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Chronic venous disease (CVD) is the most prevalent vascular disorder in developed countries^1,2 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

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.

_ 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 al⁴ made an important contribution to the field when they proposed a standard international nomenclature for the veins of the low-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 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 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 wemove forward. I recommend this issue of Medicographia to each of you and I am sure you will find it as valuable as I have. _

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;40:1248- 1252.
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 syndrome. 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 lifemeasure 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.
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

L’ insuffisance veineuse chronique (IVC) est l’affection vasculaire la plus fréquente dans les pays développés^1,2, 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 pathologiques³. 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.

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. _

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Chronic 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.

Because 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.

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- 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.

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

Terminology, classifications, and severity scoring of CVD

A great leap forward, a consensus on the use of common venous anatomical terminology^1-3 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 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

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.

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 andmanagement 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- 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

_ 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 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 another²⁰; 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 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.

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

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:

_ 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.

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.

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

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.

_ 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 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

Invasive therapy

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,” 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

Table I. Advantages of GRADE over other systems.

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 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- 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 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. _

References
1. Caggiati A, Bergan JJ, Gloviczki P, et al. Nomenclature of the veins of the lower limbs: an international interdisciplinary consensus statement. J Vasc Surg. 2002;36:416-422.
2. Caggiati A, Bergan JJ, Gloviczki P, et al. Nomenclature of the veins of the lower limbs: extensions, refinements, and clinical application. J Vasc Surg. 2005; 41:719-724.
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. J Vasc Surg. 2003;37:129-131.
4. Cavezzi A, Labropoulos N, Partsch H, et al. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs–UIP Consensus Document. Part II. Anatomy. Eur J Vasc Endovasc Surg. 2006;31:288-299.
5. Porter JM, Moneta GL; International Consensus Committee on Chronic Venous Disease. Reporting standards on venous disease: an update. J Vasc Surg. 1995; 21:635-645.
6. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248- 1252.
7. Rutherford RB, Padberg FT Jr, Comerota AJ, et al. Venous severity scoring: An adjunct to venous outcome assessment. J Vasc Surg. 2000;31:1307-1312.
8. Comerota AJ. Treatment of chronic venous disease of the lower extremities: what’s new in guidelines? Phlebolymphology. 2009;16:313-320.
9. Eklof B, Perrin M, Delis KT, et al. Updated terminology of chronic venous disorders: the Vein Term Transatlantic Interdisciplinary Consensus Document. J Vasc Surg. 2009;49:498-501.
10. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidencebased report of the VEINES task force. Venous Insufficiency Epidemiologic and 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, CriquiMH, Denenberg JO, et al. Quality of life in patients with chronic venous disease:SanDiegopopulation 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.
28. 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.
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;30:709- 717.
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.

Keywords: guidelines; chronic venous disease; update

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Bo EKLÖF,MD, PhD University of Lund Lund, SWEDEN

Michel R. PERRIN,MD Chassieu, FRANCE

One 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.

Hidden 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).

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.

Once presented with the ability tomake accurate diagnoses of the causes andmechanisms 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.

Figure 1. The Tower of Babel by Pieter Bruegel the Elder (1563).

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:
_ Primary, secondary, and congenital causes of the problem;
_ Reflux from obstructive pathophysiology;
_ And identifies the precise anatomical segments 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 bedocumented.

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.

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 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 contributed 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

Figure 2. Atrophie blanche (C4b).

Figure 3.Corona phlebectatica.

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

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:

_ 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).

_ 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).

_ 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, butmay reflect sensitization to local therapy.

_ 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).

_ 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).

Figure 4. Edema (C3).

Figure 5. Lipodermatosclerosis (+ atrophie
blanche) (C4b).

Figure 6. Pigmentation (C4a).

Figure 7. Telangiectasias (C1).

_ 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).

_ Reticular vein
Dilated bluish subdermal vein, usually 1mmto less than 3mm in diameter. Usually tortuous. Excludes normal visible veins in persons with thin, transparent skin. Synonyms include blue veins, subdermal varices, and venulectasias.

_ Telangiectasia
Confluence of dilated intradermal venules less than 1 mm in caliber. Synonyms include spider veins, hyphen webs, and thread veins (Figure 7).

_ 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).

_ 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).

Figure 8. Varicose veins (C2).

Figure 9. Active venous ulcer (C6).

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

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

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

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 andmanagement 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 under 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 _

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.
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;40:1248- 1252.
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: Butterworth- Heinemann; 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.
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. Vasc Surg. 2004;39:1048- 1052.

Keywords: chronic venous disease; definition; terminology

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The 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 ismore 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.

Chronic 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.

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, 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).

Table I. Pitfalls in performing prevalence studies and their effects
on the results.

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 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 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.

Table II. Prevalence of varicose veins (%) by sex in studies from
different countries.

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 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 increaseswith increasing age.^{7-9,11,13,17-20} Themagnitude 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 fromthese 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 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

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

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 person 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

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.

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), 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

Conclusion

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 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.

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. _

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

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Chronic 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.

Primary and secondary venous disease

Chronic 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

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 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 proposed 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.

Figure 1. Examples of reflux with ultrasound imaging from a female patient who presented with varicose veins and swelling in the right lower extremity.

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 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

Figure 2. Chronic obstruction with partial recanalization and reflux in a 58-year-old female patient with previous caval, iliofemoral, and popliteal vein thrombosis.

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 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.

_ Medication (venoactive drugs)
Many different categories ofmedication 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.

_ 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 prospective, 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

_ 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: 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

The drawback of the technique is the possible inadvertent passage of sclerosing agent into the deep veins, which is not completely prevented either with ligation or compression of the saphenofemoral junction (SFJ) with the ultrasound probe during the intervention.⁴⁰ Fortunately, complications of sclerotherapy are rare because they can be serious⁴¹: lung and brain emboli have been reported.^41,42 Long-term results from large multicenter, randomized controlled trials are still warranted to assess the durability of treatment and to define potential predictive factors to prevent adverse outcomes.

_ 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, ligation of the SFJ or saphenopopliteal junction (SPJ) with or without stripping of the GSV or SSV, has been replaced by radiofrequency ablation (RFA) or endovenous laser therapy (EVLT). The stripping of the GSV consisted of dissection and isolation of the SFJ and the distal segment of the GSV or SSV at the end point of reflux with insertion of a metallic or plastic wire through the isolated segment with subsequent stripping of the vein. The disadvantages of the technique included the risk of wound infection, postoperative pain, longer recovery time, and a significant inflammatory response in the SFJ or SPJ leading to neovascularization and the recurrence of the varicose veins.⁴³ Modifications to the traditional stripping with invagination technique and the use of tumescence have reduced complications of this technique and have made it an outpatient procedure.⁴⁴

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.

Figure 3. Nonsaphenous vein reflux.

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

Endovenous interventions have some advantages over vein stripping as an ambulatory-based intervention with same-day discharge. These include the feasibility of performing the intervention under local anesthesia with light sedation and a faster return to work. Modified stripping techniques with ultrasound guidance and local perivenous anesthesia without ligation of the junction and its triburies may have similar results.^44-47 Several trials have reported similar efficacies with GSV and SSV ablation and the resolution of symptoms using either EVLT or RFA.^48-50 Complications of endovenous ablation include skin burns and the propagation of the thrombus into the deep veins causing DVT and pulmonary embolism. Venous thromboembolic events have also been reported with ligation and stripping.⁵¹ Recent studies have demonstrated that thermal ablation procedures and surgical techniques have similar outcomes in abolishing reflux and improving quality of life.⁵²

Figure 4. Reflux in the lower thigh great saphenous vein and a knee tributary.

Two other innovative alternatives to vein ablation are the Clari- Vein™(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 froma 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 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.

_ 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 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

Figure 5. Pathology in tributaries in a patient with a normal great saphenous vein.

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 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 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. _

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Keywords: chronic venous disease; treatment; pathophysiology

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Mehmet KURTOGLU,MD

Murat AKSOY,PhD Peripheral Vascular Surgery Unit Department of General Surgery Istanbul Medical Faculty Istanbul University, Istanbul – TURKEY

Chronic 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, themodified 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.

Recently, 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.

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- 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.

hat current instruments can assess the efficacy of CVD treatment?

Since allmethods of CVDmanagement claimto 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 [Clinical- Etiological-Anatomical-Pathophysiological] and VSS [Venous Severity Score]), and functional (quality of life).

_ 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 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 amarker for indication, but may help in deciding the type of intervention required, such as sclerotherapy, laser, or radiofrequency ablation.

_ 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.

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:

_ 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.

_ 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.

_ 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.

_ 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.

_ 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 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.

_ 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 beenwidely 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.

_ 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 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.

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 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.

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 recurrence 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

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. _

References
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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. Duni ´ c I, Medenica L, Bobi ´ c B, Djurkovi ´ c-Djakovi ´ c 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.
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Keywords: chronic venous disease; guidelines; scoring systems; classifications

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Chronic 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.

Today, 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

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 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.

_ 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

_ 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 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 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

Table I. The seven major types of PROs and examples of each
type.

_ 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

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 being 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, person-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.

Table II. PRO selection criteria and questions to ask when choosing a PRO. Based on reference 7.

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

_ 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

_ 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

_ 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

_ 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. Amongthem, 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.

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 Thismarked 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. _

References
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Keywords: patient-reported outcomes; PROs; CIVIQ; quality of life; chronic venous disease; disease-specific
questionnaires

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The Grades of Recommendation Assessment, Development and Evaluation (GRADE) system was developed in 2004 as an attempt to provide systematic and explicitmethods of building guidelines for clinicians. The systemwas 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.

Treatment 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.

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- 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) Evidence- Based 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.

Table I. Criteria for an optimal grading system, according to the
ACCP Task Force.

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.

_ 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.

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.

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.

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.

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.

_ 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 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.

Strength of a recommendation in the GRADE system

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 by²:

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

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).

Table II. ACCP grades for recommendations.

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.

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 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

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- 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 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.

_

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Primary 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.

Primary 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

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- 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.

Table I. Clinical descriptions of the revised CEAP classification.

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

_ Main categories of VADs
_ Benzopyrones
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).
_ Saponins
This category includes horse chestnut seed extract (HCSE) and Ruscus extracts.
_ 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.
_ Synthetic drugs
The principal synthetic drugs are calcium dobesilate, naftazone, and benzarone.

_ 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 An- 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

Table II. Classification of the main venoactive drugs.

_ 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.

_ 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, 0.74- 0.95), 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

_ 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

Table III. Grades of recommendation of the International Consensus
Statement. Based on data from reference 11.

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.

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).

_ 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 reviews^20,21 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

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 stockings^11,16 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, andthe 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

Table IV. Summary of VAD effects on symptoms, edema, and skin changes by category of drugs.

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.

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%ofMPFF 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 ≥5 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.

_ 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 C0_{s to C6}s patients 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

Table V. Summary of tentative recommendations, according to Perrin and Ramelet.

Future challenges^17,19

_ 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:
_ 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.
_ 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
_ Promote the use of validated tools to assess symptoms,²⁹ edema,³⁰ and venous leg ulcer.³¹
_ Reach a consensus on the standard use of dressings, compression therapy, and local antiseptics in venous leg ulcer. In addition, there is a need for consensus on the following end points:
_ Symptoms: how great does the decrease on the visual analogue scale have to be in order to consider there is clinical improvement?
_ Edema: how great does the reduction in ankle volume have to be in order to consider it as clinically relevant?
_ Varicose veins: which criteria should be used to consider whether a drug treatment for varicose veins works?
_ Venous leg ulceration: when should we consider the ulcer to be healed?
_ 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 _

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 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: Edinburgh Vein Study. J Epidemiol Community Health. 1999;53:149-153.
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.
9. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidencebased report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies. Int Angiol. 1999;18:83-102.
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.
11. 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.
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.
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. MartinezMJ, 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 assessment tools: application to vein practice. Phlebology. 2008;23:259-275.
30. Perrin M, Guex JJ. Edema and leg volume: methods of assessment. Angiology. 2000;51:9-12.
31. Humbert P, Meaune S, Gharbi T. Wound healing assessment. Phlebolymphology. 2004;47:312-319.
32. 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.
33. Jones GT, Grant MW, Thomson IA, Hill BG, Van Rij A. Characterization of a porcinemodel of chronic superficial varicose veins. J Vasc Surg. 2009;49:1554-1561.

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

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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. S. M. Kulisi´c Croatia
7. A. Puskás, Romania
8. K. Roztocil, Czech Republic
9. M. Salah, Saudi Arabia
10. J. Thakore, Mexico
11. J.-F. Uhl, France
12. I. A. Zolotukhin, Russia

Khaled Abdel AAL, MD
Chairman of the Department of Vascular and Endovascular Surgery
National Institute of Diabetes
Cairo, EGYPT

Before 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.

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._

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

If 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.

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_
References
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.

Ricardo COSTA-VAL, MD, PhD
Vice-Scientific Director
Brazilian Society of Angiology
and Vascular Surgery
São Paolo, BRAZIL

The 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).

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 BrazilianMedical 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._
References
1. 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.
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.

Hendro Sudjono YUWONO, MD, PhD
Hasan Sadikin General Hospital
Jalan Pasteur 38, Bandung 40161
INDONESIA

Phlebology 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.

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._
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.

Hiep Nu Thi Hoa LE, MD, PhD
Professor, Vascular Surgery Department
Medical University Hospital of
Ho Chi Minh City, Ho Chi Minh
VIETNAM

The 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.

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._

Sandra Marinovic KULISI´C, MD, PhD
Phlebology Unit, Department of
Dermatology and Venereology
University Hospital Centre Zagreb
and School of Medicine
Zagreb, CROATIA

Chronic 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?”.

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._

Attila Puskás, MD, PhD
Associate Professor, IInd Medical
Clinic, Department of Thrombosis
and Angiology, University Hospital
Tirgu Mures/Marosvásárhely
ROMANIA

Chronic 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.

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._
References
1. 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.
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.

Karel ROZTOCIL, MD, PhD
Institute for Clinical and
Experimental Medicine
Prague, CZECH REPUBLIC

Clinical 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

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._

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.
5. 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.
6. Ramelet AA, BoisseauMR, Allegra C, et al. Veno-active drugs in themanagement of chronic venous disease. An international consensus statement: Current medical position, prospective views and final resolution. Clin Hemorheol Microcirc. 2005;33:309-319.

Mahmoud SALAH, MBBCh, MSc,
MD, FRCSI, FICS, FACS
Consultant & Head of the Department
of Vascular Surgery, Saudi German
Hospitals Group, Jeddah
SAUDI ARABIA

Clinical 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.

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.”_

References
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.

Ignacio S. ESCOTTO, MD
Assistant Professor of Angiology
Vascular and Endovascular Surgery
National Medical Center of Mexico ISSSTE
Universidad Nacional Autónoma
de México, MEXICO

Guidelines for chronic venous disease (CVD) need to be considered first in terms of their strengths and then in terms of their weaknesses. Strengths

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._
References
1. 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.
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. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40:1248- 1252.
4. Vasquez MA, Munschauer CE. Venous clinical severity score and quality-of-life assessment tools: application to vein practice. Phlebology. 2008;23:259-275.
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.

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

Chronic 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 Clinical- Etiological-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.

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._

Igor ZOLOTUKHIN, MD, PhD
Russian State Medical University
1, Ostrovitjanova str
117997 Moscow, RUSSIA

The 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.

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._

References
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