Intervention Review

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Flavonoids for treating venous leg ulcers

  1. Christopher Scallon1,*,
  2. Sally EM Bell-Syer2,
  3. Zoriah Aziz3

Editorial Group: Cochrane Wounds Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 11 FEB 2013

DOI: 10.1002/14651858.CD006477.pub2

How to Cite

Scallon C, Bell-Syer SEM, Aziz Z. Flavonoids for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD006477. DOI: 10.1002/14651858.CD006477.pub2.

Author Information

  1. 1

    Epsom, Surrey, UK

  2. 2

    University of York, Department of Health Sciences, York, North Yorkshire, UK

  3. 3

    University of Malaya, Department of Pharmacy, Faculty of Medicine, Kuala Lumpur, Malaysia

*Christopher Scallon, 298 Fir Tree Road, Epsom Downs, Epsom, Surrey, KT17 3NN, UK. chris.scallon@hotmail.co.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 31 MAY 2013

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Characteristics of included studies [ordered by study ID]
Glinski 1999

MethodsRCT: multi-centre trial involving 10 centres in Poland. Central randomisation list.


Participants140 (36 men and 104 women) patients aged over 18 years; 1 or more venous ulcers on lower extremities; ulcers 2-10 cm in diameter; ulceration present for at least 3 months; ankle-arm index (Doppler) > 0.9.


InterventionsGroup 1: Detralex® 500 mg containing diosmin 450 mg and hesperidin 50 mg (2 tablets/day) + local treatment + compression bandaging (n = 71).
Group 2: standard compression therapy and local treatment alone (n = 69).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, variation of ulcer surface area, cost-effectiveness, discomfort, pain, heavy legs, night cramps.

Primary outcomes
A. Proportion of healed ulcers:
Group 1: 33/71
Group 2: 19/69

B. Ulcer surface area (% reduction):
Group 1: 80%
Group 2: 65%

C. Time for ulcers to achieve complete healing: this outcome was not examined in the trial.

Secondary outcomes
D. Cost-effectiveness:
The cost effectiveness ratio (cost per healed ulcer) of MPFF group was EUR 1026.2 compared with EUR 1871.8 in control group. Treatment with MPFF and standard therapy was more effective and cheaper than standard therapy alone.

E. Hospitalisation (%), (mean number of days hospitalised):
Group 1: 14 (45)
Group 2: 19 (34)

F. Pain (% reduction):
Group 1: 57%
Group 2: 43% (difference not significant)

G. Adverse effects:
Slightly more adverse effects were reported in the control group than the MPFF group. The difference was not statistically significant. No other data were provided.

All other secondary outcomes were not reported.


NotesTreatment duration = 6 months.
Loss to follow-up = None.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomisation list prepared by the Biostatistics ....."

Allocation concealment (selection bias)High riskQuote: "....the allocation of each patient was known to the investigator from the randomisation list"

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskQuote:" the patients and doctors were aware of the treatment group to which the patient was allocated."
Comment: There are insufficient data to judge whether the outcome assessor was blinded in this study, however, the non-blinding of participants and personnel was unlikely to introduce bias for this outcome.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskQuote: "the patients and doctors were aware of the treatment group to which the patient was allocated."
Comment: There are insufficient data to judge whether the outcome assessor was blinded in this study.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Incomplete outcome data (attrition bias)
number of ulcers healed
Low riskComment: no loss to follow-up. Data were analysed according to ITT.

Incomplete outcome data (attrition bias)
wound surface area
Low riskComment: no loss to follow-up. Data were analysed according to ITT.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported.

Other biasUnclear riskNo other bias detected

Guilhou 1997

MethodsRCT: multi-centre trial involving 9 centres in France. Randomisation of treatment stratified according to size of ulcers (<10 cm or >10 cm).


Participants107 (41 men and 66 women) aged 18-85 years, presenting with leg ulcers of any size for 3 months. Ulcers of venous origin; open for at least 3 months; systolic pressure index (ankle-arm) > 0.8; patients willing to have elastic compression therapy.


InterventionsGroup 1: Daflon® 500 mg containing diosmin 450 mg, hesperidin 50 mg (2 tablets/day) + standardised local care + compression therapy (n = 55).
Group 2: placebo (2 tablets/day) + standardised local care + compression therapy (n = 52).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, time to complete healing, variation in ulcer surface area, appearance of ulcer and peri-ulcerous skin, evolution of symptoms, hospitalisation duration, adverse events.

Primary outcomes (The paper states that an ITT analysis was carried out on 105 participants, but it is not clear how missing data imputed)
A. Proportion of healed ulcers:
Group 1: 14/53
Group 2: 6/52

B. Ulcer surface area:
Did not present any data, however, the paper reported that the change in surface area over time was similar in the 2 groups.

C. Time for ulcers to achieve complete healing:
Time to healing was significantly shorter in the MFF group than in the placebo group (P value = 0.037).

Secondary outcomes
D. Hospitalisation:
Group 1: 7.5 days
Group 2: 14.5 days (P value = 0.113)

E. Adverse events:
Group 1; eczema (n = 2); urticaria (n = 1); pruritus of the scalp (n = 1); local pain (n = 1)
Group 2: skin changes around ulcer (n = 1); asthenia (n = 1); headaches (n = 1); exacerbation of chronic colopathy (n = 1).
All other secondary outcomes were not reported.


NotesTreatment duration = 2 months.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of the method used to generate allocation sequence.

Allocation concealment (selection bias)Unclear riskNo description of the method used to conceal the allocation sequence.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskComment: the study was described as a double-blind, randomised controlled trial, however, there was no description of how the participants, personnel and outcome assessor were blinded.

Blinding (performance bias and detection bias)
wound surface area
Low riskQuote: "Surface area was assessed by a computerised calculation blindly performed in one centre."
Comment: the study was described as a double-blind, randomised controlled trial, however, there was no description of how the participants and personnel were blinded. Nevertheless, the outcome assessor was blinded, and the non-blinding of others was unlikely to introduce bias for this outcome.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskComment: there was no description of how the participants, personnel and outcome assessor were blinded.

Incomplete outcome data (attrition bias)
number of ulcers healed
Unclear riskQuote: "107 patients were enrolled; two had no data available while under treatment. An ITT was, therefore, performed for 105 patients...."
Comment: it was not clear whether 2 patients were lost before, or after, randomisation.

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskQuote: "107 patients were enrolled; two had no data available while under treatment. An ITT was, therefore, performed for 105 patients...."
Comment: it was not clear whether 2 patients were lost before, or after, randomisation.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskComment: it was not clear whether 2 patients were lost before, or after, randomisation.

Selective reporting (reporting bias)Unclear riskComment: insufficient information for the ulcer surface area outcome. All other pre-specified outcomes were reported.

Other biasUnclear riskNo other bias detected

Roztocil 2002

MethodsRCT: multi-centre trial involving 17 centres in the Czech and Slovak Republics.


Participants150 (48 men and 102 women) aged over 18 years; venous ulcers only (2-10 cm diameter); ulcers present for at least 3 months; ankle-arm pressure index > 0.9; no history of skin grafting within 6 months prior to study.


InterventionsGroup 1: Daflon® containing diosmin 450 mg, hesperidin 50 mg (2 tablets/day) + standard local therapy + compression bandaging (n = 82).
Group 2: compression bandaging + standard local therapy alone (n = 68).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, time to complete healing, variation of the ulcer surface area, appearance of the skin in the ulcer area, clinical assessment of CVI evolution (leg heaviness, night cramps and pain).

Primary outcomes (The paper states that an ITT analysis was carried out, but it is not clear how missing data imputed)
A. Proportion of ulcers healed:
Group 1: 53/82
Group 2: 28/68

B. Ulcer surface area (% reduction from baseline):
Group 1: 77%
Group 2: 69%

C. Time for ulcers to achieve complete healing (mean):
Group 1:137 days
Group 2:166 days (P value 0.022)

Secondary outcomes
D. Pain:
Quote: "there was no significant difference between groups on the presence of night cramps and painful sensations." Other details not reported.

E. Adverse events:
Quote "No side effects in relation with treatment were observed".

All other secondary outcomes were not reported.


NotesTreatment duration = 6 months.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description of the method used to generate allocation sequence.

Allocation concealment (selection bias)Unclear riskNo description of the method used to conceal the allocation sequence.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskDescribed as a blinded study, but no information on blinding.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskDescribed as a blinded study, but no information on blinding.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskDescribed as a blinded study, but no information on blinding.

Incomplete outcome data (attrition bias)
number of ulcers healed
Unclear riskComments: imbalance in number of dropouts across the group: Treatment group 2/82; Control group 11/68. No description of how the trialists dealt with missing data.

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskVariation in wound surface area was pre-specified as secondary outcome. No descriptions of how the trialists dealt with missing data.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskNo descriptions of how the trialists dealt with missing data.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported.

Other biasUnclear riskNo other bias detected

Saveljev 2002

MethodsOpen RCT: multi-centre trial involving 3 centres in Moscow, Russia. Central randomisation list.


Participants124 (53 men and 71 women) aged 20-74 years, with venous leg ulcers only (2-10 cm diameter); ulcer present for at least 3 months.


InterventionsGroup 1: Detralex® 500 mg containing diosmin 450 mg and hesperidin 50 mg (2 tablets/day) + standard local therapy + compression bandaging (n = 62).
Group 2: standard therapy (elastic compression + local treatment) alone (n = 62).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, time to complete healing, variation of ulcer surface area, appearance of ulcers, symptoms and signs of vein diseases (heavy feeling in legs, pain, night cramps etc.), cost-effectiveness, adverse events.

Primary outcomes
A. Proportion of ulcers healed (paper states that missing data treated as if ulcer not healed)
Group 1:54/62
Group 2: 40/62

B. Ulcer surface area (% reduction from baseline):
Group 1: 82.1%
Group 2: 68.4%

C. Time to achieve complete healing (median):
Group 1: 90 days
Group 2: 119 days (P value 0.001)

Secondary outcomes
D. Cost-effectiveness:
The incremental cost-effectiveness ratio for MPFF group for the additional healing of another ulcer was RUB 10906.2, in comparison with standard therapy alone.

E. Hospitalisation:
Group 1: 1/62
Group 2: 3/62

F. Pain:
Reported no significant difference in severity or intensity in pain and frequency of night cramps between the two groups.

G. Adverse events:
Group 1: Arterial hypertension (4.8%); reduction in body mass (3.2%) - Total unwanted effects 21.0% (13/62)
Group 2: Reduction in body mass (1.6%) -Total unwanted effects 11.3% (7/62)

All other secondary outcomes were not reported.


NotesTreatment duration = 6 months.
Loss to follow up:
Group 1: 5/62
Group 2: 13/62


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "In accordance with the codes of the randomised list, all patients were randomly divided...."
Comment: insufficient information on how the randomised list was generated.

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskThis was an open randomised trial.
Comment: there are insufficient data to judge whether the outcome assessor was blinded in this study, however, the non-blinding of participants and personnel was unlikely to introduce bias for this outcome.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskThis was an open randomised trial.
Comment: there were insufficient data to judge whether the outcome assessor was blinded in this study.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskComment: there were insufficient data to judge whether the outcome assessor was blinded in this study, however, the non-blinding of participants and personnel was unlikely to introduce bias for this outcome.

Incomplete outcome data (attrition bias)
number of ulcers healed
High riskQuote: "5 patients in the main group and 13 patients in the control group left the trial early. Where this occurred, the patients were included in the category "has not healed"."

Comment: the missing data were greater in the control group (13/62) than the treatment group (5/62), and, since missing data were considered as "ulcer not healed", this would have given a greater treatment effect in favour of the treatment group.

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskInsufficient reporting on how the trialists dealt with missing data.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskInsufficient reporting of how the trialists dealt with missing data.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported.

Other biasUnclear riskComment: there was significant baseline difference between the 2 groups. Even though the trialists reported that adjustment was made to take account of the differences, it was not clear how the calculation was done. Calculation of percentage reduction without proper adjustment in wound area from baseline would have given a favourable result to the flavonoid group which had a smaller baseline ulcer area.

Schultz-Ehrenburg 1993a

MethodsRCT: multi-centre trial in 12 centres in Germany and Belgium.


Participants55 patients with CVI; minimum ulcer size 1.5 cm in 1 axis; ulcer persisted for > 1 year; minimum ankle-arm index 0.8.


InterventionsGroup 1: hydroxyethylrutosides (1 g/day) + compression bandaging + local therapy (n = 28).
Group 2: placebo tablets + compression bandaging + local therapy (n = 27).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, variation of ulcer surface area, maximal calf and minimal ankle circumferences, ulcer pain, orthostatic complaints, adverse events.

Primary outcomes
A. Proportion of wound healed:
Group 1: 12/23
Group 2: 7/25

B. Ulcer surface area (mean % reduction from baseline (SD)):
Group 1: 81 (29)
Group 2: 52 (54)

C. Time for ulcers to achieve complete healing:
This outcome was not examined.

Secondary outcomes
D. Pain:
No reference to pain was made in the publication, even though the authors reported that this outcome would be reported elsewhere.

E. Adverse events:
Adverse effects were reported to be evenly distributed between the groups and none was serious.

All other secondary outcomes were not reported.


NotesTreatment duration = 3 months.
Loss to follow up:
Group 1: 5/28
Group 2: 2/27


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: the study was described as randomised, but information about the sequence generation process was not provided.

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskComment: the study was described as double-blind but information about blinding was not provided.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskComment: the study was described as double-blind but information about blinding was not provided.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Incomplete outcome data (attrition bias)
number of ulcers healed
Unclear riskComment: unbalanced withdrawals from the two groups.

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskComment: unbalanced withdrawals from the two groups.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Selective reporting (reporting bias)Unclear riskQuote: "Results of the secondary end-points will be reported in a full publication elsewhere."
Comment: the authors did not report secondary outcomes, such as pain, probably because the paper is an extended abstract.

Schultz-Ehrenburg 1993b

MethodsRCT: multi-centre trial in 12 centres in Germany and Belgium.


Participants64 patients with CVI; minimum ulcer size 1.5 cm in 1 axis; ulcer persisted for > 1 year; minimum ankle-arm index 0.8.


InterventionsGroup 1: hydroxyethylrutosides (2 g/day) + compression bandaging + local therapy (n = 33).
Group 2: placebo tablets + compression bandaging + local therapy (n = 31).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, variation of ulcer surface area, maximal calf and minimal ankle circumferences, ulcer pain, orthostatic complaints, adverse events.

Primary outcomes
A. Proportion of wound healed:
No data provided. Reported as no difference between groups.

B. Ulcer surface area:
No data provided. Reported as no difference between groups.

C. Time for ulcers to achieve complete healing:
This outcome was not reported.

Secondary outcomes
D. Pain:
No reference to pain was made in the publication, even though the authors reported that this outcome would be reported elsewhere.

E. Adverse events:
Adverse events were reported to be evenly distributed between the groups, and none was serious.

All other secondary outcomes were not reported


NotesTreatment duration = 3 months.
Loss to follow up:
Group 1: 5/33
Group 2: 2/31


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: the study was described as "randomised" but information about the sequence generation process was not provided.

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskComment: the study was described as double-blind but information about blinding was not provided.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskComment: the study was described as double-blind but information about blinding was not provided.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Incomplete outcome data (attrition bias)
number of ulcers healed
Unclear riskComment: unbalanced withdrawals from the two groups.

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskComment: unbalanced withdrawals from the two groups.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Selective reporting (reporting bias)Unclear riskQuote: "Results of the secondary end-points will be reported in a full publication elsewhere."
Comment: the authors did not provide data for primary outcomes and secondary outcomes.

Other biasUnclear riskNo other bias detected

Stegmann 1986

MethodsRCT: multi-centre trial in 3 centres in Germany.


Participants107 men and women aged approximately 58 years.Venous ulcers; ambulatory venous pressure > 55 mm Hg; Refilling time < 8 seconds; lesion present.


InterventionsGroup 1: Paroven® containing hydroxyethylrutosides (2 × 500 mg tablets/day) + compression bandaging + local therapy (n = 55).
Group 2: compression bandaging and local topical therapy alone (n = 52).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, variation of ulcer surface area, circumference measurements of ankle, phlebitis induration, eczema, purpura, pains, night cramps, heavy and swollen legs, tingling sensations, paraesthesia.

Primary outcomes
A. Proportion of ulcers healed:
Group 1: 25/54
Group 2: 17/51

B. Ulcer surface area:
No data provided.

C. Time for ulcers to achieve complete healing:
This outcome was not examined.

Secondary outcomes:
D. Pain:
Pain was not specifically assessed, however, the study reported no significant differences between groups for venous symptoms (including pain).

All other secondary outcomes were not reported.


NotesTreatment duration = 6 weeks.
Loss to follow up:
Group 1:1/55
Group 2: 1/52


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: the study reported that patients received random allocation, but information about the sequence generation process was not provided.

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskThe method of blinding was not described.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskThe method of blinding was not described.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Incomplete outcome data (attrition bias)
number of ulcers healed
Low riskComment: missing outcome data balanced across the two groups (one missing from each group).

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskThis outcome was not reported.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskOutcome not assessed

Selective reporting (reporting bias)High riskData for variation in ulcer surface area and several pre-specified secondary outcomes were omitted.

Other biasUnclear riskNo other bias detected

Zuccarelli 1996

MethodsRCT: study conducted in France.


Participants126 patients with venous ulcers; ankle-arm index > 0.9; no other disease impairing wound healing.


InterventionsGroup 1: high dosage of troxerutin (4,000 mg/day) + standard compression + local therapy (n = 63).
Group 2: placebo + standard compression + local therapy (n = 63).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, time to complete healing, variation of ulcer surface area.

Primary outcomes
A. Proportion of ulcers healed:
Group 1: 30/63
Group 2: 15/63

B. Ulcer surface area cm2 (mean change from baseline (SD)):
Group 1: 6.2 (9.4)
Group 2: 1.6 (3.1)

C. Time for ulcers to achieve complete healing:
Faster time to complete healing observed in treatment group (logrank test:P value < 0.01).

Secondary outcomes
No secondary outcomes were reported.


NotesTreatment duration = 3 months.
Loss to follow up: no reference.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: the study was described as "randomised", but information about the sequence generation process was not provided.

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described.

Blinding (performance bias and detection bias)
number of ulcers healed
Unclear riskComment: the study was described as double-blind, but information about blinding was not provided.

Blinding (performance bias and detection bias)
wound surface area
Unclear riskComment: the study was described as double-blind, but information about blinding was not provided.

Blinding (performance bias and detection bias)
time to achieve complete healing
Unclear riskComment: the study was described as double-blind, but information about blinding was not provided.

Incomplete outcome data (attrition bias)
number of ulcers healed
Unclear riskComment: no information was given about the number lost to follow-up, even though the data were reported to be analysed according to ITT (it is not clear what assumptions were made for this ITT analysis).

Incomplete outcome data (attrition bias)
wound surface area
Unclear riskComment: no information on the number lost to follow-up was given, even though the data were reported to be analysed according to ITT (it is not clear what assumptions were made for this ITT analysis).

Incomplete outcome data (attrition bias)
time to achieve complete healing
Unclear riskComment: no information on the number lost to follow-up was given, even though the data were reported to be analysed according to ITT (it is not clear what assumptions were made for this ITT analysis).

Selective reporting (reporting bias)Unclear riskOutcomes of interest (number with complete healing and time to healing) were incompletely reported.

Other biasUnclear riskNo other bias detected

Zuccarelli 2004

MethodsRCT: multi-centre trial involving 19 centres in France (12) and Germany (7).
Block randomisation from a central randomisation list, with stratification by country.


Participants202 (73 men and 129 women) patients aged 35-86 years; with venous ulcers 2-10 cm diameter in 1 or both legs; ulceration present for at least 3 months; irrespective of the stage of debridement.


InterventionsGroup 1: Daflon® 500 mg containing diosmin 450 mg, hesperidin 50 mg (2 tablets/day) + standardised local care + compression therapy (n = 103).
Group 2: placebo (2 tablets/day) + standardised local care + compression therapy (n = 99).


OutcomesPre-specified outcomes
Proportion of fully healed ulcers, time to complete healing, variation of the ulcer surface area, aspect of peri-ulcerous skin, number and duration of hospitalisations, adverse events.

Primary outcomes (ITT analysis)
A. Proportions of healed ulcers:
Group 1: 53/103
Group 2: 54/99

B. Ulcer surface area (mean (SD) mm2):
Group 1: changed from 7.04 (6.83) to 2.97 (7.09) at endpoint.
Group 2: changed from 7.43 (9.40) to 2.75 (7.71) at endpoint.

C. Time to complete healing:
No statistical difference was observed between the two groups.

Secondary outcomes
D. Hospitalisation:
Group 1: 14/103
Group 2: 16/99 (P value not reported).

E. Adverse events:
Group 1: 29/103
Group 2: 19/99

All other secondary outcomes were not reported.


NotesTreatment duration = 6 months.

Loss to follow up:
Group 1: 17/103
Group 2: 13/99

Pains: not specifically assessed.

Cost-effectiveness: not specifically assessed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentrally-generated randomisation list.

Allocation concealment (selection bias)Low riskSequentially-coded, sealed envelopes used to conceal allocation.

Blinding (performance bias and detection bias)
number of ulcers healed
Low riskQuote: "Daflon 500 mg and placebo were supplied as identical tablets in appearance and taste: salmon pink film-coated tablets."
Comment: participants and study personnel (also outcome assessor) were blinded.

Blinding (performance bias and detection bias)
wound surface area
Low riskQuote: "Daflon 500 mg and placebo were supplied as identical tablets in appearance and taste: salmon pink film-coated tablets."
Quote: "The surface of the ulcer was assessed blindly by a computerised calculation."
Comment: participants, study personnel and outcome assessor were blinded.

Blinding (performance bias and detection bias)
time to achieve complete healing
Low riskComment: participants and study personnel (also outcome assessor) were blinded.

Incomplete outcome data (attrition bias)
number of ulcers healed
Low riskMissing data were imputed using method of last observation carried forward.

Incomplete outcome data (attrition bias)
wound surface area
Low riskMissing data were imputed using method of last observation carried forward.

Incomplete outcome data (attrition bias)
time to achieve complete healing
Low riskMissing data were imputed using method of last observation carried forward.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported.

Other biasUnclear riskNo other bias detected

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Balmer 1980Paper in German. English abstract. Participants did not have venous leg ulcers.

Belcaro 2005Not a randomised trial.

Gilly 1994Participants did not have venous leg ulcers.

Mann 1981Not a randomised trial.

Neumann 1996After trying several sources we were unable to obtain the full text of this paper for appraisal.

Shrivastava 2011Trial examined mixed wounds and did not present data on venous leg ulcers separately.

Wright 1991This trial examined the prevention of ulcer recurrence in patients with recently healed ulcers.

 
Comparison 1. MPFF versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of ulcers healed5723Risk Ratio (M-H, Random, 95% CI)1.36 [1.07, 1.74]

 2 Mean change in ulcer surface area from baseline (cm2)1150Mean Difference (IV, Fixed, 95% CI)0.93 [0.21, 1.65]

 3 Mean change in ulcer surface area from baseline (cm2)1124Mean Difference (IV, Fixed, 95% CI)-1.57 [-3.42, 0.28]

 4 Ulcer surface area (cm2) at trial-end1199Mean Difference (IV, Fixed, 95% CI)0.22 [-1.84, 2.28]

 5 Hospitalisation3466Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.47, 1.23]

 6 Adverse events3431Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.01, 2.30]

 
Comparison 2. Hydroxyethylrutosides (HR) versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of ulcers healed3279Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.24, 2.34]