Servier – Phlebolymphology

CONSENSUS COMMITTEE N°2

“EFFECTS OF VENOACTIVE AGENTS ON THE SYMPTOMS
OF CHRONIC VENOUS DISEASE”

Edema associated with chronic venous disease is a commonly mentioned clinical sign. Venoactive agents are the most usual “short cut” because of better compliance than with elastic compression. The aim of this meeting was to define the usefulness of this class of agents in management of edema and the methods for assessing their efficacy in chronic venous disease (CVD).

INTRODUCTION

Chronic venous disease (CVD) is a common disorder, and its prevalence in the general adult population is approximately 10%. In this setting, nearly 100 000 patients, ie, 0.1% to 0.2% of the population of France, suffer from venous ulcers. Consequently, venous insufficiency has an appreciable socioeconomic impact.
Unfortunately, in terms of understanding the underlying microcirculatory mechanism, treatment of CVD has not made any significant progress in about a hundred years. The majority of recommendations (in particular venous compression therapy and raising the legs) given to patients with CVD are based on principles from the last century. However, in an appreciable number of such patients, compression therapy alone often is inadequate and unacceptable in the long run.
The place of edema in the natural course of CVD has not been clearly elucidated. Unlike symptoms of CVD, edema is an objective, measurable parameter.
Members of the Committee wish to remind the reader that no study submitted to the French Medicines Agency (AFSSAPS) has been chosen as demonstrating the efficacy of venoactive agents in treatment of edema, in the setting of CVD.
Thus, the Committee met to define, in a first phase, the role of edema as well as the pathophysiological circumstances of its occurrence in the setting of CVD. An update on the latest pathophysiologic findings that promote the etiopathogenesis of edema then was made, since the participants in this meeting feel that it is important to understand what the targets of the proposed therapies are. Then, the Committee discussed the methods of measurement of edema, validated in the literature. Lastly, in light of the data from the literature on the efficacy of venoactive agents on edema, the Committee proposed conducting a study and discussed the primary methodological objectives.

DEFINITION OF EDEMA

Edema is defined as the existence of excess interstitial fluid in the tissues. However, extension of edema is limited by the skin’s elastic properties, starting with a certain degree.
Clinical findings differentiate two types of edema:
– pitting edema, defined as a “palpable indentation of the skin following firm pressure applied for ten seconds by the thumb”¹
– non-pitting edema.
If edema persists for several days, months, or even years, the extracellular matrix becomes altered, preventing healing of the edema. Thus, a considerable number of patients for whom venoactive therapy is offered already present chronic edema with an altered extracellular matrix as a result of lesions induced by the edema.
The sensation of edema is defined as an impression of tautness without the clinical existence of edema. This impression should be considered as a symptom, and not as a clinical sign.

PATHOPHYSIOLOGY

Causes of edema:

• Positive pressure in the interstitial fluid
Guyton demonstrated that pressure in the interstitial space is negative compared with atmospheric pressure in normal subjects. If a moderate amount of fluid is transferred from the intravascular compartment to the interstitial compartment with no change in pressure regimens, clinically detectable edema does not exist. On the contrary, a change to positive pressure in the interstitial medium (greater than atmospheric pressure) is responsible for clinically and physically detectable edema. Animal models have demonstrated that edema is clinically detectable, starting with a 30% increase in the volume of the extracellular medium, compared with normal.

• Absence of protective factors against edema
Traditionally, the factors, which protect against edema are grouped under three mechanisms which produce dynamic interaction: negative tissue pressure, lymphatic drainage, and constant renewal of tissue proteins. In fact, patients who consult for treatment of edema present with greater or lesser alteration of these different factors.

Specific causes of edema:
• An increase in capillary pressure, either by increased pressure or venous obstruction, or by vasodilatation of arterioles. Such abnormal conditions are found in particular in heart failure patients or in those with serious varicose veins;
•A decrease in plasma protein concentrations (eg, in severe burn patients, nephrotic syndrome, exudative enteropathy, deficiency syndrome). Interestingly, deficiency syndromes commonly occur in the elderly;
• Lymphatic obstruction caused by filaria, or lymphatic agenesis. Edema can also occur in the aftermath of cancer surgery with lymph node dissection or after a stripping procedure of the greater saphenous vein, and to a letter extent in functional lymphatic insufficiency (decreased lymphatic drainage capacity);
• Increased capillary permeability is found in venous insufficiency, in severe burn patients, or in case of an allergic reaction.

Importance of the extracellular matrix and of endothelial cells

The interstitial fluid is embedded in the extracellular matrix comprised of peptidoglycans (formerly known as mucopolysaccharides). When excess fluid accumulates in the interstitial fluid, the matrix attracts this fluid. When the matrix has increased by 30% to 50% in volume, the proteoglycans become altered, thus releasing free spaces in the interstitial tissue. As these channels open, they increasingly release space promoting the entry of fluid arising from blood vessels. Thus, edema becomes clinically detectable. The importance of the extracellular matrix in the balance between intra- and extracellular compartments and in trapping water remains to be determined.
In addition, the extracellular matrix plays a part in the nutrition of endothelial cells. At the same time, alterations in the matrix and interstitial nerves produced by chronic edema also are poorly understood.
Some authors have suggested that, in chronic venous disease, adhesion of inflammatory cells to the vascular endothelium may produce activation of the latter, with release of proteolytic enzymes and free radicals in the tissues. Endothelial cells can represent the key item in the etiopathgenesis of edema, and thus become a potential target for future venoactive agents.

MEASUREMENT OF EDEMA AND LEG VOLUME

Volumetric measurement

A previous consensus meeting considered this technique as the reference method in demonstrating and comparing the efficacy of treatments of edema in CVD.¹ This method makes it possible to demonstrate changes in leg volume under different conditions and at different times before and after treatment. Therefore, it is a method that is both reproducible in terms of its results and over time (good outcome).
One of the techniques consists of immersing the leg in a water-filled Plexiglas boot. The volume of water displaced is collected and measured.^2,3 Other methods have been described but they do not allow measurements under physiological conditions such as orthostatism.^4-7 However, in the setting of volumetric measurements, a certain number of parameters such as leg position, time of measurement, phase of menstrual cycle, room temperature, as well as that of the water used should be standardized to validate the results.
Variability of the method in two consecutive measurements, on the same leg, by two different observers was 0.7%. Intraindividual variability was 1.3%. Interindividual variability was 6.2% in normal control patients and 11.2% in patients with venous disease.³
Volumetric measurement was used to show that the most painful legs are those which have the greatest tendency to swell up.⁸ In addition, volumetric technique has shown that erect posture is responsible for an increase in leg volume, and this is correlated with the degree of venous insufficiency. Similarly, legs swell during long-haul air travel⁹ and can decrease in size after venous surgery or after different pharmacological therapies of venous or lymphatic insufficiency are initiated. Advances in study methods have made it possible to show how changes in leg volume are correlated with severity and prognosis of chronic venous disease.

Other methods of evaluation of edema

The Group validated the following methods:
– measurement of leg circumference;^10-13
– electro-optical volumetric method;^4,5,7,8,14
– digitised measurement of leg volume.^3,5
Other methods have been described in the literature: tomographic method,⁵ high-resolution magnetic resonance imaging⁵, and X-ray absorptiometry.⁵

ANALYSIS OF STUDIES TESTING VENOACTIVE AGENTS IN LEG EDEMA

Many studies can be found in the literature demonstrating the efficacy of different classes of venoactive agents on edema in CVD. The efficacy of several agents has been demonstrated on symptoms and edema by volumetric methods,^12-19 and on concomitant pathophysiological factors in patients presenting with CVD.^20-24 Thus, the factors promoting edema on which the action of therapies has been demonstrated are as follows:
Venous hypertension and venous tone,^16,25-31 increased capillary permeability,^32-37 and lymphatic drainage.^13,24,38 Why does enhanced lymphatic flow promote edema?
It is essential to demonstrate that, although venoactive agents decrease edema, it is through their action on pathophysiological factors of edema (such as venous hypertension).
Different factors that promote edema can be measured more or less routinely:
– venous hypertension;
– capillary permeability (by the radiolabelled albumin method);
– lymph flow (by isotopic lymphography).
On the contrary, other factors (for example, macrophage activity, sequestering of water, change in the gel/sol phase) cannot be measured.
Several studies have also demonstrated that after 1 or 2 months’ treatment with venoactive agents versus placebo, patients with CVD had an increase in venous tone assessed by plethysmography, and showed regression of clinical signs of edema as well as associated symptoms.^{12,20,23,39-41}
The Doppler laser method has also been used in some studies to demonstrate the effects of venoactive agents on the microcirulation, in particular on vascular motricity and arteriovenous reflex.⁴²

Effects of venoactive therapies
A certain number of randomized, controlled studies can be found in the literature showing the efficacy of venoactive agents on edema.^{6,9,12,15,17,18,37,39-45} However, efficacy criteria on regression of edema, most often assessed by leg circumference in such studies, in addition is not always very representative. Indeed, the problem of these studies is that efficacy is set at a level ranging from 4-mm reduction in circumference to a 40 mL volume. Certainly, this involves a decrease in edema, but a very small one. For example, in a calf with a circumference of 37.08 cm, a 2-mm reduction in thickness produces a 12.4-mm reduction in circumference (2 ð r). More than the reduction in edema, it is possible to speak of a “reduction in the sensation of swelling.” These two criteria are not clinically relevant, Therefore, venoactive agents decrease edema, but in a clinically minimally significant manner.
And yet, it is necessary to have studies which show a clinically significant reduction in edema with venoactive treatment. Furthermore, it is important to show how venoactive agents decrease edema, in particular which pathophysiological factors they act on. Indeed, the action of such therapies on venous tone, venous hypertension, increased capillary permeability, and lymphatic drainage can be demonstrated by the previously mentioned methods of investigation.
The conclusion that can be drawn from these results is that it is necessary to carry out a well-conducted study based on scientific principles and approved by an Ethics Committee.
Such a study should be randomized, controlled, versus a placebo group, with double-blind method, and sufficient power to answer the question raised at the stage of disease studied. Inclusion criteria for patients should be clearly defined. A classification system for patients such as the CEAP system (the Committee estimates that, in spite of its shortcomings, it is the best rating scale for CVD), should be used to assign patients to groups with increasing severity, to better define the indications.
Symptoms, signs of the disease and quality of life (rating scale) should be evaluated at the start, in the aftermath and at the end of the study. The hemodynamic evaluation will be assessed by noninvasive methods of investigation, preferably chosen for their ability to best answer the question asked. Efficacy of treatment on edema will be evaluated by a standardized volumetric method (control of room temperature, constant time of day, etc).
Although many venoactive agents have demonstrated their activity on edema, its sole existence is not a therapeutic indication. The main indication for such agents continues to be the symptoms of CVD. Therefore, it is necessary to use composite criteria in which edema and the sensation of swelling will be present and separate.

OBJECTIVES OF FUTURE STUDIES ON USE OF VENOACTIVE AGENTS IN EDEMA OF CVD

Background on the compound

Obviously, it is essential to provide an update on the in vitro efficacy of the compound tested, as well as to collect experimental and pharmacological data, (effective concentrations), clinical findings (indications chosen, results of previous studies, etc).

evel of evidence

a) The objectives of this randomized, double-blind, controlled trial (versus a placebo group and versus another “venous compression” group) must show clinically relevant real efficacy, in the reduction of edema. However, it is up to members of the Committee to determine the level of clinically relevant reduction. Indeed, the Committee was unable to reach a decision on this point, which is essential to validate the results of the study.
b) Furthermore, to give weight to the conclusions, demonstration of the evidence of efficacy of venoactive agents can be based on a dose-effect relationship which to date has never been demonstrated in the literature.
c) Lastly, it is essential to insist on showing that a pathophysiological explanation exists for the effect of the therapies initiated.

Study objectives should be chosen carefully

– Reduction of edema will be assessed clinically and measured in a standardized instrumental manner, as previously reviewed;
– Concomitant symptoms, symptom severity score (CEAP), as well as quality of life scale will also be evaluated;
– Lastly, it will be necessary to define a composite criterion in this study, which will represent an item of weight to demonstrate the efficacy of the therapy. For example, this criterion can be a 50% decrease in edema, as well as a 50% reduction in concomitant pain or heaviness.

Therefore, before conducting such a study, the Committee must resolve several items, which remain to be discussed:
– defining the studied populations as well as study inclusion criteria (usefulness of CEAP);
– what level of reduction in edema (%) represents a significantly relevant reduction?
– to what extent is this decrease in edema (%) correlated with a decrease in symptoms?
– which composite criterion has to be defined to demonstrate efficacy of the treatment?
M. Perrin commented that it was unfortunate that, in the end, members of the Committee did not select a method for measurement of edema, for example, leg circumference or volumetric method.

CONCLUSION

Venoactive agents have demonstrated their efficacy in the reduction of symptoms of edema in the setting of chronic venous disease. However, it should be noted that for the majority of patients treated, edema – unlike symptoms – is the not the primary indication for treatment. Thus, edema is not an indication for treatment with venoactive agents in the absence of symptoms of venous disease.
Therefore, the Committee has proposed conducting a study to demonstrate the efficacy of venoactive agents in patients with isolated edema in the setting of CVD. The different methodological aspects of this study have been discussed and determined by the Committee. However, a few points remain to be set such as the percentage reduction of significantly relevant edema or the composite criteria to be determined.

REFERENCES