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EDITORIALS: Joseph E Grey, David Leaper, and Keith Harding How to measure success in treating chronic leg ulcers BMJ 2009; 338: b1434 [Full text]

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Measuring outcomes in leg ulcer trials

Nicky Cullum, Martin Bland, Jo Dumville, Cynthia Iglesias, Susan O'Meara, Marta Soares, David Torgerson (all University of York) and E Andrea Nelson, Gill Worthy (University of Leeds)   (13 May 2009)

Measuring outcomes in leg ulcer trials 13 May 2009
Nicky Cullum, Deputy Head of Department (Research) Department of Health Sciences, University of York, York YO10 5DD, Martin Bland, Jo Dumville, Cynthia Iglesias, Susan O'Meara, Marta Soares, David Torgerson (all University of York) and E Andrea Nelson, Gill Worthy (University of Leeds) Send response to journal: Re: Measuring outcomes in leg ulcer trials	The authors of the editorial that accompanied our three papers on leg ulcers make some important points to which we must respond. [1] [2] [3] They have also (inadvertently) explained some of the problems associated with research in this field. Wound care research has been almost entirely driven by the pharmaceutical industry, which makes large profits from selling wound treatments of unproven effectiveness. Most wound treatments (although larval therapy is an exception) are not medicines but devices and consequently manufacturers are only required to demonstrate that devices are safe and fit for purpose rather than effective. Consequently it is not the “lack of universally accepted evidence based guidelines” that is the barrier to optimising leg ulcer care but rather the lack of actual evidence. The industry has prospered partly by selling products on the basis of one or more of the following: no evidence; studies that report only unvalidated, “important sounding surrogate endpoints” (see Richard Lehmann’s wonderful BMJ blog) and by misrepresenting the status of the evidence in advertisements to health professionals.[4] The authors of the editorial do not like our selection of time to healing as the primary outcome in both the larval therapy and bandage studies. Wounds researchers rarely, if ever, ask the patients which outcomes matter to them; although healing is obviously the most important outcome, debridement may also be highly valued. However health care professionals practise debridement because they believe that it will speed the healing process. The fact that more than 40% of patients achieved complete healing in our trial [1] (as did the vast majority of participants in the bandage trials) does not lend weight to the argument of Grey et al that healing was an inappropriate endpoint and we cannot understand their assertion that “effective debridement may have been a more useful measure of success” since in the larval therapy study we clearly measured and reported that too. By measuring both debridement and healing we are, for the first time, able to examine any potential link between these two outcomes—whilst none is evident in the primary analysis (quicker debridement was not associated with quicker healing) we are currently employing more sophisticated techniques to examine this further. Finally in relation to outcomes, within the VenUS II larval therapy study we measured several other outcomes alongside healing and debridement including health related quality of life and leg ulcer pain as well as undertaking an indepth qualitative study of how patients felt about their ulcer and its treatments, so should have most of the outcomes bases covered. Moving on to the “critique” of the cost effectiveness analysis, the authors feel that cost effectiveness is difficult to measure because randomised trials “exclude many patients with this condition”. We don’t understand this argument. Our research included consenting participants who required debridement of their ulcer – ie., the appropriate treatment group. The majority of excluded participants did not require debridement. It is important that participants in any study are representative of patients with the target condition and we feel confident that our inclusion criteria were sufficiently broad to ensure this. The pragmatic nature of this trial also improves its external validity. The economic evaluation was not, as Grey et al suggest, an afterthought (“…comprehensive evaluation should include studies specifically designed to study this measure”). The original funding application included plans for this trial based economic analysis and although these evaluations are often conducted alongside RCTs they are seldom planned at such early stage. Our approach ensured that all relevant data for the economic evaluation were collected. We are then completely baffled by the declaration that “It may be unrealistic to use complete healing as the primary outcome measure in wound healing studies, and time to healing may be an equally valid outcome measure…” since they are essentially different ways of measuring the same phenomenon (healing) and in both the larval therapy trial and bandage meta -analysis our primary endpoint was time to healing. Analysing time to healing, as opposed to the proportion of wounds completely healed at an arbitrary time point, is a more efficient use of information and also allows us to include data for participants who, for whatever reason, cannot be observed for the full period. Finally it is useful to return to the fundamental thrust of the editorial which is that systematic reviews are unhelpful as they conclude that more research is needed and that randomised trials which measure healing as the outcome are unhelpful because they do not demonstrate treatment effects. The authors claim that “…no single intervention has produced both clinically and statistically significant results, which has resulted in the limited adoption of new technologies”. This is simply not true on both counts. Compression bandaging has been shown to be a highly effective treatment for venous leg ulcers, with the four layer bandage shown to be significantly more effective than the short stretch bandage in the paper that this editorial accompanied.[3] The four layer bandage has been widely embraced by nurses who manage the care of people with leg ulcers. Furthermore the last thing one could accuse the wound healing community of is reluctance to adopt new technologies; millions of pounds worth of silver-containing wound dressings were prescribed in the NHS during 2005 on the basis of very limited evidence for their effectiveness [5] and there are many other examples of the eager uptake of costly new technologies in the face of little evidence (topical negative pressure and larval therapy being just two). Simply put, patients deserve better. Thus rather than yielding to the calls of those who call for the abandonment of healing as an outcome or for the rejection of the randomised controlled trial as an appropriate research design for wound care [6] or for animal studies to directly inform treatment decisions [7] we should be subjecting this field of care to the same level of scrutiny and high standards as all others – particularly important given the burden of disease and costs to the NHS. [1] Dumville JC, Worthy G, Bland JM, Cullum N, Dowson C, Iglesias C, Mitchell JL, Nelson EA, Soares MO, Torgerson DJ; VenUS II team. Larval therapy for leg ulcers (VenUS II): randomised controlled trial. BMJ 2009; 338:b773. doi: 10.1136/bmj.b773. [2] Soares MO, Iglesias CP, Bland JM, Cullum N, Dumville JC, Nelson EA, Torgerson DJ, Worthy G. Cost effectiveness analysis of larval therapy for leg ulcers. BMJ 2009; 338: b825. Published online 2009 March 19. doi: 10.1136/bmj.b825. [3] O'Meara S, Tierney J, Cullum N, Bland JM, Franks PJ, Mole T, Scriven M. Four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomised controlled trials with data from individual patients. BMJ. 2009 Apr 17;338:b1344. doi: 10.1136/bmj.b1344. [4] Dumville JC, Petherick ES, O'Meara S, Raynor P, Cullum N. How is research evidence used to support claims made in advertisements for wound care products? J Clin Nurs. 2009 May;18(10):1422-9. Epub 2008 Aug 20. [5] Chambers H, Dumville JC, Cullum N. Silver treatments for leg ulcers: a systematic review. Wound Repair Regen. 2007 Mar-Apr;15(2):165- 73. [6] Gottrup F. Evidence is a challenge in wound management. Int J Low Extrem Wounds 2006; 5(2):74-5. [7] Robson MC, Cooper DM, Aslam R, Gould LJ, Harding KG, Margolis DJ, Ochs DE, Serena TE, Snyder RJ, Steed DL, Thomas DR, Wiersma-Bryant L. Guidelines for the treatment of venous ulcers. Wound Repair Regen. 2006 Nov-Dec;14(6):649-62. Competing interests: Andrea Nelson has a PhD student funded by, and has been reimbursed for speaking at educational events by Convatec UK, a manufacturer of wound products. The remaining authors declare that they have no competing interests.