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Zenilman J, Valle MF, Malas MB, et al. Chronic Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Dec. (Comparative Effectiveness Reviews, No. 127.)

Methods

This topic was nominated via the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program's Web site. Our Evidence-based Practice Center established a team and a protocol to develop the evidence report. The project involved formulating and refining the questions, developing a protocol with input from selected technical experts, performing a comprehensive literature search, summarizing the state of the literature, constructing evidence tables, synthesizing the evidence, and submitting the report for peer review.

Topic Refinement

We recruited a panel of Key Informants to provide input on the selection and refinement of the questions to be examined. The Key Informants included a variety of wound care experts, including dermatologists, vascular surgeons, nurses, geriatricians, and a patient. A wound care organization recommended the patient to us because he has had chronic venous ulcers for several years and is very knowledgeable about his condition and treatment. We posted our draft Key Questions (KQs) on the AHRQ Effective Health Care Program's Web site in October 2011 for public comment.

With input from the Key Informants, representatives of AHRQ, and public comments, we developed the KQs that we presented in the Scope of Review and Key Questions section of the Introduction. The KQs focus on the effectiveness and safety of three major types of interventions in the management of chronic venous ulcers, including: (a) dressings that regulate wound moisture with or without active chemical, enzymatic, biologic, or antimicrobial components; (b) the use of systemic antibiotics; and (c) the utility of surgical procedures when compared with adequate compression or other surgical techniques.

Technical Expert Panel

We recruited a Technical Expert Panel (TEP) to review a draft of the protocol for preparing this evidence report. The TEP included a variety of wound care experts, including dermatologists, vascular surgeons, nurses, and geriatricians. The TEP reviewed our protocol and provided feedback on the proposed methods for addressing the KQs. With the feedback from the TEP and AHRQ representatives, we finalized the protocol and posted it on AHRQ Effective Health Care Program's Web site.

Search Strategy

We searched the following databases for primary studies: MEDLINE®, Embase®, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature® from January 1980 through October 2011 and updated in July 2012. We developed a search strategy for MEDLINE, accessed via PubMed®, based on an analysis of medical subject headings (MeSH®) and text from key articles we identified a priori (Appendix A). Additionally, we reviewed the reference lists of included articles and any relevant review articles.

We downloaded the results of the searches and imported them into ProCite® version 5 (ISI ResearchSoft, Carlsbad, CA). We scanned for exact article duplicates, author/title duplicates, and title duplicates using the duplication check feature in ProCite. We uploaded the articles from ProCite to DistillerSR (Evidence Partners, Ottawa, Ontario, Canada), a Web-based software package developed for systematic review data management. We used this database to track the search results at the levels of title review, abstract review, and article inclusion/exclusion.

To identify additional studies, the Evidence-based Practice Center Program's Scientific Resource Center submitted requests to the wound dressing and pharmaceutical manufacturers for any published or unpublished randomized controlled trials or observational studies. We reviewed the materials submitted by 3M™, Akorn, Inc.©, Alcorn©, Baxter Healthcare, Convatec, Inc., Fagron, Healthpoint® Biotherapeutics, and Systagenix. We searched ClinicalTrials.gov to identify any relevant on-going trials.

Study Selection

Two independent reviewers conducted title scans. For a title to be eliminated at this level, both reviewers must indicate that the study was ineligible. If the reviewers disagreed, we advanced the article to the next level (Appendix B, Title Review Form).

We designed the abstract review phase to identify studies reporting the effects of treatment options for chronic venous leg ulcers. Two investigators independently reviewed abstracts and excluded them if both investigators agreed that the article met one or more of the exclusion criteria (see the inclusion and exclusion criteria listed in Table 4 and Appendix B, Abstract Review Form). We tracked and resolved differences between investigators regarding the inclusion or exclusion of abstracts through consensus adjudication.

Table 4. Inclusion and exclusion criteria.

Table 4

Inclusion and exclusion criteria.

Two independent investigators reviewed articles that we promoted on the basis of the abstract review to determine if they should be included in the final systematic review. We tracked and resolved the differences regarding article inclusion through consensus adjudication. For articles that were not in English, we tried to find at least two people (either an investigator or a person with a medical or public health background) who could read the language to review the article.

We included studies that used any of the outcomes of interest to evaluate advanced wound dressings, systemic antibiotics, or surgical interventions among patients with chronic venous leg ulcers. Patients must have had an active ulcer for at least 6 weeks. We excluded studies that had a mixed population of patients with chronic wounds, unless the study presented a separate analysis of patients with chronic venous ulcers. We included studies that concurrently compared an intervention of interest with compression therapy or with another intervention. Based on the findings from a previous systematic review,5 we required that subjects in both the experimental and control groups received at least two layers of compression therapy. We did not have any restrictions based on language or sample size for the studies with a comparison group. We included studies with at least 4 weeks of followup. We resolved differences between investigators regarding eligibility through consensus adjudication.

For surgical interventions, we included studies without a concurrent comparison group if the study (1) included at least 30 patients with chronic venous leg ulcers for at least 6 weeks, (2) described the sampling frame, (3) provided demographic and baseline characteristics for the patients with chronic venous ulcers, and (4) assessed ulcer healing rates. We decided to include noncomparative studies evaluating surgical interventions because we anticipated finding few, if any, comparative studies. We felt that including only studies where adequate compression therapy had failed patients for at least 6 weeks would provide useful information about the effects of surgery on healing-related outcomes, despite the potential bias from not having a concurrent comparison group. By including noncomparative studies and assessing their quality, we hope to inform decisionmakers about the type of evidence available and to guide future research.

Data Abstraction

We used a systematic approach to extract all data to minimize the risk of bias in this process. We created standardized forms for data extraction (Appendix B, Study Design Form, Population Characteristics Form, Interventions Form, and Outcomes Form), which we pilot tested. By creating standardized forms for data extraction, we sought to maximize consistency in identifying all pertinent data available for synthesis.

The study investigators double-reviewed each article for data abstraction. The second reviewer confirmed the first reviewer's abstracted data for completeness and accuracy. We formed reviewer pairs to include personnel with both clinical and methodological expertise. We did not mask reviewers to the authors of the articles, their respective institutions, nor the journals that published the articles.

For all articles, the reviewers extracted information on general study characteristics (e.g., study design, study period, and followup), study participants (e.g., age, sex, duration of ulcer, smoking status, diabetes status, other systemic diseases, concomitant use of immunosuppressants or steroids, other treatment), interventions (compression types and debridement types, advanced wound dressings, antimicrobial use, surgical interventions, duration of treatment), comparisons (including type of compression used [e.g., two-layer, short stretch, long stretch, multilayer, or Unna boot]), outcome measures, definitions, and the results of each outcome, including measures of variability. We collected data on subgroups of interest, including age, presence of comorbid conditions (e.g., diabetes, obesity), and setting.

The individual completing the review entered all information from the article review process into a DistillerSR database (Evidence Partners Inc., Ottawa, Canada). Reviewers entered comments into the system whenever applicable. We used the DistillerSR database to maintain the data and to create detailed evidence tables and summary tables.

Quality Assessment

Two reviewers independently assessed study quality. We used the Downs and Black quality assessment tool to assess the quality of all included studies.17 We supplemented this tool with additional quality-assessment questions based on recommendations in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews (hereafter Methods Guide).18 Our quality assessment tool included items on the reporting, internal validity, power, and conflicts of interest (Appendix B, Study Quality Form). The reporting questions evaluated clear descriptions of the objectives, main outcomes, subject characteristics, interventions of interest, distribution of principal confounders, main findings, estimates of random variability, adverse events, characteristics of subjects lost to followup, and actual p-values. Internal validity questions assessed the blinding of the study subjects and outcome assessors, a priori specification of the results, adjustment for different lengths of followup, appropriateness of the statistical tests, compliance of the interventions, accuracy of the main outcome measures, selection of patients in the different intervention groups, randomization, allocation concealment, adequate adjustment for confounding, and accounting for loss to followup.

Applicability

We assessed the applicability of studies in terms of the degree to which the study population (age, duration of ulcer, comorbidities), interventions (treatment, cointerventions, duration of treatment), outcomes, and settings (nursing home, wound care center, primary care, hospital/inpatient) are typical for the treatment of individuals with chronic venous leg ulcers who are receiving treatment. For example, if the study included a very old population in nursing homes, then it may have limited applicability to patients in other settings.

Data Analysis and Synthesis

We had planned to conduct meta-analyses when there was sufficient data (at least three studies on a given outcome for a specific comparison) and studies were sufficiently homogenous. We qualitatively assessed the homogeneity of the studies with respect to key variables (population characteristics, study duration, and comparisons). We qualitatively summarized studies not amenable to pooling. Where possible for the outcomes of proportion of ulcers healed and wound recurrence, we calculated the risk difference and relative risk for the individual studies. We commented on relevant subgroup analyses that the studies reported, but we lacked sufficient data to conduct any additional sensitivity analyses.

Data Entry and Quality Control

A second reviewer checked the data that had been entered into DistillerSR. Second reviewers were generally more experienced members of the research team. We discussed any problems with a reviewer's data abstraction at a meeting with the reviewers.

Rating the Strength of the Body of Evidence

At the completion of our review, at least two reviewers independently rated the strength of the body of evidence on each of the comparisons of classes of interventions. We graded the strength of evidence addressing KQs 1, 2, and 3 by adapting an evidence grading scheme recommended in the Methods Guide.19 We applied evidence grades to the bodies of evidence about each class comparison for the outcome of wound healing (i.e., proportion of ulcers healed) and wound recurrence (for surgical studies). We included evidence from intermediate outcomes if this was the only data available. We assessed the risk of bias of individual studies according to internal validity measures described in the Quality Assessment section. We rated the body of evidence as “consistent” if most of the studies showed the same direction of effect. We rated the consistency of a single study as “not applicable,” without downgrading the strength of evidence. We rated the body of the evidence as “direct” if most of the studies evaluated the proportion of ulcers healed and “indirect” if most of the studies only evaluated intermediate outcomes, such as wound healing rates. We based our rating of precision on the width of the confidence intervals of the risk difference. If the width of the confidence interval was less than or equal to 30 percent, then we considered the body of evidence to be “precise.” When we were unable to calculate a risk difference, we used our judgment based on the data available.

We classified the strength of evidence pertaining to the KQs into four basic grades: (1) “high” grade (indicating high confidence that the evidence reflects the true effect and that further research is very unlikely to change our confidence in the estimate of the effect), (2) “moderate” grade (indicating moderate confidence that the evidence reflects the true effect and that further research may change our confidence in the estimate of the effect and may change the estimate), (3) “low” grade (indicating low confidence that the evidence reflects the true effect and that further research is likely to change our confidence in the estimate of the effect and is likely to change the estimate), and (4) “insufficient” grade (evidence is unavailable or does not permit a conclusion).

Peer Review and Public Commentary

Experts in wound care, including dermatologists, vascular surgeons, nurses, and geriatricians, and individuals representing stakeholder and user communities were invited to provide external peer review of this Comparative Effectiveness Review; AHRQ and an associate editor also provided comments. The draft report was posted on the AHRQ Effective Health Care Program's Web site for 4 weeks to elicit public comment. We addressed all reviewer comments, revising the text as appropriate, and documented everything in a “disposition of comments report” that will be made available 3 months after the Agency posts the final Comparative Effectiveness Review on the AHRQ Effective Health Care Program Web site.

Cover of Chronic Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities
Chronic Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities [Internet].
Comparative Effectiveness Reviews, No. 127.
Zenilman J, Valle MF, Malas MB, et al.

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