Appendix 1. Pressure ulcer grading

One of the most widely recognised systems for categorising pressure ulcers is that of the National Pressure Ulcer Advisory Panel (NPUAP). Their international classification recognises four categories or stages of pressure ulcer and two categories of unclassifiable pressure injury, in which wound depth and/or extent, or both, cannot be accurately determined; unclassifiable pressure ulcers are generally severe and would be grouped clinically with Stage 3 or Stage 4 ulcers (EPUAP‐NPUAP‐PPPIA 2014; NPUAP 2016):

• Category/Stage 1: Non‐blanchable erythema of intact skin: Intact skin with a localized area of non‐blanchable erythema, which may appear differently in darkly pigmented skin. Presence of blanchable erythema or changes in sensation, temperature, or firmness may precede visual changes. Color changes do not include purple or maroon discoloration; these may indicate deep tissue pressure injury.

• Category/Stage 2: Partial‐thickness skin loss with exposed dermis: Partial‐thickness loss of skin with exposed dermis. The wound bed is viable, pink or red, moist, and may also present as an intact or ruptured serum‐filled blister. Adipose (fat) is not visible and deeper tissues are not visible. Granulation tissue, slough and eschar are not present. These injuries commonly result from adverse microclimate and shear in the skin over the pelvis and shear in the heel. This stage should not be used to describe moisture associated skin damage (MASD) including incontinence associated dermatitis (IAD), intertriginous dermatitis (ITD), medical adhesive related skin injury (MARSI), or traumatic wounds (skin tears, burns, abrasions).

• Category/Stage 3: Full‐thickness skin loss: Full‐thickness loss of skin, in which adipose (fat) is visible in the ulcer and granulation tissue and epibole (rolled wound edges) are often present. Slough and/or eschar may be visible. The depth of tissue damage varies by anatomical location; areas of significant adiposity can develop deep wounds. Undermining and tunneling may occur. Fascia, muscle, tendon, ligament, cartilage and/or bone are not exposed. If slough or eschar obscures the extent of tissue loss this is an Unstageable Pressure Injury.

• Category/Stage 4: Full‐thickness skin and tissue loss: Full‐thickness skin and tissue loss with exposed or directly palpable fascia, muscle, tendon, ligament, cartilage or bone in the ulcer. Slough and/or eschar may be visible. Epibole (rolled edges), undermining and/or tunneling often occur. Depth varies by anatomical location. If slough or eschar obscures the extent of tissue loss this is an Unstageable Pressure Injury.

The two additional categories of unclassifiable wounds are:

• Unstageable/unclassified ‐ Obscured full‐thickness skin and tissue loss: Full‐thickness skin and tissue loss in which the extent of tissue damage within the ulcer cannot be confirmed because it is obscured by slough or eschar. If slough or eschar is removed, a Stage 3 or Stage 4 pressure injury will be revealed. Stable eschar (i.e. dry, adherent, intact without erythema or fluctuance) on the heel or ischemic limb should not be softened or removed.

• Deep Tissue Pressure Injury ‐ Persistent non‐blanchable deep red, maroon or purple discoloration: Intact or non‐intact skin with localized area of persistent non‐blanchable deep red, maroon, purple discoloration or epidermal separation revealing a dark wound bed or blood filled blister. Pain and temperature change often precede skin color changes. Discoloration may appear differently in darkly pigmented skin. This injury results from intense and/or prolonged pressure and shear forces at the bone‐muscle interface. The wound may evolve rapidly to reveal the actual extent of tissue injury, or may resolve without tissue loss. If necrotic tissue, subcutaneous tissue, granulation tissue, fascia, muscle or other underlying structures are visible, this indicates a full thickness pressure injury (Unstageable, Stage 3 or Stage 4). Do not use DTPI to describe vascular, traumatic, neuropathic, or dermatologic conditions.

Photographs of the different PU stages are included in the US Agency for Healthcare Research and Quality guideline (AHRQ 2013).

Appendix 2. Glossary of NMA terms

Arm‐specific outcomes/arm‐level data: raw outcome data (e.g. mean (SD) or risk) for each arm of the trial (see treatment contrast).

Assumptions for NMA: in common with all meta‐analysis, the true treatment effect across trials is assumed to be described by a fixed‐effect or random‐effects model. Additionally, transitivity is assumed and, concurrently, exchangeability and consistency.

Baseline risk: the absolute risk of the outcome in the 'control' group. This is affected by the presence of prognostic factors. Some authors have used the baseline risk as a proxy effect modifier, but in general the effect estimate (RR/OR/HR) is independent of the baseline risk; on the other hand, the absolute risk difference depends on baseline risk.

Bayesian approach: the explicit quantitative use of external evidence in the design, monitoring, analysis, interpretation of a health‐care evaluation. In the Bayesian paradigm, prior beliefs about parameters in the models are specified and factored into the estimation. Posterior distributions of model parameters are then derived from the prior information and the observed data. In NMA, it is common to use non‐informative priors for effect estimates.

Coherence/consistency: the direct effect estimate (e.g. mean difference or log odds ratio) is the same as the sum of the indirect effect estimates.

Connected network: a group of linked interventions, such that every trial in the network has at least one intervention in common with at least one other trial. Sometimes individual comparisons are not connected to the rest of the network (disconnected network) and can sometimes be joined in by extending the network to include supplementary interventions.

Contour‐enhanced funnel plot: contour‐enhanced funnel plots show areas of statistical significance, and they can help in distinguishing publication bias from other possible reasons for asymmetry. In a network of interventions, each study estimates the relative effect of different interventions, so asymmetry in the funnel plot cannot be judged. To account for this, an adaptation of the funnel plot can be used, in which the standard error is plotted against an adjusted effect size for each study: the adjusted effect size for a comparison is the study‐specific effect size minus the mean for the meta‐analysis for that comparison.

Contrast/comparison/study‐level data: outcome data for the comparison (e.g. mean difference, odds ratio).

Credible interval (CrI): the 95% credible interval is the range within which the mean value lies with posterior probability of 95%.

Decision space/decision set: the interventions in the decision set are the focal treatments of interest to systematic review authors.

Direct evidence/direct comparison/direct contrast: head‐to‐head comparison of two treatments, for example, A versus B (see indirect evidence).

Edge: line representing a direct contrast on a network diagram.

Effect modifier: effect modification occurs when the effect of A versus B (as the RR/OR/HR for binary outcomes) is significantly different in two or more subgroups, and this leads to heterogeneity, either within trials or between trials, or both. Factors that give rise to subgroup effects are called effect modifiers, and it is important to identify potential effect modifiers and allow for them in the analysis. The identification of significant effect modifiers may lead to stratification (separate analyses for each subgroup) or to a decision not to combine data from different trials in a meta‐analysis. In general, trials have different distributions of effect modifiers (e.g. proportion of people with and without diabetes), leading to inconsistency between trials in the treatment effect. This is often magnified when there is a network of different contrasts.

Exchangeability: it is assumed that treatments in a NMA are exchangeable, so, if treatment B had been given to participants in the indirect A versus C trials and if A had been given in the B versus C indirect trials, then the true AB differences in these indirect studies would be identical to the true AB difference in direct A versus B trials, or at least from the same common distribution. Furthermore, if participants in other trials within the wider linked network (e.g. D versus E trials) were given A and B, the AB differences would also be the same or from the same distribution. This assumption breaks down when there are effect modifiers.

Fixed‐effect: the true treatment effect is assumed to be constant across trials (fixed‐effect) ‐ see also random‐effects and transitivity.

Global inconsistency: inconsistency across a network is described as global inconsistency. It can be evaluated statistically by fitting models that allow and do not allow for inconsistency. See also: Inconsistency/incoherence:

Heterogeneity in a NMA: participants are not randomised to different trials. Therefore, there may be systematic differences in study characteristics or the distribution of participant characteristics across trials. If these characteristics influence the treatment effects (i.e. are effect modifiers), then there are systematic differences in treatment effects across trials, which is called between‐trial heterogeneity. There may also be within‐trial heterogeneity if there are subgroups of an effect modifier for which results are reported separately. In a NMA, the term, 'heterogeneity' applies to variation in effect modifiers within a single contrast (e.g. A versus B); the term, 'inconsistency' refers to the imbalance in effect modifiers between contrasts.

Heterogeneity variance parameter (tau²): in a random‐effects model we assume there is heterogeneity for each pairwise comparison (e.g. A versus B) with variance (tau²_AB), but in a NMA we often assume that there is a common heterogeneity amongst all the contrasts in the network; this common heterogeneity has a variance (tau²), which is called the 'heterogeneity variance parameter'. It can be compared with empirical distributions of heterogeneity values typically found in meta‐analyses (Salanti 2014; Turner 2012).

Inconsistency/incoherence: this occurs when the effect estimate derived from an indirect contrast is not the same as the effect estimate derived from a direct contrast. For example, in a network of three interventions, there is inconsistency if d_AB(direct) ǂ d_AB(indirect), where d_AB(indirect) = d_AC(direct) ‐ d_BC(direct); the effect estimates are given as mean differences or log(odds ratios/risk ratios/hazard ratios). Note that in order to investigate inconsistency there must be both indirect and direct evidence (loops in the network). See also global inconsistency.

Inconsistency factor: this is the absolute difference between the direct and indirect estimates on the log scale (or the logarithm of the ratio of the two odds/hazard ratios) for one of the contrasts in a loop. A statistically low powered z‐test and a 90% or 95% confidence interval (CI) of the inconsistency is computed to determine whether this difference is significant.

Indirect evidence/indirect comparison/indirect contrast: comparison of two treatments, for example, A versus B, obtained from combinations of other comparisons (e.g. trials comparing A versus C and trials comparing B with C) (see direct evidence).

Indirect comparison meta‐analysis: meta‐analysis of a set of treatments that are linked via common comparator(s), but none are compared directly; evidence is combined in a single internally consistent model.

Leverage: this is the effective number of parameters of the model, which is calculated differently for fixed‐effect and random‐effects models, with the latter having greater complexity.

Likelihood (function): the likelihood function is a tool for inferring the underlying distribution of the observed data. To do this, we propose a model to represent the data ‐ often a parametric distribution is assumed (e.g. binomial) ‐ and unknown parameters of that distribution are determined, given the data, by maximising the likelihood (the larger the likelihood, the closer the model fit).

Loop (of evidence): combination of direct and indirect evidence, such that the interventions in the network diagram can be linked to form a closed loop.

Meta‐analysis: a statistical synthesis of the results from two or more separate studies. Methods involve calculating a weighted average of effect estimates from the separate studies.

Mixed treatment comparison meta‐analysis: another name for network meta‐analysis.

Model: a statistical model is a (simplified) mathematical representation of the system we wish to learn about, and which generates our observed data. The model will usually depend on some known factors, such as other variables measured alongside the data, and some unknown parameters that we wish to determine. Then having determined the unknown parameters, the model should be able to simulate data that are an approximation of the real data, allowing us to make inferences from the data.

Multi‐arm trial: individual trial that compares more than two interventions.

Network: trials must be linked in a network of interventions, such that every trial in the network has at least one intervention in common with at least one other trial.

Network diagram: graphical representation of the interventions in the network. It consists of nodes representing the interventions and edges representing the contrasts. The amount of available information can be presented by 'weighting' the nodes and edges using different node sizes and line thicknesses according to the number of studies reporting that treatment or contrast respectively. Other types of weighting are discussed in Chaimani 2013b.

Network meta‐analysis (NMA): NMA is the simultaneous combination of data from randomised comparisons of multiple competing treatments (A versus B, A versus C, A versus D, B versus D, and so on), to deliver an internally consistent set of estimates while respecting the randomisation in the evidence. The use of indirect estimates can provide information on contrasts for which no trials exist. It can also improve the precision of the direct estimate by reducing the width of the CIs compared with the direct evidence alone.

Node: intervention represented on a network diagram, usually by a circle of weighted size.

Node splitting: a method of assessing inconsistency. A 'leave‐one comparison‐out' approach, often called 'node splitting,' is applied, with each direct contrast being excluded from the network and then estimating the difference between this direct evidence and the indirect evidence from the network.

Pairwise meta‐analysis: meta‐analysis of one or more trials of direct comparisons (e.g. A versus B) ‐ see direct evidence.

Prognostic factors: population or study characteristics that affect the risk of the outcome. In a sufficiently large randomised trial that is free from bias, prognostic factors are distributed evenly between intervention groups and do not affect the effect estimate (RR/OR/HR for binary outcomes) unless they are effect modifiers, but they do affect the baseline risk and absolute risk difference.

Random‐effects: trial‐specific treatment differences are assumed to be from a common distribution ‐ see also fixed‐effect and transitivity.

Ranking: ordering of treatments according to their relative effectiveness.

Rankogram: graph of probability versus rank order for a particular treatment. Rankograms are based on the uncertainty in the effect estimates. So if two treatments A and B are each compared with the reference intervention and the CIs for the effect overlap, then each treatment will have some probability of being the most effective. If there is no overlap and A is better than B, then the probability of A being the best will be 1.

Sparse data: data with wide CIs because of few events as a consequence of small studies or short follow‐up periods.

Study‐level data: see contrast.

SUCRA: Surface Under the Cumulative RAnking. This is a measure of the probability that the given treatment is the best. Thus, a SUCRA would be 1 (or 100%) when a treatment was certain to be the best and 0 (0%) when a treatment was certain to be the worst.

Supplementary set (of interventions): interventions added to the network to provide additional evidence on relative treatment effects of the decision set. This may be to connect an otherwise unconnected network of treatments, to increase the precision of the treatment effect estimates or to help address between‐trial heterogeneity.

Transitivity: NMA requires a transitivity assumption, such that there is no imbalance in the distribution of effect modifiers across the different types of treatment contrasts (see also exchangeability).

'Unadjusted' meta‐analysis: meta‐analysis of all the treatment arms for a particular treatment (e.g. all A arms). This breaks the randomisation and should not be done.

References include: Caldwell 2005; Caldwell 2014; Chaimani 2013a; Chaimani 2013b; Cipriani 2013; Dias 2013; Dias 2016; Grant 2013; Jansen 2013; Lu 2004; Salanti 2008; Salanti 2011; Salanti 2014; Soares 2014; Thorlund 2012; Tu 2012; White 2012.

Appendix 3. Search strategies

The Cochrane Central Register of Controlled Trials (CENTRAL)

#1MeSH descriptor: [Bandages] explode all trees
#2MeSH descriptor: [Alginates] explode all trees
#3MeSH descriptor: [Hydrogels] explode all trees
#4MeSH descriptor: [Honey] explode all trees
#5MeSH descriptor: [Silver] explode all trees
#6MeSH descriptor: [Silver Sulfadiazine] explode all trees
#7MeSH descriptor: [Charcoal] explode all trees
#8MeSH descriptor: [Silicones] explode all trees
#9(dressing* or pad or pads or gauze or tulle or film or bead or foam* or non‐adherent or "non adherent" or hydrocolloid* or "sodium hyaluronate" or alginat* or hydrogel* or silver* or honey* or matrix or iodine* or "protease modulat*" or "capillary action" or charcoal or silicon* or polymer*):ti,ab,kw
#10((odour or odor) near/3 absorb*):ti,ab,kw
#11(primapore or curasorb or seasorb or sorbsan or advadraw or vacutex or tegaderm or opsite or allevyn or biatain or medihoney or activon tulle or granuflex or "nu derm" or aquacel or iodoflex or iodozyme or xeroform or carboflex or cutimed sorbact or promogran or acticoat or "urgosorb silver" or mepitel or urgotul):ti,ab,kw
#12{or #1‐#11}
#13MeSH descriptor: [Metronidazole] explode all trees
#14metronidazole:ti,ab,kw
#15MeSH descriptor: [Anti‐Bacterial Agents] explode all trees
#16MeSH descriptor: [Administration, Topical] explode all trees
#17{and #15‐#16}
#18(topical near/2 (antibiotic* or antimicrobial* or antibacterial*)):ti,ab,kw
#19MeSH descriptor: [Iodophors] explode all trees
#20{and #16, #19}
#21((topical near/2 iodin*) or ("cadexomer iodine")):ti,ab,kw
#22MeSH descriptor: [Collagenases] explode all trees
#23{and #16, #22}
#24(topical near/2 collagen*):ti,ab,kw
#25MeSH descriptor: [Phenytoin] explode all trees
#26{and #16, #25}
#27(topical near/2 phenytoin):ti,ab,kw
#28MeSH descriptor: [Zinc Oxide] explode all trees
#29{and #16, #28}
#30(topical near/2 zinc):ti,ab,kw
#31(iodosorb or actiformcool or aquaflo or flamazine or silvadene):ti,ab,kw
#32MeSH descriptor: [Ointments] explode all trees
#33(ointment* or lotion* or cream* or powder* or gel or gels):ti,ab,kw
#34(topical next (agent* or preparation* or therap* or treatment*)):ti,ab,kw
#35{or #13‐#14, #17‐#18, #20‐#21, #23‐#24, #26‐#27, #29‐#34}
#36{or #12, #35}
#37MeSH descriptor: [Pressure Ulcer] explode all trees
#38(pressure next (ulcer* or sore* or injur*)):ti,ab,kw
#39(decubitus next (ulcer* or sore*)):ti,ab,kw
#40((bed next sore*) or bedsore*):ti,ab,kw
#41{or #37‐#40}
#42{and #36, #41} in Trials

Ovid MEDLINE

1 exp Bandages/
2 exp Alginates/
3 exp Hydrogels/
4 exp Honey/
5 exp Silver/
6 exp Silver Sulfadiazine/
7 exp Charcoal/
8 exp Silicones/
9 (dressing* or pad or pads or gauze or tulle or film or bead or foam* or non‐adherent or "non adherent" or hydrocolloid* or "sodium hyaluronate" or alginat* or hydrogel* or silver* or honey* or matrix or iodine* or "protease modulat*" or "capillary action" or charcoal or silicon* or polymer*).tw.
10 ((odour or odor) adj3 absorb*).tw.
11 (primapore or curasorb or seasorb or sorbsan or advadraw or vacutex or tegaderm or opsite or allevyn or biatain or medihoney or activon tulle or granuflex or "nu derm" or aquacel or iodoflex or iodozyme or xeroform or carboflex or cutimed sorbact or promogran or acticoat or "urgosorb silver" or mepitel or urgotul).tw.
12 or/1‐11
13 exp Metronidazole/
14 metronidazole.tw.
15 exp Administration, Topical/
16 exp Anti‐Bacterial Agents/
17 and/15‐16
18 (topical adj2 (antibiotic* or antimicrobial* or antibacterial*)).tw.
19 exp Iodophors/
20 and/15,19
21 ((topical adj2 iodin*) or "cadexomer iodine").tw.
22 exp Collagenases/
23 and/15,22
24 (topical adj2 collagen*).tw.
25 exp Phenytoin/
26 and/15,25
27 (topical adj2 phenytoin).tw.
28 exp Zinc Oxide/
29 and/15,28
30 (topical adj2 zinc).tw.
31 (iodosorb or actiformcool or aquaflo or flamazine or silvadene).tw.
32 exp Ointments/
33 (ointment* or lotion* or cream* or powder* or gel or gels).tw.
34 (topical adj (agent* or preparation* or therap* or treatment*)).tw.
35 or/13‐14,17‐18,20‐21,23‐24,26‐27,29‐34
36 or/12,35
37 exp Pressure Ulcer/
38 (pressure adj (ulcer* or sore* or injur*)).tw.
39 (decubitus adj (ulcer* or sore*)).tw.
40 (bedsore* or bed sore*).tw.
41 or/37‐40
42 and/36,41
43 randomized controlled trial.pt.
44 controlled clinical trial.pt.
45 randomi?ed.ab.
46 placebo.ab.
47 clinical trials as topic.sh.
48 randomly.ab.
49 trial.ti.
50 or/43‐49
51 exp animals/ not humans.sh.
52 50 not 51
53 and/42,52

Ovid Embase

1 exp "bandages and dressings"/
2 exp honey/
3 exp hydrogel/
4 exp Calcium Alginate/
5 (dressing* or pad or pads or gauze or tulle or film or bead or foam* or non‐adherent or "non adherent" or hydrocolloid* or "sodium hyaluronate" or alginat* or hydrogel* or silver* or honey* or matrix or iodine* or "protease modulat*" or "capillary action" or charcoal or silicon* or polymer*).ti,ab.
6 ((odour or odor) adj3 absorb*).ti,ab.
7 (primapore or curasorb or seasorb or sorbsan or advadraw or vacutex or tegaderm or opsite or allevyn or biatain or medihoney or activon tulle or granuflex or "nu derm" or aquacel or iodoflex or iodozyme or xeroform or carboflex or cutimed sorbact or promogran or acticoat or "urgosorb silver" or mepitel or urgotul).ti,ab.
8 or/1‐7
9 exp metronidazole/
10 metronidazole.ti,ab.
11 topical drug administration/
12 exp Antibiotic Agent/
13 and/11‐12
14 (topical adj2 (antibiotic* or antimicrobial* or antibacterial*)).ti,ab.
15 exp cadexomer iodine/
16 and/11,15
17 "cadexomer iodine".ti,ab.
18 exp silver/ or exp sulfadiazine silver/
19 and/11,18
20 exp collagenase/
21 and/11,20
22 (topical adj2 collagen*).ti,ab.
23 phenytoin/
24 and/11,23
25 (topical adj2 phenytoin).ti,ab.
26 exp zinc oxide/
27 and/11,26
28 (topical adj2 zinc).ti,ab.
29 (iodosorb or actiformcool or aquaflo or flamazine or silvadene).ti,ab.
30 exp ointment/
31 (ointment* or lotion* or cream* or powder* or gel or gels).ti,ab.
32 (topical adj (agent* or preparation* or therap* or treatment*)).ti,ab.
33 or/9‐10,13‐14,16‐17,19,21‐22,24‐25,27‐32
34 or/8,33
35 exp decubitus/
36 (pressure adj (ulcer* or sore* or injur*)).tw.
37 (decubitus adj (ulcer* or sore*)).tw.
38 (bedsore* or bed sore*).tw.
39 or/35‐38
40 and/34,39
41 Randomized controlled trials/
42 Single‐Blind Method/
43 Double‐Blind Method/
44 Crossover Procedure/
45 (random* or factorial* or crossover* or cross over* or cross‐over* or placebo* or assign* or allocat* or volunteer*).ti,ab.
46 (doubl* adj blind*).ti,ab.
47 (singl* adj blind*).ti,ab.
48 or/41‐47
49 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
50 human/ or human cell/
51 and/49‐50
52 49 not 51
53 48 not 52
54 and/40,53

EBSCO CINAHL Plus

S57 S43 AND S56
S56 S44 OR S45 OR S46 OR S47 OR S48 OR S49 OR S50 OR S51 OR S52 OR S53 OR S54 OR S55
S55 TI allocat* random* or AB allocat* random*
S54 MH "Quantitative Studies"
S53 TI placebo* or AB placebo*
S52 MH "Placebos"
S51 TI random* allocat* or AB random* allocat*
S50 MH "Random Assignment"
S49 TI randomi?ed control* trial* or AB randomi?ed control* trial*
S48 AB ( singl* or doubl* or trebl* or tripl* ) and AB ( blind* or mask* )
S47 TI ( singl* or doubl* or trebl* or tripl* ) and TI ( blind* or mask* )
S46 TI clinic* N1 trial* or AB clinic* N1 trial*
S45 PT Clinical trial
S44 MH "Clinical Trials+"
S43 S37 AND S42
S42 S38 OR S39 OR S40 OR S41
S41 TI decubitus or AB decubitus
S40 TI ( bed sore* or bedsore* ) or AB ( bed sore* or bedsore* )
S39 TI ( pressure ulcer* or pressure sore* ) or AB ( pressure ulcer* or pressure sore* )
S38 (MH "Pressure Ulcer+")
S37 S13 OR S36
S36 S14 OR S15 OR S18 OR S19 OR S21 OR S22 OR S24 OR S25 OR S27 OR S28 OR S30 OR S31 OR S33 OR S34 OR S35
S35 TI (topical N3 agent* or topical N3 preparation* or topical N3 therap* and topical N3 treatment*) OR AB (topical N3 agent* or topical N3 preparation* or topical N3 therap* and topical N3 treatment*)
S34 TI (ointment* or lotion* or cream* or powder* or gel or gels) OR AB (ointment* or lotion* or cream* or powder* or gel or gels)
S33 (MH "Ointments")
S32 TI (iodosorb or actiformcool or aquaflo or flamazine or silvadene) OR AB (iodosorb or actiformcool or aquaflo or flamazine or silvadene)
S31 TI (topical N2 zinc) OR AB (topical N2 zinc)
S30 S16 AND S29
S29(MH "Zinc Oxide")
S28TI (topical N2 phenytoin) OR AB (topical N2 phenytoin)
S27S16 AND S26
S26(MH "Phenytoin+")
S25 TI (topical N2 collagen*) OR AB (topical N2 collagen*)
S24 S16 AND S23
S23 (MH "Collagen")
S22 TI "cadexomer iodine" OR AB "cadexomer iodine"
S21 S16 AND S20
S20 (MH "Iodophors+")
S19 TI (topical N2 (antibiotic* or antimicrobial* or antibacterial*)) OR AB (topical N2 (antibiotic* or antimicrobial* or antibacterial*))
S18 S16 AND S17
S17 (MH "Antiinfective Agents+")
S16 (MH "Administration, Topical+")
S15 TI metronidazole OR AB metronidazole
S14 (MH "Metronidazole")
S13 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12
S12 AB (primapore or curasorb or seasorb or sorbsan or advadraw or vacutex or tegaderm or opsite or allevyn or biatain or medihoney or activon tulle or granuflex or "nu derm" or aquacel or iodoflex or iodozyme or xeroform or carboflex or cutimed sorbact or promogran or acticoat or "urgosorb silver" or mepitel or urgotul)
S11 TI (primapore or curasorb or seasorb or sorbsan or advadraw or vacutex or tegaderm or opsite or allevyn or biatain or medihoney or activon tulle or granuflex or "nu derm" or aquacel or iodoflex or iodozyme or xeroform or carboflex or cutimed sorbact or promogran or acticoat or "urgosorb silver" or mepitel or urgotul)
S10 TI odor N3 absorb* or AB odor N3 absorb*
S9 TI odour N3 absorb* or AB odour N3 absorb*
S8 AB (dressing* or pad or pads or gauze or tulle or film or bead or foam* or non‐adherent or "non adherent" or hydrocolloid* or "sodium hyaluronate" or alginat* or hydrogel* or silver* or honey* or matrix or iodine* or "protease modulat*" or "capillary action" or charcoal or silicon* or polymer*)
S7 TI (dressing* or pad or pads or gauze or tulle or film or bead or foam* or non‐adherent or "non adherent" or hydrocolloid* or "sodium hyaluronate" or alginat* or hydrogel* or silver* or honey* or matrix or iodine* or "protease modulat*" or "capillary action" or charcoal or silicon* or polymer*)
S6 (MH "Silver") or (MH "Silver Sulfadiazine")
S5 (MH "Honey")
S4 (MH "Charcoal")
S3 (MH "Silicones")
S2 (MH "Alginates")
S1 (MH "Bandages and Dressings+")

Appendix 4. STATA routines

We used the following specialist NMA STATA routines in addition to the standard STATA meta‐analysis routines of metan and mvmeta.

• network meta consistency ‐ a multivariate network meta‐analysis routine; 'consistency' means assuming the heterogeneity variance is the same for all contrasts

• network meta inconsistency ‐ multivariate network meta‐analysis routine: 'inconsistency' means account is taken of different study designs (e.g. pairwise/3‐arm trials) ‐ heterogeneity is assumed to be different amongst contrasts

• intervalplot ‐ output of all NMA results (follows network meta routines)

• netleague ‐ gives a 'league table' of results (follows network meta routines)

• network rank ‐ produces ranking of interventions (follows network meta routines)

• netweight ‐ calculates all direct pairwise summary effect sizes with their variances, creates the design matrix, and estimates the percentage contribution of each direct comparison to the network summary estimates and in the entire network.

• ifplot ‐ identifies all triangular and quadratic loops in a network of interventions and estimates the respective inconsistency factors and their uncertainties

We also used STATA routines to visually display the data

• network plot ‐ produces a network diagram, can be modified to add risk of bias

• network rank ‐ produces rankograms

• network forest ‐ plots results grouped by study design

• netfunnel ‐ plots a comparison‐adjusted funnel plot for assessing small‐study effects within a network of interventions

Appendix 5. Group Network

Interventions and comparisons

The group network comprised 22 studies (which is less than half of the 51 included studies) (Alm 1989; Banks 1994b; Barrois 1992; Brown‐Etris 1997; Burgos 2000b; Colwell 1993; Graumlich 2003; Hollisaz 2004; Kaya 2005; Kraft 1993; Matzen 1999; Muller 2001; Neill 1989a; Oleske 1986; Parish 1979; Payne 2009; Piatkowski 2012; Romanelli 2001; Sipponen 2008; Thomas 1998; Xakellis 1992; Zeron 2007), The median (range) study size was 38.5 (10 to 100). Only three contrasts were informed by more than one study.

The network comprised 10 interventions. Two studies were three‐arm trials (Hollisaz 2004; Parish 1979), so the total number of comparisons was 26, encompassing a total of 959 participants, experiencing 362 events (complete healing). There were eight direct contrasts and three triangular loops (one of which was exclusive to the Parish 1979 study). This is only 32.5% of the participants in the 51 included studies. The network diagram is shown in Figure 10. Only three contrasts were informed by more than one study:advanced dressing versus basic dressing (11 studies); antimicrobial dressing versus advanced dressing (2); and collagenase ointment versus advanced dressing (2).

Figure 10

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Key: green = low/unclear risk of bias; yellow = high risk of bias; red = very high overall risk of bias for the contrast. The number of studies for each contrast is given in Table 4.

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4. Direct evidence for grouped interventions ‐ proportion healed

Contrast/comparison	Number of studies (participants)	RR (95% CI) direct evidence Random‐effects (inverse variance) Heterogeneity statistics	NMA results (consistency assumption) RR (95% CI)
Advanced dressings versus basic dressings (Alm 1989; Banks 1994b; Colwell 1993; Hollisaz 2004; Kraft 1993; Matzen 1999; Neill 1989a; Oleske 1986; Payne 2009; Thomas 1998; Xakellis 1992)	11 (532)	1.55 (1.10 to 2.19) Tau² = 0.13; P = 0.02; I² = 52%	1.36 (0.95 to 1.93)
Phenytoin versus basic dressing (Hollisaz 2004)	1 (40)	3.02 (0.97 to 9.35)	1.12 (0.52 to 2.44)
Protease‐modulating dressing versus basic dressing (Zeron 2007)	1 (24)	1.25 (0.44 to 3.55)	1.49 (0.91 to 2.46)
Antimicrobial dressings versus advanced dressings (Barrois 1992; Kaya 2005)	2 (125)	0.69 (0.48 to 0.99) Tau² = 0.00; P = 0.46; I² = 0%	0.71 (0.45 to 1.13)
Collagenase ointment versus advanced dressings (Burgos 2000b; Muller 2001)	2 (61)	1.51 (0.93 to 2.43) Tau² = 0.00; P = 0.61 ; I² = 0%	1.48 (0.83 to 2.64)
Phenytoin versus advanced dressing (Hollisaz 2004)	1 (39)	0.71 (0.41 to 1.24)	0.83 (0.43 to 1.59)
Protease‐modulating dressing versus advanced dressing (Brown‐Etris 1997; Graumlich 2003; Piatkowski 2012)	3 (112)	1.13 (0.80 to 1.60) Tau² = 0.00; P = 0.84 ; I² = 0% (Stata: 1.12 (0.79 to 1.59))	1.10 (0.74 to 1.64)
Tripeptide copper gel versus advanced dressing (Romanelli 2001)	1 (12)	2.50 (0.76 to 8.19)	2.50 (0.72 to 8.63)
Antimicrobial dressing versus advanced antimicrobial dressing (Sipponen 2008)	1 (37)	2.29 (0.91 to 5.77)	2.29 (0.85 to 6.16)
Collagenase versus dextranomer (part of 3‐arm trial) (Parish 1979)	1 (12)	0.35 (0.05 to 2.26) (Stata 0.44 (0.10 to 2.02))	0.44 (0.09 to 2.11)
Collagenase ointment versus sugar + egg white (part of 3‐arm trial) (Parish 1979)	1 (10)	3.00 (0.15 to 59.89) (Stata 3.00 (0.15 to 59.79))	3.00 (0.15 to 61.18)
Dextranomer versus sugar + egg white (part of 3‐arm trial) (Parish 1979)	1 (12)	6.75 (0.44 to 102.80)	6.75 (0.43 to 105.22)
TOTAL	22 (959)

The characteristics of studies and participants in the group network are described in Table 1.

Risk of bias

We have summarised the all‐domain risk of bias for each study in the group network in Figure 11. We judged one study to be at low risk of bias (Graumlich 2003) and eight at unclear risk of bias (Banks 1994b; Barrois 1992; Hollisaz 2004; Parish 1979; Piatkowski 2012; Romanelli 2001; Thomas 1998; Zeron 2007). We judged three studies to be at very high risk of bias, that is, to have high risk of bias for two or more domains (Banks 1994a; Burgos 2000b; Oleske 1986). The rest of the studies we assessed to be at high risk of bias. We grouped the low and unclear categories together in the network.

Figure 11

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Risk of bias summary ‐ group network: review authors' judgements about each risk of bias item for each included study

For each direct comparison, the overall risk of bias is shown colour coded in Figure 10. There is a relatively large amount of evidence at high or very high risk of bias.

For each contrast in the network, we calculated the overall risk of bias as described in Appendix 8, and the risk of bias ratings are also shown beside the results in Figure 7.

Network meta‐analysis results

The group NMA generated results for 45 mixed treatment contrasts. The network was dominated by the contrast advanced dressing versus basic dressing and the rest of the data were sparse.

Figure 7 shows all NMA results, with the all‐domain risk of bias shown alongside the forest plot contrasts.

As in the individual network, the evidence for the majority of contrasts was informed by studies at high risk of bias, and CIs were wide or very wide, such that we downgraded all evidence at least once for imprecision. There was also heterogeneity or inconsistency, or both, for some contrasts. Consequently, evidence was of low or very low certainty, with the exception of one contrast, for which we assessed the evidence to be of moderate certainty. As for the individual network, this moderate‐certainty evidence should be interpreted in the light of the very low‐certainty evidence for the network as a whole.

We report the representative set of contrasts of each intervention versus basic dressings (Table 3 and Figure 7 first subgroup). Further details of the GRADE assessment can be found in Appendix 8 and Appendix 9.

It is not clear whether protease‐modulating dressings increase the probability of healing compared with basic dressings (RR 1.49; 95% CI 0.91 to 2.46, moderate quality evidence). This corresponds to an absolute risk difference of 94 more people healed per 1000 (95% CI 17 fewer to 279 more). We downgraded the evidence once for imprecision (low risk of bias).

For each of two contrasts (collagenase ointment and tripeptide copper gel) it is unclear whether the intervention increases the probability of healing compared with basic dressings (collagenase: RR 2.01, 95% CI 1.05 to 3.88 and tripeptide copper gel: RR 3.39, 95% CI 0.94 to 12.30); Figure 7). This was low certainty evidence, downgraded once for risk of bias and once for imprecision for collagenase ointment, and twice for imprecision for tripeptide copper gel (for which the direct evidence involved only six participants experiencing five events (complete healing)).

It is unclear whether the remaining six interventions affect the probability of healing compared with basic dressings (advanced dressings, advanced and antimicrobial dressings; antimicrobial dressings, dextranomer, phenytoin and sugar plus egg white) because the evidence is of very low certainty (downgraded mainly for risk of bias (once) and imprecision (twice), although two contrasts (phenytoin and advanced dressings versus basic dressings) had inconsistency.

Ranking of treatments

The rank probability data are shown in Figure 12 and Table 6. The rankograms have maximum probabilities more sharply defined in the group network compared with the individual network for the treatments advanced dressings, advanced‐antimicrobial dressings, collagenase ointment and dextranomer, but there is still overlap of the rankograms for different treatments (Figure 8). The mean rank was 2.0 for dextranomer and 2.3 for tripeptide copper gel, and two treatments had a mean rank of 10 (out of 10): advanced‐antimicrobial dressings and sugar plus egg white. However, no SUCRA value was 0 or 1, indicating uncertainty in the group network.

Figure 12

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Group network ‐ rankograms

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6. Ranks of interventions ‐ group network

Group intervention	Mean rank	SUCRA	Probability at maximum	Rank at maximum probability
Basic dressing	7.3	0.3	30.6	8
Advanced dressing	5.2	0.5	38.8	5
Advanced ‐ antimicrobial dressing	9.4	0.1	57.0	10
Antimicrobial dressing	7.4	0.3	31.9	8
Collagenase ointment	3.3	0.7	39.4	3
Dextranomer	2	0.9	55.3	1
Phenytoin	6.5	0.4	20.5	7
Protease‐modulating dressing	4.6	0.6	31.2	4
Sugar + egg white	7	0.3	36.5	10
Tripeptide copper gel	2.3	0.9	36.2	2

As with the individual network, the results must be interpreted in the light of the considerable uncertainty in the network and individual estimates, which can give misleading results. Numerically, dextranomer and tripeptide copper gel had the highest probabilities of being the best treatments (55% and 34%, respectively), but these high rankings are likely to be an artificial result. . Across all treatments there was very low certainty in the ranking of interventions (see quality assessment below).

Comparison of results from standard meta‐analysis versus NMA findings

We compared the NMA results with the direct comparison (pairwise) results for the proportion completely healed for the eight different comparisons informing the group network (Table 4). Three comparisons had two or more direct comparison studies (Analysis 2.1). The direct evidence shows some heterogeneity for the comparison of advanced dressing versus basic dressing (I² = 52%, P = 0.02 and some variation in the point estimates). Appendix 11 shows direct evidence results for the time‐to‐healing outcome for three comparisons in five studies.

Certainty/quality assessment of the network

Overall we downgraded the evidence certainty three times for the network as a whole, because of risk of bias (once), imprecision (once) and inconsistency and publication bias (once): the weighted average risk of bias across the network was high (Appendix 8). For inconsistency, the global Wald test was borderline significant at the 90% significance level (P value was 0.095) (see Appendix 9), however, there were relatively few contrasts with conflicting results for direct and indirect estimates. We downgraded the evidence once for imprecision: there is some overlap of the individual rankograms and no SUCRA value was zero or 1, suggesting uncertainty around treatment estimates and ranking in this network. A contour‐enhanced funnel plot (Figure 9) suggested there may be some asymmetry in the plot (which may be a consequence of publication bias).

Overall, we have little confidence in the findings in this group network, either in terms of the effect estimates or in the ranking of interventions.

Sensitivity analyses ‐ group network

We did not pre‐specify sensitivity analyses for the group network, mainly because the group network itself is based on the assumption that a variety of dressings can be grouped as advanced dressings or basic dressings (as defined by the BNF 2016). We attempted to investigate this assumption by examining the network contrasts for the individual network that compared two advanced dressings, expecting the effect estimates to be close to 1 if the assumption was valid. Results can be seen in Figure 4. Most point estimates were fairly close to 1, but CIs were usually wide or very wide around the estimates. Without exception, the risk of bias for each contrast was either high or very high, and the CI crossed at least one GRADE default MID. Thus, there is no clear evidence either to support or refute the group assumption.

A post‐hoc sensitivity analysis (Appendix 12) examined the original assumption of combining topical agents and dressings in the same NMA, by restricting the group NMA to dressings. There may have been less imprecision in the network as a whole, but results for the contrasts with basic dressings were similar to those in the full group network.

Appendix 6. Assessment of risk of bias

1. Was the allocation sequence randomly generated? (Part of 'Selection bias')

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random‐number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process provided to permit a judgement of low or high risk of bias.

2. Was the treatment allocation adequately concealed? (Part of 'Selection bias')

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based and pharmacy‐controlled randomisation); sequentially‐numbered drug containers of identical appearance; sequentially‐numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information provided to permit a judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

3. Blinding ‐ was knowledge of the allocated interventions adequately prevented during the study? (Performance bias for blinding of participants and caregivers; detection bias for outcome assessors)

Low risk of bias

Any one of the following.

• No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

• Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

• Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others was unlikely to introduce bias.

High risk of bias

Any one of the following.

• No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

• Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken and the outcome or outcome measurement is likely to be influenced by lack of blinding.

• Either participants or some key study personnel were not blinded, and the non‐blinding was likely to introduce bias.

Unclear

Either of the following.

• Insufficient information provided to permit a judgement of low or high risk of bias.

• The study did not address this outcome.

4. Were incomplete outcome data adequately addressed? (Attrition bias)

Low risk of bias

Any one of the following.

• No missing outcome data.

• Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

• Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

• For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate.

• For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size.

• Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following.

• Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

• For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in intervention effect estimate.

• For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was enough to induce clinically relevant bias in observed effect size.

• 'As‐treated' analysis done with substantial departure of the intervention received from that assigned at randomisation.

• Potentially inappropriate application of simple imputation.

Unclear

Either of the following.

• Insufficient reporting of attrition/exclusions to permit a judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).

• The study did not address this outcome.

5. Are reports of the study free of suggestion of selective outcome reporting? (Outcome reporting bias)

Low risk of bias

Either of the following.

• The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way.

• The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

High risk of bias

Any one of the following.

• Not all of the study's pre‐specified primary outcomes have been reported.

• One or more primary outcomes are reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified.

• One or more reported primary outcomes of the study were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

• One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.

• The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information provided to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category.

6. Other sources of potential bias

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important additional risk of bias. For example, the study:

• had a potential source of bias related to the specific study design used; or

• has been claimed to have been fraudulent; or

• had some other problem.

Unclear

There may be a risk of bias, but there is either:

• insufficient information to assess whether an important risk of bias exists; or

• insufficient rationale or evidence that an identified problem will introduce bias.

Appendix 7. Studies included in the individual network

The 51 included studies compared 39 different interventions in 59 comparisons, summarised in Table 7.

One study (Ashby 2012) had a range of advanced dressings as the comparator, so was ineligible for the individual intervention NMA (but was eligible for the group NMA). Thus there were 50 eligible studies for the individual NMA, comparing 37 different interventions in 58 comparisons with 2952 participants.There were nine interventions eligible for the individual network, which, on their own, did not meet the inclusion criteria of the review, but were compared with interventions that did meet the inclusion criteria ‐ we have called these 'ineligible interventions'.

The network diagram for all interventions in the individual NMA is shown in Figure 13. Ten interventions (including one ineligible intervention) were isolated from the network and are shown in red in Figure 13. Two further ineligible interventions (radiant heat and skin substitute) linked two of the eligible interventions and so were included in the joined network; the other six ineligible interventions (shown in blue) did not link eligible interventions and their studies were therefore omitted from thejoined network. Two of these omitted studies were three‐arm trials each with two ineligible interventions (Nussbaum 1994; Ramos‐Torrecillas 2015). Therefore, ten studies could not be included in the joined network (Gorse 1987; Imamura 1989; Nisi 2005; Nussbaum 1994; Payne 2004; Ramos‐Torrecillas 2015; Rees 1999; Sipponen 2008; Van De Looverbosch 2004; Yapucu Güneş 2007). The results for the isolated studies in which both interventions were eligible are reported in Analysis 5.1. Another study (Sebern 1986) only partially reported their results and was not considered further.

Figure 13

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Network diagram ‐ all interventions
Key: red = isolated interventions; blue = ineligible interventions joined to only one eligible intervention. Line and node weights not to scale

Thus 39 studies were included in the individual network (Aguilo Sanchez 2002; Alm 1989; Bale 1997a; Banks 1994b; Banks 1994a; Banks 1994c; Barrois 1992; Belmin 2002; Brod 1990; Brown‐Etris 1996; Brown‐Etris 1997; Brown‐Etris 2008; Burgos 2000b; Colwell 1993; Darkovich 1990; Graumlich 2003; Hollisaz 2004; Hondé 1994; Kaya 2005; Kraft 1993; Matzen 1999; Meaume 2003; Motta 1999; Muller 2001; Neill 1989a; Oleske 1986; Parish 1979; Payne 2009; Piatkowski 2012; Price 2000; Romanelli 2001; Seeley 1999; Serena 2010; Sopata 2002; Thomas 1997a; Thomas 1998; Thomas 2005; Xakellis 1992; Zeron 2007).

Appendix 8. Contributions and risk of bias in the individual and group networks

7.1. Individual network

The percentage contributions to the mixed treatment contrasts from each direct contrast are shown in Figure 14 for the individual network contrasts versus saline gauze. We calculated the risk of bias for each contrast in the NMA and results for each mixed treatment contrast are shown in the last column of the table in Figure 14 and represented on the forest plot (see Assessment of risk of bias in included studies).

Figure 14

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Contributions matrix ‐ interventions versus saline gauze (independent network)

Key: 1 = saline gauze dressing; 2 = alginate dressing; 3 = sequential hydrocolloid alginate dressings; 4 = basic wound contact dressing; 5 = collagenase ointment; 6 = dextranomer; 7 = foam dressing; 8 = hydrocolloid dressing; 9 = hydrocolloid +/‐ alginate (hydrocolloid with/without alginate filler); 10 = hydrogel dressing; 11 = ineligible intervention: radiant heat; 12 = ineligible intervention: skin substitute; 13 = iodine‐containing dressing; 14 = phenytoin; 15 = protease‐modulating dressing; 16 = PVP + zinc oxide; 17 = silicone + foam dressing; 18 = soft polymer dressing; 19 = sugar + egg white; 20 = tripeptide copper gel; 21 = vapour‐permeable dressing.

The contributions to the whole network from each direct contrast are given in the last row of the table in Figure 14. The overall risk of bias was high and the largest contributions to the network were from the direct contrasts: foam versus hydrocolloid; collagenase ointment versus sugar plus egg white; and protease‐modulating dressings versus alginate dressings (but all contributions were still 10% or less).

Appendix 9. Inconsistency

Appendix 10. Ranking interventions

Data for each intervention were shown as the probability that each intervention is the best, second best, third best treatment, etc. (see Figure 5, and Table 15). There was substantial overlap of the individual rankograms, illustrated in Figure 15, which intentionally shows the confusion, together with some indication that dextranomer and tripeptide copper gel may be the best treatments and that the worst treatments may be the sequential hydrocolloid‐alginate dressings and sugar plus egg white. Across all treatments there was considerable uncertainty in the ranking of interventions and no intervention had more than 50% probability of being the best treatment. This, together with the mean rank being no higher than 3.6 and no lower than 18.6 (out of 21), and no SUCRA value being 0 or 1, reinforces our view of the considerable uncertainty around treatment estimates in this network.

Figure 15

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Rankograms combined ‐ individual network
Key to interventions: 1: saline gauze; 2: alginate dressing; 3: sequential hydrocolloid alginate dressings; 4: basic wound contact dressing; 5: collagenase ointment; 6: dextranomer; 7: foam dressing; 8: hydrocolloid dressing; 9: hydrocolloid +/‐ alginate (hydrocolloid dressing with/without alginate filler); 10: hydrogel dressing; 11: ineligible radiant heat; 12: ineligible skin substitute; 13: iodine‐containing dressing; 14: phenytoin; 15: protease‐modulating dressing; 16: PVP + zinc oxide
17: silicone + foam dressing; 18: soft polymer dressing; 19: sugar + egg white; 20: tripeptide copper gel; 21: vapour‐permeable dressing

Appendix 11. Time to event data: direct evidence

The duration of follow‐up ranged from 3 to 26 weeks, but the distribution was insufficient to allow modelling of time dependence in the network.

Seven studies (Alm 1989; Brod 1990; Graumlich 2003; Muller 2001; Payne 2009; Thomas 2005; Xakellis 1992) reported time‐to‐event data. We calculated the hazard ratio using the method and spreadsheet from Tierney 2007; one study (Xakellis 1992) reported the hazard ratio directly, adjusted for exudate level. The time‐to‐healing data are shown in Analysis 3.1 and summary statistics for the time‐to‐healing and the proportion healed are compared in Table 16 for the studies that report both healing outcomes.

In the individual network, two studies in 95 participants suggested that the time to healing may have been quicker for hydrocolloid versus saline gauze (HR 1.75, 95% CI 1.00 to 3.05); there was no heterogeneity (unlike the risk ratio). One study in 24 participants suggested healing may have been quicker for collagenase ointment compared with hydrocolloid (HR 2.58, 95% CI 1.00 to 2.65). In the other studies, the CI showed much uncertainty.

There was some suggestion of a time dependent effect because there were qualitative and quantitative differences between the HR and the RR: for shorter studies (4‐6 weeks), the HR gave a smaller effect than the RR, but for the medium and longer term studies the HR gave a larger effect than the RR, suggesting that wounds that heal do so relatively quickly.

For the group network, time‐to‐healing data are shown in Analysis 4.1. Three studies in 131 participants suggested that the time to healing may have been quicker for advanced dressing versus basic dressing (HR 1.57, 95% CI 0.97 to 2.55); there was no heterogeneity. This compared with the same three studies analysed as the proportion healed: RR (random‐effects) 1.48 (95% CI 0.79 to 2.77); I² = 66%, P = 0.05.

Appendix 12. Sensitivity analyses

We conducted pre‐specified sensitivity analyses for the individual network and a post‐hoc sensitivity analysis for both networks.