Horse Chestnut Seed Extract for the Treatment of Chronic Venous Insufficiency
March 1999; Volume 2: 25-28
By Philippe O. Szapary, MD and Michael D. Cirigliano, MD
Chronic venous insufficiency (CVI) describes persistent incompetence of the deep and perforating veins in the lower extremities. Clinically, edema, hemosiderin deposition, atrophic skin changes, and ulcerations accompany leg pain, tiredness, and itching. CVI prevalence ranges from 10-15% in men and 20-25% in women.1 Traditional treatment includes external compression (support stockings) and for some, vascular surgery (venous stripping or sclerotherapy).
Extracts of horse-chestnut seeds (HCSE) have been extensively studied and used in German-speaking countries in the treatment of CVI. The Commission E has approved the use of HCSE for the treatment of CVI, especially when used as an adjunct to compressive therapy.2 The American College of Phlebology does not have an official position on the use of HCSE. There are good data to suggest HCSE’s efficacy.
History
The horse chestnut tree (Aesculus hippocastanum) belongs to the same family as the sweet chestnut and Ohio buckeye trees. Only the fruit of the sweet chestnut is edible while the fruits of the others are toxic.
Native to Greece and Albania, the horse chestnut tree was introduced in the United States in the 1740s as a shade tree. Growing up to 35 meters high, it bears long clusters of white flowers in May and a prickly fruit in the fall. Inside the fruit lie one to three large seeds; the extract of these seeds has been used in Europe since the 1800s as an oral remedy for various venous diseases. Published reports from France starting in 1896 discuss its use in varicose veins with insufficiency, hemorrhoids, and phlebitis.3
Pharmacology
The medicinal portion comes from the dried leaves and seeds.4 Most commonly, the dried seeds are pulverized and mixed with water and alcohol to yield a solution that contains triterpene saponins, hydroxycoumarins, flavonoids, and tan-nins.4,5 The most active ingredients are thought to be in the saponin mixture and are called escins (a- and b-escin). The escin fraction, measured as a percent and reported in milligrams, has been standardized by some pharmaceutical manufacturers. The primary hydroxy- coumarin isolated from horse chestnut seeds is aesculin, which is responsible for the majority of toxic side effects from this plant.6
Mechanism of Action
In general, escins are thought to act as anti-exudative and anti-inflammatory agents, decreasing vascular permeability and thus preventing edema formation. In vitro studies have shown that escins increase venous tone of isolated animal saphenous veins.5 Pure escins have been shown to decrease capillary hyperpermeability induced by histamine or serotonin, and decrease the formation of chemically induced inflammation in rats.7 Escins exhibit a dose-responsive inhibition of the early exudative stage of inflammation.
Human studies have shown that HCSE inhibits three serum lysosomal enzymes.8 These enzymes are important in the pathogenesis of CVI as they degrade proteoglycans in capillary walls allowing proteins to leak into the interstitium. By inhibiting these enzymes, HCSE may decrease capillary permeability and fragility. A "veno-tonic" effect lasted up to 14 days after HCSE was discontinued in one case series,9 demonstrating a significant carryover effect.
Clinical Trials
To date, there are approximately 18 published randomized controlled clinical trials (RCTs) evaluating the safety and efficacy of HCSE in patients with CVI. These studies have all been performed and published in Germany or France between 1973 and 1996.
A recent criteria-based systematic review of 13 of the best RCTs suggests the benefit of oral HCSE over placebo both in objective and subjective measurements in patients with CVI.1 HCSE was equally as effective as O-(b-hydroxyethyl) rutosides in three RCTs and to compression therapy in one trial. Most RCTs used a standardized HCSE preparation containing 50 mg of escins given twice a day. RCTs lasted between two and 12 weeks and used a wide variety of subjective (complaint scales) and objective (leg volume) endpoints. Two of these RCTs merit special consideration.
Rudofsky et al reported on the effects of 50 mg escin bid vs. placebo over 28 days in 40 subjects (67% women) with grade I or II CVI as defined by strict clinical and plethysmographic criteria.10
The results showed a statistically significant reduction in leg volume by 78 ml in the evening as measured by liquid plethysmography, while leg volume increased by 34 ml in placebo treated patients. While this study failed to show a significant effect on venous capacity, it did show a statistically significant change in both calf and foot circumference at 28 days (P < 0.01). Also, a Likert scale showed significant improvements in pain, pruritus, fatigability, and fullness in the HCSE treated group.
Diehm et al11 conducted a 12-week single-blind trial comparing 50 mg escin bid vs. compression stockings vs. placebo in 240 patients with varying degrees of CVI. The primary endpoint was logarithmically transformed leg volume as measured by water displacement plethysmography. Subjects assigned to compressive therapy also received a seven-day course of a thiazide diuretic prior to being individually fitted with a class II compression stocking.
Compliance with HCSE was better (98%) than with compressive therapy (90%). While the compression group achieved a peak effect at four weeks, the HCSE group achieved a similar effect at 12 weeks. At the conclusion of the study, there was a non-significant trend favoring compression (47 ml decrease) over HCSE (44 ml decrease), but both therapies were clearly superior to placebo (10 ml increase). Whether changes in leg volume were clinically significant is unknown, as there was no mention of symptom or function changes.
Most trials, including the latter two, were in part sponsored by Klinge Pharma, makers of Venostasin (a German brand of standardized HCSE). The lack of uniformity in the definition and grading of CVI, and the lack of standardization of endpoints diminish somewhat the scientific value of these studies.
Adverse Effects and Drug Interactions
While horse chestnut pollen is allergenic in sensitized individuals, oral HCSE appears to be well-tolerated.12
The most common side effects are pruritus, nausea, dyspepsia, headache, and dizziness.1 Most studies show no difference when compared to placebo. A recent observational study found that adverse events occurred in 0.6% of 5,000 patients treated with HCSE in therapeutic doses.13 There are no studies on the use of HCSE in pregnancy or lactation, and no reported drug-drug interactions.
However, there are two reports of toxic nephropathy and one report of hepatic injury in patients given large doses of escins.4 When given in supratherapeutic doses to animals, escins have also been reported to cause fatal hemolysis.4 It is possible that HCSE may interfere with warfarin, as HCSE possesses some coumarin constituents.
Formulation and Dosage
Oral HCSE preparations vary in their total milligram dosage, but usually report a % triterpene glycosides (calculated as escin) ranging from 16-21%. The recommended dose is 50 mg escins PO bid, with a maximum daily dose of 150 mg/d. Occasionally, HCSE is a component of a multiherbal preparation that often includes Ruscus aculeatus or butcher’s broom, for which there are few good clinical data.
Three combination products that contain HCSE rank among the most commonly prescribed herbal remedies in Germany.3 Until recently, standardized HCSE preparations were only available in Europe. In 1998, Pharmaton, a division of Boehringer Ingelheim Pharmaceuticals, released Venastat in the United States for the "promotion of leg vein health." This standardized HCSE represents one of the first examples of large pharmaceutical companies producing herbal preparations.
Topical HCSE solutions also exist but there are few clinical data to support their use.14
Conclusions
Standardized HCSE appears to be an effective treatment for the edema and symptoms associated with CVI. While there is mounting clinical evidence to suggest that HCSE is better than placebo, there is only one trial comparing HCSE to the current gold standard treatment of compressive therapy.
When used at the recommended dose, HCSE appears to be both safe and effective and compares favorably to other currently available therapies for CVI in the United States. (See Table 1.)
| Table 1 | |||
| Comparison of therapies for CVI available in the United States | |||
|
|
|
Recommended Dose or Usage | Cost# |
| Venastat (Pharmaton) | 300 mg HCSE, 16% TTG* | 48 mg PO bid | $20/month |
| Horse-Chestnut (Nature’s Life) | 300 mg HCSE, 16-20% TTG* | 56 mg PO bid | $10/month |
| Support hosiery | anti-embolism elastic stockings (TED) | 18 mm Hg worn during waking hours | $15/pairº knee high |
| fitted, compressive stockings (Jobst) | 20-30 mm Hg or 30-40 mm Hg worn during waking hours | $60/pairº knee high | |
| Surgical therapy | sclerotherapy | localized injections PRN | $300/session |
| vein ligation and stripping | one-time surgery | $10,832 | |
| * TTG = triterpene glycosides
# For HCSE and stockings, cost is average retail cost. For sclerotherapy, cost depends largely on the number of treatments needed (average of three). Surgical cost includes physician and hospital charges at a university hospital. º One pair of support hosiery provides reliable compression for up to three months. _______________________________________________________________________________________________________ |
|||
Recommendation
Standardized HCSE should be considered in the treatment of non-pregnant, non-lactating patients with CVI. HCSE can be used alone, and probably in combination with compressive therapy. While compression stockings are still considered first-line therapy, HCSE can be used as monotherapy in patients who cannot tolerate or comply with compressive therapy. Because of the lack of data, HCSE should not be used in patients with acute or chronic DVT, in patients on coumadin, or in patients with renal or hepatic insufficiency. Longer clinical trials in patients with similar grade CVI, using validated symptom measures and standardized leg volume measurements are still needed prior to HCSE becoming part of standard medical formularies.
Dr. Cirigliano and Dr. Szapary are Assistant Professors in the Department of Medicine at the University of Pennsylvania in Philadelphia.
References
1. Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency. A criteria-based systematic review. Arch Dermatol 1998;134:1356-1360.
2. Blumenthal M., ed. Horse Chestnut Seed. In: The Complete German Commission E Monographs, Therapeutic Guide to Herbal Medicines, 1st ed., Austin, Texas: American Botanical Council; 1998:148-149.
3. Schulz V, et al. Chronic Venous Insufficiency. In: Rational Phytotherapy, A Physicians’ Guide to Herbal Medicine, 3rd ed., New York: Springer-Verlag; 1998:128-138.
4. Aesculus hippocastanum (horse chestnut). In: PDR for Herbal Medicines, 1st ed., Montvale, NJ: Medical Economics Company; 1998:613-616.
5. Newell CA, et al., eds. Horse-chestnut Monograph. In: Herbal Medicines: A Guide to Health-Care Professionals, 1st ed., London, England: Pharmaceutical Press; 1996:166-167.
6. Lawrence Review of Natural Product. Horse Chestnut. St Louis, MO: Facts and Comparisons; October 1998: 1-3.
7. Matsuda H, et al. Effects of escins Ia, Ib, IIa, and IIb from horse chestnut, the seeds of Aesculus hippocastanum L., on acute inflammation in animals. Biol Pharm Bull 1997;20:1092-1095.
8. Kreysel HW, et al. A possible role of lysosomal enzymes in the pathogenesis of varicosis and the reduction in their serum activity by Venostasin. Vasa 1983;12:377-382.
9. Klemm J, Enghofer E. The influence of Venostasin on blood flow in varicose veins of the lower limbs. Munch Med Wochenschr 1982;124:579-582.
10. Rudofsky G, et al. Demonstration of the anti-oedematous effect and the clinical efficacy of horse-chestnut extract in a double-blind study. Phlebol Proktol 1986;15:47-54.
11. Diehm C, et al. Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet 1996;347:292-294.
12. Popp W, et al. Horse chestnut (Aesculus hippocastanum) pollen: A frequent cause of allergic sensitization in urban children. Allergy 1992;47:380-383.
13. Greeske VK, Pohlmann BK. Rosskastaniensamenextrakt: Ein wirksames therapieprinzip in der praxis (Horse-chestnut seed extract—An effective therapy principle in general practice. Drug therapy of chronic venous insufficiency.) Fortschr Med 1996;114:196-200.
14. Mashour NH, et al. Herbal medicine for the treatment of cardiovascular disease: Clinical considerations. Arch Intern Med 1998;158:2225-2234.
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