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this issue

Medicographia
Vol 33, No. 3, 2011
108
A
Ser vier
publication
Chronic venous disease
guidelines and
daily clinical practice
E DITORIAL
231
Guidelines in chronic venous disease: providing clinicians with better
decision-making tools. Directives sur l’insuffisance veineuse chronique :
fournir aux cliniciens de meilleurs outils de décision
A. J. Comerota, USA
T HEMED
238
ARTICLES
Updating guidelines in chronic venous disease: what is needed?
C. Allegra, Italy
245
Chronic venous disease guidelines and terminology:
sharing a common language
M. R. Perrin, France, and B. Eklöf, Sweden
253
Prevalence and socioeconomic data in chronic venous disease:
how useful are they in planning appropriate management?
D. J. Milic, Serbia
259
Treatment of chronic venous disease: pathophysiological underpinnings
R. D. Malgor, N. Labropoulos, USA
268
Classifications, severity scorings, and chronic venous disease guidelines
ğ M. Aksoy, Turkey
M. Kurtoglu,
274
Current status of patient-reported outcomes and chronic
venous disease guidelines
A. Mansilha, Portugal
280
Rating the quality of evidence and the strength of recommendations:
the new GRADE system in venous disease
G. Le Gal, Z. Alavi, France
285
European and American guidelines on primary chronic venous disease:
what’s new?
J.-L. Gillet, France
Contents continued on next page
Medicographia
Vol 33, No. 3, 2011
108
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
293 Are chronic venous disease guidelines adapted to daily practice?
K. A. Aal, Egypt - H. S. Caldevilla, Argentina - R. Costa-Val, Brazil ğ ć,
H. S. Yuwono, Indonesia - H. N. T. H. Le, Vietnam - S. M. Kulisi
ğ Czech Republic Croatia - A. Puskás, Romania - K. Roztocil,
M. Salah, Saudi Arabia - I. S. Escotto, Mexico - J.-F. Uhl, France I. A. Zolotukhin, Russia
DAFLON 500
MG
306 The place of Daflon 500 mg in recent guidelines on the management of
chronic venous disease
F. Pitsch, France
I NTERVIEW
315 Are we any better at identifying the risk factors for chronic venous
disease progression?
M. Flour, Belgium
F OCUS
320 Identifying and accessing patients with chronic venous disease:
the large-scale VCP International Study
E. Rabe, Germany
U PDATE
325 Pain in chronic venous disease: perspectives for research
N. Danziger, France
A
TOUCH OF
F RANCE
334 Theory and practice: European Renaissance medicine
S. Daynes-Diallo, France
344 Écouen: from château to museum, or Beauty is in the detail
S. Deprouw, France
EDITORIAL
‘‘
For many years, the description of patients with venous disease
and measurement of outcomes
were subjective and arbitrary. Ambiguity in clinical descriptors led
to confusion and misunderstanding. Standardized nomenclature is
the first step in developing clear,
objective documentation and communication regarding patients, disease status, and outcome measures. Guidelines for venous disease
must begin with a standard nomenclature regarding the anatomy of
the venous system.”
Guidelines in chronic
venous disease: providing
clinicians with better
decision-making tools
b y A . J . C o m e rot a , U S A
hronic venous disease (CVD) is the most prevalent vascular disorder in
developed countries1,2 and it may be the single most common chronic
disease overall. Therefore, standard descriptors of the disease—its location, presentation, etiology, pathophysiology, impact on patients, response to therapy, and cost—are crucial, if not mandatory. Reporting standards
and 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 outcomes
of therapy for venous disease has lagged behind other disease categories.3 During the past several years, there has been growing interest in the development of
guidelines for venous anatomy (nomenclature),4 the description of patient presentation,5 the severity of venous disease,6-8 and the outcome measures following
therapy.9,10
C
Anthony J. COMEROTA
MD, FACS, FACC
University of Michigan
Michigan; Jobst Vascular Center
The Toledo Hospital
Toledo, Ohio, USA
Use of guidelines for disease description and measurement of treatment outcomes
is the first step in the process of implementing evidence-based care. Evidencebased medicine has been defined as “the conscientious, explicit, and judicious
use of the current best evidence in making decisions about the care of individual
patients.”11
This article highlights areas of standardized nomenclature, patient presentation,
severity of venous disease, and standardized and validated outcome measures
following therapy. It is hoped that all physicians will incorporate these guidelines
into their clinical care of patients with CVD.
Need for standard definitions
For many years, the description of patients with venous disease and measurement
of outcomes were subjective and arbitrary. Ambiguity in clinical descriptors led to
confusion and misunderstanding. Standardized nomenclature is the first step to
developing clear, objective documentation and communication regarding patients,
disease status, and outcome measures.
Address for correspondence:
Anthony J. Comerota, MD, FACS,
Jobst Vascular Center,
2109 Hughes Dr Suite 400,
Toledo, OH 43606, USA (e-mail:
marilyn.gravett@promedica.org)
Medicographia. 2011;33:231-237.
www.medicographia.com
N Anatomic nomenclature
Guidelines for venous disease must begin with a standard nomenclature regarding the anatomy of the venous system. Until 2002, the veins of the lower extremity were often incorrectly characterized, and physicians used numerous eponyms
to refer to specific veins. Caggiati et al 4 made an important contribution to the field
when they proposed a standard international nomenclature for the veins of the low-
Guidelines in CVD: providing clinicians with better decision-making tools – Comerota
MEDICOGRAPHIA, Vol 33, No. 3, 2011
231
EDITORIAL
er extremity. Examples of their contribution include precise
definitions of perforating veins, which penetrate the muscular fascia to connect superficial veins to deep veins, and
communicating veins, which connect veins within the same
compartment.
A major misnomer that existed for decades was the term
“superficial femoral vein,” referring to the major deep vein of
the thigh that connects the popliteal vein to the common
femoral vein. That vein is now appropriately termed the femoral
vein. Noninvasive imaging has led to our increased understanding of the saphenous subcompartment and saphenous fascia. Standardization of the terms “great saphenous
vein” and “small saphenous vein” has added greater clarity
to the superficial venous nomenclature.
The saphenofemoral junction, previously a major point of contention, is now called the confluence of the superficial inguinal
veins, which refers to that segment of the great saphenous
vein extending from the inferior epigastric vein to its junction
with the common femoral vein.
International nomenclature has discarded eponyms and renamed veins appropriately, according to proper anatomic
terms, eg, by replacing the name “vein of Giacomini” with “intersaphenous vein.”
This international nomenclature consensus statement4 is an
important reference that allows us to ensure that a standardized nomenclature is incorporated into all our communication
regarding patient care, clinical studies, and reports of patient
outcomes.
Standardizing investigations
Tools are necessary to build strong and enduring structures.
With few exceptions, the better the tools available, the more
rapidly the job is done and the more enduring the product.
Investigative tools have been developed to describe, characterize, and monitor the outcome of venous disease. Perhaps the most important metric is patients’ view of how the
SELECTED
ABBREVIATIONS AND ACRONYMS
CEAP
CIVIQ-20
CVD
SF-36
VCSS
VDS
VEINES-QOL
VSDS
232
Clinical-Etiological-Anatomical-Pathophysiological
ChronIc Venous dIsease quality of life
Questionnaire [20]
Short Form 36 [health survey]
Venous Clinical Severity Score
Venous Disability Score
VEnous INsufficiency Epidemiological and
economic Study–Quality Of Life
Venous Segmental Disease Score
disease has affected their life. Just as no single tool can build
a large and durable building, no single tool fully meets the
investigative needs in CVD.
It is appropriate to identify what is needed and then to choose
the appropriate instrument. Instruments can be broadly categorized into discriminative and evaluative instruments. A
discriminative instrument is one that clearly describes the
patient (current status of venous disease) and is capable of
identifying differences between patients, whereas evaluative
instruments are designed to detect changes over time, either
deterioration due to disease or improvement with treatment.12
Perhaps the best discriminative instrument available is the
CEAP (Clinical-Etiological-Anatomical-Pathophysiological)
classification. The CEAP classification describes the clinical
severity of a patient’s venous disease, its etiology, its anatomic location, and the patient’s underlying pathophysiology.5 Patients presenting with venous disease should be classified according to the CEAP classification.
One potential weakness of current discriminative instruments
is our inability to identify and quantify venous obstruction. Since
noninvasive evaluation of venous disease is now standard
for most patients, we know that imaging methods understate the magnitude of venous luminal obstruction (short of
showing venous occlusion), with the possible exception of
intravascular ultrasound. Noninvasive physiological testing
using maximal venous outflow techniques are notoriously insensitive at detecting venous obstruction13; much more work
is required to identify a noninvasive method to more clearly
delineate this element of venous pathophysiology.
Other deficiencies include our inadequate understanding of
the effects of venous disease on the microcirculation and why
microcirculatory dysfunction occurs in some patients and not
in others. This likely explains why there are different clinical
venous categories of CVD in patients with similar venous hemodynamics.14 It becomes evident that until we develop diagnostic techniques to assess these important end points,
classification systems that include pathophysiology as part
of their description will remain potentially inaccurate if not misleading.
A number of good evaluative instruments exist that can monitor changes in patients’ status over time and are responsive
to disease progression or therapeutic intervention. Each instrument should be carefully studied to ensure that it is valid
(capable of quantifying what it is intended to measure), reliable (produces consistent results when used repeatedly on
stable subjects), and responsive (capable of detecting clinically important changes).12 Two of the better evaluative instruments are the Venous Clinical Severity Score (VCSS)6,15 and
the Villalta scale.7,16 Other evaluative instruments focus on patients’ quality of life, arguably the most important outcome of
EDITORIAL
all. Examples include the SF-36 (Short Form 36 [health survey]),17,18 VEINES-QOL (VEnous INsufficiency Epidemiological
and economic Study–Quality Of Life),11 CIVIQ-20 (ChronIc
Venous dIsease quality of life Questionnaire [20]),19 and Aberdeen questionnaires.20
Adjuncts to the VCSS are the Venous Segmental Disease
Score (VSDS) and the Venous Disability Score (VDS).21 The
VSDS is designed to anatomically localize venous disease
and describe whether the identified segment has reflux or is
obstructed. Points have been arbitrarily assigned for each
segment. The VSDS has not yet been validated, and it is likely that further modification will be required after appropriate
prospective clinical studies are performed.
The VDS is a 4-point scale (4 categories) of disability ranging
from 0 (asymptomatic) to 3 (unable to carry out usual activities, even with compression and/or limb elevation). Like the
VSDS, the VDS requires validation. However, in light of its
broad categories and their limited number, the VDS is likely
to be insensitive as an evaluative instrument and more appropriately used as a descriptive measure.
Guidelines and the treatment of CVD
Objective outcome measures and guidelines for the management of patients with venous disease are more important now
than ever and will assume even greater importance in the
future. Management of patients with CVD is rapidly evolving
from open surgical procedures to endovascular techniques.
In patients with the most complex forms of CVD, hybrid procedures that include both open and endovascular components are being performed.22 To assess whether a particular
treatment is appropriate, reliable, standardized, and objective,
evaluation instruments are required. These should be prospectively applied to all patients; that is, prior to treatment, patients
should be objectively classified according to the CEAP classification and a validated quality-of-life instrument and a good
evaluative instrument should be used. Following treatment
at appropriate time intervals, evaluative and quality-of-life
measures should be repeated. These objective measures
can then be assessed and integrated into a cost analysis to
determine the true value of a treatment for specific patient
groups.
Handbook of Venous Disorders: Guidelines of
the American Venous Forum
An excellent source of guidelines for the clinician to follow is
the 3rd edition of the Handbook of Venous Disorders: Guidelines of the American Venous Forum, edited by Peter Gloviczki, MD.23 This is perhaps the best single volume of guidelines for the management of venous disease available today.
The handbook, comprised of 65 chapters divided into seven
sections, contains the latest information on epidemiology, basic science, and investigation of venous and lymphatic diseases, as well as modern venous imaging techniques. Both
acute and chronic venous diseases are covered, and the increasing enthusiasm for minimally invasive and endovenous
technology is appropriately addressed.
Perhaps the most important and enduring aspect of this volume is the addition to each chapter of evidence-based clinical guidelines regarding the evaluation and management of
venous disease. Evidence scores are given to assist the reader in assessing the strength of the evidence and the grade of
recommendation. In the final chapter, the volume culminates
with a list of all the evidence-based guidelines of the American Venous Forum.
Summary
The important topics in Medicographia No.108 are addressed
in a timely manner by an international collection of experts focusing on areas of venous disease in which they have a special interest and have made major contributions. The specific topics are important for all of us to recognize, as they will
have practical implications for the care of patients with CVD
as we move forward. I recommend this issue of Medicographia
to each of you and I am sure you will find it as valuable as I
have. I
References
1. Task Force on Chronic Venous Disorders of the Leg. The management of chronic venous disorders of the leg: an evidence-based report of an international task
force. Phlebology. 1999;14(suppl 1):1-126.
2. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous
insufficiency. 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 interdisciplinary
consensus statement. J Vasc Surg. 2002;36:416-422.
5. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for
chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:12481252.
6. Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH,
Moneta GL. Venous severity scoring: An adjunct to venous outcome assessment. J Vasc Surg. 2000;31:1307-1312.
7. Villalta S, Bagatella P, Piccioli A, Lensing AW, Prins M, Prandoni P. Assessment
of 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 scoring 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-related 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 quality
of 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 was
a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006;59:1049-1056.
12. Guyatt G, Walter S, Norman G. Measuring change over time: assessing the usefulness of evaluative instruments. J Chronic Dis. 1987;40:171-178.
13. Comerota AJ, Katz ML, Grossi RJ, et al. The comparative value of noninvasive testing for diagnosis and surveillance of deep vein thrombosis. J Vasc Surg.
1988;7:40-49.
233
EDITORIAL
14. Welkie JF, Comerota AJ, Katz ML, Aldridge SC, Kerr RP, White JV. Hemodynamic deterioration in chronic venous disease. J Vasc Surg. 1992;16:733-740.
15. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the venous clinical severity score. J Vasc Surg. 2002;36:889-895.
16. Kahn SR. Measurement properties of the Villalta scale to define and classify the
severity 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 Manual for Users of Version 1. 2nd ed. Boston: The Health Institute, New England
Medical Center; 2001.
18. Garratt AM, Ruta DA, Abdalla MI, Russell IT. Responsiveness of the SF-36 and
a condition-specific measure of health for patients with varicose veins. Qual Life
Res. 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 Endovasc Surg. 2010;40:783-789.
20. Garratt AM, Macdonald LM, Ruta DA, Russell IT, Buckingham JK, Krukowski
ZH. Towards measurement of outcome for patients with varicose veins. Qual
Health Care. 1993;2:5-10.
21. Rutherford RB, Padberg FR, Comerota AJ, Kistner RL, Meissner MH, Moneta
GL. Venous Outcomes Assessment. In: Gloviczki P, Yao JS, eds. Handbook
of Venous Disorders. 2nd ed. London, UK: Hodder Arnold; 2001:497-508.
22. Comerota AJ, Grewal NK, Thakur S, Assi Z. Endovenectomy of the common
femoral vein and intraoperative iliac vein recanalization for chronic iliofemoral
venous occlusion. J Vasc Surg. 2010;52:243-247.
23. Gloviczki P, ed. Handbook of Venous Disorders. 3rd ed. London, UK: Oxford
University Press; 2009.
Keywords: guidelines; chronic venous disease; decision-making
234
ÉDITORIAL
‘‘
La description des symptômes de l’insuffisance veineuse
chronique (IVC) et la mesure des
résultats thérapeutiques ont longtemps été subjectives et arbitraires.
L’ambiguïté des descriptions cliniques a conduit à la confusion et
aux méprises. Une nomenclature
standardisée, en particulier concernant l’anatomie du système veineux, constitue le préalable à une
documentation et communication
claires et objectives sur les patients, le stade de la maladie et les
critères d’évaluation, et donc aux
directives pour l’IVC »
Directives sur l’insuffisance
veineuse chronique : fournir
aux cliniciens de meilleurs
outils de décision
p a r A . J . C o m e rot a , É t a t s - U n i s
L’
insuffisance veineuse chronique (IVC) est l’affection vasculaire la plus fréquente dans les pays développés1,2, et pourrait constituer la pathologie
chronique 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 réponse
au traitement et les coûts, sont essentielles, si ce n’est obligatoire. Les normes et les
directives de notification des paramètres précédents organisent l’évaluation et le
traitement des patients, standardisent la nomenclature et offrent des outils d’évaluation de la sévérité et de l’histoire naturelle de la maladie, ainsi que de la réponse
au traitement. Malheureusement, l’expression des résultats thérapeutiques dans
l’insuffisance veineuse est restée en retrait par rapport aux autres domaines pathologiques 3. Au cours de ces dernières années, un intérêt croissant est né pour le
développement de directives sur l’anatomie veineuse (nomenclature) 4, la description du tableau clinique5, la sévérité de l’insuffisance veineuse 6-8, et la mesure des
résultats thérapeutiques 9,10.
L’utilisation de directives pour la description de la maladie et la mesure des résultats
thérapeutiques est le premier pas dans le processus de mise en œuvre des soins
factuels. La médecine factuelle est définie comme « l’utilisation consciencieuse,
explicite et judicieuse des meilleures preuves actuelles dans la prise de décision
pour les soins prodigués aux patients11. » Cet article présente certains aspects d’une
nomenclature standardisée, du tableau clinique, de la sévérité de l’insuffisance veineuse et des mesures standardisées et validées des résultats thérapeutiques. Il faut
espérer que tous les médecins tiendront compte de ces directives dans les soins
qu’ils prodigueront à leurs patients atteints d’IVC.
Nécessité de définitions standard
Depuis de nombreuses années, la description des symptômes de l’insuffisance
veineuse et la mesure des résultats thérapeutiques étaient subjectives et arbitraires.
L’ambiguïté des descriptions cliniques a conduit à la confusion et à l’incompréhension. Une nomenclature standardisée constitue la première étape pour développer
une documentation et une communication claires et objectives sur les patients, le
stade de la maladie et les critères d’évaluation.
N Nomenclature anatomique
Les directives sur l’insuffisance veineuse doivent débuter par une nomenclature
standard concernant l’anatomie du système veineux. Jusqu’en 2002, les veines des
membres inférieurs ont été souvent caractérisées de manière incorrecte, et les mé-
Directives sur l’IVC : fournir aux cliniciens de meilleurs outils de décision – Comerota
235
ÉDITORIAL
decins ont utilisé de nombreuses appellations éponymes pour
désigner certaines veines spécifiques. Caggiati et al.4 ont apporté une contribution importante à ce domaine en proposant une nomenclature internationale standard pour les veines
des membres inférieurs. Citons par exemple dans cette contribution des définitions précises des veines perforantes, qui
pénètrent les aponévroses musculaires pour connecter les
veines superficielles aux veines profondes, et les veines communicantes, qui connectent les veines appartenant au même
compartiment.
L’un des principaux termes impropres utilisés depuis des décennies concernait la « veine fémorale superficielle », qui faisait référence à la principale veine profonde de la cuisse qui
connecte la veine poplitée à la veine fémorale commune. Cette
veine porte désormais l’appellation appropriée de veine fémorale. L’imagerie non invasive a permis d’améliorer notre
connaissance du sous-compartiment saphène et de l’aponévrose saphène. La standardisation des termes « veine grande
saphène » et « veine petite saphène » a apporté une plus
grande clarté à la nomenclature des veines superficielles.
La jonction saphéno-fémorale, un point litigieux important auparavant, est désormais dénommée « confluence des veines
inguinales superficielles », faisant ainsi référence au fait qu’un
segment de la veine grande saphène s’étend de la veine épigastrique inférieure jusqu’à sa jonction avec la veine fémorale
commune.
La nomenclature internationale a éliminé les éponymes et a
renommé les veines de façon appropriée, en leur donnant des
termes anatomiques propres, par exemple en remplaçant le
nom de « veine de Giacomini » par « veine intersaphène ».
Cette déclaration de consensus concernant une nomenclature internationale 4 est une référence importante qui nous permet d’assurer qu’une nomenclature standardisée sera utilisée dans toutes nos communications concernant les soins
aux patients, les études cliniques et les notifications de résultats thérapeutiques.
Il convient d’identifier ce qui est nécessaire, puis de choisir
l’instrument approprié. Les instruments peuvent être classés globalement en instruments de distinction et d’évaluation. Un instrument de distinction permettra de décrire clairement le patient (stade actuel de l’insuffisance veineuse) et
d’identifier les différences entre les patients, tandis qu’un instrument d’évaluation sera conçu pour détecter des changements au cours du temps, ou une détérioration due à la maladie ou une amélioration apportée par le traitement 12.
La classification CEAP (clinique – étiologique – anatomique –
physiopathologique) peut être considérée comme le meilleur
instrument de discrimination disponible. La classification CEAP
décrit la sévérité clinique de l’insuffisance veineuse, son étiologie, sa localisation anatomique et les processus physiopathologiques sous-jacents chez le patient 5. Tous les patients
présentant une insuffisance veineuse devraient être classés
avec la classification CEAP.
L’une des faiblesses potentielles des instruments actuels de
distinction est notre incapacité à identifier et quantifier l’obstruction veineuse. Dans la mesure où l’évaluation non invasive
de l’insuffisance veineuse est désormais la norme pour la
plupart des patients, nous savons que les méthodes d’imagerie minimisent l’ampleur de l’obstruction luminale veineuse
(réduction de l’importance de l’occlusion veineuse), à l’exception éventuelle de l’échographie intravasculaire. Il est
également établi que les épreuves physiologiques invasives
utilisant les techniques de débit veineux maximal ne sont pas
sensibles à la détection de l’obstruction veineuse 13 ; beaucoup d’efforts doivent encore être accomplis pour identifier
une méthode non invasive permettant de définir clairement
cet élément de la physiopathologie veineuse.
Des outils sont nécessaires pour élaborer des structures fortes
et durables. À quelques exceptions près, plus les outils sont
efficaces, plus le travail est fait rapidement et plus le produit
est durable.
Les autres inconvénients comprennent notre mauvaise compréhension des effets de l’insuffisance veineuse sur la microcirculation, et les raisons de la survenue d’un dysfonctionnement microcirculatoire chez certains patients et non chez
d’autres. Cela explique vraisemblablement pourquoi il existe
différentes catégories cliniques d’IVC chez des patients présentant des caractéristiques hémodynamiques veineuses
similaires 14. Il est certain que, jusqu’à ce que nous développions des techniques diagnostiques permettant d’évaluer ces
critères importants, les systèmes de classification incluant la
physiopathologie dans leur description resteront potentiellement inexacts, si ce n’est trompeurs.
Des outils d’investigation ont été développés pour décrire, caractériser et contrôler l’évolution de l’insuffisance veineuse.
L’une des mesures peut-être la plus importante est l’opinion
des patients concernant la manière dont leur maladie a affecté
leur vie. Exactement de la même manière qu’un seul outil ne
permet pas de construire un édifice important et durable, de
même aucun outil isolé ne pourra répondre aux besoins d’investigation dans l’IVC.
Un certain nombre d’instruments d’évaluation satisfaisants
permettent actuellement de surveiller l’évolution de l’état des
patients avec le temps, et sont sensibles à une progression
de la maladie ou à une intervention thérapeutique. Chaque
instrument doit être étudié avec attention pour s’assurer de
sa validité (capacité de quantifier ce qu’il est supposé mesurer), fiable (produisant des résultats constants lorsqu’il est
utilisé de façon répétée chez des sujets stables) et sensible
Standardiser les investigations
236
ÉDITORIAL
(en mesure de détecter des changements cliniquement importants)12. Deux des meilleurs instruments d’évaluation sont
le score de sévérité clinique de l’insuffisance veineuse ( Venous Clinical Severity Score, VCSS) 6,15 et l’échelle de Villalta 7,16.
D’autres instruments d’évaluation portent sur la qualité de vie
du patient, qui peut être considérée comme le paramètre le
plus important, par exemple : le questionnaire de santé SF-36
(Short Form 36)17,18, le questionnaire de l’étude épidémiologique et économique sur l’insuffisance veineuse – qualité
de vie ( VEnous INsufficiency Epidemiological and economic
Study–Quality Of Life, VEINES-QOL)11, le questionnaire de
qualité de vie dans l’insuffisance veineuse chronique (ChronIc
Venous dIsease quality of life Questionnaire, CIVIQ-20 [20])19,
et le questionnaire d’Aberdeen 20.
Deux outils supplémentaires complètent le VCSS, le score
segmentaire de l’insuffisance veineuse ( Venous Segmental
Disease Score, VSDS) et le score d’incapacité veineuse ( Venous Disability Score, VDS)21. Le VSDS est conçu pour localiser anatomiquement l’insuffisance veineuse et décrire si le
segment identifié présente un reflux ou une obstruction. Des
points ont été arbitrairement assignés à chaque segment. Le
VSDS n’a pas encore été validé, et il est probable que certaines modifications seront nécessaires après la réalisation
des études cliniques prospectives appropriées.
Le VDS est une échelle en 4 points (4 catégories) pour l’évaluation de l’incapacité, comprise entre 0 (asymptomatique)
et 3 (incapable d’effectuer les activités usuelles, même avec
une compression et/ou une élévation des membres). Comme
le VSDS, le VDS nécessite une validation. Cependant, compte
tenu de ses larges catégories et de leur nombre limité, le VDS
ne sera probablement pas assez sensible comme instrument
d’évaluation, et sera utilisé de façon plus appropriée comme
mesure descriptive.
Directives et traitement de l’IVC
Des mesures objectives des résultats thérapeutiques et des
directives pour la prise en charge des patients atteints d’insuffisance veineuse sont aujourd’hui plus importantes que
jamais, et le seront encore davantage à l’avenir. La prise en
charge des patients atteints d’IVC évolue rapidement des
procédures chirurgicales ouvertes vers les techniques endovasculaires. Chez les patients souffrant de formes plus complexes d’IVC, des procédures hybrides comprenant des composantes ouvertes et endovasculaires sont actuellement
réalisées 22. Afin d’évaluer si un traitement particulier est approprié, fiable, standardisé et objectif, des instruments d’évaluation sont nécessaires. Ils devront être appliqués de façon
prospective à tous les patients ; cela signifie qu’avant le traitement les patients devront être classés de manière objective selon la classification CEAP, et qu’un instrument de qualité de vie validé et un instrument d’évaluation satisfaisant
devront être utilisés. Après le traitement, à intervalles déterminés, les mesures d’évaluation et de qualité de vie devront
être répétées. Ces mesures objectives pourront ensuite être
évaluées et intégrées dans une analyse coût-efficacité afin de
déterminer la valeur réelle d’un traitement dans des groupes
de patients spécifiques.
Manuel des troubles veineux : directives du
forum américain sur l’insuffisance veineuse
Une excellente source de directives pour le clinicien se trouve
dans la troisième édition du Manuel des troubles veineux : Directives du Forum Américain sur l’insuffisance veineuse (Handbook of Venous Disorders: Guidelines of the American Venous Forum), de Peter Gloviczki, MD 23. Il s’agit peut-être du
meilleur ouvrage sur les directives relatives à la prise en charge
de l’insuffisance veineuse disponible aujourd’hui. Le manuel,
composé de 65 chapitres divisés en sept parties, contient
les informations les plus récentes sur l’épidémiologie, les données scientifiques fondamentales et l’investigation des maladies veineuses et lymphatiques, et sur les techniques d’imagerie veineuse modernes. Les maladies veineuses aiguës et
chroniques y sont traitées, et le livre rend compte de l’enthousiasme croissant suscité par les techniques mini-invasives
et endoveineuses.
L’aspect le plus important et pérenne de ce manuel pourrait
être l’ajout à chaque chapitre des directives cliniques factuelles concernant l’évaluation et la prise en charge de l’insuffisance veineuse. Les scores de preuves sont fournis pour
aider le lecteur à évaluer le niveau de la preuve et la classe
de recommandation. Dans son dernier chapitre, le livre présente une liste de l’ensemble des directives factuelles de
l’American Venous Forum.
Résumé
Les sujets importants abordés dans le nº 108 de Medicographia sont traités à point nommé par un groupe international
d’experts spécialisés dans le domaine de l’insuffisance veineuse, et auquel ils ont apporté des contributions majeures.
Les sujets spécifiques sont particulièrement importants, car ils
nous font comprendre qu’ils auront des applications pratiques
dans les soins des patients atteints d’IVC à l’avenir. Je recommande fortement à chacun d’entre vous la lecture de ce numéro de Medicographia, et je suis persuadé qu’il suscitera
pour vous autant d’intérêt qu’il en a fait naître chez moi. I
237
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The setting up of the CEAP
classification and its adjuncts was
a great leap forward in the management of CVD. The CEAP classification can be used by physicians
to keep records of diagnostic information, while the adjuncts to
CEAP (VCSS, VSDS, and VDS) are
scoring schemes that are quantifiable and include elements that
change in response to treatment.
These instruments may be used
to evaluate any stage of CVD in
patients, although they are imperfect in the early stages.”
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Updating guidelines
in chronic venous disease:
what is needed?
b y C . A l l e g ra , I t a l y
C
Claudio ALLEGRA, MD
Servizio di Angiologia
Ospedale San Giovanni
Rome, ITALY
hronic venous disease (CVD) is a highly prevalent disorder among populations of Western countries and one with which both general practitioners and specialists have to deal. A lack of precision in the description of CVD, which induces pain, discomfort, and significant deleterious
alterations to the quality of life of affected patients, and in the reporting of
study results had led to conflicting conclusions and to a poor understanding
of the management of this venous pathology. The rectification of these failings was the spur for the current efforts of the medical community to better
define the field of CVD, to clarify the anatomical and clinical terminology and
nomenclature, to standardize investigations, and to introduce new therapeutic approaches, which will be highlighted in this article. In addition, to these
major prerequisites for developing venous disease guidelines, it has been acknowledged that adequate prevalence data are needed to better grasp the
magnitude of the problem, together with knowledge of the underlying mechanisms of the manifestations of venous disease in order to develop appropriate therapies. For the production of a set of guidelines, a universal consensus on the assessment tools needed to measure treatment-induced changes
using either physician-generated tools or patient questionnaires is mandatory, but some of these tools remain to be validated. Last but not least, an
optimal grading system that is easily understood by all clinicians is the main
tool required, so that any guidelines proposed are accepted by the medical
community.
Medicographia. 2011;33:238-244 (see French abstract on page 244)
ecause the venous system is in many respects more complex than the arterial 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 that
no consensus on guidelines is possible without the sharing of a common international scientific language for the investigation and management of CVD.
B
Claudio Allegra, MD, Ospedale
San Giovanni, Servizio di Angiologia,
Via S. Giovanni Laterano 155,
00184 Rome, Italy
(e-mail: allegra@mclink.it)
238
What is also important for building guidelines is to have reliable prevalence data
that can serve as a valuable basis for the planning of appropriate actions to deal with
problems, and by repeating an epidemiological survey within a defined geographical area to allow the assessment of the effect of treatment changes. Better knowl-
Updating guidelines in chronic venous disease: what is needed? – Allegra
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edge of the underlying mechanisms of CVD will create the
basis for correctly targeted treatment and, in a certain way,
will improve the recommendations in guidelines. In addition,
validated assessment tools to measure changes to treatment
and their proper use would improve the management of CVD.
A rigorous system for rating the quality of evidence and grading the strength of a recommendation has to be used in order
to offer proper recommendations to the clinical community
that are easy to understand, transparent, and pragmatic. This
is challenging.
Outcomes, which consists of three scores: the Venous Clinical Severity Score (VCSS) that includes 10 hallmarks of venous disease that are likely to show the greatest change in
response to therapy and are scored on a scale of severity
graded 0-3; the Venous Segmental Disease Score (VSDS),
which uses the anatomical and pathophysiological classifications of the CEAP system to generate a grade based on
venous reflux or obstruction; and the Venous Disability Score
(VDS), which assesses the ability to work with or without a
“support device.”7
All the above aspects are of the utmost importance for guidelines to be adopted and will be reviewed in the present article.
VCSS, one of the components of the VSSS, has been studied and shown to be valid, in that its score increases in a linear fashion with CEAP clinical class, and VCSS is reliable, as
demonstrated in tests of intraobserver variability.8 A change
in the score of this instrument could therefore be used as an
outcome measure to assess treatment. Unfortunately, the responsiveness of VCSS has not been adequately evaluated;
therefore, it cannot as yet be used to calculate sample sizes
for clinical trials.
Terminology, classifications, and severity scoring
of CVD
A great leap forward, a consensus on the use of common
venous anatomical terminology1-3 for a standardized classification system—CEAP (Clinical-Etiological-Anatomical-Pathophysiological)—and on the use of duplex ultrasound investigation to assess the anatomy of superficial and perforating
veins by ultrasound imaging4 and its derivatives has now been
universally adopted, which has facilitated and improved communication on and served as a foundation for the accurate
reporting of the severity of CVD.3,5,6
Because the CEAP classification is descriptive, with static
components that do not change in response to treatment,
it cannot be used for venous severity scoring. As a result, a
Venous Severity Scoring System (VSSS) has been proposed
by the American Venous Forum (AVF) Ad Hoc Committee on
SELECTED
ACCP
AVF
AVVQ
CEAP
American College of Chest Physicians
American Venous Forum
Aberdeen Varicose Veins Questionnaire
CIVIQ
ChronIc Venous dIsease quality of life Questionnaire
CVD
GRADE
Grading of Recommendations Assessment,
Development and Evaluation
MOS SF-36 Medical Outcome Study health survey Short
Form 36
PREVAIT
PREsence of Varices (residual or recurrent) After
InTervention
QOL
quality of life
RCT
randomized controlled trial
VCSS
VDS
VEINES
VEnous INsufficiency Epidemiological and
economic Study
VSDS
VSSS
Venous Severity Scoring System
Updated definitions of terms related to CVD by the Vein-Term
Transatlantic Interdisciplinary Consensus Group of international experts have decreased problems of interpretation and
improved communication and reporting in the investigation
and management of CVD.9 The consensus document includes
33 broadly used venous terms relating to the management of
CVD of the lower extremities, which were agreed to have variable applicability and interpretation in reports in venous literature. The terms selected for inclusion in the VEIN-Term consensus document are stratified into three different groups:
clinical, physiological, and descriptive. It is worth noting that
13 terms had not to our knowledge been previously defined in
venous literature. They are: the acronym PREVAIT (PREsence
of Varices (residual or recurrent) After InTervention), axial reflux,
venous occlusion, venous obstruction, venous compression,
recanalization, iliac vein obstruction syndrome, venous ablation, perforating vein interruption, perforating vein ligation, perforating vein ablation, miniphlebectomy, and sclerotherapy.
Some commonly used terms, such as chronic venous disorders, chronic venous disease, and chronic venous insufficiency, were clarified for the first time and given disease stage
limits. For instance, a consensus was reached for the term
“chronic venous insufficiency,” which covers patients from C3
to C6 of the CEAP classification; some doctors had until then
used it to describe C4 to C6 patients, while others had used
it for all patients, whatever their stage of CVD. The frequently encountered term “venous symptoms,” which had a very
vague definition, has now been given the description: “Complaints related to venous disease, which may include tingling,
aching, burning, pain, muscle cramps, swelling, sensations of
throbbing or heaviness, itching skin, restless legs, leg tiredness, and/or fatigue. Although not pathognomonic, these
may be suggestive of CVD, particularly if they are exacerbat-
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ed by heat or worsen during the course of the day, and are relieved by leg rest and/or elevation.” The VEIN-Term consensus document is intended to clarify venous terminology. It is
to be hoped that it will result in a more precise use of venous
terms in English-language articles and guidelines on CVD in
the future. Nevertheless, one challenge still remains, and that
is to translate the English definitions as accurately as possible into other languages for national documents. This is not
easy, although it has already been done for CEAP classification and anatomic nomenclature. Lastly, VEIN-Term has not
covered all the imprecise terms in phlebology, and further
refinements are needed to complete this work.
Prevalence data
CVD is a common condition with a major socioeconomic impact due to its high prevalence. The cost of CVD includes its
investigation, its treatment, and the loss of working days of the
afflicted patients.10 Mild forms of venous disease, such as
reticular veins and telangiectasias, are present in 80%-85%
of the population, while varicose veins are present in 40% of
men and 60% of women and ankle edema in 7% of men and
16% of women.11 Venous ulceration occurs in 0.3% of the
population on an annual basis and approximately 1% of the
population in Western countries has either an active or healed
venous ulcer.10-12 The prevalence of CVD increases with age.
Age can be considered a “dose-related risk factor,”10,11 but
varicose veins are not restricted to adults: 27% of the school
children between the ages of 10 and 16 years old in the Bochum study (from 11 German secondary schools)13 presented with varicose disease. From a French survey in 199914 of
representative samples of the adult population aged 15 and
over, it appeared that almost half this population suffered from
lower-limb venous complaints and that 43% of them were
untreated.
The proportion of patients presenting with chronic venous
symptoms increases in a linear fashion with increasing clinical scale of the CEAP classification.6 Quality-of-life (QOL) studies have shown that CVD is associated with increased pain,
reduced physical function and mobility, and increased feelings
of depression and social isolation,15 and QOL assessment is
directly associated with the severity of venous disease.16 Patients who have or have had venous ulcers report a QOL similar to patients suffering from congestive heart failure.17
N Why are prevalence data important?
Epidemiological studies are used to assess the prevalence
(occurrence) of diseases or disorders within populations in order to establish the magnitude of a certain problem. Usually
cross-sectional studies have been used to assess the number of patients with a certain disease within the health-care
system. Large random samples have been used to assess
populations and have the advantage of including people who
self-treat. Prevalence data from such studies serve as a valuable basis for the planning of appropriate action(s) to deal
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with a problem, in this case venous leg ulcers. By repeating
a prevalence study within a defined geographical area, we
have a unique opportunity to assess the effect of treatment
changes.18
There are many pitfalls in performing a prevalence study of
venous leg ulcers that can introduce a risk of misinterpretation 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 a
smaller population. Validation of all or a randomly selected
sample of the reported patients is mandatory to determine
the number of false positives and to establish the diagnosis,
which is usually done nowadays by performing a duplex scan
investigation in combination with a clinical examination.19 Without objective validation, there is a high risk of overestimating
the prevalence of CVD.
The use of only the “C” of CEAP, as is usually done in prevalence studies, presents weaknesses because of the difficulty in distinguishing between C1 and C2 patients, as shown
by the wide variation in disease prevalence in epidemiological studies from one paper to another 20; it is not clearly stated in the CEAP classification whether the edema of C3 patients is a permanent edema (ie, a preliminary stage leading
to skin changes and CVD complications) or if it is a reversible
edema that occurs at the end of the day and disappears after rest.20-22 Despite corona phlebectatica (corona) being a
clinical sign associated with CVD, it is not yet included in the
CEAP classification. Corona is defined by fan-shaped intradermal telangiectasias in the medial and sometimes lateral
portions of the ankle and foot. It has been shown that corona strongly correlates with the clinical severity and hemodynamic disturbances of the disease.23 The inclusion of corona in the C3 class would probably improve the reliability of
the clinical classes of CEAP.
Pathophysiology of CVD
Understanding the pathophysiology of a disease state is basic to effective treatment. Results from studies that demonstrate treatment efficacy lead to guideline recommendations.
CVD is defined as: “morphological and functional abnormalities of the venous system of long duration manifested either
by symptoms and/or signs indicating the need for investigation and/or care.”9 It is caused by venous valvular incompetence with or without associated venous outflow obstruction, which may affect the superficial venous system, the deep
venous system, or both. Venous dysfunction may result from
either a congenital or an acquired disorder. CVD is the consequence of venous hypertension.
Chronic venous hypertension leads to disturbances of the
microcirculation, which is responsible for exchange with interstitial tissues. This results in a local inflammatory reaction,
which is associated with an increase in capillary permeability
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and fragility. The lymphatic system can compensate for the
increase in fluid outflow into the surrounding tissues in the
early stages of the disease.24,25 However, if CVD persists or
worsens, edema develops because the lymphatic system becomes overloaded and can no longer handle the drainage of
excess fluid. Studies of the mechanism of tissue injury at the
different stages of CVD show how changes in venous pressure and hemodynamic forces (particularly fluid shear stress,
the force exerted on venous walls that is predominantly linked
to blood speed) lead to cellular and biochemical disorders.
Of the various instruments that are available to physicians to
measure symptoms such as pain, the most widely validated
is the 10-cm visual analogue scale. This type of scale provides
patients with an easy and rapid means to express the intensity of their pain and has numerous applications, including in
CVD. Other types of scale, such as numerical rating scales, are
usually graded from 0 to 4, 0 to 5, or 0 to 10. These scales
allow the measurement of pain both during the medical visit
and retrospectively, and are also used in the evaluation of treatment in CVD.
Leukocytes, due to their ability to respond to physical stimulation, are now known to play a key role in the resultant tissue
injury that leads to the development of CVD symptoms, varicose veins, edema, and ulcers.26 Recent data suggest that
valve damage may be acquired rather than congenital and
may be caused by inflammatory factors, notably leukocyte activation triggered by venous hypertension. Immunohistochemical studies using monoclonal antibodies have demonstrated monocyte/macrophage infiltration into the valve leaflets
and venous walls of patients with varicose veins, and leukocyte infiltration was found to be greater on proximal surfaces
of venous valves. A key event in CVD is valve failure, which
leads to increased venous hypertension, maintains a vicious
circle of inflammatory events, and causes eventual venous
complications.27
Besides physician-guided tools, there is an increasing need
for patients’ impressions of treatment outcomes and consequently a need for patient-reported outcome tools. The tools
used to assess patient-reported outcomes consist mainly of
QOL scales that may be either generic or disease-specific.
Of the specific QOL scales, the following are noteworthy: the
13-item Aberdeen Varicose Veins Questionnaire (AVVQ), the
Charing Cross Venous Ulceration Questionnaire, the VEINES
questionnaire, and the 20-item ChronIc Venous dIsease quality of life Questionnaire (CIVIQ-20) and its recently shortened
version, CIVIQ-14. CIVIQ has been used extensively, as reported in numerous studies some of which included large
samples of patients.28
Assessment tools in CVD
Both general practitioners and specialist doctors have to deal
with CVD. The treatments of this pathology are usually evaluated on the basis of clinical outcomes, but such evaluation
does not take into account patients’ perception of the disease and the impact of treatment on their QOL, which is significantly altered by the disease. Specific tools capable of assessing the full spectrum of CVD, its signs and symptoms,
impact on QOL, and treatment effects are key to the efficient
management of the disease.
Assessment tools in CVD can be categorized into two classes (those for symptoms and those for CVD-related signs) and
are summarized below20:
N Regarding symptom assessment
The first step should be to ascribe symptoms to CVD, since
they are not pathognomonic. The scoring system by P. Carpentier is a patient-administered diagnostic tool combining 4
criteria worth 1 mark each, which allows leg symptoms to be
ascribed to CVD if the threshold level is equal to or greater
than 3. The VEINES-Sym (VEnous INsufficiency Epidemiological and economic Study), developed by D. L. Lamping,
is a 10-item self-administered questionnaire that includes
questions on the frequency of 9 symptoms encountered in
CVD, while the 11-item Phleboscore® of P. Blanchemaison,
which includes questions about the frequency of symptoms,
helps predict the risk of developing CVD.
All four specific questionnaires above were used in conjunction with the 36-item Medical Outcome Study health survey
Short Form (MOS SF-36), a generic health-related QOL instrument whose validity, reproducibility, and responsiveness
to changes over time have been well demonstrated.
N Regarding assessment of signs
As mentioned in the section, “Terminology, classifications
and severity scoring of CVD,” above, the setting up of the
CEAP classification and its adjuncts was a great leap forward in the management of CVD. The CEAP classification can
be used by physicians to keep records of diagnostic information, while the adjuncts to CEAP (VCSS, VSDS, and VDS) are
scoring schemes that are quantifiable and include elements
that change in response to treatment. These instruments may
be used to evaluate any stage of CVD in patients, although
they are imperfect in the early stages.29 Besides these “global” assessment tools, signs such as varicose veins, edema,
and venous ulcers can be specifically assessed. Vein diameter can be measured on duplex scan investigation. Leg edema can be assessed by measuring either leg circumference
(tape, Leg-o-Meter®) or volume (water displacement volumetry, optoelectronic methods, computed tomography [CT]
scanning, magnetic resonance imaging [MRI], or dual x-ray
absorptiometry).20
Numerous techniques are available for the assessment of
venous ulcers, ranging from the simple use of tracings to
more sophisticated methods requiring the use of cameras,
videos, and computers.30 The parameters most frequently
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used to measure a wound are the length of the principal
axes (length and width of the wound), the projected surface
area, and the perimeter.30
from the American College of Chest Physicians (ACCP) 8th
consensus conference, has recently been published to help
physicians care for patients with venous disease.40
Invasive therapy
These recent ACCP guidelines have made specific changes
with recommendations and suggestions linked to objective
grades. The so-called “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) method of
determining the strength and quality of the recommendations
deserves mention. The strength of the recommendation (1:
“We recommend,” or 2: “We suggest”) is no longer based, as
was the case only a few years ago, solely on the type and
quality of available studies. It is a true judgement of the overall value of the balance between the benefits and risks incurred by following this recommendation, a judgement based
New minimally invasive techniques for the treatment of primary and secondary varicose veins, such as radio frequency
ablation and Endolaser™, have existed for some years. Both
these techniques are designed to eliminate the larger and/or
lesser saphenous veins, collateral varices, or recurrent varicosity. With either treatment of the greater saphenous vein,
the tributary veins at the femoral saphenous junction are
spared, leaving a long saphenous stump. Currently, two of
the most frequently cited causes of restripping are inadequate sectioning of saphenous vein tributaries at the saphenous junction and leaving too long a saphenous stump. Despite this, it would seem that the 5-year results using these
techniques are at least similar to and in fact often better than
those of traditional stripping.31-35
Another great addition to these techniques is foam sclerotherapy, which gives the same excellent results at remarkably
low cost.36,37 A comparative consensus conference is needed to clarify the specific indications and the long-term effectiveness and complications of each of these different methods, so that we are able to better inform patients and help
them choose the most appropriate treatment for them.
Methods of determining the strength and quality
of the recommendations
Guideline developers have used a bewildering variety of systems to rate the quality of the evidence underlying their recommendations. Some are facile, some confused, and others
sophisticated but complex. The recent documents that reported recommendations in CVD used several systems.
The one used by Cochrane’s group consists of applying a random effects statistical model as used in meta-analyses to a
selection of randomized controlled trials (RCTs). Selection of
RCTs 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). A
total of 10 Cochrane reviews have been published in CVD
since 2000.38
In European guidelines on CVD management, studies were
classified as: grade A (at least two RCTs with large sample
sizes, meta-analyses combining homogeneous results), grade
B (RCTs with small sample sizes, single RCT), or grade C
(other controlled trials, nonrandomized controlled trials).38 This
was the case in an important document on the “Management
of Chronic Venous Disorders of the Lower Limbs: Guidelines
According to Scientific Evidence,” prepared by an international consensus group under the auspices of the leading societies for venous disease.39 Another recent document, “Antithrombotic Therapy for Venous Thromboembolic Disease,”
242
N Developed by a widely representative group of international
guideline developers
N Clear separation between quality of evidence and strength
of recommendations
N Explicit evaluation of the importance of outcomes of alterna-
tive management strategies
N Explicit, comprehensive criteria for downgrading and upgrad-
ing quality of evidence ratings
N Transparent process of moving from evidence to recommen-
dations
N Explicit acknowledgment of values and preferences
N Clear, pragmatic interpretation of strong versus weak recom-
mendations for clinicians, patients, and policy makers
N 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, Development
and Evaluation.
Reproduced from reference 41: Guyatt et al. BMJ. 2008;336;924-926. © 2008,
BMJ Publishing Group Ltd.
not only on the expected health benefits, treatment-related
risks, and patients’ values and preferences, but also on economic considerations and the allocation of resources. In the
later document, recommendations are accompanied by a
number which refers to the strength of the recommendation
(“1” for a strong and “2” for a weak recommendation), and a
letter, which refers to the quality of evidence supporting the
recommendation (“A” for “high quality,” which is consistent
evidence from randomized trials; “B” for “moderate quality,”
which is evidence from nonrandomized trials or inconsistent
evidence from randomized trials; and “C” for “low quality,”
which is suggestive evidence from nonrandomized trials, observational reports, or expert opinion).
The advantages of GRADE over other systems are summarized by the developers themselves41 in Table I. This new approach provides a system for rating the quality of evidence
and the strength of recommendations that is explicit, com-
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prehensive, transparent, and pragmatic. That is why it is widely used in North America: 25 organizations have already
adopted it, and it is increasingly being adopted by other organizations worldwide.
The task of building international guidelines is challenging,
particularly in the venous field. This is because of the large
spectrum of disease manifestations and either the lack of
validated methods or the weak consensus for methods that
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have been adopted for assessing symptoms, signs, and QOL,
not to mention the resource constraints that vary considerably from region to region. Even if much still remains to be
done to get the high-quality scientific studies needed to support the development of guidelines, we are at a point where
a lot of progress in standardization, classification, fundamental research, and assessment methods has been made in a
short time. Let us hope that we can continue to advance in
the same way. I
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3. Allegra C, Antignani PL, Bergan J, et al. The “C” of CEAP: suggested definitions
and refinements: an International Union of Phlebology conference of experts.
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Economic Studies. Int Angiol. 1999;18:83-102.
11. Evans CJ, Fowkes FG, Ruckley CV, Lee AJ. Prevalence of varicose veins and
chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.
12. Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration.
J Gen Intern Med. 1997;12:374-383.
13. International Task Force. The management of chronic venous disorders of the
leg: 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 chronic venous disease: San Diego population study. J Vasc Surg. 2003;37:1047-1053.
17. Andreozzi GM, Cordova RM, Scomparin A, et al. Quality of life in chronic venous
insufficiency. 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 decreased
by broad-scale intervention: a follow-up cross-sectional study of a defined geographical population. Acta Derm Venereol. 2008;88:252-256.
19. Nelzén O. Prevalence of venous leg ulcer: the importance of the data collection
method. Phlebolymphology. 2008;15:143-150.
20. Jawien A. Unmet needs in the assessment of symptoms and signs related to
chronic venous disease. Application to Daflon 500 mg. Phlebolymphology. 2009;
16:331-339.
21. Allegra C, Carlizza A. Oedema in chronic venous insufficiency: physiopathology
and 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 significance 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 Microcirculation. Munich, Germany, August 25-30, 1996. Abstracts. Effectiveness of
Daflon 500 mg on microlymphatics in chronics venous insufficiency. Int J Microcirc Clin Exp.1996;16(suppl 1):1-308.
25. Bartolo M Jr, Carioti B, Cassiani D, Allegra C. 18th European Conference on
Microcirculation. Rome, Italy, 4-8 September 1994. Abstracts. Lymphatic capillaries 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 review
of 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.
Chronic Venous Disease quality of life Questionnaire (CIVIQ-20). Eur J Vasc
Endovasc Surg. 2010;40:783-789.
29. Perrin M, Dedieu F, Jessent V, Blanc MP. Evaluation of the new severity scoring
system in chronic venous disease of the lower limbs: an observational study
conducted by French angiologists. Phlebolymphology. 2006;13:6-16.
30. Humbert P, Meaune S, Gharbi T. Wound healing assessment. Phlebolymphology. 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 laser
and radiofrequency. A literature analysis at March 1st 2004 [in French]. Phlébologie. 2004;57:125-133.
33. Nicolini P; Closure Group. Treatment of primary varicose veins by endovenous
obliteration with the VNUS closure system: results of a prospective multicenter
study. Eur J Vasc Endovasc Surg. 2005;29:433-439.
34. Hinchiffe RJ, Ubhi J, Beech A, Ellison J, Braithwaite BD. A prospective randomised controlled trial of VNUS closure versus surgery for the treatment of recurrent long saphenous varicose veins. Eur J Vasc Endovasc Surg. 2006;31:
212-218.
35. Merchant RF, DePalma RG, Kabnick LS. Endovascular obliteration of saphenous 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 Sclerotherapy, April, 4-6, 2003, Tegernsee, Germany. Dermatol Surg. 2004;30:709717.
38. Nicolaides A. Venoactive medications and the place of Daflon 500 mg in recent guidelines on the management of chronic venous disease. Phlebolymphology. 2009;16:340-346.
39. Nicolaides A, Allegra C, Bergan J, et al. Management of chronic venous disorders of the lower limbs. Guidelines according to scientific evidence. Int Angiol. 2008;27:1-59.
40. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S-545S.
41. Guyatt GH, Oxman AD, Kunz R, et al. GRADE: an emerging consensus on
rating quality of evidence and strength of recommendations. BMJ. 2008;336;
924-926.
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Keywords: guidelines; chronic venous disease; update
MISE À JOUR DES RECOMMANDATIONS DANS
LA MALADIE VEINEUSE CHRONIQUE : DE QUOI AVONS - NOUS BESOIN
?
La maladie veineuse chronique (MVC) est un trouble très fréquent dans la population occidentale, que doivent traiter à la fois les généralistes et les spécialistes. Un manque de précision dans la description de la MVC (qui entraîne
douleur, gêne et altérations significatives de la qualité de vie des patients), et dans les résultats des études, a conduit
à des conclusions contradictoires et à compréhension limitée de la prise en charge de la pathologie veineuse. Dans
le but de rectifier ces manques, la communauté médicale s’efforce actuellement de mieux définir le domaine de la
MVC, de clarifier la terminologie et la nomenclature anatomique et clinique, de standardiser les examens et d’introduire de nouvelles approches thérapeutiques, qui seront présentées dans cet article. En plus, à ces prérequis importants pour l’élaboration de recommandations sur la maladie veineuse, s’ajoute la nécessité de données de prévalence
adéquates pour mieux appréhender l’amplitude du problème, tout en reconnaissant les mécanismes sous-tendant
les manifestations de la maladie veineuse afin de développer des traitements appropriés. Afin d’établir des recommandations, il faut obligatoirement un accord général sur des outils d’évaluation pouvant mesurer les changements
induits 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 tous
les cliniciens afin que la communauté médicale accepte toutes les recommandations proposées.
244
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‘‘
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AND
The imprecise diagnoses that
were the norm in 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 mechanisms of chronic disease in individual segments of the
lower extremity veins, it became
necessary to devise a classification system capable of organizing
the data in a meaningful way.”
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Chronic venous disease
guidelines and terminology:
sharing a common language
b y M . R . Pe r r i n , Fra n c e ,
a n d B . E k l ö f, S w e d e n
O
Bo EKLÖF, MD, PhD
University of Lund
Lund, SWEDEN
ne of the important lessons from the biblical story of the Tower of Babel is that a common language allows men to achieve extraordinary
things. For all those involved in the management of chronic venous
disease (CVD), the American Venous Forum (AVF) has created a “common language” in the classification of CVD, the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification. The need for an accurate classification
system is fundamental to understanding the clinical disease processes and to
interinstitutional communication about the disease. The CEAP classification
system was established in 1994 and was followed by REVAS (REcurrence after VAricose vein Surgery), created in Paris in 1998, and the Venous Clinical
Severity Score (VCSS), in 2000. Several consensus documents from the Union
Internationale de Phlébologie (UIP) led to the revision of the CEAP classification system in 2004. The latest update of terminology for CVD was the VEINTERM consensus document published in the Journal of Vascular Surgery in
2009. All these efforts have led to the creation of a common language in CVD,
which is essential for the establishment of clinical practice guidelines.
idden within the main story of the Tower of Babel (Figure 1, page 246) from
the Bible lies an interesting and valuable lesson: that with a common language, men can achieve extraordinary things. Without a common language,
not only would this project have been impossible (as it later transpires), but it also
would have been unimaginable. In creating the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification as a “common language” for chronic venous
disorders, the American Venous Forum (AVF) has laid the foundations for future progress in chronic venous disease (CVD).
H
Michel R. PERRIN, MD
Chassieu, FRANCE
The need for an accurate classification system in venous disease is fundamental to
the understanding of the clinical disease processes and to interinstitutional communication about the separate entities. The imprecise diagnoses that were the norm
in venous disease in the past have been replaced by accurate imaging studies,
since the introduction of noninvasive ultrasound scans in the 1980s.
Prof Bo Eklöf, Batteritorget 8,
SE-252 70 Helsingborg, Sweden
(e-mail: moboek@telia.com)
Once presented with the ability to make accurate diagnoses of the causes and mechanisms of chronic disease in individual segments of the lower extremity veins, it became necessary to devise a classification system capable of organizing the data in
a meaningful way.
CVD guidelines and terminology: sharing a common language – Perrin and Eklöf
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N Reflux from obstructive pathophysiology;
N And identifies the precise anatomical seg-
ments affected by reflux or obstruction using
18 named segments of the lower extremity
venous tree.
In this way, clinical manifestations can be coupled with the precise pathological entity. Using this, the natural history of the pathological
processes and the effects of management alternatives for like clinical states can be identified and studied. The classification describes
the status of the disease process at a point
in time; these details can change over time
with the introduction of interval treatments and
with the natural history of the disease process. By CEAP examination at regular intervals, the longitudinal changes that occur over
time or after interventions can be documented.
Figure 1. The Tower of Babel by Pieter Bruegel the Elder (1563).
This classification addressed the considerations imposed by modern diagnostic and
treatment capabilities. It was incorporated
into the updated Reporting Standards for Venous Disease in 1995 and became known as the CEAP classification. Its acceptance was engendered around the world
by venous authorities in America, Asia, Australia, and Europe,
and the classification has now been published in at least 11
languages (Chinese, English, French, German, Greek, Italian,
Japanese, Polish, Portuguese, Spanish, and Swedish). The
worldwide dissemination addresses the need for a universal
classification that enables accurate communication between
institutions and countries about the details of CVD and the
results of different forms of treatment. The CEAP classification was originally intended as a preliminary document; it was
meant to be amended in light of future experience with usage.
Since this time, several evaluations of the clinical categories
and of the appended scoring systems based upon CEAP have
been published, which have both validated and appraised their
content.
The biblical story of the Tower of Babel illustrates why a common language is so important and what
happens when people fail to understand each other. Oil on oak panel (114 × 155 cm). Kunsthistorisches
Museum Wien, Vienna, Austria. © Kunsthistorisches Museum Wien.
In 1994, the AVF convened a subcommittee of world experts
in CVD to address this challenge. Recognizing that a modern classification of CVD must now embrace more than just
the clinical state of the patient, this committee created the
CEAP classification, which provides a system whereby the
multiple variations of CVD can be communicated in a clinically and scientifically meaningful manner, allowing analysis and
comparison of treatment modalities for like conditions.1
Because identical clinical presentations of CVD spring from
different etiologies, and the distribution of specific pathological processes have different implications for treatment and
long-term prognosis, the CEAP classification organizes these
elements into the methodology. In the CEAP system, the
“C”-linical state is complemented by the “E”-tiological basis
for the disease in each case, and this is described in terms
of the “A”-natomical distribution of the “P”-athophysiological
process throughout the axial venous drainage system, from
the calf to the diaphragm. This organization of information
has been successfully promulgated around the world by the
international body that devised it. Its widespread acceptance has become fundamental to interinstitutional communication and to describing chronic venous disorders.
Development of the CEAP classification
The CEAP classification provides a framework around which
the clinical manifestations found in CVD are paired with key
pathological elements of causation and physiological mechanisms in specific anatomical locations of the lower extremity.
Specifically, for each clinical condition it distinguishes:
N Primary, secondary, and congenital causes of the problem;
246
In 1998, at an international consensus meeting in Paris, Perrin
et al established a classification for recurrent varicose veins
(REcurrent Varices After Surgery [REVAS]).2 Two years later in
SELECTED
AVF
CEAP
CVD
LDS
REVAS
UIP
American Venous Forum
lipodermatosclerosis
REcurrent Varices After Surgery
Union Internationale de Phlébologie [International
Union of Phlebology]
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2000, Rutherford et al and the Ad Hoc Outcomes Committee
of the AVF published an upgraded version of the original venous severity scoring system.3 Uhl et al established a European Venous Registry based on CEAP and reported studies on intraobserver and interobserver variability that showed
significant discrepancies in the clinical classification of CEAP,
which prompted the improvement of definitions of clinical
classes C0 to C6.4 Further changes regarding definitions and
refinements of the clinical classification, the “C” in CEAP, were
suggested soon after at the Union Internationale de Phlébologie [International Union of Phlebology] (UIP) international
consensus meeting in Rome in 2001,5 which not only con-
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Terminology and new definitions
The CEAP classification deals with all forms of CVD. The term
“chronic venous disorder” includes the full spectrum of morphologic and functional abnormalities of the venous system,
from telangiectasias to venous ulcers. Some of these, such
as telangiectasias, are highly prevalent in the healthy adult
population, and in many cases use of the term “disease” is
not appropriate. The term “chronic venous insufficiency” implies a functional abnormality of the venous system, and is
usually reserved for more advanced disease, including edema (C3), skin changes (C4), and venous ulcers (C5-C6).
It was agreed to maintain the present overall structure of the
CEAP classification, but to add more precise definitions. The
following recommended definitions apply to the clinical (“C”)
class of CEAP:
N Atrophie blanche (white atrophy)
Localized, often circular whitish and atrophic skin areas surrounded by dilated capillaries and sometimes hyperpigmentation. Sign of severe CVD, and not to be confused with healed
ulcer scars. Scars of healed ulceration may also exhibit atrophic skin with pigmentary changes, but are distinguishable
by history of ulceration and appearance from atrophie blanche,
and are excluded from this definition (Figure 2).
Figure 2. Atrophie blanche (C4b).
N Corona phlebectatica
Fan-shaped pattern of numerous small intradermal veins on
medial or lateral aspects of ankle and foot. Commonly thought
to be an early sign of advanced venous disease. Synonyms
include malleolar flare and ankle flare (Figure 3).
N Eczema
An erythematous dermatitis that may progress to blistering,
weeping, or scaling eruption of skin of the leg. Most often located near varicose veins, but may be located anywhere on
the leg. Usually seen in uncontrolled CVD, but may reflect sensitization to local therapy.
Figure 3. Corona phlebectatica.
tributed to CEAP, but ultimately formed the basis for its modification. At the same meeting, Caggiati et al published a consensus document on nomenclature of the veins of the lower
limbs, which was updated a couple of years later.6,7
After a decade (in 2004), a new international subcommittee
of the American Venous Forum decided to review the validity
and usefulness of CEAP and to make revisions if needed. This
new version affirmed and retained the fundamental structure of the CEAP categories, but included additions to classification, such as specific definitions of terms, clarification of
details within the “C” class, and improvements in the method
of recording of findings to render classification more complete
in its long form, and more user-friendly in its short form.8
N Edema
Perceptible increase in volume of fluid in skin and subcutaneous tissue, which is characteristically indented with pressure. Venous edema usually occurs in the ankle region, but
may extend to the leg and foot (Figure 4, page 248).
N Lipodermatosclerosis
Lipodermatosclerosis (LDS) is a localized chronic inflammation and fibrosis of the skin and subcutaneous tissues of the
lower leg, sometimes associated with scarring or contracture
of the Achilles tendon. LDS is sometimes preceded by diffuse inflammatory edema of the skin, which may be painful
and which often is referred to as hypodermitis. Lymphangitis,
erysipelas, or cellulitis must be differentiated from LDS by their
characteristically different local signs and systemic features.
LDS is a sign of severe CVD (Figure 5, page 248).
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Figure 4. Edema (C3).
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Figure 5. Lipodermatosclerosis (+ atrophie
blanche) (C4b).
Figure 6. Pigmentation (C4a).
Courtesy of Albert-Adrien Ramelet (Bern, Switzerland).
N Pigmentation
Brownish darkening of skin, resulting from extravasated blood.
Usually occurs in the ankle region, but may extend to the leg
and foot (Figure 6).
N Reticular vein
Dilated bluish subdermal vein, usually 1 mm to less than 3 mm
in diameter. Usually tortuous. Excludes normal visible veins
in persons with thin, transparent skin. Synonyms include blue
veins, subdermal varices, and venulectasias.
Figure 7. Telangiectasias (C1).
N Telangiectasia
Confluence of dilated intradermal venules less than 1 mm in
caliber. Synonyms include spider veins, hyphen webs, and
thread veins (Figure 7).
N Varicose vein
Subcutaneous dilated vein 3 mm in diameter or larger, measured in upright
position, may involve saphenous veins,
saphenous tributaries, or nonsaphenous
superficial leg veins.
Varicose veins are usually tortuous, but
tubular saphenous veins with demonstrated reflux may be classified as varicose veins. Synonyms include varix,
varices, and varicosities (Figure 8).
Figure 8. Varicose veins (C2).
248
Figure 9. Active venous ulcer (C6).
N Venous ulcer
Full-thickness defect of skin, most frequently in the ankle region, that fails to
heal spontaneously and is sustained by
CVD (Figure 9).
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Chronic venous disorders: include all clinical abnormalities
(symptoms or signs) resulting from disease of the lower
limb veins and progressing chronically.8
Chronic venous disorders: this term includes the full spectrum of morphological and functional abnormalities of the
venous system.
Chronic venous disease: is defined as an abnormally
functioning venous system caused by venous valvular
incompetence with or without associated venous outflow
obstruction, which may affect the superficial venous system, the deep venous system, or both.10
Chronic venous disease: morphological and functional
abnormalities of the venous system of long duration
manifested either by symptoms and/or signs indicating
the need for investigation and/or care.
Chronic venous insufficiency: implies a functional abnormality of the venous system, and is usually reserved for more
advanced disease, including edema (C3), skin changes
(C4), or venous ulcers (C5-C6).8
Chronic venous insufficiency (C3*-C6): a term reserved for
advanced chronic venous disorders, which is applied to
functional abnormalities of the venous system producing
edema,* skin changes, or venous ulcers. [C3*: moderate
or severe edema, as stratified by Rutherford et al 3]
Venous symptoms: may be associated with telangiectasic,
reticular, or varicose veins and include lower extremity
aching, pain, and skin irritation.10
Venous symptoms*: complaints related to venous disease,
which may include tingling, aching, burning, pain, muscle
cramps, swelling, sensations of throbbing or heaviness,
itching skin, restless legs, and leg tiredness and/or fatigue. Although not pathognomonic, these may be suggestive of chronic venous disease, particularly if they are
exacerbated by heat or dependency in the day’s course,
and relieved with leg rest and/or elevation.
Venous signs: described in the “C” of the CEAP
classification.5,10
Venous signs: visible manifestations of venous disorders,
which include dilated veins (telangiectasiae, reticular
veins, varicose veins), leg edema, skin changes, and ulcers, as included in the CEAP classification.8
Recurrent varices: the presence of varicose veins in a lower
limb previously operated on for varices (with or without adjuvant therapies).2
Recurrent varices: reappearance of varicose veins in an
area previously treated successfully.
Persisting or residual varices: original varicosities that may
persist so that the failure of treatment is apparent from
an early stage after surgery.11
Residual varices: varicose veins remaining after treatment.
No previous definition
New acronym PREVAIT: this acronym stands for:
PREsence of Varices (residual or recurrent) After operatIve Treatment)
Postthrombotic syndrome: the term may be used if the
patient has experienced an objectively documented prior
episode of deep vein thrombosis.10
Postthrombotic syndrome: chronic venous symptoms
and/or signs secondary to deep vein thrombosis.
Pelvic congestion syndrome: characterized by chronic
pelvic pain in the setting of pelvic venous varicosities.
The syndrome has been shown to be the result of engorgement of the pelvis due to gross dilatation and incompetence of one or both the ovarian veins.12
Pelvic congestion syndrome: chronic symptoms, which may
include pelvic pain, perineal heaviness, urgency of micturition, and postcoital pain, caused by ovarian and/or pelvic
vein reflux and/or obstruction, and which may be associated with vulvar, perineal, and/or lower extremity varices.
No venous literature definition
Varicocele: presence of scrotal varicose veins.
Venous aneurysm: the diameter above which a vein is con
sidered to be aneurysmal is debated: it is generally accepted that its diameter must be twice that of the normal vein.
Aneurysms are classified into saccular and fusiform.13
Venous aneurysm: localized saccular or fusiform dilatation
of a venous segment with a caliber at least 50% greater
than the normal trunk.
*In the original article, the definition is followed by the sentence: “Existing venous signs and/or (noninvasive) laboratory evidence are crucial in associating these symptoms with chronic venous disorder,” which conflicts with the acknowledged existence of the clinical CEAP category C0s En
An Pn, corresponding to patients complaining of leg symptoms, but presenting with no visible signs and without detectable pathophysiological
abnormalities identifiable by routine investigations. This is why we removed this paragraph from the present brochure.
Table I. VEIN-TERM definitions/Clinical venous terms.2,3,5,8-13
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Venous valvular incompetence: abnormal functioning of
the veins of the lower extremities is recognized clinically
as venous dysfunction.14
Venous valvular incompetence: venous valve dysfunction
resulting in retrograde venous flow of abnormal duration.
Venous reflux: reversal of flow in a segment of vein following its dilatation and/or anatomical or functional incompetence of its valves.15
Primary valve dysfunction: absence of complete
closure of the valves.15
Secondary valve dysfunction: valves irreversibly
damaged by the thrombotic process.15
Congenital valve dysfunction: atrophy or absence
of valve.15
Venous reflux: retrograde venous flow of abnormal duration
in any venous segment.
No previous definition
Axial reflux: uninterrupted retrograde venous flow from the
groin to the calf.
Superficial: confined to the superficial venous system.
Superficial: reflux in the entire great saphenous vein to below
the knee.16
Deep: superficial femoral vein and popliteal vein or the
deep femoral vein and popliteal vein when those are connected.17
No precise previous definition
Primary: caused by idiopathic venous valve dysfunction.
Secondary: caused by thrombosis, trauma, or mechanical, thermal, or chemical etiologies.
Congenital: caused by the absence or abnormal development of venous valves.
Deep: confined to the deep venous system.
Combined: involving any combination of the three
venous systems (superficial, deep, perforating)
Segmental reflux: localized retrograde flow in venous segments of any of the three venous systems (superficial,
deep, perforating) in any combination in the thigh and/or
the calf, but NOT in continuity from the groin to calf.
Perforator incompetence: retrograde (outward) outflow
flow lasting greater than 0.3 s or longer than antegrade
flow during the relaxation phase after release of manual
compression.18
Perforator incompetence: perforating veins with outward
flow of abnormal duration.
Neovascularization: recurrence of varices after vein transection restored by growth of new vessels in the surrounding tissue and vein wall.19
Neovascularization: presence of multiple new, small tortuous veins in anatomic proximity to a previous venous
intervention.
Venous occlusion: total obliteration of the venous lumen.
Venous obstruction: partial or total blockage of venous flow.
Venous compression: compression by external structures.20
Venous compression: narrowing or occlusion of the venous
lumen as a result of extraluminal pressure.
Recanalization: development of a new lumen in a previously
obstructed vein.
Iliac vein obstruction syndrome: venous symptoms and
signs caused by narrowing or occlusion of the common
or external iliac vein
May-Thurner syndrome: Compression of the left common
iliac vein by vascular bone entrapment. The anterior surface entrapment is the common iliac artery, the posterior
is formed by vertebral column.13
May-Thurner syndrome: venous symptoms and signs
caused by obstruction of the left common iliac vein due
to external compression at its crossing posterior to the
right common iliac artery.
Table II. VEIN-TERM definitions/Physiological venous terms.9,13-20
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High ligation and division: ligation and division of the long
saphenous vein and its tributaries at the saphenofemoral
junction.21
High ligation and division: ligation and division of the great
saphenous vein (GSV) at its confluence with the common
femoral vein, including interruption of all upper GSV
tributaries.
Stripping: removal of the saphenous vein.22
Stripping: removal of a long vein segment, usually most of
the GSV or the small saphenous vein by means of a device.
Venous ablation: removal or destruction of a vein by
mechanical, thermal, or chemical means.
Perforating vein interruption: disconnection of a perforating
vein by mechanical, chemical, or thermal means.
Perforating vein ligation: interruption of a perforating vein
by mechanical means.
Perforating vein ablation: disconnection or destruction of a
perforating vein by mechanical, chemical, or thermal means.
Miniphlebectomy: removal of a vein segment through a
small skin incision.
Sclerotherapy: obliteration of a vein by introduction of a
chemical (liquid or foam).
Endophlebectomy: surgical disobliteration of chronically
obstructed venous segment.23
Endophlebectomy: removal of postthrombotic residue from
the venous lumen.
Table III. VEIN-TERM definitions/Descriptive venous terms.9,21-23
Abbreviation: GSV, great saphenous vein.
Need for updated CVD terminology
Despite the revision of the CEAP classification and the updated nomenclature of the venous anatomy of the leg, many
terms need a better definition to create a common scientific
language for the investigation and management of CVD. In October 2007 onboard M/S Trollfjord, we organized the Arctic
Fjords Conference and workshops on CVD. During this voyage, an interdisciplinary faculty of experts under the auspices
of the European Venous Forum, the AVF, the UIP, the International Union of Angiology, the American College of Phlebology, and the Society for Vascular Surgery met in order to provide recommendations for fundamental venous terminology.
The group met again in February 2008 at the of AVF meeting
in Charleston, South Carolina, to finalize the document that was
endorsed by the organizations and published in the Journal
of 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 and
prior venous nomenclature refinements were excluded.9
The aim of Table I (page 249),2,3,5,8-13 Table II,9,13-20 and Table III 9,21-23 is to summarize the venous terms relating to the
management of chronic venous disorders of the lower extremities that are widely used and recognized to vary in applicability and interpretation in reports in the venous literature.
The venous terms newly defined in the VEIN-TERM consensus document are compared with those in previous literature
definitions. The definitions presented in VEIN-TERM testify to
a continued effort to create a common language upon which
we can build clinical practice guidelines (presented by Peter
Gloviczki in his editorial).9 I
References
1. Bergan JJ, Eklof B, Kistner RL, et al. Classification and grading of chronic venous 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 after
surgery (REVAS), a consensus document. Cardiovasc Surg. 2000;8:233-245.
3. Rutherford RB, Padberg FT, Comerota AJ, Kistner RL, Meissner MH, Moneta
GL. 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. Reproducibility 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 definitions and refinements: an International Union of Phlebology conference of experts. J Vasc Surg. 2003;37:129-131.
251
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6. Caggiati A, Bergan JJ, Gloviczki P, Jantet G, Wendell-Smith CP, Partsch H.
Nomenclature of the veins of the lower limbs: an international interdisciplinary
consensus statement. J Vasc Surg. 2002;36:416-422.
7. Caggiati A, Bergan JJ, Gloviczki P, Eklöf B, Allegra C, Partsch H. Nomenclature
of 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 for
chronic venous disorders: Consensus statement. J Vasc Surg. 2004;40:12481252.
9. Eklöf B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminology
of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg. 2009:49:498-501.
10. Porter IP, Moneta GM; International Consensus Committee on Chronic Venous
Disease. 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: ButterworthHeinemann; 1992:112.
12. Richardson G. Pelvic congestion syndrome: diagnosis and treatment. In: Bergan 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: Elsevier Masson; 2008:41-48.
CLINICAL
PRACTICE
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: Elsevier
Masson; 2008:61-62.
16. Danielsson G, Eklöf B, Grandinetti A, Lurie F, Kistner RL. Deep axial reflux, an
important contributor to skin changes or ulcer in chronic venous disease. J Vasc
Surg. 2003;38:1336-1341.
17. Puggioni A, Lurie F, Kistner RT, Eklöf B. How often is deep venous reflux eliminated after saphenous vein ablation? J Vasc Surg. 2003;38:517-521.
18. Gloviczki P, Lewis BD, Lindsey JR, McKusick MA. Preoperative evaluation of
chronic venous insufficiency. In: Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. London, UK: Springer Verlag; 1998:81-91.
19. Glass GM. Neovascularization in recurrence of the varicose great saphenous
vein 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 postthrombotic deep veins—endophlebectomy—is feasible. J Vasc Surg. 2004;39:10481052.
Keywords: chronic venous disease; definition; terminology
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 commun permet aux hommes de réaliser des choses extraordinaires. À l’intention de tous ceux impliqués dans la prise
en charge de la maladie veineuse chronique (MVC), l’American Venous Forum a créé un « langage commun » permettant la classification de la MVC, la classification CEAP (Clinique – Étiologique – Anatomique – Physiopathologique). Il est essentiel de disposer d’une classification précise pour appréhender en détail les aspects cliniques de
la MVC et pour communiquer au plan international sur le sujet. La classification CEAP a été établie en 1994 et a
été suivie par la classification REVAS (REcurrence After VAricose vein Surgery) élaborée à Paris en 1998 et par le
score de sévérité clinique (VCSS : Venous Clinical Severity Score), en 2000. Plusieurs documents de consensus de
l’Union Internationale de Phlébologie ont conduit à la révision de la classification CEAP en 2004. La dernière mise à
jour de la terminologie pour la MVC est le document de consensus VEIN-TERM publié dans le Journal of Vascular
Surgery en 2009. Tous ces efforts ont conduit à la création d’un langage commun dans la MVC, ce qui est essentiel
pour l’établissement de recommandations en pratique clinique.
252
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AND
The balance of evidence supports the finding that the prevalence of venous disease increases
with increasing age. The magnitude of risk appears to differ depending on the classification criteria, and estimates vary in published
studies. The prevalence of varicose veins in men aged 30 to 40
years old is about 3%, while in the
age group over 70 years old, it increases up to about 40%. Similar
results were also found in women.”
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Prevalence and socioeconomic
data in chronic venous disease:
how useful are they in planning
appropriate management?
by D. J. Milic, Serbia
T
Dragan J. MILIC, MD, PhD
Clinic for Vascular Surgery
Clinical Center Nis
Nis Medical School
University of Nis
Nis, SERBIA
he exact prevalence of chronic venous disease (CVD) remains difficult
to determine because of variations in study population, selection criteria, 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 budgets
and patients’ quality of life, it is still an underestimated condition. CVD is more
common with increasing age, and in recently published studies there were no
significant sex differences. Family history, obesity, prolonged standing, and
diet have been proposed as risk factors, but further studies are needed to
clarify the influence of potential risk factors on the development of CVD. The
financial burden on the health-care system is enormous, with recent estimates
placing 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. Existing
evidence highlights the need for good quality longitudinal and cross-sectional studies measuring the incidence and prevalence of CVD. These studies
may help to reduce the magnitude of the problem of CVD by raising awareness among public and health-care authorities, and health-care professionals. Furthermore, prevalence and socioeconomic data may serve as a valuable basis for the planning of appropriate steps to deal with CVD and for the
education and hire of skilled personnel.
hronic venous disease (CVD) of the lower extremities is one of the most
widespread diseases in the populations of Western European countries and
the USA. Data from undeveloped countries are scarce, and the true magnitude of the problem is not known. Unfortunately, even in developed Western European countries and the USA, where the problem of CVD is well recognized, the
prevalence of CVD is still underestimated by both patients and health-care professionals. This underestimation comes from the fact that chronic venous insufficiency
(CVI) is not a lethal condition and that the consequences of this chronic disorder
are 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 as
telangiectasias, reticular veins, and varicose veins. The term “chronic venous insufficiency” describes a condition that affects the venous system of the lower extremities with venous hypertension, causing various pathologies including pain, swelling,
edema, skin changes, and ulcerations.
C
Dr Dragan J. Milic, Bulevar
Nemanjica 72A/25, 18 000 Nis,
Serbia (e-mail:
drmilic@beotel.net/dmilic@ptt.rs)
Prevalence and socioeconomic data in chronic venous disease – Milic
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Published studies
Data from available epidemiological literature published during the last 30 years are very difficult to compare due to the
fact that different evaluation criteria of CVD were used. Lawrence1 confirms that the prevalence of varicose veins depends
on the definition of this disease because dilated veins ranging from telangiectasias to massive varicosities come under
the general category of varicose veins. In order to standardize the evaluation of severity of venous disease in 1994, a new
classification system was suggested by the American Venous
Forum. The CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification system includes not only the clinical
symptoms of CVD, but also considers the etiology, anatomic distribution, and the pathogenic mechanisms and produces a score based on the severity of the disease.2 The
clinical signs in the affected leg are categorized into seven
classes designated C0 to C6. CVD encompasses the full
spectrum of signs and symptoms associated with classes
C0 to C6, whereas the term “chronic venous insufficiency”
is generally restricted to disease of greater severity, such as
edema, trophic skin changes (such as pigmentation and lipodermatosclerosis), and ulceration.3
CVD is extremely common, although the prevalence estimates
in the literature vary because of differences in the methods of
evaluation, criteria for definition, and the geographic regions
analyzed.4 In order to establish the magnitude of the problem, epidemiological studies are used to assess the prevalence of diseases or disorders within a population. Cross-sectional studies have usually been used to assess the number
of patients with a certain disease within a health-care system.
Large random samples have been used to assess populations and have the advantage of including people who selftreat. Prevalence data from such studies are a valuable basis for the planning of appropriate actions to deal with the
problem. By repeating a prevalence study within a defined
geographical area, we have an opportunity to assess the effect of treatment changes, which is important.5 Unfortunately,
SELECTED
CEAP
CIVIQ
ChronIc Venous dIsease Questionnaire
CVD
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 improvEment
with micronized Flavonoids [study]
YLD
years lived with disability
YLL
years of life lost
254
Pitfall
Effect on results of the study
Population sample
Not all age groups are
represented
Cross-sectional studies
Patients who self-treat are
not included
Follow-up studies
May affect patient recruitment
negatively
Different evaluation criteria
of CVD
Possible high drop-out rate
Too small a sample
Uncertain prevalence estimate
Selection bias
Prevalence not representative
for the general population
Low response rate
Risk of underestimation of
prevalence
Extensive primary
questionnaire
Noncomparable results
Table I. Pitfalls in performing prevalence studies and their effects
on the results.
Abbreviation: CVD, chronic venous disease.
published epidemiological studies often misuse prevalence
data by mixing overall prevalence figures with point prevalence data, giving an inaccurately wide range that leads to
incorrect interpretations of prevalence data between countries and studies. Therefore, in order to provide the most reliable data and to generate accurate comparisons, it is essential to analyze the methods used in various epidemiological
studies. However, we still have many pitfalls that can lead to
inaccurate conclusions and interpretations6 (Table I).
Prevalence data are often harvested from cross-sectional
studies or large population samples. The former investigate
a defined cohort, generally all patients receiving treatment
from health-care professionals within a relatively short time
frame, usually one to three months. The latter usually consist
of randomly selected people in a certain age range who have
not necessarily been in previous contact with the healthcare system. The benefit of population samples is that people who self-treat are included, unlike cross-sectional studies.6 The drawback of a population sample is that usually not
all age groups are represented.5
To facilitate recruitment, it is important to avoid approaching
carers and patients with lengthy questionnaires. Such forms
take time to fill in and introduce a risk of dropout because
of lack of time of the carer, patient, or both. A cross-sectional study involves selection bias since only patients treated
within the health-care system will be included. Such a study
will give an indication of the workload for health-care professionals, but there are, in addition, people who treat the disease on their own. A population sample overcomes this by
including all people within the selected sample. The biggest
problem of population sample studies is that they need to be
fairly large (more than 10 000 people) in order to detect enough
CHRONIC
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DISEASE
patients with the disease so that a reliable prevalence estimate can be made. These studies are expensive, time consuming, and difficult to perform.6
Prevalence of chronic venous insufficiency
The prevalence of varicose veins reported in studies ranges
from 2%-56% in men and from 1%-60% in women3 (Table II).
Seven general population surveys have been conducted to
date,7-13 and only a few studies have measured the incidence
of varicose veins. The Framingham Study was a longitudinal
study that followed up men and women living in Framingham,
USA, over a 16-year period from 1966.14 Every second year
over 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 629
out of the 2012 women who were free from venous disease
in 1966 developed varicose veins. On average, the two-year
incidence rate of varicose veins was 39.4 per 1000 for men
First
author
Year
Study
Country sample size
Men Women
Mekky
Mekky
Coon
Abramson
Maffei
Franks
Komsuoglu
Sisto
Evans
Criqui
1969
1969
1973
1981
1986
1992
1994
1995
1999
2003
Egypt
England
USA
Israel
Brazil
England
Turkey
Finland
Scotland
USA
–
–
12.9
10.4
37.9
17.4
34.5
6.8
39.7
15
467
504
6389
4802
1755
1338
850
8000
1566
2211
5.8
32.1
25.9
29.5
50.9
31.6
38.3
24.6
32.2
27.7
Table II. Prevalence of varicose veins (%) by sex in studies from
different countries.
After reference 3: Robertson et al. Phlebology. 2008;23:103-111. © 2008, The
Royal Society of Medicine Press.
and 51.9 per 1000 for women. However, further studies are
required to determine the incidence and progression of venous disease in the general population. One such study is
the Edinburgh Vein Follow-Up Study. Subjects examined at
baseline in 1994-1996 are currently undergoing a follow-up
examination to determine the incidence and natural history
of CVD as well as to establish the risk factors relating to progression.
A cross-sectional study of a random sample of 1566 subjects
18 to 64 years of age from the general population in Edinburgh, Scotland,12 found that telangiectasias and reticular
veins were each present in approximately 80% of men and
85% of women. Varicose veins were present in 40% of men
and 16% of women, whereas ankle edema was present in
7% of men and 16% of women.12 In this study, duplex ultrasound found reflux in 9.4% of men and 6.6% of women and
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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 reduce
venous reflux. Jantet16 in the RELIEF (Reflux assEssment and
quaLity of lIfe improvEment with micronized Flavonoids) study
found that venous reflux was absent in 57% of patients diagnosed as suffering from CVI belonging to CEAP classes C0
to C4. Moreover, during treatment with micronized purified
flavonoid fraction, all symptoms showed a decrease in both
groups of patients (with and without venous reflux).16
The balance of evidence supports the finding that the prevalence of venous disease increases with increasing age.7-9,11,13,17-20
The magnitude of risk appears to differ depending on the classification criteria, and estimates vary in published studies. The
prevalence of varicose veins in men aged 30 to 40 years old
is about 3%, while in the age group over 70 years old, it increases up to about 40%.11,13 Similar results were also found
in women: a prevalence of 20% at the age of 30 to 40 years
old increases gradually with age and by 70 years of age, it
exceeds 50%.12 The prevalence of trunk varices rose from
11.5% in persons aged 18 to 24 years old to 55.7% in the
population between 55 to 64 years of age.12 The occurrence
of skin changes in CVI depends on the patient’s age as well.
In the Tecumseh Health Study,7 the prevalence of skin changes
in women aged 30 to 39 years old was 1.8%, whereas in
patients aged over 70 years old a prevalence of 20.7% was
reported.
The San Valentino Vascular Screening Project found a prevalence of 7% for varicose veins and 0.86% for “symptomatic”
CVI among the 30 000 subjects evaluated by clinical assessment and duplex ultrasound.21 As in previous studies,
CVI was more common with increasing age, but there was
no significant sex difference.
Active or healed venous leg ulcers occur in approximately 1%
of the general population.12,22 Although not restricted to the
elderly, the prevalence of CVD, especially leg ulcers, increases with age.22,23 It has been estimated that 2.5 million people have CVI in the United States, and of those, 20% develop
venous ulcers.24 The overall prognosis of venous ulcers is poor
with delayed healing and recurrent ulceration.25 More than
50% of venous ulcers require prolonged therapy lasting more
than 1 year.26
Most studies have shown that CVI is more prevalent among
women, although in a recent study, the difference between
sexes was small.4 Selection bias may be a problem in some
of these studies, as more women than men may be aware of
their varicose veins or consider them to be a problem and,
thus, may be more likely to participate in such studies. Moreover, many of the results from these studies have not been adjusted for age, a factor that may contribute to the observed
gender differences.3 In the Framingham Study,14 the annual
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incidence of varicose veins was 2.6% among women and
1.9% among men, and in contrast to the Edinburgh Vein
Study, the prevalence of varicose veins was higher in men.12
In the San Diego Population Study, CVD was more prevalent
in populations of European origin than in blacks or Asians.13
Geographic differences in the prevalence of varicose veins
suggest a correlation with race. In particular, the prevalence
of CVD has been found to be higher in more developed, industrialized countries than in underdeveloped regions. Mekky
et al observed that the prevalence of varicose veins in English
women was more than five times as great as that in Egyptian
women.27
Risk factors for CVD include heredity, age, female sex, obesity (especially in women), pregnancy, prolonged standing,
and greater height.10,28-30
Socioeconomic burden of chronic venous
insufficiency
The high prevalence of CVI, cost of investigation and treatment, and loss of working days mean that CVD has a considerable socioeconomic impact. The problem is compounded by the fact that CVI is progressive and has a propensity
to recur.31 In France, 2.24 billion Euros are spent for the treatment of CVI, of which 41% was for drugs, 34% for hospital
care, and 13% for medical fees. In France in 1991, there were
200 000 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 healthcare budget for that year.32 In Germany, in-patient direct costs
were 250 million Euros, out-patient costs were 234 million
Euros, and drug costs were 207 million Euros.33
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son could expect to live in a defined state of health. Health
gaps measure the difference between actual population health
and some specified norm or goal. The principle characteristic defining a health gap measure is the population norm (age)
chosen to define the period before which death or disability
is considered premature. Methods for defining health states
and for eliciting health state valuations, as well as incorporation of other social values also affect the calculation and interpretation of health gaps, as for health expectancies. The
best known of the health gap measures is the disability-adjusted life year (DALY), developed for use in burden of disease
studies by Murray and Lopez.37 The DALY combines a measurement of premature mortality and disability and expresses years of life lost to premature death together with years
lived with disability of specified severity and duration. One
DALY is thus one lost year of healthy life. This indicator is the
aggregate of years of life lost (YLL) and years lived with disability (YLD) at a population level, and reflects the burden of
disease in a population: DALY = YLL + YLD.
An even more useful tool for assessing the importance of CVI
is the quality-adjusted life year (QALY), a measure of disease
burden that includes both the quality and the quantity of life
lived. It can be used to assess the value for money of a medical intervention. Unfortunately, to date, there are no studies
that have assessed DALYs and QALYs in patients with CVI.
Quality of life in patients with chronic venous
insufficiency
In Sweden, the average weekly cost of treating venous leg
ulcers in 2002 was 101 Euros, with an estimated annual cost
of 73 million Euros.34 Indirect costs of venous disease in terms
of working days lost were the most important cost factor in
1990 in Germany, amounting to 270 million Euros.33 In the
USA, venous ulcers cause the loss of 2 million workdays per
year,35 while in France 6.4 million workdays were lost in 1991
due to venous disease.32 The socioeconomic impact of venous ulceration is dramatic, resulting in an impaired ability to
engage in social and occupational activities, a reduction in
patients’ QOL, and the imposition of financial constraints. In
a population study in the United Kingdom, the median duration of ulceration was nine months, but 20% of ulcers had not
healed within two years, and ulcer recurrence meant that 66%
of patients had episodes of ulceration lasting longer than five
years.25 Published data show that venous ulcers may cause
the early retirement of a substantial portion, up to 12.5%, of
workers with this condition.36
CVI has a huge impact on patients’ QOL.38,39 Clinical assessment of CVD severity may be carried out using different reported outcome tools: physician reported outcomes (VDS
[Venous Disability Score], VCSS [Venous Clinical Severity
Score]) and patient reported outcomes, such as QOL scales
(generic: SF-12 and SF-36 [Short Form 12 and 36]; or specific: VEINES [VEnous INsufficiency Epidemiological and economic Study], AVVQ [Aberdeen Varicose Veins Questionnaire],
CIVIQ [ChronIc Venous dIsease Questionnaire], SQOR-V [Specific Quality Of life Response–Venous]). In the study published
by Jantet, patients with venous reflux had lower CIVIQ scores
than patients without reflux, reflecting a poorer QOL (62.2 versus 66.7; P=0.0001).16 This was observed not only for the
global index scores (GIS), but for all aspects of the CIVIQ
(psychological, pain, physical, and social). The subgroup with
both short and long saphenous vein involvement had significantly lower QOL scores, and hence poorer QOLs, than
the subgroups of patients with isolated reflux of the short
saphenous vein or of the long saphenous vein only (GIS =
59.3 versus 64.1 and 64.7, respectively; P=0.0001). It is also
interesting to observe from this study that only 21.8% of all
patients with CVI were treated for this condition.
A useful tool to determine the burden of CVI in population
is to calculate health expectancies, which are population indicators that estimate the average time (in years) that a per-
The CIVIQ questionnaire is a specific instrument for assessing the impact of venous disease on patients’ QOL. This scale
consists of 20 items that assess physical limitation (4 items),
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Conclusion
for good quality longitudinal studies measuring the incidence
and prevalence of CVD. Varicose veins and CVI are often ignored as an important public health issue even though evidence from research indicates that venous disease affects
a significant proportion of the population, causes considerable morbidity, and adversely impacts the QOL of those affected. All of these factors have an influence on health-care
budgets and public spending.
The exact prevalence of CVD remains difficult to determine
because of variations in study population, selection criteria,
and disease definition between different studies. The prevalence of varicose veins, as reported in studies, ranges from
2%-56% in men and from 1%-60% in women. Evidence suggests that the prevalence of venous disease increases with
age. Varicose veins appear to be more prevalent in women,
but pregnancy and the fact that women report the presence
of varicose veins more often than men may play a role in this
variation. Family history, obesity, prolonged standing, and diet
have been proposed as risk factors, but further studies are
needed to clarify the influence of potential risk factors on the
development of CVI. Existing evidence highlights the need
Future prevalence and socioeconomic studies may help to
reduce the magnitude of the problem of CVI. This type of CVI
assessment could raise awareness among the public, healthcare authorities, and health-care professionals. In turn, this
could mean that patients in the early stages of CVI receive
adequate treatment preventing the development of more severe stages of CVI. Furthermore, prevalence and socioeconomic data may serve as a valuable basis for the planning of
appropriate actions to deal with CVD and for the education
and hire of skilled personnel. By repeating an epidemiological
survey within a defined geographical area, these studies make
it possible to assess the effects of treatment protocols. I
physical pain (4 items), social relationships (3 items), and psychological limitations (9 items). The CIVIQ questionnaire uses
a Likert response scale, in which each item is scored from 0
to 5. A score per item (a value of 1-5) or a global score (a value of 0-100) can then be calculated. These questionnaires
have been successfully used in previous studies.38,40
References
1. Lawrence PF, Gazak CHE. Epidemiology of chronic venous insufficiency. In:
Gloviczki P, Bergan JJ, eds. Atlas of Endoscopic Perforator Vein Surgery. 1st
ed. London, UK: Springer Verlag; 1998:31-41.
2. Porter JM, Moneta GL; International Consensus Committee on Chronic Venous
Disease. Reporting standards in venous disease: an update. J Vasc Surg. 1995;
21:634.
3. Robertson L, Evans C, Fowkes FG. Epidemiology of chronic venous disease.
Phlebology. 2008;23:103-111.
4. Eberhardt R, Raffetto J. Chronic venous insufficiency. Circulation. 2005;111:
2398-2409.
5. Forssgren A, Fransson I, Nelzén O. Leg ulcer point prevalence can be decreased by broad-scale intervention: a follow-up cross-sectional study of a defined geographical population. Acta Derm Venereol. 2008;80:252-256.
6. Nelzen O. Prevalence of venous leg ulcer: the importance of the data collection
method. Phlebolymphology. 2008.15:143-150.
7. Coon WW, Willis PW, Keller JB. Venous thromboembolism and other venous
disease in the Tecumseh community health study. Circulation. 1973;48:839-846.
8. Abramson JH, Hopp C, Epstein LM. The epidemiology of varicose veins: a survey of western Jerusalem. J Epidemiol Community Health. 1981;35:213-217.
9. Franks PJ, Wright DDI, Moffat CJ, et al. Prevalence of venous disease: a community study in West London. Eur J Surg. 1992;158:143-147.
10. Laurikka JO, Sisto T, Tarkka MR, et al. Risk indictors for varicose veins in forty
to sixty-year-olds in the Tampere Varicose Vein Study. World J Surg. 2002;26:
648-651.
11. Sisto T, Reunanen A, Laurikka J, et al. Prevalence and risk factors of varicose
veins in lower extremities. Mini-Finland Health Survey. Eur J Surg. 1995;161:
405-414.
12. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins
and chronic venous insufficiency in men and women in the general population:
Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.
13. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethnically diverse population: the San Diego Population Study. Am J Epidemiol.
2003;158:448-456.
14. Brand FN, Dannenberg AL, Abbott RD, et al. The epidemiology of varicose
veins: the Framingham study. Am J Prev Med. 1988;4:96-101.
15. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous
disorders in the general population. J Vasc Surg. 2002;36:520-525.
16. Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study.
Reflux assessment and quality of life improvement with micronized flavonoids.
Angiology. 2002;53:245-256.
17. Maffei FHA, Magaldi C, Pinho SZ, et al. Varicose veins and chronic venous
insufficiency in Brazil: prevalence among 1755 inhabitants of a country town.
Int J Epidemiol. 1986;15:210-217.
18. Komsuoglu B, Goldelli O, Kulan K, Cetinarslan B, Komsuoglu SS. Prevalence
and risk factors of varicose veins in an elderly population. Gerontology. 1994;
40:25-31.
19. Arnoldi CC. The heredity of venous insufficiency. Dan Med Bull. 1958;5:169-176.
20. Da Silva A, Widmer LK, Martin H, et al. Varicose veins and chronic venous insufficiency – prevalence and risk factors in 4376 subjects of the Basle Study II.
Vasa. 1974;3:118-125.
21. Casarone MR, Belcaro G, Nicolaides AN, et al. Real epidemiology of varicose
veins and chronic venous disease: the San Valentino Vascular Screening Project. Angiology. 2002;53:119-130.
23. Moffatt CJ, Franks PJ, Doherty DC, Martin R, Blewett R, Ross F. Prevalence of
leg ulceration in a London population. QJM. 2004;97:431-437.
24. Rhodes JM, Gloviczki P, Canton LG, Rooke T, Lewis BD, Lindsey JR. Factors
affecting clinical outcome following endoscopic perforator vein ablation. Am
J Surg. 1998;176:162-167.
25. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic ulcer of the leg: clinical history. BMJ. 1987;294:1389-1391.
26. Scott TE, LaMorte WW, Gorin DR, Menzoian JO. Risk factors for chronic venous insufficiency: a dual case-control study. J Vasc Surg. 1995;22:622-628.
27. Mekky S, Schilling RSF, Walford J. Varicose veins in women cotton workers.
An epidemiological study in England and Egypt. BMJ. 1969;2:591-595.
28. Lee AJ, Evans CJ, Allan PL, Ruckley CV, Fowkes FG. Lifestyle factors and the
risk of varicose veins: Edinburgh Vein Study. J Clin Epidemiol. 2003;56:171-179.
29. Fowkes FG, Lee AJ, Evans CJ, Allan PL, Bradbury AW, Ruckley CV. Lifestyle
risk factors for lower limb venous reflux in the general population: Edinburgh
Vein Study. Int J Epidemiol. 2001;30:846-852.
30. Chiesa R, Marone EM, Limoni C, Volonte M, Schaefer E, Petrini O. Demographic 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.
31. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence. Int Angiol. 2008;27:1-59.
32. Lafuma A, Fagnani F, Peltier-Pujol F, Rauss A. Venous disease in France: an unrecognized 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.
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34. Tennvall GR, Andersson K, Bjellerup M, Hjelmgren J, Oien R. Treatment of venous leg ulcers can be better and cheaper. Annual costs calculation based
on an inquiry study. Lakartidningen. 2004;101:1506-1510,1512-1513.
35. McGuckin M, Waterman R, Brooks J, Cherry G, Porten L, Hurley S, Kerstein
MD. Validation of venous leg ulcer guidelines in the United States and United
Kingdom. Am J Surg. 2002;183:132-137.
36. Da Silva A, Navarro MF, Batalheiro J. The importance of chronic venous insufficiency: various preliminary data on its medico-social consequences. Phlebologie. 1992;45:439-443.
37. The global burden of disease: a comprehensive assessment of mortality and
disability 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,
CLINICAL
PRACTICE
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 through
quality of life questionnaires. Int Angiol. 2005;24:258-264.
39. Guex JJ, Zimmet SE, Boussetta S, Nguyen Le C, Taieb C. Construction and
validation of a patient reported outcome dedicated to chronic venous disorder: SQOR-V (Specific Quality of Life and Outcome Response-Venous). J Mal
Vasc. 2007;32:135-137.
40. Guex JJ, Enrici E, Boussetta S, Avril L, Lis C, Taieb C. Correlations between
ankle circumference, symptoms, and quality of life demonstrate the clinical relevance of minimal leg swelling reduction: results of a study in 1,036 Argentinean patients. Dermatol Surg. 2008;34:1666-1668.
Keywords: chronic venous insufficiency; prevalence; socioeconomic data; chronic venous disease
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 des
populations des études, des critères de sélection et de la définition de la maladie entre les différentes études. La prévalence de la MVC, rapportée dans les études, varie de 2 % à 56 % chez les hommes et de 1 % à 60 % chez les
femmes. Cette pathologie reste encore sous-estimée malgré son impact énorme sur les dépenses de santé et sur la
qualité de vie des patients. La MVC augmente avec l’âge et d’après des études récemment publiées, il n’y avait aucune différence significative entre les sexes. Les antécédents familiaux, l’obésité, la station debout prolongée et
le régime alimentaire sont des facteurs de risque, mais d’autres études sont nécessaires pour évaluer l’influence
des facteurs de risque potentiels sur le développement de la MVC. Le poids financier sur le système de santé est
énorme, 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 souligne le besoin d’études croisées et longitudinales de bonne qualité permettant de mesurer l’incidence et la prévalence de la MVC. Ces études pourraient permettre de réduire l’ampleur du problème de la MVC en éveillant la
conscience du public, des autorités et des professionnels de santé. De plus, la prévalence et les données socioéconomiques pourraient servir de base précieuse à la mise en œuvre d’étapes appropriées pour la prise en charge
de la MVC et pour éduquer et recruter du personnel qualifié.
258
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The identification and location of reflux can be accurately assessed with duplex ultrasound, so
the vascular laboratory should 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
only patients with chronic venous
insufficiency, but those with telangiectasias and varicose veins undergo duplex ultrasound examination of the superficial, deep, and
(selectively) perforator veins.”
DA I LY
DISEASE
GUIDELINES
CLINICAL
PRACTICE
Treatment of chronic venous
disease: pathophysiological
underpinnings
by R. D. Malgor
a n d N . L a b ro p o u l o s , U S A
C
L
Nicos LABROPOULOS,
BSc (Med), PhD, DIC, RVT
Rafael D. MALGOR, MD
hronic venous disease (CVD) causes a significant negative socioeconomic impact in society. Its indolent course confers a high tolerance
until treatment is pursued. The initial phase of the disease is often neglected by most patients and many seek treatment when the disease is advanced. The most common pathology is reflux in the superficial veins, while
isolated deep vein reflux is uncommon. Obstruction alone is rare, but is frequently found in combination with reflux, a scenario that has the worst prognosis. Several modalities of treatment are available, from medication using
venoactive drugs through to open and endovenous interventions. A comprehensive understanding of the causative mechanisms involved in the development of CVD is mandatory for choosing the most appropriate and tailored
treatment for each patient. This review focuses on the pathophysiological underpinnings involved in the treatment of CVD.
Division of Vascular Surgery
Stony Brook Medical Center
Stony Brook, New York
USA
Primary and secondary venous disease
hronic venous disease (CVD) is a worldwide affliction affecting a great portion of the world’s population.1 Despite its widespread prevalence, there are
several reasons why CVD treatment is delayed and why it attracts little attention for major research funding: it has an indolent course; clinical presentation
is late, with skin changes; and there is no risk of loss of limbs or mortality. There are
several factors involved in the pathophysiology of CVD. In recent years, the inflammatory pathway in CVD, on which certain medications act, has become better
known.2,3 Inflammatory processes, such as leukocyte migration, plasma-granulocyte activation, and increased metalloproteinase activity, all cause degradation of
the valve leaflets.4,5 Another factor involved in the pathophysiology of the CVD is calf
pump function. The calf pump increases blood flow velocity and maintains fluid
balance.6 Patients with dysfunctional calf pumps are more prone to develop skin
changes and more severe venous ulcer disease.7
C
Dr Nicos Labropoulos, Professor
of Surgery and Radiology, Director,
Vascular Laboratory, Department of
Surgery, HSC T19 Rm90, Stony
Brook University Medical Center,
Stony Brook, NY 11794-8191, USA
(e-mail: nlabrop@yahoo.com)
CVD is classified into two types: primary and secondary. Essentially, primary venous
disease is caused by venous reflux and affects two-third of limbs with CVD. Initially, increased venous pressure causes smooth muscle relaxation, endothelial damage, and extracellular matrix degradation.1,4 Subsequently, the vein wall becomes
weak 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 in
80% of cases, followed by reflux in perforator veins (PVs) and deep veins. Isolated
Treatment of CVD: pathophysiological underpinnings – Malgor and Labropoulos
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Figure 1. Examples of reflux with
ultrasound imaging from a female
patient who presented with varicose veins and swelling in the
right lower extremity.
(A) Reflux in the saphenofemoral junction. The common femoral vein and
greater saphenous vein (GSV) tributaries
in the groin were normal. (B) The GSV
at the knee is mildly dilated. The mild
dilatation in the center of the image and
the reflux pattern (blue color in each
valve cusp) during the release of the
compression indicate the presence of a
valve. (C) The GSV in the lower calf has
a small diameter, but a high velocity, very
prolonged retrograde flow. (D) Varicose
tributaries of the GSV from the lower
thigh to the calf. This particular segment
is actually one vein, although there appears to be many due to the tortuosity
of the tributary. The patient underwent
endovenous thermal ablation of the
GSV from the upper calf to a point 2 cm
from the saphenofemoral junction and
phlebectomies of the tributaries. The
remaining GSV was treated with foam
sclerotherapy.
involvement of deep veins is rare.8 Likely deep vein reflux is
noted when longstanding superficial vein reflux affects the venous junctions (Figure 1) and the PVs in turn render the deep
veins incompetent. Often, isolated primary deep vein reflux is
found in the common femoral vein, followed by the femoral
and popliteal vein. Deep vein reflux can be found in association with superficial vein reflux in up to 40% of cases.9-11
PV reflux is another component of CVD commonly related
to superficial vein reflux.12 Two mechanisms have been proSELECTED
AVF
CEAP
CT
CVD
CVI
DVT
ESCHAR
EVLT
GSV
MR
PTFE
PTS
PV
RFA
SFJ
SPJ
SSV
SVS
260
arteriovenous fistula
computed tomography
deep vein thrombosis
Effect of Surgery and Compression on Healing And
Recurrence [study]
endovenous laser therapy
great saphenous vein
magnetic resonance
polytetrafluoroethylene
postthrombotic syndrome
perforator vein
radiofrequency ablation
saphenofemoral junction
saphenopopliteal junction
small saphenous vein
Steam Vein Sclerosis™ [system]
posed to explain how PV valves become incompetent. The
first mechanism is an ascending extension of superficial vein
reflux causing progressive vein dilation and reflux that propagates proximally rendering the perforator vein dilated and incompetent. The second mechanism is a descending propagation where re-entry PVs drain reflux blood into the deep
veins. Over a long period of time, the high flow volume in the
PVs causes dilatation and reflux in these veins.12,13 PV reflux
most often originates in the GSV system and may render the
deep veins incompetent.12 In cases of deep vein reflux secondary to PV reflux, frequently only a short segment is affected.
Secondary venous disease is less common than primary CVD
and is caused by either a thrombotic event or arteriovenous
fistula (AVF). Trauma has been mentioned as a cause of secondary CVD, but this occurs through deep venous thrombosis (DVT) of an AVF that can occur after trauma. Increasing
venous pressure secondary to AVF formation creates local
venous hypertension causing endothelium damage, vein wall
weakening, and dilation faster but similar to that observed in
primary CVD.2,14
DVT is the most common cause of secondary CVD. Many
risk factors are involved in the development of DVTs, such as
pregnancy, operations, immobilization, malignancy, trauma,
and obesity. In addition, patients who have a hypercoagulation disorder (ie, mutation of coagulation factors, active protein C resistance, protein S and antithrombin III deficiency) are
likely to develop DVT. Reflux, obstruction, and a combination
of reflux and obstruction are the three possible patterns present in secondary CVD. The worst prognosis is when reflux and
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Figure 2. Chronic obstruction
with partial recanalization and
reflux in a 58-year-old female
patient with previous caval,
iliofemoral, and popliteal vein
thrombosis.
She had significant thigh and calf
swelling bilaterally. (A) Chronic thrombosis of the common femoral vein.
Echogenic material is seen in the lumen and there is a lack of compressibility. (B) Irregular flow channels are
seen in the lumen. Flow is detected
in collateral veins on either side of
the thrombosed segment. (C) The
femoral vein is partially recanalized
and has reflux. Chronic thrombus is
seen mostly towards the far wall. (D)
Reflux in a perforator vein in the lower
calf. The vein is dilated with a diameter of 5 mm. Reflux was found in the
posterior tibial vein, and the calf posterior accessory tributary. The great
saphenous vein was normal at this
level, but chronically thrombosed at
the saphenofemoral junction. The patient was treated conservatively with
compression.
obstruction are present in the same limb, rendering the limb
prone to skin changes, such as discoloration, and to venous
ulcers. Ipsilateral recurrent DVT, iliofemoral thrombosis, and
persistent intensity of signs and symptoms in the first month
after the episode of DVT are important predictors for developing postthrombotic syndrome (PTS).15-17
Partial recanalization (Figure 2) is seen more frequently than
total recanalization or complete occlusion of veins after an
episode of thrombosis.18 The location of reflux and obstruction also plays a role in the development of PTS, which is defined as a group of signs and symptoms comprising heaviness, edema, itching, and eventually skin damage including
venous ulcers.18 Lastly, in a minority of cases, congenital venous malformations are to blame for CVD. Agenesis, hypoplasia, and the absence of valves in a short or long segment
of superficial or deep veins are the most common findings.19
Although the clinical course of CVD is indolent, over time it
causes a negative impact on health and quality of life. In order
to create a standardized method to describe patients with
CVD, a classification based on clinical (“C”—telangiectasias to
skin damage), etiological (“E”—primary, secondary, or congenital), anatomical (“A”—superficial, deep, or perforators), and
pathophysiological (“P”—reflux, obstruction, or both) findings
has been created, which is known by the acronym CEAP:
Clinical-Etiological-Anatomical-Pathophysiological. The majority of patients are at an initial stage of the disease (C1-C2)
and have telangiectasias and varicose veins. Chronic venous
insufficiency (CVI) occurs when patients present with edema
or skin damage (discoloration or venous ulcers).
Treatment
Treatment modalities for CVD, for which there are many,
should be tailored to the specifics of each patient based on
pathophysiological findings. Patients should then be stratified according to disease severity, and nonoperative and invasive treatments used alone or in combination. All patients
with CVD should be referred to specialists for general and focused history taking and physical examination. Many options
for venous disease workup are available, including direct and
indirect noninvasive methods and other imaging studies, such
as computed tomography (CT)/CT venograms, magnetic resonance (MR) imaging/MR venograms, and contrast venography (ascending and descending).
The identification and location of reflux can be accurately assessed with duplex ultrasound, so the vascular laboratory
should 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 only
patients with CVI, but those with telangiectasias and varicose veins undergo duplex ultrasound examination of the
superficial, deep, and (selectively) perforator veins to evaluate valvular incompetence prior to initial treatment of CVD.
Laboratory workup for screening of patients with positive familial histories of hypercoagulation states or venous ulcers
should be individually tailored.
Recently, the role of CT venograms and MR venograms for
the identification of iliofemoral and caval obstructions in patients with skin damage has been investigated. A positive result showing significant stenosis or obstruction can change
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the treatment approach and therapy and potentially reduce
the recurrence of the venous disease. However, the routine
indication of noninvasive and invasive treatments with intravascular ultrasound assessment of iliofemoral and caval obstructive disease is not yet recommended for routine use.
N Medication (venoactive drugs)
Many different categories of medication have been used for the
treatment of CVD: alpfa-benzopyrones (coumarin), gammabenzopyrones (ie, purified flavonoids), saponins (escin and
ruscus extract), plant extracts (ie, ginkgo biloba), and synthetic products (ie, benzaron).20 The use of medication for varicose veins is based on the targeting of inflammatory pathways involved in the development of CVD. The best results of
all the medication regimens are achieved in early cases of
CVD where no significant structural changes of the vein wall
and valves have occurred. However, certain venoactive drugs
have been used successfully in patients with more advanced
disease (with edema and venous ulcers). A meta-analysis of 5
prospective, randomized trials in 723 patients demonstrated
encouraging 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 (Daflon
500 mg) was found to decrease the levels of granulocyte and
macrophage infiltration in the valves preventing valve damage and delaying the development of reflux.22 Another class
of flavonoids, the oxerutins, are also utilized for their anti-inflammatory properties. Low cost, widespread availability, and
rare side effects are advantages of treating CVD with medication. The only contraindication to the use of venoactive drugs
is allergy to one of the components of the formula, but this
is rare.
N Compression therapy, structured exercise,
and wound care
Compression therapy has long been considered the first-line
treatment for all symptomatic patients with CVD (C1-C6) where
venoactive drugs are unavailable (USA, for example). The rationale for using compression hosiery is to increase venous
blood flow velocity, thus improving venous reflux, and also to
assist the calf muscle pump, therefore reducing leg edema.23,24
The local inflammatory response also decreases with a reduction in cytokine production and the shift of local cutaneous
fluid from the interstitial space to the lymphatic system.25,26
There are several advantages of compression therapy. First, all
patients are eligible for use except for those with severe peripheral arterial insufficiency (ankle-brachial index [ABI] <0.5).
Second, patients with CVI (C3-C6), especially those with venous stasis ulcers, benefit significantly from therapy with good
levels of ulcer healing and they remain ulcer-free for a reasonable length of time. In a prospective, multicenter randomized
study that examined 200 limbs with venous ulcers that were
randomized for compression or surgical treatment, the ulcer
healing rate was similar in both groups (53%).27 A larger pros-
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pective, randomized trial of 500 patients, the ESCHAR (Effect
of Surgery and Compression on Healing And Recurrence)
trial, demonstrated that compression therapy is as effective
as surgery plus compression therapy for ulcer healing, but
recurrence rates were higher when compression was used
alone.28 A document detailing multiple modalities of compression therapy (ie, simple component, two- or four-component, elastic, nonelastic) was produced by the Cochrane
Collaborative Group. The results of the Cochrane systematic
review show that elastic multicomponent systems, ie, containing an elastic bandage, appear more effective than those
that have inelastic components.29 Regardless of the high efficacy of the different compression garments and techniques
in ulcer healing and preventing ulcer recurrence, the most
challenging aspect of treatment remains the lack of compliance: four in five patients are noncompliant.30
Exercises to strengthen the calf muscle pump and intermittent pneumatic devices have proven beneficial as an adjuvant therapy in patients with CVD. Calf muscle pump conditioning can lead to a subsequent improvement in venous
blood return.31 A randomized controlled trial in 31 patients with
skin damage or ulcers who were divided into two groups (a
structured exercise group [n=18] and controls [n=13]) showed
that the calf pump function did improve venous blood return,
but the quality of life and severity scores of the groups were
similar.32 However, this study only provides short-term results
with a 6-month follow-up. Large trials with mid- and long-term
follow-ups are warranted to gauge the actual impact of calf
pump function on quality of life, venous ulcer healing, and ulcer recurrence. Compression therapy should not be viewed as
a definitive therapy, but rather as a valuable adjuvant tool that
can be utilized in all symptomatic patients with CVD to hinder
the progress and prevent the recurrence of venous ulcers.
Venous ulcers are responsible for lost work productivity and
high health-care costs.33,34 Patients with skin damage who
develop ulcers must be evaluated and treated in specialized
wound care centers by a multidisciplinary team.35 The initial
treatment of venous ulcers targets the underlying cause of
CVD (venous obstruction, reflux, or a combination of obstruction and reflux).28 In addition, infected areas require treatment with appropriate antibiotic regimens (guided by culture
biopsies) and debridement, which is performed in operating
rooms.36 There has been progress in the field of ulcer debridement recently. A new technique for the debridement of
venous ulcers, low-frequency ultrasound, has been developed, but for the moment limited experience and low-quality evidence mean the routine use of this technique is not
recommended.37
N Sclerotherapy
Venous injection of sclerosing agents has gained popularity
due to the minimal material, low cost, and short learning curve
required. Currently, two types of sclerotherapy are available:
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liquid and foam (Figure 3). Whatever formulation is utilized
for the ablation of the GSV or SSV, ultrasound guidance is
mandatory in order to gauge the amount of foam necessary
to obliterate the segment of interest and, more importantly,
to control the extent of sclerotherapy.
The advantages of foam over liquid are better control during
injection, less volume required to fill the target vessel, greater
circumferential contact area between the treatment and endothelial cells, and a longer sclerosing time due to a slower
absorption compared to the liquid preparation. A multicenter randomized controlled trial of 95 patients showed that a
polidocanol foam preparation was
twice as effective at achieving and
maintaining venous occlusion over
a 2-year follow-up as the liquid version.38 Furthermore, other studies
have demonstrated that more dilute
solutions, such as 1% polidocanol,
are as effective as stronger solutions
of 3% in obliterating GSV <8 mm.39
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EVLT and RFA are ultrasound-guided, catheter-based techniques that obliterate the lumen of the GSV and SSV and
occasionally perforator veins via a totally endovascular approach. First, diluted local anesthetic in saline solution is injected abundantly prior to the venous ablation in the subcutaneous tissue around the GSV, SSV, or accessory veins to
create a fluid barrier between the vein and the skin and to reduce the size of the vein lumen. The purpose of the tumescent local anesthesia is to prevent skin damage (such as
thermal injury or discoloration), to increase the effectiveness
of the procedure (via vein wall compression), and to provide
intra- and postoperative analgesia.
The drawback of the technique is
the possible inadvertent passage of
sclerosing agent into the deep veins, Figure 3. Nonsaphenous vein reflux.
which is not completely prevented (A) Prolonged reflux in the left ovarian vein in a patient who presented with pelvic congestion syndrome and
either with ligation or compression of varicose veins in the groin medial to the saphenofemoral junction extending down to posteromedial thigh. The
patient was treated with selective catheterization of the left ovarian vein. Foam sclerotherapy was used for the
the saphenofemoral junction (SFJ) distal tributaries in the pelvis and the ovarian vein was coiled with long coils. The varicosities in the thigh were
with the ultrasound probe during the removed with phlebectomy and those in the inner groin with foam sclerotherapy. (B) Prolonged reflux in the vein
the popliteal fossa in a patient who presented with varicosities in the posterior and later calf. The small sapheintervention.40 Fortunately, complica- of
nous vein was intact. Phlebectomies were performed with adjunct foam sclerotherapy.
tions of sclerotherapy are rare because they can be serious 41: lung and brain emboli have been The RFA or EVLT catheter is then inserted into the vein and
reported.41,42 Long-term results from large multicenter, ran- positioned up to 2 cm away from the SFJ or SPJ in order to
domized controlled trials are still warranted to assess the avoid thermal injury or extension of the thrombus into the comdurability of treatment and to define potential predictive fac- mon femoral or popliteal vein. Different wavelengths of laser
(ie, 810-1470 nm) and two different types of energy transtors to prevent adverse outcomes.
mission (ie, pulsed or continuous) are commercially available
in the USA.
N Stripping, stab phlebectomy, and ablation procedures
The treatment of superficial venous reflux has evolved greatly
over the past three decades. The old standard of care, liga- Endovenous interventions have some advantages over vein
tion of the SFJ or saphenopopliteal junction (SPJ) with or with- stripping as an ambulatory-based intervention with same-day
out stripping of the GSV or SSV, has been replaced by radio- discharge. These include the feasibility of performing the interfrequency ablation (RFA) or endovenous laser therapy (EVLT). vention under local anesthesia with light sedation and a faster
The stripping of the GSV consisted of dissection and isolation return to work. Modified stripping techniques with ultrasound
of the SFJ and the distal segment of the GSV or SSV at the guidance and local perivenous anesthesia without ligation of
end point of reflux with insertion of a metallic or plastic wire the junction and its triburies may have similar results.44-47 Sevthrough the isolated segment with subsequent stripping of eral trials have reported similar efficacies with GSV and SSV
the vein. The disadvantages of the technique included the ablation and the resolution of symptoms using either EVLT or
risk of wound infection, postoperative pain, longer recovery RFA.48-50 Complications of endovenous ablation include skin
time, and a significant inflammatory response in the SFJ or burns and the propagation of the thrombus into the deep
SPJ leading to neovascularization and the recurrence of the veins causing DVT and pulmonary embolism. Venous thromvaricose veins.43 Modifications to the traditional stripping with boembolic events have also been reported with ligation and
invagination technique and the use of tumescence have restripping.51 Recent studies have demonstrated that thermal
duced complications of this technique and have made it an ablation procedures and surgical techniques have similar outoutpatient procedure.44
comes in abolishing reflux and improving quality of life.52
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Figure 4. Reflux in the lower
thigh great saphenous vein and
a knee tributary.
(A) Reflux in the great saphenous vein
(GSV) and a tributary at the knee level. High velocity prolonged retrograde
flow was seen in both veins, but was
worst in the tributary (waveform tracings not shown). (B) The GSV at this
level is dilated (8.7 mm). A valve leaflet
is seen at the 9 o’clock position.
(C) Cross-sectional view of the GSV
and tributary 1 cm below the confluence of the tributary and GSV. The GSV
is normal and the tributary is dilated.
(D) At this level, reflux is seen in the
tributary while the GSV is normal. This
patient was treated with phlebectomies
and the GSV was spared. After the
procedure, GSV diameter was reduced
in size and there was no reflux.
Abbreviation: GSV, great
saphenous vein.
Two other innovative alternatives to vein ablation are the ClariVein™ (Vascular Insights, Madison, Connecticut) and the Steam
Vein Sclerosis (SVS) system™ (Guttman Medical Services
GmbH, Geretsried, Germany). The former consists of a percutaneous 0.035" infusion catheter that contains a rotating
wire operated and activated from a DC battery-powered handheld device. The pharmacomechanical effects cause endothelial damage, intense vasospasm, and eventually thrombosis of the lumen. The SVS™ system delivers water vapor
through a heating catheter that does not require a wire inside the vein causing thermoablation comparable to that of
RFA or EVLT. Like EVLT or RFA, ultrasound guidance is needed for both ClariVein™ and SVS™, but tumescent local anesthesia is only required for the SVS™ system. The initial results of Clarivein™ 53 and SVS™ 54 for venous ablation are
promising, but further research is still needed.
In light of the fact that the varicosities of tributaries and accessory veins are far more prevalent than those of saphenous
trunks, these veins can be treated alone or in combination
with the saphenous veins.55 Treatment of varicose veins can
be easily accomplished with stab phlebectomies (Figure 4).
A microincision is carried out near the varicose vein wall to
permit the insertion of an angle-tipped instrument used to
fish and remove the varicosity. It may be a definitive treatment
for patients who have isolated varicose veins with superficial
or deep vein reflux (CEAP C2) or an adjunct therapy, frequently performed on the same day as venous stripping or ablation. Patients with segmental GSV reflux or an incompetent
GSV with a normal or mildly dilated caliber and varicose veins
264
may also be treated with stab phlebectomies alone.44,56 In a
study of 303 limbs, the incompetent GSV was not removed,
but only the varicose veins linked to the zones of reflux. In
this series, 78% of the patients reported an improvement in
symptoms or no symptoms at 4-year follow-up.57
The role of PV treatment has been controversial. Although the
number and size of incompetent PVs increases with CVD
severity, evidence for treating most of these veins is lacking
with the exception of a few cases.13,28,58,59 The role of superficial venous reflux on the development of deep venous incompetence has been investigated. Since isolated deep venous
reflux is rare, the concept of volume overload in the superficial venous system causing valve dysfunction in the perforator and deep veins has been reported.11 Treatment of superficial vein reflux has been shown to correct valve function
in deep veins.9,10 Patients with skin damage or secondary CVD
have worse results because of chronic inflammatory changes,
severe valve dysfunction, and vein wall dilation.
N Open and endovascular venous reconstruction
Venous reconstructions are frequently indicated in symptomatic patients with secondary CVD who have significant venous stenosis, obstruction, or a residual thrombus (Figure 5).
Before the endovenous era all patients with ilio-femoral and
caval obstruction were treated with open procedures including bypass graft, spiral vein interposition graft, and venoplasty.
Initially, an arteriovenous fistula (AVF) is frequently associated
with venous bypass construction aimed at reducing venous
stasis and therefore increasing the patency of the repair. The
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Figure 5. Pathology in tributaries
in a patient with a normal great
saphenous vein.
(A) The saphenofemoral junction is normal during the Valsalva maneuver. The
greater saphenous vein (GSV) has a
normal diameter and refluxing tributaries
are seen. (B) The anterior accessory
saphenous vein had reflux from the upper
thigh to the calf. The segment seen is
from the midthigh, where the vein is outside its canal. It is dilated, tortuous, and
has prolonged reflux. (C) The accessory
vein was in continuity with varicose tributaries extending from the lower anteriormedial thigh to the posterior-lateral calf.
(D) A short segment of the accessory
vein had acute and chronic thrombosis.
The bright areas from the 3 to 5 o’clock
position and the near wall are chronic
thrombus, while the dark area is fresh
thrombus. The patient had localized
inflammation and tenderness over this
area. Because of the thrombosis, the
accessory vein was partially stripped
and the tributaries were treated with
phlebectomies.
shortcoming of AVFs is that the venous hypertension generated causes vein wall dilation, valve destruction, and venous
reflux if the AVF is not monitored and ligated in a timely fashion. A series of 44 patients with nonmalignant venous obstruction who underwent different types of reconstructions
(ie, spiral vein, bypass, venoplasty, Palma procedure) reported an overall primary and secondary patency at 3-years of
54% and 62%, respectively.60 Lower primary and secondary
patency rates were found for iliofemoral and iliocaval bypasses when analyzed separately, only 38% and 54% at 2-year
follow-up, respectively, likely because the majority of repairs
were done using extended polytetrafluoroethylene (PTFE)
grafts.60
Endovenous treatment of common femoral and iliocaval obstruction comprise angioplasty and stenting. The big advantage of percutaneous treatment compared with transperitoneal
or retroperitoneal approaches under general anesthesia is
the lower morbidity and mortality. In a series of 982 chronic nonmalignant obstructive lesions of the common femoral
and iliocaval veins that were stented, complete relief of pain
and swelling occurred in 62% and 32% of cases, respectively, and ulcer healing in 58% of the patients at 5-year follow-up.61
Treatment of venous reflux, obstruction, or a combination of
reflux and obstruction in the femoropopliteal venous segment
remains challenging. Reduced blood flow and caliber of the
veins, associated with an aggressive pattern of the disease,
are some of the reasons responsible for the significant failure
rate and poorer patency.
Several open surgical valve reconstruction techniques have
been proposed to correct venous reflux and obstruction.
The main procedures described are internal and external
(transcommissural) valvuloplasty, axillary vein transfer, vein
transplantation, and valve transplant.62-64 Surgical expertise,
postprocedural care, and referral to a high-volume specialized center for these specific procedures are essential.
Briefly, with an internal valvuloplasty, the incompetent valve
is exposed and the leaflets are approximated suturing the
intercomissural space with subsequent closure of the venotomy.65 The external (transcommissural) valvuloplasty is performed without doing a venotomy with interrupted sutures
placed externally transfixing the venous wall to approximate
the intercomissural space.66 The advantage of the transcommissural repair is the possibility of treating long segments in
a shorter operating time. Valve transfer is often carried out
while dissecting, dividing, and resecting a segment of vein
that serves as a graft (ie, axillary vein) for replacement of a diseased venous segment in a lower extremity.67 Neovalve creation is now feasible with a technique developed by Maleti
and colleagues.68 In this technique, an endophlebectomy of
the venous segment is performed with dissection of the intima layer creating a flap that is positioned as a mono- or
bicuspid valve with subsequent venorraphy in a transverse
fashion.68
The use of an external sleeve of Dacron or PTFE wrapped
around the incompetent valve has been advocated by some
authors in order to narrow and approximate the valve leaflets
or as an adjunct after a vein transfer to prevent future vein
265
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wall dilation.69 Satisfactory results have been reported using
all techniques, although limited experiences in a few specialized centers are available for comparison in the US and
Europe.
Conclusion
CVD is a multifaceted entity responsible for significant negative socioeconomic impact. Treatment of the CVD requires
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PRACTICE
a complete understanding of the pathophysiological underpinnings of the disease in order to offer the most appropriate
treatment tailored to the disease specifics of each patient.
Combinations of different types of treatment may be necessary in the majority of the patients. Given that over 25% of patients with CVD have skin damage, treatment at earlier stages
may be important to slow down the progression and to reduce the prevalence of skin damage from CVD. I
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29. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane
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30. Raju S, Hollis K, Neglen P. Use of compression stockings in chronic venous
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31. Kan YM, Delis KT. Hemodynamic effects of supervised calf muscle exercise in
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32. Padberg FT Jr, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc
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33. Robertson L, Evans C, Fowkes FG. Epidemiology of chronic venous disease.
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34. Van den Oever R, Hepp B, Debbaut B, Simon I. Socio-economic impact of
chronic venous insufficiency. An underestimated public health problem. Int Angiol. 1998;17:161-167.
35. Wakefield TW, Henke PK. The Sixth Pacific Vascular Symposium: the venous
ulcer summit. Arterioscler Thromb Vasc Biol. 2010;30:2337-2338.
36. Williams D, Enoch S, Miller D, Harris K, Price P, Harding KG. Effect of sharp
debridement using curette on recalcitrant nonhealing venous leg ulcers: a concurrently 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 ulcers. Cochrane Database Syst Rev. 2010;(6):CD001180.
38. Ouvry P, Allaert FA, Desnos P, Hamel-Desnos C. Efficacy of polidocanol foam
versus liquid in sclerotherapy of the great saphenous vein: a multicentre randomised controlled trial with a 2-year follow-up. Eur J Vasc Endovasc Surg.
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39. Hamel-Desnos C, Ouvry P, Benigni JP, et al. Comparison of 1% and 3% polidocanol 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 J
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40. Ceulen RP, Jagtman EA, Sommer A, Teule GJ, Schurink GW, Kemerink GJ.
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Endovasc Surg. 2010;40:772-776.
41. Gillet JL, Guedes JM, Guex JJ, et al. Side-effects and complications of foam
sclerotherapy of the great and small saphenous veins: a controlled multicentre prospective study including 1,025 patients. Phlebology. 2009;24:131-138.
42. Bush RG, Derrick M, Manjoney D. Major neurological events following foam
sclerotherapy. Phlebology. 2008;23:189-192.
43. Jiang P, van Rij AM, Christie R, Hill G, Solomon C, Thomson I. Recurrent varicose veins: patterns of reflux and clinical severity. Cardiovasc Surg. 1999;7:
332-339.
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44. Pittaluga P, Chastanet S, Guex JJ. Great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. J Vasc
Surg. 2008;47:1300-1304; discussion 1304-1305.
45. Bush RG, Hammond KA. Tumescent anesthetic technique for long saphenous
stripping. J Am Coll Surg. 1999;189:626-628.
46. Scheltinga MR, Wijburg ER, Keulers BJ, de Kroon KE. Conventional versus invaginated 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 stripping of the long saphenous vein using the tumescent technique for local anesthesia. 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 wavelength
laser and the ClosurePLUS radiofrequency ablation methods for superficial venous 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 therapy and radiofrequency ablation of the great saphenous vein: analysis of early
efficacy and complications. J Vasc Surg. 2005;42:488-493.
50. Goode SD, Chowdhury A, Crockett M, et al. Laser and radiofrequency ablation study (LARA study): a randomised study comparing radiofrequency ablation 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 after
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52. Christenson JT, Gueddi S, Gemayel G, Bounameaux H. Prospective randomized trial comparing endovenous laser ablation and surgery for treatment of
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55. Labropoulos N, Kokkosis AA, Spentzouris G, Gasparis AP, Tassiopoulos AK.
The distribution and significance of varicosities in the saphenous trunks. J Vasc
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56. Labropoulos N, Leon L, Engelhorn CA, et al. Sapheno-femoral junction reflux
in 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 treatment of varices by phlebectomy with conservation of a refluxing saphenous vein.
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58. Nelzén O, Fransson I; Swedish SEPS Study Group. Early results from a randomized trial of saphenous surgery with or without subfascial endoscopic perforator surgery in patients with a venous ulcer. Br J Surg. 2010 Dec 24. Epub ahead
of print.
59. Kalra M, Gloviczki P. Subfascial endoscopic perforator vein surgery: who benefits? Semin Vasc Surg. 2002;15:39-49.
60. Jost CJ, Gloviczki P, Cherry KJ Jr, et al. Surgical reconstruction of iliofemoral
veins and the inferior vena cava for nonmalignant occlusive disease. J Vasc
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61. Neglen P, Hollis KC, Olivier J, Raju S. Stenting of the venous outflow in chronic
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62. Meissner MH, Eklof B, Smith PC, et al. Secondary chronic venous disorders.
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63. Neglen P, Raju S. Venous reflux repair with cryopreserved vein valves. J Vasc
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64. Taheri SA, Elias SM, Yacobucci GN, Heffner R, Lazar L. Indications and results
of vein valve transplant. J Cardiovasc Surg. 1986;27:163-168.
65. Kistner RL, Ferris EB III, Randhawa G, Kalauokalani DA. The evolving management of varicose veins. Straub Clinic experience. Postgrad Med. 1986;80:5153, 56-59.
66. Raju S, Berry MA, Neglen P. Transcommissural valvuloplasty: technique and results. J Vasc Surg. 2000;32:969-976.
67. Raju S, Fredericks RK, Neglen PN, Bass JD. Durability of venous valve reconstruction techniques for “primary” and postthrombotic reflux. J Vasc Surg. 1996;
23:357-366; discussion 366-357.
68. Lugli M, Guerzoni S, Garofalo M, Smedile G, Maleti O. Neovalve construction in
deep venous incompetence. J Vasc Surg. 2009;49:156-162, 162 e151-152; discussion 162.
69. Jessup G, Lane RJ. Repair of incompetent venous valves: a new technique.
J Vasc Surg. 1988;8:569-575.
Keywords: chronic venous disease; treatment; pathophysiology
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 souvent la phase initiale de la maladie et sont demandeurs d’un traitement lorsque la maladie est évoluée. Le reflux
veineux superficiel est la pathologie la plus courante, contrairement au reflux veineux profond isolé. L’obstruction isolée est rare mais fréquemment retrouvée en association avec un reflux, scénario au plus mauvais pronostic. Il existe
plusieurs modalités de traitement, des phlébotoniques aux interventions endoveineuses ou à ciel ouvert. Il faut une
compréhension complète des mécanismes impliqués dans le développement de la MVC pour choisir le traitement
le plus approprié et personnalisé pour chaque patient. Cet article traite des bases physiopathologiques impliquées
dans le traitement de la MVC.
267
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‘‘
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AND
In summary, it is clear that
one investigational method does
not suffice to evaluate the management of CVD. Both physicianand patient-centered methods
need to be utilized to generate
satisfactory conclusions. However,
using all these methods together
produces complex results that are
cumbersome to interpret and communicate. Thus, we need to revisit
our understanding of the etiopathogenesis of CVD to guide us
in designing evaluation methods
that focus on pathologic factors.”
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GUIDELINES
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Classifications, severity
scorings, and chronic
venous disease guidelines
b y M . Ku r t o ğ
g l u a n d M . A k s oy, Tu r key
C
Ğ
Mehmet KURTOGLU,
MD
Murat AKSOY, PhD
Peripheral Vascular Surgery Unit
Department of General Surgery
Istanbul Medical Faculty
Istanbul University, Istanbul
TURKEY
Prof Murat Aksoy, Department
of General Surgery, Istanbul Tip
Fakultesi Capa, Istanbul,
34390 Turkey
(e-mail: maksoy@tnn.net)
268
hronic venous disease (CVD) continues to impose a significant burden
on both patients and physicians since the way to manage it most effectively still remains elusive. A great deal of research has revealed
that the long-term outcomes of highly distinct treatment methods, including
invasive and completely noninvasive techniques, yield comparable results
overall. The rationales behind these techniques are very different from each
other, which raises a concern about the validity of the methods that are used
to calculate the severity of CVD before and after treatment. One of the major
obstacles to collecting consistent CVD management data is that CVD severity can be evaluated in many different ways. While a patient’s quality of life
is perhaps the most important measurement, physician-centered parameters exist and they are primarily based on the pathophysiology of the disease.
Furthermore, the variability in the perception of the disease among different
groups of patients presents another challenge in drawing conclusions from
various studies. These scoring systems need to be dynamic, since CVD management comprises the treatment of clinical issues that evolve over a long
period of time. Realization of these pitfalls has resulted in a number of modifications to previously established scoring systems. However, even today,
the modified versions individually fail to indicate the overall severity of the disease. Thus, there is still the need to generate a universally acceptable scoring system in CVD that combines the most significant parameters of the current investigation methods.
ecently, management of chronic venous disease (CVD) has embraced new
methods of treatment. In the 20th century, the only treatment for CVD was various methods of surgery with some forms of conservative therapy, ie, stockings. Although all of these methods were claimed to be effective, the long-term
outcomes as well as the efficacy of these treatments have never been compared to
each other. Until recently, it was assumed that surgery was more efficacious than
conservative approaches, and therefore the latter form of treatment was saved for
patients who were not eligible for surgery.
R
The move towards surgical management of CVD has generated newer forms of
methods, such as ASVAL (incompetent sAphenouS Vein preservAtion with phLebectomy [Ablation Sélective des Varices sous Anesthésie Locale]) and CHIVA (Conservative ambulatory HemodynamIc management of VAricose veins [Cure conser-
ğ and Aksoy
Classifications, severity scorings, and chronic venous disease guidelines – Kurtoglu
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DISEASE
vatrice et Hémodynamique de l’Insuffisance Veineuse en Ambulatoire]). However, postoperative analysis of these methods by Doppler ultrasonography has revealed that all of the
surgical approaches were comparable. This finding is interesting since the methodologies of these surgical approaches
were distinct from each other: CHIVA is based on correcting
descending venous reflux, while ASVAL is based on the ascending negative pressure steal phenomenon. Despite these
differences, the early anatomical, clinical, and hemodynamic results of these methods were surprisingly similar.1,2
In addition to surgical methods, newer approaches using radiofrequency, lasers, and sclerotherapy to ablate veins have
further expanded the range of methods to manage CVD.
These newer approaches are reported to be at least as effective as conventional surgical methods.3-5 It appears that
methods that are grossly different from each other claim to
have similar outcomes. The question then becomes: “How
should we define the effectiveness or success of CVD management?” From the patient’s point of view, success and satisfaction is usually based on improving quality of life, while
physicians would also focus on resolving the anatomical and
hemodynamical pathologies of CVD. Another measure of effectiveness comes from an economic standpoint: cost-effectiveness of management. Lastly, it should not be forgotten
that the severity of recurrence has its own role in defining the
efficacy and success of a treatment method.
What current instruments can assess the efficacy
of CVD treatment?
Since all methods of CVD management claim to be efficacious,
we need to elaborate on what kind of assessment tools can
be used to evaluate the efficacy of CVD management. The
following section will focus on defining these tools as well as
their validity in assessing the efficacy of CVD management.
These tools can be summarized as anatomical (color duplex),
hemodynamical (venous pressures), clinical (CEAP [ClinicalEtiological-Anatomical-Pathophysiological] and VSS [Venous
Severity Score]), and functional (quality of life).
N Anatomical investigation
The clinical outcome of venous disease is related to the extent of venous insufficiency involvement.6 In consequence,
anatomical assessment is an outstanding way of evaluating
the disease. Anatomical assessment of CVD is mainly based
on color duplex imaging of veins. This instrument-based approach generates both morphological and functional results
to evaluate CVD management. There is a widely accepted
terminology used in this method, which is based on the obstruction and reflux of superficial, perforating, and deep veins.
Therefore, color duplex imaging allows both quantitative and
qualitative assessment of the severity of pathology in these
veins. The diameter of the incompetent vein can be measured
by duplex imaging. However, diameter alone is not a valid
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method of assessment. This measurement may be of value
in cases where an increase is detected during follow-up because it may be indicative of a recently developed connection
between the greater saphenous vein and pelvic sources of reflux. Measurement of diameter is recommended at the junction and along the great saphenous vein if there is reflux. Although a definitive cutoff for all vein segments has not been
agreed, venous reflux is considered to be retrograde flow in
the reverse direction to physiological flow if it lasts for more
than 0.5 s.7,8 Finally, diameter is not a marker for indication, but
may help in deciding the type of intervention required, such as
sclerotherapy, laser, or radiofrequency ablation.
N Clinical investigation
Clinical investigations are based on the assessment of visible
pathologies that result from CVD, such as edema, varicose
veins, and ulcers. The clinical evaluation of these pathologies
is further supplemented by color duplex imaging of veins. In
the course of CVD management, these visible pathologies
can be partially or completely resolved, and clinical investigations score the level of this improvement. However, it is
important to note that these investigations are not sufficiently dynamic to assess the durability of wellness.
SELECTED
ASVAL
incompetent sAphenouS Vein preservAtion with
phLebectomy [Ablation Sélective des Varices
sous Anesthésie Locale]
AVVQ
Aberdeen Varicose Veins Questionnaire
CEAP
CHIVA
Conservative ambulatory HemodynamIc management
of VAricose veins [Cure conservatrice et Hémodynamique de l’Insuffisance Veineuse en Ambulatoire]
CIVIQ
CVD
CVI
CXVUQ
Charing X [cross] Venous Ulceration Questionnaire
EQ-5D
EuroQol 5 Dimension [mobility, self-care, usual activities, pain/discomfort, anxiety/depression health
survey]
NHP
Nottingham Health Profile
RELIEF
Reflux assEssment and quaLity of lIfe improvEment
with 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
VDS
VEINES
VEnous INsufficiency Epidemiological and economic
Study
VSDS
VSS
Venous Severity Score
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There are two main clinical investigation methods: CEAP
and VSS. The CEAP classification was first developed in the
1990s.9,10 The original classification was modified in 2004,
since at the time it was not adequately dynamic nor did it
adequately correlate with symptoms. This modification allowed better communication between physicians, which led
to improved assessment of CVD management efficacy. However, even the modified version continued to be physician-centered and hence did not always correlate with patient symptoms. These investigations are not necessarily responsive to
improvements following treatment.
Upon realization of the pitfalls of CEAP, the American Venous
Forum developed the VSS, which was designed to supplement CEAP scoring and to provide a method for serial assessment. VSS is mainly used for longitudinal follow-up of a
patient’s condition during and following treatment. The scoring system has three components10:
N Venous Disability Score (VDS)
This method is an extension of CEAP that evaluates the level
of work-based disability. Based on the ability to work with or
without support, disability is scored from 0 to 3. The total result will show the disability associated with venous disease.
N Venous Segmental Disease Score (VSDS)
This score is based on anatomical and pathophysiological
components of CEAP, obstruction and reflux. This part requires
assessment with Doppler ultrasonography or phlebography.
N Venous Clinical Severity Score (VCSS)
This is a dynamic form of CEAP evaluation that has been designed to include 9 hallmarks of the most severe complications of CVD. These include skin changes, inflammation, induration, and ulcers. Each hallmark is scored on a severity
scale ranging from 0 to 3. VCSS is an easy-to-apply, standalone scoring system. This part of the VSS has been studied expansively and is frequently used for longitudinal surveillance of venous disease.
N Physiological investigation
These are hemodynamic investigations that are usually performed for academic purposes. This method uses plethysmography, which monitors the change in ambulatory venous
pressures following treatment of CVD. The patterns of venous
flow in different vein segments are also evaluated by either duplex scan or phlebography.
N Functional investigation
These are generic and disease-specific assessments of quality of life. The generic assessments are SF-36 (Short Form 36
[-item health survey]), SF-12 (Short Form 12 [-item health survey]), EQ-5D (EuroQol 5 Dimension [mobility, self-care, usual
activities, pain/discomfort, anxiety/depression health survey]),
while the disease specific ones are AVVQ (Aberdeen Varicose
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Veins Questionnaire), SQOR-V (Specific Quality Of life Response–Venous), CIVIQ-2 (ChronIc Venous dIsease Questionnaire 2), and VEINES (VEnous INsufficiency Epidemiological
and economic Study). Generic methods are geared toward
evaluating the subjective assessment of quality of life, while
the disease-related surveys examine specific elements associated with a particular disease process. Since the latter
ones are more specific in their scope, they have become
more popular in evaluating CVD management.
N Generic instruments
– SF-36
The SF-36 is a valid assessment of quality of life. The scoring
system is based on two types of health aspect: physical health
and mental health.11 The former is assessed via the patient’s
level of functioning, whilst the latter is assessed via an indicator of well-being. These two types include eight domains:
assessment of physical and social functioning, role limitations
due to physical and emotional problems, mental health, pain,
vitality, and health perception. The SF-36 is a good way of assessing changes in quality of life in CVD. It has been widely used
in studies concerning patients affected with venous disorders.
– Nottingham Health Profile
The Nottingham Health Profile (NHP) is intended for primary
health care to provide a brief indication of a patient’s perceived
emotional, social, and physical health problems.12 It consists
of two parts. Part I contains 38 yes/no items in 6 domains:
pain, physical mobility, emotional reaction, energy, social isolation, and sleep. Part II contains 7 general yes/no questions
concerning daily-living problems. It can be applicable to other diseases as well as to CVD.
N Disease-specific instruments
– CIVIQ
This method contains questions to assess the physical, psychological, social, and pain aspects of CVD. The first version
of this questionnaire included different numbers of questions
in each category.13 The second version, CIVIQ 2, provides a
global score covering all aspects of the questionnaire and
weighs the categories equally. Both versions of the questionnaire are reported to be valid quality-of-life measurements.
The RELIEF (Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids) study,13 which was conducted in 23 countries worldwide and included the participation of more than 10 000 patients suffering from chronic
venous insufficiency (CVI), validated CIVIQ, the first qualityof-life scale specific to chronic venous insufficiency, and assessed changes in the quality of life of patients suffering from
CVI, with or without venous reflux, treated with micronized purified flavonoid fraction.
– VEINES
Compared with CIVIQ, this method focuses more on symptoms than the psychological and social aspects of the dis-
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ease. The VEINES questionnaire consists of 25 items that estimate the effect of disease on quality of life, and the VEINES
symptom questionnaire consists of 10 items that measure
symptoms.14
– Aberdeen Varicose Vein Questionnaire
AVVQ addresses multiple aspects of varicose disease, including physical symptoms, social issues, as well as the cosmetic manifestations of treatment outcome. The overall evaluation consists of a score with a range of 0 to 100.15
– Charing Cross Venous Ulceration Questionnaire
The CXVUQ was developed to provide a valid quality-of-life
measurement of venous ulcers. This method may be combined with the SF-36 to generate valuable information on the
progression of ulcers and their treatment. This questionnaire
has been mainly designed for patients with venous ulcers.16
– Cost-effectiveness investigation
This type of investigation is independent of patient- or physician-centered assessments and plays an important role in
selecting effective treatment, although it is currently underutilized. As the use of new technologies in CVD management
becomes more widespread, their current high costs are expected to decrease, which may affect physicians’ decision
on what appropriate treatment of CVD they choose. It is important to include early economic impact measures in this
investigation, such as time away from work following treatment as well as possible costs due to recurrences. These
economic aspects of CVD are currently underemphasized
and require more attention.
Discussion
The main dilemma in evaluating these investigative methods
is whether patient- or physician-centered evaluation methods are superior. In other words, should we rely on indicators
from the perspective of the physician or the patient? Perhaps
more importantly, can we develop methods to satisfy both?
It is important to note that venous diseases are individualbased pathologies, such that patient satisfaction becomes
a hallmark of effective treatment. However, evaluation of patient satisfaction can contain obvious subjective measures,
which generate an obstacle to standardizing the method of
reporting CVD management outcomes.17
It is obvious that investigations that are patient-centered need
to remain a critical part of evaluating CVD management outcomes. However, there is a high degree of variation in the
way that patients assess the effect of CVD on their quality of
life.18 Ethnic, educational, and work-related issues play an
important role in how patients perceive CVD-related symptoms.14 A further complication of this issue is the observation
that CVD pain can manifest itself in various forms depending
on the underlying pathogenesis of the disease.
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It is evident that combining methods geared toward patients
and physicians would generate more satisfactory results.12
However, combining methods would likely compromise effective communication of results, since the methodologies
would be cumbersome and somewhat complicated. However, it is our opinion that the combination of CEAP and VCSS
yields the most complete evaluation of CVD treatment methods without compromising effective communication between
various centers.
The prevalence of venous disease is approaching 30%, as
reported in various studies worldwide.19 However, the effectiveness of the treatment of CVD is still unsatisfactory, despite the recent development of various techniques to provide alternatives to conventional surgery. As a matter of fact,
these new techniques have raised further questions, since
early, short-period, ie, 3 weeks, posttreatment follow-up has
demonstrated no differences in patient satisfaction compared
with either surgery or with other new techniques.20,21 Thus with
this equivalence, cost-effectiveness becomes an important
factor, since these new technologies cost more than surgical
methods. Balancing this, we cannot exclude the fact that
these newer technologies provide better comfort in the early posttreatment period and shorter delays in returning to
work.22 As a result, patients and therefore physicians continue to want to utilize these techniques, which may reduce
their cost in the near future. These arguments provide a basis for why more dynamic treatment evaluation methods are
needed since in addition to early outcomes in CVD management, long-term effects and recurrences need to be factored
in to draw better balanced conclusions from studies.
Different surgical approaches as well as new technologybased techniques are designed to ablate superficial venous
system and to resolve obstructions in the deep venous system. However, a fundamental difference between surgical and
newer approaches is that the former focuses on preventing
saphenofemoral junction reflux with high ligation, while the
latter minimally invasive techniques ablate the vein at least
2.5 cm below the junction in order to prevent potential complications of the common femoral vein, including deep vein
thrombosis. Interestingly, as mentioned above, these therapeutic methods are reported to result in similar outcomes,20,21
which raises the question of whether reflux of the saphenofemoral junction plays a significant role in progression of venous disease.
Anatomical investigations, ie, Doppler ultrasound, indicate the
severity of venous disease based on the investigation of the
pathway of the saphenous trunk and saphenofemoral junction reflux. If reversing the reflux appears to play no role in the
outcome of CVD management, are anatomical investigation
methods biased? On the other hand, in the deep venous system, resolving postthrombotic obstructions improves patient
symptoms, since recanalization via stents without prevent-
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ing reflux has been shown to resolve symptoms of CVD.23,24
Yet again, there is another perspective: CVD primarily due to
reflux is treated by obviating this pathology via reconstruction
of the valves.25,26 These contradictions in the use of CVD management techniques and their results reveal the lack of understanding of how venous disease progresses and show
that evaluation techniques that mainly rely on anatomical investigations, such as CEAP, may give biased results.
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rence of the disease. Furthermore, every recurrence appears
to demonstrate distinct clinical and anatomical features in
each patient: generalization of CVD treatment outcome may
be challenging in an individual-based disease. Moreover, since
CVD is a life-long progressive disease, all investigation methods should be adequately dynamic to work in parallel with the
progression of management.
Conclusion
In summary, it is clear that one investigational method does
not suffice to evaluate the management of CVD. Both physician- and patient-centered methods need to be utilized to
generate satisfactory conclusions. However, using all these
methods together produces complex results that are cumbersome to interpret and communicate. Thus, we need to revisit
our understanding of the etiopathogenesis of CVD to guide
us in designing evaluation methods that focus on pathologic
factors that play a significant role in the progression of venous
disease. All reports indicate that current treatment of pathologies that are thought to underlie CVD does not prevent recur-
Currently, there are several investigational methods available
that provide somewhat limited, but nevertheless adequate,
information regarding the management outcomes of CVD.
We believe that the reason for developing significantly distinct investigation methods is the diversity of ways in which
CVD manifests in each individual and therefore methods like
CEAP and VCSS, which are dynamic and patient- and physician-centered, appear to provide sufficient data to evaluate
the efficacy of CVD management. A better understanding of
the etiopathogenesis of CVD will facilitate further modification of investigational methods. I
References
1. Maeso J, Juan J, Escribano J, et al. Comparison of clinical outcome of stripping and CHIVA for treatment of varicose veins in the lower extremities. Ann
Vasc Surg. 2001;15:661-665.
2. Carandina S, Mari C, De Palma M, et al. Varicose vein stripping vs haemodynamic correction (CHIVA): a long term randomised trial. Eur J Vasc Endovasc
Surg. 2008;35:230-237.
3. Agus GB, Mancini S, Magi G. The first 1000 cases of Italian Endovenous-laser
Working Group (IEWG). Rationale, and long-term outcomes for the 1999-2003
period. Int Angiol. 2006;25:209-215.
4. Nael R, Rathbun S. Treatment of varicose veins. Curr Treat Options Cardiovasc
Med. 2009;11:91-103.
5. Almeida JI, Kaufman J, Göckeritz O, et al. Radiofrequency endovenous ClosureFAST versus laser ablation for the treatment of great saphenous reflux: a
multicenter, single-blinded, randomized study (RECOVERY study). J Vasc Interv Radiol. 2009;20:752-759.
6. Gillet JL, Perrin MR, Allaert FA. Clinical presentation and venous severity scoring 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 ultrasonography 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 lowerextremity veins. J Vasc Surg. 2003;38:793-798.
9. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum International
Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP
classification 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, Moneta 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 in
patients with varicose veins. In: Davies AH, Lees TA, Lane IF, eds. Venous Disease Simplified. Shropshire, England: TFM Publishing Ltd; 2006.
12. Vasquez MA, Munschauer CE. Venous clinical severity score and quality of life
assessment tools: application to vein practice. Phlebology. 2008;23:259-275.
13. Jantet G. RELIEF study: first consolidated European data. Reflux assEssment
and 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 veins
affect quality of life? Results of an international population-based study. J Vasc
Surg. 2001;34:641-648.
15. Klem TM, Sybrandy JE, Wittens CH. Measurement of health-related quality of
life with the Dutch translated Aberdeen Varicose Vein Questionnaire before and
after treatment. Eur J Vasc Endovasc Surg. 2009;37:470-476.
16. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of life
in patients with venous ulcers. J Vasc Surg. 2000;31:642-649.
17. Chassany O, Le-Jeunne P, Duracinsky M, Schwalm MS, Mathieu M. Discrepancies between patient-reported outcomes and clinician-reported outcomes
in chronic venous disease, irritable bowel syndrome, and peripheral arterial occlusive disease. Value Health. 2006;9:39-46.
18. Dunić I, Medenica L, Bobić B, Djurković-Djaković O. Patients’ reported quality of life in chronic venous disease in an outpatient service in Belgrade, Serbia. Eur J Dermatol. 2009;19:616-620.
19. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous
stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc
Surg. 2001;33:1022-1027.
20. Rasmussen LH, Bjoern L, Lawaetz M, Blemings A, Lawaetz B, Eklof B. Randomized trial comparing endovenous laser ablation of the great saphenous vein
with high ligation and stripping in patients with varicose veins: short-term results. J Vasc Surg. 2007;46:308-315.
21. Kalteis M, Berger I, Messie-Werndl S, et al. High ligation combined with stripping and endovenous laser ablation of the great saphenous vein: early results
of a randomized controlled study. J Vasc Surg. 2008;47:822-829.
22. Subramonia S, Lees T. Radiofrequency ablation vs conventional surgery for
varicose veins—a comparison of treatment costs in a randomised trial. Eur J
Vasc 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. Chronic
iliac vein occlusion: midterm results of endovascular recanalization. J Endovasc Ther. 2009;16:483-491.
25. Raju S, Neglén P, Doolittle J, Meydrech EF. Axillary vein transfer in trabeculated
postthrombotic veins. J Vasc Surg. 1999;29:1050-1062.
26. Lugli M, Guerzoni S, Garofalo M, Smedile G, Maleti O. Neovalve construction in
deep 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 RECOMMANDATIONS
DANS LA MALADIE VEINEUSE CHRONIQUE
La maladie veineuse chronique (MVC) représente toujours une charge significative pour les patients et les médecins
puisque la façon la plus efficace de la prendre en charge reste difficile à déterminer. De nombreuses recherches
ont montré que les résultats à long terme de méthodes de traitement très différentes, y compris des techniques
invasives ou non invasives, étaient globalement identiques. Les argumentaires de ces techniques sont très différents
les uns des autres, ce qui pose la question de la validité des méthodes utilisées pour calculer la sévérité de la MVC
avant et après traitement. Le fait que cette sévérité puisse être évaluée de différentes façons est un des principaux
obstacles au recueil de données pertinentes sur la prise en charge de la MVC. La qualité de vie du patient est probablement le critère le plus important mais il existe des paramètres centrés sur le médecin et basés principalement
sur la physiopathologie de la maladie. De plus, la variabilité de la perception de la maladie dans les différents groupes
de patients est une autre difficulté pour tirer des conclusions des diverses études. Ces systèmes de cotation doivent
être dynamiques puisque la prise en charge de la MVC prend en compte le traitement des problèmes cliniques qui
apparaissent sur une longue période. La compréhension de ces obstacles a entraîné de nombreuses modifications
des systèmes de cotation précédents. Cependant, même aujourd’hui, les versions modifiées prises séparément ne
parviennent pas à indiquer la sévérité de la maladie dans sa totalité. Il faut donc créer un système de cotation universel dans la MVC qui réunirait les critères les plus importants de toutes les méthodes d’investigation actuelles.
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It is widely recognized that
traditional outcomes (clinical and
laboratory measures) need to be
complemented by measures that
focus on patients’ concerns in order to evaluate interventions and
identify more appropriate forms of
health care. In this regard, patientreported outcomes are unique
and complementary indicators of
traditional outcomes, providing
additional information about disease and treatment efficacy.”
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Current status of
patient-reported outcomes
and chronic venous
disease guidelines
b y A . M a n s i l h a , Po r t u g a l
C
Armando MANSILHA
MD, PhD, FEBVS
Faculty of Medicine of Porto
University, Hospital São João
Porto, PORTUGAL
hronic venous disease (CVD) is highly prevalent in the Western world
and is associated with significant costs. Outcome studies promote
understanding of the disease and the results of treatment. The use of
patient-reported outcomes (PROs) by patients suffering from CVD is thought
to be an important step forward in the assessment of patients’ perspective of
the disease, quality-of-life (QOL) questionnaires being the best adapted instruments. Despite some limitations in the evidence available, there are eight
criteria that provide an explicit framework for selecting PROs. Eight simple
questions can help choose PROs, each question being linked to a specific
criterion: appropriateness, reliability, validity, responsiveness, precision, interpretability, 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 of
populations and treatments and are able to capture information on a broad
range of aspects of health status and disease consequences. On the other
hand, specific QOL instruments have been developed to provide patients’
perception of a specific disease, health problem, or intervention. In the latest
guidelines published in the area of venous disease, it is clear that PRO assessment is already a priority, CIVIQ (ChronIc Venous dIsease Questionnaire) being the most recent and validated specific questionnaire with psychometric
criteria.
oday, contemporary medicine places great value on patients’ perspective
of 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 perceived
health outcomes or end points assessed by patient reports, implemented by selfadministered questionnaires, and completed by patients themselves or by interviewers.2 These instruments can cover several aspects, such as preferences about care
received, health behaviors, and outcomes of care (subjective symptoms, patient satisfaction, and health-related quality of life [QOL]).3-5
T
Prof Armando Mansilha, Rua Júlio
Dinis, nº 826, 5º, 4050-322 Porto,
Portugal (e-mail:
vascular.mansilha@gmail.com)
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It is widely recognized that traditional outcomes (clinical and laboratory measures)
need to be complemented by measures that focus on patients’ concerns in order
to evaluate interventions and identify more appropriate forms of health care.6 In this
Current status of PROs and chronic venous disease guidelines – Mansilha
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regard, PROs are unique and complementary indicators of
traditional outcomes, providing additional information about
disease and treatment efficacy.4
Types and application of PROs
An enormous range of instruments in the form of questionnaires, interviews, and rating and assessment forms were
created with the objective of evaluating states of health and
illness from a patient’s perspective.7 Maybe because no exclusive and rigid classification exists, several authors have
proposed dividing these instruments into seven major types
(Table I).7
With regard to their application, PROs can be applied in different fields, particularly generic and disease-specific QOL
questionnaires. However, the majority have been developed
for clinical trials and economic evaluation to assess the healthcare needs of populations and to assist health-care professionals in the treatment of individual patients.
N Clinical trials and cost-utility studies
The number of trials and cost-utility studies that include PRO
measures is progressively increasing. Nowadays, the majority of studies include determinations of health status or QOL,
unless these outcomes are not relevant to the study.7 PRO
measures have been used as primary outcomes (eg, in the
evaluation of a drug’s treatment effect on QOL) in randomized controlled trials or in nonrandomized research designs,
despite their more complex interpretation.7
In a different way, when investigators need to obtain an overall evidence value for a health-care intervention that allows
comparisons with other interventions, in the same treatment
area or across areas, outcomes in the form of utilities are required. The most widely known form of a summary value for
the purpose of comparing treatments is the quality-adjusted life year (QALY).7
N Assessing health-care needs of populations
Apart from conventional data such as mortality and morbidity
rates, there are other measures that may also indicate healthcare needs. Among them, PRO measures provide a feasible
SELECTED
CIVIQ
CVD
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
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and valid measure of health status, particularly if such assessments are based on questionnaires with proven acceptability. There is growing evidence reinforcing the idea that poor
scores on health-status measures may be associated with elevated rates of subsequent health service use and mortality.7
Health authorities and those responsible for purchasing or
providing health care are increasingly expected to base their
decisions about health-care resource allocation on evidence,
and PRO measures add invaluable material to existing sources
Type of PRO
Examples of this type of PRO
Generic
Medical Outcomes Study 36-Item Short
Form health survey, Functional Limitations Profile
Disease-specific
Asthma Quality of Life Questionnaire,
Arthritis Impact Measurement Scales
Population-, site-, Child Health and Illness Profile-Child
or region-specific
Edition, Oxford Hip Score, Shoulder
Disability Questionnaire
Dimension-specific Beck Depression Inventory, McGill Pain
Questionnaire
Summary items
Question about limiting, long-standing illness in the General Household Survey
Individualized
McMaster Toronto Arthritis Patient Preference Disability Questionnaire,
Schedule for the Evaluation of Individual Quality of Life
Utility measures
EuroQol 5D, Health Utility Index
Table I. The seven major types of PROs and examples of each
type.
Abbreviations: PRO, patient-reported outcome.
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 key
sources of information among health-care decision-makers
owing to issues related to the measurement and interpretation of patients’ perspective.8
N Individual patient care
PROs offer an important aid to physicians in patient care. Selfcompleted questionnaires, with proven reliability and validity,
offer quick and consistent evidence of a patient’s view about
his health that complements the clinical data of physicians.7
Using PROs, health-care professionals can screen health problems that would otherwise not be apparent and can monitor the progression of disease as perceived by the patient
and the outcomes of any treatment.7 Nevertheless, it is necessary to consider that in the context of clinical care, an individual score is less precise than the one obtained for a group
of patients.7 As a consequence, the applicability of PROs in
individual patient care is more difficult.7
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Choosing a PRO
Despite clear limitations in the evidence available, there are
eight criteria that provide an explicit framework for selecting
PROs. Eight simple questions can be formulated in order to
help choose PROs, each question being linked to a specific
criterion (Table II).7,9
Chronic venous desease
In Western countries, chronic venous disease (CVD) has a
high prevalence and morbidity. Recent data indicate that the
prevalence of varicose veins is estimated to be 25% to 33%
in women and 10% to 20% in men.10 The prevalence of more
severe stages of CVD, such as edema and skin changes (hyperpigmentation and eczema), varies from 3% to 11% of the
population,10 and it is estimated that the assessment and
treatment of patients with varicose veins and leg ulcers consume 2% to 3% of the health budget of Western countries.11
For instance, the costs of dressing a leg ulcer in the UK National Health Service reaches £6000 to £20 000 per year.12
As a result of the complexity and chronicity of venous disease, the application of PROs to patients suffering from CVD
is thought to be an important step forward in the assessment
of patients’ perspective of disease, QOL questionnaires bePRO
selection criterion
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ing the most adapted instruments.1 The use of QOL questionnaires in patients suffering from CVD can provide important information regarding disease burden in patients that
would otherwise be unobtainable.1,13
Quality of life
QOL is a broad ranging concept that has been changing over
the years and, depending on the perspective, different definitions of QOL are acceptable. In 1947, the World Health Organization (WHO) defined QOL as a “state of complete physical, mental, and social well-being and not merely the absence
of disease or infirmity,” while, in 1984, Calman wrote: “Quality
of life measures the difference, or the gap, at a particular period of time, between the hopes and expectations of the individual and that individual’s experiences.” Although no single definition or theory can be considered more correct than
another, it is clear that the WHO provides the most coherent
and comprehensive definition. In 1998, the WHO updated its
definition of QOL to: “Individuals’ perception of their position
in life in the context of the culture and value systems in which
they live and in relation to their goals, expectations, standards and concerns. It is a broad ranging concept affected in
a complex way by the person’s physical health, psychological state, level of independence, social relationships, personQuestion to ask
when choosing a PRO
Comment on criterion
Appropriateness
This criterion requires that investigators consider as directly as
possible how well the content of an instrument corresponds
to the intended purpose of their specific trial.7
Is the content of the instrument appropriate to the questions which the
clinical trial is intended to address
Reliability
Reliability is related to the reproducibility and internal consistency
of an instrument. It assesses the extent to which the instrument
is free from random error and can be considered as the amount
of a score that is signal rather than noise.
Does the instrument produce results
that are reproducible and internally
consistent?
Validity
The validity of a measure is an assessment of the extent to which
it measures what it purports to measure.7
Does the instrument measure what
it claims to measure?
Responsiveness
It is essential for a health status questionnaire to detect important
changes over time within individuals, which might reflect
therapeutic effects. Responsiveness could be defined as the
ability of an instrument to detect important clinical changes.
Does the instrument detect changes
over time that matter to patients?
Precision
Precision refers to the number of distinctions that an instrument
makes. It is related to the capacity to make numerous distinctions.
How precise are the scores of the
instrument?
Interpretability
Interpretability is concerned with how meaningful the scores of
an instrument are.
How interpretable are the scores of
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
staff and researchers in collecting and processing information.
The time and resources required to collect, process, and analyze
a PRO measure.
Is the instrument easy to administer
and process?
Table II. PRO selection criteria and questions to ask when choosing a PRO. Based on reference 7.
Abbreviations: PRO, patient-reported outcome.
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al beliefs and their relationship to salient features of their environment.” This definition is the one most commonly used.14
Regarding clinical trials and health-care interventions, QOL
is considered an important outcome that provides an overall assessment of the effect of both the disease and treatment on the patient.15 More simply, QOL has been defined as:
“the extent to which our hopes and ambitions are matched
by experience,” while improving patients’ QOL through medical care has been defined as: “narrow[ing] the gap between
a patient’s hopes and expectations and what actually happens.”16 Concerning the evaluation of patients’ QOL, two types
of questionnaires can be used: generic and disease-specific
QOL questionnaires.
Generic quality-of-life questionnaires
Generic instruments are designed to be applicable across a
broad range of populations and treatments and to be able
to capture information on a wide range of aspects of health
status and disease consequences.7 Due to their broad range
of content and more general applicability, these instruments
have been used more frequently than disease-specific instruments to assess health status of nonhospital samples in
the general population.7
Regarding generic QOL questionnaires, those most used and
mentioned in international literature are: the Medical Outcomes Study Short Form 36-item (SF-36) health survey, Nottingham 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 in
clinical practice and research, health policy evaluations, and
general population surveys. This questionnaire has 36 items
that measure health status in eight categories.18,19 Another
example is FLP, which is the English version of SIP, which
was developed in the United States. It consists of 136 items
grouped into 12 categories.7
N Advantages
Regarding the advantages and drawbacks of the different
types of questionnaires, what will be mentioned are suppositions rather than firm statements, and the generalizations
are difficult to substantiate because there is little evidence
available, particularly from direct comparisons of their use.7
The main advantage of generic instruments is that they can
be used for a broad range of health problems, allowing comparisons between different treatments and their respective
effectiveness. With a generic QOL questionnaire, it is possible
to calculate “normative values,” which give scores for patients
with distinct health problems and allow comparisons to be
made.7 Another advantage of the generic QOL questionnaire
is its broad scope, so they may be of value in detecting the
unexpected positive or negative effects of an intervention.7
Finally, even though they cover a wide range of different categories, they are relatively economic and reduce patients’
burden.7
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N Drawbacks
By including items that cover a broad range of aspects
about health status, generic instruments lose some level of
detail in terms of a particular disease’s relevance.7
Disease-specific quality-of-life questionnaires
Specific QOL instruments have been developed to provide
patients’ perception of a specific disease, health problem, or
intervention.7,17 An example is the Asthma Quality of Life Questionnaire that contains 32 questions in four different categories20 or the Arthritis Impact Measurement Scale, a self-administered questionnaire for use in rheumatic diseases, which
covers 45 items in nine categories.7 Both instruments clearly
have a specific range of applications in each disease, respectively.7 In relation to CVD, some specific instruments exist: the
ChronIc Venous dIsease Questionnaire (CIVIQ),21 the VEnous
INsufficiency Epidemiological and economic Study (VEINES),22
the Aberdeen Varicose Vein Questionnaire (AVVQ),23 and the
Charing Cross Venous Ulceration Questionnaire (CXVUQ).24
N Advantages
The content of specific QOL questionnaires is relevant for a
particular disease, as all items of the instrument were developed specifically to assess a specific health problem.7 These
instruments are more likely to detect important changes that
occur over time in a particular disease.7 Another important
advantage is that with specific QOL questionnaires, acceptability and conclusion rates are usually higher compared with
generic instruments. This occurs because specific instruments
are clearly relevant to a patient’s problem.7
N Drawbacks
Generally, it is not possible to use a disease-specific instrument in samples of patients that do not have a specific condition or disease because logically it is not possible to ask a
person about a problem or condition that he/she does not
have. In the same way, disease-specific instruments do not allow easy comparison between outcomes of different treatments for patients with different health problems. This situation is a problem when certain data from a general sample
of healthy individuals must be compared with the health status scores of a study or when comparative judgments on the
relative effectiveness of different treatments in different diseases are required in order to propose resource allocation.7
Another problem of disease-specific instruments is that they
may not capture certain data associated with a disease or
a treatment when these have not been anticipated. An instrument with a broader scope may be more effective in detecting unexpected effects.7
CIVIQ
In CVD, there are several reasons, mostly linked to disease
characteristics, which justify the creation and development
of a specific questionnaire to assess patients’ QOL. Among
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them, we could highlight that CVD has a high and growing
prevalence, as one in two adults complains about symptoms and/or signs of the disease,10 CVD has a considerable
socioeconomic impact representing around 1% to 3% of the
total health-care budget of countries with developed healthcare systems,25 and CVD’s negative impact on patients’ daily life is usually underestimated by physicians due to its indolent clinical course and the absence of a relation between
symptoms and signs.21 Taking into account these previously
mentioned reasons and knowing that disease-specific instruments are usually more sensitive in key categories of QOL
than generic scales, it was crucial to develop a specific QOL
questionnaire for widespread use in CVD.
The CIVIQ questionnaire was developed and validated (relevance, acceptability, reliability, construct validity, and sensitivity) by a French group in 1996.21 Later in 2000, it was translated, adapted to the cultural habits of 18 countries, and then
revalidated in different languages to give high significant validity and reproducibility (P<0.0001).26 The CIVIQ questionnaire is a 20-item self-reported instrument that includes four
categories of questions: physical (4 items), psychological (9
items), social (3 items), and pain (4 items). Its score ranges
from 0, the worst score, to 100, the best.
As the number of publications including the CIVIQ questionnaire has increased, it has become possible to confirm that it
is extremely reliable, easy to use, and shows an excellent ability to detect changes of state among CVD patients.27 For all
these reasons, the CIVIQ questionnaire represents a step forward in the assessment of patients’ QOL in CVD.
PROs and current guidelines in venous disease
In the latest guidelines published in venous disease, it is evident that PRO assessment is already a priority and that
several instruments are mentioned. In the third edition of the
Handbook of Venous Disorders: Guidelines of the American
Venous Forum, there are 2 chapters dedicated to PROs in
which the CIVIQ questionnaire is mentioned (chapter 62, “Outcome assessment in acute venous disease,” and chapter 63,
“Outcome assessment in chronic venous disease.”). Chapter 61 details how the CIVIQ questionnaire has been successfully validated in several groups of patients, including those
with severe postthrombotic syndrome. In chapter 62, the
CIVIQ questionnaire is referred to as one of the four venous
disease–specific instruments developed for evaluating CVD
and one with excellent internal consistency and stability.
The latest guidelines of European Venous Forum, Management of Chronic Venous Disorders of the Lower Limbs: Guidelines according to Scientific Evidence, also highlight PROs.
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In the part on the assessment of efficacy of therapies, it states
that QOL has been assessed by generic and disease-specific measures in CVD patients. However, considering the fact
that specific complaints of patients with CVD have not been
identified by currently used generic QOL questionnaires, specific questionnaires have been developed to assess the functional and psychological effects of venous disease. The unique
specific QOL instrument mentioned is the CIVIQ questionnaire,
which is referred to as the most recent, validated questionnaire with psychometric criteria, including reliability, content,
construct validity, and responsiveness.
Conclusion
In the last few years, the rapid expansion in the assessment
of outcomes from the patients’ perspective has resulted in
hundreds of instruments.7 In this time, PROs have undergone
an incredible evolution from being nearly “irrelevant” to being a “priority” in population health assessment and are now
being applied in various contexts, particularly generic and disease-specific QOL questionnaires.8 This marked improvement
in the importance of PROs is related to their potential for
monitoring disease progression and response to treatment,
assessing quality of care provided, and providing important
information that is not properly expressed by the statistical
values of morbidity and mortality that physicians traditionally
use. Furthermore, these data are assessed directly from the
patients’ perspective and are invaluable outcomes that complement more conventional data, such as clinical and laboratory measures.
In CVD, the use of QOL instruments has already proven to
be reliable and much appreciated by practitioners, especially
the CIVIQ questionnaire, which is a disease-specific instrument that has been validated in different languages with high
significant validity and reproducibility. Furthermore, this questionnaire has been used successfully in different situations:
in the RELIEF (Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids) study, a worldwide study
performed in CVD; the Vein Consult Program, an international educational survey carried out under the auspices of the
International Union of Phlebology (UIP [Union Internationale
de Phlébologie]); and the study, “What do you know about
your veins?”, the first Portuguese study to evaluate the impact
of CVD on the QOL of the Portuguese population.
All the cumulative experience with the CIVIQ questionnaire, in
addition to the knowledge that QOL is likely to be responsive
to clinical changes, leads us to conclude that PROs, especially CIVIQ, could be widely used by the medical community to
improve patient health care by eliciting earlier diagnosis and
treatment, particularly in CVD. I
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References
1. Guex JJ, Myon E, Didier L, Nguyen LC, Taieb C. Chronic venous disease: Health
status of a population and care impact on this health status through quality of
life questionnaires. Int Angiol. 2005;24:258-264.
2. Valderas JM, Alonso J. Patient reported outcome measures: a model-based
classification 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 outcomes in clinical practice. Qual Life Res. 2008;17:1297-1302.
4. Wiklund I. Assessment of patient-reported outcomes in clinical trials: the example 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 patient-reported outcomes and other efficacy endpoints in approved product
labels. Control Clin Trials. 2004;25:535-552.
6. Slevin ML, Terry Y, Hallett N, et al. BACUP-the first two year: evaluation of a
national cancer information service. BMJ. 1988;297:669-672.
7. Fitzpatrick R, Davey C, Buxton MJ, Jones DR. Evaluating patient-based outcome 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 healthcare
policy, 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 and
other 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 disorders 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 disease: an update of the available evidence. Curr Vasc Pharmacol. 2009;7:303308.
12. Coleridge-Smith P. Drug treatment of varicose veins, venous edema, and ulcers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the
American Venous Forum. 3rd ed. London, UK: Hodder Arnold; 2009;31:359365.
13. Kahn SR, M'lan CE, Lamping DL, Kurz X, Bérard A, Abenhaim LA. Relationship between clinical classification of chronic venous disease and patient-reported 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 generic
quality-of-life instruments. Pharmacoeconomics. 2000;17:13-35.
18. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF36). 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 health
profile and summary measures: summary of results from the Medical Outcomes
Study. Med Care. 1995;33(4 suppl):AS264-AS279.
20. Juniper EF, Guyatt GH, Dolovich J. Assessment of quality of life in adolescents
with allergic rhinoconjunctivitis: development and testing of a questionnaire for
clinical trials. J Allergy Clin Immunol. 1994;93:413-423.
21. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality
of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life
Res. 1996;5:539-554.
22. Lamping DL, Schroter S, Kurz X, Kahn SR, Abenhaim L. Evaluating outcomes
in 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, Krukowski
ZH. Towards measurement of outcome for patients with varicose veins. Qual
Health Care. 1993;2:5-10.
24. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of life
in patients with venous ulcers. J Vasc Surg. 2000;31:642-649.
25. Bergan JJ, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR,
26. Jantet G. RELIEF study: first consolidated European data. Reflux assEssment and quaLity of lIfe improvement with micronized Flavonoids. Angiology.
2000;51:31-37.
chronic venous disease quality of life questionnaire (CIVIQ-20). Eur J Vasc Endovasc Surg. 2010;40:783-789.
Keywords: patient-reported outcomes; PROs; CIVIQ; quality of life; chronic venous disease; disease-specific
questionnaires
ÉTAT ACTUEL DES RÉSULTATS RAPPORTÉS PAR LES PATIENTS
ET DES RECOMMANDATIONS SUR LA MALADIE VEINEUSE CHRONIQUE
La maladie veineuse chronique (MVC) est hautement prévalente dans les pays occidentaux et est associée à des
coûts 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 en
avant dans l’évaluation de la perspective de sa maladie par le patient, les questionnaires de qualité de vie (QDV) étant
les instruments les mieux adaptés. Malgré des limites concernant les preuves disponibles, huit critères fournissent
un cadre explicite pour sélectionner les RRP. Huit questions simples peuvent aider à choisir les RRP, chaque question 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 questionnaires
peuvent être utilisés : les questionnaires génériques et ceux spécifiques à la maladie. Les instruments génériques
sont conçus pour être utilisés pour toutes sortes de population et de traitements et peuvent collecter de l’information sur l’état de santé et les conséquences de la maladie. Par ailleurs, des instruments spécifiques de la QDV ont été
développés pour donner aux patients la mesure d’une maladie spécifique, d’un problème de santé ou d’un traitement. Dans les dernières recommandations publiées sur la maladie veineuse, il est clair que l’évaluation des RRP est
déjà une priorité, le questionnaire CIVIQ (ChronIc Venous dIsease Questionnaire) étant le questionnaire spécifique
validé le plus récent doté de critères psychométriques.
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The most dramatic change is
that the strength of recommendation is no longer based, as was the
case only a few years ago, solely
on the type and quality of available studies. Back in 1989, panelists would first rate the level of
evidence from “large trials with
clear-cut results and low risk of
error” to “case series only,” and
the grade of recommendation depended on the level of evidence,
with no other parameter taken
into account.”
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Rating the quality of evidence
and the strength of recommendations: the new GRADE
system in venous disease
b y G . Le G a l a n d Z . A l a v i , Fra n c e
T
L
Grégoire LE GAL, MD, PhD
Zarrin ALAVI, MSc
Université Européenne de
Bretagne; Université de Brest
INSERM CIC 05-02 IFR148
CHU de la Cavale Blanche
Département de médecine
interne et de pneumologie
Brest, FRANCE
he Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was developed in 2004 as an attempt to provide 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 Guidelines
on Antithrombotic and Thrombolytic Therapy. The ACCP grades its recommendations 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 unchanged compared with previous editions, there have been significant changes
in the underlying definitions and criteria leading to these grading recommendations over the latest few editions of these guidelines. In particular, the
methodological quality of available studies is no longer the only determinant
of the quality of evidence, while the strength of a recommendation is no longer
only based on the quality of evidence, but also on the balance between benefit and harm, on values and preferences, and on cost. Guideline users need
to be aware of the way grades of recommendations are obtained in order to
fully understand and take advantage of guidelines for their patients’ care.
reatment decisions involve finding the balance between benefits on the one
hand and risks, burdens, and inherent costs on the other. In order for clinicians to integrate guideline recommendations with their own clinical judgment and fully exploit them in daily clinical practice, they need to understand the
foundation for these recommendations and to know how much confidence they
can place in them.
T
Prof Grégoire Le Gal, Centre
d’investigation clinique CHRU de la
Cavale Blanche, Boulevard Tanguy
Prigent, 29609 Brest Cedex, France
(e-mail: gregoire.legal@chu-brest.fr)
280
Many guidelines are published by medical societies, public health agencies, or journals
around the world. Unfortunately, they often use different ways of rating the quality
of evidence and of grading the strength of recommendations. As a result, clinicians,
patients, managers of health-care systems, and policy makers face challenges in
understanding the messages that grading systems are trying to convey when they
need to compare alternative strategies and diagnostic tests and weigh up their benefits and downsides. A lot of effort has been spent coming up with the much anticipated criteria and approaches for an optimal worldwide grading system, reflecting
greater awareness of the variability in patients’ values and preferences. In addition
to minimizing bias and aiding interpretation, following a systematic approach to grad-
Rating the new GRADE system in venous disease – Le Gal and Alavi
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ing the strength of recommendations enhances the usefulness of clinical guidelines. The Grades of Recommendation
Assessment, Development and Evaluation (GRADE) system
was developed in 2004 as an attempt to provide systematic
and explicit methods of making judgements.1
The American College of Chest Physicians (ACCP) EvidenceBased Practice Guidelines on Antithrombotic and Thrombolytic Therapy is “bedtime reading work” for physicians involved
in the management of patients with venous disease. In its latest edition released in 2008, the ACCP committee of methodologists and guideline developers adopted a grading system based on the GRADE approach. The criteria, displayed
in Table I, have been placed in an order that approximates
their relative significance.2 The ACCP team in charge of the
task agreed on these criteria for defining a grading system
that would be consistent with the latest developments in
the field.
In this paper, we will focus on the GRADE approach to recommendations and on how the GRADE system categorizes
the quality of evidence and strength of recommendations,
and explore the implications of these grading categories for
patients, clinicians, and policy makers.
What makes a good grading system?
For an optimal grading system, decisions regarding quality of
evidence should be separate from those regarding strength
of recommendations. Not all grading systems succeed in doing this. For instance, early systems of grading methodological quality relied primarily on the basic study design (ie, randomized control trials [RCTs] or observational studies). Study
design was used by these early grading systems as an essential component for determining our level of confidence in
estimates of beneficial and adverse treatment effects.
Over the past few years, there has been increased awareness
of a number of other factors that require consideration in order for us to be confident in the estimation of benefits, risks,
burden, and costs.
What differentiates GRADE from previous grading
systems?
Compared with previous/other grading systems, the GRADE
working group wanted a system that used explicit definitions
of strength of recommendation and of quality of evidence.
Their system takes into account various factors that can affect the quality of evidence, not only the study design and
quality, but also study limitations, imprecision, and possible
confounding. It assesses the relative importance of outcomes,
clarifies the judgement on benefit and harm by providing an
explicit definition for trade-offs between benefit and harm,
and includes judgement on whether the incremental health
benefits are worth the costs. Finally, it provides a clear interpretation of the recommendation.
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Criteria
Description
1
Separation of grades of recommendations from
quality 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 for
different outcomes
Table I. Criteria for an optimal grading system, according to the
ACCP 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.
Quality of evidence in the GRADE system
“Quality of evidence” reflects the extent to which the confidence in an estimate of an effect is adequate in supporting
a recommendation. To achieve transparency and simplicity,
the GRADE system classifies the quality of evidence at one
of 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, RCTs
without limitations constitute high-quality evidence, observational studies without special strengths or with important limitations constitute low-quality evidence, while any other study
(case series) constitutes very low–quality evidence.
N Negative factors affecting quality of evidence
There are, however, negative factors that affect the quality of
evidence that can downgrade the quality of observational
studies as well as RCTs:
a) Study limitations
If studies have major limitations that may bias their estimates
of the treatment effect, confidence in the evidence decreases.
Such limitations include a lack of allocation concealment, a
lack of blinding, a significant number of patients lost to follow-up, failure in the intention-to-treat analysis, failure to report outcomes, and early ending of a study due to benefit.
SELECTED
ACCP American College of Chest Physicians
GRADE Grades of Recommendation Assessment,
RCT
VTE
venous thromboembolism
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b) Inconsistency of results
Heterogeneity or variability in results across studies suggests
true differences in underlying treatment effect. This variability
may come from differences in populations, interventions (larger effects with higher drug doses), or outcomes (decreasing
treatment effect with time). The quality of evidence diminishes when there is heterogeneity of results, but investigators fail
to identify a credible explanation.
change our confidence in the estimate of effect. A “moderate
quality of evidence” means that further higher-quality research
may have an impact on our confidence in the estimate of effect or to change this estimate. A “low quality of evidence”
is used when further higher-quality research is likely to have
an important impact on our confidence in the estimate of effect, or to change the estimate. Finally, the evidence is graded “very low” when any estimate of effect is highly uncertain.
c) Indirectness of evidence
Two types of indirectness of evidence addressed by the guideline developers are:
- When considering the use of one of two active drugs. In
the absence of a randomized comparison of the drugs, randomized trials may compare one drug with placebo and the
other with placebo. This leads to a comparison of the magnitude of effect of both drugs, therefore, the evidence is of
a lower quality than it would have been had there been a direct head-to-head comparison of the drugs.
- When there are discrepancies between the population, intervention, intervention comparator, or outcome of interest and
those included in the applicable studies.
Strength of a recommendation in the GRADE system
d) Imprecision
The quality of evidence is reduced in cases where studies
use relatively few patients or have few events, leading to wide
confidence intervals.
The “strength of recommendation” reflects the extent to which
we can be confident that the desirable effects of adhering to
an intervention outweigh its undesirable effects. There are
two grades of recommendations: strong (1) and weak (2). A
strong recommendation means that benefits clearly outweigh risks, while a weak recommendation means that one
can’t be sure that benefits outweigh risks.
The strength of a recommendation is no longer exclusively
based on the quality of evidence. It is also determined by 2:
a) The balance between desirable and undesirable effects
This takes into account the incidence rate of the target event,
the importance of the event that treatment prevents, the
magnitude of treatment effect, the precision of estimates of
treatment effect, and the risks associated with therapy.
b) Burdens of therapy
e) Publication bias
Not reporting studies, especially those that show no effect,
downgrades the quality of evidence. A prototypical situation
would be when published evidence is limited to a small number of trials, all of which are financed by industry.
N Positive factors affecting quality of evidence
Conversely, there are also some factors that might increase
quality of evidence.
a) Even though observational studies usually result in a low
quality of evidence, strong observational studies can methodologically provide large or very large and consistent estimates
of the magnitude of a treatment effect. This gives good confidence in the results, in particular when there is no major
plausible confounder. The larger the magnitude of effect, the
stronger the evidence becomes.
b) If all the plausible confounders tend to reduce the estimation of the effect, the confidence in the evidence increases.
c) Finally, the existence of a dose-response gradient also increases 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 quality of evidence” means that further research is unlikely to
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c) Costs
A judgement may be made on whether the net benefits are
worth the incremental cost.
d) Patients’ varying values and preferences
Strong and weak recommendations may be interpreted as
follows. If the recommendation is strong, benefits clearly outweigh risks, or vice versa, and apply to most patients in most
circumstances. The use of a decision aid tool is not needed,
and the patient only needs to be informed. In the case of a
weak recommendation, the best action may differ and other alternatives may be equally reasonable. In this case, decision aid tools may be useful, and the physician needs to
make sure that the choice is in accordance with the patient’s
values. While almost all patients would make the same choice
for strong recommendations, the choice may significantly vary
for a weak recommendation.
Rating evidence and recommendations in
venous disease
The GRADE system has been implemented in the 8th edition of the ACCP Evidence-Based Clinical Practice Guidelines
on Antithrombotic and Thrombolytic Therapy. There are two
levels of strength of recommendation (1 = strong, “We recommend”; and 2 = weak, “We suggest”), and three levels of
quality of evidence (A = high; B = moderate; and C = low).
CHRONIC
Grade
1A
1B
2B
2C
DISEASE
Benefits clearly outweigh
risks, or vice versa;
recommendation can
apply to most patients
in most circumstances.
GUIDELINES
AND
DA I LY
CLINICAL
PRACTICE
Quality of evidence
Benefit vs risk
1C
2A
VENOUS
RCTs with no important limitations, or exceptionally strong evidence from observational
studies. 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
an important impact.
Benefits balanced with
risks; best action may
differ depending on
circumstances or
patient/society values.
RCTs with no important limitations, or exceptionally strong evidence from observational
studies. Further research is unlikely to change our confidence in the estimate of effect.
Benefits balanced with
risks; other alternatives
may be equally reasonable.
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 an
important impact.
RCTs with important limitations or strong evidence from observational studies.
Further higher-quality research may have an important impact.
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.
Therefore, six different grades may be used to grade a recommendation (Table II).3 The reader needs to understand the important changes made in the way the final recommendations
are obtained. The most dramatic change is that the strength
of recommendation is no longer based, as was the case only
a few years ago, solely on the type and quality of available
studies. Back in 1989,4 panelists would first rate the level of
evidence from “large trials with clear-cut results and low risk
of error” to “case series only,” and the grade of recommendation depended on the level of evidence, with no other parameter taken into account. Interestingly, until the 6th edition
in 2001, the quality of evidence rating preceded the strength
of recommendation rating in the grading system (from A1 to
C2), and the assessment of quality of evidence was mainly
based on study design, the highest level being limited to RCTs
and meta-analyses of RCTs.
the four steps of evidence-based medicine were followed for
each recommendation: clear identification of the clinical problem; literature retrieval; literature appraisal; and application of
the findings acknowledging factors other than evidence.
In 2008, quality of evidence became “only one” of the determinants of the strength of recommendation, along with beneficial
health outcomes, decreased burden of treatment, variability
in patients’ preferences, and resource use. The recommendation is a true judgement on the overall value of the balance
between the benefits and risks incurred by following this recommendation, a judgement based not only on the expected
benefits in terms of health, treatment-related risks, and patient values and preferences, but also on economic considerations and the allocation of resources.
Limitations and misunderstandings
In 2001, for first time,5 the primacy of the judgement on the
clarity of the risk-benefit trade-off of an intervention over the
methodological quality of a study alone became clear. The
grade of recommendation (1 or 2) was therefore placed before the quality of evidence (A, B, or C). Moreover, high-quality studies could lead to weak recommendations because of
uncertainty over precise estimates of benefit, harm, or costs
and small effect sizes. Conversely, in 2004, it became possible
to make a grade 1 recommendation even in the absence of
RCTs with no important limitations. If experts judged that an
extrapolation made from available RCTs was secure or that
data from observational studies were overwhelmingly compelling, the quality of evidence was marked “C+”, which could
lead to a grade 1 recommendation.6 The 2004 edition was the
first to be named, “Evidence-Based Practice Guidelines,” and
The GRADE system certainly represents a major improvement
in clinical guideline methodology. It provides the clinician with
recommendations based not only on the methodological quality of available studies, but also on other important criteria (see
above). However, one could consider that recommendations
based on the GRADE system are more demanding for the
reader. In fact, it is crucial for guideline users to carefully read
and understand the way recommendations are made. Above
all, to fully appraise a recommendation, they need to read not
only the final summary sentence, but the whole text giving the
explicit criteria leading to the recommendation.
For example, the latest edition of the ACCP guidelines is often
quoted as strongly recommending long-term treatment in patients who experience a first unprovoked deep vein throm-
283
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DISEASE
GUIDELINES
AND
DA I LY
bosis or pulmonary embolism. However, the exact recommendation reads: “For patients with a first unprovoked VTE
[venous thromboembolism], and in whom risk factors for
bleeding are absent and for whom good anticoagulant monitoring is achievable, we recommend long-term treatment
(Grade 1A).” In terms of values and preferences, this recommendation attaches a relatively high value to the prevention
of recurrent VTE and a lower value to the burden of long-term
anticoagulant therapy. This is obviously very different to the
quick summary and reveals the thinking behind how decisions are made.7
Moreover, GRADE authors insist that recommendations apply to specific settings, groups of patients, and economic
contexts. There may be significant variations across countries or hospitals that may influence the decision of whether
to adhere to a recommendation. Costs, for example, as well
as the way costs influence clinical decisions, differ widely between countries. Most of all, no recommendation can take
into account all individual clinical circumstances. The ACCP
guideline authors warn that any grade other than a grade 1A
CLINICAL
PRACTICE
recommendation indicates that the authors acknowledge
that other interpretations of evidence and other clinical policies may be appropriate. Furthermore, they suggest that even
grade 1A recommendations may not apply to all patients and
circumstances, either because of resource constraints or
because of patients’ atypical values and preferences. Finally, physicians must use their judgement and consider local
and individual circumstances along with their patients’ values
and preferences to achieve the best-tailored decisions.
Conclusion
Clinical decision-making is not simple. Guidelines help clinicians and patients facing complex choices to choose informed options, to improve quality of care, and to make the
best use of limited resources. The GRADE system provides a
standardized and explicit way of compiling recommendations,
of which physicians must be aware in order to fully make the
most of guidelines in the care of their patients. I
Acknowledgements: the author would like to thank Mrs Alavi for her
useful assistance.
References
1. Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of
evidence and strength of recommendations. BMJ. 2004;328:1490.
2. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American
College of Chest Physicians Task Force. Chest. 2006;129:174-181.
3. Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schunemann HJ. Grades of
recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;
133:123S-131S.
4. Sackett DL. Rules of evidence and clinical recommendations on the use of
antithrombotic agents. Chest. 1989;95:2S-4S.
5. Guyatt G, Schunemann H, Cook D, Jaeschke R, Pauker S, Bucher H. Grades
of recommendation for antithrombotic agents. Chest. 2001;119:3S-7S.
6. Guyatt G, Schunemann HJ, Cook D, Jaeschke R, Pauker S. Applying the
grades of recommendation for antithrombotic and thrombolytic therapy: the
Seventh 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. Antithrombotic therapy for venous thromboembolic disease: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest. 2008;133:454S-545S.
Keywords: evidence-based medicine; review; recommendations
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 en
2004 dans le but de fournir des méthodes systématiques et explicites pour établir des recommandations pour les
médecins. Le système a été adopté par l’ACCP (American College of Chest Physicians) dans la dernière édition des
Recommandations pratiques cliniques basées sur des preuves au sujet du traitement antithrombotique et thrombolytique (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 qualité de preuve (A = fort ; B = intermédiaire ; et C = faible). Bien que les chiffres et les lettres utilisés dans le système
de classification restent inchangés par rapport aux éditions précédentes, les changements ont été significatifs dans
les définitions et les critères sous-jacents, conduisant à ces nouvelles recommandations de classification. En particulier, 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 recommandations doivent être avertis de la façon dont elles sont obtenues afin de les comprendre parfaitement et
de les utiliser au mieux pour traiter leurs patients.
284
CHRONIC
‘‘
VENOUS
AND
Several well-conducted controlled trials versus placebo or
stockings have shown the efficacy
of oral venoactive drugs…. An update of the guidelines for testing
drugs for chronic venous disease
is needed to enable the pharmaceutical industry to invest the resources required to perform large
and definitive clinical trials, with a
view to improving the recommendations. Recommendations are
useful to clinicians and organizations involved in decision-making
in this important field.”
DA I LY
DISEASE
GUIDELINES
CLINICAL
PRACTICE
European and American
guidelines on primary
chronic venous disease:
what’s new?
b y J . - L . G i l l e t , Fra n c e
P
Jean-Luc GILLET, MD
Vascular Medicine
Phlebology
FRANCE
rimary chronic venous disease (CVD) is defined as morphological and
functional abnormalities of the venous system of long duration, manifested 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 synthetic origin. The objective of this article is to highlight the role and impact of
VADs in the management of primary CVD according to recent European and
American guidelines. Following analysis of the recent guidelines on primary
CVD and their recommendations regarding the place of VADs in the management of primary CVD, three VADs were given the highest level of recommendation. Calcium dobesilate, micronized purified flavonoid fraction (MPFF),
and hydroxyethylrutoside (ie, oxerutins) were assigned a Grade A recommendation, the highest level of recommendation by the International Consensus
Statement (Siena, 2005) and the Consensus Statement led by Nicolaides in
2008, with regard to CVD-related symptoms. The guidelines detailed evidence of the efficacy of several VADs in CVD-related edema, and the efficacy
of MPFF as an adjunct to standard treatment in the healing of venous ulcers.
The use of MPFF and pentoxifylline in combination with compression in longstanding or large venous ulcers was recommended and assigned Grade 1B
in the latest edition of the Handbook of Venous Disorders (2009). Suggestions regarding expected improvements in future guideline documents are
also presented.
rimary chronic venous disease (CVD) is defined as morphological and functional abnormalities of the venous system of long duration, manifested by symptoms, signs, or both. Symptoms related to CVD are diverse1: tingling, aching,
burning, pain, muscle cramp, sensation of swelling, sensation of throbbing or heaviness, itching skin, restless legs, leg tiredness, and fatigue. They are not pathognomonic, but may be suggestive of CVD if they get worse as the day progresses
or are exacerbated by heat, and relieved with leg rest and elevation.1
P
Dr Jean-Luc Gillet,Vascular Medicine,
51 bis Avenue Professeur Tixier,
38300 Bourgoin-Jallieu, France
(e-mail: gilletjeanluc@aol.com)
Clinical signs include telangiectasias, reticular and varicose veins, edema, skin
changes, and venous ulcers. They are categorized into seven classes designated
C0-C6 according to the CEAP (Clinical-Etiological-Anatomical-Pathophysiological)
classification (Table I, page 286).2 Each clinical class is characterized by a subscript
letter indicating the presence of symptoms (S, symptomatic) or absence of symp-
European and American guidelines on primary chronic venous disease: what’s new? – Gillet
285
CHRONIC
VENOUS
CEAP
classification
C0
C1
C2
C3
C4
C5
C6
DISEASE
GUIDELINES
AND
DA I LY
Clinical description
No visible or palpable signs of venous disease
Telangiectasias or reticular veins
Varicose veins; distinguished from reticular
veins by a diameter of 3 mm or more
Edema
Changes in skin and subcutaneous tissue
secondary to CVD, divided into 2 subclasses to better define the differing severity
of venous disease:
C4a: pigmentation or eczema
C4b: lipodermatosclerosis or atrophie
blanche
Healed venous ulcer
Active venous ulcer
Table I. Clinical descriptions of the revised CEAP classification.
toms (A, asymptomatic). All classes of CVD can be associated with symptoms. Epidemiological studies have shown that
CVD is extremely common in most countries and has a considerable socioeconomic impact in Western countries. In
some studies, the majority of the adult population showed
some degree of CVD. In the Edinburgh Vein Study,3 more
than 80% of people aged 8 to 64 years had mild hyphenweb or reticular varices, while a study carried out in 24 Italian
cities4 showed that only 3% of subjects examined were free
of visible signs of CVD. In the San Diego Population Study,5
featuring 2211 people, visible disease was present in 84% of
women and 57% of men.
Reported prevalences of the clinical manifestations of CVD
vary widely. The prevalence of edema and skin changes,
such as hyperpigmentation and eczema, due to CVD varies
from 3% to 11% of the population. In Western countries, it
is estimated that 1% of the population will develop one or
more episode(s) of leg ulcer.
The economic cost of CVD is thought to be very high. It has
been estimated that the cost of managing CVD represents
1%-3% of the total health-care budget in Western countries,6-9 with treatment costs amounting to approximately
US $3 billion annually in the USA.10 In addition, venous leg ulcers cause the loss of some 2 million working days per year
in the USA.10
Venoactive drugs
Venoactive drugs (VADs) are a heterogenic group of drugs
of vegetal or synthetic origin. They can be classified in 4 major categories (Table II): benzopyrones; saponins; other plant
extracts; and synthetics drugs.11
PRACTICE
N Main categories of VADs
N Benzopyrones
Abbreviations: CEAP, Clinical-Etiological-Anatomical-Pathophysiological; CVD,
chronic venous disease.
Modified from reference 2: Eklöf et al; American Venous Forum International
Ad Hoc Committee for Revision of the CEAP Classification. J Vasc Surg. 2004;
40:1248-1252. © 2004, The Society for Vascular Surgery.
286
CLINICAL
There are two classes of VAD in this category: alpha-benzopyrones and gamma-benzopyrones. Coumarin is the most
notable alpha-benzopyrone. Gamma-benzopyrones, which
are also known as flavonoids, include diosmin, micronized
purified flavonoid fraction (MPFF), and rutosides, such as
rutin, troxerutin, and hydroxyethylrutosides (HRs).
N Saponins
This category includes horse chestnut seed extract (HCSE)
and Ruscus extracts.
N Other plant extracts
All these plant extracts, such as extracts of Ginkgo biloba,
Centella asiatica, and Hamamelis, contain flavonoids, such
as anthocyans and proanthocyanidins, together with other
active substances.
N Synthetic drugs
The principal synthetic drugs are calcium dobesilate, naftazone, and benzarone.
N Mode of action of VADs
VADs have multiple effects on the venous system.11 The
mode of action varies depending on the drug. They attenuate macrocirculatory changes in the venous wall and venous valves that cause hemodynamic disturbances leading
to venous hypertension and attenuate microcirculatory effects
of venous hypertension that lead to venous microangiopathy.
They also have effects, eg, anti-inflammatory, on venous tone,
venous wall, venous valves, capillary leakage, the lymphatic
network, and hemorrheologic parameters.
Recently, attention has focused on the roles of oxidative stress
and inflammation in causing adverse changes in the vein wall
and venous valves, which lead to subsequent skin changes.12
Some VADs have free-radical scavenging actions and can
interfere with inflammatory cascades, notably in the case of
MPFF by inhibiting leukocyte-endothelial interactions.13 AnSELECTED
CEAP
CIVIQ
CONSORT
CVD
GRADE
HCSE
HR
MPFF
QOL
RCT
SF-12
SF-36
VAD
CONSOlidated standards of Reporting Trials
Grades of Recommendation Assessment,
horse chestnut seed extract
hydroxyethylrutoside
micronized purified flavonoid fraction
quality of life
venoactive drug
CHRONIC
Group
VENOUS
DISEASE
GUIDELINES
Substance
AND
DA I LY
CLINICAL
PRACTICE
Origin
Benzopyrones
Alpha-benzopyrones
Coumarin
Melinot (Melilotus officinalis)
Woodruff (Asperula odorata)
Gamma-benzopyrones
(flavonoids)
Diosmin
Ciprus sp (Sophora japonica)
Micronised purified flavonoid
fraction (MPFF)
Rutaceae aurantiae
Rutin and rutosides
Sophora japonica
O-(β-hydroxyethyl)-rutosides
Eucalyptus sp
Fagopyrum esculentum
Escin
Horse chestnut (Aesculus
hippocastanum)
Ruscus extract
Butcher’s broom (Ruscus aculeatus)
Anthocyans
Bilberry (Vaccinium myrtillus)
Grape pips (Vitis vinifera)
Proanthocyanidins (oligomers)
Maritime pine (Pinus maritima)
Extracts of ginkgo, heptaminol,
and troxerutin
Ginkgo biloba
Calcium dobesilate
Synthetic
Benzarone
Synthetic
Naftazone
Synthetic
Saponins
Other plant extracts
Synthetic products
imal studies suggest that these actions of VADs can protect
the vein wall and valves from deleterious changes, with the
potential for slowing or preventing the progression of primary CVD.14
N Recent guidelines on VADs
Numerous randomized, controlled, double-blind studies have
demonstrated the improvement of CVD-related symptoms
by VADs, and the antiedema effect of VADs has also been
objectively demonstrated in double-blind trials. The main indications for VADs are symptoms related to CVD and edema
in patients at any stage of CVD. VADs may also have a role in
the treatment of leg ulcers. A meta-analysis of MPFF, from the
benzopyrone category of VADs, confirmed its value as an adjunct to standard treatment for healing leg ulcers.15
This article will assess the role and impact of VADs in the
management of primary CVD in light of the recent European
and American guidelines. Two guidelines have been published
recently discussing the therapeutic efficacy of VADs on CVDrelated symptoms and venous edema.11,16,17 The latest edition
of the Handbook of Venous Disorders: Guidelines of the American Venous Forum18 includes a chapter on drug treatment of
varicose veins, venous edema, and ulcers. Elsewhere, Perrin
and Ramelet19 have proposed their own recommendations
for the use of VADs, based on the principle of the GRADE
(Grades of Recommendation Assessment, Development and
Evaluation) system.
Table II. Classification of the
main venoactive
drugs.
Modified from
reference 11: Nicolaides et al. Int Angiol.
2008;27:1-59.
© 2008, Edizioni
Minerva Medica.
N Therapeutic efficacy of VADs and impact on guidelines
A Cochrane review of VADs by Martinez et al (2005) examined the efficacy of such drugs in detail.20 Clinical trials of a
range of different VADs were analyzed. Studies of HCSE were
excluded because they were covered in a separate Cochrane
review (see below).21 The authors identified 110 randomized,
placebo-controlled trials, 44 of which were included in the final analysis. Studies were classified level A (low risk of bias),
level B (moderate risk of bias), or level C (high risk of bias). A
wide range of outcome variables, including objective signs
and subjective symptoms, were analyzed using a random effects statistical model. For every outcome variable except venous ulcer, the analyses showed significant treatment benefits for VADs compared with placebo when analyzed as either
a dichotomous or a continuous variable, or both in some cases. The analyses showed that VADs had significant treatment
benefits compared with placebo with regard to pain, cramps,
heaviness, and sensations of swelling and paresthesia, despite a lack of homogeneity between trials.19 The only nonsignificant effects were for venous ulcer, itching assessed as
a continuous variable, and paresthesias assessed as a continuous variable. For edema (relative risk [RR], 0.72; 95% confidence 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, 0.740.95), the analyses showed a significant benefit with VAD treatment, with no evidence of heterogeneity among the studies.
This was in contrast to most of the analyses, which showed
evidence of heterogeneity.19
287
CHRONIC
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DA I LY
N The Cochrane review of horse chestnut seed extract 21
Randomized clinical trials (RCTs) of HCSE, whose main active
component is the triterpenic saponin iscin, were the subject
of a Cochrane review published by Pittler and Ernst in 2006.
Twenty-nine studies were identified, 17 of which were included in the review. The authors concluded that HCSE was efficacious compared with placebo and of similar efficacy to
compression therapy in the short-term treatment of CVD. Adverse effects were generally mild and infrequent, so the overall risk/benefit ratio for HCSE was favorable. On the basis of
publications, including Cochrane reviews, VADs as a whole
have been assigned a weak recommendation (Grade 2B) for
improving symptoms and edema associated with CVD in the
latest edition of the Handbook of Venous Disorders.18
Number of
influential 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
CLINICAL
PRACTICE
As a result of the analysis, calcium dobesilate, MPFF, and HR
were all assigned the highest level (Grade A) recommendation, while HCSE and Ruscus extracts were assigned Grade B
(Table III).
N Management of CVD of the lower limbs
A consensus statement on the management of chronic venous disorders of the lower limbs was prepared in 200811 under the auspices of several learned societies, including the
American Venous Forum, the American College of Phlebology,
and the European Venous Forum. A set of guidelines arising
from the consensus statement covers most aspects of the
management of CVD, including investigations, treatment, and
management strategy.
With respect to VADs, the guidelines largely summarized and
endorsed the positive findings of the recent Cochrane reviews20,21 and the grades of recommendation of the International Consensus Statement of Siena.16 These guidelines used
the same grading system as the Siena Consensus, except
for meta-analyses, which were considered to have a grade B
level of evidence. Outcomes this time included not only symptoms, but also edema and venous ulcer healing.
Table IV summarizes VAD effects on symptoms, edema, and
skin changes by category of drug. Grade A status was assigned to three VADs: calcium dobesilate, MPFF, and HR, but
only symptoms were considered. Generally, no reservations
were voiced regarding the safety of VADs, except for a couple of specific cases: coumarin-rutin and benzarone (hepatotoxicity) and calcium dobesilate (some cases of transcient
agranulocytosis were reported from 1992 to 2005).11
Guidelines and VADs for venous edema
Table III. Grades of recommendation of the International Consensus Statement. Based on data from reference 11.
Abbreviations: HCSE, horse chestnut seed extract; MPFF, micronized purified
flavonoid fraction; RCT, randomized clinical trial.
International consensus
The International Consensus Statement in 200516 represents
the outcome of the International Medical Consensus Meeting on Venoactive Drugs in the Management of Chronic Venous Disease, held during the 13th Conference of the European Society for Clinical Hemorheology in Siena, Italy, from
26-29 June, 2005.
A group of 14 experts, from countries in which VADs were
available and with experience of their clinical use, analyzed
a total of 83 studies. Three grades of recommendation were
considered, based on the following levels of evidence: grade A
(several RCTs with large sample sizes, meta-analysis of homogenous results); grade B (RCTs with small sample sizes,
or a single RCT); and grade C (other controlled trials, nonrandomized controlled trials, and observational studies). Outcomes included only symptoms at any stage of CVD.
288
Although edema is a nonspecific sign, it is one of the most
frequent and typical symptoms and signs in CVD. All other
causes of edema should be excluded to confirm its venous
origin. CVD-related edema is described as sporadic, unilateral or bilateral, and limited to the legs, which may also involve
proximal parts of the lower extremities. It is enhanced by prolonged orthostatic posture, and improved by leg elevation.22
Several well-conducted controlled trials versus placebo or
stockings11,16 have shown the efficacy of oral VADs such as
MPFF, rutosides, HCSE, calcium dobesilate, proanthocyanidines, and coumarin-rutin. In these trials, the evaluation of antiedematous efficacy was based on objective measures, such
as measurement of leg circumference, strain-gauge plethysmography, and water displacement. Results of meta-analyses, including the Cochrane reviews,20,21 have confirmed the
antiedematous efficacy of VADs.
The guidelines highlighted the evidence of efficacy of several
VADs (calcium dobesilate, MPFF, rutosides, HCSE, proanthocyanidines, and coumarin + rutin) in CVD-related edema, and
CHRONIC
Compound
VENOUS
Positive results on the
following indications*
DISEASE
GUIDELINES
AND
DA I LY
CLINICAL
RCTs
Recommendation**
Trials and
meta-analyses**
Calcium dobesilate
Cramps, restless legs,
sensation of swelling,
edema
4
Grade A
2
MPFF
Pain, cramps, heaviness,
sensation of swelling,
trophic changes,
venous leg ulcer
5
Grade A
1
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.
the efficacy of MPFF as an adjunct to standard treatment in
the healing of venous ulcers (although only symptoms have
been considered in the assignation of a grade of recommendation) (Table IV).11
Guidelines and VADs for venous leg ulcers
Acceleration of venous leg ulcer healing (stage C6 of the
CEAP classification) has been demonstrated in a double-blind
study using MPFF in combination with compression.23 This
result was confirmed in 2005 by a meta-analysis of five trials
in which MPFF was used as an adjunct to standard compression treatment in 723 class C6 patients.15 HCSE and HRs were
not superior to compression in advanced chronic venous insufficiency24 or in the prevention of venous ulcer recurrence.25
The latest edition (3rd edition) of the Handbook of Venous Disorders18 includes a chapter on drug treatment of varicose
veins, venous edema, and ulcers. The method of determining the strength and quality of recommendations in this document was based on GRADE.26 GRADE recommendations
consist of a number (“1” for a “strong” or “we recommend”
recommendation, and “2” for a “weak” or “we suggest” recommendation) and a letter, which refers to the “quality of
evidence” supporting the recommendation. There are three
grades: “A” for high-quality evidence; “B” for moderate-quality evidence; and “C” for low-quality evidence. The GRADE
system is based on the distinction between the strength of
a recommendation and the quality of the evidence on which
it is based, although in practice the separation is not absolute
and the quality of evidence is an important determinant of the
strength of a GRADE recommendation.
PRACTICE
Table IV. Summary
of VAD effects on
symptoms, edema,
and skin changes by
category of drugs.
Abbreviations: HCSE,
horse chestnut seed
extract; MPFF, micronized
purified flavonoid fraction;
RCT, randomized controlled trial.
Modified from reference
11: Nicolaides et al. Int
Angiol. 2008;27:1-59.
© 2008, Edizioni Minerva
Medica.
The use of MPFF in combination with compression in longstanding or large venous ulcers was recommended and assigned a grade 1B. The evidence for the addition of MPFF is
based on the meta-analysis of 5 trials with MPFF as an adjunct to standard compression treatment in 723 patients mentioned above.15 At 6 months, complete ulcer healing had occurred in 61% of MPFF patients and in 48% of control patients
(RR reduction for persistent ulceration, 32%; 95% CI, 3% to
70%; P=0.03). Subgroup analyses suggested that the benefits of MPFF were greatest in ulcers ⱖ5 cm2 and in ulcers
of >6 months’ duration.
Pentoxifylline, a drug indicated for the management of peripheral arterial disease, has also been used in the management of venous ulcers. Its use in combination with compression in long-standing or large venous ulcers has a grade 1B
recommendation.
N Tentative recommendations for VADs
Building on recent reviews and meta-analyses and taking into
account additional evidence that was either not available or
not included in them, Perrin and Ramelet have proposed tentative recommendations for the use of VADs based on the
principles of the GRADE system.19 They stress that these recommendations reflect their own opinions and judgements,
and have not been endorsed by learned societies or other organizations to date.
These recommendations are summarized in Table V (page
290).19 A grade 1B was assigned to MPFF and rutosides for
the relief of symptoms associated with CVD in C0s to C6s pa-
289
CHRONIC
VENOUS
DISEASE
Indication
Relief of symptoms
associated with CVD
in C0s to C6s patients
with CVD-related edema
GUIDELINES
AND
DA I LY
CLINICAL
PRACTICE
Venoactive drug
Recommendation
for use
Quality
of evidence
Code
1B
MPFF
Strong
Moderate
Rutosides
Strong
Moderate
1B
Calcium dobesilate
Weak
Moderate
2B
HCSE
Weak
Low
2C
Ruscus extracts
Weak
Low
2C
MPFF
Strong
Moderate
1B
Healing of large or long-standing
venous ulcers as an adjunct to
compression and local therapy
tients with CVD-related edema. A grade 1B recommendation
was also given for the use of MPFF as an adjunct to compressive and local therapy for healing large or long-standing venous ulcers.18
Future challenges17,19
N Assessing the efficacy of treatment
An update of the guidelines for testing drugs for CVD27 is needed to enable the pharmaceutical industry to invest the resources required to perform large and definitive clinical trials,
with a view to improving the recommendations. Recommendations are useful to clinicians and organizations involved in
decision-making in this important field. Such guidelines could:
N Reiterate the basic principles that should prevail when reporting (and setting up) a clinical trial, using the CONSORT
(CONSOlidated standards of Reporting Trials) statement. This
statement is designed to help authors and investigators file
reports using a published checklist and flow diagram,28 available on the Web site: www.consort-statement.org.
N Describe patients comprehensively at study selection using
the advanced CEAP classification. This implies that not only
the “C” (Clinical) of CEAP should be completed, but also
items “E” (Etiological), “A” (Anatomical), and “P” (Pathophysiological), together with mandatory duplex color, with or without plethysmography (a level 2 investigation, according to
Eklöf et al),2 and in certain cases, invasive (level 3) investigations; the addition of new descriptors for the “E”, “A”, and
“P” items when no venous abnormality is identified may be
useful when describing patients with leg complaints, but no
visible or detectable signs of CVD.2
N Promote the use of validated tools to assess symptoms,29
edema,30 and venous leg ulcer.31
N Reach a consensus on the standard use of dressings, compression therapy, and local antiseptics in venous leg ulcer.
Table V. Summary of
tentative recommendations, according to
Perrin and Ramelet.
Abbreviations: CVD,
chronic venous disease;
HCSE, horse chestnut
seed extract; MPFF, micronized purified
flavonoid fraction.
Modified from reference
19: Perrin and Ramelet.
Eur J Vasc Endovasc
Surg. 2011;41:117-125.
© 2011, European Society
for Vascular Surgery.
In addition, there is a need for consensus on the following end
points:
N Symptoms: how great does the decrease on the visual analogue scale have to be in order to consider there is clinical
improvement?
N Edema: how great does the reduction in ankle volume have
to be in order to consider it as clinically relevant?
N Varicose veins: which criteria should be used to consider
whether a drug treatment for varicose veins works?
N Venous leg ulceration: when should we consider the ulcer
to be healed?
N Adapted patient-reported outcome tools
Early stages of CVD are difficult to assess objectively, particularly in C0s patients, as symptoms are by definition subjective. The assessment of patients’ perception of their quality of life (QOL) is desirable in such cases. Both generic and
specific QOL scales should be used: the generic SF-12 (Short
Form 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 (ChronIc
Venous dIsease Questionnaire) QOL is a good choice. It has
been extensively validated,32 is the scale most often used in
CVD, and has currently been validated in 13 languages.
Conclusion
The role of VADs in the prevention of the natural history of CVD
progression remains to be fully determined: are all VADs able
to protect CVD patients against the progression of the disease to severe complications? The use of human-sized experimental animals, such as pigs, might allow for better evaluation of the key processes involved.33 Where grading is
concerned, the consensual adoption of a simple and universally understood system of grading is desirable.26 I
References
1. Eklöf B, Perrin M, Delis KT, Rutherford RB, Gloviczki P. Updated terminology
of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary consensus document. J Vasc Surg. 2009;49:498-501.
2. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the
290
CEAP classification for chronic venous disorders: consensus statement. J Vasc
Surg. 2004;40:1248-1252.
3. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins and
chronic venous insufficiency in men and women in the general population:
CHRONIC
VENOUS
DISEASE
4. Chiesa R, Marone EM, Limoni C, Volonté M, Schaefer E, Petrini O. Chronic venous 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 ethnically 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 unrecognized public health problem [In French]. J Mal Vasc. 1994;19:185-189.
7. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology. 1997;48:67-69.
8. Van den Oever R, Hepp B, Debbaut B, Simon I. Socio-economic impact of
chronic venous insufficiency. An underestimated public health problem. Int Angiol. 1998;17:161-167.
10. McGuckin M, Waterman R, Brooks J, et al. Validation of venous leg ulcer guidelines in the United States and United Kingdom. Am J Surg. 2002;183:132-137.
12. Bergan JJ, Schmid-Schönbein GW, Coleridge Smith PD, Nicolaides AN, Boisseau MR, Eklöf B. Chronic venous disease. N Engl J Med. 2006;355:488-498.
13. Bergan J. Molecular mechanisms in chronic venous insufficiency. Ann Vasc
Surg. 2007;21:260-266.
14. Bergan JJ, Pascarella L, Schmid-Schönbein GW. Pathogenesis of primary
chronic 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 adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc
Surg. 2005;30:198-208.
16. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol
Microcirc. 2005;33:309-319.
17. Nicolaides A. Venoactive medications and the place of Daflon 500 in recent
guidelines on the management of chronic venous disease. Phlebolymphology.
2009;16:340-346.
GUIDELINES
AND
DA I LY
CLINICAL
PRACTICE
18. Coleridge Smith PD. Drug treatment of varicose veins, venous edema, and ulcers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American Venous Forum. 3rd ed. London, UK. Hodder Arnold; 2009:359-365.
19. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous
disease: rationale, results and unanswered questions. Eur J Vasc Endovasc
Surg. 2011;41:117-125.
20. Martinez MJ, Bonfill X, Moreno RM, Vargas E, Capellà D. Phlebotonics for venous
insufficiency. Cochrane Database Syst Rev. 2005;(3):CD003229.
21. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. 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 leg
ulcer healing: a double-blind, randomised, controlled versus placebo trial in 107
patients. Angiology. 1997;48:77-85.
24. Ottilinger B, Greeske K. Rational therapy of chronic venous insufficiency: chances
and limits of the therapeutic use of horse-chestnut seed extracts. BMC Cardiovasc 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: randomised, controlled trial. Br J Surg. 1991;78:1269-1270.
26. Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. GRADE: going
from evidence to recommendations. BMJ. 2008;336:1049-1051.
27. Vansheidt W, Heidrich H, Jünger M, Rabe E. Guidelines for testing drugs for
chronic venous insufficiency. Vasa. 2000;29:274-278.
28. Moher D, Hopewell S, Schulz KS, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ.
2010;340:c869.
29. Vasquez MA, Munschauer CE. Venous clinical severity score and quality-of-life
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. Phlebolymphology. 2004;47:312-319.
Res. 1996;5:539-554.
33. Jones GT, Grant MW, Thomson IA, Hill BG, Van Rij A. Characterization of a porcine model of chronic superficial varicose veins. J Vasc Surg. 2009;49:1554-1561.
Keywords: chronic venous disease; venoactive drug; guidelines; grade of recommendation
RECOMMANDATIONS EUROPÉENNES ET AMÉRICAINES
SUR LA MALADIE VEINEUSE CHRONIQUE PRIMAIRE : QUOI DE NEUF
?
La maladie veineuse chronique primaire (MVC) se définit par des anomalies morphologiques et fonctionnelles de
longue durée touchant le système veineux, se manifestant par des symptômes, des signes ou les deux. La MVC est
extrêmement courante dans la plupart des pays et son impact socio-économique est considérable dans les pays
occidentaux. Les médicaments veino-actifs (MVA) sont un groupe hétérogène de médicaments d’origine végétale
ou synthétique. L’objectif de cet article est de souligner le rôle et l’impact des MVA dans la prise en charge de la
MVC primaire selon les recommandations européennes et américaines récentes. En suivant les analyses des recommandations récentes sur la MVC primaire et leurs directives concernant la place des MVA dans la prise en charge
de la MVC primaire, trois MVA ont obtenu le plus haut niveau de recommandation. Le dobésilate de calcium, la fraction flavonoïque purifiée micronisée (FFPM) et l’hydroxyéthylrutoside (c’est-à-dire les oxérutines) ont été classés en
recommandation 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) dirigé par Nicolaïdes en 2008, en ce qui concerne les symptômes liés à la MVC. Les recommandations ont détaillé les
preuves de l’efficacité de plusieurs MVA dans l’œdème lié à la MVC et l’efficacité de la FFPM comme additif au
traitement standard dans la cicatrisation des ulcères veineux. L’utilisation de la FFPM et de la pentoxifylline associées à la compression dans les ulcères importants ou anciens a été recommandée et classée en grade 1B dans la
dernière édition du Hanbook of Venous Disorders (2009). Nous présentons également des améliorations possibles
qui devraient être apportées aux futures recommandations.
291
THE QUESTION
CONTROVERSIAL
VD guidelines are based on
well-designed studies that
use control groups, have
multiple planned follow-up visits,
and are performed by skilled personnel in dedicated facilities. However, studies are not perfect and
limitations exist: exclusion because of old age, inability or unwillingness to comply with monitoring, and contraindications. So,
do CVD guidelines reflect what
goes on in real life and are they
applicable and useful in all cases
of CVD patient management? Our
experts give their views.
QUESTION
C
Are chronic venous
disease guidelines adapted
to daily practice?
1.
K. A. Aal, Egypt
2.
H. S. Caldevilla, Argentina
3.
R. Costa-Val, Brazil
4.
H. S. Yuwono, Indonesia
5.
H. N. T. H. Le, Vietnam
6.
ğ ć, Croatia
S. M. Kulisi
7.
A. Puskás, Romania
8.
ğ Czech Republic
K. Roztocil,
9.
M. Salah, Saudi Arabia
10 .
I. S. Escotto, Mexico
11.
J.-F. Uhl, France
12 .
I. A. Zolotukhin, Russia
Are chronic venous disease guidelines adapted to daily practice?
293
CONTROVERSIAL
QUESTION
1. K. A. Aal, Egypt
Khaled Abdel AAL, MD
Chairman of the Department of
Vascular and Endovascular Surgery
National Institute of Diabetes
Cairo, EGYPT
(e-mail: dr.khaledaal@yahoo.fr)
tine practice, as shown by the fact that they were used in only
23% of studies in a recent Cochrane review. Some phlebologists also question their relevance to routine practice. The
new guidelines have clearly shown that vasoactive drugs and
compression are the cornerstones of treatment. Fitting and
applying elastic hosiery can be problematic, however, in particular in the elderly, the obese, and those with painful ulcers.
Cost and frequent renewal are other drawbacks.
efore answering this question we must first identify our
needs. These begin with a comprehensive study that
would provide a simple classification of all the signs and
symptoms of chronic venous insufficiency. Using evidencebased studies, it would identify and standardize the most appropriate investigation(s) and treatment(s) for each disease
stage. It would also be readily applicable in daily practice and
sufficiently malleable to incorporate the latest data.
B
In France, vasoactive drugs are recommended in symptomatic patients for a maximum duration of 3 months, except
if symptoms recur on treatment withdrawal. This recommendation is driven by financial considerations in that vasoactive drugs are widely prescribed in France, where they represent a major drain on the health insurance system, double
that in Germany, sevenfold that in Spain, and twentyfold that
in Belgium.
The recent guidelines largely satisfy this wish list. They represent a huge amount of work by international experts. They
incorporate recent medical and surgical treatments, such as
radiofrequency ablation, laser ablation, and foam sclerotherapy, and compare their results with conventional techniques.
However, many questions remained unanswered, such as the
recommended treatment duration and the management of
hepatic and gastric side effects. Some manufacturers claim
that long-term treatment makes their drugs more effective
against hemorrhoids, but do not mention similar effects for
chronic venous disease or varicose veins. The same applies
to the treatment of lipodermatosclerosis (many patients complain of disfigurement after postthrombotic disease). Other
topics on which we need more information are ulcer recurrence rates and evidence-based trials on methods of prevention.
But supposing we wished to use the recent Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification to
describe a typical case, how would the classification present
it? 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 reflux of the great saphenous vein above and below the knee,
incompetent calf perforators, and axial reflux in the femoral
and popliteal veins, with no signs of postthrombotic obstruction, we would need to write: C6,S , Ep , As,p,d , Pr in basic CEAP
code, and C2,3,4b,6,S , Ep , As,p,d , Pr2,3,18,13,14 (2004-05-17, L II) in
advanced CEAP code! These formulae are comprehensive
in terms of provision of a detailed patient description for research purposes, but too complicated to be applied in rou-
294
Each new set of guidelines should make a point of recommending what further studies will be required in order to
answer outstanding questions. Meanwhile, we recommend
implementing the guidelines worldwide by contacting local
societies and organizing frequent workshops (if possible, with
research committees collecting data), which will allow improved prediction of ulcer healing, decreased health-care
costs, and better quality of life. I
CONTROVERSIAL
2. H. S. Caldevilla,
QUESTION
Argentina
Hector Santiago CALDEVILLA, MD
Director, Department of Surgery
Vicente Lopez “Prof. Dr. Bernardo Houssay”
City Hospital, University of Buenos Aires
Faculty of Medicine, Buenos Aires
ARGENTINA
(e-mail: hscaldevilla@yahoo.com.ar))
I
f guidelines are understood to be the systematic development of recommendations to help doctors and patients
take the best possible decisions in specific clinical circumstances, guidelines have a number of potential benefits, but
also disadvantages.
there is no provision for the reimbursement of endovascular
procedures, for instance, then there is no possibility of appropriate training and guideline implementation.
Venous disease tends to be cared for by a variety of specialists with different skills. Some may not trust their own ability
to 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 in
surgery. Some guideline recommendations may be difficult to
implement because of the intrinsic nature of the changes in
practice required. Some evidence-based strategies may appear unconventional to certain practitioners, requiring the
acquisition of new skills or equipment, and possibly system
changes that are expensive or difficult to implement.4
Benefits
N Improved outcome
N Increased standardization of medical procedures
N Rejection of old, cost-ineffective treatments
N Scientific validation of diagnostic tests, treatments,
and results
N Justification for reimbursement
N Protection of health-care professionals from
malpractice suits.
Many doctors consider that guidelines restrict their autonomy
and flexibility, and depersonalize the doctor-patient relationship. Such doctors prefer to think of the individual patient in
front of them, who is often very different from the “typical” patient in the clinical trials that generated the guidelines. Drawing on their own accumulated experience, these doctors often see a tenuous resemblance between “their” patients and
those featured in the trials. They are therefore unsure that following the guidelines will necessarily improve their results.
Disadvantages
N Disincentive to come up with local solutions
N Absence of legal protection for doctors not following the
guidelines1
N Poor reproducibility of clinical trial settings in daily practice, due to:
– Multiple comorbidity
– Advanced age
– Polypharmacy
– Lack of social support
– Incorrect information from patients about their diseases
and treatments
– Patients’ difficulty in perceiving symptoms and recognizing
their importance, eg, “Doctor, are you sure I need to have so
many tests and complex treatments because of my ulcer and
swollen leg?”
– Frequent history of treatment nonadherence.2,3
Yet despite these impediments to their use, there is no doubt
that, as in other areas, guidelines represent the way ahead
in venous disease in terms of patient care, clinical efficacy,
health-care costs, and quality of life. Indeed, we need more
and better trials to increase the proportion of asymptomatic
patients (currently <40%), so that doctors and their patients
become confident about what to do. The future in chronic
venous disease research lies in elucidating the genetics and
epigenetics involved in the transmission, onset, and evolution of the disease. In a few years’ time, the guidelines may
well be incorporating the benefits of a personalized healthcare approach made possible by “omic” insights (from genomics, epigenomics, proteomics, and the like) that predict
the natural history of the disease in individual patients together with their response to specific treatments.5 I
References
Practicing doctors treating chronic venous disease have to
contend with the fact that even with the correct diagnosis
and most appropriate treatments, the guidelines are insufficient in themselves to guarantee improvement and control
of the disease, in particular in the cases of recurrent varicose
veins and postthrombotic syndrome. Payment and cost issues are the most frequently cited obstacles to guideline implementation, as much in venous disease as elsewhere. Stenting is impossible if nobody can afford it. If in a local institution
1. Constantino-Casas P, Viniegra-Osorio A, Médigo-Micete C, del Pilar Torres-Arreola
L, Valenzuela-Flores A. [The potential of clinical practice guidelines to improve
the 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 creating 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 and
patients 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 bestevidence clinical practice. Int J Qual Health Care. 2009;21:37-43.
5. Xu LH, Zheng H, Sedmak DD, Sadée W. The reemerging concept of personalized health care. Personalized Med. 2008;5:457-469.
295
CONTROVERSIAL
QUESTION
3. R. Costa-Val, Brazil
edema. The Handbook of Venous Disorders also awards micronized purified flavonoid fraction and pentoxifylline grade
2A recommendations for use in venous ulceration.
Ricardo COSTA-VAL, MD, PhD
Vice-Scientific Director
Brazilian Society of Angiology
and Vascular Surgery
São Paolo, BRAZIL
(e-mail: ricardocostaval@hotmail.com)
T
he latest guidelines published in journals such as International Angiology1 and Chest,2 and in the Handbook
of Venous Disorders3 edited by Gloviczki, feature a new
approach to the analysis of clinical trial data, classifying them
into three levels of evidence (1, 2, and 3) and three grading
treatment recommendations (A, B, and C), according to their
impact on the prognosis and quality of life of patients with
chronic venous disease (CVD).
Compression therapy is evaluated and classified by evidence
grades A to C, depending on indication. It emerges as a wellestablished recommendation to be used at all stages of CVD.
However, it is important to point out that it is often best combined with other treatments, in particular venotropic drugs and
various surgical and minimally invasive techniques. Venotropics are a recommended treatment, although the indications
for specific agents differ between the European and American guidelines.
Certain venotropics, in particular micronized purified flavonoid
fraction (diosmin 450 mg plus hesperidin 50 mg [Daflon® 500
mg]), have well-established effects on symptoms such as pain,
cramps, itching, leg heaviness, and restless legs. The American Venous Forum, responsible for the American guidelines,
gives venotropics a 2A level recommendation in long-term
ulcer therapy. The European guidelines, published in International Angiology on behalf of the International Union of Angiology, International Union of Phlebology, and European Venous Forum, recommend various venotropics for the signs
and symptoms of CVD, including ulcers, with micronized purified flavonoid fraction being the only drug carrying a grade
A recommendation for almost all signs and symptoms, except
296
The discrepancies in venotropic indications are probably driven by the different experience with these drugs, which is considerably more extensive in Europe than in North America.
In addition, the huge variety of apparently similar drugs with
multiple differences in physicochemical properties represents
a considerable obstacle to serious clinical and scientific analysis of their actions.
In Brazil, venotropics are commonly prescribed for almost all
stages of CVD, including ulcers. There are evidence-based
national guidelines for this purpose, designed to be applied
in daily practice, enabling practitioners to offer their patients
a better-grounded therapeutic choice. They recommend compression, venotropics, and surgery, often in combination, especially for the more severe stages of the disease. Indeed,
much of the scientific activity undertaken by the Brazilian Angiology and Vascular Surgery Society (SBACV) consists of developing such guidelines within an overarching guideline project coordinated by the Brazilian Medical Association, designed
to provide a scientific foundation to clinical practice in a range
of areas, including CVD. There are already rumors that the
Brazilian Health System will be taking the SBACV guidelines
into account in its control of therapeutic procedures. In other
words, the Society’s recommendations may soon become
the foundation for the official regulation of CVD management
by the world’s largest public health-care system. There can be
no clearer indication of the importance of these scientific and
institutional initiatives involving this challenging disease. I
References
2008;27:1-59.
2. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Practice 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.
CONTROVERSIAL
QUESTION
4. H. S. Yuwono, Indonesia
Hendro Sudjono YUWONO, MD, PhD
Hasan Sadikin General Hospital
Jalan Pasteur 38, Bandung 40161
INDONESIA
(e-mail: hsy47@bdg.centrin.net.id)
P
hlebology has benefited from the general advance in
vascular diagnostics and therapeutics achieved in the
second half of the twentieth century. The lessons of
multiple multicenter trials have been encapsulated in clinical
guidelines that should accelerate the pace of clinical research
by raising and standardizing the level of care worldwide, enabling new lessons to be learned more quickly, which can
then be ploughed back into the recommendations to produce ever better informed and relevant updates.
Guidelines play a key socioeconomic role by standardizing
best practice, ensuring that all patients with similar disease
can expect to receive approximately similar treatment, and
be reimbursed accordingly. They also encourage communication and cooperation between specialists, not only in the
preparatory stages of elaborating the guidelines themselves,
but also in encouraging their uptake by others, whether in
journal articles, scientific meetings, or simply hospital case
conferences and journal clubs. Guidelines provide a common descriptive language and a point of reference that allow specialists to compare like with like, rather than swap anecdotal, unextrapolative experiences, as tended to be the
case in the past. In other words, guidelines are essential to
scientific progress.
In chronic venous disease, as in any other area, guidelines
need to follow a number of obvious quality criteria if they are
to be fit for purpose: they must be robust, in other words
based on the evidence contained in randomized controlled
trials published in quality journals; they must be nonpartisan,
representing a consensus view of best practice; and, perhaps
most importantly, they should be updated at regular intervals, ideally by a data collection program incorporated within the guidelines themselves. An important word of warning,
however: guidelines must always be applicable to routine clinical practice. They cannot be feasible only in an academic
or clinical trial setting. If so, they remain sterile and fail as drivers of progress. This, unfortunately, has been the fate of many
guidelines. Time management issues, staffing levels, sociocultural setting, economic and organizational environment1—all
need to be taken into account if guidelines are to fulfill their
purpose.
Guidelines that are not informed by such considerations risk
accusations of irrelevance, gathering dust on academia’s
shelves. Some accusations go further, referring to potential
limitations and possible patient harm. Patients on bed rest
for 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 entirely
to gynecological patients with cancer.2
Elastic compression stockings are a mandatory precaution
for reducing the risk of postthrombotic syndrome.3 However,
they find less favor among Indonesians than among inhabitants of more temperate climates. The stockings are difficult
to wear in hot and sweaty conditions. This is an instance of a
northern recommendation falling foul of a southern geographic location.
For more detailed information on this topic, we interviewed
nine doctors treating chronic venous disease in four Bandung
hospitals. Almost none ever follow the elastic compression
stocking guideline. Only two sometimes implemented the
guideline. This decision appeared to alienate all the doctors
from the other recommendations in the guideline, with the
result that they did not understand why they should follow any
such guideline or feel obliged to do so. Instead, they manage
their patients according to the relevant textbook and maintain that this produces acceptable results. In this instance,
it could be concluded that despite all the arguments in favor of guidelines, there is little evidence of management failing without them. I
References
1. 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-pharmaceutical measures for prevention of post-thrombotic syndrome. Cochrane
Database Syst Rev. 2004;(1):CD004174.
297
CONTROVERSIAL
QUESTION
5. H. N. T. H. Le, Vietnam
Hiep Nu Thi Hoa LE, MD, PhD
Professor, Vascular Surgery Department
Medical University Hospital of
Ho Chi Minh City, Ho Chi Minh
VIETNAM
(e-mail: lenuthihoahiep1953@yahoo.com.vn)
T
he most recent guidelines for managing chronic venous disease (CVD), published in 2009 by the International Union of Angiology, represent a dramatic change
in understanding and practice for Vietnam. Their major advantage is that they are grounded in robust scientific and
clinical evidence that can be readily extrapolated into daily
practice.
The most obvious use of the CEAP (Clinical-EtiologicalAnatomical-Pathophysiological) classification is in differentiating between different types of patients. Of the many CVD
classifications available, the CEAP is the most useful because it is based on the signs and symptoms characteristic
of each stage of the disease course, from onset to ulceration.
It provides practitioners and patients with a clear vision of the
pathology and its natural history. Unsurprisingly, it has been
rapidly adopted by Vietnamese specialists, who have incorporated it into most of the recent epidemiological studies conducted in this region. CVD is caused by primary abnormalities of the vein wall and valves or secondary abnormalities
resulting from deep vein thrombosis. These lead to reflux, obstruction, or both. In my many years of clinical practice, I have
seen no case of a congenital malformation resulting in CVD.
298
CVD was once considered a disease with symptoms, but no
signs, especially in the early stages, making it especially difficult to evaluate. Duplex ultrasound has since introduced a
range of objective parameters and is the investigative technique most favored by Vietnamese specialists.
As well as providing an aid to diagnosis, the guidelines represent the first comprehensive review of CVD management.
They provide an evidence-based evaluation of all CVD treatments. In particular, they discuss the mode of action and efficacy of venoactive drugs, concluding that most fail to meet
the requisite criteria and that some should even be withdrawn.
Only diosmin, for which there is objective evidence of efficacy and a relevant mode of action, is recommended for all
stages of CVD, from incipient disease to ulceration. The guidelines thus provide specialists with an excellent diagnostic and
therapeutic framework for their clinical practice.
An understanding of its pathology at the microcirculatory level
explains why CVD is a progressive condition and hence requires venoactive treatment. Although surgery may be indicated in particular patients, venoactive drug therapy is essential in arresting changes in the venous microcirculation—a
point still not fully appreciated by some members of the Vietnamese medical community. At teaching hospital level, however, diosmin + hesperidin is our first-line therapy in daily CVD
practice, although we depart somewhat from the guidelines
in tailoring the dosage to the patient’s weight. At the same
time as raising awareness among our fellow practitioners, we
are also attempting to highlight the profile of CVD among the
general public, since this is essential if we are to improve
understanding, diagnosis, and treatment of the disease. I
CONTROVERSIAL
QUESTION
6. S. M. Kulisić, Croatia
ğ
dations and supervise their implementation, before producing
complete national guidelines based on the CEAP classification.
ğ Ć, MD, PhD
Sandra Marinović KULISI
Phlebology Unit, Department of
Dermatology and Venereology
University Hospital Centre Zagreb
and School of Medicine
Zagreb, CROATIA
(e-mail: sandra.marinovic@zg.t-com.hr)
C
hronic venous disease (CVD) guidelines were developed to help physicians cope with a formidable spectrum of signs, symptoms, and therapeutic approaches. Each fresh revision has brought the guidelines that much
closer to grass roots practice, to the extent that the current
challenge for the phlebological community may no longer
be, “How do we improve the guidelines?”, but, “How do we
ensure that clinicians implement the guidelines in their daily
practice?”.
Practical implementation of the guidelines requires a widely
accepted classification system. The consolidation of several
former systems into the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification of CVD, revised in 2004, has
achieved acceptance in all important international guidelines. It was a big step towards greater accuracy and consistency in diagnosis and better management. However, in
Croatia, we have so far failed to convince all our colleagues
to adopt the CEAP classification as the basis of the guidelines.
Reasons for this failure include:
N a clear lack of trained phlebologists to promote the guide-
The following recommendations constitute our first draft:
1. Compression therapy controls most symptoms of acute
and chronic venous disease, slows disease progression, and
prevents deep vein thrombosis (DVT) in bedridden patients.
2. Sclerotherapy is suitable for the treatment of smaller varicose veins, reticular veins, and telangiectasiae. It should be
avoided in large veins, in the vicinity of small and great saphenous veins, and in perforators, owing to the risk of deep vein
thrombosis. It is not an etiological treatment for varicose veins
and cannot prevent the emergence of new varicose veins.
3. Surgical options include phlebectomy, stripping, perforator
ligation (if it enhances function), paratibial fasciotomy, and ulcer grafting.
4. Medication comprises drugs with synthetic or naturally occurring active ingredients that act on capillary permeability
and/or venous tone to relieve chronic venous hypertension.
5. Physical therapy consists of various massage and lymphatic drainage techniques that may temporarily relieve symptoms, provided they are always combined with compression.
6. Local dermatitis therapy is based on physiological skin care,
antimicrobial and anti-inflammatory ointments, and corticosteroids. Proper wound care includes debridement of necrotic and infected tissue, exudate control, wound protection,
and pain relief. The choice of wound dressing depends on
the wound itself, surrounding skin characteristics, allergies,
and availability.
7. Prevention includes exercise, compression, and micronized
purified flavonoid fraction therapy, all of which are significantly cost-effective.
lines;
N the impossibility of implementing all requisite treatment options within a single institution; and
N medical insurance restrictions that exclude CVD as a public health problem, meaning that the patients concerned are
not the official responsibility of any institution or group and are
therefore not treated according to international CVD guidelines.
CEAP classification for all their CVD patients; and
N providing continuing medical education courses on the
pathophysiology of CVD and the advanced treatment options
available.
In this setting of low CVD awareness and with our appointment
as Croatia’s national reference center pending, our department has decided to issue some basic therapy recommen-
A huge amount of work remains to be done in this field, especially in Croatia. But it is the only solution for improving the
management of CVD and patients’ quality of life. I
We shall be following up these basic recommendations by:
N formally educating clinicians in the implementation of the
299
CONTROVERSIAL
QUESTION
7. A. Puskás, Romania
Attila Puskás, MD, PhD
Associate Professor, IInd Medical
Clinic, Department of Thrombosis
and Angiology, University Hospital
Tirgu Mures/Marosvásárhely
ROMANIA
(e-mail: puskasat@gmail.com)
C
hronic venous disease (CVD) has a high prevalence
in the general population and as such represents a
major socioeconomic burden. Quality of life in the later stages is distressing: patients with venous ulcers report a
quality of life similar to that of patients in heart failure.
CVD is usually caused by primary abnormalities of the vein
wall and valves and/or secondary abnormalities resulting from
previous 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 the
last few years in diagnosis, prevention, and treatment. Recommendations are now available for the management and
prevention of CVD in recently developed guidelines drawn up
in the US and Europe. Physicians caring for patients with venous disease have two important documents at their disposal: “Management of Chronic Venous Disorders of the Lower
Limbs: Guidelines According to Scientific Evidence,” published in International Angiology in 2008;1 and “Antithrombotic Therapy for Venous Thromboembolic Disease,” from the
American College of Chest Physicians (ACCP) 8th Consensus Conference in 2008.2
els of evidence range from 1 to 3, and recommendations are
graded A through C. Level 1 and Grade A refer to randomized
controlled trials reporting clear-cut results applicable to everyday practice. The guidelines also include meta-analyses, but
these need to be used with caution. Some meta-analyses
contain studies that have been included without due care,
ignore substantive issues and relevant variables, and use heterogeneous findings or interpret results with bias.1
Answers in the negative point to the high proportion of CVD
patients excluded from clinical trials because of old age and
an inability or unwillingness to comply with regular laboratory
monitoring during therapy. Such studies often fail to reflect the
reality of a regular outpatient clinic, in rural conditions, or routine general practice. Rarely is there a single test that can
provide all the information needed to make a clinical decision
and plan a management strategy. A number of patients are
likely to require more than one investigation.1 In addition, such
investigations may require expertise in ultrasonography/phlebology/vascular medicine that is lacking in many European
countries. CVD awareness among general practitioners differs from country to country, and does so even among specialists, to the extent that the general situation is far from ideal.
Studies also suggest that patient compliance with compression therapy is also very low in daily practice. In other words,
there is a clear discrepancy between guideline recommendations and their application.
Daily phlebological practice remains remote from guideline
recommendations in many European countries, making dissemination by field leaders of the essential information contained in these documents all the more crucial if we are to
improve the lot of patients with CVD. I
So, do these guidelines reflect real life and are they applicable
and useful in everyday CVD management?
References
Answers in the affirmative highlight the systematic approach
adopted in the guidelines, with recommendations based on
literature evidence and on studies selected for their impeccable design, rigorous criteria, and follow-up visits performed
by skilled investigators working in dedicated facilities. Lev-
300
2008;27:1-59.
CONTROVERSIAL
QUESTION
8. K. Roztocil, Czech Republic
ğ
ğ MD, PhD
Karel ROZTOCIL,
Institute for Clinical and
Experimental Medicine
Prague, CZECH REPUBLIC
(e-mail: karo@ikem.cz)
C
linical guidelines are generally designed with several
aims in mind: to educate, to improve management
standards, to eliminate inappropriate care, and to reduce costs. Their impact on the ground varies and is rarely
satisfactory in all respects. Monitoring adherence to guidelines often reveals surprising gaps between evidence-based
recommendations and actual clinical management. Notable
examples have included the care of coronary artery disease
and the treatment and prophylaxis of venous thromboembolism.1-3
A similar situation exists in the case of chronic venous disease
(CVD). Analysis of venoactive drug prescribing by 2092 general practitioners and 432 vascular specialists in the Czech
Republic4 showed significant divergence from the conclusions propounded in internationally accepted guidelines.5,6
Over half the drugs prescribed were supported by zero evidence of benefit in randomized controlled clinical trials or by
minimal evidence of efficacy from other sources. Drugs with
the strongest evidence of efficacy—diosmin-hesperidin (micronized purified flavonoid fraction [MPFF]), calcium dobesilate, hydroxyethylrutoside (oxerutins)—accounted for no more
than 10% of overall prescriptions.
There are several reasons for poor guideline adherence. First,
practitioner familiarity with the guidelines is low. Publication
is insufficient in itself to produce awareness. Second, confidence in the guidelines is low. Adherence is significantly influenced by scientific evidence. Recommendations based on a
large number of randomized controlled studies attract greater
adherence than those based on expert opinion.1 Other reasons are more subjective, eg, the impression of a nonindivid-
ualized approach to the patient or a suspicion that certain recommendations pander to cost-control considerations. There
can also be economic reasons for deviating from guidelines.
Our own analysis highlighted the important role played in
this regard by the reimbursement policy of insurance institutions. Thus, in the case of our study referred to above, prescriptions for cheaper drugs unsupported by evidence from
randomized controlled trials were fully or partially reimbursed,
in contrast with those for more expensive drugs whose use
was backed by scientific evidence. An additional reason for
guideline noncompliance, although probably theoretical in
the context of CVD, is a fresh discovery—whether a new diagnostic approach or a promising treatment—that has yet
to be incorporated in the official text.
Guidelines are most successfully introduced when they are
easy to implement, not overly complex, and useful in daily clinical practice. Brief study of the official texts currently available
on the treatment of patients with CVD5 confirms their ready
applicability to routine clinical practice. All that it is required
to circumvent the reasons for noncompliance outlined above
is that these guidelines be regularly updated, integrated into
continuing medical education programs, and broadcast by
field leaders at every opportunity—whether at international
meetings or at the grass roots departmental or practice level—with every opportunity for feedback. I
References
1. Leape LL, Weissman JS, Schneider ES, et al. Adherence to practice guidelines: 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 beliefs. J Vasc Surg. 2005;42:726-733.
3. Vallano A, Arnau JM, Miralda GP, Peréz-Bartolí J. Use of venous thromboprophylaxis 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 syndromu. Lek Listy. 2004;27:21-25.
2008;27:1-59.
6. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the management
of chronic venous disease. An international consensus statement: Current medical position, prospective views and final resolution. Clin Hemorheol Microcirc.
2005;33:309-319.
301
CONTROVERSIAL
QUESTION
9. M. Salah, Saudi Arabia
Mahmoud SALAH, MBBCh, MSc,
MD, FRCSI, FICS, FACS
Consultant & Head of the Department
of Vascular Surgery, Saudi German
Hospitals Group, Jeddah
SAUDI ARABIA
(e-mail: msalahvs@hotmail.com/
vascular1.jed@sghgroup.net)
C
linical guidelines for chronic venous disease (CVD)
are designed to help health-care professionals and
their patients reach the investigational or treatment
decisions most appropriate to their particular clinical situation. Typically they emanate from reputable bodies and represent the consensus view of field leaders.
But this raises the question of their relevance to the everyday
practice of less eminent specialists and primary care physicians. Perhaps we can reach a better understanding of the
issues involved if we approach the guidelines in terms of their
benefits and risks or their pros and cons.
The CVD guidelines have undoubted benefits. They have
helped develop a minimum standard of care and eliminated
unnecessary or inappropriate procedures, whether in diagnosis, treatment, or follow-up. Official bodies can use the guidelines to monitor the quality of care provided, and third parties (eg, insurance companies) can use them to approve or
deny applications for specific procedures. Practice guidelines
also act as excellent educational tools for trainees.1
On the other hand, this does not apply to all guidelines. Although most guidelines are based on well-designed studies
using control groups and visits at preset intervals undertaken
by skilled investigators working in dedicated facilities, some
are produced by governments or payers to control spiraling
costs. As such, they may constitute responsible public policy, but can attract the resentment of clinicians and patients
as an invasion of personal and professional autonomy.2
A further consideration is that the studies undertaken in one
country, and the guidelines that ensue, may require modification or adaptation before they can be applied in another
country. This can be due to differences in patient types, skin
types, thresholds of complaint, and many other factors.
Socioeconomic factors are not always helpful when implementing guideline protocols in investigations or treatment.
Some practitioners also dislike the more detailed kinds of
guidelines that convey, in their view, a cookbook approach to
the practice of medicine, which inevitably downgrades the
practitioner’s role to that of a technician.
Recommendations that fail to take due account of the evidence can result in suboptimal, ineffective, or harmful practice.
Guidelines that are inflexible can have an impact opposite
to that intended by leaving insufficient room for clinicians to
tailor care to a patient’s personal circumstances and medical history.2 For these reasons, it is always preferable to promote guidelines as works in progress rather than as definitive statements, as snapshots in a continuously evolving state
of the art rather than as pronouncements carved in stone.
Guidelines must always be open to ready and rapid amendment in line with advances in basic and clinical research. Many
specialists view them less as mandatory or compulsory than
as compilations of advice and suggestion, grounded in the
best available clinical evidence, to be resorted to in specific
sets of circumstances.2
In summary, clinical guidelines are excellent compendia of
evidence-based medicine and have the potential not only to
broaden patient access to optimal strategies, but also, at the
socioeconomic level, to improve the cost-effectiveness of CVD
management. However, practice guidelines can never substitute for the clinical judgment of a qualified health-care professional. My view, on balance, is one of qualified endorsement: “Yes, the CVD guidelines continue to be applicable to
our daily practice in most cases.” I
References
In addition, some experts consider the scientific quality of clinical trials published in certain fields, such as compression therapy, as grossly defective.3 Furthermore, while most clinical
trials are well-designed, some are actually over-designed, in
the sense that they exclude all but the most “typical” patients.
The atypical patients not catered for in such trials represent
a large fraction of the patients presenting in daily practice.4
302
1. Markman M. Clinical practice guidelines in oncology: pros and cons. J Cancer
Res Clin Oncol. 1996;122:381-382.
2. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential 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 compression devices in patients with venous disorders of lower limbs. Eur J Vasc Endovasc Surg. 2008;35:494-500.
4. Comerota AJ. Treatment of chronic venous disease of lower extremities: what’s
new in guidelines. Phlebolymphology. 2009;16:313-320.
CONTROVERSIAL
QUESTION
10. I. S. Escotto, Mexico
Ignacio S. ESCOTTO, MD
Assistant Professor of Angiology
Vascular and Endovascular Surgery
National Medical Center of Mexico ISSSTE
Universidad Nacional Autónoma
de México, MEXICO
(e-mail: iescott@hotmail.com)
G
uidelines for chronic venous disease (CVD) need to
be considered first in terms of their strengths and then
in terms of their weaknesses.
Strengths
The most important CVD guidelines were drawn up by panels of experts. As such, they enshrine an international consensus endorsed by major medical societies and organizations involved in the study and treatment of the disease. They
draw upon the most relevant evidence-based studies published in the highest-rated international journals. In addition
they grade their recommendations using a system similar to
that already used in consecrated guidelines for the major
specialties, all of which casts them in a robust scientific structure.1,2 As with guidelines in any specialty, the aim is to raise
minimum standards among the various categories of healthcare professionals dealing with CVD by reducing subjectivity
in diagnosis, treatment, and follow-up. Their main objective
is to standardize knowledge and issue best-practice recommendations applicable to routine use.
Most guidelines have adopted well-established clinical classifications, for example the Clinical-Etiological-AnatomicalPathophysiological (CEAP) system that standardizes disease
presentations on the comprehensive basis of the four components indicated in its title.3 Other systems, such as the Venous Clinical Severity Score (VCSS), have been useful in handling large patient populations in clinical trials and also in
evaluating treatment outcomes with greater objectivity.4
The guidelines have also helped to elucidate the role and efficacy of specific venoactive drugs in managing the symptoms
evaluated in particular studies. In the case of edema, for instance, the venoactive drug most strongly recommended for
patients with C0 to C6 disease, including for primary venous
ulcer healing, is micronized purified flavonoid fraction (diosmin + hesperidin), which is supported by good-quality evidence compared with other venoactive drugs.1,2,5
Weaknesses
The range of possible clinical presentations in CVD is very
wide. Many patients present with different stages of the dis-
ease in one or two lower limbs. Secondary CVD is more frequent in patients with postthrombotic syndrome, which represents a diagnostic and therapeutic challenge. The major
guidelines have begun to issue recommendations on the diagnosis of acute deep vein thrombosis, drawing attention
to the improved results that can be achieved with more invasive treatment. This can be expected to lower the frequency of this form of secondary CVD.
The guidelines fail to provide a convincing pathophysiological explanation for CVD recurrence in patients who have undergone open surgery or endovascular vein ablation. Nor do
they supply clear guidance as to the optimal management of
this stage of the disease.
Specialists continue to debate the place of hormone replacement therapy in menopausal patients with CVD.6 Guideline
updates will need to incorporate conclusive recommendations as to patient identification and optimal treatment in this
regard, given the rising incidence and prevalence of this combination in numerous populations.
Further study is also required of certain previously established
risk factors for CVD, in particular age, being overweight, and
female sex, given reports of the increasing prevalence of early CVD in women and the general impact of rising obesity
levels in various young populations of both sexes.1,2
Conclusion
CVD guidelines have fulfilled their brief of standardizing the
diagnosis and management of most typical presentations
of the disease. They simply need tweaking with input from
methodologically stronger studies that address less typical
disease presentations. I
References
3. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for
4. Vasquez MA, Munschauer CE. Venous clinical severity score and quality-of-life
5. Coleridge Smith PD. Drug treatment of varicose veins, venous oedema, and ulcers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American 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’s
Health Initiative Investigators. Risks and benefits of estrogen plus progestin in
healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
303
CONTROVERSIAL
QUESTION
11. J.-F. Uhl, France
Jean-François UHL, MD, FacPh
Vascular surgeon, Vice-president
of the French Society of Phlebology
Unité de Recherche et Développement
en Imagerie et Anatomie EA 4465
Université Paris 5 Descartes
Paris, FRANCE
(e-mail: jf.uhl@wanadoo.fr)
C
hronic venous disease (CVD) guidelines based on
carefully conducted therapeutic trials are very useful in clinical practice. They help us to make the best
treatment choices, but there are two main limitations to their
application in our daily practice: first, the limitations inherent in
the evaluation tools on which they rely (primarily the ClinicalEtiological-Anatomical-Pathophysiological [CEAP] scoring system); and, second, the failure of clinical trials to be universally
applicable.
Our main reference points when we use the CVD guidelines
are the CEAP parameters: symptoms, clinical class, anatomical venous lesions, and their etiology (reflux or obstruction).
Updated venous nomenclature has recently made it easier
for CVD specialists to speak a common language.
But from our daily practice we also know that, for any given
patient, other parameters are of great importance: way of
life and occupation, number of hours during the day spent
standing or walking, limitation of ankle movement, static foot
disorders, concomitant treatments (hormones, in particular),
heredity, and progression of CVD.
Any of these factors can impair venous return and quality of
life. They are not usually taken into account in the evaluation
304
tools used either to classify patients or to compare treatments.
As a consequence, we don’t find them among the guideline
parameters. It is also difficult to standardize venous investigations. The quantification of reflux and reproducibility of “provocative” maneuvers are rarely easy.
As for the second limitation, trials often exclude patients on
the grounds of old age, contraindications to therapy, inability
or unwillingness to comply with laboratory monitoring during
therapy, and other criteria that apply to swathes of the routine
population we are called upon to treat.
Our real-life patients do not necessarily fit the ideal clinical
trial subject’s profile in other respects. International guidelines
are always unlikely to provide an exact match to particular
patients rooted in their given sociocultural characteristics,
country, occupation, and language. This constitutes a major
limitation.
Moreover, new treatments are continually appearing. Rigorous evaluation takes several years, during which time fresh
techniques will have appeared, with the result that clinical research is forever playing catch-up. The guidelines therefore
require continuous updating, which makes them difficult to
apply in everyday clinical practice.
We should keep in mind that CVD is a complex and progressive disease that is both multifactorial and multidimensional,
as well as particularly fast-moving. For these reasons CVD
guidelines should not be considered as a set of directly applicable rules, but as general guides to good practice providing
a conceptual reference frame for the most common cases. It
is in the very nature of guidelines that they cannot fully take
into account the inevitable specificities of individual patients. I
CONTROVERSIAL
QUESTION
12. I. Zolotukhin, Russia
Igor ZOLOTUKHIN, MD, PhD
Russian State Medical University
1, Ostrovitjanova str
117997 Moscow, RUSSIA
(e-mail: zoloto70@bk.ru)
T
he prevalence of chronic venous disease (CVD) is widespread. Epidemiologic data from industrialized countries, where studies have essentially been centered,
indicate that the signs and symptoms of CVD can be found in
up to 70%-80% of subjects in some populations, depending
on age, gender, ethnicity, etc.
Such a vast pool of potential patients could never be catered
for effectively by vascular specialists alone. That is why multidisciplinary competence is required, extending across numerous other specialties, including primary care. This cannot
be achieved without the publication and dissemination of contemporary diagnostic and management standards. Hence,
the need for guidelines that can be consulted by any healthcare professional called upon to care for a patient with CVD.
The development of the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification was the first step in standardizing diagnosis. It proved highly successful and has
become accepted worldwide. The next step was the development of guidelines intended to reduce the improper and
unnecessary use of various diagnostic and treatment methods
and to improve CVD care. We now have a number of comprehensive CVD guidelines available to us,1-4 headed by those
proposed in 2008 by the expert group of Nicolaides et al,3
encompassing all aspects of the disease. Three years have
passed since the publication of these guidelines, which has
given us the time to consider their relevance to our daily
practice.
There are two possible views that can be taken. The first is
that of the doctors who manage CVD patients on a daily basis
(phlebologists, angiologists, etc). I believe that most of these
specialists consider the guidelines as really useful tools for analyzing and systematizing their own approaches and improving their management of CVD. However, the alternative view
is that shared by specialists for whom CVD is not central to
their 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 in
the routine treatment of CVD, they don’t only need a tool for
analyzing and systematizing their management, but also clear,
strong, and unequivocal recommendations as to how to respond to different clinical situations.
A good example of such a document would be the American
College of Chest Physicians’ guidelines.5 Despite the vagueness and uncertainty of some of the recommendations they
contain, most are direct and authoritative, enabling the doctor
to make appropriate decisions. CVD guidelines, on the other
hand, are less firm and clear-cut. They often fail to provide doctors with ready-made solutions for many clinical situations.3
Even in the case of pharmacological therapy, where a high level of evidence exists for the efficacy of venoactive drugs, the
current guidelines state that they “may be indicated” or “may
be used.” It is probable that such advice, which fails to fully
endorse the scientific evidence, will not prevent doctors reaching the right decision, assuming they have expert knowledge
in phlebology. But if not, if phlebology is not central to their
practice, it may lead them to withhold necessary and useful
medication.
Good randomized controlled trials and reliable meta-analyses of the main CVD treatments are few and far between.
They are therefore more essential than ever if the current
guidelines are to gain in authority, weight, and decisiveness.
What doctors need in their daily practice is not discussion, but
strict and simple instructions. Such practice-oriented guidelines should also be regularly and promptly updated, with
changes continuously taking place in the fast-moving field of
phlebology. I
References
1. 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 therapy of the vein and lymphatic disorders. Int Angiol. 2005;24:107-168.
2008;27:1-59.
4. Guideline Subcommittee of the European Dermatology Forum. Guidelines for
diagnostics and treatment of venous leg ulcers. http://www.euroderm.org/
content/guideline_on_venous_leg_ulcers.htm. Accessed March 8, 2011.
305
DAFLON 500
‘‘
Among the many reasons
that make guidelines useful, one is
because they provide recommendations that are based on good
quality evidence. Another is because they balance the desirable
and undesirable effects of a treatment, not to mention the cost-effectiveness of such treatment. A
robust strength of recommendation for a treatment indicates that
clinicians can offer this treatment
to almost all their patients with little or no hesitation. This is the case
for Daflon 500 mg.”
MG
The place of Daflon 500 mg
in recent guidelines
on the management of
b y F. P i t s c h , Fra n c e
C
Françoise PITSCH, PharmD
Servier International
Suresnes FRANCE
hronic venous disease (CVD) is a common condition representing a
spectrum of disorders. Much effort has been spent creating a common
language, which is essential for the establishment of clinical practice
guidelines. In addition to improved methods of defining CVD, there is now also
increased understanding of the pathological processes involved in its development. Lack of venous tone, abnormal capillary permeability, and overloaded
lymphatic vessels have been put forward as the mechanisms involved in the
development of CVD. The leukocyte-endothelium interaction and its association with valvular damage is one of the earliest pathophysiological mechanisms at work in the disease. This has focused attention on Daflon 500 mg,
the only available molecule whose activity is known to modify such inflammatory events. Besides its ability to increase venous tone, regulate capillary filtration, and speed up lymphatic drainage, it has been shown to reduce the
interaction of leukocytes with the endothelium in acute venous hypertension
and inflammation, and it is used clinically to treat CVD. Daflon 500 mg has
been intensively investigated in well-designed clinical trials and is well tolerated. Micronization of the particle size of its components to <2 애m improves
its oral absorption and bioavailability compared with those of nonmicronized
diosmins. These characteristics explain why Daflon 500 mg is listed among the
venoactive drugs in recent guidelines on the management of this disease.
hronic venous disease (CVD) covers a full spectrum of venous conditions from
telangiectasias to the ultimate complication of CVD, venous ulcers. Symptoms are commonly associated with signs of CVD. Venous symptoms are
defined as tingling, aching, burning, pain, muscle cramps, swelling, sensations of
throbbing 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 by
leg rest, elevation, or both.1 Venous signs are visible manifestations of CVD, which
include dilated veins (telangiectasias, reticular veins, varicose veins), leg edema, skin
changes, and ulcers, as described in the CEAP (Clinical-Etiological-AnatomicalPathophysiological) classification.2,3
C
Françoise Pitsch, Servier
International, 35, rue de Verdun,
92284 Suresnes Cedex, France
(e-mail: francoise.pitsch@fr.netgrs.com)
306
This article addresses some of the newer guidelines on venoactive drugs (VADs) in
general, and Daflon 500 mg in particular, in the management of CVD to help clinicians better manage patients with CVD of the lower extremity. Intentionally, only primary CVD will be tackled in this review, putting postthrombotic venous disease aside.
The place of Daflon 500 mg in recent guidelines on the management of CVD – Pitsch
DAFLON 500
What are the indications of Daflon 500 mg?
Daflon 500 mg, micronized purified flavonoid fraction (MPFF),
consists of 90% diosmin and 10% other flavonoids (hesperidin, diosmetin, linarin, and isorhoifolin). Prescribing information
may differ between countries, but in general Daflon 500 mg,
which is available in more than 100 countries, is indicated as
a first-line treatment of symptoms associated with any stage
of CVD, and in lower limb edema. In more advanced disease
stages, such as venous leg ulcer, Daflon 500 mg may be used
in conjunction with sclerotherapy, surgery, and/or compression therapy, or as an alternative treatment when surgery is
not indicated or is unfeasible.4
Pathophysiology of primary CVD and targets for
Daflon 500 mg treatment
Because they provide a rational explanation for the clinical
benefits of treatments, it is important to consider the pathophysiological mechanisms underlying any disease in guidelines. Ambulatory venous hypertension is the hemodynamic pathology related to all symptoms and signs of CVD. The
underlying components of venous hypertension are failure of
the calf muscle pump, venous valvular incompetence, and luminal obstruction.5
After prolonged standing, venous pressure in the foot is approximately 90 mm Hg in both a patient with incompetent venous valves and a person with a normal leg. However, ambulatory venous pressures in CVD patients remain high in the
lower limbs during walking (more than 40 mm Hg), whereas
normally these pressures should fall to a lower level (to 30
mm Hg). Due to valve incompetence, venous refill time on air
plethysmography is shorter in CVD patients compared with
healthy individuals.5
When venous pressures in the leg are at higher-than-normal
levels and remain elevated for prolonged periods, a progressive increase in skin damage may occur. Nicolaides reported that nearly all patients with exercising venous pressures of
>90 mm Hg experienced venous ulceration.6 How the apparently simple concept of venous hypertension is responsible
SELECTED
CEAP
CVD
ICAM
MMP
MPFF
RCT
RELIEF
intracellular adhesion molecule
matrix metalloproteinase
micronized purified flavonoid fraction
Reflux assEssment and quaLity of lIfe improvEment
with micronized Flavonoids
transforming growth factor β1
tissue inhibitor of matrix metalloproteinases
venoactive drug
TGFβ1
TIMP
VAD
MG
for CVD lies in the complex cellular and molecular processes set in motion by the abnormal venous hemodynamics it
engenders.
What initiates inflammatory events in venous valves and walls
has not yet been uncovered. It is likely that venous hypertension and subsequent stasis lead to vein distension, which in
turn causes venous flow reversal and areas of low shear stress.
Even in the absence of reflux, endothelial cells that are exposed to flow reversal become activated. Leukocytes, on the
other hand, are activated by low shear stress.
When leukocytes are activated as a result of venous hypertension, they produce adhesion molecules, which bind to intracellular adhesion molecules (ICAMs) at the endothelial surface. This permits endothelial cell adhesion of leukocytes and
initiates their migration through the vessel wall into the extravascular tissues, leading to degranulation and the release
of proteolytic enzymes (such as matrix metalloproteinases
[MMPs], tissue inhibitors of MMPs [TIMPs], and transforming
growth factor β1 [TGFβ1]).7,8 This type of leukocyte-endothelial interaction initiates and maintains inflammation.5
The consequences of inflammation in primary CVD:
the remodeling of vein wall and valves
N Vein wall and valves
Morphologic changes in venous valves occur with prolonged
pressure-induced inflammation. Wall and valve remodeling
and damage occur as a result of leukocyte infiltration into vein
wall and valve leaflets, leading to wall fibrosis together with
progressive reflux.
The production of MMPs and a greater proportion of TIMPs
leads to the accumulation of extracellular matrix material. In
addition, increased production of TGFβ1 stimulates collagen
synthesis and further increases in TIMP production. The cumulative result of these events results is the structural and hypertrophic changes in venous wall that typify patients with
varicose veins.9
N Microcirculation
An early event that occurs in CVD is elevated endothelial permeability, with the opening of leakage sites between endothelial cells. As a result of this enhanced microvascular permeability, extravasation of water and water-soluble nutrients
leads to edema.10 With further permeability, the extravasation of red blood cells leads to the hyperpigmentation of skin
in lipodermatosclerosis.
N Lymphatic network
Fluid transport through the lymphatic vasculature completes
the body’s circulatory loop. The lymphatic vessels maintain
tissue homeostasis and compensate for capillary leakage
by absorbing extravasated interstitial fluid.11 In the case of
intense capillary leakage, the lymphatic drainage capacity be-
307
DAFLON 500
Group
MG
Substance
Dosage
(mg)
Origin
Number of
doses/day
Benzyopyrones
Alphabenzopyrones
Coumarin
Melilot (Melilotus
officinalis)
Woodruff (Asperula
odorata)
90 combined
with
troxerutin (540)
Gammabenzopyrones
(flavonoids)
Diosmin
Citrus sp (Sophora
japonica)
300-600
1 or 2
Micronized purified
flavonoid fraction (MPFF)
Rutaceae aurantiae
1000
1 or 2
Rutin and rutosides
Sophora japonica
1000
1 or 2
0-(β-Hydroxyethyl)rutosides (troxerutin, HR)
Eucalyptus sp
Fagopyrum esculentum
Escin
Horse chestnut
(Aesculus
hippocastanum)
Initially 120,
then 60
Ruscus extract
Butcher’s broom
(Ruscus aculeatus)
2 to 3 tablets
Anthocyans
Bilberry (Vaccinium
myrtillus)
116
Proanthocyanidins
Maritime pine (Pinus
maritimus)
Grape pips (Vitis vinifera)
100 to 300
1 to 3
300 to 360
3
2
Saponins
Other plant
extracts
Synthetic
products
3
3
2 to 3
2
Extracts of ginkgo
Ginkgo biloba
2 sachets (extracts of
ginkgo, heptaminol,
and troxerutin)
Calcium dobesilate
Synthetic
1000 to 1500
2 to 3
Benzarone
Synthetic
400 to 600
2 to 3
Naftazone
Synthetic
30
1
Table I. Classification of the
main venoactive drugs.
Abbreviations:
CVD, chronic
venous disease;
GRADE, Grades of
Recommendation
Assessment,
Development and
Evaluation; HCSE,
horse chestnut
seed extract;
MPFF, micronized
purified flavonoid
fraction.
Modified from
reference 12:
Ramelet et al. Phlebology. 5th ed.
Issy-les-Moulineaux, France:
Elsevier Masson
SAS; 2008.
© 2008, Elsevier
Masson SAS.
comes insufficient to absorb the excess fluid and macromolecules produced. This leads to venous edema, which spares
toes, in contrast to lymphatic edema. The Kaposi-Stemmer
test allows us to distinguish between the two types of edema (Figure 1).
Mechanisms of action of Daflon 500 mg
Daflon 500 mg belongs to the gamma-benzopyrone class
of VADs, which are for the most part of plant origin, but also
of synthetic origin, too, as illustrated in Table I.12 So, what are
the mechanisms at work in the treatment of CVD by Daflon
500 mg?13
N Daflon 500 mg, like most VADs, increases venous tone,
thereby reducing venous distensibility and stasis.
N The beneficial effect of Daflon 500 mg in reducing abnormal capillary permeability has been extensively demonstrated. This effect has also been witnessed in almost all VADs.
N Lymphatic drainage improves with Daflon 500 mg. Only
two other VADs have a beneficial effect on lymphatic drainage.
308
Figure 1. The Kaposi-Stemmer test allows physicians to distinguish between venous and lymphatic edema. Lymphatic edema
affects the toes, while venous edema spares them.
DAFLON 500
MG
N Only Daflon 500 mg has documented evidence of the ability to attenuate the effects of various inflammatory cascade
mediators, particularly those involved in the leukocyte-endothelial interaction, which are important in the genesis of venous hypertension and its clinical repercussions (Figure 2).14
meability. The increased permeability causes interstitial edema. The beneficial effects of Daflon 500 mg on capillary hyperpermeability have been demonstrated in two trials.19,20 In a
6-week, placebo-controlled trial in 30 patients with idiopathic
cyclic edema, Daflon 500 mg significantly improved capillary
hyperpermeability (as measured by labeled
albumin retention) compared with placebo
(P<0.05).19 This was accompanied by a
Risk factors for chronic venous disease
mean weight loss of at least 1.5 kg and a decreased sensation of swelling, indicating a
Venous hypertension
concomitant decrease in edema. In a 4Venous dilation
week study in patients with venous hyperValve distortion and leakage
tension, Daflon 500 mg given either two or
Valve reflux
Increased hypertension
three times daily significantly decreased the
capillary filtration rate versus baseline values
Altered blood flow and shear stress
Valve and wall changes
in a dose-dependent manner (P<0.05).20
N Lymphatic drainage
In patients with advanced CVD, there is an
increase in intralymphatic pressure and diameter, and in permeability of the lymphatCapillary leakage
Edema
ic capillaries, leading to the transendothelial
diffusion of fluids (Figure 3).21 Daflon 500 mg
Figure 2. The vicious circle of venous hypertension/venous inflammation.
is thought to improve lymph flow by increasModified from reference 14: Ramelet. Phlebolymphology. 2009;16:321-330. © 2009, Les Laboraing both the frequency and amplitude of
toires Servier.
contraction of lymphatic capillaries, as well
as by increasing the number of functional capillaries. This
N Venous tone
The beneficial effect of Daflon 500 mg on venous tone has reduces edema by facilitating the drainage of interstitial fluid
been studied in three double-blind, placebo-controlled trials into the lymphatic system. In a 4-week study in 24 patients
in patient populations with varying degrees of CVD, including with severe CVD but no active ulceration, Daflon 500 mg sigwomen with venous insufficiency related to postthrombotic nificantly decreased the diameter of lymphatic capillaries and
syndrome,15 with venous insufficiency related to pregnancy,16 the intralymphatic pressure from baseline (P<0.001).22 In adand without any venous pathology.17 Daflon 500 mg, at a dose dition, the number of functional lymphatic capillaries also sigof two tablets per day, had an immediate, positive effect on nificantly increased (P<0.001).
venous tone, which started to improve 1 hour after adminis- Years after enrolment
tration in all three groups of women. In the trial in women without any venous pathology,17 Daflon 500 mg significantly improved venous distensibility for 4 hours after administration
compared with placebo (P<0.05). When treatment was continued for 1 week, the significant effect on venous distensibility
compared with placebo was maintained for 24 hours (P<0.05).
Capillary hypertension
INFLAMMATION
Skin changes
In a study aimed at determining the effect of Daflon 500 mg in
25 female volunteers aged 18-35 years with abnormal venous
elasticity but without varicose veins,18 12 women received a
single 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 Daflon
500 mg (P<0.02) compared with baseline. In contrast, venous elasticity did not change significantly versus baseline
in patients in the control group.
N Capillary hyperpermeability
When subjected to prolonged venous hypertension, capillaries become elongated and dilated and develop abnormal per-
Ulcer
Figure 3. Venous hypertension is transmitted to the microcirculation and prompts leukocyte adhesion to capillary endothelium. This
initiates an inflammatory reaction which dramatically increases capillary permeability. When transcapillary filtration exceeds lymphatic
flow, interstitial edema occurs. Thanks to its vein-specific anti-inflammatory action and its beneficial effect on lymphatic drainage,
Daflon 500 mg improves capillary reabsorption of excess fluids and
decreases edema. © Impact Médecin.
309
DAFLON 500
MG
N The leukocyte-endothelial interaction
The well-established role of leukocytes in the pathophysiology of CVD has focused attention on drugs able to block
leukocyte adhesion to the venous valves and wall and thereby stop venous inflammation very early in the disease process
A
B
secondary valvular incompetence.25 However, guidelines now
mention that early pharmacological treatment directed towards preventing or inhibiting the inflammatory response at
all stages of the disease may play a significant role in preventing or slowing the development and recurrence of the signs
and symptoms of CVD.13 Key findings with Daflon 500 mg
come from the rat fistula model of venous hypertension.24
In this model, venous hypertension caused by a femoral arterial-venous fistula resulted in the development of venous reflux and an inflammatory reaction in venous valves. In animals
treated with Daflon 500 mg, there was a significant, dose-dependent reduction in reflux rate. Daflon 500 mg also inhibited the expression of the endothelial cell adhesion molecules
P-selectin and ICAM-1, reduced leukocyte infiltration, and decreased the level of apoptosis in valves in a dose-dependent
manner. These data suggest that in the rat model of venous
hypertension, Daflon 500 mg delays the development of reflux and suppresses damage to valve structures by decreasing the interaction between leukocytes and endothelial cells.
The administration of Daflon 500 mg reduced the edema and
the fistula blood flow produced by the acute arterial-venous
fistula. Daflon 500 mg also reduced granulocyte and macrophage infiltration of valves.24
Evidence for the clinical efficacy of Daflon 500 mg
The clinical efficacy of Daflon 500 mg has been evaluated in
a number of clinical trials. Many studies with rigorous designs
have demonstrated that Daflon 500 mg improves symptoms
and signs in patients with CVD.4
Figure 4A illustrates the rolling and adhesion of leukocytes at the
surface of the endothelium before their migration into tissues.
Figure 4B shows firm adhesion of leukocytes to and migration
into the venous endothelium.
This is the starting point of an inflammatory reaction and cascade that causes
vein wall and valve remodeling, thereby prolonging venous hypertension and
eventually progression to complications. Thanks to its vein-specific anti-inflammatory action, Daflon 500 mg prevents the inflammatory cascade in the venous
system.
After reference 23: Joris et al. Am J Pathol. 1983;113:341-358. 1983, © American Journal of Pathology.
(Figure 4).23 Daflon 500 mg has up to now been the only available VAD with documented evidence of the ability to attenuate the effects of various mediators involved in the inflammatory 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 failure
of venous valves affected by inflammation.5,24 This hypothesis
was challenged recently, and evidence now seems to favor the
hypothesis that CVD is related to a preexisting weakness in
the vessel wall, which produces dilation that in turn causes
310
N Improvement of symptoms of CVD
A review of the data show that Daflon 500 mg is effective from
the earliest stages of CVD, including in patients with a C0S
classification, and that symptom relief is achieved rapidly and
in a sustained manner. The efficacy of Daflon 500 mg’s relief
of clinical symptoms has been evaluated in two placebocontrolled trials in which the following symptoms were considered: functional discomfort, leg heaviness, pain, fatigue
when 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 was
associated with a significantly greater improvement in many
of the symptoms of CVD compared with placebo with P values for global scores of P<0.001.26 In a second placebo-controlled trial of 160 patients with CVD, Daflon 500 mg was
again associated with a significant improvement in symptoms
compared with placebo.27 For the symptoms of functional
discomfort, sensation of heaviness, nocturnal cramps, and
sensation of swelling, these changes were significant after
4 weeks of treatment. The effects of Daflon 500 mg on the
symptoms of CVD have also been compared with nonmicronized diosmin in a study of 88 patients.28 While statistically significant improvements in all subjective symptoms
DAFLON 500
were noted in both treatment groups at the end of 2 months,
Daflon 500 mg was more effective than diosmin for the majority of response measures.
N Reduction of leg edema
In the three trials assessing the efficacy of Daflon 500 mg for
the relief of CVD symptoms, measures of edema were also
taken. All three trials demonstrated a significant correlation between the improvements in the symptom score of sensation
of swelling and a decrease in ankle circumference.26-28 Three
further studies that used different methods to quantify leg edema also demonstrated that Daflon 500 mg has beneficial effects. In two placebo-controlled trials of patients with either
symptoms or signs of CVD, the administration of Daflon
500 mg resulted in significant reductions in ankle circumference compared with placebo.26,28
In a third study, edema was assessed using a volumeter in patients with varicose veins. Administration of Daflon 500 mg
was associated with a significant decrease in volume of the
more affected lower leg of 263 mL (8%) in all patients and
392 mL (12%) in patients with varicose veins.29 In a Czech
study in 213 patients with venous edema receiving two tablets
a day of Daflon 500 mg for 6 months, the ankle and calf circumferences were significantly less than those at baseline—
24.4 vs 25 cm (P<0.001) for ankle circumference; and 39.9
vs 40.6 cm (P<0.001) for calf circumference.
The reduction in circumferences continued until month 6. Leg
volume 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 significantly compared with baseline in the RELIEF (Reflux assEssment and quaLity of lIfe improvEment with micronized
Flavonoids) study.31
N Leg ulcer healing
A meta-analysis that pooled 723 patients with venous ulcers
treated with Daflon 500 mg confirmed that the rate of venous ulcer healing is accelerated by adding Daflon 500 mg to
conventional treatments.32 At 6 months, the chance of healing an ulcer was 32% better in patients treated with adjunctive Daflon 500 mg than in those managed by conventional
therapy alone (relative risk reduction, 32%; 95% confidence
interval [CI], 3% to 70%; P=0.03). Subgroup analyses suggested that the benefits of Daflon 500 mg were greatest in
ulcers >5 cm2 and >6 months in age.
Summary of Daflon 500 mg in recent guidelines
N Cochrane reviews
In recent Cochrane reviews on VADs, randomized, doubleblind, placebo-controlled trials were classified as being level A
(low risk of bias), level B (moderate risk of bias), or level C (high
risk of bias).33,34 Significant and homogeneous results were
MG
found for edema reduction, decrease in restless leg symptoms, and improvement in trophic disorders for most VADs
compared with placebo.33 However, for most analyses there
was evidence of heterogeneity. No test for heterogeneity was
applied in the review of horse chestnut seed extract.34
In the subgroup analyses of individual VADs, Daflon 500 mg
was shown to have significant benefits versus placebo, based
on multiple studies, on several dichotomous and continuous
outcome variables, such as cramps, heaviness, edema, and
skin changes, albeit with evidence of heterogeneity in most
cases.33
N Consensus guidelines
In most European guidelines, studies are usually classified:
grade A (at least two randomized controlled trials [RCTs] with
large sample sizes, meta-analyses combining homogeneous
results), grade B (RCTs with small sample size, single RCT),
or grade C (other controlled trials, nonrandomized controlled
trials).13
Two of these guidelines deal with VADs (Figure 5, page 312).
The article of Ramelet et al, published in Clinical Hemorrheology and Microcirculation, represents the proceedings of the
International Medical Consensus Meeting on Venoactive Drugs
in the Management of Symptoms of Chronic Venous Disease,
held in Siena.35 Eighty-three publications on the efficacy of
VADs on venous symptoms were analyzed. The “International Guidelines on the Management of Chronic Venous Disease,” published in International Angiology,13 used the same
grading system as that of the Siena experts except for metaanalyses, which were graded B. Outcomes included not only
symptoms, but also edema and venous ulcer healing. One
hundred and twenty-eight publications on VADs were analyzed in this document.
Based on the consistency of the respective evidence from
these two recent guidelines on VADs,13,35 a grade A was assigned to two VADs: MPFF (Daflon 500 mg) and hydroxyethylrutosides (ie, oxerutins) for the effects of these VADs on symptoms, edema, and skin changes.
A new grading system for CVD guidelines
The method of determining the strength and quality of the
recommendations in American guidelines deserves mention.
Recommendations are generally accompanied by a number, which refers to the strength of the recommendation, and
a letter, which refers to the quality of the evidence supporting
the recommendation. Recent guidelines for venous disease
have used two levels to specify the strength of their recommendations depending mainly on the benefit/risk ratio: grade 1
for strong and grade 2 for weak. They go on to indicate that
statements accompanied by a grade 1 rating are “recommendations,” while statements accompanied by a grade 2 rating
are “suggestions.”36
311
DAFLON 500
MG
Europe
USA
2005
2008
2011
2009
First edition
Venoactive drugs in the
management of chronic
venous disease: an international consensus
statement
First edition
Management of chronic
venous disorders of the
lower limbs: guidelines
according to scientific
evidence
First edition
Pharmacological treatment of primary chronic
venous disease
Third Edition
Handbook of Venous
Disorders: Guidelines of
the American Venous
Forum
Clin Hemorheol Microcirc.
2005;33:309-319.
Int Angiol. 2008;27:1-60.
Eur J Vasc Endovasc Surg.
2011;41:117-125.
The quality of evidence upon which the strength of the recommendation is based ranges from “A” for high-quality evidence, which is consistent evidence from randomized trials, to “B” for moderate-quality evidence, which is evidence
from nonrandomized trials or inconsistent evidence from randomized trials. Level “C” is low-quality evidence, which is suggestive evidence from nonrandomized trials, observational
reports, or expert opinion. Writing committees are increasingly aware of the costs of care and patient values and preferences, as are physicians. These are also considered in the
strength of recommendations.
Two guidelines on venous diseases use this system (Figure 5):
N one is a recent educational article on the pharmacological
treatment of primary CVD, dealing almost exclusively with
VADs and their place in the management of such disease.25
Table II. Summary of tentative recommendations,
according to the GRADE
recommendation system.
Abbreviations: CVD, chronic venous disease; GRADE, Grades
of Recommendation Assessment, Development and Evaluation; HCSE, horse chestnut
seed extract; MPFF, micronized
purified flavonoid fraction.
Modified from reference 25:
Perrin and Ramelet. Eur J Vasc
Endo-vasc Surg. 2011; 41:117125. © 2011, European Society
for Vascular Surgery.
312
Relief of symptoms associated
with CVD in patients C0S to
C6S and with CVD-related
edema
Healing of primary venous ulcer, as an
adjunct to compressive and local
therapy (Coleridge-Smith, 2009)
Hodder Arnold: London, UK;
2009.
N the second is the latest edition (3rd edition) of the Hand-
book of Venous Disorders: Guidelines of the American Venous Forum.37
The educational article proposed a strong recommendation,
based on evidence of moderate quality, for the use of Daflon
500 mg to treat CVD symptoms and edema. The recommendations of the article reflect the opinions and judgements of
the authors, but have not been endorsed by learned societies or other organizations (Table II).25
There is evidence from a meta-analysis of RCTs that Daflon
500 mg may be effective in healing venous ulcers.32 In the absence of important safety concerns, its use in this indication
was given a strong recommendation in primary ulcers (1B).
On the basis of the meta-analysis mentioned above,32 the au-
Venoactive
drug
Indication
Figure 5.
Summary of
recent guidelines of Daflon
500 mg in the
management
of primary
European and
US guidelines
have given
Daflon 500
mg a strong
recommendation in the
treatment
of primary
Recommendation
Quality
for use
of evidence Code
Daflon 500mg (MPFF)
Strong
Moderate
1B
Rutosides
Strong
Moderate
1B
Calcium dobesilate
Weak
Moderate
2B
HCSE
Weak
Low
2C
Ruscus extracts
Weak
Low
2C
Daflon 500mg (MPFF)
Strong
Moderate
1B
DAFLON 500
thor of the chapter devoted to “Drug Treatment of Varicose
Veins, Venous Edema, and Ulcers” of the latest edition (3rd
edition) of the Handbook of Venous Disorders: Guidelines of
the American Venous Forum assigned VADs a grade 2B for
the improvement of symptoms and edema associated with
CVD. In the same chapter, only MPFF (Daflon 500 mg) was
quoted for the pharmacological treatment of venous ulcers.
The use of Daflon 500 mg in combination with compression
in long-standing or large venous ulcers of primary etiology
was recommended (grade 1B).37
MG
Among the many reasons that make guidelines useful, one
is because they provide recommendations that are based on
good quality evidence. Another is because they balance the
desirable and undesirable effects of a treatment, not to mention the cost-effectiveness of such treatment. A robust strength
of recommendation for a treatment indicates that clinicians
can offer this treatment to almost all their patients with little
or no hesitation. This is the case for Daflon 500 mg, which has
received a strong recommendation in national as well as in
international guidelines.38 I
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16. Barbe R, Amiel M: Pharmacodynamic properties and therapeutic efficacy of
Daflon 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 elasticity 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 double labelling I131-albumin and Tc99m red cells. Application to the pharmacodynamic 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 ankle
edema 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. Lymphology. 1997;31(suppl):12-16.
23. Joris I, Zand T, Nunnari JJ, Krolikowski FJ, Majno G. Studies on the pathogenesis of atherosclerosis. I. Adhesion and emigration of mononuclear cells in the
aorta of hypercholesterolemic rats. Am J Pathol. 1983;113:341-358.
24. Bergan JJ, Pascarella L, Schmid-Schönbein G. Pathogenesis of primary chronic venous disease: insights from animal models of venous hypertension. J Vasc
Surg. 2008;47:183-192.
25. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous
disease: rationale, results and unanswered questions. Eur J Vasc Endovasc
Surg. 2011;41:117-125.
26. Chassignolle J-F, Amiel M, Lanfranchi G, et al: Activité thérapeutique de Daflon
500 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 flavonoid
fraction (S 5682) in symptomatic disturbances of the venolymphatic circulation 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 clinical activities of 5682 SE in venous insufficiency. Advantages of the new micronized form. Int Angiol. 1989;8(4 suppl):61-65.
29. Blume J, Langenbahn H, de Champvallins M. Quantification of oedema using
the volometer technique: therapeutic application of Daflon 500 mg in chronic
venous insufficiency. Phlebology. 1992;(suppl 2):37-40.
30. Navratilova Z. Efficacy of a 6-month treatment with Daflon 500 mg in patients
with venous edema. Phlebolymphology. 2010;17:137-143.
Angiology. 2002;53:245-256.
32. Coleridge-Smith P, Lok C, Ramelet AA: Venous leg ulcer: a meta-analysis of
adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg. 2005;30:198-208.
33. Martinez MJ, Bonfill X, Moreno RM, Vargas E, Capellà D. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2005;(3):CD003229.
34. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev. 2006;(1):CD003230.
35. Ramelet AA, Boisseau MR, Allegra C, et al. Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution. Clin Hemorheol Microcirc. 2005;33:309-319.
36. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American
College of Chest Physicians Task Force. Chest. 2006;129:174-181.
37. Coleridge Smith PD. Drug treatment of varicose veins, venous oedema, and ulcers. In: Gloviczki P, ed. Handbook of Venous Disorders: Guidelines of the American Venous Forum. 3rd ed. London, UK: Hodder Arnold; 2009:359-365.
38. Nicolaides A. Venoactive medications and the place of Daflon 500 mg in recent guidelines on the management of chronic venous disease. Phlebolymphology. 2009;16:340-346.
Keywords: Daflon 500 mg; guidelines; management; chronic venous disease
313
DAFLON 500
MG
LA
PLACE DE DAFLON 500 MG DANS LES RECOMMANDATIONS RÉCENTES
SUR 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 nombreux efforts ont été faits pour créer un langage commun, essentiel pour établir des recommandations pratiques
cliniques. En plus de l’amélioration des méthodes pour définir la MVC, la compréhension des processus pathologiques 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 mécanismes impliqués dans le développement de la MVC. L’interaction leucocyte-endothélium et son association aux altérations valvulaires est l’un des mécanismes physiopathologiques les plus précoces impliqué dans la maladie, ce qui
a attiré l’attention sur Daflon 500 mg, la seule molécule disponible dont l’activité est connue pour modifier de tels
événements inflammatoires. En plus de son aptitude à augmenter le tonus veineux, ajuster la filtration capillaire et
accélérer le drainage lymphatique, il réduit l’interaction des leucocytes avec l’endothélium dans l’inflammation et
l’hypertension veineuse aiguë. Il est utilisé en pratique clinique pour traiter la MVC. Daflon 500 mg, bien toléré, a été
largement étudié dans des études cliniques bien conçues. La micronisation de la taille des particules de ses composés à moins de 2 µm améliore sa biodisponibilité et son absorption orales par rapport à celles des diosmines non
micronisées. C’est pourquoi, Daflon 500 mg est répertorié comme traitement veinoactif dans les recommandations
récentes sur la prise en charge de cette maladie.
314
INTERVIEW
‘‘
Ongoing studies, including
those using the genome wide association approach, look to identify relevant patterns of single nucleotide polymorphisms to predict
disease states and evaluate gene
patterns that relate to multiple
phenotypes of complex diseases.
Gender, age, ethnicity, and environment appear strong determinants of disease penetrance. We
need systematic population-based
searches for chronic venous disease susceptibility genes.”
Are we any better at
identifying the risk factors
for chronic venous
disease progression?
I n t e r v i e w w i t h M . F l o u r, B e l g i u m
T
Mieke FLOUR, MD
Dermatology Department
Leuven University Hospital
BELGIUM
he natural history of chronic venous disease (CVD) is poorly understood.
There have been too few longitudinal studies. In Northern and Western
Europe the prevalence of varicose veins without skin changes is 20%
compared to 3% for advanced CVD. Only 10% of the many individuals with C2
varicose veins progress to ulceration. The risk factors for progression are currently believed to comprise the usual combination of the environmental and
the genetic. More specifically, the Bonn Vein Study (2008) identified the main
culprits as age, hypertension, and obesity, to which other studies have added
previous deep vein thrombosis, absence of etiologic intervention, a positive
family history, reduced ankle range of motion, and impaired calf muscle pump
function. Both hemochromatosis and thrombophilia predispose to ulceration, while twin studies incriminate the FOXC2 gene on chromosome 16. Female gender barely qualifies. Yet despite an additional plethora of sophisticated studies featuring cytokine arrays and gene polymorphisms, there remains
no test, or test battery, that identifies the individual patient with early CVD at
risk of ulceration. The evidence suggests that best-practice prophylaxis comprises aggressive intervention early in the course of the disease combined
where possible with a structured exercise program to improve ankle range
of motion and calf muscle pump function.
How strong is the evidence for risk factors in the progression of
chronic venous disease?
he natural history of chronic venous disease (CVD) remains poorly understood. Longitudinal studies are few. Most information comes from cross-sectional 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 (ClinicalEtiological-Anatomical-Pathophysiological) classification and/or duplex ultrasound
(DU).1 A prospective study of superficial and deep venous reflux showed that most
patients had clinically deteriorated after 7 years: limbs treated with a superficial or
deep procedure improved or remained stable, while those treated with elastic
compression deteriorated hemodynamically and clinically.2
T
Dr Mieke Flour, Dermatology
Department, University Hospital
Leuven, Kapucijnenvoer 33,
B-3000 Leuven, Belgium
(e-mail: maria.flour@uzleuven.be)
The Bochum study explored the natural history of varicosities and calf pump function
from childhood to adulthood. Telangiectasias and reticular veins occurred early on,
independently of reflux. Large varicosities appeared in older subjects, often preceded
Are we any better at identifying the risk factors for CVD progression? – Flour
315
INTERVIEW
C0
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.
by saphenous reflux. The Bonn Vein Studies I & II, conducted
in 3072 women and men, found a 2.0% annual incidence of
progression 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 and
obstruction, ipsilateral recurrent deep venous thrombosis
(DVT), multisegmental involvement, and absence of etiologic CVD therapy. Prospective evaluation of the normal contralateral limb in 73 patients undergoing unilateral varicose
vein (VV) surgery showed that half experienced clinical deterioration and reflux within 5 years. Independent risk factors
were obesity, orthostatism, and noncompliance with the use
of elastic stockings.4 However, we have no hemodynamic
methods for identifying which patients with primary CVD and
C2-C4 disease are likely to develop ulcers, despite the disease
progressing to C4-C6 in up to 20% or more of the elderly.
Risk factors for ulcer recurrence include residual iliofemoral
vein obstruction, residual deep incompetence (in particular
axial deep reflux), residual or recurrent superficial reflux, and
persistent venous hypertension. Correction of the underlying
pathology reduces the risk of recurrence.
We need large, long-term prospective studies with DU scanning of the anatomic distribution of reflux and obstruction, and
serial quantification of reflux. A more sophisticated protocol
for longitudinal research is required, using studies of venous
hemodynamics and the microcirculation. If we could identify
the predictors of progression from C2-C4 to active ulceration,
we could plan their modification where feasible.
What are the clinical risk factors warranting early
intervention in stage C2 CVD?
isk factor studies have given inconsistent results due to
multiple methodological differences. Risk factors are
currently thought to combine the environmental with the
genetic. Age, a major risk factor, is compounded by a positive family history, although evidence for a mode of inheritance
is lacking. Twin studies in Germany point to the FOXC2 gene
on chromosome 16.5
R
316
Obesity has been incriminated in women, but appears to be
aggravating rather than causal. It precipitates severe CVD,
perhaps from functional rather than anatomical insufficiency.
Female gender is universally cited, but CVD is barely more
prevalent in women. Onset is earlier in women, at 30.8 years
(36.8 years in men). Pregnancy (multiparity) is a universally
recognized risk or aggravating factor, but not oral contraception. Major geographic differences suggest strong environmental influences. Although smoking affects the vascular
wall and impairs endothelial function and behavior, its status
as a risk factor is inconclusive. In the Framingham Study,
women with VVs were more often obese, sedentary, older at
menopause, and had higher systolic blood pressure; in men,
VVs coexisted with sedentary lifestyle and higher smoking
rates, suggesting that increased physical activity and weight
control 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 corona
phlebectatica and other skin changes may warrant early intervention to prevent ulcer formation. Risk relates to the severity of varicosity and increases after DVT. But it may also be increased in smokers, the obese, and those with reduced ankle
range of motion (ROM) and calf pump power.
Clinical hardening of the vessel wall is associated with an increase in thick disorganized collagen bundles and elastic fiber
fragmentation. Similar changes in the extracellular matrix are
found in the vein wall and skin of C2 patients. Follow-up DU
after aggressive treatment of superficial CVD supports the
case for early recognition and intervention by showing improvement or complete reversal of deep venous insufficiency
in most patients. Less aggressive treatment improved reflux
valve closure time in only 28%.6
It will be difficult to perform the prospective longitudinal and
cross-cultural studies that we need in order to measure the impact of these clinical factors on disease progression. An alternative is to identify features unique to limbs with established
ulcers (C6) and compare them to limbs with C2-C4 disease.
SELECTED
CEAP
CVD
DU
DVT
EMP
MMP
ROM
SNP
TM
TNF
VV
duplex ultrasound
deep vein thrombosis
endothelial microparticles
matrix metalloproteinases
range of motion
single nucleotide polymorphism
thrombomodulin
tumor necrosis factor
varicose vein
INTERVIEW
Do any gene polymorphisms or biomarkers
identify patients at high risk of ulceration?
n Northern and Western Europe the prevalence of VVs without skin changes is 20% compared to 3% for advanced
CVD. Only 10% of the many individuals with C2 VVs proceed
to ulceration. Genetic factors may play an important causal
role in both mild and severe disease, but we need to establish biobanks and bloodbanks for longitudinal analysis.
I
Gene polymorphism and biomarker data may identify patients
at high risk of ulceration:
N Tumor necrosis factor α (TNF-α) gene polymorphism has
been associated with increased susceptibility to ulceration.
However, others dispute that the A allele of the 308 G/A single nucleotide polymorphism (SNP) located in the promoter
region of the TNFA gene is a potential factor for ulcer susceptibility, arguing that this association is secondary and that the
primary association is probably with obesity.
N Estrogen receptor-beta polymorphism, associated with impaired healing in the elderly, predisposes to venous ulceration.
N SNPs of the fibroblast growth factor receptor 2 gene are
significantly more frequent in CVD patients with chronic nonhealing wounds.
N Hemochromatosis studies suggest a role for iron deposition,
iron trafficking genes, transglutaminases, and C282Y polymorphism of the hemochromatosis gene in ulceration. A simple C282Y blood test was highly specific in predicting ulcer
development (98%), while ulcer onset was almost 10 years
earlier in patients carrying the H63D variant.7
N Thrombophilia: venous ulceration was 2 to 30 times more
prevalent in thrombophilia patients, even with no history or DU
evidence of DVT, than in the general population.8
N Cytokine gene polymorphisms do not significantly influence
venous thrombosis risk, despite the close relationship between
venous thrombosis and inflammation.
Ongoing studies, including those using the genome-wide association approach, are looking to identify relevant patterns
of SNPs to predict disease states and evaluate gene patterns that relate to multiple phenotypes of complex diseases.
Gender, age, ethnicity, and environment appear strong determinants of disease penetrance. We need systematic population-based searches for CVD susceptibility genes.
Are there differences in skin type, metabolism,
or race that increase the risk of ulceration?
ociodemographic factors may influence CVD progression. A West London study collected age, sex, and
ethnicity data on all leg ulcer patients over one year. Ulceration was more frequent in whites than in South Asians
(odds ratio, 4.43; P=0.0004), suggesting either a real difference in prevalence or a South Asian reluctance to seek treatment.
S
The San Diego multiethnic cross-sectional study in 2211 subjects found superficial functional disease to be more common
in women, while deep functional disease was more common
in men. CVD was more common in non-Hispanic whites than
in Hispanics, African Americans, or East Asians.
Humoral or genetic factors responsible for progression to ulcer formation are related to thrombosis and inflammation. Hyperhomocysteinemia, a risk factor for venous thrombosis and
CVD development and progression, is present in about 65%
of patients with CVD. Mild to moderately elevated plasma
homocysteine was closely associated with increasing CVD
severity, confirming that various inherited and acquired factors act in concert to raise individuals above the thrombotic
threshold. Prevalence of the C677T methylene tetrahydrofolate reductase mutation was higher in complicated C4-C6
disease (20%) than in uncomplicated C2-C3 disease (10%),
and more patients overall (15%) were homozygous compared
with an estimated 5% of the healthy white population.9
Genetic variations that affect chronic inflammation may differ
across ethnic groups. Cytokine SNPs affect cytokine levels
and hence the inflammatory response.
Elevation of interleukin 6 is a well-documented
inflammatory marker, but does it predict CVD
progression?
ost people agree that markers such as interleukin
6 (IL-6) are elevated in CVD. IL-6 is produced and
released into the systemic circulation from many different cells. It is the only cytokine to stimulate synthesis of
all the acute-phase proteins involved in the inflammatory response. It is a universal marker, hence not specific to nor diagnostic of CVD progression. We need a specific biomarker
for increased ulcer risk.
M
A prospective cohort study of elderly community residents
showed an association between sociogeographic segregation and IL-6 levels. Ingredients of social disadvantage (age,
African American ethnicity, high prescription drug consumption, body mass index >30, high alcohol consumption, and
smoking) were all strong predictors of IL-6 elevation.
Elevated plasma inflammatory mediator levels are also risk
factors for venous thrombosis. Several biomarkers reflect
functional monocyte-macrophage activation and structural
endothelial lesions related to venous stasis and venous hypertension that predispose to CVD. Baseline production of
inflammatory markers is duly elevated in VV patients, and all
cytokine levels sharply increase in response to venous occlusion produced by cuff inflation. However, a systematic review
of studies of the association between inflammatory markers
and venous thrombosis concluded that plasma C reactive
protein levels do not predict venous thrombosis.10
317
INTERVIEW
Between August 1995 and June 1997, blood was collected
from 66 140 people in the second Norwegian Health (cohort)
Study of Nord-Trondelag (HUNT2); 506 cases were registered
with a first venous thrombosis. Levels of IL-1β, IL-6, IL-8, IL-10,
IL-12p70, and TNF-α, measured at baseline, showed no relationship between an altered inflammatory profile and venous
thrombosis. These results suggest that an altered inflammatory profile is more likely to be a result than a cause of venous thrombosis, although a short-term impact with transiently elevated levels cannot be excluded.11
No biomarker that accurately reflects wound healing status
in individual patients, singly or in combination, has been identified.
What information would a test of endothelial
dysfunction provide, and what are the prospects
of one being developed in the near future?
ecent studies of CVD etiology have focused on endothelial cell integrity and function. Current evidence favors a multifactorial origin involving vein wall remodeling and changes in the microcirculation and dermis. Venous
endothelial dysfunction is almost certainly implicated in the
wall dilatation and valve incompetence seen in primary CVD.
Markers of endothelial cell dysfunction are predictive of vascular events. They reflect multiple micro- or macrovascular disorders and early vascular changes, predating clinical pathology by many months or even years. Elevation is associated
with aging, endocrinopathy, arterial disease, connective tissue
disease, smoking, and exposure to air pollution, in addition
to venous disease. Endothelial function testing has great potential in cardiovascular screening, but is not yet feasible in
routine assessment: no test is sufficiently sensitive and specific for clinical use. Most studies are observational. We still
don’t know how best to investigate the multifaceted aspects
of endothelial dysfunction.
R
Three types of test are available: vascular reactivity, systemic
plasma markers, and histological immunostaining.
N Pro- and anti-inflammatory cytokines: chronic venous hypertension leading to endothelial cellular injury and activation
promotes inflammatory reaction and leukocyte recruitment
in venous valves, causing dysfunction, reflux, and upstream
venous hypertension.
N Adhesion molecules: despite reflecting early leukocyte-endothelium interaction, intercellular adhesion molecule 1 and
E-selectin expression did not differ significantly between VV
patients and controls.
N Hypoxia inducible factor 1α: Elevation of this marker of
leukocyte-endothelium interaction results from prolonged
mechanical stretching and increased vein wall tension, supporting the hypothesis of VV hypoxia.
N Soluble markers are mixtures of truly soluble molecules
with membrane-bound forms, eg, endothelial microparticles
(EMP). EMP-monocyte conjugates enhance transendothelial leukocyte migration in vitro and reflect several inflammatory diseases. But EMP elevation is not diagnostic for CVD
progression or inflammation.
N Enzyme activity (matrix metalloproteinases [MMPs] and their
inhibitors) increases in both high and low venous pressure
regions. The degree of extracellular matrix remodeling of the
venous wall and valve leaflets correlates with macroscopic
lesion morphology and changes in the microcirculation and
dermis. MMP-2 may induce venous relaxation or inhibit venous contraction.
N Plasma thrombomodulin (TM) is a marker of endothelial injury. Two cohort studies found no difference in the prevalence
of the three TM genotypes between thrombosis cases and
controls. There was no difference in age-adjusted mean soluble TM values by genotype, nor any association between
age-adjusted soluble TM or the TMA455V genotype and overall venous thromboembolism or thrombosis.
N Histological immunostaining
Immunostaining and real-time polymerase chain reaction (RTPCR) analysis reveal VV intimal changes, such as focal intimal
discontinuity and endothelial denudation. Vein wall changes
may precede valvular dysfunction. Total elastin content is lower in VVs than in healthy veins.
N Vascular reactivity tests
Vascular reactivity tests are the most widely used: they are
noninvasive, and they evaluate the peripheral macrocirculation (conduit arteries) or microcirculation (resistance arteries
and arterioles).
We need more longitudinal studies to identify prognostic markers of endothelial dysfunction. We must also identify the genetic and humoral mediators of endothelial dysfunction in
limbs with primary CVD and disease progression.
N Systemic plasma markers
How reliable are ankle mobility, calf muscle
pump function, and patient activity in rating
CVD progression?
Systemic plasma markers of endothelial damage and repair
play a minor role in individual patient assessment:
N Nitric oxide: plasma levels of this potent mediator of vascular relaxation may be modulated in CVD.
N Humoral mediators of vasoconstriction and venous dilatation: endothelin 1 levels increase and rise disproportionately
in response to venous stasis.
318
oth photoplethysmography and air plethysmography
show end-of-day deterioration in calf pump function, suggesting that venous return deteriorates with prolonged
standing. Musculoskeletal changes affect calf pump hemodynamics, complicating differentiation between cause and effect.
B
INTERVIEW
Goniometry shows significantly reduced ankle ROM across
all grades of CVD.12 ROM decreases with increasing clinical
severity, impairing calf pump function, and sustaining ambulatory venous hypertension. Gastrocnemius biopsies reveal morphologic changes suggesting that disuse, denervation, and ischemia lead to muscle dysfunction. The resultant impact on
gait and ambulation predisposes to venous ulceration. Over
two-thirds of ulcer patients have an impaired calf pump. Use
of air plethysmography and color Doppler to study the relationship between degree of venous insufficiency, calf pump dysfunction, and venous ulceration showed significantly poorer
pump function in legs with active ulcers than in those with
healed ulcers or no history of ulceration. CVD is a necessary
but limited cause of ulceration; calf pump dysfunction is a
significant contributor to the severity of venous ulceration.13
In addition to known risk factors (longer ulcer duration, large
surface area, ankle brachial pressure index <0.85), calf pump
dysfunction correlates with delayed ulcer healing even with
adequate compression. A study in 189 patients identified that
calf/ankle circumference ratio <1.3, a fixed ankle joint, and
reduced ankle ROM were the only independent parameters
associated with nonhealing.14 Prospective controlled studies
show that supervised exercise programs to improve calf pump
function, muscle strength, and endurance improve healing
rates and decrease recurrence in C6 disease, with benefit being maintained for at least 3 months.15 I
References
1. 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 7year follow-up. Int J Angiol. 1998;7:234-237.
3. Maurins U, Hoffmann BH, Losch C, Jockel KH, Rabe E, Pannier F. Distribution and prevalence of reflux in the superficial and deep venous system in the
general 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 progression and modification of predisposing factors. J Vasc Surg. 2010;51:900-907.
5. Ng MY, Andrew T, Spector TD, Jeffery S; Lymphoedema Consortium. Linkage
to 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 insufficiency 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 leg
ulcers: 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 hyperhomocysteinemia, methylene tetrahydrofolate reductase C677T mutation, and vitamin B12
and 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 thrombosis. 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 thrombosis: A prospective population-based study. PLoS Med. 2006;3:e334.
12. Padberg FT, Johnston MV, Sisto SA. Structured exercise improves calf muscle
pump 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 factors
related 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 function
in venous ulceration. J Vasc Surg. 1994;20:872-879.
15. Davies JA, Bull RH, Farrelly IJ, Wakelin MJ. A home-based exercise programme
improves ankle range of motion in long-term venous ulcer patients. Phlebology. 2007;22:86-89.
Keywords: risk factors; identification; chronic venous disease
NOUS SOMMES-NOUS AMÉLIORÉS DANS L’IDENTIFICATION DES
FACTEURS 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 été
trop 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 précoce vont jusqu’à l’ulcère. Actuellement, les facteurs de risque de progression englobent l’association habituelle
environnement 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 fonction altérée de la pompe musculaire du mollet. L’hémochromatose et la thrombophilie prédisposent à l’ulcère, des
études jumelles incriminant le gène FOXC2 sur le chromosome 16. Le sexe féminin y prédispose peu. Malgré pléthore d’études sophistiquées sur les gammes de cytokines et les polymorphismes de gène, nous ne disposons
toujours pas de tests ou de batteries de tests identifiant individuellement un patient atteint précocement de MVC à
risque d’ulcère. En pratique, les arguments d’une meilleure prévention sont en faveur d’un traitement agressif tôt
dans l’évolution de la maladie associé si possible à des exercices structurés pour améliorer la mobilité de la cheville et la fonction de la pompe musculaire du mollet.
319
FOCUS
‘‘
Some 4500 GPs from 20
countries are involved in step 1
of the Vein Consult Program. The
preliminary results from a total of
69 866 screened patients from
Brazil, France, Georgia, Hungary,
Mexico, Pakistan, Romania, Russia, Serbia, Singapore, Slovakia,
Spain, and the United Arab Emirates are already available. Seventeen percent of these patients consulted a GP especially for venous
leg problems. Signs of C1-C6 were
present in 59% of the population,
while 17% had venous symptoms
without clinical signs of venous
disease (C0S).”
Identifying and accessing
patients with chronic venous
disease: the large-scale
VCP International Study
by E. Rabe, Germany
C
Eberhard RABE, MD, PhD
Department of Dermatology
University of Bonn
Bonn, GERMANY
hronic venous disease (CVD) is defined as morphological and functional abnormalities of the venous system of long duration, manifested either by symptoms and signs indicating the need for investigations
and/or care. The impact of CVD in the general population is often underestimated and not well recognized by health systems. In recent studies and according 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%. Skin
changes, including venous ulcers, are present in less than 10% of the population. For many countries, no epidemiologic data exist. The worldwide Vein
Consult Program aims to assess the prevalence of CVD and provide a picture
of the typical adult patient and the management of their disease, in varying
geographical areas. This is the largest ever CVD detection program to be undertaken. The Vein Consult Program is being carried out under the auspices
of the International Union of Phlebology with the support of an unrestricted
grant from Servier. More than 4500 selected general practitioners are participating, and it is estimated that they will screen approximately 95 000 patients. In step 1 of the program, general practitioners screen patients whom
they are consulting for any medical reason. Step 2 is a follow-up consultation
with a venous specialist. Preliminary results from 69 866 screened patients
from 13 countries worldwide are available.
hronic venous disease (CVD) is defined as morphological and functional abnormalities of the venous system of long duration, manifested either by symptoms and signs indicating the need for investigations and/or care.1 Typical
symptoms associated with CVD are heavy legs, leg pain, sensation of swelling, pins
and needles in the legs, and itching. Typical signs of chronic venous insufficiency
(CVI) are varicose veins, edema, skin changes (like pigmentation and atrophy), and leg
ulcers. CVD is graded according to the CEAP (Clinical-Etiological-Anatomical-Pathophysiological) classification, which provides an orderly framework for diagnosis.
Clinical signs in the affected legs are categorized as one of seven classes ranging
from C0-C6 (Table I), and the limbs of any clinical class may be classified symptomatic or asymptomatic.2 CVD is a progressive disease that can lead to diseaserelated complications like venous ulceration. It is a result of abnormally raised venous
pressure caused by venous inflammation, which can cause the disease to progress
from early symptoms to vessel wall deterioration and damaged venous valves, which
C
Prof. Dr. med. Eberhard Rabe,
Department of Dermatology,
University of Bonn, Sigmund Freud
Str. 25, 53105 Bonn, Germany
(e-mail:
eberhard.rabe@ukb.uni-bonn.de)
320
Identifying and accessing patients with CVD: the VCP International Study – Rabe
FOCUS
Class
SELECTED
CEAP
CIVIQ
CVD
CVI
QOL
UIP
quality of life
Union Internationale de Phlébologie [International
Union of Phlebology]
in turn lead to the appearance of signs of CVD such as varicose veins, skin changes, and leg ulceration.3,4 CVD is also a
risk factor for the development of thromboembolic complications. Disease progress can be prevented by early detection
and intervention. The impact of CVD in the general population
is often underestimated and not well recognized by health
systems. It is also often overlooked in primary care and cardiovascular care because of an underappreciation of its scale
and of the impact of the disease.5
Prevalence of chronic venous disease
In the last few decades, epidemiological CVD studies have
been performed in many countries worldwide, mainly focus-
Reference,
year
Male/female
ratio
Age
(%/%)
(years)
Country
Criqui,**
USA
200318
Jawien,**
Poland
200319
Rabe,**
Germany
200314
Carpentier,*** France
200415
Chiesa,***
Italy
200516,17
Reference,
year
All
(%)
Criqui,**
5.8
200318
Jawien,**
4.5
200319
Rabe,**
13.4
200314
Carpentier,***
200415
Chiesa,***
13.6
200516,17
C3
M
(%)
7.4
Sample
size
C0
C1
C2
Varicose veins (distinguished from reticular
veins by a diameter of >3 mm)
C3
Edema
C4
Skin changes secondary to chronic venous disease
C4b: 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.
ing on varicose veins.6-13 The results have not been homogeneous; different definitions of CVD, different age groups, and
different methods of investigation in these studies led to differing results. In recent years, a few studies based on the CEAP
classification have been published.14-19 In the CEAP-based
epidemiological studies, the reported prevalence is similar for
most items (Table II). Classes C0 and C1 together are prevalent in more than 60% of the population. Varicose veins (C2)
C0
M
(%)
F
(%)
All
(%)
C2
M
(%)
F
(%)
19.0 33.6 11.0
51.6 43.6 55.9
23.3
15.0
27.7
51.5
16.5
21.8
59.1 58.4 59.5
14.3
12.4
15.8
23.7
46.3
29.3
11.4
29.4*
13.9°
All
(%)
35.3/64.7
40-79
2211
16.0/84.0
16-97
40 095
43.9/56.1
18-79
3072
67.7/32.3
>18
14.1/85.9
18-90
F
(%)
All
(%)
F
(%)
All
(%)
4.9****
6.2
7.8
5.3
(including C4-C6)
4.6
1.0
2.9
0.6
11.6
14.9
1.1
2.2
11.4
13.9
409
5187
C4
M
(%)
3.1
2.7
4.0
2.1
3.4
5.2
3.1
(including C4a only)
Definition
F
(%)
9.6 13.6
All
(%)
6.4
48.7
(including C0+C1)
22.7 36.0 20.6
C5
M
(%)
C1
M
(%)
64.8 33.4 69.9
F
(%)
All
(%)
C6
M
(%)
F
(%)
0.5
0.6
0.6
1.4
0.7
0.1
0.1
0.1
0.0
0.0
8.6 11.6 8.1
(including C4b-C6)
* nonsaphenous varicose veins; ° saphenous varicose veins; ** highest assigned clinical category; *** all clinical categories listed;
**** edema in the whole population.
29.4
13.6
Table II (above
and left).
Prevalence of
CEAP classes
C0-C6 in recent
studies in Western countries.
Based on references 14 to 19.
Abbreviation:
CEAP, Clinical-Etiological-AnatomicalPathophysiological.
321
FOCUS
are prevalent in more than 20%, with a higher prevalence in
women. Skin changes due to venous diseases, including venous ulcers, are present in less than 10% of the population
with no significant gender differences. Older age, family history of varicose veins, female gender, and pregnancy are established risk factors for varicose veins; obesity is an important additional risk factor for CVI. Unfortunately, such data is
only available for a few countries, and the epidemiologic situation in many regions of the world remains unclear.
Quality of life and burden of chronic venous
disease
CVD can negatively affect patients’ quality of life (QOL), as it is
a painful and disabling disease that can restrict physical functioning and mobility and that is associated with depression
and social isolation.4 In consequence, CVD can result in limitation to daily activities, decreased productivity at work, and
patients needing to take sick leave, as well as having a negative effect on their self-esteem. Disease severity appears
to be a good indicator of QOL. The higher the CEAP clinical
class, the poorer the disease-specific QOL, as demonstrated by low scores for physical and social functioning in QOL
questionnaires.4
One such questionnaire, CIVIQ (ChronIc Venous dIsease Questionnaire), is a 20-item questionnaire that provides a global
index score and a profile in four different categories: pain, physical, psychological, and social functioning. It is valid across a
range of different languages and cultures.20 A shortened version, CIVIQ-14, has been used in the Vein Consult Program.
CVD represents a significant socioeconomic burden in terms
of health-care costs due to its high prevalence, the costs of
investigation and treatment of complications, and lost working days.3 The overall cost of venous disease in Germany was
€2.18 billion in 2006.21 A recent evaluation in Germany revealed the mean total yearly cost of an ulcer patient to be almost €10 000.22
International Union of Phlebology
The International Union of Phlebology (Union Internationale
de Phlébologie [UIP]), founded in 1959, is an association of
national phlebology societies from Europe, North America,
Latin America, Asia, Africa, Australia, and New Zealand. The
UIP represents 50 phlebology societies in 47 countries. The
UIP is governed by its Executive Committee consisting of
the president, the president elect/the past president, 5 vice
presidents, a general secretary, an assistant general secretary, and a treasurer.
The aims of the UIP are:
N to strengthen the links between societies or associations,
either existing or to be created, which have a special interest
in the study and the treatment of CVDs
N to spread recommendations on the teaching of phlebolo-
322
gy, as well as the training and continuing medical education
of phlebologists
N to promote consensus on all aspects of CVD
N to encourage studies and research on disorders of venous
origin
N to promote joint meetings or international congresses
N to encourage the creation and activities of national societies
or 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 scientific
research in phlebology to help answer some of the many questions that still exist in venous disease. One of the important
goals is to gain more information on venous epidemiology
and on the burden of disease worldwide. For this reason, the
UIP is cooperating with Servier on the Vein Consult Program.
Vein Consult Program
The Vein Consult Program is an international educational effort to raise awareness of CVD amongst physicians, patients,
the scientific community, and health authorities. The worldwide screening program aims to assess the prevalence of
CVD and provide a picture of the typical adult patient and the
management of their disease, in varying geographical areas.
This is the largest ever CVD detection program to be undertaken, and it will help to evaluate how general practitioners
(GPs) and venous specialists manage patients with CVD and
to better understand at which stage of the disease specialists take over from GPs in the management process. The
program aims to detect CVD early, with the goal of improving
the process of management of this chronic disease. It will also
assess the impact of CVD on the QOL of patients, healthcare resources, and the economy.
The Vein Consult Program is being carried out under the auspices of the UIP with the support of an unrestricted grant from
Servier. The program will be scientifically validated by the UIP
via its operational board members and scientific advisory
committee. The research is being coordinated in participating
countries by national societies that are affiliated to the UIP. In
each country, a local research organization will be responsible
for data entry and its validation. An international research organization will then pool all national data and be responsible
for statistical analysis of these data, under the supervision of
the UIP’s scientific advisory committee.
The Vein Consult Program, which started in 2009, is an international observational, multicenter, descriptive survey of
CVD. More than 4500 selected GPs are participating, and it
is estimated that they will screen approximately 95 000 patients (Table III). In step 1 of the program, GPs screen patients
whom they are consulting for any medical reason (except an
emergency) and assess their suitability for inclusion in the
program. There are several criteria: the patient (male or female) must be over 18 years old; they must be informed of
FOCUS
Procedure
Step 1
Screening of patients
for any medical reason
within the framework
of general practice
Countries
No. of
doctors
Brazil, Columbia,
4500 genFrance, Georgia,
eral practiHungary, Indonesia, tioners
Mexico, Pakistan,
Romania, Russia,
Serbia, Singapore,
Slovakia, Slovenia,
Spain, Thailand, United
Arab Emirates, Ukraine,
Venezuela, Vietnam
Step 2
Diagnosis confirmation
Mexico, Romania,
by selected specialists
Russia, Spain
500 specialists
Patient self-questionnaire
Examination of quality
All
of life + costs
Table III. Initial procedures in the Vein Consult Program.
their involvement in a screening program and accept to take
part; they must be informed that they have the right to refuse
to participate fully or partly; and they should not be consulting for an emergency or for an acute episode of an ongoing
event. Patients need to be enrolled consecutively within a
short period of time.
If the patient fits the criteria, participating GPs need to complete a standardized case report form assessing their patient’s
history, list any CVD risk factors, screen for CVD symptoms,
and perform a routine leg examination. The patient is then
classified according to the CEAP clinical classification. If the
patient shows signs of having any CVD symptoms and the
GP considers them to be eligible to participate in step 2 of the
program, the patient will next be asked to complete a short,
self-administered, 14-item QOL questionnaire, CIVIQ-14. The
GP will then recommend a follow-up consultation with a venous specialist.
Step 2 is the follow-up consultation with a venous specialist.
In step 2 of the Vein Consult Program, 500 selected specialists will potentially follow up 6500 patients. For each patient,
the specialists will complete a 21-item questionnaire to establish the patient’s history of CVD and CVD risk factors,
carry out a lower leg examination, and assess whether treatment is required. The results from this program will help to
characterize the typical CVD patient and to establish a better understanding of the prevalence of this chronic disease
in the participating countries.
N Preliminary results
Some 4500 GPs from 20 countries are involved in step 1of the
Vein Consult Program. The preliminary results from a total of
69 866 screened patients from Brazil, France, Georgia, Hungary, Mexico, Pakistan, Romania, Russia, Serbia, Singapore,
Slovakia, Spain, and the United Arab Emirates are already
available. Seventeen percent of these patients consulted a
GP especially for venous leg problems. Signs of C1-C6 were
present in 59% of the population, while 17% had venous
symptoms without clinical signs of venous disease (C0S).
The prevalence of CVD in its early stages, stages C1-C3, was
significantly higher in women than in men, whereas in stages
C0S, C4, C5, and C6, there was no statistical significant difference between the sexes. The mean number of symptoms
increased with increasing classification from stage C2-C5.
Leg pain was significantly more prevalent in the higher classification stages (C3-C6) in 18%-19%. The CIVIQ-14 score increased significantly with severity of CVD. Patients in the C4C6 stages had a significantly worse QOL compared with
those in the C1-C2 stages. Patients with venous symptoms
had a worse QOL in CIVIQ-14 than those without symptoms.
Summary
The Vein Consult Program, a cooperative venture between
the International Union of Phlebology and Servier, is the largest
ever CVD detection program to be undertaken with 95 000
patients from 20 countries. The program will help us to better
understand the prevalence and risk factors of CVD, the impact of CVD on the QOL of patients and health resources,
and the burden of the disease on the patient and on the economy. The Vein Consult Program will also help to increase the
awareness of CVDs among health-care professionals and officials, politicians, and insurance companies. This is vital if we
are to prevent an upcoming increase in the prevalence of CVD
in the general population caused by demographic changes
(eg, an increasing elderly population) and by changes in lifestyle (eg, an increasing prevalence of obesity). The issue of
improved awareness needs to be urgently addressed. I
References
1. Eklöf B, Perrin M, Delis KT, Rutherford RB, Glovizki P. Updated terminology
of chronic venous disorders: The VEIN-TERM transatlantic interdisciplinary
consensus document. J Vasc Surg. 2009;49:498-501.
2. Eklöf B, Rutherford RB, Bergan JJ, et al; American Venous Forum’s International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the
CEAP classification for chronic venous venous disorders. A consensus statement. J Vasc Surg. 2004;40:1248-1252.
3. Nicolaides AN, Allegra C, Bergan JJ, et al. Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence. Int Angiol. 2008;27:1-59.
4. Bergan JJ, Schmid-Schönbein GW, Coleridge-Smith PD, Nicolaides AN, Boisseau 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-Dimmer JL, Pfeifer J, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15:175-184.
7. Evans CJ, Fowkes FGR, Hajivassiliou CA, Harper DR, Ruckley C. Epidemiology
of varicose veins. A review. Int Angiol. 1994;13:263-270.
8. Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins and
chronic venous insufficiency in men and women in the general population:
323
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9. Fischer H. (Hrsg.), Venenleiden – Eine repräsentative Untersuchung in der Bundesrepublik Deutschland ( Tübinger Studie ). München: Urban und Schwarzenberg; 1981.
10. Fowkes FGR, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous
insufficiency. Angiology. 2001;52:S5-S15.
11. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous
stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc
Surg. 2001;33:1022-1027.
12. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg. 2002;36:520-525.
13. Widmer LK, Stählin HB, Nissen C, Da Silva A (Hrsg.). Venen-, Arterien-Krankheiten, koronare Herzkrankheit bei Berufstätigen, Prospektiv-epidemiologische
Untersuchung Baseler Studie I-III 1959-1978. Bern Stuttgart Wien: Verlag Hans
Huber.
14. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen
Gesellschaft für Phlebologie – epidemiologische Untersuchung zur Frage der
Häufigkeit und Ausprägung von chronischen Venenkrankheiten in der städtischen 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. Demographic 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.
17. Chiesa R, Marone EM, Limoni C, Volonté M, Schaefer E, Petrini O. Chronic venous 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 ethnically 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 men
and women in Poland: multicenter cross-sectional study in 40 095 patients.
Phlebology. 2003;18:110-121.
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 in
Germany. Int Wound J. 2010;7:97-102.
Keywords: Vein Consult Program; chronic venous disease; CEAP; CIVIQ; epidemiology; International Union of Phlebology; UIP
IDENTIFICATION ET CONSULTATION DES PATIENTS ATTEINTS DE
MALADIE VEINEUSE CHRONIQUE : L’ ÉTUDE INTERNATIONALE À GRANDE ÉCHELLE
VCP
La maladie veineuse chronique (MVC) se définit par des anomalies morphologiques et fonctionnelles de longue
durée touchant le système veineux et se manifestant par des signes et des symptômes nécessitant des examens
complémentaires et/ou des soins. L’impact de la MVC dans la population générale est souvent sous-estimé et mal
reconnu par les systèmes de santé. Dans les études récentes et selon la classification CEAP (Clinique [sévérité] Étiologie-Anatomie-Physiopathologie), les classes C0 et C1 sont toutes les deux prévalentes dans plus de 60 % de la
population. Les varices (C2) sont prévalentes chez plus de 20 % de la population. Les modifications cutanées, y
compris les ulcères, se retrouvent dans moins de 10 % de la population. Il n’existe pas de données épidémiologiques
pour de nombreux pays. Le Vein Consult Program mondial a pour but d’évaluer la prévalence de la MVC et fournit
une 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 œuvre
sous les auspices de l’Union Internationale de Phlébologie avec le soutien de Servier. Plus de 4500 généralistes
sélectionnés y participent, et l’on estime qu’ils dépisteront environ 95 000 patients. À la première étape du programme, les généralistes trient les patients qui consultent pour n’importe quelle raison médicale. La deuxième étape
est une consultation de suivi avec un spécialiste veineux. Les premiers résultats du dépistage de 69 866 patients de
13 pays sont disponibles.
324
U P DAT E
‘‘
The intensity of the sensation
of pain increases exponentially
with the intensity of the stimulus
and completely disappears after
injection of a local anesthetic in the
isolated venous segment. Regardless of the source of the pain stimulus, the stimulus-sensation curves
(intensity of sensation of pain with
increasing intensity of applied
stimulus) are all the same. These
intriguing results suggest that the
different stimuli activate the same
venous nociceptors.”
Pain in chronic
venous disease:
perspectives for research
b y N . D a n z i g e r, Fra n c e
P
Nicolas DANZIGER, MD, PhD
Department of Clinical
Neurophysiology and Pain
Center, Groupe Hospitalier
Pitié-Salpêtrière
Paris, FRANCE
ain is the complaint that most often leads to a diagnosis of venous disease, and it has a significant impact on patients’ quality of life. For all
those involved with chronic venous disease (CVD), pain is difficult to
assess both because of its multidimensional nature and because of the lack
of a close relationship between pain as a symptom and severity of venous disease. Current hypotheses on the mechanisms of pain induction in CVD highlight its local inflammatory origin. A variety of inflammatory mediators are released locally in the early stages of CVD, which activate unmyelinated C-fibers
in the venous wall, leading to pain. In the last five years, there has been a veritable explosion in the number of indicators suggesting an inflammatory reaction in varicose veins. The precise mechanisms governing the interaction
between venous nociceptors and mediators of inflammation, which may account for the variability of pain experienced in venous disease, remain difficult to explain.
he quality of life of chronic venous disease (CVD) patients is greatly affected
by pain,1,2 the complaint that most often leads to diagnosis of venous disease.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 do
not belong in the range of nociceptive symptoms, eg, pruritus or a sensation of
cramp, heaviness, or tension in the legs.3 The intensity of pain can also fluctuate substantially, from patient to patient or in the same patient with progression of the disease over a period of time.
T
A causal relationship between CVD and pain of venous origin remains difficult to
clarify, both clinically and experimentally. This difficulty could be attributed to the
absence of a close link between pain and the severity of CVD. Nevertheless, the
future looks promising as the neurophysiological mechanisms of pain of venous
origin are now better understood,5 and several biochemical and cellular processes involved in varicose vein remodeling have been explained.6-8
Nicolas Danziger, Faculté de
Médecine Pitié-Salpêtrière, 91,
boulevard de l'Hôpital,
75013 Paris, France
(e-mail: nicolas.danziger@psl.aphp.fr)
Venous innervation and the physiological properties of venous
and perivenous nociceptors
Veins are innervated by sensory nerve fibers whose cell body is situated in the dorsal root ganglia of the spinal cord.5 Sensory fibers are located along the venous wall
and subdivide into collateral branches. Some cross the tunica adventitia and termi-
Pain in chronic venous disease: perspectives for research – Danziger
325
U P DAT E
Isolated
venous
segment
Inflow
Outflow
Occlusive
pneumatic
cuffs
Figure 1. Experimental set-up to study pain evoked by stimulation of an isolated venous segment in man.
A venous segment in the back of the hand located between two Teflon canulas
is isolated from the rest of the circulation by two occlusive pneumatic cuffs.
Local anesthesia of the skin around the isolated venous segment ensures that
sensations 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.
nate in the venous wall between endothelial cells and smooth
muscle cells of the tunica media. Other collateral branches
penetrate the connective tissue of the perivenous space
where they branch further into unmyelinated free nerve endings in proximity to the microcirculation. These subendothelial and perivascular nerve endings are nociceptors: their sole
purpose is the transmission of nociceptive afferent signals
generated both in the venous wall and in the perivenous connective tissue, respectively.
Recently, these types of nerve endings have been shown to
be present in the wall of human varicose veins.9 These nociceptors account for the stimuli that generate pain sensations
of venous origin. This type of pain can be induced by a variety
of different stimuli. Mechanical stimuli used include traction
exerted on a vein, venipuncture, or the presence of a catheter,
while nonphysiological chemical stimuli used include the injection of a strongly acidic (pH <4) or alkalinic (pH >11) solution, the injection of hyperosmolar saline or a glucose solution, or the injection of “cold” isotonic saline (<20°C).10
Animal studies have shown that there are two types of afferent fibers that transmit nociceptive signals of venous origin. Electrophysiological tracings of nerve fibers innervating
venous wall have shown that there is a type Aδ myelinated
afferent nerve fiber and a type C unmyelinated afferent nerve
fiber.11 Aδ fibers, with their higher conduction velocities, are
responsible for the acute, sharp sensation of pain that is felt
first. They respond to a weaker intensity of stimulus than Cfibers. C-fibers, which are deemed polymodal because they
respond to an assortment of stimuli, are responsible for the
sensation of longer-lasting, slow, dull pain.
326
Other sources of acute pain of venous origin include superficial venous inflammation or deep vein thrombosis, both of
which are often observed in clinical practice. Traditionally, the
properties of venous nociceptors have been elucidated experimentally in humans by mechanically, thermally, or chemically stimulating an isolated venous segment and asking the
subject to grade the intensity of the sensation induced (Figure 1).12 This pain model has shown that a variety of nonphysiological endovenous stimuli, such as the application of
cold or heat, balloon dilation of the vein, electrical stimulus,
and infusion of hyperosmolar saline, produce a painful sensation that starts at a particular threshold and whose quality is the same whatever the method of stimulation used.
Furthermore, the intensity of the sensation of pain increases exponentially with the intensity of the stimulus and completely disappears after injection of a local anesthetic in the
isolated venous segment.5 Regardless of the source of the
pain stimulus, the stimulus-sensation curves (intensity of sensation of pain with increasing intensity of applied stimulus) are
all the same. These intriguing results suggest that the different
stimuli activate the same venous nociceptors, which means
that most nociceptors located in the venous wall are polymodal nociceptors.
These experiments have shown that venous dilation is unlikely to be an important factor in the sensation of venous pain.
Mechanical venous balloon dilation has to increase the diameter of a vein by three times its normal value before pain
begins to be experienced. If we add to this observation the
fact that venous dilation is not normally perceived as painful
when induced by pharmacological methods such as the local application of adenosine,13 it appears that even major venous dilation is not in itself a significant source of venous pain
in normal subjects. Moreover, arteriovenous fistulae created
for the purpose of hemodialysis are painless, another strand
of support for this conclusion.
Pain experienced and clinical severity of
venous disease
Numerous epidemiological studies have shown that the existence, intensity, or both of lower limb symptoms associated
with CVD do not correlate with the severity of clinically evaluated venous disease. The quantitative evaluation of CVD is
normally based on the CEAP (Clinical-Etiological-AnatomicalPathophysiological) classification,14 a system for classifying
clinical signs in one of seven classes (C0 to C6) (Table I) according to their severity. In a population study of over 1500
SELECTED
CEAP
CVD
PAF
platelet-activating factor
U P DAT E
subjects aged 18 to 64 years, the Edinburgh Vein Study, Bradbury et al demonstrated a correlation between the presence
of truncular varices and three lower limb symptoms in women:
pain, sensation of heaviness or tension, and pruritus.3 Even
though the correlations were statistically significant, they were
insufficient to determine a causal relationship with the discomfort or pain associated with confirmed venous disease.
In fact, 45% of patients who complained of lower limb pain
compatible with CVD did not have varicose veins, while about
40% of women presenting with varicose veins in the clinical
examination were asymptomatic. Moreover, in men, no significant correlation was found between pain and the existence of truncular varices.
Class
C0
C1
C2
C3
C4
C5
C6
Definition
Varicose veins; distinguished from reticular veins by
a diameter of 3 mm or more
Edema
Changes in skin and subcutaneous tissue secondary
to CVD, divided into 2 subclasses to better define
the differing severity of venous disease:
C4b: lipodermatosclerosis or atrophie blanche
Healed venous ulcer
Active venous ulcer
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 moderate CVD,16 no correlation was seen between pain intensity
and clinical severity of venous disease based on the CEAP
classification.
Furthermore, Howlader and Smith reported no statistical relation between the pain score or heaviness score of a patient,
evaluated on a 10-point visual analogue scale, and the clinical severity of venous disease, in a cohort study of 132 patients.17 The median pain score was 2.8 in the group of patients with class C2 venous disease, 4.5 in class C3, only 0.5
in class C4 and 0 in patients with class C5 venous disease.
No difference was noted in pain scores between patients presenting with superficial venous reflux and those presenting
with deep venous reflux. These results fully uphold the findings of a French survey on the frequency of clinical symptoms
according to the duration of venous disease.4
The French survey illustrated a very significant decrease in
the frequency of functional signs of venous disease, in particular pain, over time. So, for example, the frequency of the
painful heaviness sensation dropped from 71% in the group
with symptoms of less than 5 years’ duration to 50% in the
group whose symptoms were of 30 years’ duration or longer.
These findings concur with the results of a Swiss epidemiological study that indicate the prevalence of varicose veins
increases with age, while pain decreases with age.18
Table I. The CEAP classification.
The essential aim of this classification is to assess quantitatively the stage of
chronic venous disease. The clinical classification is the one most widely used
and consists of 7 classes, which can be symptomatic (S) or asymptomatic (A).
Abbreviation: CEAP, Clinical-Etiological-Anatomical-Pathophysiological; CVD,
Regardless of the sex of the patient, no symptoms seemed to
vary according to the severity of varicose veins. Several studies of patients with advanced CVD (classes C4 to C6) have
shown that there is a relation between the degree of Doppler
scanning–identified venous reflux and the severity of venous
clinical signs and symptoms. Nonetheless, this does not
seem to be the case for early-stage CVD. The search for such
a correlation in the Edinburgh Vein Study, which focused primarily on patients presenting with early-stage venous disease, proved disappointing.15 In the Edinburgh Vein Study,
the correlation observed between pathologic superficial venous reflux (duration greater than or equal to 0.5 seconds)
and sensation of swelling, heaviness, or tension was low. In
addition, this correlation was limited either solely to men (sensation of swelling) or solely to women (sensation of heaviness
or tension). Strictly speaking, no significant correlation was
observed between superficial venous reflux and pain.
A lack of correlation between the presence of venous symptoms and pain was not only limited to superficial veins; this
was also the case for deep veins, too. When venous symp-
Inflammatory autoamplification and pain
mechanisms in venous disease
Present-day hypotheses on how pain mechanisms act in
venous disease focus on a local inflammatory origin, related
to venous stasis. The processes that generate pain in venous
disease in the short term seem to be identical to those involved
in the process of varicose vein remodeling, defined as all of
the qualitative and quantitative alterations in the cellular and
matrix components of the venous wall, in the longer term.19
Local hypoxia associated with capillary stasis is probably the
origin of these mechanisms. The partial pressure of oxygen
has been demonstrated to fall significantly in lower limb veins
in venous disease after 30 minutes in a standing position,8
and many studies have shown that capillary stasis–induced
hypoxia activates endothelial cells.7 This type of activation is
signaled by the elevation of calcium concentrations in the cytoplasm of endothelial cells,20 which upregulate phospholipase A 2 activity.21
Activation of phospholipase A 2 , in turn, leads to the synthesis and local release of proinflammatory mediators such as
platelet-activating factor (PAF), bradykinin, prostaglandins E2
and D2 , and leukotriene B4.22,23 PAF seems to play a key role:
it boosts the local release of histamine and serotonin; it caus-
327
U P DAT E
Upstream
Micropipette
Downstream
Flow direction
Pre
60 min
120 min
Figure 2. Photomicrographs of propidium iodide–positive cells along the upstream (elevated micropressure) and downstream (low micropressure) 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 of
occlusion 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.
es abnormal adherence of neutrophils to the venous endothelium, prior to their infiltration through the venous wall itself;
and, finally, it stimulates the synthesis of leukotriene B4 by activated neutrophils. In the last few years, the amount of evidence for the existence of this type of inflammatory reaction
in patients with varicose veins has snowballed,24 and the biochemical changes identified point to endothelial cells and neutrophils as the source of this local inflammation (Figure 2).8,25-29
There are a plethora of indicators of inflammation in venous
disease: the presence of neutrophils, monocytes, and activated T lymphocytes; the accumulation of macrophages and
mast cells; the expression of adhesion molecules on the surface 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, von
Willebrand factor) are all indicators of inflammation in venous
disease.14,30 Venous nociceptors can be activated by proinflammatory mediators released locally as a result of hypoxia.
The intravenous or perivenous application of one such mediator, bradykinin, evoked a sensation of pain in healthy subjects, which unambiguously establishes the role of this neuromediator in venous pain.31
Many studies have highlighted the vital role of nitric oxide release by endothelial cells, smooth muscle cells in the wall of
the vein, or both32 and the subsequent activation of cyclic
guanosine monophosphate synthesis33 in the production of
pain by bradykinin. Local administration of prostaglandin E2
potentiates this algogenic action of bradykinin.34 Prostaglandin
E2 , whose application by itself is painless, appears to sensitize venous nociceptors. This type of autoamplification re-
328
action cascade causes the release of an “inflammatory mixture,” which activates venous and perivenous nociceptors as
well as causing the extravasation of plasma leading to transmural and tissue edema. Over time, varicose vein remodeling occurs, and this is characterized by cellular and matrix
changes that compromise the structural integrity of the venous wall and its elastic properties.19
A finding that substantiates this hypothesis comes from a
study by Howlader and Smith, which demonstrated that nitric oxide concentrations measured in blood collected in the
saphenous vein or in a vein in the dorsal aspect of the foot
were significantly higher in patients with the most severe stage
of venous disease.35 Likewise, certain studies have reported
higher levels of markers of endothelial activation in experimental venous hypertension in the most advanced stages of venous disease.36
Given the importance of these inflammatory processes in pain
production as well as in varicose vein remodeling, a correlation between levels of inflammatory markers and the intensity of pain in venous disease might be expected to exist. However, this is not the case, in much the same way that the clinical
estimation and evaluation of venous pain by venous Doppler
scanning proved negative.17 No significant correlation was
found between levels of 12 inflammatory markers (measured
in a vein on the dorsal aspect of the foot) and pain intensity
score on a visual analogue scale in a population of 132 patients with CVD ranging from class C2 to C5. The relationship
between the venous wall inflammatory cascade and pain associated with venous disease seems difficult to demonstrate
formally.
U P DAT E
Pain and objective markers of venous disease
N Pain, clinical severity, and inflammatory markers
If the intensity of pain of venous origin does not correlate with
the extent of truncular varices observed in clinical examination, the severity of reflux measured with Doppler scanning,
or levels of inflammatory markers measured in a lower limb
vein, could hypoxia offer a possible explanation? It is entirely
possible that many painful hypoxia-related conditions may occur transiently in patients, eg, after standing for a prolonged
period, at the end of the day, or during certain periods of the
menstrual cycle, if hypoxia is indeed a major factor that triggers pain of venous origin.
If venous and perivenous nociceptor-activating chemical cascades were to occur before significant remodeling of large venous vessels arises, this might explain the frequency of functional signs, such as pain or heaviness in the legs, in patients
who do not have varicose veins and the lack of abnormal reflux seen in a Doppler scan, as in the Edinburgh Vein Study.
While the same essentially inflammatory biochemical and cellular processes are implicated in pain and varicose vein remodeling, the time frame over which these pathological mechanisms occur is different.
Pain appears to be a short-term consequence of venous hypoxia, while varicose vein remodeling seems to take place
at a much later stage of CVD. Because the occurrence of
pain does not appear to be closely related to objective parameters of varicose vein remodeling, incompetent venous
valves, or inflammation, this suggests the primary site of venous/perivenous nociceptor activation may not be the large
venous vessels. In light of this fact, the hypothesis of local
activation of nociceptors in the microcirculation, where contact between nerve endings, the arteriole, the vein, and the
capillary is probably much closer than at the macrovascular
level, seems highly conceivable.
As a result, several studies looked at microcirculatory parameters of venous disease.37,38 In addition, several studies using
an experimental model of acute venous occlusion in the rat
showed that an increase in microvascular pressure triggered
an inflammatory reaction characterized by infiltration of neutrophils into the endothelium and adjacent tissues.27
Shear stress on the endothelium produced by blood flow is
another essential factor that promotes inflammation of the
venous wall.24 Shear stress can influence many intracellular
biochemical processes, such as protein G phosphorylation,
activation of tyrosine kinases, free radical production, and the
synthesis of different nuclear transcription factors, via integrins
anchored in the endothelial cell membrane.39-41 Physiologically normal shear stress produces a potent, local anti-inflammatory effect, while a reduction or an increase in this force
below or above a given physiological threshold can lead to
overexpression of proinflammatory genes.24,30
N Explaining the disappearance of pain in advanced
stages of CVD
Alteration of innervation of the venous wall and the perivenous tissue may explain the significant decrease in the frequency and intensity of pain in the most advanced stages of
venous disease. This change in nerve fibers may reflect sensory peripheral neuropathy, perhaps related to ischemia secondary to venous microangiopathy, and an increase in endoneural pressure.42 The threshold of tactile, vibrational, and
thermal sensation in the extremities in patients with CVD is
significantly higher than normal, suggesting the loss of sensory axons.43,44 This sensory threshold elevation was significantly more distinct in class C5 than in class C2 disease.44 A
reduction in the number of venous and perivenous nociceptors could well account for a lessening of pain in the most
advanced stages of venous disease.
N Interindividual pain variability in venous disease
The range and intricacy of mechanisms involved in the pathogenesis of venous disease pain are a significant source of
interindividual variability. Both the reactivity of the cellular
components involved (endothelial cells, neutrophils, and venous and perivenous nociceptors) and the ways in which nociceptive stimuli are processed in the brain produce this variability. At a cellular level, for example, experimental studies of
human umbilical cord venous endothelial cells have demonstrated that the quantity of different prostaglandins released
as a result of hypoxia can differ by a factor of 10 depending on
the donor.7 By the same token, neutrophil reactivity to other
inflammatory signals varies with age and previous sensitization
(“priming”). What’s more, the density of venous and perivenous
innervation as well as the presence of nociceptors in ion channels, which allows the conversion of a chemical message into
a nerve impulse relaying nociceptive information, can also
vary considerably from one person to another.
Interindividual variability in the way the brain reacts to pain
stimuli will also play a part. The intensity of brain modulation
of nociceptive signals resulting from the release of endogenous opioids, whose concentrations vary from subject to subject due in part to genetic factors, is also likely to account for
some of the pain sensitivity in a given individual with regard
to venous nociceptive stimuli. For instance, the genotype of
the catechol-O-methyl-transferase enzyme, which determines
the quantity of endogenous opioid released during a pain
stimulus, significantly affects pain sensitivity.45
However, all these variables are just relative obstacles in the
elucidation of pain mechanisms in venous disease. In the absence of a correlation between the state of large venous vessels and the degree of pain reported, perhaps we ought to
be examining the interaction between the mediators of inflammation and venous nociceptors in more detail, with a
mind to developing a method of testing nociceptive function
in venous disease microcirculation. I
329
U P DAT E
References
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17. Howlader MH, Smith PD. Symptoms of chronic venous disease and association with systemic inflammatory markers. J Vasc Surg. 2003;38:950-954.
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19. Badier-Commandier C, Jacob MP, Michel JB. Le remodelage variqueux. Médecine Thérapeutique. 2000;6:718-723.
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38. Virgini-Magalhaes CE, Porto CL, Fernandes FF, Dorigo DM, Bottino DA, Bouskela E. Use of microcirculatory parameters to evaluate chronic venous insufficiency. J Vasc Surg. 2006;43:1037-1044.
39. Resnick N, Yahav H, Khachigian LM, et al. Endothelial gene regulation by laminar 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-induced gene expression. J Biomech. 1995;28:1451-1457.
41. Chen KD, Li YS, Kim M, et al. Mechanotransduction in response to shear stress.
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42. Reinhardt F, Wetzel T, Vetten S, et al. Peripheral neuropathy in chronic venous
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43. Shami SK, Shields DA, Farrah J, Scurr JH, Coleridge Smith PD. Peripheral nerve
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Keywords: pain; chronic venous disease; inflammation; nociceptors; C-fibers
330
U P DAT E
DOULEUR
DANS LA MALADIE VEINEUSE CHRONIQUE
PERSPECTIVES POUR LA RECHERCHE
(MVC) :
La douleur est la plainte qui mène le plus souvent au diagnostic de maladie veineuse et elle influe significativement
sur la qualité de vie des patients. Pour tous ceux qui se préoccupent de la MVC, la douleur est difficile à évaluer à
la fois à cause de sa nature multidimensionnelle et à cause du manque de relation étroite entre la douleur en tant
que symptôme et la sévérité de la maladie veineuse. Des hypothèses actuelles sur le mécanisme d’induction de la
douleur dans la MVC soulignent son origine locale inflammatoire. De nombreux médiateurs inflammatoires sont libérés localement aux stades précoces de la MVC, activent des fibres C démyélinisées dans la paroi veineuse, entraînant la douleur. Ces 5 dernières années, on a assisté à une véritable explosion du nombre d’indicateurs suggérant
une réaction inflammatoire dans les varices. Il est toujours difficile d’expliquer les mécanismes précis à l’origine de
l’interaction entre les nocicepteurs veineux et les médiateurs de l’inflammation, qui pourraient contribuer à la variabilité de la douleur observée dans la maladie veineuse.
331
A TOUCH
OF FRANCE
nder this heading, each
issue of Medicographia
features two cultural articles. The first one touches on the
history of medicine, based around
a great figure from French history,
while the second one addresses
broader aspects of France’s heritage, such as history, art, literature, and the description of museum collections.
U
Theory and practice:
European Renaissance
medicine
S . D a y n e s - D i a l l o , Fra n c e
Dissection scene from
De Proprietaribus
Rerum, by Barthélemy
l’Anglais (vellum). End
15th century. Bibliothèque
Nationale, Paris.
© Archives Charmet/The
Bridgeman Art Library.
Écouen: from château
to museum, or Beauty is
in the detail
S . D e p ro u w, Fra n c e
Dish with intertwined
flowers (detail).
Iznik, Turkey, circa 1580.
© RMN/René-Gabriel Ojéda.
333
A TOUCH
lthough Renaissance medicine has not had the impact of Renaissance art,
there were nevertheless major advances in the field of medicine at
this time, notably in a Humanist
reassessment of the medical legacy from antiquity, a ratification of
medical education at medical institutions, and an explosion in the
dissemination of medical knowledge. In addition, Renaissance
medicine developed the first treatments for firearm wounds and welcomed the arrival in Europe of new
remedies from far-flung shores.
OF
FRANCE
A
Theory and practice:
European Renaissance
medicine
b y S . D a y n e s - D i a l l o , Fra n c e
© All rights reserved
A
Sophie DAYNES-DIALLO
Musée du Louvre, Paris, FRANCE
n Africa specialist with a university background in the arts, human sciences,
and museology, Sophie Daynes-Diallo has found herself stumbling repeatedly 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–Hôpitaux
de Paris) on the 1935-2005. Avicenna Hospital: a history without borders exhibition, the catalogue for which she coproduced with Katia Kukawka. In 2006, after
passing the Ministry of Culture’s competitive documentalist examination with distinction, she was appointed to the National Museum of the Renaissance, where she
commissioned the exhibition Ars medicina: medicine and knowledge in the 16th
century, held in the spring of 2008. In the fall of 2009, she moved to the Louvre
to become a registrar in the Department of Egyptian Antiquities.
R
Sophie Daynes-Diallo, Régisseur
d’œuvres d’art, Département des
Antiquités Égyptiennes, Musée du
Louvre, 75058 Paris CEDEX 01,
France
(e-mail: sophie.daynes-diallo@louvre.fr)
enaissance medicine amalgamated the theory and practice of medical
knowledge inherited from Antiquity and the Middle Ages. Although it
built on much from the past, it also innovated—Renaissance medicine
was determined to shake off its Medieval trappings. In spite of the fact that
medicine in the 16th century did not experience a renaissance comparable to
that seen in the arts—the medical revolution was still a century away—it could
not fail to be caught up in the Humanist wave sweeping through Europe, and
it made genuine progress as a result. While the Copernican revolution turned
Medieval cosmology on its head, the Reformation undermined Catholic dogma and questioned the relationship between God and Man, and technical
advances—spearheaded by printing—led to an unprecedented transformation in knowledge and practice, medicine swung between a form of Humanism that was extremely deferent to the Ancient Greeks and Romans, but which
eventually opened the way for textual criticism, and an increasingly empirical
form of clinical practice in response to the century’s two main scourges: epidemics and the arquebus—one natural, the other man-made. It was also in the
16th century that medical fraternities organized themselves into institutions
and prepared the ground for modern medicine and the completion of the synthesis of theory and practice.
334
Theory and practice: European Renaissance medicine – Daynes-Diallo
A TOUCH
enaissance* medicine amalgamated
the theory and practice of medical
knowledge inherited from Antiquity
and the Middle Ages. In response to
the humanism of the age, its attitude
constantly oscillated between atavism and innovation, which produced
tangible progress and prepared the
ground for the blossoming of modern medicine that occurred
in the 17th century.
OF
FRANCE
the human microcosm, so that the laws governing the one also
governed the other. The ambition of Renaissance man was
to unveil and understand God’s creation across both spheres.
Medical doctrine inherited the synthesis of three great intellectual traditions from the Middle Ages: the Arabic teachings
of Antiquity, Christian doctrine, and Middle Eastern culture
and science. The corpus of a Renaissance medical library
comprised the works of Hippocrates (circa 460 – circa 370
BC), Aulus Cornelius Celsus (circa 25 BC - circa 50 AD), Pedanius Dioscorides (circa 40-90), and Galen (129-199/217),
along with those of Avicenna (circa 980-1037), Averroes (11261198), and the teachings of the Salerno School of Medicine
from its heyday between the 10th and 13th centuries.
Medical science was based on the doctrine of humors expounded by Hippocrates and his “prophet” Galen. Being a
microcosm of the universe, the human body was naturally
composed, like the universe itself, of the four “fundamental
elements” of earth, water, air, and fire. Each of these elements
was in turn characterized by four essential “qualities”: hot,
dry, cold, and wet. In addition, the human body was bathed
in four “fluids” or “humors,” characterized by two essential
“qualities” and one “fundamental element”: blood—hot and
wet—was associated with air; phlegm—cold and wet—with
water; yellow bile—hot and dry—with fire; and black bile—
cold and dry—with earth. In normal circumstances, the humors acted in harmony to produce a healthy, “temperate” individual.
Prosthetic hand designed by French surgeon Ambroise Paré
(1510-1590), a specialist of battle medicine and royal surgeon to
four kings. From: Instrumenta Chyrurgiae et Icones Anathomicae,
by Ambroise Paré, published 1564. © Wellcome Library.
The legacy of the past
The medical world of the Renaissance inevitably bore the
stamp of its Medieval counterpart. Medicine in this era was
a component of physica—the Latin echo of Aristotle’s τα
φυσικα—incorporating the natural sciences, philosophy, and
religion. It perceived the world as a macrocosm reflected in
* Decorated initial from the Basel 1555 edition of Andreas Vesalius's De
Humani Corporis Fabrica published by Johannes Oporinus. Woodcut.
© Wellcome Images.
The Four
Humours,
from Quinta
Essentia by
Leonhart
Thurneisser
zun Thurn
(1531-95/6)
published in
Leipzig, 1574
(engraving)
(b/w photo),
German
School,
(16th century)/private
collection.
© Archives
Charmet/Bridge
man Giraudon.
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Dutch surgeon. 1569, oil on wood, 16×21 cm. Theodore
M. Davis Collection, Bequest of Theodore M. Davis, 1915,
The Metropolitan Museum of Art, New York.
Distributed by RMN/© The Metropolitan Museum of Art.
on practical experience and folk wisdom. Although Renaissance physicians came from a wide range of social origins,
the possession of a university doctorate of medicine conferred a relatively exalted social status on its holder. Attachment to the university was associated with a number of privileges, an oath, and obligations. In provincial cities without a
university, organization into corporations or colleges ensured
the integrity and protection of the physicians’ guild.
Nevertheless, the gulf in status between the ennobled senior
court physician and the provincial physician, or between the
private physician of an important figure such as a prince,
prelate, or minister and the town-council physician caring for
paupers, was huge. In general, however, physicians confined
their practice to an urban and well-to-do clientele.
Disharmony resulted in illness and disease. Thus an excess
of all four humors, especially blood, gave rise to “plethora”
(forming the doctrinal basis for bloodletting), while the relative
excess of a single humor produced a state of “cacochymy.”
The humors were complemented by three spirits animating
the body: the “natural” spirit residing in the liver, the “vital”
spirit in the heart, and the “animal” spirit in
the brain. The aim of Renaissance medicine
was to understand more about these humors,
recognize their disharmony in patients, and
correct them with a set of defined interventions and long-established remedies.
Physicians dressed austerely, in black cassock and cloak,
turned down cuffs and collar, and wide-brimmed hat. Above
all they were men of letters who taught natural science and
literature in universities or at the Collèges de France. They
tended to be humanists and poets, and were far more adept
in doctoral discourse than in clinical practice or intervention,
which they delegated to students, barber surgeons, or even
apothecaries.
In France, apothecaries joined with grocers to form the second of the six merchant guilds. Like physicians, they enjoyed
important privileges in the Renaissance period, which also
came with obligations and an oath very similar to that of the
A medley of medical professions
and skills
The three guilds of physicians, apothecaries,
and surgeons formed the basis of the practice of Renaissance medicine. Over the century, they gradually established themselves
into separate institutions, but not without
clashes and competition. In addition to these
three professions at the top of the medical
hierarchy, headed by physicians, 16th century citizens could also access the services
of a huge spectrum of artisans prepared, in
the absence of the three notables, to undertake medical interventions based essentially
336
Interior of a pharmacy (fresco), Italian School, 15th century/Castello di Issogne,
Val d’Aosta, Italy. © Giraudon/Bridgeman Giraudon.
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current Hippocratic oath. Pharmaceutical studies had been
organized since the previous century into several years’ apprenticeship crowned by the presentation of a “masterpiece,”
according to the term’s original meaning: a piece of work produced by an apprentice aspiring to become a master craftsman in his chosen guild. Apprenticeship was supplemented
from the second half of the 16th century onwards by the teaching of theory that foreshadowed that dispensed in modern schools of pharmacy.
Apothecaries dressed similarly to physicians, whom they served by dispensing
their prescriptions.
The professional world of surgery during
the Renaissance was extremely complex
and beset by conflict, the primary although
not exclusive source of which lay in the
contempt that had been shown for this
“manual” discipline by physicians since the
Middle Ages: in the 13th century, at a time
when medical science was still the privilege of churchmen, Canon 18 of the Fourth
Lateran Council forbade the “shedding
of blood.” This amounted to the de facto
exclusion of surgery from both churchmen’s medical practice and the university
curriculum. Thus secularized, surgery was
left to surgeons, who taught it in schools
that varied in the nature of their relationships with the universities.
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of religious orders, and recommendations and cure-alls endorsed by ladies in the aristocracy or bourgeoisie were available alongside healers, sorcerers, soothsayers, astrologists,
and peddlers of potions. Together they formed a motley army
of charlatans purveying an illicit and generally peripatetic medicine that was condemned by the university medical authorities. In addition to this array of dubious practitioners, not
forgetting the constant and insistent recourse to faith (ranging from regular devotion to supplications to healer-saints, not
to mention a whole gamut of processions,
prayers, pilgrimages, and penances), there
existed a number of artisans who plied a
specialist trade across the class divide:
bonesetters, peripatetic barbers, lithotomists (extractors of human kidney, bladder, and gall stones), specialists in hernias and cataracts, toothdrawers, and
midwives.
Regulated university medical
training
Renaissance universities comprised four
faculties. Students had to pass through
the first, the faculty of arts—where they
studied grammar, the humanities, rhetoric, and philosophy—before they could accede to any of the other three major faculties (theology, medicine, and canon law).
From the 13th century onwards, the faculThe second source of conflict in the world
ty of medicine was separate from the facof surgery lay in the huge disparities in
ulty of arts. Access required the degree of
knowledge and practice within the proMaster of Arts, accompanied by a certififession, from the educated master of surcate of baptism in Paris, but granted “regery at the pinnacle of the profession to
gardless of nationality or religion” in Padua.
the barber surgeon, who had learned his
craft on the job and who was licensed to
The university course consisted of three
practice minor surgery, bloodletting, and
consecutive qualifications: baccalaureate,
Anatomical manikin made of ivory
used by midwives. Germany, beginthe dressing of wounds, at the bottom. In
degree, and doctorate. The cycle was varining of 17th century. Ecouen, Musée
the struggle to obtain recognition for their
able, but generally extended over some ten
National de la Renaissance.
profession, both groups had to fight off
years. Although in practice some provin© RMN/René-Gabriel Ojéda.
antagonism and encroachment from the
cial physicians only had a baccalaureate
university-trained medical profession throughout the 16th cen- or a simple certificate, in theory none were allowed to practury. Below both these groups—mainly in the countryside, tice medicine without having obtained a degree. A doctorate,
but also in towns and villages—a whole range of practitioners on the other hand, opened the door to recognition within the
served the swathes of population denied access to a physi- profession and to employment on the university teaching or
cian or surgeon, whether for geographic or financial reasons. administrative staff.
Folk wisdom based on a combination of magic, religion, and
time-honored empiricism enabled everyone either to treat
themselves or to consult someone more experienced, higher born, better educated, or better off who was prepared to
treat a fellow human being out of charity or neighborliness.
Thus, folk remedies, charitable acts by priests or members
Studies were conducted in Latin. They consisted essentially
of reading and analyzing the texts from Antiquity, mixed increasingly with those of more contemporary authors. In the
early 16th century, theoretical teaching was structured around
the study of “natural things” (anatomy, physiology, botany),
“non-natural things” (hygiene and diet), and “contra-natural
337
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things” (pathology and therapeutics). Theoretical learning was
supplemented by practical sessions in botany and anatomy.
Paris, Montpellier, Padua, and Bologna were the major 16th
century universities and were all originally founded in the Middle Ages. These major centers of learning were not isolated,
however. For example, France numbered over twenty faculties of medicine or medical study centers. Students liked to
travel from one center to another to study and accumulate
qualifications from each.
A number of private medical teaching establishments coexisted with the faculties. In Paris, some colleges that taught
medicine gradually merged with the university, such as the
Colleges of Tricquet and Cornouailles; similarly, in Montpellier,
there was the College of the Twelve Physicians. There were
also schools of surgery (colleges of Saint Cosmo), which gradually became incorporated into universities. The Collège de
France, set up in 1530 by François I, boasted a chair in medicine from as early as 1542.
A change of intellectual direction: medical
Humanism
Humanism informed the entire Renaissance, most visibly in
the arts and sciences. Positioning Man and human values at
the center of thought, the new philosophy was characterized by a return to the writings and practices of the Ancient
Greeks and Romans, deliberately breaking from the supposed
legacy of the Middle Ages. The change of intellectual direction that took place initially in Italy between the late 14th and
mid-15th centuries spread rapidly throughout Europe. Humanism took its name from the Latin humanitas, meaning the
“humanities” or the study of Latin and Greek in the broadest
sense: the idea was to follow the paths laid down by the Ancient Greeks and Romans in knowledge, ethics, philosophy,
and politics.
The Humanism of the Renaissance was thus characterized by
a desire to return to the writings and practices of the ancients
stripped of their Medieval dross: these writings had, after all,
Botanical
drawing from
the Great
Herbal of
Leonhart Fuchs
(1501-166): De
Historia Stirpium
Commentarii
Insignes (1542).
© Chelsea Physic
Garden, London,
UK/The Bridgeman
Art Library.
Frontispiece of
De Re Medica by
Aulus Cornelius
Celsus (Rome,
≈1st century BC/
1st century AD).
Published in Paris
by Chrestien
Wechel, 1529.
© BIU Santé—Bibliothèque Inter-Universitaire de Santé, Paris.
Universities were thus not the only institutions that taught medicine. But in addition to teaching and conducting research,
they had other prerogatives. For example, they were consulted on issues of general interest to the State, such as public
health and hygiene. They also produced the majority of physicians employed by royalty. Universities were also given the duty
of overseeing apothecaries, barber surgeons (to a lesser extent), and midwives.
been translated, annotated, and added to throughout the Middle Ages. Humanists in all branches of knowledge therefore
embarked on the vast undertaking of rereading, reanalyzing,
and republishing the texts of Antiquity that had been handed down to them. In medicine, for example, the last quarter of
the 15th century saw the republication of De re medica by
Aulus Cornelius Celsus, along with central works by Hippocrates and Galen.
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Dissection scene from
De Proprietaribus Rerum, by
Barthélemy l’Anglais (vellum). End 15th
century. Bibliothèque Nationale, Paris.
© Archives Charmet/The Bridgeman
Art Library.
Consequently, the entire century
witnessed a vast dissemination of
Humanist thought, aided and abetted by the development of printing
in particular, but also by university
teaching and Humanist practice.
Magnificent testimony to the movement comes in the form of manuscripts and printed works specifically composed and published for
the great Humanist libraries founded by princes and prelates, kings
and emperors, and the religious
foundations of which the universities were a part. Two compendia
of Greek and Roman surgical writings organized by the celebrated
Florentine physician Guido Guidi
(aka Vidus Vidius [1508-1569]) for
the Humanist library of François I and illustrated by the Florentine artist Francesco Salviati (1510-1563) are exemplary
in this regard. This sublime work, published in 1544, was a
crystallization of the scientific and artistic excellence to which
Humanists aspired. Reproduction of its plates throughout the
16th century to adorn multiple works on allied topics, such
as those by the French royal surgeon Ambroise Paré (circa
1510-1590), provide a perfect illustration of the dissemination
of the Humanist movement.
now the 10th arrondissement of Paris. Other objects of dissection included animals, colleagues, and even friends (who
could thus be said to have bequeathed their bodies to science!). An additional source of bodies was pauper cadavers
from hospices.
The Renaissance updated the practice of anatomy to Humanist times. Anatomical dissection, a practice inherited from Antiquity, had been officially conducted in Italy since the 13th
century and in France since the 14th century. The papal bull
issued by Boniface VIII in the 13th century had secured its approval by the Church for the sole purposes of legal autopsy
and university demonstration.
The most remarkable expression of the new anatomy was the
masterpiece by Vesalius, De humani corporis fabrica libri septem. Published in 1543, the same year as De revolutionibus
orbium coelestium by Copernicus, it incarnated the urge to
question the all-powerful work of Galen and its reverential exponents, which had begun at the turn of the century with the
first pre-Vesalian anatomists: members of the Padua School,
the English Humanist Thomas Linacre (circa 1460-1524), and
the Paris School, one of whose graduates, Charles Estienne
(1504-1564), produced (some time before 1539) De dissectione partium corporis humani. This work was very similar to
Fabrica, except that unlike Vesalius, Estienne did not engage
a pupil of Titian to take care of the illustrations.
At the start of the 16th century, dissection was only used in university teaching to illustrate the writings of Antiquity. Its role
and status grew steadily throughout the century. It began to be
performed outside universities, for instance, in independent
colleges, at the Collège de France, in schools of surgery, by
private individuals (students and barber surgeons), and also by
artists. The practice was almost always illegal, but generally
tolerated. The details of cadaver provenance remain murky.
Andreas Vesalius (1514-1564) is believed to have fetched his
supplies from the multistorey gibbet of Montfaucon in what is
Such fastidiousness was emblematic of the Vesalian revolution: at the same time as Vesalius was insisting on the necessity of the teaching of anatomy and the superiority of handson experience over medical scripture and its associated
iconography, he was calling on one of the great art workshops of his day for illustrations, regardless of the expense.
After all, it was the workshops of Leonardo da Vinci, Verrocchio, Michelangelo, and Dürer that had pioneered the study
of anatomy, in terms of representing the human body, in the
very early Renaissance. These studies originated mainly from
Emergence and celebration of anatomy as
a discipline
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Scenes of
medical life
during the
Renaissance.
Frontispiece of
Der Gantzen
Artzenei, by Johann Eichmann
(Dryander)
(1500-1560),
published by
Christian
Egenolph,
1542, Frankfurt
am Main. Engravings outside frame—
upper left: doctor examining a
patient’s urine;
upper right:
bloodletting;
main engraving,
clockwise from
top left: examining a bedridden
patient; selection, picking,
and preparation
of medical
herbs; discussion among
doctors; apothecary preparing
medicines.
© BIU Santé—
Bibliothèque InterUniversitaire de
Santé, Paris.
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Anatomy of human veins and arteries. From
De Humani Corporis Fabrica, by Andreas Vesalius,
published by J. Oporinus in Basle, 1543. © Wellcome Library.
Leonardo’s workshop and were unknown to immediate contemporaries. But their direct influence was displayed for all to
see in Fabrica, in an explosion of magnificent yet elegant detail that symbolized the quest for meaning by an entire epoch
obsessed with the human body.
Anatomy thus came into its own in the 16th century, as pictorial representation, descriptive treatise, and clinical method.
It was to retain its central status for centuries to come. In addition, by encouraging the investigation and elucidation of
the human body, the commitment to research and empirical
method that drove Vesalius and those who came after him
put clinical intervention and hands-on experience back into
the heart of medical practice, thereby opening the door to
the surgeons.
Surgical progress: the impact of the arquebus
Surgery in the 16th century was marked by the beginning of
a rise in the social status of surgeons and the normalization
of their profession. In addition to celebrated anatomists and
surgeon-physicians such as Vesalius, a number of barber
surgeons helped their specialty to recover its scientific status. Under the direct challenge of their century’s two main
scourges—epidemics and the first firearms—these surgeons
led a revolution in surgery that extended way beyond the
battlefield and the hospitals where they practiced.
Battlefield surgeons such as Paré, their most celebrated representative, were also responsible for the extensive dissemination of surgical knowledge. In direct contrast to the illiterate
caricatures disdained by faculty physicians, they produced
surgery and anatomy manuals in vernacular language, which
were often richly illustrated and went hand in hand with Humanists’ dissemination of knowledge in similar areas.
combining realism, clarity, sobriety, and a talent for disseminating knowledge. The works are also a treasure trove of the
surgical arsenal of the time, only very rare items of which have
come down to us. They are particularly valuable for identifying contemporary surgical implements because these can be
difficult to tell apart from the tools used by butchers, huntsmen, and even gardeners.
It was the battlefield that generated the major surgical advances of the 16th century. Surgeons routinely joined army
units, replacing the charlatans that had been used up to that
time. Their presence was a necessary response to the increasing violence of battle due to the development of shortrange firearms—the arquebus, then the musket—and the novel wounds they produced.
Paré introduced new methods of treating multiple wounds,
and a new approach to firearm wounds. Like the personal
physician to Henri III, Laurent Joubert (1529-1582), the Swiss
surgeon Félix Würtz (dates uncertain), and Hans von Gersdorf
(circa 1455-1529) in Strasbourg, he also had an interest in amputations, prostheses, and orthopedic corrective techniques,
making some striking contributions in these fields. He published his studies in a large number of works with illustrations
Surgical instruments. From La Méthode Curative des Playes, et
Fractures de la Teste Humaine, by Ambroise Paré, published in
1561 by Jehan le Roer, Imprimeur du Royès Mathématiques, Paris.
© Wellcome Library.
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Philippus Theophrastus Aureolus Bombast von Hohenheim,
or Paracelsus (1493-1541). Swiss physician, pharmacist, botanist,
alchemist, and astrologer. Oil on wood, 72×54 cm. Paris, Louvre
Museum. © RMN/Hervé Lewandowski.
The documentary evidence for the ordinary medical practice
described above is fairly extensive. In particular, it is backed by
an impressive catalogue of iconography. It is also documented in brilliant detail in the remarkable diary of Jean Héroard
(1551-1628), physician to Louis XIII, which is held at the Bibliothèque nationale de France.
Apothecaries and their therapeutic arsenal
Designed to restore humoral harmony, the therapeutic arsenal available in the Renaissance was boosted by new ingredients from the Americas (such as tobacco or the hardwood
lignum vitae) and by increasing trade relationships with other distant lands. The basis of apothecary practice nevertheless remained the Antidotarium by Nicholas of Salerno (12th
century), along with numerous pharmacopoeias, compendia,
and recipes.
Ordinary medical practice
On the ground, far from the lofty heights of major surgery and
anatomical research, there existed during the Renaissance,
as at any other time, ordinary medical practice comprising a
set of medical interventions and remedies. Patients were attended in their homes by all levels of practitioner, whether by
the prestigious doctors of medicine, who once at
the bedside mutated into practicing physicians,
or by the humbler physicians themselves, along
with their assistants (apothecaries, barbers, and
students). The consultation consisted of eliciting and interpreting signs and symptoms, issuing recommendations as to diet or hygiene, performing medical interventions, and writing an
extemporaneous prescription for medication.
In addition to the patient interview, the consultation used the following techniques to elicit signs
and symptoms: inspection and interpretation of
the pulse, urine, and feces, and in some cases
blood; and assessment of the patient’s “heat”
(temperature), appearance, and complaints.
Once interpreted, the condition could be treated with a variety of interventions: bleeding, enema, and cauterization, selected according to
the most propitious planetary movement or sign
of the zodiac.
342
The remedies made up by apothecaries against physicians’
prescriptions fell into three main classes, termed “alterative,”
“evacuative,” and “specific.” Although almost all were of plant
or animal origin, some preparations were mineral (ie, metals
such as the antimony prized by Paracelsus [1493-1541],
pearls and precious stones, marble, crystal, chalk, and various earths) and a few were of human origin (eg, milk, blood,
bone, urine, excrement, and a mellified human mummy confection known, in a variety of spellings, as mumie). Distillation
was increasingly used to obtain active ingredients and led to
advances in medicinal chemistry. Panaceas were taken as infusions, decoctions, tinctures, syrups, pills, preserves, and
confections (the most famous of which was the
theriac of Andromachus
[1st century] or theriaca
Andromachi). Alternatively, they were applied topTheriac jar, 1641, Italy.
Science Museum, London.
Theriac was a syrupy medicine originally prepared in
Ancient Greece in the 1st
century AD as an antidote
for animal bites and poisoning, then as a panacea. It was
made of over 60 ingredients,
some highly exotic such as
dried viper and opium, and
used throughout Europe until the 18th century, and as
late as 1884 in France.
© Science Museum, London/
Wellcome Images.
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ically as ointments, cerates, plasters, poultices, or eye salves;
inserted as suppositories or pessaries; or pinned to the clothes
or attached to the skin as powder-filled bonnets and sachets.
Explosion in the dissemination of medical
knowledge
The discovery and rapid development of printing proved extraordinarily effective in disseminating medical science and
distributing the texts required for its practice: antidotaria; manuals of surgery, day-to-day medicine, and pharmacy; and almanachs of planetary movements and signs of the zodiac to
guide the selection and timing of interventions. As Humanist
scholars, physicians saw the dissemination of medical knowledge as an honorable mission. Writing in everyday language
also made them accessible to humbler colleagues: French or
German editions of works by Paracelsus, Jean-François Fernel (1497-1558), or Paré could be read by apothecaries and
THÉORIE
ET PRATIQUE
:
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barber surgeons. Humanist reinterpretations and republications of works by the ancients (to which some physicians, such
as Niccolo Leoniceno [1428-1524], devoted themselves almost exclusively) not only transmitted the knowledge inherited from Classical antiquity along with some critical reflection,
but were also paralleled by the dissemination of a rich body
of contemporary literature that improved rapidly in terms of
illustrations and structure as the century unfolded. Thus, 16th
century medicine may not have undergone a true Renaissance, but it was nevertheless a true child of its time. Viewing its twin Classical and Medieval inheritance through the
prism of Humanism, it inevitably reflected the influence of contemporary religious and philosophical debate. In addition, it
managed to bring about a synthesis of the key components
in its heritage and, thanks to some remarkable men, to prepare the ground for the blossoming of modern Western medicine the following century. I
LA MÉDECINE DANS L’E UROPE DE LA
RENAISSANCE
Entre théorie et pratique, la médecine à la Renaissance opère une synthèse du savoir hérité de l’Antiquité et du
Moyen Âge. Elle reçoit beaucoup de son passé mais innove également et va, de manière forte, vouloir se défaire
de ses limbes médiévales. Si l’on ne peut pas parler de Renaissance médicale au sens où l’on parle de Renaissance des Arts, car la révolution en ce domaine se fera au siècle suivant, la médecine au siècle de la Renaissance
n’échappe pas pour autant à la vague humaniste qui anime le siècle, et connaît de réels progrès. Alors que
l’ébranlement du cosmos médiéval se produit avec la révolution copernicienne, que la Réforme bouscule le
dogme catholique et questionne le rapport entre Dieu et les hommes, que l’on assiste à des progrès techniques
qui – imprimerie en tête – permettent une révolution du savoir et des pratiques sans précédent, la médecine oscille entre un humanisme faisant preuve d’une extrême déférence envers les Anciens mais ouvrant enfin la porte à
la 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 et
construisent le berceau de la médecine moderne, dans laquelle théorie et pratique se seront réconciliées.
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he Château d’Écouen, where
the prestigious Renaissance
collections from the former
Cluny Museum in Paris (today the
French National Museum of the
Middle Ages) are now held, was
converted into a museum at the
behest of De Gaulle’s Minister of
Culture, André Malraux, and
opened to the public in 1977. It is
home to a wide range of artwork—
tapestries, paintings, ceramics,
stained glass, furniture, gold antiques, and silverware—from the
Age of Discovery until the early
17th century.
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T
Écouen: from château
to museum, or Beauty is
in the detail
b y S . D e p ro u w, Fra n c e
© All rights reserved
A
Stéphanie DEPROUW
French National Museum of the
Renaissance, Écouen, FRANCE
ppointed in July 2009, Stéphanie Deprouw is the curator of the scientific
instrument and ceramic collections at the French National Museum of the
Renaissance that includes pieces retrieved from Bernard Palissy’s Tuileries
workshop. As an archivist-paleographer with a master’s degree in history from
Paris University I, specializing in the history of science, her training spans all aspects of the Renaissance, from the intellectual to the technical. Having curated two
exhibitions at Écouen, one on a set of enamels by Léonard Limosin (2010), the
other on Geoffroy Tory, printer to King Francis I of France (2011, along with the National Library of France), she is now devoting herself to the study of a masterpiece
from Écouen's collections, the wire-drawing bench built for prince Augustus of
Saxony in 1565—see www.musee-renaissance.fr/bancdorfevre/.
T
Stéphanie Deprouw, Conservatrice
du patrimoine, Musée national de
la Renaissance, Château d’Écouen,
95440 Écouen, France (e-mail:
stephanie.deprouw@culture.gouv.fr)
he Château d’Écouen, a major Renaissance home built for one of the
most important figures in 16th century France, Duke Anne de Montmorency, was converted into a museum at the behest of De Gaulle’s Minister of Culture, André Malraux, and opened to the public in 1977. It has since
housed the prestigious Renaissance collections from the former Cluny Museum in Paris (now the French National Museum of the Middle Ages). Far from
confining themselves to French art, these collections offer a rich panorama of
works from Europe and parts of the world with which Europeans had forged
regular contact—the Near East, Africa, and America—from the Age of Discovery until the early 17th century. Whether in the form of tapestries, paintings,
ceramics, stained glass, furniture, or gold and silverware, the same culture
was expressed through an infinite number of materials and colors, celebrating Nature and creations of the mind in equal measure. The principles of the
Château’s design set the tone for what awaits inside: symmetry and geometry, set off by a skilled sense of decorative detail. Visitors who delve into the
detail of the collections will marvel at the challenges that artists and craftsmen set themselves in competing with one another and with Nature. Quality
of line and clarity of composition quickly became as crucial in identifying the
best artists—the finest painters, sculptors, and architects—as they were in determining their best artisan counterparts—the top embroiderers, goldsmiths,
silversmiths, and enamel workers.
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Écouen: from château to museum, or Beauty is in the detail – Deprouw
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ocated1 20 km north of Paris, the
Château d’Écouen was built in several stages beginning in 1538 for the
French soldier, statesman, and diplomat Anne de Montmorency (14931567)—Anne being not uncommon
at the time as a name for boys—
shortly after his childhood friend,
King François I, appointed him Constable of France, a post
that combined the functions of First Officer of the Crown and
Commander-in-Chief of the Army. Montmorency had the existing medieval structure demolished to make way for an unabashedly modern château on top of a hill overlooking the flat
region just north of Paris, known as the Plain of France.
A palace to host the Royal Court
A proponent of sustainable development centuries before the
concept was coined, Montmorency installed a particularly sophisticated rainwater conveyance and harvesting system,
much of it underground, to supply his vaulted bathrooms in
the basement of the north wing: this suite dedicated to relaxation—after exertion following hunting or tennis, for example—
is one of the last two remaining in France, the other being in
the Château de Maulnes in the department of Yonne. It epitomizes the Château d’Écouen’s claim to refinement.
1 Decorated
initial from the Basel 1555 edition of Andreas Vesalius's De
Humani Corporis Fabrica published by Johannes Oporinus. Woodcut.
© Wellcome Images.
Stone sewer drain, Château d’Écouen, circa 1540.
© RMN Droits Réservés.
In opting for an architectural style that was both sober and
radical—originally a square bounded by projecting rectangular wings—the Château d’Écouen resembles the Château
d’Ancy-le-Franc (Yonne) built by Sebastiano Serlio for Antoine
de Clermont (1498-1578) during the same period (1542 to
around 1550). There is no record of Écouen’s first architect or
The
Château
d’Écouen
in the fall.
Courtesy
Musée de la
Renaissance.
All rights
reserved.
345
A TOUCH
OF
FRANCE
Michelangelo’s Slaves in the courtyard of the Château d’Écouen. © Ferrante Ferranti. With kind permission.
project manager. Jean Bullant, who was to become Anne de
Montmorency’s favorite architect and who later built the Petit Château for him at Chantilly, appears only to have been involved at Écouen at a later stage (1552), when he redesigned
the staircase and north front to accommodate the frequent
visits of the King and his Court. The accounts of the château’s
construction were unfortunately lost during the French Revolution, but we know that work continued on the château almost until Montmorency’s death in 1567. Although built primarily for gracious living, the château remained defensive in
appearance at least, in particular because of its moats, which
346
were dry from the outset. A distinctive feature of the building
is the elaborate classical ornamentation of the windows set in
the sloping roof. The Constable’s coat of arms (a sword with
the motto “APLANOS”—“Unswerving”) is repeated all along
the south wing, which housed his apartments and those of
his wife, Madeleine de Savoie, on the second floor. Opposite
these apartments were the royal apartments, with Catherine
de Médicis on the first floor and Henri II on the second floor.
Each set of apartments was identified by the occupant’s respective coats of arms, a rainbow and double K for Catherine
and an H double D (for “deux,” ie, second) for Henri.
A TOUCH
As Constable, Montmorency was the second most important figure in the kingdom, as is borne out by the place of his
name next to Henri II’s signature on some royal decrees. It
was therefore entirely appropriate for him to have a palace
fit to receive a king. Henri was particularly close to Anne de
Montmorency, who returned to royal favor after losing the
confidence of Henri’s father François I, following his failure to
secure the Duchy of Milan, a state in northern Italy from 1395
to 1797, in his negotiations with the Holy Roman Emperor
Charles V.
The château’s finest ornamental sculptures were the two
slave statues that Michelangelo had designed for the tomb
of Pope Julius II, but which he left unfinished. Two members
of the Florentine Strozzi family had acquired them from
Michelangelo and gifted them to the French king, Henri II,
when requesting the protection of their cousin Catherine de
Médicis. Gifted in turn to Montmorency by Henri II shortly after he acceded to the throne in 1547, they were set in the recesses of the south wing’s courtyard portico. The originals,
now in the Louvre, have been replaced by casts. The columns
flanking them, inspired by the Pantheon in Rome, are the first
recorded example in France of the colossal order (spanning
two floors).
OF
FRANCE
which has since been removed to the Château de Chantilly.
The Château of Écouen comprised a gallery connecting the
apartments of Madeleine de Savoie to those of the King, running right the way along the west wing. The decoration of this
gallery was sumptuously colorful: stained glass windows told
the story of Psyche; under foot were ornamental tiled floors
from the workshops of Masséot Abaquesne (circa 15001564) in Rouen; while the walls would have been hung with
tapestries, not to mention the painted ceilings. The stained
glass and tiled floors are inscribed with the date “1542”. A
contemporary portrait of the château has come down to us
in Les Plus Excellents Bastiments de France (1576-1579), a
priceless work by the engraver-architect Jacques I Androuet du Cerceau (circa 1515-1585) that depicts all the most
daring architectural innovations of the French Renaissance.
His engravings give us an idea of what the east wing must
have looked like. It was demolished at the end of the Ancien
Régime for esthetic reasons, and also no doubt because it had
been heavily damaged. The wing is believed to have contained
a gallery with frescos by Nicolo dell’Abbate (died 1571) and a
multicolored tiled floor. Through the portico could be glimpsed
a life-sized statue of Montmorency on horseback. There was
also a tennis court built on sloping ground below the north
wing, close to the bathing suite. Further below were the stables, which now house municipal offices.
Moving between his home in Paris and his châteaux at Écouen,
Chantilly, and Fère-en-Tardenois (Aisne)—the latter a wedding
present from François I—Montmorency displayed the same
remarkable curiosity in each, along with a deep appreciation of works of art. His collection included paintings by the
Florentine master Rosso Fiorentino (1494-1540), sculptures
by Jean Goujon (circa 1510 - circa 1572), painted enamels by
Léonard Limosin (circa 1505 - circa 1577), illuminated manuscripts and other sumptuously bound books, and items of
the rare Saint-Porchaire pottery produced between the 1520s
and 1540s, which were too Mannerist, light, and fragile to be
of practical use.
Anne de Montmorency was also the first to discover the rustic potter, Bernard Palissy (circa 1510 - circa 1589), who found
inspiration in Saint-Porchaire ware. He commissioned Palissy
to create a make-believe ceramic grotto, perhaps for the gardens at Écouen, except that it appears that it was never completed. Partly as a result of his wide breadth of interest in art,
Montmorency was one of the principal patrons of the French
Renaissance. Not only could he spot young talent, but he
seems on occasion to have been instrumental in guiding their
choice of subject matter. Although a fervent Catholic, he displayed, like his Protestant rivals, a taste for the rarer Old Testament subjects. He had these painted on the château’s fireplaces by members of the family workshop, founded by Jean
Cousin the Elder (born in 1500). One example, the story of
Jacob and Esau, relates to his own story as a younger sibling on whom destiny had smiled. Similarly in the chapel he
commissioned a relief, Abraham’s Sacrifice, from Goujon,
Painted fireplace in Anne de Montmorency’s bedroom (oil, mid16th century, detail). © RMN/Gérard Blot.
347
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The château remained in the family’s hands until the line was
cut short in 1632 by the execution for lèse-majesté, treason,
of Montmorency’s grandson, Henri. It then passed to the
House of Joyeuse, ennobled by Henri III, and was subsequently inherited by the House of Condé. It underwent few
modifications apart from the demolition of the east wing. The
château escaped the Revolution relatively unscathed, although
it was put to various characteristically novel uses, such as a
patriots’ club, a prison, and finally a hospital. It embarked on
a new chapter, however, when Napoleon, in a decree dated
December 15, 1805, turned it into a school for educating the
daughters of members of the Legion of Honor. He returned
the Château to its original four-square design by building a
new, but lower, east wing, which was designed by AntoineFrançois Peyre (1739-1823).
The building opened for the 1807 academic year. Except for
the period between 1814 and 1850, when ownership reverted to the House of Condé and it became increasingly neglected, the château has remained the official property of the
Legion of Honor to this day. The marble courtyard, which was
no doubt in very poor condition, was repaved with the Legion’s arms at its center. Students were accommodated in
new mezzanines and shielded from unhealthy thoughts by
Detail of David and Bathsheba tapestry series, David’s adultery
(Brussels, circa 1520). © RMN Droits Réservés.
348
Stained
glass with
angel
holding
a shield
bearing
Constable
Anne de
Montmorency’s
arms. 16th
century.
© RMN/
Gérard Blot.
the whitewashing of the painted chimney-pieces and grottesche friezes, thereby mercifully preserving them for posterity, save for some damage to the fireplaces caused by the insertion of stove pipes into the flues. The last students left the
château in 1962.
The sharing of the Château’s fate between the Houses of
Montmorency and Condé accounts for the presence at the
Château de Chantilly of many artifacts and works of art from
Écouen. Prince Henri, Duke of Aumale (1822-1897), who inherited the lands and colossal wealth of the House of Condé
at the tender age of 8, may have lost possession of the Château d’Écouen, but he was driven by a passionate interest in
art and history. He amassed a superb collection in an attempt
to retrieve and recreate his ancestors’ heritage. The collection
included books bound with the arms of Anne de Montmorency, including Anne’s Book of Hours, but also, more strikingly,
the stained glass windows from the Psyche gallery, Goujon’s
bas-reliefs, wall tiling by Masséot Abaquesne, and the altar
and stained glass windows that had adorned the chapel at
Écouen. In fact, the chapel at Chantilly sought to reproduce
the dimensions and decorations of its counterpart at Écouen,
which has fortunately been preserved and retains its fine ogival vaults, painted with the coats of arms of Anne de Montmorency and his wife. Écouen was inaccessible to researchers
during the development of historical studies in French Renaissance architecture. As a result, its virtues were never extolled
in a full monograph or promoted as much as it deserved. The
first director of the museum, Alain Erlande-Brandenburg, produced a useful introductory work. The current director, Thierry
Crépin-Leblond, is working on a weightier presentation that
will assemble all the available documentation and give a clearer idea of the château’s interior design, which is still largely
unknown.
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The Château d’Écouen
as a showcase for national
collections
The French National Museum of
the Renaissance is a young
museum, a contemporary of
the Pompidou Center—both
opened to the public in
1977. The idea of devoting
the Château d’Écouen to
Renaissance civilization
was for André Malraux, De
Gaulle’s minister for cultural affairs, a solution to two
problems.
It found a use for the château,
which had stood silent since the
academy for young girls closed in
1962, and it was a place to display
the Renaissance collections from the
Museum of Cluny. The former Paris residence
of the abbots of Cluny had, since the 19th century,
housed the collection built up by the archeologist Alexandre
Du Sommerard (1779-1842), which comprised essentially
decorative art works ranging from Greco-Roman antiquity
to the end of the Middle Ages. After the Second World War,
when all the works put into safekeeping had to be put back
on display, it was decided to devote the Hôtel de Cluny exclusively to the Middle Ages. As a result, collections of works
from later periods remained in their crates for some 15 further
years, while the State looked for a suitable setting in which
to display them.
An initial proposal was the
Château de Chambord, but
Malraux rejected the idea as
he wanted to keep the material closer to Paris. Eventually,
in 1972, the State agreed to
an ultralong lease on Écouen
with the Legion of Honor, undertaking to upgrade the
building. As a result, the Ministry of Cultural Affairs became
its quasi-proprietor. Écouen
had the advantage of possessing the Gallery of Psyche,
which was ideally suited for
displaying a 75-meter masterpiece, the Tapestry of David
and Bathsheba (circa 15101515). After extensive conversion, a part of the Château
opened as a museum in 1977.
FRANCE
Dish with intertwined flowers. Iznik, Turkey,
circa 1580. © RMN/René-Gabriel Ojéda.
Subsequent work resulted in the
near-complete opening that we
have today, with 36 rooms
open to the public.
In addition to the tapestry
already mentioned, the collections reflect the variety
and complexity of Renaissance art, principally from
Europe, but also from further afield. Striking examples
include ivory carvings from
Portuguese Africa, a feather
mosaic triptych created by
Aztecs under the Spanish occupation, and, above all, a set of 400
Ottoman ceramic pieces, the most important 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, furniture, marquetry, manuscripts, and scientific instruments.
Only the graphic arts are truly underrepresented in the Museum’s collections. Bolstered by the many pieces acquired
since 1977, the collections total some 11 000 works, on top
of which there are some 14 000 fragments from Bernard Palissy’s ceramic workshop in the Tuileries that came to light
during the archeological excavations of the Louvre in the
1980s. With no real place for
them in the Louvre, they were
transferred to the Museum of
the Renaissance to be studied and displayed in a new
set of rooms.
Ornamental ceramic floor from the Château de Polisy (Champagne, 1545). © RMN/Stéphane Maréchalle/René-Gabriel Ojéda.
OF
The Écouen collections range
from the rarest of objects to
pieces representative of a
shared pan-European Renaissance taste. The rare objects are on a par with those
in the great museums in Europe (the Victoria and Albert
Museum and British Museum in London, the Dresden
museums, and the Kunst-historisches Museum in Vienna)
or the United States (the Metropolitan Museum of Art in
349
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Charles V’s mechanical galleon. Table ornament constructed by Hans Schlottheim, Augsburg, circa 1580. © RMN/Gérard Blot.
350
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New York, Walters Art Museum in Baltimore,
or the Philadelphia Museum of Art). One
such object is the famed silver-gilt
mechanical galleon made for Holy
Roman Emperor Charles V (Nef de
Charles Quint), an intricate clock
cum automaton built by Hans
Schlottheim (1545-1625), a
German goldsmith and clockmaker, of which there are only
three extant models in the
world, the two others being at
the British Museum in London
and the Kunst-historisches
Museum in Vienna. There is of
course a clock—though quite
small, which a keen eye will discover at the base of the middle mast,
with bells ringing the hours in the crow’s
nests. But this was a mere excuse for the
mechanical marvels displayed by the ship:
set on a dinner table, with princely guests agog, it
would roll on wheels, playing mechanical music and firing its
cannon, amidst flares and smoke, the sailors on board moving and revolving to the beating of a drum and the blowing
of trumpets.
The fact that the Écouen collection complements other major French collections so well (those in the Departments of
Painting, Sculpture, and Objets d’art in the Louvre, the Château de Fontainebleau Museum, the National Ceramics Museum in Sèvres, the Army Museum, the Arts et Métiers Museum, etc) probably explains Écouen’s inclusion in the network
of French national museums.
Pair of spectacles and pear-shaped leather case. France, 17th
century. © RMN/Stéphane Maréchalle.
OF
FRANCE
The Judgment of Paris: reverse side of a painted enamel dish by Léonard Limosin (1562,
Limoges, France). © RMN/René-Gabriel Ojéda.
In recent years, several major acquisitions have added to this core
of masterpieces. In particular,
two tapestries from the Tapestry of the Story of Diana produced for Diane de Poitiers
around 1550, in a remarkable
state of preservation that sets
off their sharp colors to good
effect. The second tapestry in
the set represents the birth of
Apollo—the nymph Latona gives
birth to the god between a palm
tree and olive tree with help from his
elder twin Diana, a midwife already although just born!
Another notable acquisition was the ornamental
flooring from the Château de Polisy in Champagne. This is a
skillful combination: a ceiling design published by the Italian
Mannerist Sebastiano Serlio
(1475- circa 1554) with alternating crosses, octagons, and
diamonds, each bordered by
different foliage, allegories of
virtues engraved by a pupil of
Albrecht Dürer, Georg Pencz
(circa 1500-1550), and ancient
and modern battle trophies,
each encircled by strapwork
design, broken by an ornamental fleuron at each corner. Designed for one of the bishops of
Auxerre, François de Dinteville,
brother of the ambassador immortalized by Holbein a few years
later (National Gallery, London.
1533), the tiled floor suggests
that attaining virtue is a slow process, even a struggle: “VIRTVTI
FORTVNA COMES”—“Good
fortune attendant on virtue,” runs
the motto. This moralistic work
was acquired in 2008 as a national treasure, thanks to a contribution from the AXA insurance group.
Embroidered silk sheath
with peacock.
Venice, late 16th century.
© RMN/René-Gabriel Ojéda.
351
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FRANCE
Marriage chest (cassone) depicting the story of Tiberius
Gracchus and Cornelia (circa 1470). Attributed to Giovanni di
Ser Giovanni (1406-1486), Masaccio’s younger brother, known as
Lo Scheggia (“the Splinter”). © RMN/Gérard Blot.
We need to don a pair of spectacles if we’re to do justice to
the quality of smaller works, such as a superb enameled dish
by Léonard Limosin, bearing a discreet signature, “LL”, and the
date “1562” on the back; the obverse reproduces Raphael’s
Judgment of Paris. Decorated with a female upper body in
profile serenaded by trumpeting putti, there is almost as
much work on this side as on the other—a frequent characteristic of the Renaissance decorative arts, particularly in
France. Smaller still is a sheath that typifies the extreme refinement of Renaissance textile work, often difficult to appreciate today as most such pieces are worn or destroyed.
Far from being anecdotal, the detail inscribed on everyday
objects reflects a mentality preoccupied with the grandest of
principles. A marriage chest from the 1470s brings together
the moral lesson in Plutarch’s tale of Tiberius Gracchus—who
sacrificed himself in order to save his much younger wife
Cornelia—and the fashionable dress of the contemporary
Florentine elite set against the backdrop of Santa Maria
Novella 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 often
staged an ongoing dialogue of opposites, between internal
and external, sacred and profane, large and small, natural and
artificial, typically recounted with wisdom and humor. Similarly, the essence of Écouen invites us to cross the multiple
bridges leading to the tastes and skills of an era of cultural
upheaval that remains our close and still recognizable forebear. I
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 National de la Renaissance; 1995.
ÉCOUEN :
– Crépin-Leblond L, ed. Album du Musée d’Écouen, Musée National de la Renaissance. Paris, France: Réunion des Musées Nationaux, Musée National de la Renaissance; 2010.
– Erlande-Brandenburg A. The Château of Ecouen: The National Museum of the
Renaissance. Paris, France: Réunion des Musées Nationaux & Albin Michel;
1988.
– Ferranti F. Le château d’Écouen sous l'œil du photographe. Paris, France: Réunion des Musées Nationaux, Musée National de la Renaissance; 2010.
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 personnages les plus importants du royaume de France au XVI e siècle, Anne de Montmorency. Transformé en musée
par la volonté d’André Malraux, il a ouvert ses portes au public en 1977. Il accueille depuis lors les prestigieuses collections Renaissance du musée de Cluny qui, loin de se limiter à l’art français, offrent un panorama extrêmement varié de la création en Europe et dans les zones où les Européens avaient noué des contacts réguliers, au ProcheOrient, en Afrique et en Amérique, du temps des Grandes découvertes jusqu’au début du XVII e siècle. Tapisseries,
peintures, céramiques, vitraux, mobilier, orfèvrerie… à travers une infinité de matières et de couleurs, c’est la même
culture qui s’exprime, une culture du beau, célébrant la nature autant que les créations de l’esprit. Le décor du château donne le ton de ce que l’on peut découvrir à l’intérieur : symétrie, formes géométriques, complétés d’un sens
aigu de l’ornement. En abordant les collections sous l’angle du détail, on se rend compte des défis que se sont lancés artistes et artisans, pour rivaliser entre eux et avec la nature. La qualité du dessin, la clarté de la composition deviennent bientôt aussi cruciaux pour distinguer les excellents peintres, sculpteurs et architectes, que les orfèvres,
brodeurs ou émailleurs.
352
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Ettawfik la Colline
20190 Casablanca
Tel: (212) 522 97 48 49
Italy
Mr O. VILAGINES
Servier Italia SpA
Via Luca Passi, 85 - 00166 Roma
Tel: (39-06) 669 081
Netherlands
Mr F. DEBAILLON-VESQUE
Servier Nederland Farma BV
Einsteinweg 5B
2333 CC Leiden
Tel: (31-71) 5246700
Japan
Mr E. DELARGE
Nihon Servier Company Ltd
Hongo MK Building 5F
1-28-34, Hongo
Bunkyo-Ku
113-0033 Tokyo
Tel: (81-3) 5842 7111
Pakistan
Dr R. MAJEED
Servier Research &
Pharmaceuticals, (Pakistan)
PVT Ltd, 65 Main Boulevard
Gulberg - Lahore
Tel: (92-42) 5879500

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