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Improving the quality of evidence in wound management

F Gottrup
MD DMSci
Professor of Surgery Chair of the EWMA Patient Outcome Group
Bispebjerg University Hospital, Copenhagen, Denmark

J Apelqvist
MD PhD
Senior Consultant, Associate Professor, Executive member of the EWMA Patient Outcome Group Malmö University Hospital, Sweden University of Lund Sweden

P Price
PhD CHPsychol
Dean and Head of School of Healthcare Studies Executive member of the EWMA Patient Outcome Group
Cardiff University

This article is a summary of the document 'Outcomes in controlled and comparative studies on non-healing wounds: Recommendations to improve the quality of evidence in wound Management' (a EWMA Patient Outcome Group Document) published in Journal of Wound Care 19(6):237-68. For more information about EWMA and the document, please visit
www.ewma.org

The document of recommendations, produced by the EWMA group and published by the Journal of Wound Care, identifies criteria for producing precise outcomes in both randomised, controlled trials (RCTs) and clinical studies, and describes how to ensure studies are consistent and reproducible.1 This summary gives a short presentation of the content of the
full document.  

Background
Non-healing wounds are a significant problem for healthcare services worldwide, and there is an urgent need to review wound strategies and treatments to reduce the burden of care in an efficient and cost-effective way.

Ongoing controversy surrounds the value of various approaches to wound management and care. There is a need to consider alternative ways of achieving the highest level of evidence required for this patient group. From a clinical perspective, the question is which interventions, technologies and dressing materials are the best from the point of view of a single patient or group of patients, where the primary focus is healing and the absence of complications.

Wound management has a paucity of high-quality evidence, as studies are often based on inadequate sample sizes, have short follow-up periods, non-random allocation to treatment groups, non-blinded assessment of outcomes, and poorly described control groups and concurrent interventions. Too few good-quality clinical or economic studies in wound care have resulted in challenges to the reimbursement of modern dressings in favour of supposedly better value traditional products.

The aim of the document is to provide recommendations on how to achieve rigorous endpoints/ outcomes in studies on wound management and to describe an approach that will enable the design of randomises, controlled trials, and clinical studies to be both consistent and reproducible to reach a higher quality of evidence in wound management.

Definition of endpoints/outcomes
Study endpoints or outcomes are the keystone in the evidence discussion. To clarify the basic premises of the discussion, the terminology needs to be clarified.
An endpoint/outcome parameter is defined as the objective of an evaluation or study. The objectives should include:

  • A precise statement of the degree of benefit expected from the intervention, and its duration.
  • Clear statements on the time frame of the study (especially in relation to how quickly the benefits might start).
  • A definition of the patients for whom the benefit is sought.

In the past, the most commonly used clinical outcome (endpoint that directly relates to outcome) was visible reduction in wound size, particularly intact skin (full healing).

The development of tests and techniques to improve tissue sampling and analysis, imaging technology and scientific progress in cellular and molecular biology has enabled the development of more "objective" wound outcome parameters (surrogate outcome parameters) that relate to both the wound condition and the treatment intervention being assessed (for example, exudation rate, pain, granulation rate, resolution of necrosis or infection).

A surrogate endpoint/outcome parameter is defined as a physical sign or a laboratory measurement that can be used as a substitute for a clinically meaningful endpoint, effectively directly measuring how a patient feels, functions or survives.
The challenge, in non-healing wounds, is that these types of endpoints/outcome parameters are difficult to achieve and maintain. If the only gold standardwas total wound closure, no therapy would ever be considered efficacious. Thus, alternative endpoints are, needed.

Material and methods
Material
The background information, evaluations and recommendations of the document are based on a collection of a large amount of available guidance for evidence collection and an analysis of recent RCTs and comparative studies. To achieve an updated status (2003-09) on how endpoints/outcome parameters are used, defined and evaluated, we performed a literature search on chronic/problem wounds/ulcers, with the objective of examining and registering their use of endpoints, the quality of their endpoint definitions and the robustness of their methodologies.

Discussions with various stakeholders within and outside the framework of the EWMA Patient Outcome Group have also provided a basis for the structure and content of the document.

Methods
To establish a basis for the recommendations and statements related to study designs and use of outcome measures in wound management, data collection issues, concepts and terms were discussed and used in the document.

The challenge has been to control the heterogeneity of individual patients, concurrent disease states and confounding factors, as well as variations in the type, site and condition of wounds and differences in health-care organisations. These problems cannot be solved by enrolling more subjects into a study.

Currently, the majority of wound management studies recruit patients with one wound aetiology. However, the development of more targeted strategies specific to different phases of treatment (eg, debridement) means that the condition of the wound (eg, exudate rate, pain and necrosis) may be a better inclusion criterion.

Furthermore, the following perspectives and terms have been taken into consideration:
From the clinical research perspective there is a need to be aware of the strengths and limitations of different study designs if they are to effectively evaluate which healthcare practices are worth considering for different patients in different health contexts. Key issues are, for example, use of a study protocol, problems related to heterogeneity of the study population and underlying conditions.

From an industry perspective, external evidence needs are set by the requirements of national regulatory and reimbursement authorities, and other payers. When developing a new product, there are also internal needs for evidence, which mirror the phases of the development process. When focusing on payment or reimbursement for a new product, the key issue will often be budgetary impact and/or cost-effectiveness, rather than healing.

The document also discusses the importance of a generally accepted definition of "standard care" in connection with data collection in wound management. "Standard care" refers to generally accepted wound care procedures and the management of underlying disease, outside of the investigational product/device or drug that will be used in the clinical trial/evaluation. It is essential that the standard care procedures/regimens used are consistent as this will minimise variability and enable assessment of the treatment effect.

Results
Following an evaluation of abstracts from the recent RCTs and comparative studies by three reviewers, 176 articles found in the literature search were selected for analysis. Many studies measured multiple endpoints/outcome parameters - in total, this analysis generated a list of 313 different endpoints.
The endpoints were divided into the following categories (the percentages represent each category's proportion of the 313 registered endpoints):

  • Reduction rate (24.1%).
  • Wound closure (16.9%).
  • Healing time (9%).
  • Change in wound condition (9%).
  • Biomarkers and bacteriology (4.5%).
  • Circulation (1.9%).
  • Infection signs (4.5%).
  • Symptoms and signs (13.2%).
  • Dressing performance (7.0%).
  • Quality of life (5.8%).
  • Costs and resources used (4.5%).

The findings of the analysis were used as a basis for discussing and suggesting procedures for the successful measurement of each of the types of endpoint categories defined.

In general, it was found that a substantial number of endpoints (45%) were either not predefined or insufficiently defined. As part of the analysis, the degree of robustness of the measurement techniques used in studies and the degree of reproducibility were evaluated. In 70% of cases, a standardised or clearly defined measurement technique was used to examine the endpoint (eg, computerised planimetry or a standardised evaluation method). These were defined as meeting the criteria for an acceptable degree of robustness. However, 76% of these did not meet the criteria for reproducibility.

The analysis and discussion resulted in a number of recommendations ("statements") on use of endpoints in RCTs and comparative studies on non-healing wounds (See Table 1).

Discussion
When evaluating interventions in wound management it is a challenge to avoid performance bias. Designing studies with the aim of obtaining sufficient information regarding outcomes is particularly hazardous. The document, therefore, discusses and provides recommendations regarding some of the considerations that should be made when designing studies on interventions for the treatment of wounds.

The definition of non-healing wounds is still discussed. We suggest that the definition "chronic" be replaced with the definition "non-healing" as this better reflects the clinical problems experienced by such patients. It is also suggested that multicentre trials should imply great efforts to enrol sufficient numbers at each site and a high degree of protocol standardisation. Another issue brought forward is the selection of an appropriate study period.

[[Tab 1 Endpoints]] 

Conclusion
The document provides recommendations to improve the quality of evidence in wound management. This is achieved by formulating a set of statements within the following areas:

  • Different types of evidence required by different authorities.
  • Evaluation of outcome.
  • Outcome: endpoints in RCTs and comparative studies on non-healing wounds.
  • Performance bias and interpretation of findings.

A full list of statements is found in the article published in Journal of Wound Care.1

Reference
1. Gottup F, Appelqvist J, Price P. Outcomes in controlled and comparative studies on non-healing wounds: Recommendations to improve the quality of evidence in wound management. J Wound Care 2010;19:237-68.