“Does horse chestnut have any effect on treating varicose veins?”
By Lucy Bell, . Medical Student, Royal Free Hospital
Current Varicose vein treatments include compression therapy; lifestyle measures such as weight loss and regular walking; injection sclerotherapy; laser coagulation; and surgical treatments to remove the veins, which is accepted as the most effective treatment in terms of long term prognosis (Paraskeva, 2010). However, as rates of recurrence and ineffectuality of treatments remain a problem – as well as the advantages that a completely non-invasive treatment would offer – finding a pharmaceutical treatment for CVI and varicose veins is an attractive prospect. A suggested source for such an agent is the extract of the nuts of the horse chestnut tree (aesculus hippocastanum), a dedicuous tree found widely throughout the temperate world (Alt. Med. Rev., 2009), which was first suggested in British Medical Journal as a treatment for venous conditions in 1928 in a letter, claiming the extract as an effective treatment for phlebitis (Patterson & Cyriax, 1928). Horse chestnut seed extract (HCSE) is currently used in Germany and, increasingly, in the USA in the treatment of CVI, as well as other conditions such as haemorrhoids and post-operative oedema. However, the mode of action by which the agent acts is a matter of discussion, as is the evidence for their efficacy in treating highly progressed CVI including varicose veins.
HCSE is a mixture of substances including bioflavinoids such as quercetin and kaempferol, proanthocyanidin A2 (an anti-oxidant), coumarins such as fraxin and aesculin, and the constituent which is proposed as the primary active agent in treatment of venous disease – aescin, a mixture of αand βtriterpine saponins, the latter of which is suggested to have anti-oedematous, anti-inflammatory and vasoprotective properties (Alt. Med. Rev., 2009). The chemical structure of aescin is shown in Figure 1.
Figure 1: chemical structure of aescin. (Sirtori, 2001).
The vast majority of the research into the action of aescin was carried out in Germanyin the 1960s and 1970s. Recent translations of research postulate it acts by selectively increasing the calcium sensitivity of smooth muscle in the walls of veins, and thus increases venous tone (Sirtori, 2001), as well as inhibiting hypoxia in the vessel walls and thus inhibiting the release of vasoactive substances and hence reducing vascular permeability. This is additionally combined with suggested actions reducing the adherence or activation of leukocytes in veins. All of these mechanisms could potentially reduce dilation of vessels and oedema, and preserve venous function (Guillame et al, 1994). An alternative or concomitant foundation of the action of aescin is suggested to involve inhibition of enzymes such as elastase and hyaluronidase which are involved in proteoglycan degradation, leading to a shift in balance of proteoglycan metabolism towards net synthesis rather than net breakdown, which could potentially “firm” vessel walls and prevent leakage and dilation (Pittler & Ernst, 1998).
The experiments used to elucidate these actions include studies of animal models in which aescin has been shown to prevent oedema from veins in its initial exudative stages, as well as significantly increasing venous contraction in experiments in which dog veins were exposed to aescin in vitro (Sirtori, 2001). However, one study which tested the constriction/relaxation function in vitro of non-varicose and varicose segments of human saphenous vein showed that while vasoactive contraction-stimulating drugs tested – aescin and phenylephrine – could stimulate contraction in the non-varicose veins but not in the varicose specimens (Brunner et al, 2000). The authors of this study suggest that venotonic drugs cannot be expected to work in veins which have walls which are severely diseased and insufficient, and thus that agents such as HCSE may only be effective in treatment of CVI in early stages and not when it has progressed to varicose veins due to inherent features of their pathophysiology. These conclusions are somewhat ramified by the clinical studies which have examined the efficacy of HCSE in the treatment of venous disease.
The Clinical Efficacy
An assortment of clinical trials have been performed which examine the use of HCSE in the treatment of CVI and/or varicose veins, including double-blind randomised control trials (RCTs) comparing HCSE to placebo controls or to reference medication controls. HCSE was typically trialled as an orally dosed capsule containing 100-150mg of aescin, taken twice daily; use of a topical gel was also examined, although not in any RCTs. Eight placebo controlled RCTs reviewed by Pittler & Ernst, 1998 suggested that HCSE can cause significant decreases in CVI clinical indicators such as lower leg volume and leg circumference at the calf and ankle. Patients also reported significant reduction of symptoms such as leg pain, fatigue and tenseness. Five reference medication controlled RCTs reviewed by the same authors reported similar findings, with HCSE showing similar efficacy to reference medications such as 0-rutosides. In all studies, patients generally reported tolerance to HCSE as a treatment option. Adverse drug reactions such as nausea, headache, dizziness and pruritis occurred in a minority of patients (0.9-3.0%), with no major oral toxicity, mutagenic/teratogenic effects or anaphylaxis reported. It must be noted that half of these trials involved small sample sizes (<100 patients) and that is likely that any trials producing negative results may have remained unpublished, due to some bias present in alternative medicine journals in which they are reported; before any definitive conclusions about efficacy of HCSE for widespread acceptable clinical use can be drawn, larger RCTs will be necessary.
An additional factor which must also be examined when considering HCSE as a clinical option is whether it has increased or comparable efficacy compared to other treatments for varicose veins and CVI. Two clinical studies have been undertaken which compare oral HCSE vs. placebo to compression therapy vs. placebo in the treatment of CVI; one in patients with early stage CVI without varicose veins and one in patients in later stage CVI when varicose veins are present (Ottillinger & Greeske, 2001). The former study found HCSE and compression therapy to be significantly and equally better than placebo in reducing leg volume (again used as a clinical indicator), but the latter found only compression therapy to demonstrate a significant effect with HCSE falling in efficacy as CVI severity increased. The results of this study are shown in Figure 2.
Figure 2: reduction of leg volume in CVI patients using HCSE vs. placebo and compression therapy vs. placebo. Grade I is defined as early CVI, Grade II and IIIa are defined as advanced CVI, by the Widmer/Marshall classification. (Ottillinger & Greeske, 2001).
This corroborates the basic science findings that aescin exhibits vasocontractive effects on non-varicose veins and not on varicose veins, as it may be that in early CVI, venous walls are not yet permanently damaged and so HCSE may have use in limiting or slowing the disease process, or at least in reducing symptoms, whereas later in disease progression, i.e. at the point of varicose veins, it is not an effective treatment option – thus compression therapy or surgery is likely to offer a better option at this point.
Chronic venous insufficiency (CVI), with the possibility of varicose veins as a consequence of disease progression, affects 25% of the population of Western Europe (Ottillinger & Greeske, 2001), and due to the severe morbidity that insufficient treatment may lead to, effective treatment options are clinically essential. Horse chestnut seed extract (HCSE), and in particular one constituent of the extract, aescin, has been suggested as a potential source of a pharmaceutical agent which may be effective in the treatment of these diseases. Examination of the scientific and clinical evidence investigating this claim suggests that aescin may indeed have some vasoactive effects which may be useful in the treatment of early stage CVI due to vaso-protective actions which can slow disease progression and prevent symptoms while veins are still capable of responding to vasoactive agents. However, in later stage disease, including when varicose veins are present, the pathophysiology of the disease state means that aescin may no longer be an effective treatment option; the fact that varicose veins are insufficient and do not respond to vascular control can be considered one of their cardinal clinical features and treatment must recognise this. Taken as a whole, these findings indicate that HCSE may have a use in early stage CVI in the prevention of varicose veins and other complications of venous insufficiency, but in treating varicose veins themselves, it is unlikely that HCSE will be of any significant benefit. However, before any widespread clinical use for any condition is ratified, there is still a requirement for larger and more thorough RCTs comparing HCSE to placebo and to alternative treatments including surgery, in order to fully verify it as a safe and effective treatment option.
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