Types of studies

We considered all randomized controlled trials (RCTs), including cluster trials, that addressed the effects (both benefits and harms) of topical phenytoin on the healing of pressure ulcers of any grade, irrespective of blinding status, language, and publication status.

Types of participants

We included studies involving people of any age, of any gender and race/ethnicity, and in any care setting, who were described as having a pressure ulcer (pressure sore, bed sore or decubitus ulcer) of any grade.

Types of interventions

The topical application of phenytoin (administered as either powder, impregnated dressing, cream and/or other preparation) to treat pressure ulcers compared with placebo or alternative treatments or no therapy.

Types of outcome measures

Electronic searches

We searched the following databases with the assistance of Cochrane Wound's Information Specialist:

• the Cochrane Wounds Specialised Register (searched 10 September 2016);

• the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 9);

• Ovid MEDLINE (1946 to 27 September 2016);

• Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations) (searched 27 September 2016);

• Ovid Embase (1974 to 27 September 2016);

• EBSCO CINAHL Plus (1937 to 27 September 2016).

CENTRAL was searched using the strategy in Appendix 1.This strategy was adapted where appropriate for the Cochrane Wounds Specialised Register. The MEDLINE search was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity and precision‐maximizing version (2011 revision) (Lefebvre 2011). The Embase and CINAHL Plus searches were combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2015). There was no restriction on the basis of date or language of publication.

The search strategies for Ovid MEDLINE, Ovid Embase and EBSCO CINAHL Plus are listed in Appendix 1.

Searching other resources

We handsearched conference proceedings from the European Pressure Ulcer Advisory Panel, the European Wound Management Association and the Tissue Viability Society from inception to 27 September 2016. We searched the reference sections of the retrieved trial reports to identify further relevant trials.

We also searched the following clinical trials registries for any ongoing and unpublished studies (searched 27 September 2016):

• Clinical Trials.gov (clinicaltrials.gov);

• WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en);

• Chinese Clinical Trial Registry (ChiCTR) (www.chictr.org.cn/searchprojen.aspx).

Selection of studies

Two review authors (XYH and YFS) identified the trials for inclusion according to the selection criteria independently of each other. When it was unclear from the title or abstract whether a paper fulfilled the criteria, we obtained a copy of the full text and the two review authors jointly decided whether the study met the inclusion criteria. We listed the excluded studies with the reasons for their exclusion. We resolved disagreement by discussion with a third review author (TKG). We set out a study flow diagram as recommended by the PRISMA statement to illustrate the process of screening and selecting studies for inclusion in the review (Figure 1) (Liberati 2009).

Figure 1

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Study flow diagram.

Data extraction and management

Two review authors (XYH and YFS) independently extracted the following data from each study:

• first author

• year the trial was conducted

• year of publication

• country

• inclusion and exclusion criteria

• baseline characteristics such as age, sex ratio, concurrent disease, and presence of existing pressure ulcers on entering the study (site, number, grade and size of ulcer(s)), by treatment group

• description of interventions and co interventions and number of participants in each group

• data for the primary and the secondary outcomes

• risk of bias (described below)

• duration of follow‐up

• source of funding.

We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt about whether the trials shared the same participants, completely or partially (by identifying common authors and centres), we contacted the authors of the trials to clarify whether the trial had been published in duplicate. We resolved any differences in opinion through discussion.

Assessment of risk of bias in included studies

Two review authors (XYH and YFS) independently assessed each included study using the Cochrane tool for assessment of risk of bias (Higgins 2011a). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (e.g. extreme baseline imbalance; see Appendix 2 for details of criteria on which the judgements were based). Blinding and completeness of outcome data were assessed for each outcome separately. We completed a 'Risk of bias' table for each eligible study. We discussed any disagreement amongst all review authors to achieve a consensus.

We have presented an assessment of risk of bias using a 'Risk of bias' summary figure, which presents all of the judgments in a cross‐tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Measures of treatment effect

We carried out this systematic review according to Cochrane methods (Higgins 2011a), and used the Cochrane software package Review Manager 5 (RevMan 2014). For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). For continuous variables, we calculated the mean difference (MD) with 95% CI. We carried out the analysis according to the number of pressure ulcers in each group. For time to complete healing, we checked the time to complete healing of participants who reached complete healing in each intervention group, and these original data were then presented and analysed in this review.

Unit of analysis issues

We considered individual participants as the unit of analysis. We checked how participants, or ulcers, had been randomized and whether there was evidence that more than one pressure ulcer on a single person had been analysed by examining the number of participants and the number of pressure ulcers in each trial. We did not include any cluster‐randomized studies and cross‐over trials in this review.

Dealing with missing data

We attempted to contact the original investigators of trials to request information re missing data. As we received no response, we assessed the risk of attrition bias according to our risk of bias criteria and based on available data (Higgins 2011b). We reported the number and percentage of dropouts/withdrawals. Studies that had missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups, we assessed as being at a low risk of bias for attrition. If the percentage of dropouts/withdrawals was less than 10%, we classed the trial as being at a low risk of bias, but if dropouts/withdrawals exceeded 10%, we classed the trial as being at high risk of bias.

Where we considered data to be missing at random, we analysed the available information. Where outcome data were missing, we used an available‐case analysis, based on the numbers of participants for whom outcome data were known. We also addressed the potential impact of the missing data on the findings of the review in the discussion section (Higgins 2011c).

Assessment of heterogeneity

We intended to explore heterogeneity using the Chi² test, with P values of less than 0.1 considered to be statistically significant, and to measure heterogeneity using the I² statistic (Higgins 2003). We considered that an I² value greater than 50% represented substantial heterogeneity. We intended to explore clinical heterogeneity by examining potentially influential factors, for example, care setting or participant characteristics. No studies were pooled in this review, but this was largely due to a lack of suitable data for pooling rather than because of heterogeneity.

Assessment of reporting biases

In future, if 10 or more studies are included for meta‐analysis, we will assess visual asymmetry of funnel plots to identify any potential reporting or publication bias (Sterne 2011).

Data synthesis

We had decided to use a fixed‐effect model to pool all results when there was no evidence of heterogeneity between studies (DeMets 1987). If there was evidence of heterogeneity, we would have used a random‐effects model (DerSimonian 1986). Where pooling was not appropriate, because there was substantial heterogeneity or lack of suitable data for pooling, we presented the outcomes in a descriptive way. No pooling of results occurred in this review due to a lack of suitable data.