CONTENTS  •  Volume 9  Number 2 1994

Pharmacological treatment is widely used to manage the symptoms of venous disease in some countries in Europe, and yet rarely used in others. In France and Italy ‘phlebotonic’ drugs are in common usage, to the extent that half the healthcare expenditure on venous disease is spent on pharmacological treatments. In the United Kingdom and other northern European countries very few of these are prescribed. In the UK only one drug (Paroven / Venoruton, Zyma Healthcare) has a product licence and expenditure on this amounts to less than I % of the total healthcare costs for the management of venous disease.

So. are doctors in countries where phlebotonic drugs are not used denying their patients a useful alternative to surgical treatment! Or are physicians where these drugs are widely prescribed guilty of needless extravagance? There are many studies which show that these are effective in managing the symptoms of venous disease when compared to controls. The paper by Pillion et at. in this issue demonstrates efficacy of a flavonoid fraction in the mitigation of venous disease symptoms, and the paper by Vin et al. shows the efficacy of Troxerutin in the management of venous disease. These papers concentrate on the influence of the drug on the symptomatic response, but also include objective measures of physiological or haematological response. The studies were conducted in a double-blind study design and clearly show a therapeutic response. Ernst et at. have investigated the placebo effect of pharmacological treatments. They have shown that ‘pills for veins’ have a powerful placebo effect, which may be exceeded by the placebo effect of an ointment to rub on the affected limb.

Some studies have shown more rapid ulcer healing in response to pharmacological treatment, but one large study failed to show any efficacy in preventing ulcer recurrence when using hydroxylrutosides in patients with healed ulcers. The most important issue to resolve is whether drug treatment has a large enough effect to avert the need for surgical intervention. I am not aware of any study in which this question has been properly addressed. The future of pharmacological treatments for venous disease may depend upon properly conducted studies which answer this point.

The presently used phlebotonic treatments do not make venous valvular incompetence disappear. Drugs which restore the competence of varicose veins are unlikely to he developed in the next decade, although drugs which heat and maintain the healing of venous ulcers might he. Our rapidly expanding understanding of the biology of blood vessels may lead to the possibility of developing drugs which might he effective in such areas. A full knowledge of the mechanisms leading to venous disease is highly desirable so that appropriate mechanisms of action for the new generation of drugs may be designed. Considerable research effort is currently expended to resolve the complex series of events which occur during critical ischaemia. The mechanisms responsible are almost certainly fundamental to mammalian microvascular metabolism and therefore drugs which manipulate them may he effective in many inflammatory disorders, including those which culminate in venous ulceration.

Design: Single patient group study in patients with trophic skin changes in chronic venous insufficiency.

Setting: Department of Dermatology, Medical University of Lübeck.

Patients: Ten patients with venous leg ulcers.

Interventions: Biopsies were taken from areas of LDS and compared with clinically normal-appearing skin of the affected leg and with ulcer tissue.

Main outcome measures: Comparison of the morphological features on light and electron microscopy.

Results: Superficial dermis. Histologically, the ulcer tissue and LDS skin show dilated tortuous vessels in a glomerulus-like arrangement in the superficial parts of the dermis. Ultrastructurally, the superficial vessels are surrounded by a cuff, which contains amorphous and basal membrane material and is most pronounced in LDS. Immunofluorescence studies reveal ill-defined perivascular staining after incubation with antibodies against flbrin(ogen), laminin and type IV collagen. The exact ultrastructural localization of type IV collagen within the perivascular cuff is observed by immunoelectron microscopy. Deep dermis. In deeper parts of the dermis, the vessels of both ulcer tissue and LDS are surrounded by cellular cuffs with pericytes, fibroblasts and compact collagen bundles.

Conclusions: We suggest that the severe morphological changes in LDS and ulcer tissue play an important role in the pathogenesis of venous ulceration.

Design: Prospective study of patients with varicose veins compared with a group of control subjects with no history or clinical findings of varicose veins.

Setting: The Middlesex Hospital Vascular Laboratory, Mortimer Street, London W1N 8AA. UK.

Patients: Patients referred to the Middlesex hospital Vascular Laboratory for investigation of venous disease. Control subjects were obtained from within the laboratory and hospital staff, and from a group of patients attending the London Foot Hospital for routine chiropody. Neither group had arterial disease nor any other illness or medication known to alter white cell activity.

Interventions: 10 ml of blood taken from an arm vein into EDTA for a neutrophil count and measurement of plasma lactoferrin using an ELISA.

Results: Significantly raised plasma lactoferrin was found in all four groups of patients compared with their controls (p = 0.0156 for uncomplicated varicose veins, p = 0.01 for lipodermatosclerosis. p = 0.0413 for active venous ulceration, and p = 0.0005 for healed ulcers, Mann-Whitney U-test). Differences between medians (95% confidence interval) for the four groups were 269 (62—603). 199 (60—314), 133 (44—218) and 215 (98—349) ng/ml respectively. There was no difference in the neutrophil count between the patient and control groups, and correcting plasma lactoferrin for the neutrophil count did not remove significance in any group.

Conclusions: This study shows evidence of increased neutrophil activation as shown by increased degranulation in patients with venous disease.

Design: Morphological study of the intervalvular distance of the long saphenous vein.

Setting: Department of Morfologia, Facultad de Ciencias de la Salud (Universidad de Las Palmas de Gran Canaria, Spain) and Academic Vascular Surgery Unit. St Mary’s Hospital, London, UK.

Material: Twenty lower extremities from adult cadavers with no evidence of lower limb venous disease.

Methods: Anatomical dissection of the long saphenous vein, with accurate measurement of valve distribution.

Results: There were on average 8.7 valves in the long saphenous vein, with 6.3 above the knee and 2.4 below the knee.

Conclusion: Contrary to classical anatomical texts on this subject there are more valves in the long saphenous vein in the thigh than in the calf.

Design: Prospective, controlled trial with two parallel treatment groups.

Setting: Social security system related rehabilitation centre in Germany with nationwide assignment of inpatients.

Patients: Sixty-one patients with the clinical diagnosis of varicose veins.

Interventions: Group A (n=30) received an oral placebo, group B (n=31) applied a topical placebo preparation to both legs. The treatment period was 24 days; both therapies were applied daily.

Main outcome measures: Foot volume, ankle circumference, light reflex rheography and subjective complaints.

Results: In both groups there were significant improvements in several outcome measures concerning both objective signs and subjective symptoms. Light reflex rheography yielded significantly better results in the topically compared with the orally treated group. Other variables followed this trend without, however, reaching the level of statistical significance.

Conclusions: Symptoms of varicose veins are highly prone to respond to placebo. There are some indications to suggest that a topical placebo induces stronger effects than an oral one.

Design: Double-blind, randomized, placebo-controlled, parallel group trial conducted in two centres.

Setting: Department of Internal Medicine, La Palmosa Hospital, Menton, France, and Department of Vascular Surgery, Kremlin-Bicétre University Hospital, Le Kremlin-Bicêtre, France.

Patients: One hundred and sixty patients with symptomatic disturbances of the venolymphatic system, including chronic venous insufficiency, were included in the study.

Interventions: Treatment lasted 8 weeks and consisted of the daily administration of two tablets of either S 5682 (n=80) or placebo (n=80).

Main outcome measures: The primary end-point was the evolution of eight symptoms of disturbance of the venolymphatic system over the 2-month observation period. The secondary end-point was the change of circumference of each affected leg over the same observation period.

Results: When compared with placebo, S 5682 led to a significant improvement in four symptoms (functional discomfort, sensation of heaviness, nocturnal cramps, sensation of swelling) at week 4 and in two additional symptoms (pain and sensation of heat or burning) at week 8. Similarly, S 5682 was associated with a significant decrease in calf muscle and supramalleolar circumferences at week 4 (p<0.001) and week 8 (p<0.001) reflecting a reduction of oedema. The decrease of the supramalleolar circumference correlated well with the improvement of the swelling sensation (r<0.56; p<0.001). The clinical and biological acceptability of S 5682 was good.

Conclusions: These results indicate that S 5682 shows early and prolonged efficacy in the treatment of symptomatic disturbances of the venolymphatic system, including chronic venous insufficiency, without significant side-effects.

Design: Randomized, double-blind, multicentre, prospective controlled trial.

Setting: Hotel Dieu Hospital and Notre Dame de Bon Secours Hospital, Paris, France.

Patients: Sixty-nine patients with truncal varicose veins.

Intervention: After a single-blind 15-day placebo run-in period, one group (n=34) received troxerutin 3500 mg daily for 2 months. The other group (n=35) received a placebo.

Main outcome measures: Subjective symptoms, ankle circumference, venous refilling time with photoplethysmography, erythrocyte aggregation using the SEFAM aggregameter and fibrinogen level.

Results: Leg aching (p<0.00l) and venous function score (p<0.001) improvements were significantly higher in the troxerutin group (83% and -3.7) compared with the placebo group (23% and -0.7). A significant difference in favour of troxerutin was found for erythrocyte aggregation kinetic indexes (,p<O.OO1) and dissociation threshold (p<0.1).

Conclusions: This study confirmed the dual action of the drug: a parietal effect and a rheological effect.

Design: Prospective haemodynamic study during postural changes in 14 patients with venous insufficiency with no other concomitant cardiovascular disease or disturbances in autonomic nervous system.

Setting: Department of Cardiology and Angiology, University Hospital, Gent, Belgium.

Patients: Fourteen patients with venous valve insufficiency in the lower limbs.

Interventions: Measurements of arterial blood pressure, heart rate, stroke volume and cardiac output were performed in the supine position after 30 mm rest and 5, 15 and 30 mm after standing and during the recovery. Venous pressure at the ankle and calf circumference were also measured.

Main outcome measures: Changes in cardiac output and total peripheral vascular resistance in order to maintain blood pressure during postural changes.

Results: Arterial blood pressure was maintained constant owing to an increase in total peripheral vascular resistance despite a decrease in cardiac output. Venous pressure is also related to arterial blood pressure.

Conclusions: The arterial and venous systems, even in venous insufficiency, are integrated to maintain blood pressure constant during postural changes.

Design: Patients were interviewed using a standard questionnaire, and then reinterviewed after 12 weeks of compression bandaging to observe changes.

Setting: Community ulcer clinics held in health centres within Riverside Health District.

Patients: All new patients presenting to community leg ulcer clinics up to 6 months from the start of a clinic and treated with four-layer compression bandaging.

Main outcome measures: Changes in quality of life, interference in daily activities caused by leg ulceration and general health after 12 weeks of treatment.

Results: Treatment over 12 weeks resulted in a mean reduction in anxiety (2.79 v 1.73, p <0.001), depression (2.61 v 1.89, p <0.001), hostility (1.59 v l.00, p <0.001) and cognition (1.29 v 0.87,p = 0.015). Pain significantly improved following treatment (x² trend = 103.7, ld.f., p <0.001). Changes in depression and hostility were related to complete ulcer healing.

Conclusions: There were clear changes in quality of life following 12 weeks in a community leg ulcer clinic, which were related to the healing of the ulcer. Systems of care that offer rapid healing and improve patients’ well-being must be considered when planning an effective leg ulcer service.

Setting: Lothian and Forth Valley Leg Ulcer Study (patients) and Edinburgh Artery Study (controls).

Patients: 331 leg ulcer patients aged 55-74 years identified in a population survey and 331 age- and sex-matched population controls.

Interventions: Questionnaires which included cardiovascular history. Measurement of ankle and brachial systolic pressures.

Main outcome measures: History of intermittent claudication, previous heart attack, hypertension, diabetes mellitus. Lower ankle brachial pressure index (ABPI) of either leg.

Results: Frequencies of intermittent claudication, previous heart attack, hypertension and diabetes mellitus were very similar between the study groups. Mean (SE) ABPI was 1.1 (0.01) in patients and 1.0 (0.01) in controls (p.<0.001), although the difference was due partly to variation in measurement techniques.

Conclusions: Arterial disease was not found more frequently in patients than in controls, suggesting that arterial disease is not a risk factor for chronic leg ulceration, but clarification is required from other studies.