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Advanced - Managing venous disease with red vine leaf extract

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VOL: 102, ISSUE: 44, PAGE NO: 54

Martyn Butcher, RGN, Dip HSW, CertMHS tissue viability clinical nurse specialist, Plymouth Hospitals NHS Trust, Plymouth

Chronic venous insufficiency (CVI) is mainly caused by venous and capillary hypertension and this leads to a persistent, chronic, venous stasis in the skin of the lower leg. Typical CVI complaints, such as tired, heavy and swollen legs, and tension and pain in the legs, are the warning signs of a progressive, chronic condition.

The effects of venous hypertension include deposition of haemosiderin (iron deposits) and fibrin in the perivessel tissues, along with subtle changes in skin texture that can eventually lead, if untreated, to trophic skin changes and varicose leg ulcers.

Management of venous hypertension

Physical mobilisation, avoidance of prolonged sitting or standing, and elevation of the legs reduce the venous pressure and facilitate venous return in the affected areas. Treatment centres around the application of external pressure to the limb to mechanically splint the vessels, preventing their distortion and engorgement by the physical narrowing of blood vessel lumen. In this way, faulty valves can be supported and intravessel blood velocity increased (Oduncu et al, 2004).

Drug therapy is a treatment option in incipient and mild to moderate CVI. Leach’s (2004) review of leg ulceration included the evidence for systemic therapy, namely orally administered phlebotonic (venotonic) agents. Such drugs are often plant-derived substances for which an anti-exudative (anti-inflammatory) and anti-oedematous action and efficacy have been confirmed in experimental studies and clinical trials. Experimentally, most have a membrane-stabilising action, leading to a decrease in capillary permeability. Some also have antioxidant properties.

Anti-oedematous drugs can - depending on the severity of the condition - be used in combination with other therapeutic measures to combat congestion symptoms such as oedema, pain and sensations of tiredness, heaviness and tension in the legs, caused by venous hypertension with or without symptoms of CVI (Fricke, 1998).


Recent studies have investigated the action of flavonoids in preventing atherosclerotic plaques (Hollman and Katan, 1997). Bioflavonoids or flavonoids are a class of water-soluble substances found in a number of plants or plant-derived products. It is believed that flavonoids have a wide range of beneficial effects when taken in the diet, including anti-inflammatory, antihistaminic and antiviral action. Formica and Regelson (1995) concluded that flavonoids are important in the maintenance of capillary wall integrity and resistance.

A source of flavonoids that has undergone extensive preclinical and clinical investigation is the red vine leaf extract AS 195. This has shown that its flavonoids may have significant benefits for patients with pre-ulcer venous hypertension.

Red vine leaf extract AS 195

The dried aqueous extract of standardised red vine leaves (AS 195) is a food supplement available in capsules. Red vine leaf extract has been available in France for the treatment of symptoms associated with venous insufficiency. In the UK it is sold as a dietary supplement for the maintenance of healthy leg-vein circulation, in particular to avoid tired, heavy and aching legs that result from long periods of standing or sitting.

The extract contains a number of bioflavonoids including flavone/flavonol glycosides and glucuronides, in particular quercetin-3-O-b-D-glucuronide, isoquercitrin and kaempferol-3-glucoside. It is registered as an over-the-counter medicine in several European countries.

What evidence is available for its use?

Several preclinical and clinical trials have demonstrated the tolerability and efficacy of AS 195. Two double-blind randomised placebo-controlled efficacy clinical trials that conformed with good clinical practice were conducted to assess its efficacy, while two additional trials (an open uncontrolled observational study and a randomised placebo-controlled double-blind parallel group study) investigated its safety and tolerability (Schaefer et al, 2003). The three most significant preclinical and clinical studies are briefly described here.

Nees et al (2003) undertook an in vitro study to increase understanding of the effects of endothelial inhibitors and to explore the possible role of venular endothelial cells in the development of connective tissue failure characteristically seen in CVI. It was discovered that a standardised extract of red vine leaves (AS 195) not only protected venular endothelial cells but also, when applied to previously damaged cells, could prompt cellular repair.

Kiesewetter et al’s (2000) randomised double-blind placebo-controlled parallel group multicentre study aimed to assess the efficacy of AS 195 in treating symptoms of CVI. Success was measured in terms of limb volume and ankle and calf circumference reduction, as well as by subjective questioning of the trial subjects about their symptoms. Patients were recruited into one of three study arms: 360mg red vine leaf extract AS 195 per day; 720mg red vine leaf extract AS 195 per day; or placebo.

The placebo group demonstrated an increase in lower leg volume at six weeks and at 12 weeks. Patients treated with red vine leaf extract AS 195 showed a decrease in mean volume compared with the control group. The results of changes in ankle circumference were similarly positive, with reductions in the active treatment groups but little change in the placebo group. All patients in the active treatment groups had subjective improvements in symptoms at six weeks, and the changes were significantly greater after 12 weeks.

This study showed a marked improvement in patients under treatment, both subjectively in terms of symptoms and objectively in limb measurements. Those receiving the higher-dose preparation experienced a slightly greater effect, and this was sustained for a longer period after the trial had been discontinued.

Kalus et al’s (2004) study was designed to identify the improvement of cutaneous microcirculation and oxygen supply. This double-blind randomised placebo-control crossover trial involved 71 patients with cutaneous microcirculation. Group one (n=36) received red vine leaf extract AS 195 360mg daily for six weeks followed by a four-week washout (break between treatments) and six-week placebo treatment. Group two (n=35) received placebo, then washout, then red vine leaf extract AS 195 360mg daily for six weeks. After six weeks of treatment, the intervention group had an increase in microvascular bloodflow values compared with a decrease in the placebo group. Transcutaneous oxygen increased in the intervention group, while in the placebo group it decreased. Leg circumference decreased in the intervention group compared with the placebo group.

Evaluating the evidence

These studies appear to have been well designed -while the numbers involved were small, the results achieved statistical significance and good control systems were used. Further studies will be required to assess whether or not red vine leaf extract AS 195 can achieve improvements in microvascular bloodflow in patients with other microvascular diseases such as diabetes.

The safety of red vine leaf extract AS 195 has been demonstrated in all trials performed so far and has been confirmed by post-marketing surveillance data. No severe adverse events have so far been reported. Minor gastrointestinal complaints constitute the most common side-effects associated with red vine leaf extract AS195 in all of the clinical studies carried out to date. All reported adverse events were of a mild nature and resolved quickly either during treatment or after its discontinuation.


Although the red vine leaf extract studies were small in number, the available evidence suggests that AS 195 has properties that may help to maintain healthy leg-vein function. As such, its role in the prevention of CVI and in ameliorating established venous disease could be further explored. Such investigations may include evaluation of the correction of early vein changes to prevent venous ulceration and the role of red vine leaf extract in maintaining leg-vein integrity, thus leading to enhanced treatment options and a recurrence-prevention strategy.

Availability of a pill to help reduce the burden of venous disease would be of benefit to clinicians and patients alike. Although further work is undoubtedly required and sound research needs to be done, red vine leaf extract AS 195 may be a new tool in the ongoing management of our patient group.

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