CONTENTS  •  Volume 11  Number 1 1996

I have discussed the efficacy of phlebotonic drugs on a number of previous occasions. These are widely prescribed in France, Germany and much of southern Europe, but are little used in the UK and Scandinavia. This issue of Phlebology contains a series of articles prepared by eminent authors who met in Frankfurt am Main on January 1995. They have reviewed the published data available on these drugs. Many readers will he familiar with the myriad of studies that show symptomatic improvement in response to phlebotonics. More recently, a number of double-blind clinical trials have been published which confirm the efficacy of phlebotonic drugs on the symptoms of venous disease. Objective data concerning the influence of these drugs on aspects of physiology of the venous system and the microcirculation are harder to come by. In this issue. Professor Diehm considers the available evidence showing the effects of diosmin, hydroxy-rutosides, and horse-chestnut extract (aescin) on physiologically relevant processes. Professor Markwardt presents a review of the pharmacology of this group of drugs. Readers are invited to assess the conclusions reached by these authors and write to the editor with any comments they may have.

The authors also present their conclusions from a consensus debate on the role of phlebotonic drugs. They consider that recent studies show that there is objective evidence that oedema can be reduced by these drugs. The mechanism by which this is achieved has not been elucidated, but may be a consequence of the way in which phlebotonic drugs bind to the vascular endothelium. However, although oedema is often present in the lower limbs of patients with venous disease it is not necessarily the most important symptom to moderate. Professor Charles Michel has recorded his reservations about the role of oedema in the development of venous ulceration. It would be more useful for varicose veins to be diminished or venous ulcers healed. There is no evidence that the former can be achieved, although one recent study (presented at the UIP World Conference in London, September 1995) suggests that venous ulcer healing may be hastened by diosmin, one of this class of drugs.

Data sources: MEDLINE search 1980—94 plus scanning of reference lists in articles obtained.

Study selection: Studies on venous disease in subjects not attending health services.

Data synthesis: A formal systematic review of meta-analysis was not carried out because of the heterogeneity of the few available studies. Skin changes were found to occur in over 3% of adults, more so in women than men. The prevalence was higher in subjects with varicose veins and depended on the definition of skin changes and the severity of varicose veins. Approximately 0.3% of adults had an open varicose ulcer, and around 1 % had an open or healed ulcer. Prevalence was higher in women and increased with age.

Conclusions: The prevalence of chronic venous insufficiency was found to be common in the general population, but more studies of distribution and aetiology are required.

This paper reviews data on the socio-economic aspects of venous disease and venous insufficiency. It will cover data on the burden of disease and the effects of venous insufficiency on quality of life, it will also cover varicose veins, chronic venous insufficiency and venous ulcers of the leg. The use of the WHO International Classification of Diseases allows for comparisons across countries, with costs expressed not only in local currency, but also in terms of ECUs and as a percentage of health care costs.

The paper presents estimates on the costs of venous disease in the UK, France and Germany. Using standard diagnoses, costs are estimated to amount to 1.5—2.0% of total health care expenditure in these three countries. This is divided between inpatient, outpatient and community nursing programmes. Prescribing costs for venous diseases range from 0.26% of the total in the UK to 5.38% in France, with Germany in the middle of the range at 2.87%. The paper also summarizes costs in terms of reduced quality of life and loss of work-time. In Germany venous diseases contributed significantly to total disability, accounting for 1.2%. of invalidity days in the late 1980s.

As a result of dissatisfaction with current treatment programmes there have been moves towards new ones. The paper sets out the evidence on innovations in care through investment programmes aimed at reducing costs and improving efficacy. Current developments in Britain, Germany and France are set out, summarizing likely costs and benefits.

Data sources: Published papers referring to the pharmacology of drugs used in the management of chronic venous insufficiency and varicose veins of the lower limb.

Study selection: Sixty-four papers referring to the use of horse chestnut extract (aescin), flavonoids, tribnoside and calcium dobesilate have been included.

Data extraction: Papers were examined to establish the mechanism of action of ‘oedema protective’ drugs.

Data synthesis: Oedema protective drugs modify the permeability of the microcirculatory endothelium in animal models of oedema and probably in patients with venous disease to reduce transcapillary loss of fluid into the tissues. The exact mechanisms of action remain unclear.

Conclusion: Animal and clinical studies demonstrate that drugs of the four types included in this review moderate the development of tissue oedema.

Background: Congenital valve incompetence, thrombotic damage or venous outflow obstruction result in the development of chronic venous hypertension which frequently leads to ulceration. One major aetiological factor of trophic changes in the skin of patients with CVI is the phenomenon of leucocyte trapping.

Hypothesis: It has been suggested that endothelial dysfunction, effectively resulting in a decrease in cellular levels of NO, is a key event in the initiation of enhanced adhesion molecule expression.

Data: P-selectin, monocyte chemoattractant protein-I and vascular cell adhesion molecule-i expression can be enhanced by attenuating endothelial NO production. The mechanism by which NO alters the expression of genes encoding these adhesion molecules would appear to involve an interaction with transcription factors, in particular NFxB.

Conclusion: Impaired endothelial NO synthesis associated with CVI may enhance the expression of adhesion molecules and chemotactic factors and lead to leucocyte adhesion and extravasation.

Data selection: Relevant clinical studies were selected if they were performed using a double-blind, placebo-controlled design with validated instrument measurement of objective criteria and measurement of subjective criteria by standardized methods.

Data synthesis: Judgement of clinical effectiveness of drug treatment with venoprotective/venotropic agents was based on the signs and symptoms of CVI. Measureinents accepted for consideration included reduction of leg oedema, related subjective symptoms, improvement of haemodynamics and microcirculation, and improved healing of venous ulcers. Tolerability of the compounds in therapeutic use was assessed by comparing the frequency of side-effects in treatment and placebo groups.

Conclusion: Oedema protective agents such as diosmin, horse chestnut extract and O-(B-hydroxyethyl)-ruto-sides are an appropriate option in the management of CVI. The clinical efficacy can be measured objectively and quantified by assessing oedcma reduction or in the case of venous ulcers by ulcer healing rates. The extent of oedema reduction in patients with CVI is equivalent to the reduction achieved by compression therapy with elastic stockings as seen in a recent clinical study. Combined treatment of oedema protective agents and compression therapy has a better clinical benefit compared with treatment with either alone. The compounds have a favourable benefit/risk ratio. They combine proven therapeutic efficacy with excellent safety of use confirmed in a large number of patients treated in clinical trials.

Design: Comparison of the legs with severe CVI with the healthy legs and with the patients’ contralateral legs.

Setting: Department of Dermatology, University of Turku, Turku, Finland.

Patients and control subjects: Ten patients and eight age-matched subjects with healthy legs.

Interventions: A single treatment using intermittent

pneumatic compression (IPC) of 45 mm duration.

Main outcome measures: Laser Doppler flowmetry with the subjects in a recumbent and a sitting position.

Results: The LDF values were higher for the legs with severe CVI than for the legs of healthy subjects (p<0.001 in a recumbent and p<0.01 in a sitting position). A single IPC increased the LDF in a recumbent position in the patients’ legs with severe CVI (p=0.019) but had no significant effect on the LDF value in the sitting position. The venoarteriolar response was significantly better in the legs with severe CVI than in the legs of healthy subjects (p<0.05).

Conclusions: The LDF is increased in legs with severe CVI and a single IPC further increases it in a recumbent position. The venoarteriolar response is not impaired in legs with severe CVI.

Design: Case report.

Setting: Academic Vascular Surgery and Radiology Units, St Mary’s Hospital, London, UK.

Patients, Interventions and Results: The aneurysm occurred in a 34-year-old woman and was diagnosed with venography, duplex scanning and magnetic resonance venography. It underwent acute thrombosis and, as the thrombus was well organized and extensive, thrombectomy was not possible. The patient was treated with standard heparin followed by oral anticoagulants for 5 months. Thirty months after the operation the right calf remains swollen but soft and non-tender and the patient is currently treated with grade II full-length compression stockings. Since there were no findings of vein compression or malignancy it seems that the formation of the aneurysm resulted from a congenital weakness of the venous wall.

Conclusions: The most common presentation of these aneurysms is of a mass of the abdomen or the iliac fossa, while thromboembolism is not uncommon. The main causes are arteriovenous (AV) fistula formation and congenital weakness of the vein wall. For the first the preferred treatment is AV fistula ligation while for the rest ligation with or without vein reconstruction has been successfully used.