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Improving the quality of evidence about treating non-healing wounds

F Gottrup and J Apelqvist
15 June, 2011  

Professor F Gottrup 
MD, DMSci 

Professor of Surgery, 
Bispebjerg University Hospital, Copenhagen, Denmark, Chairman of 
the EWMA Patient 
Outcome Group

Dr J Apelqvist 
MD, PhD

Senior consultant, Malmö University Hospital, 
Sweden; Associate 
professor, University of Lund, Sweden, Executive member of the EWMA Patient Outcome Group

Professor P Price 
PhD, CHPsychol

Dean and head of school of Healthcare Studies, Cardiff University, UK; Executive member of the EWMA Patient Outcome Group

Evidence-based clinical practice is difficult to achieve due to confusion about the various approaches to wound management. The European Wound Management Association (EWMA) set up a Patient Outcome Group to produce recommendations on clinical data collection.

The document, produced by the group and published by Journal of Wound Care,1 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. This is article is a summary of the full document.  

Background
Non-healing wounds are a significant problem for health-care systems world-wide. In the industrialised world, between 1% and 1.5% of the population will have a problem wound at any one time. Furthermore, wound management is expensive: for example in Europe, the average cost per episode is €6,650 for leg ulcers and €10,000 for foot ulcers, which accounts for 2%–4% of healthcare budgets. For these reasons, there is an urgent need 
to review wound strategies and treatments to reduce care in an efficient and cost-effective way.

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.

  • From the clinical perspective: what  are the best interventions, technologies and dressing materials for a single patient or group of 
patients, where the primary focus is healing and the absence of complications?
  • 
From the policy maker and healthcare system perspectives: whether or not a particular product or intervention is safe and effective when used as indicated; and what represents a cost-effective use of funds? Too few good-quality clinical or economic studies in wound care have resulted in changes to the costs of modern dressings in favour of supposedly 
better-value traditional products
  • From the industry perspective (medical 
device industry): the problem is that the 
standard of care and requirements  of evidence for reimbursement may be different in each country. Large investments in evidence are rarely justified by the pace of innovation and size of markets for most wound care products.

The document provides recommendations on how to achieve rigorous endpoints/outcomes in studies on wound management and to describe an approach that will enable RCTs and clinical studies to be consistent and reproducible in order to reach a higher quality of evidence.

Definition of endpoints/outcomes
In discussing the evidence, we must clarify the terminology. An endpoint/outcome parameter is defined as the objective of an evaluation or study. The objectives should include: a precise statement of the benefit expected from the intervention; a clear statements on the time-frame of the study (especially in relation to how quickly the benefits might start); and 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 full healing of skin.

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. Examples of these parameters include 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.

But these types of endpoints/outcome parameters are difficult to achieve and maintain in non-healing wounds. If wound closure was considered the endpoint, then no therapy would ever be considered efficacious. Alternative endpoints are therefore needed.

Research data and method
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.

Discussions with the EWMA Patient Outcome Group and with others have also provided a basis for the structure and content of the document.

There was also a discussion about data collection issues, concepts and terms  in order to establish a basis for study designs and use of outcome measures in wound management.

The problem was to account for 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 healthcare organisations.

Currently, most wound management studies recruit patients with one wound aetiology. However, the development of more targeted strategies specific to different phases of treatment (for example, debridement) means that the condition of the wound such as 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. Key issues are use of a study protocol, problems related to heterogeneity of the study population and underlying conditions
  • From an industry perspective: 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 an accepted definition of “standard care” for 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. It is essential that the standard care procedures/regimens used are consistent, as this will minimise variability and enable assessment of the treatment.

Results
The analysis generated a list of 313 different endpoints, which 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 many endpoints (45%) were either not predefined or insufficiently defined. The degree of robustness of the measurement techniques used in studies (so that others could replicate it) and the degree of reproducibility (such as including photos as verification) were evaluated. In 70% of cases, a standardised or clearly defined measurement technique was used to examine the endpoint (for example, 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 study resulted in recommendations on use of endpoints in RCTs and comparative studies on non-healing wounds (see Table 1).

Conclusion
The full article provides recommendations to improve the quality of evidence in wound management in 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.

The full document provides recommendations regarding some of the considerations that should be made when designing studies on interventions for the treatment of wounds and avoiding performance bias.

We also suggest that the definition of non-healing wounds as “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 raised is the selection of an appropriate study period.

Recommendations from various institutions vary from two weeks to 12 months. We recommend that the types of ulcer and relevant natural outcome are also considered when selecting the study duration.

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, Journal of Wound Care 2010;19:237-268