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Study |

Horse-Chestnut Seed Extract for Chronic Venous Insufficiency:  A Criteria-Based Systematic Review FREE

Max H. Pittler, MD; Edzard Ernst, MD, PhD, FRCP, (Edin)
[+] Author Affiliations

From the Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, United Kingdom.


Arch Dermatol. 1998;134(11):1356-1360. doi:10.1001/archderm.134.11.1356.
Text Size: A A A
Published online

Objective  To assess the evidence for or against horse-chestnut seed extract (HCSE) as a symptomatic treatment of chronic venous insufficiency (CVI).

Data Sources  Computerized literature searches were performed in MEDLINE, EMBASE, BIOSIS, CISCOM, and the Cochrane Library (all from their respective institution to December 1996). The search terms were "horse chestnut," "Aesculus hippocastanum," "escin," and "Rosskastanie" (German for "horse chestnut"). There were no restrictions on the language of publication.

Study Selection  Double-blind, randomized controlled trials of oral HCSE for patients with CVI were included. Identifiers were removed from all publications before assessment.

Data Extraction  Data were extracted in a standardized, predefined manner. Trial outcomes and the methodological quality of each trial were independently assessed by the 2 reviewers.

Data Synthesis  The superiority of HCSE is suggested by all placebo-controlled studies. The use of HCSE is associated with a decrease of the lower-leg volume and a reduction in leg circumference at the calf and ankle. Symptoms such as leg pain, pruritus, and a feeling of fatigue and tenseness are reduced. Five comparative trials against the reference medication indicate that HCSE and O-(β-hydroxyethyl)-rutosides are equally effective. One trial suggests a therapeutic equivalence of HCSE and compression therapy. Adverse effects are usually mild and infrequent.

Conclusions  These data imply that HCSE is superior to placebo and as effective as reference medications in alleviating the objective signs and subjective symptoms of CVI. Thus, HCSE represents a treatment option for CVI that is worth considering.

WITH A prevalence of 10% to 15% in men and 20% to 25% in women, chronic venous insufficiency (CVI) is among the most common conditions afflicting humans.1,2 It is more than a mere "cosmetic problem" because patients often require hospital admission and surgical treatment. At least two thirds of leg ulcers have evidence of venous disease in the affected limb.2 The burden of suffering is high, and the economic costs for society are considerable. Although the therapy of choice is mechanical compression,3 compliance is often poor, which renders oral drug treatment an attractive option.

Horse chestnut (Aesculus hippocastanum) is an herbal remedy traditionally used for CVI.4 Horse-chestnut seed extract (HCSE), the active component of which is escin, a triterpenic saponin,57 has shown enzyme-inhibiting activity.8 The accumulation of leukocytes in CVI-affected limbs9,10 with their subsequent activation11 is considered an important pathophysiological mechanism of CVI. Horse-chestnut seed extract may work by preventing leukocyte activation.8 Regardless of the postulated mechanism of action, the most important question concerns HCSE's clinical effectiveness. Our aim in this systematic review is to summarize the evidence from randomized controlled trials (RCTs) for or against the effectiveness of HCSE in the symptomatic treatment of CVI.

Computerized literature searches were performed to identify all RCTs of HCSE for CVI. Databases included MEDLINE, EMBASE, BIOSIS, CISCOM, and the Cochrane Library (on CD-ROM; available from the Cochrane Collaboration) (all from their respective institution to December 1996). The search terms used were "horse chestnut," "Aesculus hippocastanum," "escin," and "Rosskastanie" (German for "horse chestnut"). All manufacturers of HCSE preparations were asked to contribute published and unpublished material, and our own extensive files were scanned. The bibliographies of the studies thus retrieved were searched for further trials. There were no restrictions on the language of publication.

Identifiers of all publications were concealed by eliminating (by a person not involved in the review) the names of the author(s), journal, and institution before assessment. Trial outcomes and the methodological quality of each trial were independently assessed by both of us using a standard scoring system to measure the likelihood of bias12 (Table 1). Disagreements in the evaluation of individual trials were resolved by discussion. Randomized controlled trials were included if performed on patients with CVI treated with HCSE monopreparations and if conducted double blind against placebo or the reference medication. Articles scoring below 3 (maximum, 5) points on the quality scale12 were excluded. A meta-analysis of trial results for leg-volume assessment in placebo-controlled RCTs had initially been planned. Because of variations in devices used for assessment and insufficient reporting of data, this plan had to be abandoned.

Table Graphic Jump LocationTable 1. Scoring System to Measure the Likelihood of Bias*

Sixteen RCTs were retrieved.1328 Relevant unpublished trials were not found. Three studies had to be excluded from this review, 213,14 because they were duplicate publications and 115 because it was not conducted with an HCSE monopreparation. Thirteen studies1628 fulfilled the inclusion-exclusion criteria. Eight of these1623 were placebo controlled, and 52428 were controlled against reference medications. All trials scored at least 3 of 5 points on a standard scoring system to measure the likelihood of bias.12 Two trials16,17 scored 5 points on this scale, suggesting the superiority of the use of HCSE over placebo for the symptomatic treatment of CVI. Table 2 summarizes key data of all included trials ranked in a hierarchical order according to their methodological quality score.

Table Graphic Jump LocationTable 2. Double-blind Randomized Controlled Trials (RCTs) of Horse-Chestnut Seed Extract (HCSE) for Chronic Venous Insufficiency (CVI)*

The placebo-controlled RCTs suggest a decrease in lower-leg volume and a reduction in leg circumference at the calf and ankle with the use of HCSE. Edema provocation before and after the treatment period revealed protective effects against edema. A decrease of the capillary filtration rate by 22% in HCSE-treated patients was suggested.17 The prevalence of symptoms such as leg pain, pruritus, and the feeling of fatigue and tenseness was reduced. All 5 RCTs against reference medications demonstrated evidence for the effectiveness of HCSE for the treatment of CVI. Although in 1 study,28 HCSE was stated to be superior to O -(β-hydroxyethyl)-rutosides in protecting against edema, most trials suggest that both drugs are of equal value. One trial26 suggests a therapeutic equivalence of HCSE and compression therapy. This trial was not properly blinded, however, so its results are subject to bias.

Significant beneficial effects for patients with CVI are reported in trials that administered HCSE standardized to 100 to 150 mg of escin per day. Two studies16,23 assessing the use of 100 mg of escin per day found a significant (P<.001 and P =.009, respectively) reduction of mean leg volumes after 2 weeks of treatment compared with placebo. The persistence of treatment effects is suggested by 1 study.25 At the end of a 6-week follow-up, the mean leg volume was not significantly different from posttreatment values. Most studies used the classification system by Widmer and Stähelin29 for categorizing patients and defining inclusion criteria (stage I: ankle edema without trophic changes; stage II: edema, hyperpigmented or depigmented areas, indurations; stage III: open or healed leg ulcer). Because no universally accepted classification of CVI exists to date, this seems the best available.1 Eleven trials1620,2328 used criteria of this classification system for including patients with CVI. Of the 1083 studied patients, 388 (35.8%) were categorized into CVI stages I to II. Three studies17,20,26 included patients with stages I to III. Two trials,21,22 comprising 29% of the studied patients, did not refer to this classification. The placebo response in trials assessing subjective variables as the main end point20,22 ranged from 20% to 27%. Changes of objective variables during placebo use are summarized in Table 2.

Eight studies16,18,2023,25,26 reported on adverse drug reactions (ADRs). Gastrointestinal tract symptoms, dizziness, nausea, headache, and pruritus were reported. The reported frequency of ADRs ranged from 0.9% to 3.0%. In 3 studies,18,21,23 the frequency of ADRs was not significantly different from that of placebo.

This criteria-based, systematic review suggests that HCSE is an effective therapy for CVI. Experts from Europe and the United States,30,31 however, remain unconvinced of its effectiveness for this condition. Herbal medicine is clearly more accepted in German-speaking countries than in England or the United States. Thus, it is not surprising that most of the studies are published by German authors. This may be 1 reason why this treatment option has gone unappreciated by English-speaking clinicians.

Even though our search strategy was comprehensive, that some trials have been missed cannot be entirely ruled out. Trials with negative results have a tendency to remain unpublished.32 In particular, in journals of complementary or alternative medicine, studies with positive findings may be overrepresented.33 The results of these trials might conceivably be biased and, thus, present a false-positive picture. All trials scored at least 3 of 5 points on a scale assessing the likelihood of bias (Table 1).12 Two studies16,17 reporting that HCSE was superior to placebo scored the maximum of 5 points. Despite this, none of the studies were completely flawless. Thus, the uncertain quality of the original data might be another source of bias. Future trials of CVI should be executed and reported in a uniform manner to enable subsequent statistical pooling in meta-analyses. Attention must be paid to the control of patient compliance, and the assessment of venous function would require standardization.34 Randomization and double-blinding procedures should be detailed in the published reports. Finally, carryover effects in crossover studies need to be taken into account.25

If, despite these caveats, HCSE is accepted as effective therapy for CVI, its mechanism of action may be of interest. The active component of HCSE is the saponin escin.5 It has been shown in vitro to inhibit the activity of elastase and hyaluronidase, both involved in the enzymatic proteoglycan degradation, which constitutes part of the capillary endothelium and is the main component of the extravascular matrix.8 Other studies9,10 have shown increased levels of leukocytes in CVI-affected limbs and suggest a possible subsequent activation with the release of such enzymes.11 An earlier study35 found increased serum activity of proteoglycan hydrolases in patients with CVI that was reduced with the use of HCSE. Treatment with HCSE may shift the equilibrium between the degradation and synthesis of proteoglycans toward a net synthesis, thus preventing vascular leakage. This hypothesis has been supported by a study of animals 36 ; using electromicroscopy, it demonstrated a marked reduction in vascular leakage after treatment with HCSE. Uncertainty exists about the effects of HCSE on venous tone. In vitro, HCSE increases the venous pressure of normal and pathologically altered veins. This is corroborated by studies of laboratory animals that demonstrate an increase in venous pressure and venous flow after HCSE administration.6 Studies16,17 of humans, however, have failed to replicate effects on venous capacity.

The conservative treatment of CVI comprises a variety of other modalities. Compression therapy improves venous return and is widely accepted as the treatment of choice.37 In combination with heparin, it prevents venous stasis and reduces the risk of deep-vein thrombosis. The use of O-(β-hydroxyethyl)-rutosides has beneficial short-term effects by reducing edema and relieving symptoms of CVI. Its efficacy during long-term use has yet to be established, however.38 The extract of Ruscus aculeatus decreases the capillary filtration rate in healthy volunteers and patients with CVI.39 One recent review40 concludes that combined treatment with edema protective agents and compression therapy has a better clinical benefit than either treatment alone.

Pruritus, nausea, gastrointestinal tract symptoms, headache, and dizziness were reported as ADRs to HCSE. In 3 studies,18,21,23 the frequency of ADRs with HCSE use was not significantly different from that with placebo. In a recent observational study41 involving more than 5000 patients with CVI, ADRs occurred in 0.6% of patients during treatment with HCSE. Gastrointestinal tract symptoms and calf spasm were reported most frequently. Adverse drug reactions are also reported from other symptomatic treatment options for CVI. Those of Ruscus extract include gastrointestinal tract symptoms and nausea, and ingesting O-(β-hydroxyethyl)-rutosides can cause allergic skin reactions.42 About a third of Scottish surgeons reported43 at least 1 case of skin necrosis or ulcers induced by compression therapy. These cumulative data imply that HCSE use is relatively safe.

The evidence presented here implies that HCSE is safe and effective as a symptomatic, short-term treatment of CVI. Publication bias and methodological shortcomings are important caveats. More rigorous RCTs are required to verify the usefulness of the treatment, especially for long-term use and as an adjunct to compression therapy.

Accepted for publication April 22, 1998.

Corresponding author: Edzard Ernst, MD, PhD, FRCP (Edin), Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom (e-mail: E.Ernst@exeter.ac.uk).

Callam  MJ Epidemiology of varicose veins. Br J Surg. 1994;81167- 173
Link to Article
Callam  M Prevalence of chronic leg ulceration and severe chronic venous disease in western countries. Phlebologie. 1992;7(suppl 1)6- 12
Partsch  H Compression therapy of the legs. J Dermatol Surg Oncol. 1991;17799- 805
Link to Article
Bombardelli  EMorazzoni  PGriffini  A Aesculus hippocastanum L. Fitoterapia. 1996;57483- 511
Lorenz  DMarek  ML Das therapeutische wirksame prinzip der rosskastanie (Aesculus hippocastanum). Arzneimittelforschung. 1960;10263- 272
Guillaume  MPadioleau  F Veinotonic effect, vascular protection, antiinflammatory and free radical scavenging properties of horse chestnut extract. Arzneimittelforschung. 1994;4425- 35
Schrader  ESchwankl  WSieder  CHChristoffel  V Vergleichende untersuchung zur bioverfügbarkeit von β-aescin nach oraler einmalverabreichung zweier rosskastaniensamenextrakt enthaltender, galenisch unterschiedlicher darreichungsformen. Pharmazie. 1995;50623- 627
Facino  RMCarini  MStefani  RAldini  GSaibene  L Anti-elastase and anti-hyaluronidase activities of saponins and sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency. Arch Pharm (Weinheim). 1995;328720- 724
Link to Article
Moyses  CCederholm-Williams  SAMichel  CC Haemoconcentration and accumulation of white cells in the feet during venous stasis. Int J Microcirc Clin Exp. 1987;5311- 320
Thomas  PRNash  GBDormandy  JA White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J (Clin Res Ed). 1988;2961693- 1695
Link to Article
Sarin  SAndaz  AShields  DAScurr  JHColeridge Smith  PD Neutrophil activation in venous disease. J Vasc Surg. 1993;17444
Jadad  ARMoore  ACarroll  D  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;171- 12
Link to Article
Pauschinger  P Klinisch experimentelle untersuchungen zur wirkung von roßkastaniensamenextrakt auf die transkapilläre filtration und das intravasale volumen an patienten mit chronisch venöser insuffizienz. Phlebol Proktol. 1987;1657- 61
Steiner  M Ausmaß der ödemprotektiven wirkung von roßkastaniensamenextrakt. Vasa. 1991;20(suppl 33)217
Dustmann  HOGodolias  GSeibel  K Verminderung des fußvolumens bei der chronischen venösen insuffizienz im stehversuch durch eine neue wirkstoffkombination. Therapiewoche. 1984;345077- 5086
Rudofsky  GNeiß  AOtto  KSeibel  K Ödemprotektive wirkung und klinische wirksamkeit von roßkastaniensamenextrakt im doppeltblindversuch. Phlebol Proktol. 1986;1547- 54
Bisler  HPfeifer  RKlüken  NPauschinger  P Wirkung von roßkastaniensamenextrakt auf die transkapilläre filtration bei chronisch venöser insuffizienz [Effects of horse-chestnut seed extract on transcapillary filtration in chronic venous insufficiency]. Dtsch Med Wochenschr. 1986;1111321- 1329
Link to Article
Pilz  E Ödeme bei venenerkrankungen. Med Welt. 1990;401143- 1144
Diehm  CVollbrecht  DAmendt  KComberg  HU Medical edema protection: clinical benefit in patients with chronic deep vein incompetence: a placebo controlled double blind study. Vasa. 1992;21188- 191
Friederich  HCVogelsberg  HNeiss  A Ein beitrag zur bewertung von intern wirksamen venenpharmaka. Z Hautkr. 1978;53369- 374
Lohr  EGaranin  GJesau  PFischer  H Ödempräventive therapie bei chronischer veneninsuffizienz mit ödemneigung. MMW Munch Med Wochenschr. 1986;12859- 81
Neiss  ABöhm  C Zum Wirksamkeitsnachweis von roßkastaniensamenextrakt beim varikösen symptomenkomplex. MMW Munch Med Wochenschr. 1976;118213- 216
Steiner  M Untersuchungen zur ödemvermindernden und ödemprotektiven wirkung von roßkastaniensamenextrakt. Phlebol Proktol. 1990;19239- 242
Kalbfleisch  WPfalzgraf  H Ödemprotektiva: äquipotente dosierung: roßkastaniensamenextrakt und O -β-hydroxyethylrutoside im vergleich. Therapiewoche. 1989;393703- 3707
Rehn  DUnkauf  MKlein  PJost  VLücker  PW Comparative clinical efficacy and tolerability of oxerutins and horse chestnut extract in patients with chronic venous insufficiency. Arzneimittelforschung. 1996;46483- 487
Diehm  CTrampisch  HJLange  SSchmidt  C Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet. 1996;347292- 294
Link to Article
Erdlen  F Klinische wirksamkeit von venostasin retard im doppelblindversuch. Med Welt. 1989;40994- 996
Erler  M Roßkastaniensamenextrakt bei der therapie peripherer venöser ödeme: ein klinischer therapievergleich. Med Welt. 1991;42593- 596
Widmer  LKStähelin  HB Peripheral Venous Disorders.  Bern, Switzerland Hans Huber1978;
Kelley  WN Textbook of Internal Medicine. 2nd ed Philadelphia, Pa JB Lippincott1992;
Kappert  A Lehrbuch und Atlas der Angiologie. 12th ed Bern, Switzerland Hans Huber1989;
Easterbrook  PJBerlin  JAGopalan  RMatthews  DR Publication bias in clinical research. Lancet. 1991;337867- 872
Link to Article
Ernst  EPittler  MH Alternative therapy bias [letter]. Nature. 1997;385480
Link to Article
Vayssairat  MDebure  CMaurel  AGaitz  JP Horse-chestnut seed extract for chronic venous insufficiency [letter]. Lancet. 1996;3471182
Link to Article
Kreysel  HWNissen  HPEnghofer  E Erhöhte serumaktivität lysomaler enzyme bei varikosis. Therapiewoche. 1983;331098- 1104
Enghofer  ESeibel  KHammersen  F Die antiexsudative wirkung von rosskastaniensamenextrakt. Therapiewoche. 1984;344130- 4144
Tooke  JELowe  GDO A Textbook of Vascular Medicine.  London, England Arnold1996;
Wadworth  ANFaulds  D Hydroxyethylrutosides. Drugs. 1992;441013- 1032
Link to Article
Rudofsky  G Beeinflussung der kapillären filtrationsrate durch phlebodril. Phlebologie. 1991;2014- 16
Diehm  C The role of oedema protective drugs in the treatment of chronic venous insufficiency: a review of evidence based on placebo-controlled trials with regard to efficacy and tolerance. Phlebology. 1996;1123- 29
Greeske  KPohlmann  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;114196- 200
Not Available, Bundesverband der Pharmazeutischen Industrie.  Frankfurt, Germany Editio Cantor1993;
Callam  MJRuckley  CVDale  JJHarper  DR Hazards of compression treatment of the leg: an estimate from Scottish surgeons. Br Med J (Clin Res Ed). 1987;2951382
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Scoring System to Measure the Likelihood of Bias*
Table Graphic Jump LocationTable 2. Double-blind Randomized Controlled Trials (RCTs) of Horse-Chestnut Seed Extract (HCSE) for Chronic Venous Insufficiency (CVI)*

References

Callam  MJ Epidemiology of varicose veins. Br J Surg. 1994;81167- 173
Link to Article
Callam  M Prevalence of chronic leg ulceration and severe chronic venous disease in western countries. Phlebologie. 1992;7(suppl 1)6- 12
Partsch  H Compression therapy of the legs. J Dermatol Surg Oncol. 1991;17799- 805
Link to Article
Bombardelli  EMorazzoni  PGriffini  A Aesculus hippocastanum L. Fitoterapia. 1996;57483- 511
Lorenz  DMarek  ML Das therapeutische wirksame prinzip der rosskastanie (Aesculus hippocastanum). Arzneimittelforschung. 1960;10263- 272
Guillaume  MPadioleau  F Veinotonic effect, vascular protection, antiinflammatory and free radical scavenging properties of horse chestnut extract. Arzneimittelforschung. 1994;4425- 35
Schrader  ESchwankl  WSieder  CHChristoffel  V Vergleichende untersuchung zur bioverfügbarkeit von β-aescin nach oraler einmalverabreichung zweier rosskastaniensamenextrakt enthaltender, galenisch unterschiedlicher darreichungsformen. Pharmazie. 1995;50623- 627
Facino  RMCarini  MStefani  RAldini  GSaibene  L Anti-elastase and anti-hyaluronidase activities of saponins and sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: factors contributing to their efficacy in the treatment of venous insufficiency. Arch Pharm (Weinheim). 1995;328720- 724
Link to Article
Moyses  CCederholm-Williams  SAMichel  CC Haemoconcentration and accumulation of white cells in the feet during venous stasis. Int J Microcirc Clin Exp. 1987;5311- 320
Thomas  PRNash  GBDormandy  JA White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J (Clin Res Ed). 1988;2961693- 1695
Link to Article
Sarin  SAndaz  AShields  DAScurr  JHColeridge Smith  PD Neutrophil activation in venous disease. J Vasc Surg. 1993;17444
Jadad  ARMoore  ACarroll  D  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;171- 12
Link to Article
Pauschinger  P Klinisch experimentelle untersuchungen zur wirkung von roßkastaniensamenextrakt auf die transkapilläre filtration und das intravasale volumen an patienten mit chronisch venöser insuffizienz. Phlebol Proktol. 1987;1657- 61
Steiner  M Ausmaß der ödemprotektiven wirkung von roßkastaniensamenextrakt. Vasa. 1991;20(suppl 33)217
Dustmann  HOGodolias  GSeibel  K Verminderung des fußvolumens bei der chronischen venösen insuffizienz im stehversuch durch eine neue wirkstoffkombination. Therapiewoche. 1984;345077- 5086
Rudofsky  GNeiß  AOtto  KSeibel  K Ödemprotektive wirkung und klinische wirksamkeit von roßkastaniensamenextrakt im doppeltblindversuch. Phlebol Proktol. 1986;1547- 54
Bisler  HPfeifer  RKlüken  NPauschinger  P Wirkung von roßkastaniensamenextrakt auf die transkapilläre filtration bei chronisch venöser insuffizienz [Effects of horse-chestnut seed extract on transcapillary filtration in chronic venous insufficiency]. Dtsch Med Wochenschr. 1986;1111321- 1329
Link to Article
Pilz  E Ödeme bei venenerkrankungen. Med Welt. 1990;401143- 1144
Diehm  CVollbrecht  DAmendt  KComberg  HU Medical edema protection: clinical benefit in patients with chronic deep vein incompetence: a placebo controlled double blind study. Vasa. 1992;21188- 191
Friederich  HCVogelsberg  HNeiss  A Ein beitrag zur bewertung von intern wirksamen venenpharmaka. Z Hautkr. 1978;53369- 374
Lohr  EGaranin  GJesau  PFischer  H Ödempräventive therapie bei chronischer veneninsuffizienz mit ödemneigung. MMW Munch Med Wochenschr. 1986;12859- 81
Neiss  ABöhm  C Zum Wirksamkeitsnachweis von roßkastaniensamenextrakt beim varikösen symptomenkomplex. MMW Munch Med Wochenschr. 1976;118213- 216
Steiner  M Untersuchungen zur ödemvermindernden und ödemprotektiven wirkung von roßkastaniensamenextrakt. Phlebol Proktol. 1990;19239- 242
Kalbfleisch  WPfalzgraf  H Ödemprotektiva: äquipotente dosierung: roßkastaniensamenextrakt und O -β-hydroxyethylrutoside im vergleich. Therapiewoche. 1989;393703- 3707
Rehn  DUnkauf  MKlein  PJost  VLücker  PW Comparative clinical efficacy and tolerability of oxerutins and horse chestnut extract in patients with chronic venous insufficiency. Arzneimittelforschung. 1996;46483- 487
Diehm  CTrampisch  HJLange  SSchmidt  C Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet. 1996;347292- 294
Link to Article
Erdlen  F Klinische wirksamkeit von venostasin retard im doppelblindversuch. Med Welt. 1989;40994- 996
Erler  M Roßkastaniensamenextrakt bei der therapie peripherer venöser ödeme: ein klinischer therapievergleich. Med Welt. 1991;42593- 596
Widmer  LKStähelin  HB Peripheral Venous Disorders.  Bern, Switzerland Hans Huber1978;
Kelley  WN Textbook of Internal Medicine. 2nd ed Philadelphia, Pa JB Lippincott1992;
Kappert  A Lehrbuch und Atlas der Angiologie. 12th ed Bern, Switzerland Hans Huber1989;
Easterbrook  PJBerlin  JAGopalan  RMatthews  DR Publication bias in clinical research. Lancet. 1991;337867- 872
Link to Article
Ernst  EPittler  MH Alternative therapy bias [letter]. Nature. 1997;385480
Link to Article
Vayssairat  MDebure  CMaurel  AGaitz  JP Horse-chestnut seed extract for chronic venous insufficiency [letter]. Lancet. 1996;3471182
Link to Article
Kreysel  HWNissen  HPEnghofer  E Erhöhte serumaktivität lysomaler enzyme bei varikosis. Therapiewoche. 1983;331098- 1104
Enghofer  ESeibel  KHammersen  F Die antiexsudative wirkung von rosskastaniensamenextrakt. Therapiewoche. 1984;344130- 4144
Tooke  JELowe  GDO A Textbook of Vascular Medicine.  London, England Arnold1996;
Wadworth  ANFaulds  D Hydroxyethylrutosides. Drugs. 1992;441013- 1032
Link to Article
Rudofsky  G Beeinflussung der kapillären filtrationsrate durch phlebodril. Phlebologie. 1991;2014- 16
Diehm  C The role of oedema protective drugs in the treatment of chronic venous insufficiency: a review of evidence based on placebo-controlled trials with regard to efficacy and tolerance. Phlebology. 1996;1123- 29
Greeske  KPohlmann  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;114196- 200
Not Available, Bundesverband der Pharmazeutischen Industrie.  Frankfurt, Germany Editio Cantor1993;
Callam  MJRuckley  CVDale  JJHarper  DR Hazards of compression treatment of the leg: an estimate from Scottish surgeons. Br Med J (Clin Res Ed). 1987;2951382
Link to Article

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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