Date Last Updated: 21/07/04

Horse chestnut seed extract for the treatment of chronic venous insufficiency

Overview

Chronic venous insufficiency (CVI) is the pooling of blood in the lower leg, due to the inability of veins in the lower leg to transport blood back towards the heart. Common signs of CVI occur in the lower leg and include skin changes, pain on walking or after prolonged standing, swelling (oedema), and the development of non-healing wounds. An extract made from the seed of the horse chestnut tree is often used in herbal medicine as a treatment for CVI. This evidence summary identified three systematic reviews, 18 clinical trials (involving 1,258 people), and three observational studies (involving 10,725 people) on the use of horse chestnut seed extract (HCSE) for CVI. Overall, trial results indicate that HCSE significantly improves the majority of symptoms associated with CVI (such as leg pain, swelling and itching), compared to a placebo. These findings are supported by evidence from the observational studies conducted in this area. Trial results also indicate that HCSE is a more effective treatment for itching, flushing, fatigue and calf swelling than standard drugs used to reduce swelling in the lower legs. Mild but reversible side effects (such as constipation, diarrhea, vomiting, nausea, headache, itching and dizziness) can occur when using HCSE for the treatment of CVI, but are uncommon. No serious side effects associated with the use of HCSE for the treatment of CVI have been reported. Unprocessed horse chestnut seeds are extremely poisonous and should not be confused with the edible seeds of the sweet chestnut.

Background

Chronic venous insufficiency
Chronic venous insufficiency (CVI) is the inability of veins in the lower leg to transport blood back towards the heart, due to damage to the one-way valves within the leg veins. This damage is caused by blood clots (deep vein thromboses) or other factors, such as congenital disorders. As a result, blood within the veins begins to “pool” in the lower legs, leading to an increase in pressure within the veins in the leg¹. Signs of CVI include tired and aching legs, dry scaly skin, brown discolouration of the skin, swelling (oedema), eczema, varicose veins^1,2, hard, woody feeling skin (lipodermatosclerosis)³, and/or leg ulcers (open wounds on the lower legs that don’t heal after six weeks)¹. Pain is not a usual feature of CVI, although some people do experience a severe, bursting pain in the calf when walking (referred to as venous claudication) or pain in the leg muscles that occurs after prolonged standing¹. Some people also experience painful leg ulcers¹. CVI severity is often graded into three categories - stage I: swelling (oedema); stage II: swelling (oedema) plus skin changes; stage III: the presence of open or healed leg ulcers⁴. Stage III is considered the most severe stage of CVI. Other, more comprehensive classification systems also exist, but have yet to be used extensively in the literature^{5, 6}.

It is estimated that between 20-25% of adult women and 10-15% of adult men suffer from CVI, with the prevalence increasing with age⁷. CVI is sometimes referred to as the post-phlebitic syndrome, post-thrombotic syndrome or post-thrombophlebitic syndrome. The usual form of treatment for this condition is vascular surgery or the use of compression stockings or bandages to help the blood move back up the leg. However compliance with the use of compression can be poor, particularly if the stockings/bandages are uncomfortable. A recent review concluded that a combination of both compression and drugs that help prevent swelling, such as O-hydroxythyl rutosides or diosmin, improves CVI more than either treatment alone⁸.

Horse Chestnut
The horse chestnut (Aesculus hippocastanum L.) is a large, round-shaped tree growing to about 25-30 metres in height. The trunk is thick and usually short. The large leaves are divided into five or seven leaflets and have finely toothed margins. The tree is native to northern and central Asia, but is now widespread throughout the world⁹. Horse chestnut is also known as Rosskastanien (German), Buckeye, Chestnut, Escine, Hippocastani Cortex, Hippocastani Flos, Hippocastini folium, Hippocastani Semen, Marron Europeen, Marron d’Inde, or Spanish Chestnut. The fruit of the horse chestnut is a spiny, green sphere about 4 cm in diameter. When it ripens, the thick green husk splits to reveal one or more large, smooth, shiny brown nuts/seeds (often referred to as conkers). The seeds of the horse chestnut are extremely poisonous and can cause severe gastrointestinal (vomiting, diarrhea)¹⁰ reactions and neurotoxic reactions (muscle twitching, weakness, loss of coordination, dilated pupils, paralysis and stupor)¹⁰, if eaten. The seeds of the horse chestnut should not be confused with the edible seeds of the sweet chestnut (Castanea sativa L.)¹¹.

Unprocessed horse chestnut seeds contain a toxin called esculin (also spelled aesculin). This toxin may increase the risk of bleeding due to its ability to stop blood clots forming (antithrombotic)¹². Horse chestnut seeds are therefore processed to remove the toxic component, resulting in purified horse chestnut seed extract (HCSE). Trade names for HCSE include Aescorin, Catarrh cream, Noricaven, Hoevenol, Reparil, Tecura, Venastat, Venosin, Venoplant, Venostat, Venostasin, Venalot, Veinotonyl 75^{9, 13}. The active component of horse chestnut is a compound found in the seed extract, called escin (also spelled aescin)¹⁴. CVI-affected legs have an accumulation of white blood cells (leucocytes). The presence of these leucocytes results in the activation and release of certain enzymes (elastase and hyaluronidase). These enzymes are involved in breakdown of protein within the capillary (very small veins) walls¹⁵, which in turn leads to swelling and the skin changes associated with CVI. Cellular studies have shown that escin from HCSE can stop the activity of the elastase and hyaluronidase enzymes¹⁶. Escin also has a diuretic effect (promotes the passing of urine)^{17, 18.}

Traditionally, people have taken horse chestnut seeds for the treatment of varicose veins, haemorrhoids, vein inflammation (phlebitis), diarrhoea, fever, and enlarged prostate^{9, 19}. Horse chestnut bark has traditionally been used for the treatment of malaria and dysentery^{9, 19}. Horse chestnut leaf has traditionally been used to treat eczema, menstrual pain, soft tissue swelling, cough, arthritis and rheumatism^{9, 19}. As a topical application, horse chestnut bark is sometimes used to treat lupus and skin ulcers¹⁹. HCSE is administered orally for the treatment of CVI and a variety of other conditions, or as a topical preparation for the treatment of lupus and skin ulcers¹¹. HCSE is the third most common herbal product sold in Germany²⁰. A daily dose of 600 mg of standardised HCSE will contain between 100 - 150 mg of escin²¹.

HCSE can be obtained as an “over the counter” product from health food shops, supermarkets, pharmacies, etc. A medical herbalist may also prescribe HCSE. The practice of herbal medicine is not currently regulated by legislation in New Zealand, however many herbal medicine practitioners are affiliated with a self-regulated professional body (such as the New Zealand Association of Medical Herbalists).

Evidence reviewed in this summary

Efficacy information

Systematic reviews: Three systematic reviews have been conducted on this topic. The first was published in 1998²¹ and identified 13 clinical trials. The second review identified 18 clinical trials and three observational studies, and was published in 2002⁷. The third review is an update of the first review and was conducted by the same authors as part of the Cochrane Peripheral Vascular Diseases Group²². This review was completed in 2001 (but was last updated on the 26th February 2003) and identified 14 relevant clinical trials. All three reviews had slightly different selection criteria for trials. An additional review by the Cochrane Peripheral Vascular Diseases group is currently underway on “Phlebotonics for venous insufficiency”, and will include trials on HCSE²³.
Clinical trials: The above reviews identified 18 relevant randomised double-blind clinical trials, representing 1,258 people^24-41. Fourteen of the trials involved a placebo^{24-28, 31, 33-37, 39-41} and six trials compared HCSE to another treatment (either compression stockings²⁷ or drugs that help prevent swelling, such as O-hydroxythyl rutosides^{29, 30, 32, 38} or diosmin³⁴). Two trials were unpublished^{25, 34}. Since the above reviews were published one additional trial has been published looking at the effect of HCSE (as a mono-preparation) on CVI⁴². No clinical trials of HCSE for CVI are known to be currently underway (see http://www.controlled-trials.com/).
Other studies: Three observational studies^43-45 on this topic, representing 10,725 people, were identified by the systematic review conducted by Siebert, 2002⁷. Given the extensive coverage of the above studies, no other types of studies were assessed for this evidence summary.

Safety information

Systematic reviews: The above three systematic reviews reported information on side effects associated with the use of HCSE for the treatment of CVI^{7, 21, 22}.
Clinical trials: Nine^{25, 27, 31, 35-39, 41} of the 18 clinical trials identified by the above systematic reviews reported adverse event data.
Other studies: All three observational studies identified in the systematic review conducted by Siebert, 2002⁷ reported adverse event data. Side effects associated with the use of horse chestnut in general have been described in case reports^46-49, laboratory studies⁵⁰, and descriptive studies^51-55.

Evidence on efficacy

Trial results
Information of the use of HCSE for the treatment of CVI is available from three systematic reviews^{7, 21, 22} summarising results from 18 clinical trials^24-41. These trials involved a total of 1,258 people, with the trials ranging in size from 16 people to 240 people and the treatment period running from two to 12 weeks. It should be noted that the three systematic reviews used slightly different search criteria, and so different trials were identified in each. Overall, the identified trials were reasonably well conducted, although patient compliance (ie. did the person actually take the treatment) appeared only to be monitored in three trials^{27, 38, 39}, sample sizes were generally small (only four trials are known to have involved more than 100 people^{27, 31, 36, 38}), at least two trials did not state how they defined CVI^{33, 36}, and at least two trials reported that a large number of people stopped participating before the trial was finished (eg. drop out rates of 13.3%³⁸ and 19.5%³¹are known). These factors have the potential to bias the study findings. The authors of all three systematic reviews acknowledged that they might have missed identifying some trials/studies. Results from the reviews indicate that:

Overall, HCSE significantly improves the signs and symptoms of CVI, compared to a placebo.
Leg pain was assessed in six placebo-controlled trials (involving 552 people), and all found a significant reduction in leg pain in patients treated with HCSE compared to placebo^{25, 31, 33, 35, 36, 39}. Meta-analysis results from three of the trials (involving 312 people) indicated that people taking HCSE had a four-fold reduction in pain^{31, 36, 39}. One trial that compared HCSE to O-hydroxythyl rutosides reported no difference in leg pain between the two groups³².
Swelling was assessed in five placebo-controlled trials (involving 512 people)^{25, 31, 33, 35, 36}. Four of the trials (involving 461 people) found a significant reduction in this outcome in patients taking HCSE compared to a placebo. One trial found that HCSE may also protect against the development of leg swelling³⁰.
Itching (pruritus) was assessed in six placebo-controlled trials (involving 542 people)^{31, 33, 35, 36, 39, 40}. Four of the trials (involving 404 people) reported a significant reduction in this outcome. Meta-analysis results from three of the trials (involving 194 people) found an almost two-fold improvement in itching in those taking HCSE compared to a placebo^{31, 36, 39}. Results from two other trials (one that compared HCSE to baseline⁴⁰ and one that compared to O-hydroxythyl rutosides³²) support these findings.
Leg volume was assessed in six placebo-controlled trials (involving 440 people)^{26-28, 33, 39, 40}. Meta-analysis results using data from three trials (involving 200 people) indicated that leg volume was reduced by an average of 46ml in the HCSE group compared to the placebo group^{27, 28, 39}. There was no clear difference in leg volume in those taking HCSE compared to those taking O-hydroxythyl rutosides³⁸ or using compression stockings²⁷. There is evidence from one trial that the reduction in mean leg volume observed with the use of HCSE, may persist for up to six weeks after treatment has stopped³⁸.
Calf and ankle circumference was assessed in seven placebo-controlled trials (involving 480 people)^{25-27, 33, 37, 39, 40}. The differences in the size of effects seen below are likely due to the fact that different trials were summarized by each review, and that these trials differed according to patient characteristics, especially CVI stage.
1. Four trials reported that HCSE significantly reduced ankle circumference. The review by Pittler²² reported an average 4.7 mm reduction in ankle circumference, based on data from three trials (involving 80 people)^{25, 37, 40}. The review by Siebert⁷ reported an average 45 cm reduction in ankle circumference based on data from three trials (involving 208 people)^{27, 37, 39}. Results from two trials comparing HCSE with O-hydroxythyl rutosides found not clear difference between the two treatments for ankle circumference^{29, 32}.
2. Two trials (involving 60 people) reported that HCSE significantly reduced calf circumference. The review by Pittler²² reported an average 3.5 mm reduction in calf circumference based on data from three trials (involving 80 people)^{25, 37, 40}. The review by Siebert⁷ reported an average 40 cm reduction in calf circumference based on data from three trials (involving 208 people)^{27, 37, 39}. One trial reported that HCSE was more effective than O-hydroxythyl rutosides at reducing calf circumference (an average 6.8 mm reduction)³².
Calf cramps were assessed in two trials (involving 241 people)^{31, 36}. Meta-analysis results indicated that HCSE appeared to have no clear effect on calf cramps compared to a placebo.
Leg fatigue/heaviness was assessed in three trials (involving 332 people)^{31, 36, 39}. Meta-analysis results indicated that HCSE appeared to have no clear effect on leg fatigue/heaviness compared to a placebo.
None of the reviews presented results according to the different stages of CVI.

Since the identified reviews were last published/updated, one additional randomised trial (involving 40 people) has been published, which looked at the effectiveness of HCSE (Venostasin) compared to French maritime pine bark extract (Pycnogenol) for the treatment of CVI⁴². Results indicated that HCSE had no significant effect on the signs and symptoms of CVI or lipid (a type of fat) levels.

Observational study results
Information of the use of HCSE for the treatment of CVI is also available from three observational studies^43-45. These studies involved 10,725 people, with the treatment period running from four weeks to six months. Results from two studies^{43, 44} indicated that after treatment with HCSE,

Swelling improved by 84% in people with CVI.
Pain was reduced by 91% in people with CVI.
Leg heaviness was improved by 85% in people with CVI.

The above findings were supported by the result of the third observational study⁴⁵.

Evidence on safety

Adverse event data from the three systematic reviews^{7, 21, 22}, the nine clinical trials^{25, 27, 31, 35-39, 41}, and the three observational studies^43-45 reviewed for this summary indicate that:

Overall there is no clear difference in the number of adverse events experienced in people taking HCSE compared to those taking placebo⁷.
Mild but reversible side effects associated with the use of HCSE for CVI include gastrointestinal complaints (constipation, diarrhea, vomiting and nausea), headache, itching (pruritus), flushing, fatigue, and dizziness^{31, 35, 36, 38, 45, 56}.
Such side effects are uncommon. Combined results from three observational studies (involving 10,725 people)^43-45 suggest that three in every 200 people using HCSE for CVI will experience a side effect⁷, while trial data (involving 575 people) suggests that about five in every 200 people using HCSE for CVI will experience a side effect²².
No severe adverse events were reported in any of the trials or observational studies.
No clear difference in the occurrence of adverse events has been noted in people taking HCSE compared to those taking diosim³⁴ or using compression stockings²⁷ for the treatment of CVI.

In terms of using horse chestnut in general, three main types of side effects have been reported.

Kidney failure: Kidney failure has been documented in children^{47, 54} and adults⁵⁵ after receiving injections of escin, and in adults after taking high doses of escin⁴⁹.
Liver damage: Liver damage has been documented in one person after the intramuscular injection of a product containing horse chestnut⁴⁸.
Allergic reactions: An allergic reaction has been documented in one person after the rectal administration of a product for the treatment of haemorrhoids that contained esculin⁴⁶. There is one report of a person experiencing a severe allergic reaction (anaphylactic shock) after the injection of a horse chestnut extract⁵². Pollen from the horse chestnut flower has been reported to cause allergy in children⁵¹. There are reports that people who are allergic to latex are also often allergic to horse chestnut^{50, 53}.

Eating unprocessed (and therefore poisonous) horse chestnut seeds can result in vomiting, diarrhea, muscle twitching, weakness, loss of coordination, dilated pupils, paralysis, and stupor¹⁰. A number of publications state that deaths have occurred in children who have eaten unprocessed horse chestnut seeds, however, no documented evidence of these deaths could be located for this review.

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To find out more about any of the references listed below go to the "About page" of this website and read the section titled "How can referenced articles be obtained."

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