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Antibiotics and antiseptics for venous leg ulcers

  1. Susan O'Meara1,*,
  2. Deyaa Al-Kurdi2,
  3. Yemisi Ologun3,
  4. Liza G Ovington4,
  5. Marrissa Martyn-St James5,
  6. Rachel Richardson6

Editorial Group: Cochrane Wounds Group

Published Online: 23 DEC 2013

Assessed as up-to-date: 24 MAY 2013

DOI: 10.1002/14651858.CD003557.pub4


How to Cite

O'Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD003557. DOI: 10.1002/14651858.CD003557.pub4.

Author Information

  1. 1

    University of Leeds, School of Healthcare, Leeds, UK

  2. 2

    University of York, The Cochrane Wounds Group, York, North Yorkshire, UK

  3. 3

    Chesterfield Royal Hospital, Calow, Derbyshire, UK

  4. 4

    Ethicon, Inc, Somerville, New Jersey, USA

  5. 5

    University of Sheffield, School of Health and Related Research (ScHARR), Sheffield, South Yorkshire, UK

  6. 6

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

*Susan O'Meara, School of Healthcare, University of Leeds, Room LG.12, Baines Wing, Leeds, LS2 9JT, UK. s.m.omeara@leeds.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 23 DEC 2013

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This is not the most recent version of the article. View current version (10 JAN 2014)

 
Characteristics of included studies [ordered by study ID]
Alinovi 1986

MethodsRandomised controlled trial conducted in Italy. Some details of sample size estimation described but unclear whether this was a priori


Participants48 people with 56 venous leg ulcers randomly assigned:
Group 1: 24 people/26 legs
Group 2: 24 people/30 legs
Mean ± SD baseline ulcer size, cm2:

Group 1 completers (24 people/26 legs): 12.5 ± 14.4

Group 2 completers (23 people/29 legs): 14.1 ± 15.9
Mean ± SD baseline ulcer duration (months):

Group 1 completers: 11.7 ± 12.6

Group 2 completers: 10.4 ± 8.9
Patients with clinically infected ulcers were excluded from the trial, but all included patients had wounds with positive bacterial cultures


Interventions1. Bed rest, and standard treatment of merbromin 2% solution applied to ulcer surface. Betamethasone dipropionate 0.05% cream applied to rest of leg, zinc oxide and ichthammol–impregnated gauze bandage wrapped around the leg and elastic support bandage applied from toes to knee. The bandage remained in place for 20 days
2. Bed rest with standard treatment and a 10-day course of systemic antibiotics (co-trimoxazole, gentamicin or amikacin according to sensitivity)


OutcomesAfter 20 days:
Complete healing:
1. 7/26 (27%)
2. 5/30 (17%)

Following the 20-day treatment period, participants whose ulcers had not healed were treated with bandages alone (further details of bandages not provided). Eventual rates of complete healing reported as follows (assessment point not stated):

1. 20/26 (77%)

2. 21/30 (70%)

Mean percentage decrease in ulcer area:
1. 57.2 ± 29.3
2. 61.6 ± 25.8

The trial authors reported the between-group difference as not statistically significant (P value 0.56)

Secondary outcomes:
Bacterial eradication
1. 5/24
2. 8/24

Relationship between ulcer healing and bacteriological results in people with positive pretreatment culture, excluding healed ulcers:
mean percentage decrease in ulcer area (persistent bacterial colonisation)
1. 44.8 ± 31.8 (n = 19)
2. 42.1 ± 11.9 (n = 24)

Mean percentage decrease in ulcer area (eradicated bacterial colonisation)
1. 70.8 ± 19.4 (n = 19)
2. 76.6 ± 13.6 (n = 24)

The trial authors reported that within-group differences for change in ulcer area between those with persistent bacterial colonisation and eradication were statistically significant (P value 0.04 for Group 1; and P value 0.00003 for Group 2)


NotesBacterial culture:
Staphylococcus aureus: 25.4%; Pseudomonas aeruginosa: 18.2%; B-haemolytic strep: 14.5%

Withdrawals:
Group 1: 0
Group 2: intolerant of compression bandage (1)
Total = 1

Unit of analysis:

Some participants had multiple leg ulcers studied, but this did not appear to have been accounted for in the trialists' analyses


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported that "patients were.....randomly allocated." It was not reported how the sequence was generated

Allocation concealment (selection bias)Unclear risk"randomisation was by sealed envelope", but it was not reported whether the envelopes were opaque or sequentially numbered

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High riskNot reported that those allocated to standard treatment only were given placebo

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo details about who performed the outcome assessment or how it was performed

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskOne withdrawal from Group 2 because could not tolerate compression bandage

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskNo withdrawals from Group 1; 1/24 (4%) withdrew from Group 2

Incomplete outcome data (attrition bias)
ITT analysis
Low riskParticipant withdrew from intervention Group 2 because could not tolerate bandage and was "excluded from analysis". It is unlikely that exclusion of one participant from the analysis had an important impact on estimates of treatment effect

Baseline factors comparableUnclear riskMean values reported for ulcer size and ulcer duration (these variables are often skewed), and so difficult to judge comparability

Beitner 1985a

MethodsRandomised controlled trial conducted in Sweden. Each participant had 2 leg ulcers each and acted as his or her own control. Ulcers were the unit of randomisation


Participants10 participants (20 ulcers) were recruited. There were no details of baseline characteristics, including ulcer infection status


InterventionsInterventions were applied to 10 participants with 2 leg ulcers each, acting as his or her own control. For each participant, one ulcer was treated with 10% benzoyl peroxide lotion and the other with normal saline solution. For both ulcers, treatment was applied by moistening a sterile sponge compress, cut to the exact shape of the ulcer, with the respective solution. The sponge dressings were then covered with a thick pad and kept in place with a gauze stocking. The ulcer margins were protected with zinc ointment, and a supporting elastic bandage was applied. Dressings were changed 3 times a week for 42 days


OutcomesMean ± SD percentage ulcer area remaining at 42 days:
Normal saline solution 94.7% ± 12.7%

10% benzoyl peroxide lotion 64.3% ± 14.0%

Adverse effects:

3 participants reported severe irritation from use of 10% benzoyl peroxide lotion. No information about adverse effects for ulcers treated with the normal saline solution


Notes3 participants withdrew; it was not stated whether withdrawal was related to adverse effects (severe irritation from use of 10% benzoyl peroxide lotion).

This trial report described 3 separate RCTs recruiting 31 participants in total. All participants had 2 leg ulcers each and acted as his or her own control. One other RCT was included (Beitner 1985b) and the other was excluded (Beitner 1985c).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The ulcer chosen for BPO treatment was randomised according to left or right leg and most distal or proximal location. When ulcers were situated at the same level, medial or lateral localization was randomised"

Comment: the sequence generation method was not stated

Allocation concealment (selection bias)High riskQuote: "the randomisation and treatment was given in the day care unit by personnel not involved in the evaluation of results"

Comment: the information provided suggests that group allocation was likely to be unconcealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: no information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "the randomisation and treatment was given in the day care unit by personnel not involved in the evaluation of results"

Comment: no statement that outcome assessors were blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: clearly stated that 3 participants withdrew, and reasons provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskComment: 3/10 (30%) participants withdrew

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskComment: no information provided

Baseline factors comparableUnclear riskComment: no information provided on baseline characteristics of participants/ulcers in each group

Beitner 1985b

MethodsRandomised controlled trial conducted in Sweden. Each participant had 2 leg ulcers each and acted as his or her own control. Ulcers were the unit of randomisation


Participants10 participants (20 ulcers) were recruited. There were no details of baseline characteristics, including ulcer infection status


InterventionsInterventions were applied to 10 participants with 2 leg ulcers each, acting as his or her own control. For each participant, one ulcer was treated with 20% benzoyl peroxide lotion and the other with normal saline solution. For both ulcers, treatment was applied by moistening a sterile sponge compress, cut to the exact shape of the ulcer, with the respective solution. The sponge dressings were then covered with a thick pad and kept in place with a gauze stocking. The ulcer margins were protected with zinc ointment, and a supporting elastic bandage was applied. Dressings were changed 3 times a week for 42 days


OutcomesMean ± SD percentage ulcer area remaining at 42 days:
Normal saline solution 93.7% ± 15.2%

20% benzoyl peroxide lotion 59.6% ± 12.3%

Adverse effects:

No information provided for either treatment


NotesThere were no withdrawals.

This trial report described 3 separate RCTs recruiting 31 participants in total. All participants had 2 leg ulcers each and acted as his or her own control. One other RCT was included (Beitner 1985a) and the other was excluded (Beitner 1985c).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The ulcer chosen for BPO treatment was randomised according to left or right leg and most distal or proximal location. When ulcers were situated at the same level, medial or lateral localization was randomised"

Comment: the sequence generation method was not stated

Allocation concealment (selection bias)High riskQuote: "the randomisation and treatment was given in the day care unit by personnel not involved in the evaluation of results"

Comment: the information provided suggests that group allocation was likely to be unconcealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: no information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "the randomisation and treatment was given in the day care unit by personnel not involved in the evaluation of results"

Comment: Comment: no statement that outcome assessors were blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: it was clear that there were no withdrawals

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskComment: it was clear that there were no withdrawals

Incomplete outcome data (attrition bias)
ITT analysis
Low riskComment: it was clear that there were no withdrawals, and the review authors assume that all randomised participants were included in the analysis

Baseline factors comparableUnclear riskComment: no information provided on baseline characteristics of participants/ulcers in each group

Belcaro 2003

MethodsRandomised controlled trial conducted in Italy


Participants20 people with venous ulceration with minimum and maximum ulcer diameters > 2 cm and < 5 cm
Group 1: 10
Group 2: 10

Mean ± SD baseline ulcer area (cm2): Group 1: 3.98 ± 0.4; Group 2: 3.76 ± 0.4
Mean ± SD baseline ulcer duration (months): Group 1: 2.9 ± 2.0; Group 2: 2.5 ± 1.0

All participants were treated with systemic antibiotics for 15 to 20 days before the start of trial treatment to resolve clinical infection


Interventions1. The lower limb and the area of ulceration were cleaned with water and neutral soap; skin was dried with tissue paper; 2 g of placebo cream was applied to the ulcerated area and surrounding skin, and compression below-knee stockings were applied
2. 2 g hydrogen peroxide cream 1% was used instead of placebo


OutcomesAfter 10 days, median decrease in ulcerated area:
1. 11%
2. 35%
(P value < 0.05)

Mean percentage ulcer area remaining:
1. 89%
2. 65%
(P value < 0.05)

Improvement in microcirculatory parameters was significant in Group 2
No adverse effects reported


NotesNo information given about withdrawals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"the effects of a new compound (Crystacide) were assessed in a randomised controlled study"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information given

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Low riskThe trial authors stated that participants in Group 1 received the same treatment and that: "A placebo cream, comparable in aspect and density to Crystacide, was used. The creams were given to patients in containers without labels"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information given

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNo mention of dropouts or withdrawals

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskNo information given

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskNo exclusions described

Baseline factors comparableUnclear riskMean values appear to have been reported for ulcer size and ulcer duration, and so difficult to judge comparability

Belcaro 2007

MethodsRandomised controlled trial conducted in Italy


Participants32 people with venous ulceration with ulcer diameter > 2 cm and < 4 cm
Group 1: 14
Group 2: 18

Mean ± SD baseline ulcer area (cm2): Group 1: 3.5 ± 0.8; Group 2: 3.3 ± 0.6
Mean ± SD baseline ulcer duration (months): Group 1: 1.2 ± 0.3; Group 2: 1.1 ± 0.2

All participants were treated with systemic antibiotics for 2 weeks before the start of trial treatment to resolve clinical infection


Interventions1. The lower limb and the area of ulceration were cleaned with water and neutral soap; skin was dried with tissue paper; 2 g of placebo cream was applied to the ulcerated area and surrounding skin and compression below-knee stockings were applied
2. 2 g hydrogen peroxide cream 1% was used instead of placebo


OutcomesAfter 10 days, median decrease in ulcerated area:
1.32%
2. 44.8%
P value < 0.005

Improvements in microcirculatory parameters were significant in Group 2


NotesNo information given about withdrawals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInformation from author suggested randomised sequence

Allocation concealment (selection bias)Unclear riskNo information given about how assignment to treatment groups was concealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Low riskA placebo cream comparable in aspect and density with crystacide was used. The creams were given to participants in containers without labels

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information given about blinding the outcome assessor to intervention

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNo mention of withdrawals

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskNo information given

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskNo information given

Baseline factors comparableUnclear riskMean values appear to have been reported for ulcer size and ulcer duration, and so difficult to judge comparability

Binić 2010

MethodsRandomised controlled trial (pilot study) conducted in Serbia


Participants32 people with venous leg ulcers ≤ 10 cm2 of not longer than 2 months' duration

Group 1: 15 people

Group 2: 17 people

Information given by the trial authors suggested that some people had more than one ulcer, but full details not provided

Mean ± SD baseline ulcer size (cm2): Group 1: 6.7 ± 1.09; Group 2: 7.04 ± 1.37

Mean ± SD (range) baseline ulcer duration (weeks): Group 1: 5.80 ± 2.66 (2.3 to 8); Group 2: 5.53 ± 1.95 (1.8 to 8)

Those with ulcers with signs of clinical infection at baseline were excluded. All ulcers of included patients showed signs of contamination or colonisation from swab, without signs of ulcer infection or systemic infection. All participants had at least one micro-organism identified at baseline, the most frequent isolates being Staphylococcus aureus and Pseudomonas aeruginosa


Interventions1. Topical antibiotics applied to ulcers, selected according to antibiogram results and including gentamicin, chloramphenicol 5%, enbecin, povidone-iodine 2%, metronidazole and fusidic acid. Antiexudative, anti-inflammatory and disinfectant wet dressing bandages applied (further details of these interventions not provided)

2. Plantoderm ointment applied to ulcers and Fitoven gel applied to skin on lower leg and peri-ulcer area

Plantoderm ointment contains extracts of Calendula officinalis (marigold),Symphytum officinale (comfrey),Achillea millefolium (yarrow) and Salvia officinalis (sage), and is described by the trial authors as having antimicrobial properties. Fitoven gel contains extracts of Aesculus hippocastanum (horse chestnut),Melilotus officinalis (yellow sweet clover),Rosmarinus (rosemary) and Lavandula (lavender)

All participants received the following: ulcer cleansing with sterile saline solution or sterile boric acid 3%; debridement using scissors and tweezers; routine dressings (not specified further, but excluding hydrocolloid, foam, alginate and hydrogel dressings); and routine bandages (no further details provided). Compression was not used in any participant (confirmed through correspondence with trial authors). All participants were treated twice daily, with dressings removed and reapplied each time to reapply the study treatments. The treatment duration was 7 weeks

Some information about intervention regimens was confirmed through contact with the trial authors


OutcomesAt 7 weeks:

Number of participants with healed ulcers (data confirmed by trial authors):

1. 0/15 (0%)

2. 2/17 (12%)

Mean % change in ulcer surface area:

1. -35.65%

2. -42.68%

Secondary outcomes at 7 weeks:

Number of participants with bacterial eradication of ulcer:

1. 0/15 (0%)

2. 4/17 (24%)

Number of participants with at least one bacterial isolate:

1. 15/15 (100%)

2. 13/17 (76%)

Number of participants with more than 1 bacterial isolate:

Group 1: 6/15 (40%)

Group 2: 3/17 (18%)

Most of the isolates in both groups wereStaphylococcus aureus and/orPseudomonas aeruginosa

Adverse effects:

1. 1/15 (7%) (small increment of the ulcerated area).

2. 0/17 (0%)

No details were provided defining what adverse effects were monitored, nor methods of monitoring used


NotesNo information about withdrawals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The study was opened, randomised and controlled". Report contains no statement regarding generation of random number sequence

Allocation concealment (selection bias)Unclear risk"The study was opened, randomised and controlled". Report contains no statement regarding allocation process

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskReport describes study as "open" with no further details

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskReport describes study as "open" with no further details

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskAlthough no statement, it appears from the report that all randomly assigned participants completed the trial

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskAlthough no statement, it appears from the report that all randomly assigned participants completed the trial

Incomplete outcome data (attrition bias)
ITT analysis
Low riskAlthough no statement, it appears from the report that all randomly assigned participants completed the trial

Baseline factors comparableLow riskPatients with non-infected venous leg ulcers with surface area ≤ 10 cm2 and ulcer duration not longer than 2 months were recruited. Ulcer area and duration appear comparable between groups

Bishop 1992

MethodsRandomised controlled trial (2 centres) conducted in the USA


Participants93 participants randomly assigned, with venous stasis ulcers 3 cm2 to 50 cm2 in size, of at least 3 months' duration

Group 1: 30 participants

Group 2: 31 participants

Group 3: 32 participants

Mean baseline ulcer size of completers, cm2 ± SD (median):

Group 1: 9.6 ± 8.1 (6.2)

Group 2: 11.9 ± 11.2 (6.9)

Group 3: 9.9 ± 8.5 (6.5)

Mean baseline ulcer duration of completers, months ± SD (median):

Group 1: n = 29, 38.0 ± 88.7 (12.0)

Group 2: n = 28, 44.1 ± 58.0 (19.0)

Group 3: n = 29, 57.1 ± 94.9 (11.0)

Patients with > 105 bacteria/gram ulcer tissue (confirmed by tissue biopsy) were excluded, as were those with systemic sepsis or bone infection


InterventionsGroup 1: Placebo (topical preparation comprising petroleum-based cream, vehicle of preparation used for Group 3)

Group 2: Topical preparation comprising 1% silver sulphadiazine cream

Group 3: Topical preparation comprising 0.4% tripeptide copper complex cream

All participants received ulcer cleansing with normal saline and compression; and were instructed to apply treatment daily followed by nonadherent dressing and elastic wrap, and to keep the affected limb elevated when sitting. The treatment duration was 4 weeks


OutcomesNumbers (%) of participants with ulcers healed at week 4:

Group 1: 1/30 (3)

Group 2: 6/31 (19)

Group 3: 0/32 (0)

Numbers (%) of participants whose ulcers remained healed after 1 year, having received no further topical treatment, just elastic support:

Group 1: 1/1 (100)

Group 2: 5/6 (83)

Group 3: 0/0 (0)

Mean percentage change in ulcer size % ± SE at week 4:

Group 1: -22.5 ± 10.2

Group 2: -44.0 ± 8.21

Group 3; -18.7 ± 9.07

Secondary outcomes:

No microbiological outcomes reported

Adverse events:

The trial authors reported no statistically significant between-group differences for burning, itching, pain or oedema observed (numbers of participants and P values not provided). Only placebo group complained of pain, itching or burning after 15 days. On a scale of 0 to 3+, all mean scores were less than 1+ (direction and administration of scale not explained)


NotesWithdrawals

Group 1: 1/30 (3%)

Group 2: 3/31 (10%) (2 were immediate withdrawals)

Group 3: 3/32 (9%) (1 was an immediate withdrawal)

Apart from the information about immediate withdrawals, other information, including reasons for withdrawal, was not provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients...were stratified by lesion size and randomly assigned to one of three treatment groups". No information regarding sequence generation reported

Allocation concealment (selection bias)Unclear risk"Patients meeting the inclusion criteria and completing an informed consent form were stratified by lesion size and randomly assigned to one of three treatment groups". No information regarding allocation concealment reported

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information regarding blinding of participants reported

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Low risk"Before evaluation, all medication was removed and the ulcer cleaned to keep the evaluator blinded"

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNumbers of withdrawals reported per treatment arm but reasons not provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskWithdrawals:

Group 1: 1/30 (3%)

Group 2: 3/31 (10%)

Group 1: 3/32 (9%)

Overall withdrawal rate 8%; 86/93 (92%) completed the study

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskPer protocol, "eighty-six were evaluable for efficacy". It is unclear how these withdrawals might have impacted estimates of treatment effect (this is a small RCT)

Baseline factors comparableHigh riskOn the basis of median values, Group 2 (1% silver sulphadiazine) included participants with longer ulcer duration, on average, than the other groups. Treatment groups appear comparable in terms of ulcer area

Blair 1988

MethodsRandomised, controlled trial conducted in the UK. 2 separate trials are reported in the paper; only 1 is relevant to this review


Participants60 ulcers, with surface area up to 10 cm2 were randomly assigned:

Group 1: 30 ulcers

Group 2: 30 ulcers

Initial mean ulcer surface area cm2 ± SEM: Group 1: 3.8 ± 0.6; Group 2: 3.4 ± 0.5

Ulcer duration (described as time since ulcer last healed), mean months ± SEM: Group 1: 27.8 ± 3.4; Group 2: 33.4 ± 4.1

All ulcers were initially contaminated, with 80% of wounds growing more than one organism. Most common organisms were Staphylococcus aureus (73% of ulcers) and beta-haemolytic Streptococcus (35% of ulcers). Data not presented by group


InterventionsGroup 1: non-adherent dressing

Group 2: silver sulphadiazine cream (Flamazine, Smith & Nephew)

All participants received ulcer cleansing with saline; four-layer compression bandaging designed to provide 42 mmHg initial ankle pressure; weekly change of dressings and bandages at outpatient venous leg ulcer clinic. The treatment duration was 12 weeks


OutcomesNumbers (%) of ulcers healed at 12 weeks:

Group 1: 24/30 (80)

Group 2: 19/30 (63)

Mean % healing rate per week first 6 weeks:

Group 1: -12.8%

Group 2: -11.0%

Mean % healing rate per week last 6 weeks:

Group 1: -2.5%

Group 2: -1.7%

Secondary outcomes:

Adverse effects:

Group 1: 1 participant developed cellulitis (not stated whether treatment was stopped)

Group 2: 4 participants—treatment stopped because of erythema and pruritis. 2 participants developed cellulitis (not stated whether treatment stopped)

In participants with cellulitis from both groups, the predominant organism was beta-haemolytic Streptococcus, Lancefield group G

Microbial outcomes:

In both groups, bacterial contaminants were continued throughout the study (monitored by fortnightly swabs), with only 3 ulcers having no bacterial growth at any stage during the trial (group not stated)


NotesThe units of randomisation and analysis are not clear (whether ulcers or participants)

Apart from the 4 participants in Group 2 who stopped treatment because of adverse effects, no information was presented about withdrawals; it is not clear whether these participants were included in all analyses


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Ulcers were cleaned with saline and the dressing applied according to randomization using a sequential system of sealed envelopes with treatment allocation by random number table"

Allocation concealment (selection bias)Unclear risk"Ulcers were cleaned with saline and the dressing applied according to randomization using a sequential system of sealed envelopes with treatment allocation by random number table"

No statement whether envelopes were opaque or not

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information on blinding of participants reported

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information on blinding of outcome assessors reported

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNo information on withdrawals reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskNo information on withdrawals reported

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskNo information on withdrawals reported. Apart from the 4 participants in Group 2 who stopped treatment because of adverse effects, no information was presented about withdrawals; it is not clear whether these participants were included in all analyses

Baseline factors comparableLow riskUlcer size and duration at baseline appear comparable between groups (inclusion criteria for ulcer size < 10 cm2—this will have restricted variation in size)

Cameron 1991

MethodsRandomised controlled trial conducted in the UK


Participants30 people with venous leg ulcers:
Group 1: 15
Group 2: 15

Mean baseline ulcer area (cm2—variability data not reported): Group 1: 17.3. Group 2: 16.3
Mean (range) baseline ulcer duration: Group 1: 6 years (1 month to 36 years); Group 2: 2.7 years (6 months to 9 years)

5 participants in each group had Gram-positive bacteria present in their wounds at baseline. There was no report of signs and symptoms of clinical infection.


Interventions1. White soft paraffin tulle gras and compression therapy
2. Mupirocin-impregnated tulle gras and compression therapy


OutcomesAfter 12 weeks complete healing:
1. 46%
2. 53%

Mean percentage change in ulcer area:
1. 68%
2. 50%

Eradication of Gram-positive bacteria
1. 0/5
2. 5/5


NotesNo withdrawals reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "patients were randomised into 2 treatment groups"

Comment: It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskQuote: "patients were randomised into 2 treatment groups"

Comment: allocation concealment was not mentioned

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Low riskQuote: "The study was a randomised double-blind placebo controlled pilot study"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "The study was a randomised double blind placebo controlled pilot study"

Comment: It was not stated that outcome assessors were blinded

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear risk30 patients were recruited; no withdrawals were reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskWithdrawal rate was not described

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskMethod of analysis not described

Baseline factors comparableHigh riskThe ulcers in Group 1 had longer mean duration than those in Group 2 (2.7 years versus 6 years)

Casoni 2002

MethodsRandomised controlled trial conducted in Italy


Participants74 participants with vascular leg ulcers (information from author: ABPI had to be at least 0.6 for patient to be included; some patients had leg ulcers of mixed arterial/venous aetiology):
Group 1: 22 participants
Group 2: 26 participants
Group 3: 26 participants

Mean ± SD [range] baseline ulcer area (mm2): Group 1: 162 ± 167 [40 to 810]; Group 2: 202 ± 140 [40 to 650]; Group 3: 180 ± 117 [60 to 560]
Median (interquartile range) baseline ulcer area (mm2—read from box plot): Group 1: 125 (90, 170); Group 2: 170 (90, 300); Group 3: 150 (125, 220)

Median (interquartile range) baseline ulcer duration (months—read from box plot): Group 1: 10.5 (6, 24); Group 2: 7 (4, 12.5); Group 3: 7 (3, 8)

Participants in all groups received systemic antibiotics as necessary before trial treatment


InterventionsAll participants received the following interventions 2 weeks before trial treatment: compression, local antiseptics and systemic antibiotics in cases of proven infection

Trial treatments:
Group 1: non-adherent, paraffin gauze (Vaseline) dressing plus compression
Group 2: hyaluronic acid and povidone-iodine dressing plus compression
Group 3: hydrocolloid dressing plus compression

Trial dressings and bandages were changed weekly. Compression could be in the form of Unna's boot; multilayer bandages; or stockings plus elastic bandage (removed at night)


OutcomesAt 3 months—median percentage area reduction/25th percentile (read from box plot):
Group 1: 90%/65%
Group 2: 100%/90%
Group 3: 100%/80%


NotesIn terms of the median percentage area reduction—no data are available on those whose ulcers enlarged during the trial, the box plot shows only those with area reduction; full interquartile ranges are not shown

No information given about withdrawals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: Patients were "randomised in three groups"

Comment: no information about methods for generating sequence

Allocation concealment (selection bias)Unclear riskQuote: Patients were "randomised in three groups"

Comment: no mention of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskNo information provided

Baseline factors comparableHigh riskUlcers in Group 2 were larger than those in the other groups. Ulcer in Group 1 were of longer during than those in the other groups.

Chaloner 2004

MethodsRandomised controlled trial conducted in the UK


Participants40 patients with chronic venous leg ulcers recruited from 3 centres within primary care setting:

Group 1: 20 participants

Group 2: 20 participants

Median ulcer duration, weeks (range): 52 (6 weeks to 20 years), breakdown per group not provided

Median ulcer area, cm2 (range): 4.9 (0.9 to 196.1), breakdown per group not provided

The available information suggests that all participants had bacterial colonisation of ulcers at baseline, but not stated whether any were clinically infected


InterventionsGroup 1: silver-impregnated polyurethane foam dressing (Avance)

Group 2: 5-layer silver impregnated dressing comprising two layers of an absorbent inner core sandwiched between three layers of silver-coated, low-adherent polyethylene net (Acticoat 7)

All participants received four-layer compression bandage (Profore), providing 40 mmHg at the ankle

Duration of treatment was 12 weeks unless the ulcer healed before this time


OutcomesNumber (%) of ulcers healed at 12 weeks:

Group 1: 7/20 (35)

Group 2: 10/20 (50)

Median percentage (%) change in ulcer area at 12 weeks:

Group 1: -80.4%

Group 2: -95.1%

The trial authors reported that the between-group difference was not statistically significant but did not provide the P value

Seondary outcomes:

The trial authors reported that there was a greater reduction in the total number of bacteria (colony forming units per cm2) in Group 2 compared with Group 1, but the between-group difference was not statistically significant (data and P value not provided)

The trial authors reported that more pathogenic bacterial groups were eliminated in Group 2 compared with Group 1, including Staphylococcus aureus, beta-haemolytic streptococci, anaerobes and coliforms. No further data or P values were provided

Adverse events at 12 weeks:

The trial authors reported that a higher proportion of participants in Group 2 reported no pain from the study ulcer and a healthy condition of the peri-ulcer skin compared with Group 1


NotesData were extracted from a conference poster and abstract, and further details were confirmed through correspondence with the study author. A full report was not available

Microbiological analysis (bacterial counts and bacterial identification) was by wound swabs taken at 0, 2, 4, 8 and 12 weeks. No details of techniques used were provided

The median baseline value in ulcer duration as recorded above was taken from the conference abstract (52 weeks); the conference poster reported a different value (34.7 weeks)

In the conference abstract, the trial authors reported: "the rate of healing was on average 16.8% faster" in Group 2 compared with Group 1, but did not explain how this statistic was estimated; also, contradictory information was given in the poster, which suggested that participants in Group 1 healed faster, on average

Withdrawals (available from a brief interim report only):

Group 1: 2 participants withdrew because of adverse events (further details not provided)

Group 2: no information provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom sequence generation achieved using computer-generated programme (confirmed through email communication with trial author)

Allocation concealment (selection bias)Unclear risk"A prospective, multi-centre, randomised, comparative study to compare the effects of Acticoat 7 antimicrobial barrier dressing to Avance silver impregnated foam film dressing in the treatment of chronic venous leg ulcers"

Comment: no details of allocation concealment reported

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information on participant blinding reported

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information on outcome assessor blinding reported

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear risk"In the Avance group.....2 patients had been withdrawn due to adverse reactions"

Comment: The above information was taken from a brief, interim report. No information on withdrawals was provided in relation to the Acticoat 7 group, and no information was available for either group at the final analysis

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear risk"In the Avance group.....2 patients had been withdrawn due to adverse reactions"

Comment: The above information was taken from a brief, interim report. No information on withdrawals was provided in relation to the Acticoat 7 group, and no information was available for either group at the final analysis

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskFrom conference abstract: "Results from 40 patients have demonstrated"

From conference poster: "The primary analysis could only be conducted on 18 (45%) patients who had a baseline bacteria count and at least one post baseline bacteria count"

Comment: no statement as to whether analysis conducted per protocol or according to intention-to-treat

Baseline factors comparableUnclear riskBaseline participant characteristics were not presented per group

Daroczy 2006

MethodsRandomised controlled trial conducted in Hungary


Participants63 people with ulcerated stasis dermatitis due to deep venous reflux, of < 5 cm 'size'
Group 1: 21
Group 2: 21
Group 3: 21

No information provided on baseline characteristics such as ulcer area and ulcer duration. Ulcers were described as infected, but no further details provided, and not clear if this referred to baseline status or incidence during the trial treatment.


Interventions1. Povidone-iodine with compression
2. Amoxicillin (dose, route and frequency of administration not stated) with compression
3. Povidone-iodine without compression

The treatment duration was 12 weeks


OutcomesAfter 12 weeks complete healing:
1. 82%
2. 85%
3. 62%

5 months after conclusion of trial: relapse of superficial bacterial infection:
1. 11%
2. 32%
3. 11%


NotesNo withdrawals mentioned


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"A total of 63 patients were enrolled in this prospective randomised controlled study." It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo mention of this in the paper

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information given

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information given

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskNo withdrawals or dropouts reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskNo withdrawals or dropouts reported

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskNo information given about mode of analysis

Baseline factors comparableUnclear riskNot sufficient information in tables to illustrate baseline characteristics

Dimakakos 2009

MethodsRandomised controlled trial conducted in Greece


Participants42 participants with venous leg ulcers that were classified as exclusively infected:

Group 1: 21 participants

Group 2: 21 participants

Initial ulcer diameter:

Group 1: < 1 cm, n = 3; 1 to 2 cm, n = 4; 2 to 3 cm, n = 5; 3 to 4 cm, n = 5; > 4 cm, n = 4

Group 2: < 1 cm, n = 2; 1 to 2 cm, n = 5; 2 to 3 cm, n = 4; 3 to 4 cm, n = 7; > 4 cm, n = 3

Initial ulcer depth:

Group 1: < 0.5 cm, n = 16; > 0.5 cm, n = 5

Group 2: < 0.5 cm, n = 14; > 0.5 cm, n = 7

Number of (%) participants with ulcer duration > 1 month:

Group 1: 14/21 (67)

Group 2: 12/21 (57)

Number of participants with initial ulcer pain (assessed with VAS where 0 = no pain, < 4 = mild pain, 4 to 7 = moderate pain, > 7 = severe pain, and 10 = worst imaginable pain):

Group 1: severe, n = 5; moderate, n = 8; none/mild, n = 8

Group 2: severe, n = 5; moderate, n = 11; none/mild, n = 5

Number of participants with Staphylococcus aureus identified from swab:

Group 1: 4/21

Group 2: 9/21

Number of participants with Pseudomonas aeruginosa identified from swab:

Group 1: 5/21

Group 2: 7/21

Escherichia coli, Staphylococcus capitis, Enterococcus species and other bacteria were also present in some participants in both groups

Number of participants with >1 wound isolate:

Group 1: 13/21

Group 2: 11/21

All ulcers were infected and had clinical signs of inflammation


InterventionsGroup 1: non-adhesive foam (Biatain)

Group 2: non-adhesive silver-releasing foam (Contreet Ag)

All participants received wound cleansing using sterile water and a 10% povidone-iodine solution; short stretch bandage as compression therapy; twice-weekly dressing changes; and antibiotics if wound cultures were positive

Treatment duration was 9 weeks


OutcomesNumbers (%) of ulcers healed at 9 weeks:

Group 1: 10/21 (48)

Group 2: 17/21 (81)

Number of ulcers healed at 3/4/5/6/7/8/9 weeks:

Group 1: 2/1/1/1/0/2/3

Group 2: 2/3/3/2/1/2/4

Secondary outcomes:

Adverse events:

The trial authors reported that none of the participants experienced systemic or local side effects that could be attributed to the treatments, but no further details were provided

Pain:

Group 1: 1/5 participants with severe pain and 3/8 participants with moderate pain were pain-free at 4 weeks. Moderate pain persisted in 4 participants until the end of the nine weeks. 13/21 participants were pain-free by the end of the study

Group 2: 2/5 participants with severe pain and 8/11 participants with moderate pain were pain-free at 3 weeks. 21/21 participants were pain-free by week 8.

No microbiological outcomes were reported


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Forty-two patients were included in the study and were randomised into two groups"

Comment: No information was reported on the method of random sequence generation

Allocation concealment (selection bias)Unclear risk"Forty-two patients were included in the study and were randomised into two groups"

Comment: No information was reported on the method of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information reported on participant blinding

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information reported on assessor blinding

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: It appears that all randomly assigned participants completed the study

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskComment: It appears that all randomly assigned participants completed the study

Incomplete outcome data (attrition bias)
ITT analysis
Low riskComment: It appears that all randomly assigned participants completed the study

Baseline factors comparableUnclear riskComment: Categorical data were provided for baseline ulcer diameter and depth, and groups appeared comparable. The only information regarding baseline ulcer duration was the number of participants in each group with ulcers > 1 month duration

Fischer 1984

MethodsRandomised controlled trial (multi-centre, involving 6 hospitals in Germany, 1 hospital in Austria and 1 phlebology practice in Switzerland)


Participants258 participants randomly assigned, with venous leg ulcers 3 cm to 10 cm in diameter

Group 1: 89 participants

Group 2: 88 participants

Group 3: 81 participants


InterventionsGroup 1: non-antibiotic enzymatic cleanser - topical preparation comprising 1 unit bovine fibrinolysin to 666 units desoxyribonuclease in a water-free basic ointment (Fribolan)

Group 2: enzymatic cleanser with added antibiotic - topical preparation comprising 0.6 units clostridiopeptidase A to 10 mg chloramphenicol in a lipophilic water-free basic ointment (no proprietary name provided)

Group 3: enzymatic cleanser with added antibiotic - topical preparation comprising 20 units trypsin to 20 mg framycetin sulphate in water-soluble basic ointment (no proprietary name provided)

All participants received compression bandages, according to the standard practice of each hospital. Wound cleansing was standardised across study groups (but not specified). No information regarding the frequency of dressing changes was reported

Treatment was discontinued in the following instances: after complete ulcer healing; if there were complications or allergies ('complications' not defined); or if no improvement was noted after 7 days ('no improvement' not defined)

Although not specifically reported, treatment duration appears to be 28 days


OutcomesNumbers (%) of participants healed (translated as treatment discontinued because of rapid healing; assessment point not clear but could be 28 days):

Group 1: 8/89 (9)

Group 2: 1/88 (1)

Group 3: 5/81 (6)

Secondary outcomes:

Adverse events:

Numbers (%) of participants who discontinued treatment because of ineffectiveness (not defined) or allergy:

Group 1: 3/89 (3)

Group 2: 6/88 (7)

Group 3: 8/81 (10)


NotesPaper translated from German

Clinical examinations were undertaken at baseline and at days 4, 7, 14 and 28


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The allocation of preparations was carried out with a random criteria" (translated from German)

Comment: no statement on methods used to generate the randomisation sequence

Allocation concealment (selection bias)Unclear risk"The allocation of preparations was carried out with a random criteria" (translated from German)

Comment: no statement regarding the group allocation process

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskDescribed as "open trial" (translated from German)

Comment: no further information provided about blinding participants

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskDescribed as "open trial" (translated from German)

Comment: no further information provided about blinding outcome assessors

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: The study reports treatment discontinuation because of ineffectiveness or allergy per group. Unclear if other withdrawals occurred

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskComment: The study reports treatment discontinuation because of ineffectiveness or allergy per group. No reporting on other withdrawals

Incomplete outcome data (attrition bias)
ITT analysis
Low riskComment: no information reported on whether the analyses were conducted on a per-protocol or intention-to-treat basis; however, it appears that all randomly assigned participants were included in the analyses

Baseline factors comparableUnclear riskComment: Although the study reported specific inclusion criteria for ulcer size (leg ulcers 3 cm to 10 cm diameter), no data per group are reported for baseline ulcer size or duration

Fumal 2002a

MethodsRandomised controlled trial conducted in Belgium. Each participant had 2 leg ulcers each and acted as his or her own control. Ulcers were the unit of randomisation


Participants17 participants (34 ulcers) were recruited. The minimum ulcer size was 16 cm2. Other information about baseline ulcer area and ulcer duration was not presented. Wounds were not clinically infected at baseline


InterventionsInterventions were applied to 17 participants with 2 leg ulcers each, acting as his or her own control. One ulcer was managed with usual treatment consisting of hydrocolloid dressing and compression (described as a 'compressive bandage' - no further details provided). The other ulcer was treated with 10% povidone-iodine solution applied underneath usual treatment. All dressings and bandages were changed three times per week.


OutcomesMedian (range) time to healing in weeks, estimated from Kaplan-Meier survival curves:

Usual treatment alone 18 (11 to 24)

10% povidone-iodine and usual treatment 11 (9 to 17)

The trial authors reported P value < 0.01 (log rank test) for the difference between treatments

Median (range) healing rate at 6 weeks (assessed using a healing index, see notes below for method of calculation - higher value means better outcome):
Usual treatment alone 6.8 (3.9 to 13.2)

10% povidone-iodine and usual treatment 10.2 (4.4 to 16.0)

The trial authors reported P value < 0.01 for the difference between treatments


NotesThere was no information about withdrawals.

Healing index = DA[P(t0)]-1 where: A = Area; P = Perimeter; DA = Differential Area = equal to baseline area minus follow-up area; t0 = baseline.

This trial report described 3 separate RCTs recruiting 51 participants in total. All participants had 2 leg ulcers each and acted as his or her own control. The other 2 RCTs are included in the review and described under Fumal 2002b and Fumal 2002c.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "At entry in the study the two target ulcers in each patient were randomly assigned to receive one of the two treatment modalities"

Comment: It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskComment: No information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about participants being blind to intervention

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about outcome assessors being blind to intervention

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskComment: No information provided

Baseline factors comparableUnclear riskNo clear description of baseline characteristics of participants in each group

Fumal 2002b

MethodsRandomised controlled trial conducted in Belgium. Each participant had two leg ulcers and acted as his or her own control. Ulcers were the unit of randomisation


Participants17 participants (34 ulcers) were recruited. The minimum ulcer size was 16 cm2. Other information about baseline ulcer area and ulcer duration was not presented. Wounds were not clinically infected at baseline


InterventionsInterventions were applied to 17 participants with 2 leg ulcers each, acting as his or her own control. One ulcer was managed with usual treatment consisting of hydrocolloid dressing and compression (described as a 'compressive bandage' - no further details provided). The other ulcer was treated with 1% silver sulphadiazine cream applied underneath usual treatment. All dressings and bandages were changed three times per week.


OutcomesMedian (range) time to healing in weeks, estimated from Kaplan-Meier survival curves:

Usual treatment alone 16 (9 to 22)

1% silver sulphadiazine and usual treatment 15 (7 to 23)

The trial authors reported that the difference between treatments was not statistically significant, but no P value was presented

Median (range) healing rate at 6 weeks (assessed using a healing index, see notes below for method of calculation - higher value means better outcome):
Usual treatment alone 7.2 (3.4 to 13.6)

1% silver sulphadiazine &and usual treatment 7.5 (3.6 to 14.3)

The trial authors reported that the difference between treatments was not statistically significant, but no P value was presented


NotesThere was no information about withdrawals.

Healing index = DA[P(t0)]-1 where: A = Area; P = Perimeter; DA = Differential Area = equal to baseline area minus follow-up area; t0 = baseline.

This trial report described 3 separate RCTs recruiting 51 participants in total. All participants had 2 leg ulcers each and acted as his or her own control. The other 2 RCTs are included in the review and described under Fumal 2002a and Fumal 2002c.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "At entry in the study the two target ulcers in each patient were randomly assigned to receive one of the two treatment modalities"

Comment: It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskComment: No information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about participants being blind to intervention

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about outcome assessors being blind to intervention

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskComment: No information provided

Baseline factors comparableUnclear riskNo clear description of baseline characteristics of participants in each group

Fumal 2002c

MethodsRandomised controlled trial conducted in Belgium. Each participant had two leg ulcers and acted as his or her own control. Ulcers were the unit of randomisation


Participants17 participants (34 ulcers) were recruited. The minimum ulcer size was 16 cm2. Other information about baseline ulcer area and ulcer duration was not presented. Wounds were not clinically infected at baseline


InterventionsInterventions were applied to 17 participants with 2 leg ulcers each, acting as his or her own control. One ulcer was managed with usual treatment consisting of hydrocolloid dressing and compression (described as a 'compressive bandage' - no further details provided). The other ulcer was treated with 5% chlorhexidine digluconate solution applied underneath usual treatment. All dressings and bandages were changed three times per week.


OutcomesMedian (range) time to healing in weeks, estimated from Kaplan-Meier survival curves:

Usual treatment alone 15 (7 to 19)

5% chlorhexidine digluconate solution and usual treatment 14 (7 to 17)

The trial authors reported that the difference between treatments was not statistically significant, but no P value was presented

Median (range) healing rate at 6 weeks (assessed using a healing index, see notes below for method of calculation - higher value means better outcome):
Usual treatment alone 7.3 (4.0 to 11.9)

5% chlorhexidine digluconate solution and usual treatment 7.6 (4.1 to 12.4)

The trial authors reported that the difference between treatments was not statistically significant, but no P value was presented


NotesThere was no information about withdrawals.

Healing index = DA[P(t0)]-1 where: A = Area; P = Perimeter; DA = Differential Area = equal to baseline area minus follow-up area; t0 = baseline.

This trial report described 3 separate RCTs recruiting 51 participants in total. All participants had 2 leg ulcers each and acted as his or her own control. The other 2 RCTs are included in the review and described under Fumal 2002a and Fumal 2002b.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "At entry in the study the two target ulcers in each patient were randomly assigned to receive one of the two treatment modalities"

Comment: It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskComment: No information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about participants being blind to intervention

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "51 patients were enrolled in this open study"

Comment: The 51 patients refers to all 3 RCTs reported in this paper, of which 17 were included in this RCT. There was no clear statement about outcome assessors being blind to intervention

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Unclear riskComment: No information provided

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskComment: No information provided

Baseline factors comparableUnclear riskNo clear description of baseline characteristics of participants in each group

Geske 2005

MethodsRandomised controlled trial conducted in Germany


Participants253 people with venous leg ulcers were randomly assigned (241 completed the trial and were analysed per protocol)
1. 124 randomly assigned, 119 completed
2. 129 randomly assigned, 122 completed

Median baseline ulcer area (cm2): Group 1: 7.28; Group 2: 9.3 (ranges not reported)
Median baseline ulcer duration (months): Group 1: 6.12; Group 2: 6.73 (ranges not reported)
Patients with ulcers infected with MRSA were excluded from the trial, but otherwise it was unclear whether wounds were clinically infected at baseline


Interventions1. Ulcer treated with placebo preparation in the same fashion, plus compression therapy
2. Ulcer treated with 0.1% ethacridine lactate ointment for 30 minutes twice daily for 28 days, plus compression therapy


OutcomesAfter 28 days—response indicated by > 20% decrease in ulcer surface area
Number of responders
1. 69/124 (56%)
2. 104/129 (81%)

Median decrease in ulcer surface area
1. 7.2 ± 18.17 points
2. 12.7 ± 17.43 points

NB: It is unclear what the 'points' refer to; also unclear whether the variance data refer to standard deviation or a different statistic

Mean decrease in ulcer surface area
1. 24.7%
2. 34.1%

Subjective outcomes:
Effectiveness of treatment rated as 'excellent' by physician
1. 13.6%
2. 55.7%

Effectiveness of treatment rated as 'excellent' by participant
1. 17.9%
2. 50%

Secondary outcomes:
Quality of life according to the Freiburg Quality of Life Questionnaire
Mean points reduced (reduction = improved quality)
1. 0.3 points
2. 0.75 points

Numbers (%) of participants experiencing at least one adverse event (total number of adverse events and description):
1. 12/119 (10.1%) (12 participants reported a total of 16 adverse events, mostly aches/back pain and nausea)
2. 13/122 (10.7%) (13 participants reported a total of 21 adverse events, classed as mild to moderate—headaches/migraines and pruritis)

The trial authors reported that all adverse events were unlikely to be related to treatment. Two cases of serious adverse events were noted (hip operation and erysipelas), both considered unrelated to treatment (unclear which treatment group these related to)


NotesWithdrawals:

1. 5/124 (4%)

2. 7/129 (5%)
Reasons for withdrawal (unclear which group these relate to): discontinued therapy (5); beyond inclusion criteria (6); serious adverse event (unrelated to treatment) (1)
Total = 12

Paper was published in German; data were extracted by a translator


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"We carried out a randomised placebo controlled clinical study"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk253 participants were randomly assigned, of whom 12 were classed as withdrawals (5 discontinued therapy before trial end, 6 were ineligible, 1 suffered serious adverse event)

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskIn Group 1: 5/124 (4%) withdrew; and in Group 2: 7/129 (5%) withdrew

Incomplete outcome data (attrition bias)
ITT analysis
Unclear risk241 of 253 randomly assigned participants were analysed per protocol. No mention of ITT analysis. It is unclear how these withdrawals might have impacted estimates of treatment effect

Baseline factors comparableUnclear riskLimited data presented on baseline characteristics

Gethin 2008

MethodsRandomised controlled trial conducted in Ireland (pragmatic, multicentre involving 10 study centres). A priori sample size estimation determined that 156 participants were required to show a 20% difference between treatments for the primary outcomes (healing and desloughing) at a 5% two-sided significance level, but only 108 participants were recruited because of slower than expected recruitment rates


Participants108 participants with venous leg ulcers < 100 cm2 with ≥ 50% wound area covered in slough

Group 1: 54 participants

Group 2: 54 participants

Mean wound duration weeks ± SD:

Group 1: 29.93 ± 35.20

Group 2: 39.46 ± 40.50

Mean wound area cm2± SD (median):

Group 1: 9.87 ± 12.90 (4.2)

Group 2: 10.52 ± 12.30 (5.4)

Patients with clinical diagnosis of wound infection or taking antibiotics for any reason were excluded. None of the ulcers or surrounding skin showed signs of inflammation at baseline

Coliforms, Staphylococcus aureus and Proteus species were the most common isolates at baseline and were found in 25%, 23% and 19% of all wounds, respectively (assessed with wound swab)

Numbers (%) of participants with at least one isolate:

Group 1: 44/54 (81)

Group 2: 51/54 (94)

Numbers (%) of participants with > 1 isolate:

Group 1: 22/54 (41)

Group 2: 29/54 (54)

Numbers (%) of participants with methicillin-resistant Staphylococcus aureus (MRSA):

Group 1: 6/54 (11)

Group 2: 10/54 (19)

Mean pain scores ± SD (assessed using 5-point visual analogue scale, where 0 = no pain and 5 = worst pain ever):

Group 1: 1.39 ± 1.15

Group 2: 1.41 ± 1.05


InterventionsGroup 1: Hydrogel therapy (IntraSite Gel, Smith & Nephew, Hull, UK) 3 g/20 cm2 applied weekly

Group 2: Manuka honey (topical agent) (Woundcare 18+, Comvita, Te Puke, New Zealand) 5 g/20 cm2 applied weekly

All participants received wound cleansing with warm tap water; secondary foam dressings (Allevyn); and compression therapy, usually four-layer bandage. Treatment period was four weeks. After four weeks, all participants received follow-up treatment based on clinicians' judgement; this varied between participants. The final follow-up assessment was conducted at week 12. Participants requiring antibiotics or immunosuppressants during the trial were withdrawn


OutcomesPercentage change in wound size at week 12 (unclear whether mean or median):

Group 1: -13%

Group 2: -34%

Trial authors report P value < 0.001 for between-group difference

Numbers (%) of ulcers healed at week 12:

Group 1: 18/54 (33)

Group 2: 24/54 (44)

Secondary outcomes:

Adverse events:

The trial authors reported no adverse events directly attributable to either wound agent (see information below on withdrawals for further details)

Bacterial changes during 4 weeks of treatment (detected by wound swab):

Numbers (%) of participants with at least one isolate at week 4:

Group 1: 29/54 (54)

Group 2: 35/54 (65)

Numbers (%) of participants with > 1 isolate at week 4:

Group 1: 15/54 (28)

Group 2: 22/54 (41)

Numbers of participants (%) with MRSA eradication at week 4:

Group 1: 1/6 (16)

Group 2: 7/10 (70)

Coliforms, coagulase-negative Staphylococcus and Staphylococcus aureus were the most common isolates at four weeks and were found in 16%, 15% and 13% of all wounds, respectively

The authors reported no statistically significant differences between groups in pain outcome as assessed by visual analogue scale score at any follow-up point


NotesUnit of analysis was the participant. For participants with multiple ulcers, the uppermost or largest ulcer was selected for study

Procedure for taking wound swabs at baseline, 1 week and 4 weeks: 2 swabs taken after wound cleansed with warm tap water to safeguard against loss/damage; cotton-tipped swab rotated 360 degrees in the wound bed; then swabs placed in transport media and transported immediately to the laboratory for routine qualitative culture

Numbers (%) of participant withdrawals (reasons—wound infection diagnosed on clinical presentation):

Group 1: 17/54 (31%) (infection in reference wound 12; infection elsewhere 1; participant request 3; did not attend follow-up 1)

Group 2: 9/54 (17%) (infection in reference wound 6; infection elsewhere 1; non-compliance with treatment 1; did not attend follow-up 1)

The trial authors reported that the between-group difference for time to withdrawal because of infection was not statistically significant (P value < 0.07, log rank test)

Note: A discrepancy is evident between text and table for numbers of participants with MRSA eradication; data have been extracted from the main text (relates to secondary reference of Gethin 2008)

The main primary outcome for the RCT was reduction in slough; the trial authors reported no statistically significant differences between groups in percentage reduction of slough at four weeks


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Following screening, and when consent was provided, patients were randomised via remote phone allocation to either treatment group"

Comment: This was judged to be a satisfactory method of random sequence generation

Allocation concealment (selection bias)Low risk"The allocation sequence was generated using serially numbered, sealed, opaque envelopes, prior to the study by two persons independent of the study"

Comment: This was judged to be a satisfactory method of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskDescribed as "open label" with no further information about blinding of participants

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
High riskQuote in relation to healing outcomes: "Blinded outcome assessment was not possible because of obvious differences in the colour and presentation of the products, specifically orange staining of the peri-wound skin when MH was used"

Quote in relation to microbiological outcomes: "The laboratory was blinded to treatment allocation"

Comment: judged as high risk of bias because healing is the primary outcome in the review

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskWithdrawal rate and reasons for withdrawal were reported per group

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskGroup 1: 31% of patients withdrew

Group 2: 17% of patients withdrew

Comment: the withdrawal rate in Group 1 was greater than 20%

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "All patients were included in the final analysis"

Comment: it is clearly shown in the paper that all patients received their allocated treatment and were followed up

Baseline factors comparableLow riskBoth wound size and wound duration appear comparable at baseline

Groenewald 1981

MethodsRandomised controlled trial conducted in South Africa


Participants100 people with varicose stasis ulcers
Group 1: 50
Group 2: 50

Scant data on baseline characteristics such as ulcer area and ulcer duration. Unclear whether wounds clinically infected at baseline


Interventions1. Existing dressing removed, ulcer and surrounding area washed with a soft brush in povidone-iodine solution; appropriate treatment for frequently occurring fungal infections then applied; povidone-iodine swabbed on the ulcer surface; 2.5 cm thick foam rubber pad placed directly on ulcer; whole foot and lower leg covered with zinc oxide–impregnated gauze bandage and covered by an elastic bandage
2. Treated similarly in all respects, except that dextranomer beadlets applied to the ulcer surface to form a 2 to 3 mm layer instead of the final application of povidone-iodine


OutcomesObjective outcome:
Average healing time (no information about methods of estimation):
1. 5.3 weeks
2. 4.4 weeks
(significant at 95% CI)

Secondary outcome:
Average eradication time:
for Staph aureus:
1. 18.7 days
2. 14.7 days
(significant at 99.5% CI)

Mean cleansing time:
1. 15.4 ± 6.4 days
2. 5.9 ± 2.8 days
(P value < 0.001)

People with painful ulcers:
1. 35
2. 30

Immediate improvement of pain
1. 7 /35 (20%)
2. 20/30 (66.6%)

Worsened pain:
1. 4/35 (11.4%)
2. 0/30


NotesWithdrawal total = 5
People withdrawn from the trial were replaced to keep population size N = 100


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"...a single-blind study of 100 patients randomised into two equal groups..." It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information given about how knowledge of assignment to treatment groups was concealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear risk"patients were incorporated into in a single blind randomised trial"; no other information given

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"at each visit the ulcers were evaluated by 2 independent investigators"; no other information given

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"a total of 100 patients were evaluated with 50 in each group, five dropped out"

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low risk5/50 (10%) withdrawals - withdrawal rate is acceptable

Incomplete outcome data (attrition bias)
ITT analysis
High risk"five dropped out and were replaced to keep the final number at 50/group"; no further information given

Baseline factors comparableUnclear riskInsufficient information on baseline characteristics provided to allow a judgement to be made

Hansson 1998

MethodsRandomised controlled trial conducted in Sweden


Participants153 people with non-infected venous leg ulcers randomly assigned, only withdrawals judged to be unrelated to treatment efficacy were excluded from the analysis
Group 1: 49
Group 2: 56
Group 3: 48

Mean ± SD baseline ulcer area (cm2): Group 1: 7.1 ± 7.1; Group 2: 8.8 ± 11.9; Group 3: 10.7 ± 20.6
Data on baseline ulcer duration not reported. Patients with clinically infected ulcers excluded


Interventions1. Paraffin gauze dressing, which was changed when saturated or leaking

2. Cadexomer iodine paste, which was changed when moisture saturated, indicated by a colour change

3. Hydrocolloid dressing, which was changed when saturated or leaking

All participants received a short-stretch compression bandage (Comprilan). Treatment duration was 12 weeks.


OutcomesAt 12 weeks:
Ulcers completely healed:
1. 7/49
2. 8/56
5. 5/48

Mean percentage reduction in ulcer area:
1. 23.9 ± 97.4%
2. 61.6 ± 36.9%
3. 40.7 ± 56.5%

Mean ulcer area reduction per week (%/wk)
1. 3 ± 14
2. 8 ± 10
3. 9 ± 8

Secondary outcomes:
No statistically significant difference in the time to cease exudation between groups of the study

Adverse effects:

Total number of adverse events per group (group denominators unclear):

1. 26

2. 19

3. 33

Erosions around ulcer:
1. 15
2. 0
3. 10

Pain
1. 1
2. 8
3. 2

Allergy
1. 1
2. 2
3. 6

Cost of treatment in 38 people (staff time, materials, and transport) USD/ percentage ulcer area reduction
1. 12.9
2. 8.8
3. 32.5


NotesWithdrawals (NB 1 to 2 reasons per participant)

Group 1:
Allergy (1); increased size (8); pain (1); infection (4); adverse effects (2); not related A/Es (6); refused to continue (2)
Total = 24

Group 2:
Pain (6); infection (1); not related A/Es (4); poor compliance (1); protocol violation (1)
Total = 13

Group 3:
Allergy (5); increased size (3); infection (5); use of systemic Abx (2); not related A/Es (1); refused to continue (1)
Total = 17


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"patients were randomised to receive one of three treatments"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information about how assignment to treatment groups concealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear risk"A 12-week, randomised, open, controlled, multicentre multinational trial...."

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"A 12-week, randomised, open, controlled, multicentre multinational trial...."

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk153 participants were randomly assigned, of whom 48 withdrew

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskDropout rate > 20% in all treatment groups

Incomplete outcome data (attrition bias)
ITT analysis
High risk"28 patients (12 in cadexomer iodine, 7 in hydrocolloid, 9 in paraffin gauze group) were withdrawn from the study for reason unrelated to efficacy and were excluded from the analysis"

Baseline factors comparableUnclear riskMean values were presented for baseline ulcer area, making comparability difficult to judge. No data on baseline ulcer duration were presented

Harcup 1986

MethodsRandomised controlled trial conducted in the UK


Participants72 people over 30 years of age with venous leg ulcers
1. 31
2. 41
Statistics for baseline ulcer area in cm2 (presume mean ± SD, but not stated): Group 1: 7.74 ± 1.04; Group 2: 9.08 ± 1.37

Mean (range) baseline ulcer duration for all participants was 16.9 (1 to 256) months (breakdown per group not provided)

Unclear whether wounds were clinically infected at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Support bandaging or stocking with a dry dressing. Multiple treatment modalities used
2. Ulcer was cleaned with sterile saline swabs; cadexomer iodine applied to the surface; sterile dressing used and secured in place with bandaging or stocking. Cadexomer iodine removed daily

All patients were treated by general practitioners, in a community setting.


OutcomesAt 4 weeks:
Ulcers completely healed:
1. 1/31 (3.2%)
2. 13/41 (31.7%)

Percentage reduction in ulcer size at 4 weeks (72 participants analysed)
1. 10%
2. 36%
P value < 0.01

Secondary outcome:
Significantly improved pain, erythema, exudation, oedema, pus/debris and granulation in the group treated with cadexomer iodine


NotesWithdrawals:
Group 1:
2 participants withdrew at 6 weeks because of insufficient effect of treatment and failure to attend

Group 2:
3 participants withdrew at 2 weeks because of diarrhoea, erythema, oedema, ulcer irritation and unhappiness with treatment
3 participants withdrew at 4 weeks because of burning sensation (1) and insufficient effect (2)

2 participants withdrew at 6 weeks because of development of multiple ulcers, dry skin, itching and pain


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"patients were randomised to receive either standard dressing or Cadexomer iodine"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"the patient, or whoever was to manage the patient, was instructed on how to treat the ulcer"; those in the cadexomer iodine group had to apply CI to the wound before the dressing, while those with standard treatment did not

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information mentioned regarding this

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskDescribes number of people withdrawn at 2, 4, 6 weeks from both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskWithdrawal rates differed between groups: Group 1 6.5%; Group 2 19.5%

Incomplete outcome data (attrition bias)
ITT analysis
High risk"two patients were randomised to standard therapy, but were treated with CI during the trial. The analysis was carried out assigning these patients to the CI group"

Baseline factors comparableUnclear riskNot clear about all baseline characteristics in each group

Holloway 1989

MethodsRandomised controlled trial conducted in the USA


Participants75 people with venous leg ulcers were recruited:
Group 1: 37
Group 2: 38

Median (range) baseline ulcer area in cm2: Group 1: 9.8 (3.0 to 37.0); Group 2: 10.7 (0.6 to 136.0)
Median (range) baseline ulcer duration in months: Group 1: 4.5 (3 to 130); Group 2: 7.5 (3 to 240)

Unclear whether ulcers were infected at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Wet-to-dry dressings with saline-soaked gauze pads changed by the participant daily plus toe-to-knee elastic compression bandage
2. Ulcer irrigated with saline, cadexomer iodine sprinkled onto the surface, then covered with a dry gauze dressing; done daily plus toe-to-knee elastic compression bandage

Information provided suggests that all participants were treated in a community setting.


OutcomesOutcomes were assessed at 24 weeks, with analyses based on 54 participants overall (breakdown of completers per group not stated)

Mean (standard error of the mean) rate of ulcer healing (cm²/wk):
1. 0.41 (0.13)
2. 0.95 (0.12)

The trial authors reported a statistically significant between-group difference (P value 0.0025)

Mean (standard error of the mean) rate of ulcer healing versus baseline circumference (cm²/wk/cm)
1. 0.03 (0.01)
2. 0.04 (0.01)
The trial authors reported that the between-group difference was not statistically significant (P value 0.072)

Secondary outcomes:
Bacterial eradication

The trial authors reported: "Neither treatment was superior in causing a reduction in bacterial numbers on a semiquantitative (categorized as profuse, moderate or sparse) basis." No further information or data were provided

Adverse effects: burning, itching or pain
1. 0
2. 6


NotesWithdrawals from both groups (breakdown per group not provided):
Death (2); dropped out or failed to return (9); failed to respond to trial treatment (4)

Excluded from statistical analysis: do not satisfy inclusion criteria (2); lost to follow-up (4)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"patients were randomly assigned to either the standard or cadexomer iodine group"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information given about whether/how assignment to treatment groups was concealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High riskWound care: "treatment was repeated on a daily basis by the patient"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"each ulcer was evaluated serially by the same person as each medical centre"; no further information given

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"Of the 75 patients starting the trial,15 did not complete the study for reasons other than healing of the ulcer. Four failed to respond to one or both treatments and required more aggressive treatment. Two died during the study of causes unrelated to the ulcers, & 9 dropped out or failed to return. An additional 6 patients were excluded from statistical analysis"

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskdropout rate > 20%; breakdown per group not provided

Incomplete outcome data (attrition bias)
ITT analysis
High risk"6 patients were excluded from statistical analysis"

"A total of 12 patients switched treatments during the trial: all 12 crossed over from the control treatment to using cadexomer iodine because of a failure of healing..." It is not clear whether these participants were retained in their original groups for the purposes of data analysis

Baseline factors comparableHigh riskUlcers were larger and of longer duration in Group 2

Huovinen 1994

MethodsRandomised controlled trial conducted in Finland


Participants36 people initially recruited, 5 people withdrawn and excluded from analysis
Group 1: 11 randomly assigned, 10 completed
Group 2: 13 randomly assigned and 12 completed
Group 3: 12 randomly assigned, 9 completed

Average—unclear if this is the mean value (range) baseline ulcer area (cm2): Group 1: 27 (1 to 154); Group 2: 53 (1 to 475); Group 3: 31 (1 to 145)

Average (range) baseline ulcer duration (months): Group 1: 29 (3 to 96); Group 2: 72 (3 to 126); Group 3: 67 (4 to 252)

The trial authors stated that 26/31 (84%) ulcers had Staphylococcus aureus at baseline, but it was not clear whether wounds were colonised or clinically infected


Interventions1. Placebo tablet twice daily plus local treatment with 0.2 g zinc in 1 g petroleum-paraffin ointment and Comprilan elastic bandage
2. Ciprofloxacin 750 mg twice daily plus the above local treatment
3. Trimethoprim 160 mg twice daily plus the above local treatment

Treatment duration was 12 weeks in all groups


OutcomesAt 16 weeks:
Complete healing:
1. 3/11 (27%)
2. 5/13 (38%)
3. 3/12 (25%)

Average (range) change in ulcer size, calculated as % of original size (estimated from graph):

1. Excluding outlier -70% (+35 to -100), including outlier -20% (+200 to -100)

2. -75% (+15 to -100)

3. -35% (+70 to -100)

The trial authors did not report P values for between-group differences for change in ulcer size

Secondary outcomes:
Emergence of antibiotic-resistant flora during treatment period (30 participants included in analysis overall):
1. 1/10
2. 8/12
3. 6/9

The trial authors reported that the difference between Group 1 and the other groups was statistically significant (P value 0.02, appears to apply to Group 1 vs Group 2, and also to Group 1 vs Group 3)

Proportion of bacterial species isolated from ulcers resistant to ciprofloxacin/trimethoprim at the end of the study (16 weeks):

1. 4%/8%

2. 94%/63%

3. 12%/65%

The trial authors reported P value < 0.0001 in relation to the difference between groups for ciprofloxacin resistance; it was not stated which comparison(s) this applied to. For trimethoprim resistance, the trial authors reported the following between-group differences: P value 0.004 for Group 1 versus Group 2; and P value 0.0003 for Group 1 versus Group 3

Persistence of presence of Staph. aureus in open ulcers at 16 weeks (denominators as reported by trial authors):

1. 7/7
2. 1/7
3. 5/6

Cost of treatment in Finland, in USD:
1. not reported
2. 600
3. 120


NotesWithdrawals:
Group 1: osteitis (1)
Group 2: personal reasons (1)
Group 3: adverse effects (3—rash, mild vertigo and nausea, chest pain)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"patients randomly assigned to groups"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Low risk"The patients were.....treated in a double-blind manner...

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo mention of who the outcome assessor was and the adequacy of blinding

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskDescribes 5 patients excluded and states reasons for exclusion

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskThe dropout rate differed between groups: Group 1: 9%; Group 2: 8%; Group 3: 25%

Incomplete outcome data (attrition bias)
ITT analysis
Unclear risk"five were eventually excluded"; no other information provided about analysis

Baseline factors comparableHigh riskUlcer area and duration varied considerably across groups

Ishibashi 1996

MethodsRandomised controlled trial conducted in Japan


ParticipantsSetting: Japan (inpatients and outpatients)

Inclusion criteria: ulcer size 2 cm to 12 cm (unclear whether this is diameter or surface area); ulcer aetiology decubitus, burn injury or chronic venous insufficiency; participant aged 16 years or over

218 participants recruited in total (109 participants allocated per group)

Numbers of participants according to ulcer aetiology of 207 participants analysed (decubitus, burn injury, venous insufficiency): Group 1: 31, 41, 32; Group 2: 32, 40, 31

Numbers of participants with baseline ulcer area (in mm2 < 250, 250 to < 500, 500 to < 1000, 1000 to < 2500, ≥ 2500): Group 1: 4, 27, 24, 29, 20; Group 2: 8, 24, 29, 22, 20

Mean ± SE baseline ulcer area (mm2): Group 1: 1716.4 ± 217.8; Group 2: 1440.4 ± 153.5

Numbers of participants with baseline ulcer duration (in months, < 1, 1 to < 3, 3 to < 6, 6 to < 12, ≥ 12, unknown): Group 1: 18, 45, 15, 10, 16, 0; Group 2: 21, 42, 16, 10, 13, 1

Mean ± SD baseline ulcer duration (days): Group 1: 270.4 ± 63.4; Group 2: 300.9 ± 87.4

Numbers of participants with infected ulcer at baseline (category assessed by clinical examination—much, moderate, slight, none): Group 1: 4, 8, 32, 60; Group 2: 1, 9, 26, 67


InterventionsGroup 1: spray solution containing recombinant human basic fibroblast growth factor (KCB-1 0.01% solution 0.3 mL) to ulcer once a day after the ulcer was cleansed with antiseptic solution (unspecified). Three minutes after spraying, gauze pad was applied and secured with tape

Group 2: sugar and povidone-iodine ointment applied to ulcer once or twice daily after cleansing with antiseptic solution (unspecified), then gauze pad applied and secured with tape

No details of co-interventions such as compression


OutcomesAnalysis based on 207 participants in total: Group 1: 104 participants; Group 2: 103 participants

Numbers (%) of venous leg ulcer participants with complete healing at 4 weeks: Group 1: 9/32 (28%); Group 2: 5/31 (16%)


NotesIf participants had multiple ulcers, one was selected for study (method of selection not stated)

Withdrawals due to protocol violation (excluded from analysis):

Group 1: 5/109 (4.6%) (1 took disallowed medication before trial, 1 had traumatic ulcer, 2 previously used sugar and povidone-iodine ointment, 1 nutritionally depleted)

Group 2: 6/109 (5.5%) (1 had hypothyroidism and did not use study medication, 1 had previously used sugar and povidone-iodine ointment and did not use study medication, 1 had positive patch test for povidone-iodine and did not use study medication, 1 general condition deteriorated because of sepsis and participant did not use study medication, 1 had traumatic ulcer, 1 had ulcer smaller than 2 cm)

Further withdrawals during the trial (included in analysis):

Group 1: 4 withdrawals (1 worsening condition, 1 concomitant disease, 2 other reasons); Group 2: 9 withdrawals (3 adverse events, 1 worsening condition, 2 no effect of trial treatment, 1 discharged, 1 died, 1 other reason)

Withdrawal data were not broken down by wound aetiology

Sponsor of study not stated; KCB-1 provided by Kaken Pharmaceutical Company Ltd, and sugar and povidone-iodine ointment provided by Kowa Company Ltd


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as "randomised controlled trial", but no further information provided as to how the sequence was generated

Allocation concealment (selection bias)Unclear riskInformation from the translator suggested that central randomisation was used. From English language abstract: "The study was performed by the telephone or fax registration method." Exact methods not clear

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskDropout rate of each group described: Group 1: 109 participants randomly assigned, 5 excluded for protocol violation; Group 2: 109 participants randomly assigned, 6 excluded (5 for protocol violation, 1 for worsening clinical condition)

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskDropout rate about 5% in both groups

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskPatients excluded from analysis: Group 1: 109 - 5 = 104 patients analysed; Group 2: 109 - 6= 103 patients analysed—these values relate to the whole trial population, which consisted of people with various wound types. It is unclear how these withdrawals might have impacted estimates of treatment effect for those with venous leg ulceration

Baseline factors comparableUnclear riskUlcer area, duration and infection appear similar across all participants, but data were not provided per wound type

Jull 2008

MethodsRandomised controlled trial (multi-centre, involving 4 community-based district nursing services in New Zealand). A sample size of 400 people was estimated as required to detect a 30% between-group difference in the proportion of healed ulcers at 12 weeks, with 90% power and 5% significance level, and allowing for 10% loss to follow-up. Recruitment achieved 92% of planned target; this was deemed to retain 90% power, as the anticipated loss to follow-up did not occur


Participants368 participants with venous ulceration (ABPI > 0.8) or mixed venous and arterial ulceration (ABPI > 0.7), able to tolerate compression, were randomly assigned:

Group 1: 181 participants

Group 2: 187 participants

Ulcer duration at baseline, weeks, median (range) [mean ± SD]:

Group 1: 16 (2 to 999) [47.9 ± 118.1]

Group 2: 20 (3 to 688) [38.7 ± 76.3]

Baseline ulcer area, cm2, median (range) [mean ± SD]:

Group 1: 2.6 (0.2 to 81.0) [6.4 ± 9.8]

Group 2: 2.7 (0.1 to 193.0) [7.4 ± 18.2]

Numbers (%) of participants with mixed venous and arterial ulceration (ABPI > 0.7 but < 0.8):

Group 1: 5/181 (2.8)

Group 2: 2/187 (1.1)

Baseline SF-36 physical component summary score, mean ± SD:

Group 1: 34.0 (9.8)

Group 2: 36.7 (10.1)

Baseline SF-36 mental component summary score, mean ± SD:

Group 1: 50.5 (12.4)

Group 2: 48.7 (11.6)

The number of participants with signs and symptoms of infected ulcers at baseline is not reported


InterventionsGroup 1: usual care, with dressings applied according to district nurse choice (alginate, hydrofibre, hydrocolloid, foam, hydrogel, non-adherent, iodine or silver dressings)

Group 2: calcium alginate dressing impregnated with Manuka honey (ApiNate, Comvita, Te Puke, New Zealand) .

All participants received compression bandaging in accordance with usual practice in the study centres and dressing changes when compression bandaging was changed, with frequency determined by district nurses

Numbers (%) of participants with baseline compression system:

Group 1: short stretch 5 (3); long stretch 5 (3); three layer 65 (36); four layer 106 (59)

Group 2: short stretch 2 (1); long stretch 5 (3); three layer 74 (40); four layer 106 (57)

Treatment duration was 12 weeks


OutcomesPrimary outcomes:

Numbers (%) of participants with ulcers completely healed at 12 weeks:

Group 1: 90/181 (50)

Group 2: 104/187 (56)

The trial authors reported a 5.9% (95% CI -4.3% to 15.7%) absolute increase in healing in Group 2, P value 0.258, and stated that findings were similar with adjustment for study centre and prognostic index (statistics not provided)

Mean time to healing, days at 12 weeks:

Group 1: 65.3

Group 2: 63.5

The trial authors reported a difference in means of -1.8 days (95% CI -7.7 days to 4.1 days), P value 0.553

The trial authors reported a hazard ratio estimation of 1.1 (95% CI 0.8 to 1.5), P value 0.451, and stated that findings were similar with adjustment for study centre and prognostic index (statistics not provided)

Mean percentage change in ulcer area at 12 weeks:

Group 1: -65.5%

Group 2: -74.1%

The trial authors reported a difference in means of 8.6% (95% CI 23.9% to -4.7%), P value 0.186, and stated that findings were similar with adjustment for study centre and prognostic index (statistics not provided)

Secondary outcomes:

Numbers (%) of participants with incident ulcer infection, diagnosed by clinical assessment or wound swab:

Group 1: 40/181 (22)

Group 2: 32/187 (17)

The trial authors reported an absolute difference of 5% (95% CI -3.1% to 13.1%), P value 0.228

Number of episodes of infection:

Group 1: 49

Group 2: 37

The trial authors reported P value 0.449 for the between-group difference

Numbers (%) of participants reporting one or more adverse events:

Group 1: 84/181 (46)

Group 2: 111/187 (59)

The trial authors reported a risk ratio of 1.3 (95% CI 1.1 to 1.6), P value 0.013

Numbers (%) of participants reporting local adverse events:

Group 1: pain 18 (10); bleeding 3 (2); dermatitis 8 (4); deterioration of ulcer 9 (5); erythema 4 (2); oedema 1 (< 1); increased exudate 1 (< 1); deterioration of surrounding skin 3 (2); new ulceration 15 (8); other 3 (2)

Group 2: pain 47 (25); bleeding 3 (2); dermatitis 8 (4); deterioration of ulcer 19 (10); erythema 6 (3); oedema 4 (2); increased exudate 5 (3); deterioration of surrounding skin 5 (3); new ulceration 16 (9); other 6 (3)

The trial authors reported that the between-group difference in pain was statistically significant, P value 0.001. All other between-group differences were not statistically significant (reported P values all > 0.06)

Numbers (%) of participants reporting systemic adverse events:

Group 1: cardiovascular 3 (2); cancer 2 (1); neurological 1 (< 1); gastrointestinal 2 (1); injury 9 (5); musculoskeletal 9 (5); respiratory 3 (2); other 7 (4)

Group 2: cardiovascular 4 (2); cancer 2 (1); neurological 4 (2); gastrointestinal 4 (2); injury 10 (5); musculoskeletal 13 (7); respiratory 6 (3); other 3 (2)

All between-group differences were not statistically significant (reported P values all > 0.18)

Health-related quality of life assessed with SF-36 (8 domains scored on a scale of 1 to 100, with higher scores representing better perceived health, 100 being the best possible score):

SF-36 physical component mean summary score at 12 weeks:

Group 1: 37.9 (n = 174)

Group 2: 39.0 (n = 186)

The trial authors reported a difference in means of 1.1 (95% CI -0.8 to 3.0), P value 0.256 (not stated whether adjusted for baseline values)

SF-36 mental component mean summary score at 12 weeks:

Group 1: 50.4 (n = 174)

Group 2: 51.1 (n = 186)

The trial authors reported a difference in means of 0.7 (95% CI -1.1 to 2.4), P value 0.437 (not stated whether adjusted for baseline values)

Health-related quality of life assessed with CXVUQ (Charing Cross Venous Ulcer Questionnaire comprising four domains scored from 0 to 100, higher scores reflecting greater affliction, 100 being the worst possible score):

CXVUQ mean overall score at 12 weeks:

Group 1: 35.1 (n = 174)

Group 2: 33.5 (n = 186)

The trial authors reported a difference in means of -1.6 (95% CI -4.2 to 0.9), P value 0.204 (not stated whether adjusted for baseline values)

Health-related quality of life assessed with EQ-5D visual analogue scale (scale from 0 to 100, 0 = worst imaginable health state to 100 = best imaginable health state):

EQ-5D VAS mean score at 12 weeks:

Group 1: 73.5 (n = 174)

Group 2: 75.1 (n = 186)

The trial authors reported a difference in means of 1.6 (95% CI -1.5 to 4.7), P value 0.313 (not stated whether adjusted for baseline values)

Cost-effectiveness analysis, base case analysis of mean total health service costs per participant:

Group 1: NZD 972.68

Group 2: NZD 917.00

The trial authors reported that the ICER (incremental cost-effectiveness ratio) was -NZD 9.45 (95% CI -NZD 39.63 to NZD 16.07) favouring Group 2. Exclusion of hospitalisation costs (six participants hospitalised for a total of 40 days in Group 1 and three participants hospitalised for a total of 10 days in Group 2) reversed the ICER to NZD 11.34 (95% CI -NZD 2.24 to NZD 26.25) in favour of Group 1


NotesThis is the HALT Trial (ISRCTN 06161544)

In participants with multiple ulcers, the largest was used as the reference ulcer, and all ulcers for that participant were treated with the allocated intervention

Numbers (%) of participants lost to follow-up (reasons):

Group 1: 6/181 (3) (2 died, 3 moved, 1 uncontactable)

Group 2: 0/187 (0)

Numbers (%) of participants withdrawing from treatment (reasons):

Group 1: 0/181 (0)

Group 2: 31/187 (17) (8 deterioration of ulcer or surrounding skin, 7 healthcare professional's advice, 7 ulcer infection, 4 ulcer pain, 3 participant's choice, 1 ulcer bleeding, 1 dressing not available)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Participants were randomly assigned to one of two groups by an independent central telephone service. The allocation sequence was stratified by study centre and the Margolis Index using minimisation"

Comment: the method of random sequence generation was deemed satisfactory

Allocation concealment (selection bias)Low riskQuote: "Participants were randomly assigned to one of two groups by an independent central telephone service. The allocation sequence was stratified by study centre and the Margolis Index using minimisation"

Comment: the method of allocation concealment was deemed satisfactory

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskTrial described as "open label" but no further information provided about blinding participants

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Low riskQuote: "Outcome assessment could not be blinded. However, re-analysis of the primary outcome using healing state determined from blinded review of ulcer photographs did not affect the study findings"

Comment: The above information suggests low risk of bias in relation to blinding of outcome assessment

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskNumbers withdrawing, with reasons reported for both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskWithdrawal rate less then 20% in both groups, with patients discontinuing treatment followed up

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "Intention-to-treat analysis was undertaken with the inclusion of all participants randomised"

Comment: all participants were included in the analysis

Baseline factors comparableLow riskThe median ulcer size and the median ulcer duration appear comparable at baseline

Jørgensen 2005

MethodsRandomised controlled trial (multi-centre, 15 centres in 7 countries, including Canada, Denmark, Germany, Italy, Netherlands, UK and USA)


Participants129 participants with chronic venous or mixed venous/arterial leg ulcers (ABPI ≥ 0.65) were recruited with the following characteristics: moderately or highly exuding ulcer; minimum ulcer size of 2 cm2 and maximum size not exceeding the 10 × 10-cm dressing; delayed healing (defined as area reduction 0.5 cm2 or less during the previous 4 weeks); at least 1 clinical sign of critical colonisation (including increased exudate during previous 4 weeks, increased wound pain during previous 4 weeks, discolouration of granulation tissue or foul odour as assessed by study staff); use of compression therapy for 4 weeks before randomisation

Patients who had the following were excluded: clinical infection (including erysipelas and cellulitis of peri-ulcer skin); concomitant treatment with antibiotics or antiseptics during the week before randomisation; concomitant treatment with systemic corticosteroids exceeding 10 mg/d or other immunosuppressants from 4 weeks before randomisation; uncontrolled diabetes (HbA1c > 10%); and diseases that may interfere with ulcer healing (e.g. vasculitis, rheumatoid arthritis, severe kidney or heart disease)

Group 1: 64 participants

Group 2: 65 participants

Baseline ulcer area, median cm2 (range):

Group 1: 6.7 (1.3 to 50.6)

Group 2: 6.1 (1.1 to 53.4)

Duration of ulcer at baseline, median years (range):

Group 1: 1.0 (0.1 to 10.0)

Group 2: 1.1 (0.1 to 32.0)

Numbers (%) of participants with ulcer infections during the previous year:

Group 1: 40/64 (62)

Group 2: 44/65 (67)

Health-related quality of life baseline score, assessed with EQ-5D (EUROQoL):

Group 1: median 0.71

Group 2: median 0.69


InterventionsGroup 1: hydrocellular foam dressing 10 × 10 cm (Allevyn)

Group 2: silver foam dressing 10 × 10 cm (Contreet Ag)

All participants received wound cleansing with saline or tap water; securing of dressings with gauze or adhesive tape; treatment of peri-ulcer skin, as necessary, with a mild zinc cream or a topical steroid ointment; compression therapy according to the clinical practice of the centre, with the system unchanged throughout the trial period; dressings left in place for as long as clinically possible, to a maximum of 7 days; and weekly evaluation. Participants were treated for 4 weeks unless complete wound healing or withdrawal occurred sooner. Participants were withdrawn if treated with antibiotics or antiseptics during the trial


OutcomesPrimary outcomes:

Numbers (%) of ulcers healed at 4 weeks:

Group 1: 5/64 (8)

Group 2: 5/65 (8)

Mean ulcer area remaining relative to baseline at 4 weeks % ± SD (median, range):

Group 1: 71.0 ± 38.9 (74.6, 100 to 148)

Group 2: 53.3 ± 34.6 (54.8, 100 to 126)

Median % change in ulcer area at 4 weeks:

Group 1: -25

Group 2: -45

Weekly % wound reduction rate median (mean):

Group 1: not reported

Group 2: 11.3 (11.2)

Secondary outcomes:

Health-related quality of life scores - EQ-5D (EUROQoL) at week 4 (1 = perfect health, 0 = death):

Group 1: median 0.79
Group 2: median 0.79

Numbers (%) of participants reporting adverse events and type of events:

Group 1: 3/64 (5) device-related skin reactions: maceration, eczema and satellite ulcer

Group 2: 4/65 (6) device-related skin reactions: satellite ulcer and deterioration of peri-ulcer skin

Proportion of participants developing peri-ulcer maceration after 1 week/4 weeks of treatment:

Group 1: 55%/48%

Group 2: 34%/37%

The trial authors reported the between-group difference at 1 week as statistically significant (P value 0.008) but did not report a test of statistical significance for the 4-week data

The trial authors reported that participants in both groups indicated a decrease in pain during the treatment period, but no data are presented


NotesNumbers (%) of participants withdrawing (reasons):

Group 1: 7 (11) (5 protocol violation, e.g. ulcer did not meet defined size limits; 1 treated with antibiotics unrelated to study ulcer; 1 other protocol violation, not defined)

Group 2: 13 (20) (7 protocol violation, e.g. ulcer did not meet defined size limits; 3 treated with antibiotics unrelated to study ulcer; 2 treated with antibiotics for study ulcer infection; 1 other protocol violation, not defined)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomised to treatment with either Contreet Foam or Allevyn Hydrocellular by computer generated randomisation"

Comment: This was judged to be a satisfactory method of random sequence generation

Allocation concealment (selection bias)Unclear riskQuote: "Patients were randomised to treatment with either Contreet Foam or Allevyn Hydrocellular by computer generated randomisation"

Comment: No information regarding group allocation was provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskQuote: "The study was designed as a multicenter, open, block-randomised and controlled study"

Comment: No mention was made of participants being blind to treatment allocation

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "The study was designed as a multicenter, open, block-randomised and controlled study"

Quote: "The study personnel evaluated the patients weekly at the clinic or hospital throughout the study"

Comment: No mention was made of outcome assessors being blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: Numbers withdrawing and reasons are reported for both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskComment: A greater proportion of participants withdrew from the silver dressing group:

Group 1: n = 7 (11%)

Group 2: n = 13 (20%)

Incomplete outcome data (attrition bias)
ITT analysis
High riskQuote: "Intention-to-treat analyses were performed in connection with the safety parameters, whereas per-protocol analyses were applied for the performance parameters"

Comment: Analysis of healing outcomes was undertaken on a per-protocol basis

Baseline factors comparableLow riskComment: Baseline ulcer size and duration appear comparable. Similar rates of infection were reported per group during previous year

Kerihuel 2010

MethodsTwo separate randomised controlled trials, 1 in venous leg ulcer patients with 7 participating hospitals in France, the other in pressure ulcers. The trial authors stated that no a priori power calculation was undertaken


ParticipantsLeg ulcer study: 60 participants were randomly assigned, with ulcers of primarily venous origin (ABPI > 0.7), of ≤ 12 months' duration, area 5 to 100 cm2 and necrotic tissue covering ≥ 50% of wound bed, not contraindicated to compression bandaging. Participants with diabetes were eligible for inclusion. Participants with infected ulcers requiring systemic antibiotics were excluded:

Group 1: 30 (9 had some arterial disease)

Group 2: 30 (8 had some arterial disease)

Numbers (%) of participants with wound duration > 1 month:

Group 1: 11 (37)

Group 2: 10 (33)

Numbers (%) of participants with wound duration > 3 months:

Group 1: 1 (3)

Group 2: 9 (30)

Wound area cm2 mean ± SD (median):

Group 1: 17.5 ± 24.4 (8.2)

Group 2: 18.1 ± 18.2 (12.1)


InterventionsGroup 1: hydrocolloid dressing (Duoderm)

Group 2: charcoal dressing impregnated with silver (Actisorb 220 silver)

All participants received sharp debridement of necrotic tissue; wound cleansing with sterile saline; dressing changes 2 to 3 times per week or more frequently in cases of abundant exudate; recommendation to wear elastic compression bandage (Biflex 16) daily; and weekly assessment

Numbers (%) of participants complying with use of compression:

Group 1: 15/30 (50)

Group 2: 12/30 (40)

Treatment duration was 4 weeks


OutcomesChange in wound area, cm2 median (range) at week 4:

Group 1: -3.5 (-53.3 to 18.5)

Group 2: -4.5 (-30.9 to 22.5)

P value for between-group difference at 4 weeks not provided

Percentage change at week 4, median (range):

Group 1: -40.9 (-100.0 to 308.3)

Group 2: -35.6 (-100.0 to 182.1)

P value for between-group difference at 4 weeks not provided

Numbers (%) of participants reporting adverse events (reasons):

Group 1: 20/30 (67) (9 maceration/high exudation, 1 wound infection, 5 eczema, 1 pain, 3 skin irritation, 1 bleeding at dressing removal)

Group 2: 5/30 (17) (1 wound infection, 2 wound aggravation, 1 pain, 1 skin irritation)


NotesOne ulcer per participant was included in the study; it was not reported how the reference wound was selected in participants with multiple wounds

Numbers (%) of participants withdrawing (reasons):

Group 1: 6/30 (20) (2 local adverse event—eczema; 1 died; 2 withdrew consent; 1 was discharged home)

Group 2: 1/30 (3) (hospitalisation for heart failure)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomisation was by blocks of four: identical sealed boxes containing the allocated dressings, gauze and saline were randomly allocated to each patient. The box reference number indicated which study arm the patient had been allocated to, although this was unknown to the patient and investigator. The box reference numbers were verified by a co-ordinating centre before allocation"

Comment: Although the method of random sequence generation is not specifically stated, the details provided suggest that a satisfactory method was likely to have been used and that the trial is likely to be at low risk of bias for this domain

Allocation concealment (selection bias)Low riskQuote: "Randomisation was by blocks of four: identical sealed boxes containing the allocated dressings, gauze and saline were randomly allocated to each patient. The box reference number indicated which study arm the patient had been allocated to, although this was unknown to the patient and investigator. The box reference numbers were verified by a co-ordinating centre before allocation"

Comment: The details provided suggest a satisfactory method of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: no details provided about blinding of participants

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Low riskQuote: "All wound tracings were measured by two independent, experienced clinicians who were unaware of the treatment allocation"

Comment: The method of blinded outcome assessment was deemed satisfactory

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: The numbers of withdrawals and reasons are reported for both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High risk11.7% withdrew overall, but proportions differed between groups:

Group 1: 6/30 (20%)

Group 2: 1/30 (3%)

Incomplete outcome data (attrition bias)
ITT analysis
Low risk"All analyses used data from the intention-to-treat population (defined as all randomised patients whose wounds were traced in at least one assessment during the first four weeks of the study)"

Comment: The presentation of results suggested that all randomly assigned participants had been included in all analyses

Baseline factors comparableUnclear riskAlthough between-group wound surface area appears broadly comparable, it is difficult to judge wound duration comparability (categorical data only provided)

Kero 1987

MethodsRandomised controlled trial conducted in Finland


Participants27 people over 18 years of age with venous leg ulcers recruited
Group 1: 13 people
Group 2: 14 people

Mean ± SD (range) baseline ulcer duration in months: Group 1: 12.2 ± 23.0 (1 to 72); Group 2: 54.8 ± 108.7 (1 to 360)

Baseline ulcer area and infection status were not reported


Interventions1. Ulcer surface cleansed with normal saline, mechanical wound cleansing procedure carried out, dextranomer applied to ulcer surface, dry compress cover applied, and conventional compression bandage applied
2. Same as above but cadexomer iodine used


OutcomesComplete healing at 8 weeks:
1. 5/13 (38%)
2. 7/14 (50%)

Trial authors did not report a P value for this comparison

Mean reduction in ulcer area at 8 weeks:
1. 35%
2. 81%
Between-group difference reported as non-significant but P value not presented

Secondary outcomes:
Adverse events:
Group 1: pain (1)
Group 2: erythema (1); pain (1); stinging sensation (1)


NotesWithdrawals:
Group 1:
Drug-related S/Es (1); infection (2)

Group 2:
Drug-related S/Es (1); infection (2)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The trial was conducted under open design using random allocation to treatment with either cadexomer iodine or dextranomer"

"Each patient was allocated to the treatment by using a sealed enclosure envelope containing the treatment code of the individual patient"

Information taken from secondary publication (Tarvainen 1988)

Allocation concealment (selection bias)Unclear risk"The trial was conducted under open design using random allocation to treatment with either cadexomer iodine or dextranomer"

"Each patient was allocated to the treatment by using a sealed enclosure envelope containing the treatment code of the individual patient"

Information taken from secondary publication (Tarvainen 1988)

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear risk"The trial was conducted under open design..."
Information taken from secondary publication (Tarvainen 1988)

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"The trial was conducted under open design..."
Information taken from secondary publication (Tarvainen 1988)

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"Two patients (one in each group) withdrew because of drug related side effects"

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskDropout rate less than 20%

Incomplete outcome data (attrition bias)
ITT analysis
Unclear risk"Two patients, one in each group were excluded from the evaluation of ulcer size because of infection that made cessation of therapy necessary. Two more patients, one in each group, were also excluded because of adverse reactions"

Baseline factors comparableHigh riskUlcer duration appeared longer in the group receiving cadexomer iodine. No information about baseline ulcer area or wound infection status

Kuznetsov 2009

MethodsRandomised controlled trial conducted in Russia


Participants30 participants with venous leg ulcers recruited from surgical outpatient clinic in Moscow, Russia

Group 1: 15 participants

Group 2: 15 participants

Numbers (%) of participants with aetiological factors for VLUs:

Group 1: 11 (73) participants with varicose vein disease; 4 (27) participants post thrombophlebitis

Group 2: 12 (80) participants with varicose vein disease; 3 (20) participants post thrombophlebitis

Mean size of ulcer at baseline cm2 ± SD (range):

Group 1: 14.8 ± 3.4 (2.5 to 50.3)

Group 2: 17.4 ± 6.4 (2.2 to 99.5)

Numbers (%) of participants with ulcers > 20cm2:

Group 1: 5 (33)

Group 2: 4 (27)

Numbers (%) of participants with microbiological isolates:

Group 1: Staphylococcus aureus 10 (67);Pseudomonas aeruginosa 1 (6.7);Escherichia coli 1 (6.7)

Group 2: Staphylococcus aureus 9 (60);Pseudomonas aeruginosa 4 (27);Proteus species 1 (6.7)


InterventionsGroup 1: 10% povidone-iodine dressing (Betadine), changed daily

Group 2: different dressings used according to ulcer status. If necrotic tissue present, a moist wound dressing was used (TenderWet 24). This is a wound dressing pad used in combination with Ringer's solution to continuously irrigate the wound bed for 24 hours, changed daily. Once the necrotic tissue was cleared, a foam dressing (PermaFoam) was applied and was changed every 5th day or sooner. In the case of resistant infection, the foam dressing was combined with tulle dressing containing silver (Atrauman Ag)

Both groups received short-stretch compression bandaging (Pütter-Verband, Hartmann). No participants underwent surgery

Biological and cytological assessment was undertaken at baseline and on days 7, 14 and 21

The duration of treatment was 28 days or until complete healing (whichever came first)


OutcomesPrimary outcomes:

Numbers (%) of participants with complete healing at 21 days:

Group 1: 1/15 (7)

Group 2: 4/15 (27)

Numbers (%) of participants with complete healing at 28 days:

Group 1: 2/15 (13)

Group 2: 5/15 (33)

Mean change in ulcer size in cm2 at 7 days:

Group 1: -0.35

Group 2: -2.09

Mean change in ulcer size in cm2 at 21 days:

Group 1: -1.27

Group 2: -5.03

Mean rate of healing in cm2/d:

Group 1: -0.06

Group 2: -0.24

The study authors reported that the between-group difference was statistically significant (P value < 0.05)

Secondary outcomes:

Numbers (%) of participants with microbiological isolates at 21 days:

Group 1: Staphylococcus aureus 7 (47), Pseudomonas aeruginosa 1 (6.7), Escherichia coli 1 (6.7)

Group 2: Staphylococcus aureus 5 (33), Pseudomonas aeruginosa 3 (20), Proteus species 1 (6.7)

Mean cost of complete course of treatment per group (RUB):

Group 1: 6,669.84

Group 2: 14,360.15

Mean cost of treatment per participant, per day (RUB):

Group 1: 16.47

Group 2: 36.82


NotesArticle translated from Russian

Unit of randomisation and analysis was the participant

Withdrawals not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: Translation indicates that participants were randomly assigned to groups, but no details of randomisation methods were provided

Allocation concealment (selection bias)Unclear riskComment: The report contained no statement regarding the group allocation process

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: The trial was described as "open", but no details of blinding of participants were provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskComment: The trial was described as "open", but no details of blinding of outcome assessors were provided

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: The trial report indicates that all randomly assigned participants completed treatment

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskComment: The trial report indicates that all randomly assigned participants completed treatment

Incomplete outcome data (attrition bias)
ITT analysis
Low riskComment: The trial report indicates that all randomly assigned participants completed treatment

Baseline factors comparableUnclear riskThe upper end of the ulcer area range is larger in Group 2. No information was provided about baseline ulcer duration

Laudanska 1988

MethodsRandomised controlled trial conducted in Poland


Participants67 people with venous leg ulcers who failed to respond to outpatient treatment (dressings and compression bandages) were recruited; data from 60 people were analysed by the trial authors. Those with ulcers of diameter < 2 cm were excluded:
1. 33 people
2. 33 people

1 patient was excluded from the trial authors' analyses, for whom the treatment group was not specified

Mean ± SE baseline ulcer area, cm2: Group 1: 35.2 ± 8.1; Group 2: 27.5 ± 7.0
Mean ± SE baseline ulcer duration, months: Group 1: 15.0 ± 3.1; Group 2: 19.1 ± 4.3
No information about ulcer infection status at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Ulcers cleansed with dilute hydrogen peroxide and covered with zinc paste dressing. The following were also used if deemed necessary by the clinician: saline dressing; dilute potassium permanganate solution; and gentian violet solution

2. Cadexomer iodine applied in a 3 to 4 mm layer

All participants were treated in a hospital inpatient setting and received daily dressing changes; a light elastic bandage to keep the dressing in place; and bed rest for the 6 weeks' duration of the trial; allowed out of bed for meals and toileting


OutcomesPrimary outcomes:

Complete healing or very superficial wound remaining at 6 weeks:
1. 7/33
2. 16/33

Mean ulcer area reduction at 6 weeks:
1. 54%
2. 71%
P value < 0.01 (reported by trial authors)

Secondary outcomes:
Pain assessed using 100=cm visual analogue scale: Figure presented in paper indicates reduction in pain at 6 weeks in both groups relative to baseline, but figure not detailed enough for values to be read. The trial authors reported that pain reduction occurred more rapidly in Group 2, and that relative to Group 1, significantly less pain was reported within 1 week of commencement of treatment (P value < 0.01)

Numbers (%) of participants reporting adverse events (description):
1. 1/30 (3%) (stinging sensation in the ulcer when dressing applied)
2. 6/30 (20%) (1 peri-ulcer erythema; 5 stinging sensation in the ulcer when dressing applied)

Elevation of serum concentrations of protein-bound iodine occurred after treatment with cadexomer iodine in participants with large ulcers, but tests of thyroid function showed no changes associated with the use of cadexomer iodine


NotesOverall, 7/67 (10%) participants withdrew. 4 participants (2 per group) withdrew before the first assessment (social reasons 3 and heart failure 1; reasons not presented per group)

A further 3 participants completed the trial but were excluded from analysis, 2 because of difficulty in measuring the ulcer because of large size (1 per group) and 1 because of having an ulcer associated with severe rheumatoid arthritis, which interfered with assessment (group not stated)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly allocated to treatment with either cadexomer iodine or the standard local dressing regime"

Comment: It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskQuote: "Treatment code not broken until study was completed"

Comment: No measures were described to prevent foreseeing the intervention allocation

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "A single observer made all assessments in every patient throughout the trial and treatment code not broken until study completed"

Comment: It was not stated whether this observer was blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskQuote: "Two patients in each treatment group dropped out of the trial before the first assessment. In three instances this was due to social reasons and in one case because of cardiac failure not due to treatment..."

Quote: "The results obtained from three patients, all of whom responded to treatment, were excluded from the analysis"

Comment: Some information on withdrawals (numbers/reasons) was given in relation to the whole sample, not per treatment group

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskComment: Overall withdrawal rate was less than 20%

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskQuote: "The results obtained from three patients, all of whom responded to treatment, were excluded from the analysis"

Comment: Analysis was based on 60/67 participants. It is unclear how these withdrawals might have impacted estimates of treatment effect (this is a small RCT)

Baseline factors comparableUnclear riskDifficult to judge baseline comparability, as mean values, rather than medians, were provided

Lazareth 2008

MethodsMulti-centre randomised controlled trial (24 centres in France, including hospital dermatology and vascular medicine outpatient clinics). A minimum sample size of 96 participants was determined a priori to have 80% power to detect, at 8 weeks, 15% superiority of the silver dressing if relative wound area regression in the non-silver group was within a 20% to 25% range, with an expected standard deviation of 26% and a two-tailed 5% significance level


Participants102 participants with venous leg ulcers (ABPI > 0.8), ulcer duration < 24 months, wound area 5 to 40 cm2 and presence of at least 3 of 5 clinical signs of heavy bacterial load (pain at dressing change, peri-ulcer erythema, oedema, foul odour, and heavy exudate). Patients with diabetes were eligible for inclusion. Patients with the following were excluded: current (or within previous week) usage of local or systemic antibiotics; clinically infected wound; erysipelas; malignant wound; recent deep vein thrombosis or venous surgery; neoplastic lesion treated by radiotherapy or chemotherapy; and ongoing treatment with immunosuppressive agents or high dose corticosteroids

Group 1: 50 participants

Group 2: 52 participants

Mean duration of ulcer months ± SD (median)

Group 1: 10 ± 8 (9.0)

Group 2: 11 ± 8 (9.5)

Mean ulcer area, cm2 ± SD (median)

Group 1: 17.5 ± 14.4 (12.6)

Group 2: 22.3 ± 20.4 (16.3)

71% of patients were outpatients at recruitment


InterventionsGroup 1: contact layer dressing (Restore)—similar to test dressing, the only difference being the absence of silver

Group 2: contact layer silver dressing (Restore Silver)—non-adhesive, non-occlusive, polyester mesh impregnated with hydrocolloid particles and Vaseline. Silver incorporated as silver sulphate that releases over 7 days. 10 × 10-cm dressing

All participants received wound cleansing with normal saline; mechanical debridement, where necessary, to remove slough and necrotic tissue; secondary foam dressings (Ultrasorb); compression therapy selected by the investigators; and dressing changes every other day or less frequently, depending on the clinical condition of the wound and the volume of exudate. Local use of antiseptics (but not antibiotics) was permitted

Investigators withdrew participants from the study if dressing-related adverse events occurred, or if they considered that a different treatment was warranted (e.g. systemic antibiotics)

Treatment duration was 4 weeks, after which all participants received the non-silver dressing for a further 4 weeks


OutcomesPrimary outcomes:

Mean change in ulcer area at 4 weeks, cm2 ± SD (median):

Group 1: -1.3 ± 9.0 (-1.1), n = 48

Group 2: -6.5 ± 13.4 (-4.2), n = 51

The trial authors reported that the between-group difference was statistically significant (P value 0.023)

Mean relative change in ulcer size at 4 weeks % ± SD (median):

Group 1: -8.6 ± 54.6 (-9.5), n = 48

Group 2: -28.1 ± 36.7 (-29.1), n = 51

No P value reported for between-group difference

Mean healing rate, cm2/day ± SD (median) at 4 weeks:

Group 1: -0.08 ± 0.56 (-0.04), n = 48

Group 2: -0.20 ± 0.42 (-0.15), n = 51

The trial authors reported that the between-group difference was statistically significant (P value 0.009)

Secondary outcomes:

Numbers (%) of participants with no clinical signs of bacterial colonisation at 4 weeks:

Group 1: 8/50 (17)

Group 2: 20/52 (39)

Numbers (%) of participants with adverse events at 4 weeks (event type):

Group 1: 11/50 (22) (2 erythema/oedema, 1 infection, 4 peri-ulcer skin irritation, 1 pain, 1 over granulation, 2 other). 5 participants withdrew because of adverse events (types not specified)

Group 2: 11/52 (21) (1 erythema/oedema, 2 infection, 4 peri-ulcer skin irritation, 2 pain, 2 other). 4 participants withdrew because of adverse events (types not specified)


NotesNumbers (%) of participants withdrawing up to week 4 (reasons):

Group 1: 14 (28) (4 ulcer aggravation, 9 local adverse event, 1 other event)

Group 2: 3 (6) (1 consent withdrawal, 2 ulcer aggravation)

Further follow-up data were reported at 8 weeks, but data here were only recorded at 4 weeks to reflect the period of the controlled study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "A random list balanced by blocks of 4 patients was used"

Comment: no statement on how randomisation sequence was generated

Allocation concealment (selection bias)Unclear riskQuote: "Each centre received at least 4 sealed envelopes with a number corresponding to the chronological order of patients' inclusion. According to the centre recruitment capacities, more than one block could be provided. No randomization error or deviation was detected by the on-site audits held during the study"

Comment: not stated whether envelopes were opaque

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: trial described as "open-label". No information about blinding of participants

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Low riskQuote: "The wound area tracings were measured by an independent person who was unaware of the test dressings. Furthermore, a blind review of the planimetric and photographic data was performed at the end of the study to validate the investigators’ evaluations, by 2 independent and experienced physicians. These reviewers did not know the received dressings and classified the final target ulcer status according to a 7-point scale (from "leg ulcer strongly improved" or "healed", to leg ulcer "strongly aggravated"). This review detected no difference between investigators and reviewers evaluations and confirmed that the decision rules followed by the investigators when the treatment was prematurely discontinued were no different for patients treated with the silver releasing dressing or the control."

Comment: The details provided were judged as indicating a low risk of bias for this domain

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: Numbers withdrawing and reasons are reported for both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskGroup 1: 14 (28%)

Group 2: 3 (6%)

Comment: Withdrawal rates differed between groups, and Group 1 had withdrawal rate > 20%

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "All analyses were conducted on the intent-to-treat population defined as all randomised patients with at least one follow-up planimetry value"

Quote: "...the efficacy analysis on the ITT population included 99 subjects (51 patients treated with the silver sequential strategy [CLS] and 48 patients with the continuous strategy with the control dressing [CL])"

Comment: Presentation of data in the trial report indicated that analyses had been conducted according to intention-to-treat, as defined above

Baseline factors comparableLow riskBaseline ulcer characteristics appear comparable across groups

Lindsay 1986

MethodsRandomised controlled trial conducted in the UK. Trial was of cross-over design with cross-over point at 4 weeks


Participants28 females over 30 years of age with exuding venous leg ulcers were recruited. Patients with insulin-dependent diabetes were excluded
Group 1: 14 randomly assigned, 13 completed
Group 2: 14 randomly assigned, 12 completed

Mean ulcer area, mm2 (read from graph):

Group 1: 1300

Group 2: 1250

Mean baseline ulcer duration: 20.1 months (breakdown per group not reported)
Not stated whether wounds were clinically infected at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Standard treatment consisting of sterile, non-adherent dressing plus support bandaging or stocking changed on alternate days. Other treatments were also allowed, including topical antimicrobials

2. Ulcer cleansed with sterile saline swabs or water or saline irrigation; cadexomer iodine applied to ulcer surface in a 3-mm layer; dry sterile dressing applied and secured with support bandaging or stocking. The dressing was changed on alternate days

All participants had ulcers managed in the community by general practitioners. After 4 weeks, participants were switched to the alternative treatment or were withdrawn from the trial according to the clinician's judgement

The duration of the trial was 10 weeks


OutcomesPrimary outcomes:

Complete healing at 4 weeks:
1. 1/14
2. 4/14

Mean reduction in ulcer area at 4 weeks:
1. 4.2%
2. 33.6%
P value < 0.005 (reported by trial authors)

Secondary outcomes:
Ulcer pain assessed with 10-cm visual analogue scale. The trial authors reported that Group 2 had significantly better results for pain after 4 weeks (P value < 0.002) but no further information presented

Infection assessed using swab taken before ulcer cleansing: the trial authors reported that the most frequently isolated organisms during the trial were Enterobacteriaceae, usually polymicrobial infections. The second most frequently occurring group was Staphylococcus aureus, and 4 participants were colonised by Pseudomonas species. Streptococci groups C and G were also isolated but were quickly eliminated. Cadeomer iodine treatment resulted in elimination or decrease of organisms in most cases. These data appear to relate to the first 4 weeks of the trial, but further information and breakdown by group not provided


NotesNumbers of participants who withdrew, with reasons:
Group 1: peripheral vascular disease (1)
Group 2: allergy (1); itching and irritation (1)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"patients were randomised to receive either standard dressing or cadexomer iodine"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"The patient or whoever was to manage the patient was instructed how to treat the ulcer"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk28 participants were randomly assigned, of whom 3 withdrew, one from Group 1 (because of peripheral vascular disease) and two from Group 2 (allergic reaction, skin irritation/itching)

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskDropout rate less than 20% in each group

Incomplete outcome data (attrition bias)
ITT analysis
Unclear risk"Statistical analysis at four weeks was performed on 12 assigned to cadexomer iodine and 13 patient assigned to standard treatment." This suggests that 25 participants were analysed out of 28 recruited to the trial. It is unclear how these withdrawals might have impacted estimates of treatment effect (this is a small RCT)

Baseline factors comparableUnclear riskLimited data available

Meaume 2005

MethodsRandomised controlled trial (multi-centre, involving 13 study centres in France). Sample size estimation was described, although not in relation to healing outcomes (it was in relation to a risk of wound infection score—mASEPSIS)


Participants99 patients with venous leg ulcers (ABPI > 0.7) or pressure ulcers were recruited who were hospitalised or who could be seen daily for 14 days. To be eligible, wounds had to be 2 to 20 cm in one dimension; have at least one of the following signs—covered with > 50% yellow slough, discoloured or friable granulation tissue, pocketing or undermining at the base of the wound, or foul odour; have at least two of the following signs of critical colonisation present—continuous pain, erythema, oedema, heat and moderate to high levels of exudate. Patients with diabetes were eligible for inclusion

Patients with the following were excluded: clear signs of ulcer infection requiring antibiotics, or lymphangitis and/or fever; poor life expectancy; clinical condition that might interfere with wound healing; receiving systemic antibiotics during previous 5 days; or receiving a topical chemical debridement agent during previous 7 days

Group 1: 48 participants (33 had VLU)

Group 2: 51 participants (38 had VLU)

Mean ulcer duration of VLU participants, months ± SD (median):

Group 1: 25.0 ± 37.2 (7.0)

Group 2: 42.5 ± 96.0 (12.0)

Mean ulcer area of VLU participants, cm2 ± SD (median):

Group 1: 24.5 ± 21.3 (16.1)

Group 2: 44.8 ± 46.3 (25.7)


InterventionsGroup 1: pure calcium alginate dressing (Algosteril)

Group 2: silver-releasing hydro alginate dressing (Silvercel)

All participants received wound cleansing with sterile saline; debridement as necessary, using surgical or mechanical methods; sterile pads as secondary dressings secured with hypoallergenic adhesives; systemic antibiotic therapy in cases of wound infection; at least 5 dressing changes per week during the first 2 weeks, and at least every 2 to 3 days thereafter. All participants with venous leg ulcers were treated with compression bandaging designed to provide 15 to 35 mmHg initial ankle pressure (French classification II to III). Wound cultures were taken at the investigators' discretion, but methods used were not reported

Treatment duration was two weeks. Participants were followed up whenever possible for an additional two weeks to evaluate change in wound surface area and to continue monitoring dressing acceptability and tolerability


OutcomesPrimary outcomes:

Mean ± SD change in ulcer area (cm2, VLU participants only) at week 4:

Group 1: -6.0 ± 11.7

Group 2: -9.5 ± 17.9

The trial authors did not report a P value for the between-group difference

Mean ± SD percentage change in ulcer area (VLU participants only) at week 4:

Group 1: -28.5 ± 37.0

Group 2: -21.0 ± 45.4

The trial authors did not report a P value for the between-group difference

Mean ± SD healing rate over 4 weeks (cm2/d, VLU participants only):

Group 1: 0.21 ± 0.42

Group 2: 0.34 ± 0.64

The trial authors did not report a P value for the between-group difference

Secondary outcomes:

Mean ± SD mASEPSIS index (ITT population, VLU participants only), follow-up point unclear:

Group 1: 86.3 ± 51.0 (n = 33)

Group 2: 111.8 ± 79.1 (n = 38)

Note: The mASEPSIS index is an evaluation of the risk of wound infection, with higher scores indicating higher risk of infection. The trial authors reported that the between-group difference was not statistically significant (P value not provided) and that findings were similar for VLU participants between ITT and per protocol populations

NB: The following findings apply to all participants, separate data not available for VLU participants:

Numbers (%) of wounds in all participants who developed a clinical infection during the 4-week follow-up:

Group 1; 23/51 (46)

Group 2: 16/48 (33)

The trial authors reported that the between-group difference was not statistically significant (P value 0.223)

Numbers (%) of all participants requiring systemic antibiotics during the 4-week follow-up:

Group 1: 4/51 (8)

Group 2: 5/48 (10)

The trial authors reported that the between-group difference was not statistically significant (P value 0.736)

Numbers (%) of all participants with adverse events (event type):

Group 1: 5/48 (10)—all were VLU participants (1 pain during dressing change; 1 peri-ulcer eczema; 1 burning sensation following dressing change; 1 increased wound size and pain; 1 erythema and pain)

Group 2: 5/51 (8)—4 were VLU participants (1 peri-ulcer eczema; 1 peri-wound irritation due to maceration; 1 extension of slough and dry wound; 1 pruritis and pain; 1 pain during dressing change, peri-ulcer erythema and pruritus)


NotesNumbers (%) of all participants withdrawing (reasons):

Group 1: 9/48 (19) (1 alginate dressing no longer indicated, as wound had become dry; 1 intercurrent event; 1 wound grafting; 2 wound infection; 4 wound aggravation)

Group 2: 10/51 (20) (1 alginate dressing no longer indicated, as wound had become dry; 1 consent withdrawal; 4 intercurrent event; 1 wound grafting; 1 wound infection; 2 wound aggravation)

Numbers (%) of VLU participants withdrawing:

Group 1: 6/33 (18)

Group 2: 9/38 (24)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Two a priori randomisation lists were prepared and balanced by blocks of six"

Comment: no statement on how the randomisation sequence was generated

Allocation concealment (selection bias)Unclear riskQuote: "Two a priori randomisation lists were prepared and balanced by blocks of six"

Comment: no information on group allocation concealment provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: trial described as "open-label" with no information about participant blinding

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskComment: trial described as "open-label" with no information about outcome assessor blinding

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: The numbers withdrawing and the reasons for withdrawal were reported for both groups

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High riskGroup 1: 6/33 VLU participants (18%)

Group 2: 9/38 VLU participants (24%)

Comment: A larger proportion of VLU participants in Group 2 withdrew; withdrawal rate of VLU participants in Group 2 was > 20%

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "All patients received at least one application of the allocated dressings and had at least one clinical evaluation (ITT population)"

Comment: both ITT and per-protocol analyses presented, and clear that all randomly assigned participants included in the ITT population

Baseline factors comparableHigh riskComment: Median baseline ulcer area and duration are comparatively greater in Group 2 than in Group 1

Michaels 2009

MethodsMulti-centre pragmatic randomised controlled trial conducted in the UK. Initial sample size requirement was for 300 participants, including loss to follow-up and withdrawal; this was revised to 212 participants after slow recruitment resulting in an extension to the trial's duration, and information from an interim analysis


ParticipantsPatients with active ulceration of the lower leg ≥ 1 cm in diameter that had been present for longer than 6 weeks were included. Patients with the following were excluded: ABPI < 0.8 in the affected leg; systemic antibiotic use; and insulin-controlled diabetes mellitus

Group 1: 106 participants

Group 2: 107 participants

Numbers (%) of participants with ulcer size ≤ 3 cm in diameter:

Group 1: 76 (72)

Group 2: 77 (72)

Numbers (%) of participants with ulcer size > 3 cm in diameter:

Group 1: 30 (28)

Group 2: 30 (28)

Numbers (%) of participants with previous ulcer in either leg:

Group 1: 52 (49)

Group 2: 61 (57)

Median baseline ulcer size, cm2 (from figure):

Group 1: 2.5

Group 2: 2.5

Numbers (%) of participants with ulcer present > 12 weeks:

Group 1: 43 (40)

Group 2: 39 (36)

Mean EQ-5D health state scores:

Group 1: 0.6536 (n = 94)

Group 2: 0.6446 (n = 98)

Mean SF-6D health state scores:

Group 1: 0.6792 (n = 83)

Group 2: 0.6544 (n = 89)

No information on signs of ulcer infection or colonisation reported, but patients were excluded if using antibiotics


InterventionsGroup 1: non-antimicrobial low-adherent dressing from any manufacturer (most were knitted viscose dressings)

Group 2: approved silver-donating dressings including silver-impregnated foam, alginate, hydrocolloid, low-adherent and non-adherent dressings (Aquacel Ag, Acticoat, Acticoat 7, Acticoat Absorbant, Contreet Ag or Urgotel SSD). The most commonly used dressings were Urgotel SSD, Acticoat 7 and Aquacel Ag. Most participants remained on the same dressing during the treatment period

The choice of the specific silver-donating or non-silver dressing was the responsibility of the clinician. In both groups, the allocated dressing was placed beneath multi-layer compression, applied by a nurse trained in the technique. Dressings were changed and bandages reapplied on a weekly basis unless clinicians believed that more frequent changes were necessary. The choice of compression was based on local practice. After healing, a compression stocking was recommended. Other interventions such as debridement were used if needed

Treatment duration was until the ulcers were fully healed, or for the 12-week treatment period of the trial. Follow-up was at 1, 3, 6 and 12 months. If active ulceration was still present after 12 weeks, the decision regarding continuation or change of the dressing was made by the clinician


OutcomesPrimary outcomes:

Median time to healing, days (95% CI):

Group 1: 58 (43 to 73)

Group 2: 67 (54 to 80)

The trial authors reported that the between-group difference was not statistically significant (P value 0.408, Cox proportional hazards model)

The trial authors reported the following hazard ratio estimate for silver versus control dressings: 1.13 (95% CI 0.85 to 1.15)

Numbers (%) of participants with complete ulcer healing at 12 weeks:

Group 1: 59/106 (56)

Group 2: 62/107 (58)

Numbers (%) of participants with complete ulcer healing at 6 months:

Group 1: 78/106 (74)

Group 2: 87/107 (81)

Numbers (%) of participants with complete ulcer healing at 12 months:

Group 1: 90/106 (85)

Group 2: 95/107 (89)

Secondary outcomes:

Recurrence rates within first year.:

Group 1: 13 (14%) of 90 participants who were healed within the first year

Group 2: 11 (12%) of 95 participants who were healed within the first year

Health-related quality of life:

Mean EQ-5D health state scores at 12 weeks/1 year (adjusted for baseline EQ-5D score):

Group 1: 0.7004 (n = 76)/0.6752 (n = 58)

Group 2: 0.7255 (n = 81)/0.7526 (n = 61)

Mean SF-6D health state scores at 12 weeks/1 year (adjusted for baseline SF-6D score):

Group 1: 0.7029 (n = 68)/0.662 (n = 53)

Group 2: 0.6864 (n = 73)/0.7092 (n = 55)

The trial authors reported no significant between-group differences at any of the follow-up times (baseline, 1, 3, 6 and 12 months) in the EQ-5D and SF-6D mean utility scores. No significant difference between groups was noted with respect to mean follow-up after adjustment for age. This was also true when the mean scores for the eight SF-36 dimensions were compared.

Adverse events:

The trial authors reported no adverse events identified as being related to the dressings, although 1 participant in Group 2 stopped treatment at week 4 because of skin irritation. Also, 4 participants in each group died during the 1-year follow-up period, but after the 12-week treatment period

Costs and resource use, price year 2007:

Mean cost of clinic visits GBP (95% CI):

Group 1: 196.06 (156.95 to 235.18) (n = 67)

Group 2: 275.39 (236.83 to 313.95) (n = 74)

Mean cost per dressing GBP (95% CI):

Group 1: 5.73 (2.96 to 8.49) (n = 67)

Group 2: 30.62 (25.47 to 35.78) (n = 74)

Mean total cost per participant based on cost of clinic visits, home visits, dressings, bandages, GP and chiropody contacts, compression hosiery, antibiotics and other medicines GBP (95% CI):

Group 1: 320.12 (277.42 to 362.82) (n = 67)

Group 2: 417.97 (375.01 to 460.93) (n = 74)

Cost-effectiveness:

Silver dressings were associated with an incremental cost in GBP of 97·85 and an incremental QALY (quality-adjusted life-year) gain of 0·0002 compared with control dressings. The ICER for silver dressings was GBP 489,250 per QALY gained. Based on these data and additional sensitivity analyses, the trial authors concluded that silver dressings were unlikely to be cost-effective


NotesIn participants with bilateral ulceration, the leg with the greatest total ulcer area was the study limb, but the allocated treatment was used for both legs

Numbers (%) of participants withdrawing (reasons):

Group 1: 5 (5) (2 lost to follow-up; 3 received silver dressing; 1 was by participant request and 2 by nurses' choice)

Group 2: 8 (7) (3 lost to follow-up; 4 did not receive a silver dressing; 1 case was due to non-availability of dressing and 3 were unexplained; 1 case of skin irritation)

Numbers (%) of participants who did not receive the allocated dressing:

Group 1: 3/106 (3)—treated with silver-donating dressings

Group 2: 4/107 (4)—1 healed before dressing became available, 3 unexplained breach of protocol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Treatment allocation was carried out using a computer program to generate stratified block randomisation with variable block size"

Comment: The details provided suggested a satisfactory method of random sequence generation

Allocation concealment (selection bias)Low riskQuote: "Trial numbers and randomisation were allocated through a telephone-based service which recorded details of the patient and which proffered a checklist of questions to confirm eligibility"

Comment: The details provided suggested a satisfactory method of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High riskQuote: "It was not possible to blind either the patients or the nurses applying the dressings, because each type of dressing had different physical characteristics"

Comment: It is clear from the details provided that participants were not blind to treatment allocation

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Low riskQuote: "The research staff dealing with postal questionnaires, the staff measuring ulcer sizes based upon tracings, and the staff carrying out initial data entry and analysis were all blinded to the treatment allocation of the patient"

Comment: It is clear from the details provided that outcome assessors were blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: The numbers of participants withdrawing from each group were reported, along with reasons for withdrawal

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskGroup 1: 5/106 (5%)

Group 2: 8/107 (7%)

Comment: Withdrawal rates were low and similar between groups

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "Analysis of all outcomes was on an intention-to-treat basis"

Comment: It is clear from the trial report that an intention-to-treat analysis was conducted

Baseline factors comparableUnclear riskThe information provided on baseline ulcer area suggests between-group comparability, but the only information on baseline ulcer duration was the number of participants in each group with ulcers present > 12 weeks

Miller 2010

MethodsRandomised controlled trial (multi-centre involving 2 not-for-profit community nursing services in Australia). Sample size calculation estimation was reported, but the number of patients recruited was less than the estimated number (281 vs 360)


Participants281 participants with venous or mixed venous/arterial aetiology leg ulcers (ABPI ≥ 0.6) and ≤ 15 cm in diameter were randomly assigned. Ulcers had to present at least one of the following signs of infection or critical colonisation: cellulitis, suppuration, lymphangitis, sepsis, bacteraemia, changes in granulation tissue, increased or malodorous exudate, new areas of slough or wound breakdown, impaired healing, increased or new pain. Patients with/receiving the following were excluded: diabetes; malignant leg ulcer; topical antiseptics within 1 week of recruitment; antibiotics within 48 hours of recruitment; systemic steroids; or palliative care

74% of recruited participants had venous leg ulceration; the remainder had mixed disease (data per group not provided):

Group 1: 140 participants

Group 2: 141 participants

Mean baseline ulcer area reported for participants included in final analysis (cm2 ± SD):

Group 1: 59.7 ± 63.2 (n = 133)

Group 2: 81.2 ± 107.0 (n = 133)

Mean baseline ulcer duration reported for participants included in final analysis (weeks ± SD):

Group 1: 58.1 ± 260.6 (n = 133)

Group 2: 49.4 ± 165.9 (n = 133)


InterventionsGroup 1: silver-donating dressings (Acticoat, Acticoat Absorbant or Acticoat 7)

Group 2: cadexomer iodine dressings (Iodosorb ointment or Iodosor powder)

All participants received dressing choice determined by clinician, according to individual wound characteristics such as moisture levels; and four-layer compression bandaging (Profore or Profore Lite). Dressings in both groups were provided until all signs of critical colonisation and infection had been absent for 1 week, after which a non-antimicrobial dressing was applied according to the clinician's judgement. If signs of critical colonisation or infection recurred, the original randomised dressing was reinstated

Fifty-five participants received antibiotic treatment during the 12-week study period. Breakdown by group not reported

Duration of treatment was 12 weeks


OutcomesPrimary outcomes:

Time to healing:

Estimates not provided; the trial authors reported that the between-group difference was not statistically significant (P value 0.70, log rank test; and P value 0.80 Wilcoxon test)

Numbers (%) of ulcers healed at week 12:

Group 1: 85/140 (61)

Group 2: 84/141 (60)

Mean percentage daily healing rate ± SD:

Group 1: -2.10 ± 1.89 (n = 133)

Group 2: -1.69 ± 2.46 (n = 133)

Secondary outcomes:

Numbers of adverse events reported:

Group 1: 13

Group 2: 8

Details of the adverse events not provided; unclear whether the numbers provided refer to the numbers of participants reporting adverse events, or the number of adverse events in the group.

Bacterial profile of wounds obtained by swab, using a rotating, 10-point zigzag technique while avoiding necrotic tissue, across wound bed, which had been cleansed with sterile water before specimen collection. Gram stain and semi-quantitative analyses were conducted to identify the species and level of bacteria present. The bacterial burden was classified as nil/scant, low, moderate or heavy. In assessing the semi-quantitative bacteriology results for each swab, the highest level of growth for bacilli positive, bacilli negative, cocci positive or cocci negative was used, regardless of which organism was isolated from the wound culture. Swab data obtained from 278 participants, breakdown per group not provided

Numbers (%) of participants with nil/scant/low and mod/high degree of bacterial growth during the first 2 weeks of treatment:

Leucocytes:

Group 1: 116 nil/scant/ low; 16 mod/high

Group 2: 110 nil/scant/ low; 17 mod/high

Gram-postive bacilli:

Group 1: 90 nil/scant/ low; 5 mod/high

Group 2: 90 nil/scant/ low; 1 mod/high

Gram-negative bacilli:

Group 1: 62 nil/scant/ low; 43 mod/high

Group 2: 64 nil/scant/ low; 32 mod/high

Gram-positive cocci:

Group 1: 72 nil/scant/ low; 41 mod/high

Group 2: 73 nil/scant/ low; 35 mod/high

Gram-negative cocci:

Group 1: 87 nil/scant/ low; 0 mod/high

Group 2: 83 nil/scant/ low; 0 mod/high

Staphylococcus aureus was the most commonly isolated organism overall (isolated from around 90% of ulcers, further data and breakdown per group not provided). 16 swabs were identified with methicillin-resistant Staphylococcus aureus (not explained how many participants this relates to, nor which treatment groups)

The trial authors reported that when moderate to heavy growth was identified, no differences in healing rates were noted between treatment groups. When nil/scant or low bacterial growth was identified, Group 1 had a significantly faster healing rate compared with Group 2 in relation to leucocytes (P value < 0.01), Gram-positive bacilli (P value < 0.05), Gram-positive cocci (P value < 0.01) and Gram-negative cocci (P value < 0.05) within the first 2 weeks

Healing rates in light of bacterial colony and degree of bacterial burden were not examined for the entire 12-week study period because of variations in the timing of swabs; the baseline swab was the only consistent time when all study participants were swabbed

Dressing acceptability as rated by participants with a 4-point questionnaire—completely agree, moderately agree, moderately disagree, completely disagree that the dressing was acceptable

Proportion of participants who completely or moderately agreed that the dressing was acceptable overall:

Group 1: 91.6% (n = 107)

Group 2: 88.9% (n = 100)


NotesThe trial authors reported that baseline differences in wound size were adjusted for in the analysis.

Numbers (%) of participants withdrawing (reasons):

Group 1: 7 (5) (1 lost to follow-up, 5 withdrawn and insufficient data for analysis, 1 died)

Group 2: 8 (6) (3 lost to follow-up, 5 withdrawn and insufficient data for analysis)

When participants had multiple wounds, the wound with the most signs of critical colonisation or infection was studied, but the same randomly assigned treatment was applied to all wounds for that participant


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomization lists were generated using the random number function generator in Microsoft Excel"

Comment: The details provided suggested a satisfactory method of random sequence generation

Allocation concealment (selection bias)Unclear riskQuote: "Following recruitment, clients were randomized to their treatment group by the nurse opening the next numbered envelope in which the group allocation was concealed"

Comment: not stated whether envelopes were sealed or opaque

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High riskQuote: "The design of this trial could have been strengthened by participant and data collector blinding. However, presentation of the two antimicrobial treatments was quite distinctive and might have been discerned by sensation alone"

Comment: It was clear that participants were not blind to treatment allocation

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
High riskQuote: "The design of this trial could have been strengthened by participant and data collector blinding. However, presentation of the two antimicrobial treatments was quite distinctive and might have been discerned by sensation alone"

Comment: It was clear that outcome assessors were not blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: Numbers of participants lost to follow-up, withdrawing or died are given for each group, but reasons for withdrawal are not reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskGroup 1: 7/140 (5%)

Group 2: 8/141 (6%)

Comment: The withdrawal rates are low and similar between groups

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskQuote: "In accordance with the intention-to-treat principle, once the client was randomized to a treatment, they remained in the study regardless of variations to their treatment and completed all data collection including monitoring the treatment provided"

Quote: "All clients with at least two wound size measurements at any time during the 12-week period, for whom a healing rate could therefore be calculated, were included in the final analysis in the treatment arm to which they were randomized, even if a change in treatment had occurred. With a total of 15 clients excluded from the analysis due to missing data or loss to follow-up (seven from the silver treatment group and eight from the iodine treatment group), 266 clients (95%) were included in the final analysis"

Comment: Some randomly assigned participants were excluded from the analysis. It is unclear how these withdrawals might have impacted estimates of treatment effect

Baseline factors comparableUnclear riskDifficult to judge between-group baseline comparability of ulcer size or duration, as data are reported only for participants included in the final analysis (not all participants randomly assigned). Values are reported as mean ± SD (medians are not reported)

Morias 1979

MethodsRandomised controlled trial conducted in Belgium


Participants59 people with chronic leg ulcers, 45/59 (76%) of venous aetiology, were recruited
Group 1: 29 people
Group 2: 30 people

Median (range) baseline ulcer area (mm2): Group 1: 100 (4 to 3300); Group 2: 100 (3 to 4400)
No information about baseline ulcer duration or infection status of wounds


Interventions1. Placebo tablet identical in appearance to levamisole
2. Levamisole dosed according to body weight ranging from 100 to 250 mg, given on 2 consecutive days every week until cure or failure or for 20 weeks

Previously used topical treatment was continued for all participants; no information about whether this included compression


OutcomesAt 20 weeks
Number of ulcers cured
1. 22/29 (76%)
2. 30/30 (100%)

Secondary outcomes:
Adverse effects
1. Group 1: 0/29 (0%)
2. Group 2: 3/30 (10%) - all were gastric complaints


NotesGroup 1: evident failure (8)
Group 2: evident failure (2)

The trial authors state that double-blind treatment was stopped before the end of the trial in eight participants in Group 1 and two participants in Group 2 because of "evident failure" (defined as no improvement). However, other information in the trial report suggests that all 59 participants were followed up for 20 weeks


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"All patients were sequentially numbered and received a bottle bearing their individual sequence number and containing double-blind tablets. These tablets randomly contained either 50 mg of levamisole (30 patients) or a placebo (29 patients) and were identical in appearance." It was not stated how the randomisation sequence was generated

Allocation concealment (selection bias)Low riskReports "sequentially numbered drug containers of identical appearance"

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Low risk"these tablets randomly contained either 50mg of levamisole or a placebo and were identical in appearance"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskNo information provided

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskParticipants complete at analysis; no dropouts or withdrawals reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskNo withdrawals reported

Incomplete outcome data (attrition bias)
ITT analysis
Low riskParticipants complete, no exclusions

Baseline factors comparableUnclear riskThe two groups appeared comparable for baseline ulcer area. However, no information about baseline ulcer duration was available, and it was not stated whether wounds were clinically infected

Moss 1987

MethodsRandomised controlled trial conducted in the UK, cross-over design (with cross-over point at 6 weeks)


Participants43 outpatients with venous leg ulcers of > 3 months' duration, unresponsive to topical treatment, were randomly assigned. Some participants also had arterial disease, and no further information was provided. Data reported on 42 participants:
Group 1: 21 completers
Group 2: 21 completers

Median ± SD baseline ulcer area (cm2): Group 1: 25.5 ± 29.5; Group 2: 19.7 ± 19.8
Median ± SD baseline ulcer duration (months): Group 1: 61.0 ± 68.0; Group 2: 75.0 ± 127.0
No information about whether wounds were clinically infected at baseline


Interventions1. Ulcers cleansed with normal saline, filled with dextranomer powder, non-adhesive pad, cotton wool wadding, stockinet and a firm elastic bandage applied

2. As above, but cadexomer iodine powder used instead

All participants were allowed to receive a 2-week course of oral antibiotics during the trial for clinical infection of ulcers

After 6 weeks of randomly assigned treatment, those not improving could be changed to the other treatment for the remaining 20 weeks of the trial


OutcomesPrimary outcomes:

At 6 weeks:
Mean percentage area change: Group 1: -2%; Group 2: -3% (values read from graph)
No significant difference between groups (P value not reported)

Secondary outcomes:
Numbers (%) of participants requiring antibiotics up to week 6:

1. 5/21 (24); 3 for infection in trial ulcer and 2 for infection in another ulcer

2. 5/21 (24); 4 for infection in trial ulcer; 1 for chest infection

Proportion of participants acquiring organisms during 6 weeks of treatment (values read from graph):

1. Beta-haemolytic Streptococcus 35%;Staphylococcus aureus 18%; Pseudomonas species 10%; Proteus species 10%

2. Beta-haemolytic Streptococcus 20%;Staphylococcus aureus 15%; Pseudomonas species 0%; Proteus species 0%

Proportions of participants eradicating organisms during 6 weeks of treatment (values read from graph):

1. Beta-haemolytic Streptococcus 0%;Staphylococcus aureus 42%; Pseudomonas species 10%; Proteus species 25%

2. Beta-haemolytic Streptococcus 40%;Staphylococcus aureus 0%; Pseudomonas species 35%; Proteus species 50%

Link between bacteriology and wound healing:

Complete eradication of bacteria during the 6-week trial was associated with a reduction in mean ulcer size in both treatment groups. In terms of specific isolates, this association was statistically significant for Pseudomonas species (P value < 0.05)


Notes1 participant was withdrawn because of poor compliance (group allocation not stated)

Bacterial profile assessed by wound swab


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"n=42 were randomly allocated to treatment"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNot reported that allocation was concealed

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"...the trial was not blind because the treatments can easily be distinguished by colour..."

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
High risk"All assessments were performed by CM or AT, but could not be blind because after the dressing were removed differences in colour were still apparent"

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskDropout rate described (1 participant from unspecified group, because of "poor compliance")

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskDropout rate < 20%

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskOne participant dropped out, and it is not clear whether that participant was included in the 6-week analysis

Baseline factors comparableHigh riskUlcers in Group 1 were of shorter duration but larger area compared with Group 2. It is not clear whether wounds were clinically infected at baseline

Münter 2006

MethodsRandomised controlled trial. Multi-centre—80 study centres, 9 countries (Belgium, Brazil, Canada, Denmark, Germany, Italy, Slovenia, Switzerland, UK). From an interim analysis, a sample of 272 participants per treatment group was estimated as required to detect a difference in means of 17.1 relative surface area with standard deviation 71.0, at 80% power and 5% significance level. To ensure adequate recruitment, while allowing for a withdrawal rate of 15%, a target of "over 600" was set


Participants619 participants with chronic wounds exhibiting delayed healing and producing moderate to high levels of exudate were recruited. Ulcers had to be < 0.5 cm in depth and characterised by at least one of the following: delayed healing due to bacteria (< 0.5 cm ulcer reduction or no change or increase in wound volume or surface area over past 4 weeks); being at risk of infection (such as diabetic wounds or sacral pressure ulcers); discolouration of granulation tissue; malodour; or clinical infection requiring treatment with systemic antibiotics

Group 1: 293 participants

Group 2: 326 participants

Breakdown of proportions of participants according to wound type:

Group 1: venous leg ulcers 50%; mixed venous/arterial leg ulcers 17%; pressure ulcers 7%; diabetic foot ulcers 8%; other wounds 18%

Group 2: venous leg ulcers 46%; mixed venous/arterial leg ulcers 21%; pressure ulcers 8%; diabetic foot ulcers 8%; other wounds 17%

Numbers of participants with leg ulcers, with breakdown according to aetiology:

Group 1: 197—venous 147/197 (75%); venous/arterial 50/197 (25%)

Group 2: 218—venous 150/218 (69%); venous/arterial 68/218 (31%)

Mean baseline ulcer size in cm2 ± SD (median, range) for all wound types (separate data not presented for participants with leg ulcers):

Group 1: 36.6 ± 64.4 (12.0, 0.1 to 400)

Group 2: 52.9 ± 90.0 (20.0, 0.1 to 700)

No data on baseline wound duration were provided

Participants with clinically infected wounds, or wounds deemed at risk of infection, were eligible for inclusion, but no data related to prevalence of infection at baseline were presented


InterventionsGroup 1: local best practice, including the following dressings—foams/alginates (53%), hydrocolloids (12%), gauze (3%), silver dressings (17%), other antimicrobial dressings (9%), other active dressings (6%)

Group 2: silver-donating foam dressing (Contreet Ag). Both adhesive and non-adhesive versions of the dressing were used

Wound management for all participants (including compression therapy) was performed in line with local protocols, guidelines and dressing manufacturers’ instructions. All dressings were changed between weekly assessments when judged necessary by the wound care practitioners

Duration of treatment was 4 weeks


OutcomesPrimary outcomes:

Median percentage change in ulcer area at 4 weeks for venous and venous/arterial leg ulcer participants:

Group 1: -28.8 (n = 197)

Group 2: -45.5 (n = 218)

The trial authors reported that the between-group difference was statistically significant (P value 0.0001)

Median percentage change in ulcer area at 4 weeks for venous leg ulcer participants:

Group 1: -26.9 (n = 147)

Group 2: -46.2 (n = 150)

The trial authors reported that the between-group difference was statistically significant (P value 0.0001)

Secondary outcomes:

Numbers (%) of participants with pain at dressing change for venous and venous/arterial leg ulcers:

Group 1: 2/197 (1%)

Group 2: 1/218 (< 1%)

The trial authors reported that the between-group difference was statistically significant (P value < 0.0001)

Numbers (%) of participants with ulcer pain between dressing changes for venous and venous/arterial leg ulcers:

Group 1: 2/197 (1%)

Group 2: 1/218 (< 1%)

The trial authors reported that the between-group difference was statistically significant (P value 0.0003)

Adverse events—numbers (%) of participants with macerated peri-ulcer skin at 4 weeks for venous and venous/arterial leg ulcer participants:

Group 1: 27/197 (13.7%) (22.1% at baseline)

Group 2. 26/218 (12.0%) (28.6% at baseline)

The trial authors reported that the between-group difference at week 4 was not statistically significant, but no P value was provided

Health-related quality of life (EQ-5D) for venous leg ulcer participants:

The trial authors reported that the between-group difference for the overall EQ-5D score at 4 weeks was not statistically significant, but no data were provided apart from the P value (P value 0.0878) When analysed separately, significantly less pain/discomfort was reported in Group 2 compared with Group 1; again, no data shown other than the P value (P value 0.0426). Not stated whether values were adjusted for baseline scores (and no baseline scores were presented)

Cost-effectiveness parameters—mean wear time of dressing for venous and venous/arterial leg ulcer participants:

Group 1: 2.1 days

Group 2: 3.5 days

The trial authors reported that the between-group difference was statistically significant (P value < 0.0001)


NotesNo outcome data on infection-related or microbiological outcomes were presented

No information about withdrawals was provided

Note: 17% of participants in the control group received silver dressings


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Using a computer-generated list in sealed envelopes, patients were randomly assigned to a four-week treatment period of either silver foam or LBP"

Comment: The above information suggested a satisfactory method of random sequence generation

Allocation concealment (selection bias)Unclear riskQuote: "Using a computer-generated list in sealed envelopes, patients were randomly assigned to a four-week treatment period of either silver foam or LBP"

Comment: No statement was made as to whether envelopes were opaque

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: The trial was described as "open", and no mention was made of participant blinding

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskQuote: "The study personnel at the participating centres completed the data collection forms"

Comment: The trial was described as "open", and no mention was made of outcome assessor blinding

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskComment: Although no explicit statement is made, tabulated outcome data for leg ulcers indicate that analyses were based on all participants

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskComment: Although no explicit statement is made, tabulated outcome data for leg ulcers indicate that analyses were based on all participants

Incomplete outcome data (attrition bias)
ITT analysis
Low riskQuote: "Data were analysed on the principle of last observation carried forward"

Quote: "The obtained data were analysed as intention to treat (ITT)"

Comment: Although no explicit statement is made, tabulated outcome data for leg ulcers indicate that analyses were based on all participants

Baseline factors comparableUnclear riskBaseline ulcer size was reported for all wound types together, not separately for the leg ulcer participants. For the overall group, the baseline ulcer size was larger in Group 2. No information on baseline ulcer duration was provided

Ormiston 1985

MethodsRandomised controlled trial conducted in the UK with optional cross-over point at 12 weeks


Participants61 participants with chronic venous ulcers (ABPI ≥ 0.7) were recruited; the trial authors presented data on 60 participants
Group 1: 30 participants
Group 2: 31 participants

Mean ± SD baseline ulcer area (cm2): Group 1: 10.2 ± 8.7; Group 2: 12.1 ± 13.9
Median [10th to 90th percentile] (range) baseline duration of ulcer (months): Group 1: 6.0 [4 to 36] (3 to 96); Group 2: 8.5 [3 to 144] (3 to 517)
No information about ulcer infection status at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Ulcers cleansed with saline; polymyxin and bacitracin ointment (Polyfax) and gentian violet applied; ulcer covered with non-adherent dressing (Melolin)

2. Ulcers cleansed with saline; cadexomer iodine powder sprinkled in a layer 3 to 5 mm deep; ulcer covered with gauze pad

All participants were treated at home; were trained by study nurses how to dress and bandage their ulcers; changed dressings and bandages daily; and received below-knee bandaging with a crepe bandage followed by a cotton crepe compression bandage


OutcomesPrimary outcomes:

At 12 weeks:
Complete healing:
1. 7/30
2. 12/31

Mean ± SEM healing rate (cm²/wk):
1. 0.46 ± 0.1
2. 0.89 ± 0.1

P value 0.0001 (reported by trial authors)

Mean healing rate (cm²/wk/cm circumference)
1. 0.03 ± 0.004
2. 0.06 ± 0.005
P value 0.0001 (reported by trial authors)

Secondary outcomes:

No significant difference in improvement in pain, erythema, exudate, oedema, pus/debris and granulation between both groups of the study

The trial authors reported no significant effect of treatment on bacterial colonisation, but no data were presented

Numbers of participants reporting adverse events:
1. Eczema, pruritus, rashes (2)
2. Difficulty in removing cadexomer iodine from ulcer (2—not stated whether 1 of these participants was the one who withdrew); stinging or itching on application of cadexomer iodine (3); eczema, pruritis, rashes (5)


NotesWithdrawals:
Group 1: none
Group 2:
Death (1, included in analysis)
Difficulty in removing cadexomer iodine from ulcer (1, included in analysis)
Admitted to hospital for routine surgery and received inappropriate dressing (1, excluded from analysis)
Total = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"subjects were randomised to treatment with cadexomer iodine or standard"; it was not stated how the sequence was generated

Allocation concealment (selection bias)Low risk"patients were then allocated a code number according to sequence of selection for the trial. for each number there was a double sealed envelope that contained a paper stating which treatment the patient should receive. The sequence of treatments was randomised, and the code of randomisation was not available to the investigators"

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"A nurse specially attached to the study taught the patients how to dress and bandage their ulcers..."

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"At the 12th week each case was reviewed by a clinician not associated with the routine assessment of the ulcer to see whether it was healing satisfactorily."

Not stated whether clinician was blind to treatment allocation

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"Sixty one patients entered this study. One patient receiving cadexomer iodine was admitted to hospital for routine surgery and his ulcer was dressed inappropriately.He was withdrawn from the trial"

Study further describes 2 participants who failed to complete the study

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskDropout rate acceptable

Incomplete outcome data (attrition bias)
ITT analysis
Low risk"Sixty one patients entered this study. One patient receiving cadexomer iodine was admitted to hospital for routine surgery and his ulcer was dressed inappropriately. He was withdrawn from the trial. This left 30 in each group. Two patients, both receiving cadexomer iodine, failed to complete the study. One died of a perforated ulcer and the other had difficulty removing the cadexomer iodine from the ulcer. The data on these two patient were included in the analysis."

It is unlikely that exclusion of one participant from the analysis had an important impact on estimates of treatment effect

Baseline factors comparableHigh riskMedian values indicate that ulcers in Group 2 were of longer duration than those in Group 1. It is difficult to interpret comparability for ulcer area, as mean rather than median values are presented. It is unclear whether ulcers were clinically infected at baseline

Skog 1983

MethodsRandomised controlled trial conducted in Sweden (multi-centre, 10 study centres), with optional cross-over point at 6 weeks


Participants95 participants with chronic infected venous ulcers of ≥ 3 months' duration, ≥ 2 cm diameter and ≥ 3 cm2 surface area were recruited, of whom 21 were excluded from analyses. Some included participants had mixed venous/arterial aetiology leg ulcers

Group 1: 45 randomly assigned, 36 analysed
Group 2: 50 randomly assigned, 38 analysed

Numbers (%) of participants with venous/mixed venous/arterial leg ulcers:

Group 1: 30/36 (83)/6/36 (17)

Group 2: 37/38 (97)/1 (3)

Mean ± SEM baseline ulcer area, cm2:

Group 1: 34.0 ± 5.7 (n = 36)

Group 2: 20.1 ± 4.4 (n = 38)
Mean ± SEM baseline ulcer duration, months:

Group 1: 22.2 ± 14.3 (n = 36)

Group 2: 26.5 ± 18.3 (n = 38)

Mean ± SEM baseline pain score (assessed by 100-point visual analogue scale divided into increments of 10, where 0 = no pain and 100 = severe pain):

Group 1: 33.0 ± 4.3 (n = 36)

Group 2: 32.0 ± 4.7 (n = 38)

All participants had infected ulcers at baseline (infection was defined as a colony count of +++ using a standard plating technique).


Interventions1. Ulcers cleansed daily with dilute hydrogen peroxide or dilute potassium permanganate baths, then non-adherent dressing applied (most commonly paraffin-impregnated dressings, also saline dressings and bland ointments used). Other treatments were allowed, including systemic antibiotics

2. Ulcers cleansed with running water, then cadexomer iodine powder applied to a depth of 3 mm followed by application of a dry dressing

All participants received care at home or at a hospital clinic; compression bandages (system unspecified, applied by nurse or participant); twice-daily dressing changes, if necessary, during the first few days of the trial, thereafter once-daily changes. If no improvement in the ulcer was noted at 6 weeks, the participant was switched to the other treatment for a further 12 weeks


OutcomesPrimary outcomes:

At 6 weeks:
Mean (SEM) percentage change in ulcer area (SEM values read from figure):
Group 1: increase of 5% (SEM 15) (n = 36)
Group 2: reduction of 34% (SEM 5) (n = 38)
The trial authors reported that the between-group difference was statistically significant (P value < 0.02)

Secondary outcomes:
Numbers of participants with eradication or reduction of staphylococcal infection/infection persisted or new infection during treatment:

Group 1: 0/18

Group 2: 16/7

The trial authors reported that the between-group difference was statistically significant (P value < 0.001)

Numbers of participants with eradication or improvement of Pseudomonas aeruginosa infection/infection persisted or new infection during treatment:

Group 1: 1/6

Group 2: 3/0

The trial authors reported that the between-group difference was statistically significant (P value < 0.05)

Numbers of participants with eradication or improvement of infection from other pathogenic organisms (Streptococcus, Proteus, Enterococcus, Enterobacteria and Klebsiella)/infection persisted or new infection during treatment:

Group 1: 3/17

Group 2: 15/5

The trial authors reported that the between-group difference was statistically significant (P value < 0.01)

Relationship between ulcer healing and bacteriological response to treatment: The trial authors reported that a statistically significant association was evident between eradication of Staphylococcus aureus and a more rapid rate of healing (P value < 0.002). Figure presented in a secondary reference, but no detailed description of methods or outcomes was provided to allow assessment of this association

Mean ± SEM pain score at 6 weeks (assessed by 100-point visual analogue scale divided into increments of 10, where 0 = no pain and 100 = severe pain) [change in means relative to baseline, calculated by review authors]:

Group 1: 23.0 ± 3.7 [-10] (n = 36)

Group 2: 10.0 ± 2.5 [-22] (n = 38)

The trial authors reported that the between-group difference was statistically significant (P value < 0.01)

Numbers of participants (%) with adverse events with description:
1. 1/36 (3%) pain following application of dressing
2. 4/38 (11%) pain following application of dressing; 1/38 (3%) itching in the peri-ulcer area; 1/38 (3%) rash resulting in withdrawal


NotesBacteriological outcomes assessed by wound swab (further details of specimen acquisition not provided)

Numbers of participants who withdrew:

Group 1:
Ineligible (3); beta-haemolytic strep. infection (4); squamous cell cancer (1); dramatic increase in ulcer size (1) total = 9

Group 2:
Ineligible (4); beta-haemolytic strep. infection (2); rash (1); holiday (2); missing information (2); recurrence of pain (1) total = 12


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were allocated blindly and at random to the standard treatment or to cadexomer iodine." It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear risk"Patients were allocated blindly and at random to the standard treatment or to cadexomer iodine." The method of allocation concealment was not stated

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskNo information was provided

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"at each centre the same observer always made these observations"; it was not stated whether observer was blinded

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskStudy reported number of dropouts and provided reasons

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High risk21/95 withdrew overall (22%)

Incomplete outcome data (attrition bias)
ITT analysis
High risk"ninety five sets of data were received for evaluation, of which 21 were excluded from the statistical analysis"

Baseline factors comparableUnclear riskMean values were reported for ulcer area and ulcer duration; therefore it was difficult to assess comparability

Smith 1992

MethodsRandomised controlled trial conducted in the UK


Participants200 people with venous leg ulcers (ABPI ≥ 0.75) ≥ 2 cm in diameter were recruited. Those with the following were excluded: diabetes; rheumatoid arthritis; infected ulcers requiring treatment that precluded dressings being left in situ; infection requiring immediate antibiotics; known intolerance to iodine; and neurological disease causing tropic impairment
Group 1: 99
Group 2: 101

Participants with smaller baseline ulcer diameter (2 to 4 cm)
Group 1a: 64
Group 2a: 62

Participants with larger baseline ulcer diameter > 4 cm
Group 1b: 35
Group 2b: 39

Median (interquartile range) baseline ulcer area (cm2) in participants with smaller/larger ulcers: Group 1: 3.1 (2.0 to 5.0)/13.3 (9.0 to 27.0); Group 2: 2.6 (2.0 to 4.0)/17.6 (9.0 to 38.0)

Median (interquartile range) baseline ulcer duration (months) in participants with smaller/larger ulcers: Group 1: 5 (3 to 9)/14 (2 to 45); Group 2: 3 (2 to 10)/17 (6 to 58)

Ulcers were not clinically infected at baseline. Most had bacteria present at initial assessment


Interventions1. Ulcers cleansed with sterile isotonic saline and ulcers filled with hydrocolloid powder (Biofilm powder) until level with the ulcer margins, before a hydrocolloid dressing (Biofilm dressing) was applied. Participants were allowed to remove their compression bandages and bathe or shower with the dressing in place

2. Ulcers cleansed with sterile isotonic saline, then povidone-iodine dressing applied (Betadine), cut to fit exactly the shape of the ulcer, and an absorbent pad placed over. Participants could not bathe or shower with the dressing in place

All participants were treated in a community setting and received graduated compression in the form of an elasticated tubular bandage (2 layers of shaped Tubigrip) or a stocking (Venosan 2002)


OutcomesFrequency of complete healing at 4 months:

1a: 38/64 (59%)
2a: 43/62 (69%)
P value 0.27

1b: 12/35 (34%)
2b: 4/39 (10%)
P value 0.02 (reported by trial authors)

Cox proportional hazards model found that the following 4 variables were significant independent predictors of time to healing (P value < 0.01): baseline ulcer area, ulcer duration, age, deep vein involvement. No significant interaction was detected between treatment and baseline ulcer area. Hazard ratio estimate of treatment effect not reported

Median (interquartile range) healing rate (cm²/d) at 1 month (analysis based on 151 participants):
1a(50 participants analysed): 0.056 (0.027 to 0.085)
2a (52 participants analysed): 0.062 (0.039 to 0.086)
P value 0.40 Mann-Whitney U-test

1b (25 participants analysed): 0.184 (0.115 to 0.338)
2b (24 participants analysed): 0.017 (0.001 to 0.267)
P value 0.09 Mann-Whitney U-test

Numbers (%) of participants reporting moderate or severe ulcer pain, assessed using 5-point scale (1 = no pain and 5 = worst pain) at 1 month (analysis based on 123 participants):

1a: 6/34 (18%)
2a: 16/36 (44%)
P value 0.02

1b: 12/27 (44%)
2b: 14/26 (54%)
P value 0.02

Estimated cost of dressings and nursing time over 4 months (GBP, price year not stated, analysis based on all 200 participants):

Participants with smaller wounds, defined as baseline diameter < 6 cm:
1a: 48.96
2a: 38.95

Participants with large wounds, defined as baseline diameter ≥ 6 cm:
1b: 526.63
2b: 183.75


NotesIn participants with bilateral ulceration, the right leg was included as the study limb

Numbers of participants (%) who withdrew, with reasons:
Group 1: total = 27/99 (27%)
Refused treatment (12); acute infection (1); admission (7); allergy (6); moved (1)
Group 2: total = 33/101 (33%)
Refused treatment (11); acute infection (12); admission (5); allergy (2); died (2); moved (1)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"200 patients with VLUs assessed by continuous wave ultrasound and plethysmography were randomly allocated to each treatment group, stratified by initial maximum ulcer diameter 2-4 cm and >4 cm, using a block length of 4 within each strata." It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"this was not a blind study"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
High risk"this was not a blind study"

Incomplete outcome data (attrition bias)
Drop out rate described
Low riskDropout rate described (60/200 participants)

Incomplete outcome data (attrition bias)
Drop out rate acceptable
High risk"70% completed the trial"

Incomplete outcome data (attrition bias)
ITT analysis
High risk"Five patients did not receive their randomly allocated treatment because of clerical errors. Two patients received biofilm instead of Betadine and three patients received Betadine instead of biofilm. Statistical analysis was performed on basis of treatment received"

Baseline factors comparableHigh riskOf those with larger ulcers at baseline (> 4 cm diameter), Group 2 included more participants with larger ulcers and wounds of longer duration

Steele 1986

MethodsRandomised controlled trial conducted in the UK (Northern Ireland)


Participants60 participants with active venous leg ulcers for at least 3 months and at least 2 cm2 surface area were recruited; data on 57 participants are presented:
Group 1: 29 (completers)
Group 2: 28 (completers)

Mean ± standard error baseline ulcer area, mm2: Group 1: 1759 ± 397; Group 2: 1264 ± 291
Mean ± standard error baseline ulcer duration, months: Group 1: 16.3 ± 2.5; Group 2: 16.6 ± 2.7

Day-to-day ulcer pain reported as none/mild/moderate/severe at baseline:

Group 1: 12/5/3/9 (n = 29)

Group 2: 9/8/4/7 (n = 28)

Unclear whether wounds were clinically infected at baseline (but it appeared that those with infected ulcers might have been allowed into the trial).


Interventions1. Various topical agents including antibiotics, antiseptics, hydrophilic agents, topical steroids and bland agents. Compression bandage applied to the whole leg, and changes occurred 3 times a week
2. Ulcer cleaned with normal saline, sprinkled with cadexomer iodine and dressed with gauze. Compression bandage applied to whole leg, and changes occurred 3 times a week

All patients were treated in a community setting


OutcomesPrimary outcomes:

Complete healing at 6 weeks:
1: 1/29
2: 3/28

Mean percentage change in ulcer area at 6 weeks (values read from figure):

1. -18% (n = 29)

2. -22% (n = 28)

The trial authors reported that the between-group difference was not statistically significant (P value 0.31)

Secondary outcomes:

Numbers of participants reporting pain after treatment at 2/4/6 weeks:

1. 2/2/4

2. 14/11/11

The trial authors reported that between-group differences were statistically significant at 2 weeks (P value 0.001), 4 weeks (P value 0.008) and 6 weeks (P value 0.032)

Day-to-day ulcer pain reported as none/mild/moderate/severe at 2 weeks:

Group 1: 7/4/9/9 (n = 29)

Group 2: 10/13/1/4 (n = 28)

The trial authors reported that the between-group difference was statistically significant (P value 0.03)

Day-to-day ulcer pain reported as none/mild/moderate/severe at 4 weeks:

Group 1: 8/7/8/6 (n = 29)

Group 2: 15/7/3/3 (n = 28)

The trial authors reported that the between-group difference was not statistically significant (P value 0.17)

Day-to-day ulcer pain reported as none/mild/moderate/severe at 6 weeks:

Group 1: 9/8/6/6 (n = 29)

Group 2: 16/4/3/5 (n = 28)

The trial authors reported that the between-group difference was not statistically significant (P value 0.31)


NotesThree withdrawals were reported overall. Reasons for withdrawal were given as hospital admission and lack of cooperation, but breakdown of numbers/reasons per group was not provided


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"patients were divided into 2 groups using random numbers"

Allocation concealment (selection bias)Unclear riskNo description of allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
High risk"cadexomer iodine did not lend itself to a double blind trial"

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
High risk"Measurements were recorded on the Proforma at 0, 2, 4 and 6 weeks by each patient's nurse." "Cadexomer iodine did not lend itself to a double blind trial"

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"57 of the 60 patients completed the trial"; reasons given for the three withdrawals were hospital admission and lack of cooperation

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskWithdrawal rate 5%

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskAnalyses were based on 57 of 60 randomly assigned participants. It is unclear how these withdrawals might have impacted estimates of treatment effect (this is a small RCT)

Baseline factors comparableUnclear riskMean, rather than median, values were reported for baseline ulcer area and ulcer duration and so it is difficult to judge comparability

Valtonen 1989

MethodsRandomised controlled trial conducted in Finland


Participants27 participants with Pseudomonas aeruginosa or other Gram-negative rod colonised chronic leg ulcers of ≥ 2 months' duration were recruited. Patients with diabetes were eligible for inclusion. Those with ulcer flora resistant to ciprofloxacin were excluded:
Group 1: 8 participants
Group 2: 18 participants

Numbers (%) of participants with venous/arterial insufficiency:

Group 1: 6/8 (75%); 8/8 (100%)

Group 2: 16/18 (89%); 13/18 (72%)

Mean ± SD sum of maximum length plus width of ulcer (cm) at baseline: Group 1: 16.9 ± 11.4; Group 2: 16.7 ± 8.2

Range for baseline ulcer duration, months: Group 1: 29 to 35; Group 2: 60 to 71

Proportions of participants with isolation of Pseudomonas aeruginosa at baseline: Group 1: 63%; Group 2: 61%

Unclear whether wounds had signs and symptoms of clinical infection at baseline or whether just colonised


Interventions1. Standard care consisting of: daily ulcer cleansing with warm water and disinfectants (chlorhexidine or potassium permanganate); mechanical or enzymatic debridement; coverage with dextranomer paste or hydrocolloid (DuoDerm) dressing. Topical antibiotic creams were not used

2. Oral ciprofloxacin 750 mg twice daily for 3 months in addition to standard care as above. Some participants received a lower dose as the study progressed (250 or 500 mg twice daily) to achieve a maximum serum level of 2 to 4 mg/L.

All participants were treated as inpatients or outpatients according to clinical status; additional systemic antibiotics based on clinical features of infection, and the resistance pattern of the bacteria isolated. Use of compression not mentioned


OutcomesPrimary outcomes:

Numbers (%) of participants with complete healing at 3 months:
1. 0/8 (0)
2. 3/18 (17)

Numbers (%) of participants with clinical improvement (defined as those with complete healing plus those with reduction of at least 10% of sum of maximum length and width of ulcer) at 3 months:
1. 1/8 (13)
2. 12/18 (67)

Secondary outcomes:
Numbers of participants with adverse events:
Group 1: (0)
Group 2: mild, transient nausea that did not result in discontinuation of treatment (3)

Numbers (%) of participants who needed extra antimicrobial treatment during the trial:
1. 6/8 (75)
2. 3/18 (17)

Numbers (%) of participants with bacterial eradication or no bacteriological growth during trial:
1. 1/8 (13)
2. 6/18 (33)

Numbers (%) of participants with eradication of original strain during trial:

1. 2/8 (25)

2. 15/18 (83)

Numbers (%) of participants with ciprofloxacin-resistant strain in ulcer during trial:
1. 0/8 (0)
2. 12/18 (67)


NotesOne participant excluded from analysis because of malignant tumour in leg ulcer (group allocation not stated)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomised to two treatment groups." It was not stated how the sequence was generated

Allocation concealment (selection bias)Unclear riskNo information was provided

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear risk"We have studied, using an open, comparative study design, the efficacy of..."

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear risk"We have studied, using an open, comparative study design, the efficacy of..."

Incomplete outcome data (attrition bias)
Drop out rate described
Low risk"Altogether 27 patients enrolled..." One was excluded from analysis

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskOne participant was excluded because of malignancy in ulcer

Incomplete outcome data (attrition bias)
ITT analysis
Low riskParticipants were analysed in the groups into which they were enrolled at the beginning of the study

Baseline factors comparableHigh riskLonger baseline ulcer duration in ciprofloxacin group

Wunderlich 1991

MethodsRandomised controlled trial conducted in Germany


Participants40 participants with venous leg ulcers were recruited:

Group 1: 20 participants

Group 2: 20 participants

Mean ulcer duration in years:

Group 1: 7.9

Group 2: 7.6

Mean ulcer area in mm2 (values taken from graph):

Group 1: 2000

Group 2: 3000

No information about ulcer infection/colonisation status at baseline


InterventionsGroup 1: various topical agents used for different stages of wound healing, including mineral oil or mixture of sea salt and povidone-iodine paste for granulation phase; and paraffin-impregnated gauze or oil-and-water emulsion with panthenol for epithelialisation phase

Group 2: silver-impregnated activated charcoal dressing (Actisorb plus, Johnson & Johnson) used for all stages of wound healing

All participants received initial debridement (mechanical or enzymatic) for 5 days; intermittent debridement as necessary during the trial (up to 4 times in 6 weeks) for large ulcers; and daily dressing changes. No mention was made of using compression therapy

Treatment duration was 6 weeks


OutcomesPrimary outcomes:

Numbers (%) ulcers healed at 6 weeks:

Group 1: 2/20 (10)

Group 2: 6/20 (30)

Median percentage change in ulcer area at 6 weeks (from graph):

Group 1: -60%

Group 2: -75%

The trial authors did not report P values for between-group differences

Secondary outcomes:

Semi-quantitive bacterial colony growth was assessed at weeks 2, 4 and 6 (details of method not reported). Assessment was reported on a scale: 0 = no growth, 1 = low growth, 2 = medium growth, 3 = high growth. The trial authors reported a non-significant reduction in colonisation over the whole study period in Group 2 and a reduction only at week 2 in Group 1. No data were presented


NotesTranslated from German

One withdrawal per group (reasons not reported)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote, from translation: "Randomized in each group were 20 patients treated with SIAX or with conventional control therapy"

Comment: no information regarding the method of random sequence generation

Allocation concealment (selection bias)Unclear riskQuote, from translation: "Randomized in each group were 20 patients treated with SIAX or with conventional control therapy"

Comment: no information regarding allocation concealment

Blinding (performance bias and detection bias)
Participant blinded to the intervention
Unclear riskComment: The trial was described as "an open randomised study", but no participant blinding was described

Blinding (performance bias and detection bias)
Outcome assessor blinded to the intervention
Unclear riskComment: The trial was described as "an open randomised study" but no description of outcome assessor blinding was provided

Incomplete outcome data (attrition bias)
Drop out rate described
Unclear riskComment: The trial authors report that 19 of the 20 participants in each arm completed the study, but no details of the participants not completing are reported

Incomplete outcome data (attrition bias)
Drop out rate acceptable
Low riskGroup 1: 1/20 (5%)

Group 2: 1/20 (5%)

Comment: Withdrawal rates are low in both groups, with identical rates

Incomplete outcome data (attrition bias)
ITT analysis
Unclear riskComment: The trial authors report that the analyses were undertaken on 19/20 participants randomly assigned to each arm, but no analysis methods were reported

Baseline factors comparableUnclear riskComment: Limited information was presented on baseline ulcer area and duration

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Allen 1980Not RCT

Allen 1996No healing outcomes reported

Altman 1976Primary outcomes not reported

Anonymous 1982Not an RCT

Bazzigaluppi 1991No control group

Beele 2010Patients with various wound types recruited. Results not available for VLU patients only (communication with study author)

Beitner 1985cNo antimicrobial intervention evaluated (comparison was vehicle of benzoyl peroxide lotion versus saline solution). Two other RCTs were reported in the same paper, and are included in this review (Beitner 1985a; Beitner 1985b)

Bender 1982Not RCT (confirmed by translator)

Bourgeois 1963No control group

Brauman 2008Not RCT (confirmed by study author)

Brzeziska 1990Not an RCT

Castellano 2007Not an RCT

Chaparro 2003CCT

Chaudhary 2008Not an RCT

Cherry 2003Not an RCT - single arm study

Chirwa 2010Mixed wound aetiologies, 20% of patients had venous leg ulcers. Conference abstract with no further details available (unable to establish contact with trial authors)

Colombo 1993Participants with various wound types recruited, unclear if venous leg ulcers included. No objective healing outcomes reported

Colonna 2004Mixed wound aetiologies, 28% of patients had venous leg ulcers. Conference abstract with no further details available following contact with trial authors

Contretas-Ruiz 2004Antimicrobial intervention is not the only systematic difference between treatment groups; different methods of debridement are used (confirmed through contact with trial authors)

Coutts 2005Not an RCT

Daltrey 1981Primary outcomes not reported

Danielsen 1997No control group

Dharap 2008No control group

Ferra 2007Interventions evaluated do not include antimicrobials

Fox 1966CCT

Friedman 1984Mixed aetiologies, minority venous, CCT

Garcia 1984Antimicrobial intervention not clearly defined

Gottrup 2003Not RCT.

Haler 1964Not randomised, no objective outcomes of healing reported

Hanft 2006Available only as conference abstracts with no outcome data. Unable to establish contact with the trial authors in order to request further information

Heggers 2003Not a controlled trial

Howell-Jones 2005Not a controlled trial

Hutchinson 1993No healing outcomes reported

Ivins 2006Not an RCT (random allocation of only some patients from one treatment group of a previously reported trial to receive either the treatment or comparator for a further 4 weeks)

Karap 2008Not an RCT (confirmed by study author)

Karas 1984No control group

Katelaris 1987CCT

Kordestani 2008Quasi randomised, intervention not antimicrobial

Kosicek 2004CCT

Lanzara 2008Available only as a conference abstract. Unable to establish contact with the trial authors in order to request further information

Lischka 1980CCT

Locati 1994No control group, mixed aetiology

Magana Lozano 1980Primary outcome not reported

Maiques Nadal 1976Case series

Mancuso 1994Primary outcomes not reported

Markoishvili 2002No control group

Marzin 1982CCT

McKnight 1965No control group

Mehtar S 1988Mixed aetiology

Mogabgab 1984Soft tissue infections, not venous leg ulcers

Morely de Benzaquen 1990From abstract, appears to be RCT evaluating silver sulphadiazine versus placebo in participants with lower limb ulcers. Not clear if venous leg ulcers included or if healing reported. Full study report unavailable from overseas and unable to locate contact details for study authors

Motta 2004Not venous leg ulcers

Nakagawa 1997Mixed aetiology, no control group

Ouvry 1989Not an RCT

Pardes 1993Primary outcome not reported

Paul 1990Not an RCT

Pegum 1968CCT

Pereira 2004Mixed aetiology, primary outcome not reported

Pierard-Franchimont 1997CCT

Planinsek 2006Available only as a conference abstract. Unable to establish contact with the trial authors in order to request further information

Pollice 1989CCT

Privat 1979No control group

Robson 2009Patients with various types of wounds recruited. Less than 75% had leg ulcers, and aetiology of leg ulcers not explained. Unable to obtain further information from trial authors

Rogers 2000Not RCT

Romanelli 2010Insufficient report of outcomes and unable to obtain further information from trial authors.

Rubisz Brzeziska 87Not RCT.

Rucigaj 2007aAvailable only as a conference abstract. Unable to establish contact with the trial authors in order to request further information

Rucigaj 2007bIntervention has no microbial properties

Salim 1991No antibacterial or antiseptic intervention

Sanchez-Vasquez 2008Isosorbide dinitrate spray, not antibiotic

Serra 2005Not randomised (confirmed by translator - paper published in Spanish)

Sibbald 2007Intervention not antimicrobial

Sibbald 2011Partcicipants with various types of wounds recruited. Less than 75% had leg ulcers, and aetiology of leg ulcers not explained. Unable to obtain further information from trial authors

Steenvoorde 2007Not an RCT

Subrahmanyam 1993Unable to obtain data for VLU patients only. Confirmed by study author (email communication)

Thebbe 1996Mixed aetiology, silver used

Thorne 1965No control group

Wuite 1974No healing outcomes reported

 
Comparison 1. Systemic antibiotic given according to sensitivities versus standard care

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

 1 Complete healing at 3 weeks156Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.22, 1.72]

 2 Complete healing—eventual, assessment point not stated156Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.66, 1.25]

 3 Bacterial eradication148Risk Ratio (M-H, Fixed, 95% CI)1.6 [0.61, 4.19]

 
Comparison 2. Ciprofloxacin versus standard care/placebo

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

 1 Frequency of complete healing250Risk Ratio (M-H, Fixed, 95% CI)1.74 [0.57, 5.30]

 2 Emergence of antibiotic-resistant strains248Risk Ratio (M-H, Fixed, 95% CI)8.65 [1.76, 42.60]

 3 Bacterial eradication126Risk Ratio (M-H, Fixed, 95% CI)2.67 [0.38, 18.67]

 
Comparison 3. Ciprofloxacin versus trimethoprim

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

 1 Frequency of complete healing125Risk Ratio (M-H, Fixed, 95% CI)1.54 [0.46, 5.09]

 2 Emergence of antibiotic-resistant strains121Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.54, 1.84]

 
Comparison 4. Trimethoprim versus placebo

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

 1 Frequency of complete healing123Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.23, 3.63]

 2 Emergence of antibiotic-resistant strains119Risk Ratio (M-H, Fixed, 95% CI)6.67 [0.98, 45.29]

 
Comparison 5. Amoxicillin plus compression verus povidone-iodine alone

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

 1 Frequency of complete healing142Risk Ratio (M-H, Fixed, 95% CI)1.38 [0.95, 2.02]

 
Comparison 6. Amoxicillin plus compression verus povidone-iodine plus compression

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

 1 Frequency of complete healing142Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.81, 1.39]

 
Comparison 7. Levamisole versus placebo

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

 1 Frequency of complete healing159Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.06, 1.62]

 
Comparison 8. Cadexomer iodine versus standard care

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

 1 Frequency of complete healing at 4 to 12 weeks4212Risk Ratio (M-H, Fixed, 95% CI)2.17 [1.30, 3.60]

 2 Adverse events2134Risk Ratio (M-H, Fixed, 95% CI)4.59 [1.40, 15.05]

 
Comparison 9. Cadexomer iodine versus dextranomer

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

 1 Frequency of complete healing127Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.55, 3.09]

 
Comparison 10. Cadexomer iodine versus hydrocolloid dressing

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

 1 Frequency of complete healing1104Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.48, 3.91]

 
Comparison 11. Cadexomer iodine versus paraffin gauze

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

 1 Frequency of complete healing1105Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.39, 2.56]

 
Comparison 12. Cadexomer iodine dressing versus silver dressing

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

 1 Frequency of complete healing1281Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.19]

 2 Participant satisfaction1207Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.89, 1.06]

 
Comparison 13. Povidone-iodine plus sugar versus growth factor

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

 1 Frequency of complete healing at 4 weeks163Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.22, 1.52]

 
Comparison 14. Povidone-iodine plus compression versus hydrocolloid plus compression

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

 1 Frequency of complete healing1200Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.69, 1.23]

 
Comparison 15. Povidone-iodine plus compression versus moist or foam dressings plus compression

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

 1 Complete healing at 4 weeks130Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.09, 1.75]

 
Comparison 16. Peroxide-based topical preparation versus control

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

 1 Mean percentage ulcer area remaining1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    1.1 10% benzoyl peroxide dressing vs normal saline dressing
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 20% benzoyl peroxide dressing vs normal saline dressing
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 17. Honey products versus alternatives

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

 1 Complete healing at 12 weeks2476Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.96, 1.38]

 2 Incidence of ulcer infection during the 12-week trial period2476Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.49, 1.04]

 3 Participants with MRSA eradication at 4 weeks116Risk Ratio (M-H, Fixed, 95% CI)4.2 [0.67, 26.30]

 4 Participants reporting at least 1 adverse event1368Risk Ratio (M-H, Fixed, 95% CI)1.28 [1.05, 1.56]

 
Comparison 18. 1% silver sulphadiazine cream versus placebo cream

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

 1 Complete healing at 4 weeks161Risk Ratio (M-H, Fixed, 95% CI)5.81 [0.74, 45.40]

 
Comparison 19. 1% silver sulphadiazine cream versus 0.4% tripeptide copper complex cream

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

 1 Complete healing at 4 weeks163Risk Ratio (M-H, Fixed, 95% CI)13.41 [0.79, 228.32]

 
Comparison 20. 1% silver sulphadiazine cream versus non-adherent dressing

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

 1 Complete healing at 12 weeks160Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.57, 1.10]

 
Comparison 21. Silver dressing (Avance) versus silver dressing (Acticoat 7)

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

 1 Complete healing at 12 weeks140Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.68, 3.00]

 
Comparison 22. Silver dressing versus non-antimicrobial dressing

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

 1 Complete healing at 4 to 12 weeks4424Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.95, 1.45]

 2 Complete healing at 6 months1213Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.96, 1.28]

 3 Complete healing at 12 months1213Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.16]

 4 Ulcer recurrence within first year1185Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.38, 1.70]

 5 Change in ulcer surface area (cm squared) at 4 weeks2170Mean Difference (IV, Fixed, 95% CI)-4.70 [-8.46, -0.94]

 6 Change in ulcer surface area (%) at 4 weeks2Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 Healing rate (cm squared per day)2170Mean Difference (IV, Fixed, 95% CI)-0.12 [-0.28, 0.03]

 8 Proportion of participants reporting any type of adverse event4706Risk Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.33]

 
Comparison 23. Chloramphenicol-containing ointment versus enzymatic cleanser

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

 1 Complete healing at 4 weeks1177Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 0.99]

 2 Participants discontinuing treatment because of ineffectiveness or allergy1177Risk Ratio (M-H, Fixed, 95% CI)2.02 [0.52, 7.84]

 
Comparison 24. Framycetin sulphate-containing ointment versus enzymatic cleanser

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

 1 Complete healing at 4 weeks1170Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.23, 2.01]

 2 Participants discontinuing treatment because of ineffectiveness or allergy1170Risk Ratio (M-H, Fixed, 95% CI)2.93 [0.80, 10.67]

 
Comparison 25. Chloramphenicol-containing ointment versus framycetin sulphate-containing ointment

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

 1 Complete healing at 4 weeks1169Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.54]

 2 Participants discontinuing treatment because of ineffectiveness or allergy1169Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.25, 1.90]

 
Comparison 26. Mupirocin versus control

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

 1 Frequency of complete healing130Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.56, 2.35]

 2 Eradication of gram-positive bacteria110Risk Ratio (M-H, Fixed, 95% CI)11.0 [0.77, 158.01]

 
Comparison 27. Topical antibiotics versus herbal ointment

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

 1 Complete healing at 7 weeks132Risk Ratio (M-H, Fixed, 95% CI)4.44 [0.23, 85.83]

 2 Participants with bacterial eradication at 7 weeks132Risk Ratio (M-H, Fixed, 95% CI)8.0 [0.47, 137.35]

 
Comparison 28. Ethacridine lactate versus control

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

 1 Number of responsive ulcers1253Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.21, 1.73]

 2 Participants reporting at least 1 adverse event1241Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.50, 2.22]

 3 Participant satisfaction (treatment rated as excellent)1241Risk Ratio (M-H, Fixed, 95% CI)2.83 [1.85, 4.34]