Types of studies

Randomised controlled trials (RCTs), either published or unpublished, that have evaluated the effects of any type of alginate dressing in the treatment of venous ulcers irrespective of publication status or language will be included. Trials reported in abstract form only will be eligible for inclusion, provided adequate information is either presented in the abstract or available from the trial author. Studies using quasi‐randomisation will be excluded.

Types of participants

Trials recruiting people described in the primary report as having venous leg ulcers will be eligible for inclusion. As the method of diagnosis of venous ulceration may vary, we will accept definitions as used in the trials. We will include trials recruiting samples comprising people with venous leg ulcers and people with other types of wounds (e.g., arterial ulcers, diabetic foot ulcers) if the results for people with venous ulcers are presented separately, or if the majority of participants (≥ 75% in each arm) have leg ulcers of venous aetiology.

Types of interventions

The primary intervention of interest is alginate wound dressings. For ease of comparison we will group dressings according to categories presented in the British National Formulary (BNF 2012). We will report generic names where possible, also providing trade names and manufacturers where these are available. However, it is important to note that manufacturers and distributors of dressings may vary from country to country, and dressing names may also differ. We will not include trials evaluating alginate dressings impregnated with antimicrobial, antiseptic or analgesic agents as these interventions are evaluated in other Cochrane reviews (Briggs 2010; O'Meara 2010) and will be captured in the proposed overview of reviews (see Why it is important to do this review). Trials evaluating wound dressing pads, foam dressings, hydrocolloid dressings and hydrogels will be covered in other Cochrane reviews and included in this review only if they evaluate a comparison with alginate dressings. Forthcoming, related Cochrane reviews on dressings for venous leg ulcers will, along with this review, update the review by Palfreyman 2006.

We will include any RCT in which the presence or absence of an alginate dressing is the only systematic difference between treatment groups; and in which an alginate dressing is compared with other wound dressings (including alternative alginate dressings), non‐dressing treatments (for example, topical applications) or no dressing. We will include RCTs of alginate dressings, irrespective of whether compression is reported as a concurrent therapy.

Types of outcome measures

Electronic searches

We will search the following electronic databases for potentially relevant trials:

• the Cochrane Wounds Group Specialised Register;

• the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) (latest issue);

• Ovid MEDLINE (1948 to present);

• Ovid EMBASE (1974 to present);

• EBSCO CINAHL (1982 to present)

We will use the following search strategy in the Cochrane Central Register of Controlled Trials (CENTRAL):

#1 MeSH descriptor Alginates explode all trees
#2 (alginate* or activheal or algisite or algosteril or curasorb or kalostat or melgisorb or seasorb or sorbalgon or sorbsan or suprasorb a or tegaderm or tegagel or urgosorb):ti,ab,kw
#3 (#1 OR #2)
#4 MeSH descriptor Leg Ulcer explode all trees
#5 ((varicose NEXT ulcer*) or (venous NEXT ulcer*) or (leg NEXT ulcer*) or (stasis NEXT ulcer*) or (crural NEXT ulcer*) or "ulcus cruris" or "ulcer cruris"):ti,ab,kw
#6 (#4 OR #5)
#7 (#3 AND #6)

We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We will not restrict studies with respect to language, date of publication or study setting.

We will search for ongoing trials in the World Health Organization International Trial Registry Platform (http://www.who.int/ictrp/en/), the ISRCTN (International Standard Randomised Controlled Trial Number) register (http://www.controlled‐trials.com/isrctn/) and ClinicalTrials.gov (http://www.clinicaltrials.gov).

Searching other resources

We will attempt to contact trialists to obtain unpublished data and other information as required. We will also contact manufacturers to request information about ongoing or unpublished trials (for a list of manufacturers see Appendix 3). We will also examine the reference lists of eligible trials and other relevant review articles.

Selection of studies

Two review authors will independently assess the titles and abstracts for relevance. After this initial assessment, we will obtain all trial reports felt to be potentially relevant in full text. Two review authors will then independently check the full papers for eligibility, with disagreements resolved by discussion and, where required, referral to the editorial base of the Cochrane Wounds Group. We will record all reasons for exclusion.

We will present our study selection process as a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram (Liberati 2009).

Data extraction and management

We will extract and summarise details of the eligible trials using a data extraction sheet. We will extract the data from trial reports using an Excel spreadsheet designed to capture the trial information detailed below. Initially, we will pilot the spreadsheet with a sample of eligible studies, to explore any issues that may arise in relation to the data extraction process. We will expand and amend the spreadsheet as necessary after the piloting process. Two review authors will perform independent data extraction of all included RCTs after which both data extractions will be compared for agreement. We will resolve any disagreements by discussion. If data are missing from reports we will attempt to contact the trial authors to obtain the missing information. We will include trials published as duplicate reports (parallel publications) once, using all associated trial reports to maximally extract trial information, but ensuring that the trial data are not duplicated in the review. We will extract the following information:

• trial authors;

• year of publication;

• country where trial was undertaken;

• setting of care;

• trial design details;

• ethical approval;

• participant consent;

• unit of investigation – participant, leg or ulcer;

• overall sample size and methods used to estimate statistical power (relates to the target number of participants to be recruited, the clinical difference to be detected and the ability of the trial to detect this difference);

• participant selection criteria;

• number of participants randomised to each treatment arm;

• baseline characteristics of participants per treatment arm (gender, age, baseline ulcer area, ulcer duration, prevalence of co‐morbidities such as diabetes, prevalence of clinically infected wounds or colonised wounds, previous history of ulceration, baseline levels of wound exudate, and participant mobility);

• details of the dressing/treatment regimen prescribed for each arm including details of any concomitant therapy, for example, compression;

• duration of treatment;

• duration of follow‐up;

• statistical methods used for data analysis;

• primary and secondary outcomes measured;

• primary and secondary outcome data by treatment arm;

• adverse effects of treatment (per treatment arm with numbers and type);

• withdrawals (per treatment arm with numbers and reasons); and

• source of trial funding.

Assessment of risk of bias in included studies

Two review authors will independently assess each included trial report using The Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). This tool addresses specific domains, namely: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcome reporting (see Appendix 4 for details of the criteria on which the judgement will be based). For blinded outcome assessment we will make separate judgements for primary and secondary outcomes. As assessment of healing (the primary outcome) is likely to be subject to potential observer/measurement bias, blinding of outcome assessment is important. Similarly we will make separate judgements for primary and secondary outcomes for the domain of incomplete outcome data. In order to assess selective outcome reporting, we will attempt to obtain protocols for all included trials. We will classify trials as being at overall high risk of bias if they are rated as 'high' for any one of three key domains (allocation concealment, blinding of outcome assessors and completeness of outcome data).

We will present our assessment of risk of bias findings using a 'Risk of bias' summary figure, which presents all of the judgements in a cross‐tabulation of trial. This display of internal validity indicates the weight the reader may give the results of each trial.

Measures of treatment effect

We will present a narrative overview of all included trials, with results grouped according type of comparator (e.g., foam dressings compared with alginates, hydrocolloids compared with alginates). We will undertake statistical pooling of outcome data on groups of trials considered to be sufficiently similar in terms of trial design and characteristics of participants, interventions and outcomes. We will analyse data using Cochrane RevMan software (version 5.1) (RevMan 2011). We will report estimates for dichotomous outcomes (e.g., number of ulcers healed) as risk ratio (RR) with associated 95% confidence intervals (CI). We will report estimates for continuous data outcomes (e.g., absolute or relative change in ulcer area and healing rate) as a mean difference (MD) with 95% CI. We will report estimates of time to healing and plot hazard ratios where available from the trials. Where log hazard ratios with standard errors obtained from Cox proportional hazards regression models are reported, we will plot these using the generic inverse‐variance method in RevMan 5.1. Where hazard ratios are not reported we will attempt, where possible, to extrapolate these using other reported data (Parmar 2004). Where trials report adverse events in sufficient detail (e.g., the number of participants who experienced at least one adverse event) we will analyse these data as dichotomous. Where it is unclear whether the denominator is the total number of adverse events or the number of participants we will report these data narratively. Where adverse events are reported as dressing‐related we will analyse these data separately.

Unit of analysis issues

We will record whether trials reports specify participants, limbs or ulcers as the units of allocation and analysis. In cases where multiple limbs or ulcers on the same individual are studied, we will note whether the trialists' analysis is appropriate (i.e., correctly taking account of highly correlated data) or inappropriate (i.e., considering outcomes for multiple ulcers on the same participant as independent). Where the number of wounds appears to equal the number of participants, we will assume that the ulcer is the unit of analysis unless otherwise stated.

Dealing with missing data

Missing data are a common problem in trials. Excluding randomised participants from the analysis or ignoring those participants lost to follow‐up can, in effect, compromise the process of randomisation and thus potentially introduce bias into the trial results. Where trials report complete healing outcomes for only those participants who complete the trial (i.e., participants withdrawing and lost to follow‐up are excluded from the analysis), we will treat the participants who are not included in the analysis as if their wound did not heal (that is, they will be considered in the denominator but not the numerator for healing outcomes). Where trials report results for participants who complete the trial without specifying the numbers initially randomised per group, we will present only complete case data. For other outcomes we will present data for all patients randomised where reported; otherwise we will base estimates on complete cases only.

Assessment of heterogeneity

We will consider clinical heterogeneity (that is where trials appear dissimilar in terms of level of participants, intervention type and duration and outcome type) and statistical heterogeneity. We will assess statistical heterogeneity using the Chi² test (a significance level of P < 0.10 is considered to indicate significant heterogeneity) in conjunction with the I² statistic (Higgins 2003). The I² statistic examines the percentage of total variation across trials due to heterogeneity rather than chance (Higgins 2003). We will consider I² values ≤ 40% to indicate a low level of heterogeneity and ≥75% to represent very high heterogeneity (Deeks 2011).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Sterne 2011). Publication bias is one of a number of possible causes of 'small study effects' – a tendency for estimates of the intervention effect to be more beneficial in smaller trials (Sterne 2011). Funnel plots allow a visual assessment of whether small study effects may be present in a meta‐analysis. A funnel plot is a simple scatter plot of the intervention effect estimates from individual trials against some measure of each trial’s size or precision (Sterne 2011). We will present funnel plots for meta‐analyses comprising 10 trials or more using RevMan 5.1.

Data synthesis

We will present a narrative overview of the included trials. Where appropriate, we will present meta‐analyses of outcome data using RevMan 5.1. The decision to pool data in a meta‐analysis will depend on the availability of outcome data and assessment of between‐trial heterogeneity. For comparisons where there is no apparent clinical heterogeneity and the I² value is ≤ 40%, we will apply a fixed‐effect model. Where there is no apparent clinical heterogeneity and the I² value is > 40%, we will apply a random‐effects model. However, we will not pool data where heterogeneity is very high (I² values ≥ 75%).

For the dichotomous outcomes we will present the summary estimate as a risk ratio (RR) with 95% confidence intervals (CI). Where continuous outcomes are measured in the same way across trials, we will present a mean difference (MD) with 95% CI. We will present a standardised mean difference (SMD) where trials measure the same outcome using different methods. For time to event data, we plan to plot (and if appropriate pool) estimates of hazard ratio and 95% CI as presented in the trial reports using the generic inverse variance methods in RevMan 5.1. 

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses according to whether trials assess the dressing of interest with or without the application of compression therapy. Where either the presence or absence of compression therapy is not clearly indicated in the trial report, we will not include these trials in this subgroup analysis.

Sensitivity analysis

Where data permit, we will undertake sensitivity analyses according to overall risk of bias, excluding trials judged as being at overall high risk of bias (i.e., rated as 'high' for any one of three key domains ‐ allocation concealment, blinding of outcome assessors and completeness of outcome data). We will also undertake a sensitivity analysis, excluding those trials that report complete healing outcomes for only those participants who complete the trial and trials that report results for participants who complete the trial without specifying the numbers initially randomised per treatment group.