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Meta-Analysis
. 2016 Apr 6;4(4):CD003229.
doi: 10.1002/14651858.CD003229.pub3.

Phlebotonics for venous insufficiency

Maria José Martinez-Zapata  1 , Robin W M Vernooij, Sonia Maria Uriona Tuma, Airton T Stein, Rosa M Moreno, Emilio Vargas, Dolors Capellà, Xavier Bonfill Cosp
Affiliations
Meta-Analysis

Phlebotonics for venous insufficiency

Maria José Martinez-Zapata et al. Cochrane Database Syst Rev. .

Update in

  • Phlebotonics for venous insufficiency.
    Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X. Martinez-Zapata MJ, et al. Cochrane Database Syst Rev. 2020 Nov 3;11(11):CD003229. doi: 10.1002/14651858.CD003229.pub4. Cochrane Database Syst Rev. 2020. PMID: 33141449 Free PMC article.

Abstract

Background: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005.

Objectives: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI.

Search methods: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015).

Selection criteria: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease.

Data collection and analysis: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses.

Main results: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events.

Authors' conclusions: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.

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Conflict of interest statement

Dr D Capellà, Dr X Bonfill Cosp, Dr RM Moreno and Dr E Vargas were part of an advisory group of the Safety Committee of the Spanish Drug Agency, whose objective was to assess the efficacy and safety of phlebotonics during 2002. Dr MJ Martínez assisted with technical work for this group.

Dr RM Moreno, Dr X Bonfill Cosp and Dr MJ Martínez‐Zapata were authors of a published double‐blind, placebo‐controlled clinical trial (Martinez‐Zapata 2008) that is included in this review. This study was sponsored by Laboratorios Dr Esteve, which markets calcium dobesilate (Doxium). Laboratorios Dr Esteve signed a written commitment to fully respect the researchers' independence and to allow dissemination of results, whatever they could be. Furthermore, Dr RM Moreno, Dr X Bonfill Cosp and Dr MJ Martínez‐Zapata were researchers in the included clinical trial DOBESILATO500/2, which was prematurely interrupted because of lack of funding.

Dr MJ Martínez‐Zapata: none known. Dr RWM Vernooij: none known. Dr SM Uriona Tuma: none known. Dr AT Stein: none known. Dr RM Moreno: none known. Dr E Vargas: none known. Dr D Capellà: chair of the Independent Drug Monitoring Committee of the clinical trial "Neurodegeneration as an early event in the pathogenesis of diabetic retinopathy: a multicentric, prospective, phase II‐III, randomised controlled trial to assess the efficacy of neuroprotective drugs administered topically to prevent or arrest diabetic retinopathy", carried out by the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) with support from the European Commission, FP7‐HEALTH‐2011‐GA No. 278040 and sponsored by BCN Peptides. Dr X Bonfill Cosp: none known.

Figures

1
1
Study flow diagram.
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Funnel plot of comparison: 1 Phlebotonics vs placebo, outcome: 1.1 Oedema in the lower legs (dichotomous variable).
5
5
Forest plot of comparison: 1 Phlebotonics vs placebo, outcome: 1.1 Oedema in the lower legs (dichotomous variable).
6
6
Forest plot of comparison: 1 Phlebotonics vs placebo, outcome: 1.22 Adverse events.
1.1
1.1. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 1 Oedema in the lower legs (dichotomous variable).
1.2
1.2. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 2 Ankle perimeter circumference (mm).
1.3
1.3. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 3 Volume of the leg (mL).
1.4
1.4. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 4 Ulcer cured.
1.5
1.5. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 5 Trophic disorders (dichotomous variable).
1.6
1.6. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 6 Pain in the lower legs (dichotomous variable).
1.7
1.7. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 7 Pain in the lower legs (continuous variable).
1.8
1.8. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 8 Cramps in the lower legs (dichotomous variable).
1.9
1.9. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 9 Cramps in the lower legs (continuous variable).
1.10
1.10. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 10 Restless legs (dichotomous variable).
1.11
1.11. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 11 Itching in the lower legs (dichotomous variable).
1.12
1.12. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 12 Itching in the lower legs (continuous variable).
1.13
1.13. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 13 Heaviness in the lower legs (dichotomous variable).
1.14
1.14. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 14 Heaviness in the lower legs (continuous variable).
1.15
1.15. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 15 Swelling in the lower legs (dichotomous variable).
1.16
1.16. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 16 Swelling in the lower legs (continuous variable).
1.17
1.17. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 17 Paraesthesia in the lower legs (dichotomous variable).
1.18
1.18. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 18 Paraesthesia in the lower legs (continuous variable).
1.19
1.19. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 19 Quality of life.
1.20
1.20. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 20 Global assessment by the participant (dichotomous variable).
1.21
1.21. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 21 Global assessment by the participant (continuous variable).
1.22
1.22. Analysis
Comparison 1 Phlebotonics versus placebo, Outcome 22 Adverse events.
2.1
2.1. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 1 Oedema in the lower legs (dichotomous variable).
2.2
2.2. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 2 Ankle perimeter circumference (mm).
2.3
2.3. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 3 Volume of the leg (mL).
2.4
2.4. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 4 Ulcer cured.
2.5
2.5. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 5 Trophic disorders (dichotomous variable).
2.6
2.6. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 6 Pain in the lower legs (dichotomous variable).
2.7
2.7. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 7 Pain in the lower legs (continuous variable).
2.8
2.8. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 8 Cramps in the lower legs (dichotomous variable).
2.9
2.9. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 9 Cramps in the lower legs (continuous variable).
2.10
2.10. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 10 Restless legs (dichotomous variable).
2.11
2.11. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 11 Itching in the lower legs (dichotomous variable).
2.12
2.12. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 12 Itching in the lower legs (continuous variable).
2.13
2.13. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 13 Heaviness in the lower legs (dichotomous variable).
2.14
2.14. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 14 Heaviness in the lower legs (continuous variable).
2.15
2.15. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 15 Swelling in the lower legs (dichotomous variable).
2.16
2.16. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 16 Swelling in the lower legs (continuous variable).
2.17
2.17. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 17 Paraesthesias in the lower legs (dichotomous variable).
2.18
2.18. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 18 Paraesthesias in the lower legs (continuous variable).
2.19
2.19. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 19 Quality of life.
2.20
2.20. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 20 Global assessment by the participant (dichotomous variable).
2.21
2.21. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 21 Global assessment by the participant (continuous variable).
2.22
2.22. Analysis
Comparison 2 Sensitivity analysis excluding studies that allowed the use of elastic stockings, Outcome 22 Adverse events.
3.1
3.1. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 1 Oedema in the lower legs (dichotomous variable).
3.2
3.2. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 2 Ankle perimeter circumference (mm).
3.3
3.3. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 3 Volume of the leg (mL).
3.4
3.4. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 4 Patients with ulcer (dichotomous variable).
3.5
3.5. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 5 Trophic disorders (dichotomous variable).
3.6
3.6. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 6 Pain in the lower legs (dichotomous variable).
3.7
3.7. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 7 Pain in the lower legs (continuous variable).
3.8
3.8. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 8 Cramps in the lower legs (dichotomous variable).
3.9
3.9. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 9 Cramps in the lower legs (continuous variable).
3.10
3.10. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 10 Restless legs (dichotomous variable).
3.11
3.11. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 11 Itching in the lower legs (dichotomous variable).
3.12
3.12. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 12 Itching in the lower legs (continuous variable).
3.13
3.13. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 13 Heaviness in the lower legs (dichotomous variable).
3.14
3.14. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 14 Heaviness in the lower legs (continuous variable).
3.15
3.15. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 15 Swelling in the lower legs (dichotomous variable).
3.16
3.16. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 16 Swelling in the lower legs (continuous variable).
3.17
3.17. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 17 Paraesthesias in the lower legs (dichotomous variable).
3.18
3.18. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 18 Paraesthesias in the lower legs (continuous variable).
3.19
3.19. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 19 Quality of life.
3.20
3.20. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 20 Global assessment by the participant (dichotomous variable).
3.21
3.21. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 21 Global assessment by the participant (continuous variable).
3.22
3.22. Analysis
Comparison 3 Sensitivity analysis of published studies only, Outcome 22 Adverse events.
4.1
4.1. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 1 Oedema in the lower legs (dichotomous variable).
4.2
4.2. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 2 Ankle perimeter circumference (mm).
4.3
4.3. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 3 Volume of the leg (mL).
4.4
4.4. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 4 Pain in the lower legs (dichotomous variable).
4.5
4.5. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 5 Pain in the lower legs (continuous variable).
4.6
4.6. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 6 Cramps in the lower legs (continuous variable).
4.7
4.7. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 7 Itching in the lower legs (dichotomous variable).
4.8
4.8. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 8 Itching in the lower legs (continuous variable).
4.9
4.9. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 9 Heaviness in the lower legs (dichotomous variable).
4.10
4.10. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 10 Heaviness in the lower legs (continuous variable).
4.11
4.11. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 11 Swelling in the lower legs (dichotomous variable).
4.12
4.12. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 12 Swelling in the lower legs (continuous variable).
4.13
4.13. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 13 Quality of life.
4.14
4.14. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 14 Global assessment by the participant (dichotomous variable).
4.15
4.15. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 15 Global assessment by the participant (continuous variable).
4.16
4.16. Analysis
Comparison 4 Sensitivity analysis based on low risk of bias, Outcome 16 Adverse events.
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References

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Koscielnny 1996 {published data only}
    1. Koscielnny J, Radtke H, Hoffmann, Jung F, Müller A, Grützner KI, et al. Fagorutin buckwheat herb tea in chronic venous insufficiency. Zeitschrift für Phytotherapie 1996;17(3):147‐59.
Kriner 1985 {published data only}
    1. Kriner E, Braun R, Hirche H, Laak HH. Treatment of venous insufficiency. A double‐blind trial with Phlebodril. Zeitschrift für Allgemeinmedizin 1985;61(9):309‐13.
Labs 2004 {published and unpublished data}
    1. Jaeger K. Efficacy and safety of doxium in chronic venous insufficiency. OM PHARMA (LAB. ESTEVE). Study number: DX‐1994/2.
    1. Jaeger K. Efficacy and safety of doxium in chronic venous insufficiency. Double‐blind, placebo‐controlled multicentre study. International Angiology 2001;20(2 Suppl 1):239. - PubMed
    1. Labs KH, Degischer S, Gamba G, Jaeger KA, on behalf of the CVI Study Group. Effectiveness and safety of calcium dobesilate in treating chronic venous insufficiency: randomized, double‐blind, placebo‐controlled trial. Phebology 2004;19(3):123‐9.
Languillat 1988 {published data only}
    1. Languillat N. Trial of Cyclo 3 Fort in venous insufficiency of the lower limbs: Xenon 133 functional investigation of venous circulatory velocity. Pierre Fabre Medicament Laboratories (Novartis). No. Report DC982GEC130(2), 1988.
Laurent 1988 {published data only}
    1. Laurent R, Gilly R, Frileux C. Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg. International Angiology 1988;7(2 Suppl):39‐43. - PubMed
Lazzarini 1982 {published data only}
    1. Lazzarini A, Danieli L. Clinical controlled trial of aminaphtone in lower limbs' phlebopathies and phlebopathic ulcers [Sperimentazione clinica controllata del l´aminaftone flebopatie degli arti inferiori e nelle flebopatiche]. Rassegna Internazionale di Clinica e Terapia 1982;62(12):825‐44.
MacLennan 1994 {published data only}
    1. Dikland WJ. A clinical trial on the effect of hydroxyethylrutosides on venous refilling time as measured by light reflection rheography. Scripta Phlebologica 1995;3:4‐7.
    1. MacLennan WJ, Wilson J, Rattenhuber V, Dikland WJ, Vanerdonckt J, Moriau M. Hydroxyethylrutosides in elderly patients with chronic venous insufficiency. Its efficacy and tolerability. Gerontology 1994;40(1):45‐52. - PubMed
Mann 1981 {published data only}
    1. Mann RJ. A double‐blind trial of oral O‐beta‐hydroxyethyl rutosides for stasis leg ulcers. British Journal of Clinical Practice 1981;35:79‐81. - PubMed
Marinello 2002 {published and unpublished data}
    1. Marinello J, Videla S. Chronic venous insufficiency of the lower limbs: suitability of transcutaneous blood gas monitoring as an endpoint to evaluate the outcome of pharmacological treatment with calcium dobesilate. Methods and Findings in Experimental and Clinical Pharmacology 2004;26(10):775‐80. - PubMed
    1. Marinello J, et al. Multicentric, randomised, double‐blind, placebo controlled, clinical trial that assess the efficacy of calcium dobesilate in the treatment of venous hypertension in patients with chronic venous insufficiency [Ensayo clínico multicéntrico, doble ciego, aleatorizado, controlado con placebo sobre la eficacia de dobesilato de calcio en el tratamiento de la hipertensión venosa en pacientes afectos de insuficiencia venosa crónica en sus extremidades inferiores. Código: ESCLIN‐004/99]. Laboratorios Dr. Esteve.
Martinez‐Zapata 2008 {published data only}
    1. Martinez‐Zapata MJ, Moreno RM, Gich I, Urrútia G, Bonfill X, Chronic Venous Insufficiency Study Group. A randomized, double‐blind multicentre clinical trial comparing the efficacy of calcium dobesilate with placebo in the treatment of chronic venous disease. European Journal of Vascular and Endovascular Surgery 2008;35(3):358‐65. - PubMed
Nocker 1990 {published data only}
    1. Nocker W, Diebschlag W. An investigation of dosage effects with drinking solutions of o‐(beta hydroxyethyl)‐rutosides. Vasa 1987;16:365‐9. - PubMed
    1. Nocker W, Diebschlag W, Lehmacher W. Clinical trials of the dose‐related effects of o‐(beta‐hydroxyethyl)‐rutosides in patients with chronic venous insufficiency. Phlebology 1990;5 Suppl 1:23‐6.
    1. Nocker W, Diebschlag W, Lehmacher W. Three‐month, randomized, double‐blind, dose‐response study with O‐(beta‐hydroxyethyl)‐rutosides drinking solution. Vasa 1989;18(3):235‐8. - PubMed
Padros 1972 {published data only}
    1. Padros W. Double blind investigation of clinical effectiveness of calcium dobesilate in the venous insufficiency syndrome (Dutch). Ars Medici Internationaal Tijdschrift voor Praktische Therapie 1977;6(8):1977.
    1. Padros W. Double blind study of the action of calcium dobesilate on venous insufficiency syndromes. Ars Medici Revue Internationale de Therapie Pratique 1977;32(8):783‐90.
    1. Padrós W. Controlled study of the effect of calcium dobesilate on syndromes of venous insufficiency. Medicina Clínica 1972;58(6):515‐9.
Parrado 1999 {published data only}
    1. Parrado F, Buzzi A. A study of the efficacy and tolerability of a preparation containing Ruscus aculeatus in the treatment of chronic venous insufficiency of the lower limbs. Clinical Drug Investigation 1999;18(4):255‐61.
Pecchi 1990 {published data only}
    1. Pecchi S, Franco V, Damiani P, Guerrini M, Perri T. Calcium dobesilate in the treatment of primary venous insufficiency of the lower limbs. A controlled clinical study [Il dobesilato di calcio nel trattamento del l´insufficienza venosa primitiva degli arti inferiori]. Clinica Terapeutica 1990;132(6):409‐17. - PubMed
Pedersen 1992 {published data only}
    1. Pedersen FM, Hamberg O, Sorensen MD, Neland K. The effect of O‐(beta‐hydroxyethyl)‐rutoside (Venoruton) on symptomatic venous insufficiency in the lower limbs. Ugeskrift for Laeger 1992;154(38):2561‐3. - PubMed
Petrassi 2000 {published data only}
    1. Petrassi C, Mastromarino A, Spartera C. Pycnogenol in chronic venous insufficiency. Phytomedicine 2000;7(5):383‐8. - PubMed
Planchon 1990 {published data only}
    1. Planchon B. Venous insufficiency and Daflon 500 mg [Insuffisance veineuse et Daflon 500 mg]. Artères et Veines 1990;IX(4):376‐80.
Pointel 1986 {published data only}
    1. Pointel JP. Titrated extract of centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1986;37(5):420‐1. - PubMed
    1. Pointel JP, Boccalon H, Cloarec M, Devehat C, Joubert M. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38(1 Pt 1):46‐50. - PubMed
Prerovsky 1972 {published data only}
    1. Prerovsky I, Roztocil K, Hlavova A, Koleilat Z, Razgova L, Oliva I. The effects of hydroxyethylrutosides after acute and chronic oral administration in patients with venous diseases. A double blind study. Angiologica 1972;9(3‐6):408‐14. - PubMed
Pulvertaft 1983 {published data only}
    1. Pulvertaft TB. General practice treatment of symptoms of venous insufficiency with oxerutins. Results of a 660 patient multicentre study in the UK. Vasa 1983;12(4):373‐6. - PubMed
    1. Pulvertaft TB. Paroven in the treatment of chronic venous insufficiency. Practitioner 1979;223(1338):838‐41. - PubMed
Rabe 2011 {published data only}
    1. Rabe E, Jaeger KA, Bulitta M, Pannier F. Calcium dobesilate in patients suffering from chronic venous insufficiency: a double‐blind, placebo‐controlled, clinical trial. Phlebology 2011;26:162–8. - PubMed
Renton 1994 {published data only}
    1. Renton S, Leon M, Belcaro G, Nicolaides AN. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. International Angiology 1994;13(3):259‐62. - PubMed
Rose 1970 {published data only}
    1. Rose SS. A report on the use of an hydroxyethylrutoside in symptoms due to venous back pressure and allied conditions in the lower limbs. British Journal of Clinical Practice 1970;24(4):161‐4. - PubMed
Rudofsky 1989 {published data only}
    1. Rudofsky G, Diehm C, Grub J, Hartmann M, Schultz‐Ehrenburg HU, Bisler H. Ruscus saponines and the flavonoid hesperidinmethylchalcone in the treatment of chronic venous insufficiency. Proceedings of the Union Internationale de Phlebologie ‐ 10th World Congress, Strasbourg, 25‐29 September. London and Paris: John Libbey Eurotext Ltd, 1989:728‐30.
    1. Rudofsky G, Diehm C, Gruss JD, Hartman M, Schultz‐Ehrenburg HK, Bisler H. Chronic venous insufficiency: treatment with Ruscus extract and trimethyl hesperidine chalcone. Münchener Medizinische Wochenschrift 1990;132(13):205‐10.
Schultz‐Ehrenburg 1993 {published data only}
    1. Schultz‐Ehrenburg U, Müller B. Two multicentre clinical trials of two different dosages of O‐(beta‐hydroxyethyl)‐rutosides in the treatment of leg ulcers. Phlebology 1993;8 Suppl 1:29‐30.
Sentou 1984 {published data only}
    1. Sentou Y. Double blind study of the activity of Cyclo 3 in man. International Angiology 1984;3:106‐9.
Serralde 1990 {published data only}
    1. Serralde CF, Aceves AQ. Clinical trial of the O‐(β‐hydroxy‐ethyl‐rutosides) in patients with chronic venous insufficiency [Ensayo clínico de o‐(beta‐hidroxietil‐rutósidos) en pacientes con insuficiencia venosa crónica]. Revista Médica del Hospital General de México 1990;53(2):102‐6.
Thebaut 1985 {published data only}
    1. Thebaut JF, Thebaut P, Vin F. Trial of vasculoprotective agent (plant products of the flavan class) in functional manifestations of peripheral venous insufficiency (double‐blind trial in 92 cases). Gazette Medicale 1985;92(12):96‐100.
Tsouderos 1989 {published data only}
    1. Tsouderos Y. Are the phlebotonic properties shown in clinical pharmacology predictive of a therapeutic benefit in chronic venous insufficiency. Our experience with Daflon 500 mg. International Angiology 1989;8(4):53‐9. - PubMed
    1. Tsouderos Y. Venous tone: are the phlebotonic properties predictive of a therapeutic benefit? A comprehensive view of our experience with Daflon 500 mg. Zeitschrift fur Kardiologie 1991;80 Suppl 7:95‐101. - PubMed
Unkauf 1996 {published data only}
    1. Unkauf M, Rehn D, Klinger J, Motte S, Grobmann K. Investigation of the efficacy of oxerutins compared to placebo in patients with chronic venous insufficiency treated with compression stockings. Arzneimittel‐Forschung 1996;46(5):478‐82. - PubMed
Vanscheidt 2002a {published data only}
    1. Vanscheidt W, Rabe E, Naser‐Hijazi B, Ramelet AA, Partsch H, Diehm C, et al. The efficacy and safety of a coumarin‐/troxerutin‐combination (SB‐LOT) in patients with chronic venous insufficiency: a double blind placebo‐controlled randomised study. Vasa 2002;31(3):185‐90. - PubMed
Vanscheidt 2002b {published data only}
    1. Vanscheidt W, Jost V, Wolna P, Lücker A, Muller A, Theurer C, et al. Efficacy and safety of a Butcher's broom preparation (Ruscus aculeatus L. extract) compared to placebo in patients suffering from chronic venous insufficiency. Arzneimittel‐Forschung 2002;52(4):243‐50. - PubMed
Vin 1994 {published data only}
    1. Vin E, Chabanel A, Taccoen A, Ducros J, Grufaz J, Hutinel B, et al. Action of Veinamitol 3500 mg on clinical and hemorheological data in CVI. International Angiology 1995;14(Suppl 1):99.
    1. Vin F, Chabanel A, Taccoen A, Ducros J, Gruffaz J, Hutinel B, et al. Action de la troxérutine sur les paramètres cliniques, pléthysmographiques et rhéologiques de l'insuffisance veineuse des membres inférieurs. Etude contrôlée contre placebo. Artères et Veines 1992;XI:333‐42.
    1. Vin F, Chabanel A, Taccoen A, Ducros J, Gruffaz J, Hutinel B, et al. Double‐blind trial of the efficacy of troxerutin in chronic venous insufficiency. Phlebology 1994;9(2):71‐6.
Welch 1985 {unpublished data only}
    1. Welch W, Moriau M, Gysel JP. A double‐blind, placebo controlled trial of o‐(beta‐hydroxyethyl)‐rutosides in patients with chronic venous insufficiency. Novartis 1985.
Widmer 1990 {published data only}
    1. Widmer L, Biland L, Barras JP. Doxium 500 in chronic venous insufficiency: a double‐blind placebo controlled multicentre study. International Angiology 1990;9(2):105‐10. - PubMed
Zucarelli 1987 {published data only}
    1. Zucarelli F. Clinical efficacy and tolerability of rutin. Double blind, placebo controlled clinical trial. [Efficacité clinique et tolerance de la coumarine rutine. Étude controlée en double aveugle versus placebo]. Gazette Médicale 1987;94(32):80‐6.

References to studies excluded from this review

Akbulut 2010 {published data only}
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Allaert 1992 {published data only}
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Bastide 1976 {published data only}
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Batchvarova 1989 {published data only}
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Batchvarova 1989a {published data only}
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Behar 1993 {published data only}
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Belcaro 1986 {published data only}
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Belcaro 1989 {published data only}
    1. Belcaro G, Rulo A, Candiani C. Evaluation of the microcirculatory effects of Venorutin in patients with chronic venous hypertension by laser Doppler flowmetry, transcutaneous PO2 and PCO2 measurements, leg volumetry and ambulatory venous pressure measurements. Vasa 1989;18:146‐51. - PubMed
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Belcaro 1995 {published data only}
    1. Belcaro G, Cesarone MR, Sanctis MT, Incandela L, Laurora G, Fevrier B, et al. Laser doppler and transcutaneous oxymetry: modern investigations to assess drug efficacy in chronic venous insufficiency. International Journal of Microcirculation: Clinical and Experimental 1995;15(Suppl 1):45‐9. - PubMed
Belcaro 2002 {published data only}
    1. Belcaro G, Cesarone MR, Bavera P, Ricci A, Renton S, Leon M, et al. HR (Venoruton1000, Paroven, 0‐[beta‐hydroxyethyl]‐rutosides) vs. Daflon 500 in chronic venous disease and microangiopathy: an independent prospective, controlled, randomized trial. Journal of Cardiovascular Pharmacology and Therapeutics 2002;7(3):139‐45. - PubMed
Belcaro 2003 {published data only}
    1. Belcaro G, Cesarone MR, Nicolaides AN, Geroulakos G, Acerbi G, Candiani C, et al. The LONFLIT4‐VENORUTON study: a randomized trial prophylaxis of flight‐edema in normal subjects. Clinical and Applied Thrombosis/Hemostasis 2003;9(1):19‐23. - PubMed
    1. Cesarone MR, Belcaro G, Brandolini R, Renzo A, Bavera P, Dugall M, et al. The LONFLIT4‐Venoruton Study: a randomized trial‐‐prophylaxis of flight‐edema in venous patients. Angiology 2003;54(2):137‐42. - PubMed
Belcaro 2008 {published data only}
    1. Belcaro G. Rosaria Cesarone M, Ledda A, Cacchio M, Ruffini I, Ricci A, et al. O‐(beta‐hydroxyethyl)‐rutosides systemic and local treatment in chronic venous disease and microangiopathy: an independent prospective comparative study. Angiology 2008;59(Suppl 1):7S‐13S. - PubMed
Belcaro 2008b {published data only}
    1. Belcaro G, Cesarone MR, Ledda A, Cacchio M, Ruffini I, Ricci A, et al. 5‐Year control and treatment of edema and increased capillary filtration in venous hypertension and diabetic microangiopathy using O‐(β‐hydroxyethyl)‐rutosides: a prospective comparative clinical registry. Angiology 2008;59(1):14S‐20S. - PubMed
Bello 1990 {published data only}
    1. Bello AA, Meyer K, Garcia AT, Reinaga VV. Calcium dobesilate combined with a heparinoid in the topical treatment of chronic venous insufficiency: a double‐blind study. Acta Therapeutica 1990;16(1):79‐87.
Beltramino 1999 {published data only}
    1. Beltramino R, Penenory A, Buceta AM. An open‐label, randomised multicentre study comparing the efficacy and safety of CYCLO 3 FORT versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. International Angiology 1999;18(4):337‐42. - PubMed
    1. Beltramino R, Penenory A, Buceta AM. An open‐label, randomized multicenter study comparing the efficacy and safety of Cyclo 3 Fort versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. Angiology 2000;51(7):535‐44. - PubMed
Bento 2006 {published data only}
    1. Bento C, Branda˜o DDC, Smith P. A multicentric, IV phase, multidisciplinary, prospective, randomized, double blinded, comparative study to evaluate the castanha‐da‐india, rutina, smilax japicanga and polygonum punctatum combination efficacy and tolerability in the treatment of patients suffering from symptomatic venous insufficiency comparing to placebo treatment. Revista Brasileira de Medicina 2006;63(8):422‐6.
Berson 1976 {published data only}
    1. Berson I. A double blind clinical trial in cases of CVI with doxivenil gel and another gel containing only a heparinoid [Expérimentation clinique dans l'IVC (double aveugle) du gel Doxivenil et d' un gel contenant un héparinoïde seul]. Schweizerische Rundschau fur Medizin Praxis 1976;65(32):991‐3. - PubMed
Berson 1978 {published data only}
    1. Berson I. About a new medicamentous treatment of the varicose syndrome. Schweiz Rundschau Med (PRAXIS) 1978;67:981‐3. - PubMed
Berson 1980 {published data only}
    1. Berson I, Geiser J‐D. An open comparative study of two phlebotoniques. Etude Comparative Ouverte Entre Deux phl ‚Botropes Chez Deux Groupes r‚ Partis au Hasard 1980;69(35):1244‐6.
Blume 1996 {published data only}
    1. Blume J. Therapy of venous oedema [Tratamento do edema de origem venosa. Eficácia de um tratamento medicamentoso em combinaçao com o tratamento compresivo]. Revista Brasileira de Medicina 1994;51(3):283‐8.
    1. Blume J, Wüstenberg P. Chronic vein insufficiency. Treatment results with benzopyrones during and after compression therapy [Cronisch‐venöse Insuffizienz (CVI). Behandlungsergebnisse mit benzopyronen und nach Kompressiontherapie]. Therapiewoche 1996;46(10):540‐4.
Boccalon 1989 {published data only}
    1. Boccalon H. Cyclo 3 fort and antagonism of plethysmographic disturbances observed upon exposure to heat: preliminary results. Phlebologie 1989;4(1):59‐62.
Bohm 1989 {published data only}
    1. Bohm C. Venodiuretics: a new combination of diuretic and edema protective drugs. Medizinische Welt 1989;40(30‐31):887‐8.
Boisseau 1995 {published data only}
    1. Boisseau MR, Taccoen A, Garreau C, Vergnes C, Roudaut MF, Garreau‐Gomez B. Fibrinolysis and hemorheology in chronic venous insufficiency: a double‐blind study of troxerutin efficiency. Journal of Cardiovascular Surgery 1995;36(4):369‐74. - PubMed
Bolliger 1972 {published data only}
    1. Bolliger AA. Results of a double blind trial of percutaneously administered rutoside. Angiologica 1972;9:397‐400. - PubMed
Bort 1995 {published data only}
    1. Bort H, Hahn M, Klyscz T, Junger M. The influence of rutosides on increased capillary permeability in chronic venous insufficiency as measured by video capillaroscopy. Proceedings of the Union Internationale de Phlebologie ‐ 12th World Congress, London, 3‐8 September. 1995.
Bosse 1985 {published data only}
    1. Bosse K, Drieschner P, Klose L. Comparative studies concerning the effectiveness of therapeutic agents in chronic venous insufficiency. Phlebologie und Proktologie 1985;14:111‐4.
Brami 1983 {published data only}
    1. Brami C, Morere MCNK, Megret G, Elbaz C. Double‐blind controlled trial against placebo of dihydroergocryptine mesilate plus caffeine in chronic venous insufficiency. Angeiologie 1983;35(8):281‐3.
Brock 1991 {published data only}
    1. Brock FE. Arnica montana and vein disease. Zeitschrift fur Phytotherapie 1991;12(5):141‐5.
Brock 2001 {published data only}
    1. Brock FE. Synergystic effect of vein ‐ typical hydrotherapy according to Kneipp and topical arnica ‐ treatment in patients with chronic venous insufficiency. Erfahrungsheilkunde 2001;50:357‐63.
Carstens 1985 {published data only}
    1. Carstens C, Hampel H. Treatment of oedemata in chronic venous insufficiency by means of an additional therapy with DIU Venostatin. Die Medizinische Welt 1985;36:867‐70.
Cataldi 2001 {published data only}
    1. Cataldi A, Gasbarro V, Viaggi R, Soverini R, Gresta E, Mascoli F. Effectiveness of the association of alphatocopherol, rutin, melilotus and centella asiatica in the treatment of patients affected by chronic venous insufficiency [Efficacia clinica di un'associazine di alfatocoferoli, rutina, meliloto e centella asiatica nel trattamento di pazienti con insufficienza venosa cronica]. Minerva Cardioangiologica 2001;49(2):159‐63. - PubMed
Cesarone 1992 {published data only}
    1. Cesarone MR, Laurora G, Ricci A, Belcaro G, Pomante P, Candiani C, et al. Acute effects of hydroxyethylrutosides on capillary filtration in normal volunteers, patients with venous hypertension and in patients with diabetic microangiopathy (a dose comparison study). Vasa 1992;21(1):76‐80. - PubMed
Cesarone 1994 {published data only}
    1. Cesarone MR, Laurora G, Sanctis MT, Incandela L, Grimaldi R, Marelli C, et al. Microcirculatory activity of centella asiatica in venous insufficiency. Minerva Cardioangiologica 1994;42(6):299‐304. - PubMed
Cesarone 2001 {published data only}
    1. Cesarone MR, Sanctis MT, Incandela L, Belcaro G, Griffin M, Bavera P, et al. Microvascular changes in venous hypertension due to varicose veins after standardized application of Essaven gel‐‐a placebo‐controlled, randomized study. Angiology 2001;52 Suppl 3:S11‐6. - PubMed
Cesarone 2001a {published data only}
    1. Cesarone MR, Belcaro G, Sanctis MT, Incandela L, Cacchio M, Bavera P, et al. Effects of the total triterpenic fraction of Centella asiatica in venous hypertensive microangiopathy: a prospective, placebo‐controlled, randomized trial. Angiology 2001;52 Suppl 2:S15–8. - PubMed
Cesarone 2001b {published data only}
    1. Cesarone MR, Incandela L, Belcaro G, Sanctis MT, Ricci A, Griffin M. Two‐week topical treatment with Essaven gel in patients with diabetic microangiopathy‐‐a placebo‐controlled, randomized study. Angiology 2001;52 Suppl 3:S43‐8. - PubMed
Cesarone 2001c {published data only}
    1. Cesarone MR, Belcaro G, Rulo A, Griffin M, Ricci A, Ippolito E, et al. Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2‐CO2, and leg volumetry 93. Angiology 2001;52 Suppl 2:S45‐8. - PubMed
Cesarone 2001d {published data only}
    1. Cesarone MR, Incandela L, Sanctis MT, Belcaro G, Geroulakos G, Griffin M, et al. Flight microangiopathy in medium‐ to long‐distance flights: prevention of edema and microcirculation alterations with total triterpenic fraction of Centella asiatica. Angiology 2001;52 Suppl 2:S33‐7. - PubMed
Cesarone 2001e {published data only}
    1. Cesarone MR, Incandela L, Sanctis MT, Belcaro G, Bavera P, Bucci M, et al. Evaluation of treatment of diabetic microangiopathy with total triterpenic fraction of Centella asiatica: a clinical prospective randomized trial with a microcirculatory model. Angiology 2001;52 Suppl 2:S49‐54. - PubMed
Cesarone 2002a {published data only}
    1. Cesarone MR, Belcaro G, Incandela L, Geroulakos G, Griffin M, Lennox A, et al. Flight microangiopathy in medium‐to‐long distance flights: prevention of edema and microcirculation alterations with HR (Paroven, Venoruton; 0‐(beta‐hydroxyethyl)‐rutosides): a prospective, randomized, controlled trial. Journal of Cardiovascular Pharmacology and Therapeutics 2002;7 Suppl 1:S17‐20. - PubMed
Cesarone 2002b {published data only}
    1. Cesarone MR, Incandela L, DeSanctis MT, Belcaro G, Dugall M, Acerbi G. Variations in plasma free radicals in patients with venous hypertension with HR (Paroven, Venoruton; O‐(beta‐hydroxyethyl)‐rutosides): a clinical, prospective, placebo‐controlled, randomized trial. Journal of Cardiovascular Pharmacology and Therapeutics 2002;7 Suppl 1:S25‐8. - PubMed
Cesarone 2003 {published data only}
    1. Cesarone MR, Belcaro G, Geroulakos G, Griffin M, Ricci A, Brandolini R, et al. Flight microangiopathy on long‐haul flights: prevention of edema and microcirculation alterations with Venoruton. Clinical and Applied Thrombosis/Hemostasis 2003;9(2):109‐14. - PubMed
Cesarone 2005 {published data only}
    1. Cesarone MR, Belcaro G, Pellegrini L, Ledda A, Renzo A, Vinciguerra G, et al. HR, 0‐(beta‐hydroxyethyl)‐rutosides, in comparison with diosmin+hesperidin in chronic venous insufficiency and venous microangiopathy: an independent, prospective, comparative registry study. Angiology 2005;56(1):1‐8. - PubMed
Cesarone 2006 {published data only}
    1. Cesarone MR, Belcaro G, Rohdewald P, Pellegrini L, Ledda A, Vinciguerra G, et al. Rapid relief of signs/symptoms in chronic venous microangiopathy with pycnogenol: a prospective, controlled study. Angiology 2006;57:569‐76. - PubMed
Cesarone 2006a {published data only}
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Henriet 1995 {published data only}
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Incandela 2001 {published data only}
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Incandela 2001b {published data only}
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References to ongoing studies

ISRCTN18841175 {published data only}
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NCT01532882 {published data only}
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NCT01848210 {published data only}
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