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[b]The Drug Treatment of Chronic Venous Insufficiency and Venous Ulceration
Philip D Coleridge Smith DM FRCS
Reader in Surgery, Royal Free and University College Medical School, London UK
Introduction
The management of venous diseases has relied on compression treatments and surgical interventions for many years. The growth of drug treatment in some sectors of medicine has been considerable. However, I think that it is fair to say that no huge advance has been made in the drug treatment of patients with venous disease to match those in many other medical specialities where revolutions in management have occurred with advances in pharmacology. In many countries, drugs remain widely used in patients with venous diseases as adjunctive treatments. The aim of this chapter is to discuss these for patients with varicose veins and chronic venous diseases leading to skin changes and leg ulceration. Which drugs should be used in treating venous diseases and when?
Varicose veins
In patients with varicose veins compression treatment, sclerotherapy or surgical removal of veins remain the most effective therapeutic measures in achieving relief of symptoms. No drug has so far been shown to result in the resolution of varicose veins, other than when used as part of a regime of sclerotherapy. This is true of truncal varices as well as telangiectases and reticular varices. However, varicose veins are often associated with two groups of symptoms which commonly trouble patients. These include oedema and unpleasant feelings in the legs such as aching in the region of varices, ‘restless legs’ or a feeling of swelling of the lower limbs. These may be addressed by treatment of the underlying condition using compression stockings, sclerotherapy or surgery. However, in many countries ‘venotonic’ drugs are used to manage these problems. Patients living in regions of hot weather find wearing compression stockings unbearable at some times of the year and surgeons may abandon surgical treatment during the summer season. This has opened a long-established market for the use of drugs. Many of the drugs used for this purpose are derived from plants, although more recently synthetic drugs have been developed. This groups of drugs was originally developed during the 1960s and 1970s when lesser standards of scientific proof were required than is the case today. The studies that supported the use of these drugs did not use hard clinical endpoints, since the symptoms which they were designed to treat were highly subjective. More recently double-blind studies have confirmed the efficacy of some of these drugs against the symptoms of venous disease.
‘ Venoactive drugs’
A classification of the venoactive drugs based on published literature is shown in table 1. , A wide range of compounds is shown here and by no means all of these are available as drugs in every country.
The mechanisms by which this class of drugs act remain unclear. As various possible causes of venous disease have been advanced with scientific advance, the possibility that these mechanisms are modified by these drugs has been suggested. Until recently, very little work had been done to assess how venoactive drugs modify the physiology of the microcirculation of the leg to reduce oedema and symptoms related to venous disease.
Hydroxyrutosides
Hydroxyrutosides are a class of flavonoid drug derived from plant glycosides (fig 1, 2). They initially gained favour 30 years ago when experimental studies indicated that they reduced capillary permeability following burns in dogs. A number of clinical studies evaluating their effect on symptoms associated with CVI followed , . In general these indicated that hydroxyrutosides appeared to be more effective than placebo in reducing aching, tiredness, muscle cramps and other symptoms which are difficult to evaluate objectively.
Hydroxyrutosides are commonly used to treat oedema and several clinical trials and other studies have been reported. Treatment with doses between 1g and 2g per day have been studied in detail. Calf circumference, a measurement prone to substantial variability, has been used as an assessment of leg oedema. Four weeks treatment with hydroxyrutosides resulted in a mean reduction in calf circumference of 2.1 to 2.5 mm greater in the rutoside compared to the placebo group , . The mean reduction was 6.1 mm greater in the rutoside group after 8 weeks of treatment, with a similar trend in the reduction of ankle circumference. Pitting oedema was also reduced more by rutosides than placebo .
The water displacement method is a more reliable method of assessing calf volume. The leg volume measured by this technique increased significantly during a 4 week period of placebo, but this increase was not observed during rutoside treatment . A similar trend was observed in another investigation which employed electrical conductivity to assess the amount of extracellular fluid in the limb. 7 In a study carried out in 40 patients undergoing surgery for varicose veins, there was no difference in leg volume between placebo and rutosides treatment groups in the first 6 post operative weeks. Compression stockings were worn during the study, and the effect of these on leg oedema hid any additional effect of the drug treatment .
The change in leg oedema has also been assessed by strain gauge plethysmography . A single intravenous bolus of rutosides increased the reserve venous volume and decreased capillary filtration rate as compared to placebo. In the same study, oral treatment increased the reserve venous volume and venous emptying, but did not change the capillary filtration rate.
The influence of hydroxyrutosides on the microcirculation has been assessed in one study, in which capillary filtration was assessed by a strain gauge method. Forty patients with ankle oedema due to mild to moderate venous hypertension were assigned to receive either rutosides 2000 mg per day or placebo for 4 weeks. No differences were observed between the two treatment groups in the microcirculatory parameters assessed in this 4 week trial. Our own investigations of capillary filtration using a similar technique showed little difference between patients with venous disease and control subjects. Therefore, assessment of capillary filtration by this method may not be appropriate method of measuring of the effects of treatment for venous disease.
The use of hydroxyrutosides in venous disease appears to have significant symptomatic value , , , reducing swelling cramps and oedema. Its use could be considered in patients suffering these symptoms in whom compression treatments are contraindicated or not tolerated by the patient.
Calcium dobesilate
This synthetic drug has also been investigated in its effects on oedema. Two randomised clinical trials in which a total of 275 patients were included have been published , . Calcium dobesilate decreased the maximum circumference of the calf and the minimum circumference of the ankle to a greater extent than placebo at day 28, while calf circumference was also significantly reduced at day 14. Relative leg volume was reduced by 3.8% with calcium dobesilate and 1.2% with placebo (p<0.001). A ‘malleolar swelling’ clinical score ranging from 3 (total relief) to +1 (deterioration) was reported to be 1.70 with calcium dobesilate and 0.48 with placebo (p<0.001). This ‘malleolar swelling’ matched strain gauge plethysmography measures of limb circumference.
This drug has a measurable effect on the oedema and symptoms attributable to venous disease.
Horse chestnut extract (aescin)
Little objective evidence of efficacy is available for horse chestnut extract. In 125 female patients with chronic venous insufficiency, neither horse chestnut extract nor placebo reduced ankle circumference after 2 months of treatment. The rate of improvement of swelling was identical in both groups. There is no published evidence that horse chestnut extract assists ulcer healing or prevents recurrence. Aescin continues to be widely used in medicines sold for the purpose of treating the symptoms of venous disease.
Diosmin
Diosmin is a member of the flavonoid family (fig 3). It has been shown that the intestinal absorption and therefore bio-availability of this drug may be increased by micronization. This is a high-tech process in which the particle size of the active ingredient is reduced from 60 ?m to less than 2 ?m. The clinical efficacy of micronized diosmin (Daflon 500 mg, Detralex, Arvenum 500, Capiven, Venitol, Variton, Ardium, Servier, Courbevoie, France) is significantly reinforced by this process , . Several studies indicate its efficacy on oedema and the symptoms of venous disease. The symptoms which have been investigated include heaviness, discomfort, itching, cramps, pain and swelling. These must be quantified using scores or a visual analogue scale rather than objective measurements, but these data tend to result in considerable variance of data. Consequently, large numbers of patients must be included in studies based on this type of measurement to be confident of conclusions reached. Laurent examined the efficacy of micronized diosmin in 200 patients in a double blind, placebo-controlled trial lasting 2 months. Outcome measures assessed the symptoms of venous disease using visual analogue scales. Micronized diosmin improved functional and organic venous insufficiency (symptoms of venous disease not associated with major venous valvular incompetence) by 71% and 66% respectively compared to 36% and 38% for placebo. However, although symptomatic improvement is important to patients, objective evidence of efficacy on measures of severity of venous disease are more reassuring! Micronized diosmin has also been investigated in the context of oedema reduction. In Laurent’s study, the mean difference in the reduction of supra-malleolar circumference was 6.7 mm (right limb) and 6.1 mm (left limb) in favour of micronized diosmin in patients with functional symptoms. In patients with varicose veins or post thrombotic syndrome the reduction was 6.8 mm (right limb) and 6.5 mm (left limb). The supra-malleolar circumference remained unchanged in the placebo group.
The mode of efficacy of this drug is incompletely understood. Studies have shown that it increases venous tone , and lymphatic flow , , . It also decreases hyperpermeability and increases capillary resistance . A recent paper has shown that it modifies the interaction of leucocytes with endothelium in a hamster skin fold model used to investigate the effect of Daflon 500mg on the microcirculation following ischaemia-reperfusion. The group of animals pre-treated with Daflon 500 mg exhibited less neutrophil adhesion in the post-capillary venules at 30 mins, 2 hours and 24 hours after reperfusion, compared to the control group . In another model of the microcirculation, small bowel and cremaster of rats, Korthuis showed that Daflon 500 mg inhibits leucocyte adhesion and migration induced by ischaemia/reperfusion . Bouskela has also confirmed this in the hamster cheek pouch model of the microcirculation . The mechanism by which this is achieved has not been defined, although these are important observations since they implies that Daflon 500 mg may protect the tissues in experimental models of ischaemia. Bouskela has reported further findings in the hamster cheek pouch . Fluorescein-isothiocyanate labelled dextran was used to study the microcirculation. The number of microvascular ‘leakage points’ were identified in the cheek pouch using fluorescence microscopy. Histamine, bradykinin and leukotriene B4 were applied topically to cause microvascular disturbance. These increased the number of leakage points. This effect could be prevented by pre-treating the animals with Daflon 500 mg. Daflon 500 mg appears to protect the microcirculation against inflammatory mediators in this model.
The effect of Daflon 500 mg on the microcirculation in man has been investigated in a study in which laser Doppler fluxmetry, transcutaneous oxygen and carbon dioxide levels were assessed in the skin . Patients with mild venous disease (no skin changes) were randomised to receive 500mg, 1g or 2g of Daflon per day. Small increases in tcPO2 and decreases of tcPCO2 were observed in all groups after three months treatment, with no difference seen between the different dosage regimes. No changes in laser Doppler flux were found. Since patients without skin changes show only minor disturbances in tcPO2 and tcPCO2 levels the scope for improvement in these measures of mild venous disease is limited. It is only in liposclerotic skin that these parameters show large changes and where improvement would be expected following effective treatment. No study has so far been reported in which Daflon 500 mg has been used in this patient group with transcutaneous oximetry used as an outcome measure.
Diuretics
Generalised leg oedema is a feature of proximal large vein obstruction, while localised oedema is commonly associated with areas of lipodermatosclerosis (LDS) . Simple diuretics are not generally used in oedema due to venous disease, since the increased permeability to proteins seen in venous hypertension leads to a protein rich oedema which is unsuitable for such treatment . In addition, haemoconcentration may occur, leading to reduced capillary blood flow and the risk of deep venous thrombosis.
Oedema reduction per se is probably not an important consideration in the treatment of venous ulcers. Myers et al have shown that healing of ulcers is unrelated to the amount of leg swelling; in their words: “the edema and the ulcer are due to the same cause, probably venous stasis, and any therapy which does not improve venous drainage is probably doomed to failure” . Although the concept of venous stasis is now thought to be unsound, the second half of their statement is likely to remain true.
Other treatments
Advertisements have appeared in newspapers in the USA and in the UK in recent months promoting vitamin K containing creams as useful in the treatment of telangiectases of the leg. I can find no published literature to support the claims made in these advertisements. One published item mentions these treatments and dismisses them as useless in view of the lack of supporting scientific evidence! A clinical trial has now confirmed the lack of efficacy of vitamin K creams in the treatment of telangiectases of the legs.
Venoactive drugs summary.
In summary, venoactive drugs remain widely used against the common symptoms of varicose veins and have clear efficacy in some areas, particularly in addressing oedema. They do not influence the progress of the development of varicose veins themselves. The mechanism of action of these drugs remains to be explained fully. There is reasonable evidence that flavonoids influence the process of leucocyte-endothelial interaction which probably modifies many other inflammatory events that may be the cause of symptoms experienced by patients with venous disease.
Chronic venous disease resulting in skin changes and leg ulceration.
Venous ulceration and the skin changes which precede ulceration are best managed by careful objective evaluation of the venous system of the lower limb followed by compression bandaging or stockings and surgical treatment where appropriate. Systemic drugs and topical applications are widely used in the management of leg ulceration but what should we use and when? Surgical intervention is appropriate where leg ulceration is attributable mainly to superficial venous incompetence alone in a patient fit enough for this procedure. In some studies this would apply to as many as half the patients presenting with venous ulceration. , A number of studies show that healing usually progresses well in such patients and recurrent ulceration is not a common problem . A relatively small proportion of patients are suitable for deep vein reconstructive procedures, many excluded because of age and infirmity or medical unfitness for a large vascular procedure. In general, such patients are best managed by compression treatments alone. Unfortunately whilst compression treatment can usually achieve healing if high enough levels of compression are used, recurrence is common problem with an annual recurrence rate of 25% per year. Perhaps drugs can speed healing or prevent recurrence? Many clinical studies have been published over the years which study this problem and examination of them is informative and revealing!
Antibiotics
“ Virtually every antibiotic that has ever been produced has been used to treat venous ulcers but there is very little evidence that they help healing unless the ulcer is contaminated by a single pathogenic organism” 34. This quotation from Browse et al summarises the present position regarding systemic antibiotic treatment in venous ulceration. Naturally, clinical infection of an ulcer must be treated, but this is best done by local ulcer toilet, unless cellulitis or septicaemia supervene. The possible exception to this rule is the use of metronidazole. There is some evidence that this compound given orally increases the rate of healing of both venous and pressure ulcers when they are infected with Clostridium and other anaerobes . Even then, systemic treatment may not be superior to topical application; Jones et al have demonstrated the rapid effectiveness of metronidazole soaked dressings in such cases . In general, systemic antibiotics do not play a role in the management of the uncomplicated venous ulcer.
Zinc
Adequate nutrition is essential for leg ulcer healing as it is for wound healing of other types. For a number of years, special attention was given to the concept that, in particular, zinc levels were depressed in patients with venous ulcers and that supplementation might speed healing. Greaves and Skillen, in an old but widely quoted paper, reported complete healing in 13 of 18 patients with previously intractable ulceration after a four month course of 220 mg Zinc sulphate three times daily . During this period they continued with their previous conservative treatment as out-patients. Pre-treatment serum zinc levels were found to be significantly lower in the patient group than in controls. In a later report, Greaves and Ive published their results over a longer period, in a double-blind trial of oral zinc in 38 patients with venous ulcers . They were unable to confirm their initial good results, with only 3 of the treated group and 2 of the placebo group showing complete healing after four months. Serum zinc levels were not measured in this study. These negative results were confirmed by Myers and Cherry in a study of 40 ulcer patients and by Phillips et al in 42 patients; in both studies, healing occurred at the same rate in zinc-treated and control patients.
More recently, Schraibmann and Stratton have compared the nutritional status of venous ulcer patients with that of age- and sex-matched controls . Of 11 indices thought to represent nutritional deficiency, only one (haemoglobin) was significantly lower in patients with venous ulcers. Serum zinc was, in fact, slightly higher on average in this group than in controls. It would seem, therefore, that zinc supplements to the diet are unlikely to be of much benefit to the majority of patients, although they may have a role in the management of those few patients with severe nutritional problems. No subsequent publication has studied zinc as a therapeutic treatment in venous ulceration.
Fibrinolytic Therapy
The concept of an oxygen diffusion barrier causing skin hypoxia was first proposed by Browse and Burnand in 1982 . This theory led to attempts to reverse the damaging cutaneous effects of venous hypertension by enhancing fibrinolysis. The effect of stanozolol, an anabolic steroid with pro-fibrinolytic properties, was evaluated in 14 patients with longstanding LDS, without active ulceration . After three months, all showed clinical improvement both subjectively and objectively (by mapping the area of LDS). Serum parameters of fibrinolytic activity improved in all cases. One might criticise the study for including 3 patients in whom the LDS was not associated with any venous abnormality. However, this pilot study justified a larger trial of fibrinolytic treatment in CVI.
This was performed as a 6 month double-blind crossover trial on 23 patients with long-standing LDS which had not responded to compression hosiery . All patients continued with stockings during the trial. The area of liposclerotic skin fell during treatment with both stanozolol and placebo. The rate at which it fell was faster on stanozolol than on placebo, although this difference did not reach statistical significance. Leg volume as measured by plethysmography increased on the steroid, presumably as a result of fluid retention. Skin biopsy analysis suggested but did not prove that tissue fibrin was reduced by stanozolol treatment; foot vein pressure reduction on exercise was improved to the same extent on both active and placebo treatment. All but one patient described subjective improvement during the trial but were unable to differentiate between the active and placebo periods. The exception to this was in pain relief which was significantly better while taking the steroid.
A further double-blind study of 60 patients was performed to evaluate the efficacy of this drug . Stanozolol combined with compression stockings caused a reduction of liposclerotic skin area of 28% over 6 months. However, when the separate contributions of the two treatment elements (compression and stanozolol) were calculated using multivariate analysis of variance, the effect attributable to stanozolol alone was not statistically significant.
One of the problems in evaluating the response of LDS to treatment is the paucity of hard end-points that can be measured; how does one quantify, for example, lightening of pigmentation, or reduction of induration? Treatment of venous ulceration, by contrast, allows the simple question to be asked: healed or not healed? Fibrinolytic treatment for venous ulceration has been evaluated in one trial of 75 patients . Patients were allocated to receive either stanozolol or placebo for up to 420 days, with conventional compression treatment in all cases. In an interim report, the authors found complete healing in 26 of 40 ulcers in the stanozolol group and 27 of 44 in the placebo group, indicating no benefit from active over placebo treatment.
In summary, one may say that fibrinolytic enhancement may be of minor benefit in the symptomatic treatment of LDS, but that it does not appear to improve ulcer healing. Before dismissing the concept, one must note that only one agent, stanozolol, has been extensively studied for this purpose, and it is possible that more potent, less toxic fibrinolytic agents could be more effective. Stanozolol has now been withdrawn from use in the UK for the treatment of patients with venous disease.
Drugs which modify leucocyte metabolism
Disappointment with existing pharmacological treatments, together with some theoretical objections to the notion of impaired oxygen diffusion in LDS , has led to the search for alternative lines of drug treatment on venous skin damage. The discovery of the involvement of leucocytes in the development of venous ulceration has opened new avenues of investigation in this area . A number of drugs which modify white cell activation have been evaluated in patients with venous ulceration with interesting results.
Prostaglandin E1
Prostaglandin E1 (PGE1) has a number of profound effects on the microcirculation, including reduction of white cell activation, platelet aggregation inhibition, small vessel vasodilatation and reduction of vessel wall cholesterol levels . It has been evaluated in the treatment of various aspects of arterial disease; less work has been done on its use in venous ulceration. An early trial of the use of intravenous PGE1 in ulcers of both arterial and venous aetiology reported improvement in 4 out of 5 venous ulcers on PGE1 as opposed to 4 out of seven on placebo - hardly a dramatic result . A recent trial has yielded rather more impressive findings . 44 patients with proven venous ulceration took part in a double-blind placebo-controlled trial. Each received an infusion of PGE1 (or placebo) over three hours daily for 6 weeks, in addition to standard dressings and compression bandaging. Those on PGE1 showed a significant improvement in such parameters as oedema reduction, symptoms and "ulcer score", based on depth, diameter etc. Perhaps more importantly, 8 of 20 patients on active treatment healed their ulcers completely within the trial period, whereas only 2 of 22 controls did so.
The reason for the different outcomes in these two trials probably relates to the dose of PGE1 given. In Beitner et al’s study, only two infusions were given. These consisted of 360 µg of PGE1 in 3 litres of isotonic saline over 72 hours, a month apart. In the second trial, 60 µg were given over three hours every day for six weeks - a total dose 3.5 times bigger than that in the earlier study. Although this rather intensive way of treating ulcers is not, at first sight, attractive, the cost of such treatment must be weighed against the many millions of pounds spent each year in this country on the out-patient care of unhealed ulcers.
Unfortunately no further studies have been published and the regular use of PGE1 in the management of leg ulceration has proceeded no further.
Prostacyclin analogues
Iloprost (Schering, Berlin), a synthetic prostacyclin analogue, has been used with success in the treatment of arterial and diabetic ulcers . The mechanism of action of prostacyclin includes increased fibrinolytic activity ; the drug also has profound effects on leucocyte activity by reducing aggregation and adherence to endothelium , in addition to its better known effects on platelet behaviour . However, a study in which this was applied topically to venous ulcers was disappointing . The trial design was a randomised, double-blind, placebo controlled study in 11 centres in Germany with 49 patients allocated to placebo; 49 patients to 0.0005% Iloprost and 50 patients to 0.002% Iloprost. The study solutions were applied twice weekly for a period of eight weeks on the ulcer edge and ulcer surrounding. This study failed to show any statistically significant reduction in the ulcer size as a result of the Iloprost treatment compared to the placebo treatment. Perhaps this was true failure of efficacy of this drug, or perhaps the drug delivery system did not achieve therapeutic levels in the tissues. No further data has been published concerning Iloprost in the management of venous disease and it is not in common use in the management of leg ulceration.
Pentoxifylline
Pentoxifylline has been used for the treatment of claudication for a number of years, with moderate success . It was thought that it may act by improving red cell deformability and thus improve oxygen delivery to ischaemic tissue. Recent work on the drug indicates that it actually has a potent effect on inhibition of cytokine-mediated neutrophil activation . The same workers also showed it to reduce white cell adhesion to endothelium and to reduce the release of superoxide free radicals produced in the so-called respiratory burst characteristic of neutrophil degranulation. Theoretically, therefore, it should be of benefit in venous disease if the white cell activation model described above is valid.
Weitgasser evaluated the effect of the drug in a double blind placebo-controlled trial of 59 patients with venous ulcers . Of 30 patients on active treatment, 26 “improved”; this was assessed by comparing photographs of the ulcer before and after treatment. Only 13 of 29 patients on placebo improved, a statistically significant difference. Unfortunately no firm data are given regarding the numbers of healed and unhealed ulcers at the end of the trial, which rather dilutes its impact. Herger subsequently studied the effect of the drug on 73 patients with ulceration, in 42 of whom the cause was venous insufficiency . The protocol of drug administration was rather vague; the dosages “in most cases” were 400 mg three or four times a day, and some patients also received pentoxifylline infusions. Treatment lasted for 8 weeks. 62 of the 73 ulcers healed; we do not know how many of the specifically venous ulcers are included in this figure. The trial was not placebo-controlled.
A Greek study in 1989 examined the effect of 1200 mg pentoxifylline per day on 10 patients with proven venous ulcers, with partial or complete healing in 8 after six weeks . Unfortunately this trial did not use a control group. A more rigorous trial has been reported by Colgan et al . This was a multi-centre placebo-controlled double-blind prospective study of 80 patients with venous ulcers. After 6 months of treatment with 1200 mg/day of pentoxifylline or placebo, 23 of 38 patients in the active arm had a healed ulcer, while 12 of 42 in the placebo-treated arm had the same result. This difference was statistically significant. (In both trials, patients continued with conventional hosiery and general ulcer care).
A further study in 200 patients has now been completed and the results published . This was a complex study of 2 x 2 x 2 factorial design, testing pentoxifylline against placebo, hydrocolloid dressing against a viscose dressing, and a single layer bandage against 4 layer bandaging. In essence, half the patients received high levels of compression and half received much lower levels of compression. There was a trend towards more rapid healing in the pentoxifylline group, but this did not reach statistical significance. Perhaps the use of higher levels of compression concealed any effect of pentoxifylline. Clearly this is a treatment with some efficacy, but of small magnitude. Its exact role in the management of patients with venous ulceration remains unclear.
Aspirin
The use of aspirin has been reported in a number of patients undergoing treatment for leg ulceration . The authors describe a measurable effect of aspirin on the rate of ulcer healing. However, this study includes 20 patients of whom only 4 healed their ulcers after 4 months treatment. This is extremely preliminary data on which to base any conclusions concerning treatment of patients. One paper proposes that abnormalities in coagulation measurements (fibrinogen, factor VIII related antigen, von Willebrand antigen and plasminogen activator inhibitor-1 (PAI-1)), which are perturbed in patients with venous disease, may be modified by the therapeutic use of aspirin . Currently the mode of action of aspirin and the extent of its efficacy in the management of venous ulceration remain to be shown. No further paper has been published since 1995 which addresses the efficacy of aspirin in venous leg ulceration, so the actual effect of aspirin on leg ulceration has never been reliably established. This is clearly because of the lack of possible commercial exploitation should any positive effect be discovered but perhaps other platelet antagonists could be studied.
Ifetroban
Effects of the oral thromboxane A2 receptor antagonist Ifetroban (250 mg daily) on healing of chronic lower-extremity venous stasis ulcers has been studied. This drug has a profound inhibitory effect on platelet activation and therefore could be a commercially viable successor to aspirin should efficacy be shown. In a prospective, randomised, double blind, placebo-controlled multi-centre study , 165 patients were randomised to Ifetroban (n = 83) versus placebo (n = 82) for a period of 12 weeks. Both groups were treated with sustained graduated compression and hydrocolloid dressings for the ulcers. Complete ulcer healing was achieved after 12 weeks in 55% of patients receiving Ifetroban and in 54% of those taking a placebo with no significant differences; 84% of ulcers in both groups achieved greater than 50% area reduction in size. This was a well-conducted study with a clear primary endpoint (complete ulcer healing in a patient). The findings strongly refute the suggestion that platelet inhibition will lead to leg ulcer healing.
Venoactive drugs in leg ulceration
Far less has been written about the efficacy of this group in the management of leg ulceration that in the management of the symptoms of varicose veins. Interest in this field has increased in recent years and a few studies have been published.
A study on the effect of rutosides on symptoms in 112 patients with venous insufficiency included four with ulceration. All four took rutosides for eight weeks; only one showed any evidence of improvement . Other studies have shown no evidence that hydroxyrutosides improve venous ulcer healing or prevent its recurrence. In 138 patients with recently healed venous ulcers, Wright compared the efficacy of below the knee elastic stockings combined with hydroxyrutosides (Paroven 500 mg b.d.) or placebo. The recurrence rates at 12 months were 23% with hydroxyrutosides and 22% with placebo. After 18 months the figures were 34% and 32%. These results show no evidence that hydroxyrutosides prevent ulcer recurrence when combined with elastic compression. It is clear that rutosides have a measurable effect on oedema in patients with venous disease. Unfortunately they do not have any effect on preventing venous leg ulcer recurrence. A possible extension of this conclusion is that treatment of oedema alone (where rutosides have efficacy) is insufficient to treat leg ulceration. Some additional factor must be influenced in order to speed ulcer healing (in which rutosides have not been tested) or to prevent recurrence of ulceration.
Flavonoids
The effect of Daflon 500 mg in a venous ulcer healing study has been recently reported . Patients were randomised to receive Daflon 500mg or placebo combined with standard compression bandaging during an 8 week follow-up period. In 91 patients with an ulcer diameter of 10cm or less, 14 of 44 (32%) patients receiving Daflon 500 mg compared to 6 of 47 (13%) receiving placebo healed their ulcers (p=0.028, chi square) after 8 weeks treatment. The time to achieve healing was shorter in the Daflon 500 mg group than in the placebo group (p=0.037). This is the only member of the ‘oedema protective’ drug group which has been shown to modify ulcer healing. Despite the fact that the study was relatively small and the duration of treatment was short (8 weeks) the results are encouraging. A larger clinical trial is currently in progress in which more patients are followed for 6 months in order to confirm the promising results already obtained. The possible mechanism of action of this drug is not yet clear, although several of its effects have been described above in the section on treatment of varicose veins.
Recent pilot study has been conducted using micronized purified flavonoid fraction, (MPFF) (Daflon? 500mg, Servier, Paris, France). 20 patients with chronic venous disease (CEAP clinical stage 2-4) were treated for 60 days with Daflon 500 mg twice daily taken orally. There was no placebo control group in this pilot study. Blood samples before and after the treatment were collected from a foot vein. Plasma levels of the soluble endothelial adhesion molecules sVCAM-1, sICAM-1, sP-selectin and sE-selectin were determined. In addition the endothelial derived von Willibrand factor (vWF), the neutrophil secondary granule enzyme lactoferrin and vascular endothelial growth factor (VEGF) levels were determined using a standard sandwich ELISA method. In addition, the neutrophil and monocyte surface adhesion molecules CD11b and L-selectin (CD62L) were assessed by a flow cytometric technique.
The expression of the leucocyte adhesion molecule CD62L was substantially decreased on monocytes and neutrophils by MPFF treatment, however, CD11b expression was not modified. This finding suggests that leucocyte L-Selectin interaction with endothelial selectins responsible for the initial stages of adhesion may be modulated by MPFF treatment, reducing the likelihood of leucocyte adhesion and presumably acting as an anti-inflammatory mechanism.
Significant down regulation of plasma levels of sVCAM-1 and sICAM-1 activity following therapy was observed indicates that endothelial damage which ensues in venous disease from chronic venous hypertension was mitigated by MPFF treatment. More detailed study is required to determine whether these measurable anti-inflammatory effects of flavonoids are central to the efficacy of flavonoids in the management of venous disease.
Topically applied preparations
A wide range of preparations is applied to venous leg ulcers in an attempt to heal them. A review of these would constitute a chapter in itself! A particular feature of patients with chronic venous disease of the leg and leg ulceration is their ability to become sensitised to many topically applied compounds. In most leg ulcer clinics, extreme care is used in topical applications since many commonly used drugs can produce skin sensitisation. Antibiotics are common culprits. Aminoglycoside antibiotics commonly present in preparations for topical use, may cause skin sensitisation. They have no effect on the healing of venous leg ulcers and should never be used! Topical steroids are often invaluable in the management of skin eczema resulting from sensitivity to one of the many chemicals used in the treatment of leg ulcers. Sometimes sensitisation occurs to one of the components of steroid creams and occasionally to the steroids themselves.
‘ Active’ treatments which might be applied topically include antiseptics such as cadexomer iodine. Cadexomer iodine paste has been compared to hydrocolloid dressings or paraffin gauze dressings and been found to lead to more rapid reduction in ulcer surface area. However, this paper did not assess time to complete healing of ulcers and therefore falls short of modern levels of proof of efficacy. The use of local antiseptic agents might address the bacterial colonisation of ulcers but since it seems unlikely that infection is the main cause of the continuation of a leg ulcer the effect of this type of treatment might be limited.
The work of Knighton suggested to many that venous leg ulcer healing could be speeded by the use of growth factors derived from platelets . This has led to preparations of platelet growth factors being licensed in the USA for use in non-healing leg and foot ulcers in patients with diabetes . However, there is little convincing evidence of efficacy of this type of compound in venous leg ulcers. Some authors have investigated granulocyte-macrophage colony stimulating factor (GM-CSF) in the treatment of venous leg ulcers . However, no large-scale leg ulcer healing study has been published showing an advantage of this type of treatment. A number of problems present themselves with this method of management. Firstly, it makes the assumption that venous leg ulceration is the result of faulty healing as well as the mechanisms which resulted in leg ulceration in the first place. It presumably makes the assumption that levels of growth factors in healing ulcers are pathologically reduced. There is no published evidence to support this assumption. Studies which have investigated the levels of tissue growth factors in ulcers mainly show greatly increased levels of tissue growth factors. Finally, there are the logistics of delivering a drug to an ulcer at a dose which is sustained and effective. This is especially difficult since ulcer dressings may remain in place for several days. To me it seems highly improbable that such an approach will be effective in patients with venous leg ulcers.
Conclusions
To return to the original question that I posed, what should we use and when? In the case of varicose veins, no drug will remove or diminish the varices except when used as sclerosant during sclerotherapy for varices. Where mitigation of symptoms is required compression stockings are very effective in temperate countries. In hot countries and where it is desirable to treat oedema, venoactive drugs should be considered if they are available. Hydroxyrutosides and drugs containing diosmin and hesperidine are effective.
In the management of leg ulceration, the following systemically administered drugs are ineffective at achieving healing of ulcers: aspirin, ifetroban, stanozolol, antibiotics, hydroxyrutosides. Topical growth factors have yet to be shown to have efficacy in this context. The following drugs have some efficacy in achieving ulcer healing when given systemically: pentoxifylline, flavonoids. It is clear that the available pharmacological treatments for venous disease are less effective than compression treatments or surgery in achieving healing of ulcers and that drug treatments should always be used as part of a regime of management rather than as an isolated treatment.
References
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Table 1 - Classification of venotonic drugs.
Natural products:
Benzopyrones
? Benzopyrones (coumarins)
coumarin (1,2-benzopyrone; 5,6-?-benzopyrone), melitot coumarinic derivatives
esculetin (6,7-dihydrooxycoumarin)
umbelliferone (7-hydroxycoumarin)
dicoumarols (dimers of 4-hydroxycoumarins): oral antocoagulants
gamma benzopyrones (flavenoids)
flavone and flavonols:
diosmine , kaempferol, diosmetin, quercetin,
rutine and derivatives, troxerutine, O-(?-hydroxyethyl) rutosides (HR or oxerutins)
flavanes and flavanones:
hesperetin, hesperidene, catechin, methylchalcone, flavonoic acid etc.
saponosides:
aescine, horse-chestnut extracts (protoescigenin, barringtogenol, ?-and ? -aescin, cryptoescin)
extracts of Ruscus (ruscosides), Centella asiatica
other plant extracts
anthocyanosides: blueberry extract
pycnogenols: leucocianidol, procyanidolic oligomeres: grape seed extracts
Ginkgo biloba
Ergot derivatives: dihydroergotamine, dihydroergocristine, dihydroergocryptine
Synthetic products
Calcium dobesilate
Benzarone
Naftazone
Tribenoside
Chromocrabe
Diethylamine
Adenosine phosphate
Heptaminol
Drug treatment of chronic venous insufficiency and venous ulceration
Key Points for Curriculum:
1. The most effective methods for achieving leg ulcer healing are strong compression bandaging or stockings. Surgical intervention to treat superficial venous reflux and incompetent assist healing and prevent recurrence.
2. Drugs are widely used in the management of venous ulceration. Few have activity in promoting venous ulcer healing. Those currently available should always be used in conjunction with compression treatment and surgery, where indicated.
3. In recent years drugs which modulate the inflammatory processes at work in the mechanisms have been the target of drug trials. Drugs which have been shown to have influence on venous healing are also known to influence leucocyte metabolism or leucocyte-endothelial interaction.
4. The following drugs have been shown to speed leg ulcer healing in randomised clinical trials: micronised purified flavonoid fraction (Daflon 500 mg®, Servier, Paris), pentoxifylline (Trental®, Aventis Pharma) and prostaglandin E1 analogue (Prostavasin, Schwarz Pharma).
5. The following systemically administered drugs are ineffective at achieving healing of ulcers: aspirin, ifetroban, stanozolol, antibiotics, hydroxyrutosides.
6. Topically applied growth factors have not been systematically shown to exhibit efficacy at accelerating wound healing in venous leg ulcers.
Selected references:
Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, Taylor M, Usher J, Wakely C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004; 363:1854-9.
Effect of surgical treatment or superficial veins on venous leg ulcer healing and recurrence.
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.
Efficacy of MPFF in healing venous leg ulcers.
Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2002;(1):CD001733.
Efficacy of pentoxifylline in healing venous leg ulcers.
Milio G, Mina C, Cospite V, Almasio PL, Novo S. Efficacy of the treatment with prostaglandin E-1 in venous ulcers of the lower limbs. J Vasc Surg. 2005; 42:304-8.
Efficacy of prostaglandin E1 in healing leg ulcers.
Introduction
Drugs are widely used as part of the management of chronic venous insufficiency and venous ulceration. In this paper I consider those which are used with the specific intention of influencing venous disease to achieve ulcer healing rather than in addressing complications of the disease such as infection or thrombotic events.
Mechanisms of venous disease
A great deal more is now known about the biological processes that are involved in the development of chronic venous insufficiency and leg ulceration. However, we still don’t know which are the crucial steps that might be influenced by drugs in the treatment of venous disease. Genetic factors are important in the development of superficial venous disease is inherited. , In patients with venous ulceration there is an increased incidence of inherited thrombophilias compared to control populations. , This probably reflects the cause of venous valvular incompetence rather than being integral to the mechanisms of development of leg ulcers since long term anticoagulation prevents further episodes of thrombosis but does not necessarily lead to healing of the ulcer. A great deal has been written on the subject of mechanisms in the microcirculation which give rise to leg ulceration. Understanding these mechanisms should suggest candidate drugs to promote leg ulcer healing. Some of these are discussed below.
We should consider firstly where drugs would be useful in the management of venous disease. In superficial venous disease traditional surgical techniques and sclerotherapy work well when appropriately applied. The more recent techniques of radiofrequency ablation, endovenous laser treatment and ultrasound guided foam sclerotherapy each have their advantages in the management of varicose veins. There is little scope here for systemic drug treatment. In any case, no drug has yet been found which will resolve valvular incompetence in any vein. However, drug treatment is commonly used for some of the milder symptoms which arise from superficial venous disease including aching, itching and feelings of swelling of the lower limb. ‘Phlebotonic’ drugs are commonly used in southern European countries where compression stockings are less popular.
However, in patients where deep venous incompetence is present there would be considerable advantage to the use of effective drug treatments. There is no widely used method of restoring competence to damaged valves. Surgical techniques for achieving this are well known but have limited efficacy and scope for application. The conventional method of managing lower limb oedema, lipodermatosclerosis and leg ulceration is the application of compression. There is considerable evidence of efficacy of this treatment but many elderly patients experience difficulty in managing the application of high levels of compression . In hot climates the use of compression hosiery is unpopular. The development of drugs which could be used alongside bandages or stockings to achieve more rapid ulcer healing than could be achieved by compression alone is highly desirable. Certainly, the use of high levels of compression (45 mm Hg at the ankle) can achieve rapid ulcer healing with 69% ulcers reported healed at 12 weeks in one study. This should remain the main modality of treatment in patients with deep venous incompetence once superficial venous reflux has been addressed by one of the methods mentioned above. As yet no drug has been shown to achieve the same level of healing as high levels of compression.
Our knowledge of why compression results in healing is also very limited. If we could understand how compression influences the mechanisms which lead to ulceration we might possess the knowledge required to unlock the problem of venous ulcer healing.
Drugs used to treat venous disease.
The first group of drugs used in the management of venous disease have long been used to address the symptoms of venous disease. These are mostly plant extracts although there is a small number of synthetic drugs. This group includes hydroxyrutosides, diosmin and herperidine all of which are flavonoids. Another widely used compound is aescin, which is present in many proprietary medications used in venous disease.
Diosmin is poorly absorbed from the GI tract and its oral use has been enhanced by micronisation, a process by which the drug is reduced to very small particles. Laurent investigated micronised purified flavonoid fraction (MPFF) and showed that this drug reduced the symptoms of venous disease (aching, itching, feeling of swelling) and also reduced ankle oedema. More recently MPFF has been studied for its effects on venous leg ulcer healing. A meta-analysis has been published in which five prospective, randomised, controlled studies involving 723 patients with venous ulcers were included. Patients were treated with compression bandaging and local wound care in all cases. In two studies MPFF was compared to placebo and in thee studies MPFF was compared to standard treatment alone. At 6 months, the chance of healing ulcer was 32% better in patients treated with adjunctive MPFF than in those managed by conventional therapy alone. The main benefit of MPFF was present in the subgroup of ulcers between 5 and 10 cm2 in area and those present for 6–12 months duration. MPFF therefore may be a useful drug to combine with compression management in countries where it is licensed. At present it is available in some European countries (but not the UK), in many Asian and South American countries but not the United States.
Pentoxifylline has been used for the treatment of claudication for a number of years, with moderate success. Its mechanism of action is probably throug
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Viktor Knyazhev
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