor animal bites and poison-ing, then as a panacea. It wasmade of over 60 ingredients,some highly exotic such asdried viper and opium, andused throughout Europe un-til the 18th century, and aslate as 1884 in France.© Science Museum, London/Wellcome Images.

ically as ointments, cerates, plasters, poultices, or eye salves;inserted as suppositories or pessaries; or pinned to the clothesor attached to the skin as powder-filled bonnets and sachets.

Explosion in the dissemination of medicalknowledgeThe discovery and rapid development of printing proved ex-traordinarily effective in disseminating medical science anddistributing the texts required for its practice: antidotaria; man-uals of surgery, day-to-day medicine, and pharmacy; and al-manachs of planetary movements and signs of the zodiac toguide the selection and timing of interventions. As Humanistscholars, physicians saw the dissemination of medical knowl-edge as an honorable mission. Writing in everyday languagealso made them accessible to humbler colleagues: French orGerman editions of works by Paracelsus, Jean-François Fer-nel (1497-1558), or Paré could be read by apothecaries and

barber surgeons. Humanist reinterpretations and republica-tions of works by the ancients (to which some physicians, suchas Niccolo Leoniceno [1428-1524], devoted themselves al-most exclusively) not only transmitted the knowledge inherit-ed from Classical antiquity along with some critical reflection,but were also paralleled by the dissemination of a rich bodyof contemporary literature that improved rapidly in terms ofillustrations and structure as the century unfolded. Thus, 16thcentury medicine may not have undergone a true Renais-sance, but it was nevertheless a true child of its time. View-ing its twin Classical and Medieval inheritance through theprism of Humanism, it inevitably reflected the influence of con-temporary religious and philosophical debate. In addition, itmanaged to bring about a synthesis of the key componentsin its heritage and, thanks to some remarkable men, to pre-pare the ground for the blossoming of modern Western med-icine the following century. �



THÉORIE ET PRATIQUE : LA MÉDECINE DANS L’EUROPE DE LA RENAISSANCE

Entre théorie et pratique, la médecine à la Renaissance opère une synthèse du savoir hérité de l’Antiquité et duMoyen Âge. Elle reçoit beaucoup de son passé mais innove également et va, de manière forte, vouloir se défairede ses limbes médiévales. Si l’on ne peut pas parler de Renaissance médicale au sens où l’on parle de Renais-sance des Arts, car la révolution en ce domaine se fera au siècle suivant, la médecine au siècle de la Renaissancen’échappe pas pour autant à la vague humaniste qui anime le siècle, et connaît de réels progrès. Alors quel’ébranlement du cosmos médiéval se produit avec la révolution copernicienne, que la Réforme bouscule ledogme catholique et questionne le rapport entre Dieu et les hommes, que l’on assiste à des progrès techniquesqui – imprimerie en tête – permettent une révolution du savoir et des pratiques sans précédent, la médecine os-cille entre un humanisme faisant preuve d’une extrême déférence envers les Anciens mais ouvrant enfin la porte àla critique textuelle et une pratique médicale progressivement décomplexée et enhardie par les fléaux du siècle :l’arquebuse et les épidémies. C’est en effet au XVIe siècle que les corps médicaux s’institutionnalisent etconstruisent le berceau de la médecine moderne, dans laquelle théorie et pratique se seront réconciliées.

MEDICOGRAPHIA, Vol 33, No. 3, 2011 Écouen: from château to museum, or Beauty is in the detail – Deprouw344


T he Château d’Écouen, a major Renaissance home built for one of themost important figures in 16th century France, Duke Anne de Montmo-rency, was converted into a museum at the behest of De Gaulle’s Min-

ister of Culture, André Malraux, and opened to the public in 1977. It has sincehoused the prestigious Renaissance collections from the former Cluny Mu-seum in Paris (now the French National Museum of the Middle Ages). Far fromconfining themselves to French art, these collections offer a rich panorama ofworks from Europe and parts of the world with which Europeans had forgedregular contact—the Near East, Africa, and America—from the Age of Discov-ery until the early 17th century. Whether in the form of tapestries, paintings,ceramics, stained glass, furniture, or gold and silverware, the same culturewas expressed through an infinite number of materials and colors, celebrat-ing Nature and creations of the mind in equal measure. The principles of theChâteau’s design set the tone for what awaits inside: symmetry and geome-try, set off by a skilled sense of decorative detail. Visitors who delve into thedetail of the collections will marvel at the challenges that artists and crafts-men set themselves in competing with one another and with Nature. Qualityof line and clarity of composition quickly became as crucial in identifying thebest artists—the finest painters, sculptors, and architects—as they were in de-termining their best artisan counterparts—the top embroiderers, goldsmiths,silversmiths, and enamel workers.


by S . Deprouw, France

Stéphanie DEPROUWFrench National Museum of theRenaissance, Écouen, FRANCE

TheChâteau d’Écouen,wherethe prestigious Renaissancecollections from the former

Cluny Museum in Paris (today theFrench National Museum of theMiddle Ages) are now held, wasconverted into a museum at thebehest of De Gaulle’s Minister ofCulture, André Malraux, andopened to the public in 1977. It ishome to a wide range of artwork—tapestries, paintings, ceramics,stained glass, furniture, gold an-tiques, and silverware—from theAge of Discovery until the early17th century.

Écouen: from châteauto museum, or Beauty is

in the detail

A ppointed in July 2009, Stéphanie Deprouw is the curator of the scientificinstrument and ceramic collections at the French National Museum of theRenaissance that includes pieces retrieved from Bernard Palissy’s Tuileries

workshop. As an archivist-paleographer with a master’s degree in history fromParis University I, specializing in the history of science, her training spans all as-pects of the Renaissance, from the intellectual to the technical. Having curated twoexhibitions at Écouen, one on a set of enamels by Léonard Limosin (2010), theother on Geoffroy Tory, printer to King Francis I of France (2011, along with the Na-tional Library of France), she is now devoting herself to the study of a masterpiecefrom Écouen's collections, the wire-drawing bench built for prince Augustus ofSaxony in 1565—see www.musee-renaissance.fr/bancdorfevre/.

©Allrightsreserved

Address for correspondence:Stéphanie Deprouw, Conservatricedu patrimoine, Musée national dela Renaissance, Château d’Écouen,95440 Écouen, France (e-mail:[email protected])


ocated1 20 km north of Paris, theChâteau d’Écouen was built in sev-eral stages beginning in 1538 for theFrench soldier, statesman, and diplo-mat Anne de Montmorency (1493-1567)—Anne being not uncommonat the time as a name for boys—shortly after his childhood friend,

King François I, appointed him Constable of France, a postthat combined the functions of First Officer of the Crown andCommander-in-Chief of the Army. Montmorency had the ex-isting medieval structure demolished to make way for an un-abashedly modern château on top of a hill overlooking the flatregion just north of Paris, known as the Plain of France.

A palace to host the Royal CourtA proponent of sustainable development centuries before theconcept was coined, Montmorency installed a particularly so-phisticated rainwater conveyance and harvesting system,much of it underground, to supply his vaulted bathrooms inthe basement of the north wing: this suite dedicated to relax-ation—after exertion following hunting or tennis, for example—is one of the last two remaining in France, the other being inthe Château de Maulnes in the department of Yonne. It epit-omizes the Château d’Écouen’s claim to refinement.

In opting for an architectural style that was both sober andradical—originally a square bounded by projecting rectangu-lar wings—the Château d’Écouen resembles the Châteaud’Ancy-le-Franc (Yonne) built by Sebastiano Serlio for Antoinede Clermont (1498-1578) during the same period (1542 toaround 1550). There is no record of Écouen’s first architect or


Écouen: from château to museum, or Beauty is in the detail – Deprouw MEDICOGRAPHIA, Vol 33, No. 3, 2011 345

TheChâteaud’Écouenin the fall.CourtesyMusée de laRenaissance.All rightsreserved.

Stone sewer drain, Château d’Écouen, circa 1540.© RMN Droits Réservés.

1Decorated initial from the Basel 1555 edition of Andreas Vesalius's DeHumani Corporis Fabrica published by Johannes Oporinus. Woodcut.© Wellcome Images.

project manager. Jean Bullant, who was to become Anne deMontmorency’s favorite architect and who later built the Pe-tit Château for him at Chantilly, appears only to have been in-volved at Écouen at a later stage (1552), when he redesignedthe staircase and north front to accommodate the frequentvisits of the King and his Court. The accounts of the château’sconstruction were unfortunately lost during the French Rev-olution, but we know that work continued on the château al-most until Montmorency’s death in 1567. Although built pri-marily for gracious living, the château remained defensive inappearance at least, in particular because of its moats, which

were dry from the outset. A distinctive feature of the buildingis the elaborate classical ornamentation of the windows set inthe sloping roof. The Constable’s coat of arms (a sword withthe motto “APLANOS”—“Unswerving”) is repeated all alongthe south wing, which housed his apartments and those ofhis wife, Madeleine de Savoie, on the second floor. Oppositethese apartments were the royal apartments, with Catherinede Médicis on the first floor and Henri II on the second floor.Each set of apartments was identified by the occupant’s re-spective coats of arms, a rainbow and double K for Catherineand an H double D (for “deux,” ie, second) for Henri.



Michelangelo’s Slaves in the courtyard of the Château d’Écouen. © Ferrante Ferranti. With kind permission.

As Constable, Montmorency was the second most impor-tant figure in the kingdom, as is borne out by the place of hisname next to Henri II’s signature on some royal decrees. Itwas therefore entirely appropriate for him to have a palacefit to receive a king. Henri was particularly close to Anne deMontmorency, who returned to royal favor after losing theconfidence of Henri’s father François I, following his failure tosecure the Duchy of Milan, a state in northern Italy from 1395to 1797, in his negotiations with the Holy Roman EmperorCharles V.

The château’s finest ornamental sculptures were the twoslave statues that Michelangelo had designed for the tombof Pope Julius II, but which he left unfinished. Two membersof the Florentine Strozzi family had acquired them fromMichelangelo and gifted them to the French king, Henri II,when requesting the protection of their cousin Catherine deMédicis. Gifted in turn to Montmorency by Henri II shortly af-ter he acceded to the throne in 1547, they were set in the re-cesses of the south wing’s courtyard portico. The originals,now in the Louvre, have been replaced by casts. The columnsflanking them, inspired by the Pantheon in Rome, are the firstrecorded example in France of the colossal order (spanningtwo floors).

Moving betweenhis home in Paris and hischâteaux atÉcouen,Chantilly, and Fère-en-Tardenois (Aisne)—the latter a weddingpresent from François I—Montmorency displayed the sameremarkable curiosity in each, along with a deep apprecia-tion of works of art. His collection included paintings by theFlorentine master Rosso Fiorentino (1494-1540), sculpturesby Jean Goujon (circa 1510 - circa 1572), painted enamels byLéonard Limosin (circa 1505 - circa 1577), illuminated man-uscripts and other sumptuously bound books, and items ofthe rare Saint-Porchaire pottery produced between the 1520sand 1540s, which were too Mannerist, light, and fragile to beof practical use.

Anne de Montmorency was also the first to discover the rus-tic potter, Bernard Palissy (circa 1510 - circa 1589), who foundinspiration in Saint-Porchaire ware. He commissioned Palissyto create a make-believe ceramic grotto, perhaps for the gar-dens at Écouen, except that it appears that it was never com-pleted. Partly as a result of his wide breadth of interest in art,Montmorency was one of the principal patrons of the FrenchRenaissance. Not only could he spot young talent, but heseems on occasion to have been instrumental in guiding theirchoice of subject matter. Although a fervent Catholic, he dis-played, like his Protestant rivals, a taste for the rarer Old Tes-tament subjects. He had these painted on the château’s fire-places by members of the family workshop, founded by JeanCousin the Elder (born in 1500). One example, the story ofJacob and Esau, relates to his own story as a younger sib-ling on whom destiny had smiled. Similarly in the chapel hecommissioned a relief, Abraham’s Sacrifice, from Goujon,

which has since been removed to the Château de Chantilly.The Château of Écouen comprised a gallery connecting theapartments of Madeleine de Savoie to those of the King, run-ning right the way along the west wing. The decoration of thisgallery was sumptuously colorful: stained glass windows toldthe story of Psyche; under foot were ornamental tiled floorsfrom the workshops of Masséot Abaquesne (circa 1500-1564) in Rouen; while the walls would have been hung withtapestries, not to mention the painted ceilings. The stainedglass and tiled floors are inscribed with the date “1542”. Acontemporary portrait of the château has come down to usin Les Plus Excellents Bastiments de France (1576-1579), apriceless work by the engraver-architect Jacques I Androu-et du Cerceau (circa 1515-1585) that depicts all the mostdaring architectural innovations of the French Renaissance.His engravings give us an idea of what the east wing musthave looked like. It was demolished at the end of the AncienRégime for esthetic reasons, and also no doubt because it hadbeen heavily damaged. The wing is believed to have containeda gallery with frescos by Nicolo dell’Abbate (died 1571) and amulticolored tiled floor. Through the portico could be glimpseda life-sized statue of Montmorency on horseback. There wasalso a tennis court built on sloping ground below the northwing, close to the bathing suite. Further below were the sta-bles, which now house municipal offices.



Painted fireplace in Anne de Montmorency’s bedroom (oil, mid-16th century, detail). © RMN/Gérard Blot.

The château remained in the family’s hands until the line wascut short in 1632 by the execution for lèse-majesté, treason,of Montmorency’s grandson, Henri. It then passed to theHouse of Joyeuse, ennobled by Henri III, and was subse-quently inherited by the House of Condé. It underwent fewmodifications apart from the demolition of the east wing. Thechâteau escaped the Revolution relatively unscathed, althoughit was put to various characteristically novel uses, such as apatriots’ club, a prison, and finally a hospital. It embarked ona new chapter, however, when Napoleon, in a decree datedDecember 15, 1805, turned it into a school for educating thedaughters of members of the Legion of Honor. He returnedthe Château to its original four-square design by building anew, but lower, east wing, which was designed by Antoine-François Peyre (1739-1823).

The building opened for the 1807 academic year. Except forthe period between 1814 and 1850, when ownership revert-ed to the House of Condé and it became increasingly neg-lected, the château has remained the official property of theLegion of Honor to this day. The marble courtyard, which wasno doubt in very poor condition, was repaved with the Le-gion’s arms at its center. Students were accommodated innew mezzanines and shielded from unhealthy thoughts by

the whitewashing of the painted chimney-pieces and grot-tesche friezes, thereby mercifully preserving them for poster-ity, save for some damage to the fireplaces caused by the in-sertion of stove pipes into the flues. The last students left thechâteau in 1962.

The sharing of the Château’s fate between the Houses ofMontmorency and Condé accounts for the presence at theChâteau de Chantilly of many artifacts and works of art fromÉcouen. Prince Henri, Duke of Aumale (1822-1897), who in-herited the lands and colossal wealth of the House of Condéat the tender age of 8, may have lost possession of the Châ-teau d’Écouen, but he was driven by a passionate interest inart and history. He amassed a superb collection in an attemptto retrieve and recreate his ancestors’ heritage. The collectionincluded books bound with the arms of Anne de Montmoren-cy, including Anne’s Book of Hours, but also, more strikingly,the stained glass windows from the Psyche gallery, Goujon’sbas-reliefs, wall tiling by Masséot Abaquesne, and the altarand stained glass windows that had adorned the chapel atÉcouen. In fact, the chapel at Chantilly sought to reproducethe dimensions and decorations of its counterpart at Écouen,which has fortunately been preserved and retains its fine ogi-val vaults, painted with the coats of arms of Anne de Mont-morency and his wife. Écouen was inaccessible to researchersduring the development of historical studies in French Renais-sance architecture. As a result, its virtues were never extolledin a full monograph or promoted as much as it deserved. Thefirst director of the museum, Alain Erlande-Brandenburg, pro-duced a useful introductory work. The current director, ThierryCrépin-Leblond, is working on a weightier presentation thatwill assemble all the available documentation and give a clear-er idea of the château’s interior design, which is still largelyunknown.



Detail of David and Bathsheba tapestry series, David’s adultery(Brussels, circa 1520). © RMN Droits Réservés.

Stainedglass with

angelholdinga shieldbearing

ConstableAnne deMont-

morency’sarms.16thcentury.© RMN/

Gérard Blot.

The Château d’Écouenas a showcase for nationalcollectionsThe French National Museum ofthe Renaissance is a youngmuseum, a contemporary ofthe Pompidou Center—bothopened to the public in1977. The idea of devotingthe Château d’Écouen toRenaissance civilizationwas for André Malraux, DeGaulle’s minister for cultur-al affairs, a solution to twoproblems.

It found a use for the château,which had stood silent since theacademy for young girls closed in1962, and it was a place to displaythe Renaissance collections from theMuseum of Cluny. The former Paris residenceof the abbots of Cluny had, since the 19th century,housed the collection built up by the archeologist AlexandreDu Sommerard (1779-1842), which comprised essentiallydecorative art works ranging from Greco-Roman antiquityto the end of the Middle Ages. After the Second World War,when all the works put into safekeeping had to be put backon display, it was decided to devote the Hôtel de Cluny ex-clusively to the Middle Ages. As a result, collections of worksfrom later periods remained in their crates for some 15 furtheryears, while the State looked for a suitable setting in whichto display them.

An initial proposal was theChâteau de Chambord, butMalraux rejected the idea ashe wanted to keep the mate-rial closer to Paris. Eventually,in 1972, the State agreed toan ultralong lease on Écouenwith the Legion of Honor, un-dertaking to upgrade thebuilding. As a result, the Min-istry of Cultural Affairs becameits quasi-proprietor. Écouenhad the advantage of pos-sessing the Gallery of Psyche,which was ideally suited fordisplaying a 75-meter master-piece, the Tapestry of Davidand Bathsheba (circa 1510-1515). After extensive con-version, a part of the Châteauopened as amuseum in 1977.

Subsequent work resulted in thenear-complete opening that wehave today, with 36 roomsopen to the public.

In addition to the tapestryalready mentioned, the col-lections reflect the varietyand complexity of Renais-sance art, principally fromEurope, but also from fur-ther afield. Striking examplesinclude ivory carvings fromPortuguese Africa, a feather

mosaic triptych created byAztecs under the Spanish occu-

pation, and, above all, a set of 400Ottoman ceramic pieces, the most im-

portant collection of Iznik ceramics in Europe.

The tastes of the Du Sommerard family were highly eclectic:painting, sculpture, tapestry and other textile work, weapons,precious metalwork, ceramics, glass, enamels, ironwork, fur-niture, marquetry, manuscripts, and scientific instruments.Only the graphic arts are truly underrepresented in the Mu-seum’s collections. Bolstered by the many pieces acquiredsince 1977, the collections total some 11 000 works, on topof which there are some 14 000 fragments from Bernard Pa-lissy’s ceramic workshop in the Tuileries that came to light

during the archeological ex-cavations of the Louvre in the1980s. With no real place forthem in the Louvre, they weretransferred to the Museum ofthe Renaissance to be stud-ied and displayed in a newset of rooms.

The Écouen collections rangefrom the rarest of objects topieces representative of ashared pan-European Re-naissance taste. The rare ob-jects are on a par with thosein the great museums in Eu-rope (the Victoria and AlbertMuseum and British Muse-um in London, the Dresdenmuseums, and the Kunst-his-torisches Museum in Vienna)or the United States (the Met-ropolitan Museum of Art in



Dish with intertwined flowers. Iznik, Turkey,circa 1580. © RMN/René-Gabriel Ojéda.

Ornamental ceramic floor from the Château de Polisy (Cham-pagne, 1545). © RMN/Stéphane Maréchalle/René-Gabriel Ojéda.

New York, Walters Art Museum in Baltimore,or the Philadelphia Museum of Art). Onesuch object is the famed silver-giltmechanical galleon made for HolyRoman Emperor Charles V (Nef deCharles Quint), an intricate clockcum automaton built by HansSchlottheim (1545-1625), aGerman goldsmith and clock-maker, of which there are onlythree extant models in theworld, the two others being atthe British Museum in Londonand the Kunst-historischesMuseum in Vienna. There is ofcourse a clock—though quitesmall, which a keen eye will dis-cover at the base of themiddle mast,with bells ringing the hours in the crow’snests. But this was a mere excuse for themechanical marvels displayed by the ship:set on a dinner table, with princely guests agog, itwould roll on wheels, playing mechanical music and firing itscannon, amidst flares and smoke, the sailors on board mov-ing and revolving to the beating of a drum and the blowingof trumpets.

The fact that the Écouen collection complements other ma-jor French collections so well (those in the Departments ofPainting, Sculpture, and Objets d’art in the Louvre, the Châ-teau de Fontainebleau Museum, the National Ceramics Mu-seum in Sèvres, the Army Museum, the Arts et Métiers Muse-um, etc) probably explains Écouen’s inclusion in the networkof French national museums.

In recent years, several major ac-quisitions have added to this coreof masterpieces. In particular,two tapestries from the Tapes-try of the Story of Diana pro-duced for Diane de Poitiersaround 1550, in a remarkablestate of preservation that setsoff their sharp colors to goodeffect. The second tapestry inthe set represents the birth ofApollo—the nymph Latona givesbirth to the god between a palm

tree and olive tree with help from hiselder twin Diana, a midwife already al-

though just born!

Another notable acquisition was the ornamentalflooring from the Château de Polisy in Champagne. This is askillful combination: a ceiling design published by the ItalianMannerist Sebastiano Serlio(1475- circa 1554) with alter-nating crosses, octagons, anddiamonds, each bordered bydifferent foliage, allegories ofvirtues engraved by a pupil ofAlbrecht Dürer, Georg Pencz(circa 1500-1550), and ancientand modern battle trophies,each encircled by strapworkdesign, broken by an ornamen-tal fleuron at each corner. De-signed for one of the bishops ofAuxerre, François de Dinteville,brother of the ambassador im-mortalized by Holbein a few yearslater (National Gallery, London.1533), the tiled floor suggeststhat attaining virtue is a slow pro-cess, even a struggle: “VIRTVTIFORTVNA COMES”—“Goodfortune attendant on virtue,” runsthe motto. This moralistic workwas acquired in 2008 as a na-tional treasure, thanks to a con-tribution from the AXA insur-ance group.



Pair of spectacles and pear-shaped leather case. France,17thcentury. © RMN/Stéphane Maréchalle.

The Judgment of Paris: reverse side of a paint-ed enamel dish by Léonard Limosin (1562,Limoges, France). © RMN/René-Gabriel Ojéda.

Embroidered silk sheathwith peacock.

Venice, late 16th century.© RMN/René-Gabriel Ojéda.



ÉCOUEN : DU CHÂTEAU AU MUSÉE, OU LA BEAUTÉ SE NICHE DANS LES DÉTAILS

Cet article évoque l’histoire d’un édifice majeur de la Renaissance, le château d’Écouen, construit pour l’un des per-sonnages les plus importants du royaume de France au XVIe siècle, Anne de Montmorency. Transformé en muséepar la volonté d’André Malraux, il a ouvert ses portes au public en 1977. Il accueille depuis lors les prestigieuses col-lections Renaissance du musée de Cluny qui, loin de se limiter à l’art français, offrent un panorama extrêmement va-rié de la création en Europe et dans les zones où les Européens avaient noué des contacts réguliers, au Proche-Orient, en Afrique et en Amérique, du temps des Grandes découvertes jusqu’au début du XVIIe siècle. Tapisseries,peintures, céramiques, vitraux, mobilier, orfèvrerie… à travers une infinité de matières et de couleurs, c’est la mêmeculture qui s’exprime, une culture du beau, célébrant la nature autant que les créations de l’esprit. Le décor du châ-teau donne le ton de ce que l’on peut découvrir à l’intérieur : symétrie, formes géométriques, complétés d’un sensaigu de l’ornement. En abordant les collections sous l’angle du détail, on se rend compte des défis que se sont lan-cés artistes et artisans, pour rivaliser entre eux et avec la nature. La qualité du dessin, la clarté de la composition de-viennent bientôt aussi cruciaux pour distinguer les excellents peintres, sculpteurs et architectes, que les orfèvres,brodeurs ou émailleurs.

Further reading– Androuet du Cerceau J. 1er. Les Plus Excellents Bastiments de France. 2 vol. Paris,France; Androuet du Cerceau J.; 1576 & 1579. Available online at http://www.richesheures.com to subscribers (€10/year).

– Arasse D. Le Détail. Pour une histoire rapprochée de la peinture. Paris, France:Flammarion; 1992.

– Béguin S, Délenda O, Oursel H.Cheminées et frises peintes du Château d’Écouen.Preface: Salet F. Paris, France: Réunion des Musées Nationaux, Musée Nation-al de la Renaissance; 1995.

– Crépin-Leblond L, ed. Album du Musée d’Écouen, Musée National de la Renais-sance. Paris, France: Réunion des Musées Nationaux, Musée National de la Ren-aissance; 2010.

– Erlande-Brandenburg A. The Château of Ecouen: The National Museum of theRenaissance. Paris, France: Réunion des Musées Nationaux & Albin Michel;1988.

– Ferranti F. Le château d’Écouen sous l'œil du photographe. Paris, France: Réu-nion des Musées Nationaux, Musée National de la Renaissance; 2010.

We need to don a pair of spectacles if we’re to do justice tothe quality of smaller works, such as a superb enameled dishby Léonard Limosin, bearing a discreet signature, “LL”, and thedate “1562” on the back; the obverse reproduces Raphael’sJudgment of Paris. Decorated with a female upper body inprofile serenaded by trumpeting putti, there is almost asmuch work on this side as on the other—a frequent char-acteristic of the Renaissance decorative arts, particularly inFrance. Smaller still is a sheath that typifies the extreme re-finement of Renaissance textile work, often difficult to appre-ciate today as most such pieces are worn or destroyed.

Far from being anecdotal, the detail inscribed on everydayobjects reflects a mentality preoccupied with the grandest ofprinciples. A marriage chest from the 1470s brings togetherthe moral lesson in Plutarch’s tale of Tiberius Gracchus—whosacrificed himself in order to save his much younger wifeCornelia—and the fashionable dress of the contemporaryFlorentine elite set against the backdrop of Santa MariaNovella just after its completion by Leone Battista Alberti(1404-1472), one of the first theoreticians of perspective.

It was in such decorative detail that Renaissance art so oftenstaged an ongoing dialogue of opposites, between internaland external, sacred and profane, large and small, natural and

artificial, typically recounted with wisdom and humor. Simi-larly, the essence of Écouen invites us to cross the multiplebridges leading to the tastes and skills of an era of culturalupheaval that remains our close and still recognizable fore-bear. �

Marriage chest (cassone) depicting the story of TiberiusGracchus and Cornelia (circa 1470). Attributed to Giovanni di

Ser Giovanni (1406-1486), Masaccio’s younger brother, known asLo Scheggia (“the Splinter”). © RMN/Gérard Blot.


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