Dealing with heterogeneous populations in randomized wound trials: Challenges and potential solutions

Abstract

Chronic wounds have a great variety of etiologies and manifestations that influence wound healing. Such heterogeneity potentially threatens the validity and clinical usefulness of trials if not considered appropriately. In 82 randomized wound trials retrieved from 10 Cochrane reviews, we assessed if and how authors considered wound and other prognostically important characteristics in the conduct and analysis of wound trials. We assessed whether these characteristics were discussed, reflected in the eligibility criteria, used for prestratification or for adjustments to ensure comparability of treatment groups, and whether subgroup analyses were conducted to identify heterogeneity of treatment effects. Nine percent of all trials explicitly discussed characteristics that influence wound healing in the introduction and 43% in the Discussion section. Ninety percent of trials had at least one prognostically important characteristic as eligibility criterion. Only 11% of trials used prestratification, and 6% adjusted the results for imbalances between treatment groups. Twenty-seven percent performed subgroup analyses with prognostically important characteristics defining subgroups. Chronic wound trials use simple randomization, but rarely adapt the study design and analysis to take the heterogeneity of patients into consideration. Collaborative multicenter trials would overcome many of the limitations and provide statistical power to detect important treatment effects both overall and in subgroups.

Eutectic mixture of local anaesthetics (EMLA®) as a primary dressing on painful chronic leg ulcers: a pilot randomised controlled trial

“…Considering the prevalence of chronic leg ulcers in society, most chronic wound trials have small sample sizes reflecting the difficulty in recruiting patients if the eligibility criteria are too restrictive [ 42 ]. It became apparent that two of the exclusion criteria were considered unnecessary hence amendments were made to the exclusion criteria to increase the recruitment rate previously described.…”

“…To increase the ability to meet our required sample size, patients with any of the above CLU types were included. We acknowledge that such heterogeneity can threaten study validity and usefulness of a clinical trial [ 42 ]. Subgroup analysis would be a solution however, a much larger sample size would be required [ 42 ] which was not realistic for this single-centre pilot study.…”

“…We acknowledge that such heterogeneity can threaten study validity and usefulness of a clinical trial [ 42 ]. Subgroup analysis would be a solution however, a much larger sample size would be required [ 42 ] which was not realistic for this single-centre pilot study. Additionally, simple randomisation may not be sufficient to provide well-balanced treatment groups regarding confounders in this broadly defined study; a large, multicentre RCT using stratified randomisation may be appropriate [ 42 ].…”

Fundamentals of randomized clinical trials in wound care: Reporting standards

“…19,20 Woundspecific barriers (e.g., variety of etiologies and multiple factors influencing wound healing) and the lack of specification in the CONSORT statement for wound care may prevent the uniform implementation of reporting standards in wound care research. 21 Despite international recognition of RCTs as the putative "gold standard" for effectiveness, 3,22,23 this design is relatively seldom used for wound care treatments. [2][3][4][24][25][26] Specific barriers to perform RCTs in the realm of wound care 27,28 include the large diversity of etiologies and comorbidities, the plethora of treatment options, and invalid or unreliable assessment of outcome measures, which hamper adequate performance and reporting of RCTs.…”

Controversies in performing a randomized control trial and a systemic review

“…In this issue of Wound Repair and Regeneration ( WRR ), the article “Dealing with heterogeneous populations in randomized wound trials: Challenges and potential solutions” is published . This publication brings focus on one of the present problems in wound management today: obtaining evidence and how valid is the evidence produced.…”