Multicentre, randomised controlled trial of four-layer bandaging versus shortstretch bandaging in the treatment of venous leg ulcers

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1 Wilhelminenspital, Wien, Austria 1, Ziekenhuis Nij Smallinghe, Drachten, The Netherlands 2, Ziekenhuis Tjongerchans, Heerenveen, The Netherlands 3, Universitätsklinik für Dermatologie, Graz, Austria 4, Ziekenhuis Antoninius, Sneek, The Netherlands 5, Academisch Ziekenhuis, Nijmegen, The Netherlands 6, Leiden, The Netherlands 7, Smith and Nephew Group Research Centre, York, UK 8 Multicentre, randomised controlled trial of four-layer bandaging versus shortstretch bandaging in the treatment of venous leg ulcers H. Partsch 1, R. J. Damstra 2, D. J. Tazelaar 3, S. Schuller-Petrovic 4, A. J. Velders 5, M. J. M. de Rooij 6, R. R. M. Tjon Lim Sang 7 and D. Quinlan 8 Summary Zusammenfassung 108 Background: Aim of the study was to compare the healing rates of venous ulcers obtained with four-layer bandages (4LB) versus short stretch bandages (SSB). Design: Multicentre, randomised controlled trial performed in 5 centres of the Netherlands and in 2 centres in Austria ( PADS-study = Profore Austrian Dutch Study). Patients and methods: 112 patients (53 treated with 4LB and 59 treated with SSB) completed at least one post-treatment follow-up, 90 completed the study. Bandaging and ulcer assessment was performed at weekly intervals. Randomisation was carried out for each centre and was stratified according to the size (more or less than 10 cm 2 ) of the ulcerated area. Local therapy consisted of plain absorbing, non-adherent dressings. Time to complete healing was recorded up to a maximum of 16 weeks. The two treatment-groups were comparable regarding their baseline-characteristics. Results: In total 33/53 (62%) of ulcer-patients were healed in the 4LB group, compared with 43/59 (73%) in the SSB group (difference 11%, 95% CI 28% to 7%). 77% of the ulcers with an initial area less than 5cm 2 healed as compared with 33% of the larger ulcers. The different healing rates in the centres could be explained by the different sizes of the treated ulcers. Based on Kaplan-Meier estimates the median healing time was 57 days for the 4LB (95% CI days) and 63 days for the SSB (95% CI days). Conclusion: The ulcer healing rate and the median healing time did not differ among the two types of bandages. The main discriminant criterion for healing was the initial ulcer size. In centres who are experienced users of short-stretch bandages, no statistically significant different healing rates of venous ulcers could be found after 4LB or SSB. Key words Ulcer-healing, compression bandage, four-layer-bandage, short-stretch bandage Submitted / Accepted after revision Multizentrische randomisierte und kontrollierte Studie zum Vergleich von Four layer Bandagen und Kurzzugbinden des venösen Ulkus Hintergrund: Zweck der Studie war ein Vergleich der Heilraten von venösen Ulzera unter Four layer-bandagen (4LB) gegenüber Kurzzugbinden (KZB). Design: Randomisierte, kontrollierte Multizenterstudie, durchgeführt in 5 Zentren der Niederlande und in 2 Zentren in Österreich. («PADS-study» = Profore Austrian Dutch Study). Patienten und Methoden: 112 Patienten (53 mit 4LB und 59 mit KZB) haben zumindest eine Nachuntersuchung im Anschluss an die Behandlung absolviert, 90 beendeten die Studie. Die Bandagierung und die Ulkusmessung erfolgte in wöchentlichen Intervallen. Die Randomisierung wurde für jedes Zentrum durchgeführt und war entsprechend der Ulkusgröße stratifiziert (mehr oder weniger als 10 cm 2 ). Die Lokalbehandlung bestand in indifferenten, absorbierenden, nicht-verklebenden Wundauflagen. Die Zeit für eine komplette Heilung wurde bis zu einem Maximum von 16 Wochen registriert. Die beiden Behandlungsgruppen waren bezüglich der Ausgangscharakteristika vergleichbar. Ergebnisse: Insgesamt waren 33/53 (62%) der Ulkuspatienten in der 4LB Gruppe geheilt verglichen mit 43/59 (73%) in der KZB Gruppe (Unterschied 11%, 95% CI, 28% bis 7%). 77% der Ulzera mit einer Ausgangsfläche kleiner als 5 cm 2 heilten im Vergleich zu 33% der größeren Ulzera. Die verschiedenen Heilraten in den einzelnen Zentren könnten durch die unterschiedliche Größe der behandelten Geschwüre erklärt werden. Auf Grund einer Kaplan-Meier-Analyse war die mediane Heilungszeit unter 4 LB 57 Tage (95% CI Tage) und unter KZB 63 Tage (95% CI Tage). Zusammenfassung: Die Heilrate der Ulzera und die mittlere Zeit bis zur Heilung unterschied sich nicht bei den beiden Bandagegruppen. Das entscheidende diskriminierende Kriterium für die Heilung war die initiale Ulkusgröße. Verlag Hans Huber Bern 2001

2 Introduction It is now well accepted that the application of graduated compression improves the rate of healing of venous ulcers and should be used routinely for uncomplicated cases [7]. Many different compression systems are used in the treatment of venous leg ulceration, although there is very limited evidence to allow differentiation with respect to efficacy between the different systems. Further good quality randomised controlled trials are urgently needed to compare the different compression systems [7]. One commonly used method of delivering compression is via the use of short-stretch bandages (SSB) which have a long tradition of use in a number of mainland European countries. These bandages are relatively inelastic and as the calf muscle expands during exercise the force is not absorbed by the stretching of the bandage but is reflected back to the leg. They exert high pressure peaks during walking creating a massaging effect [11, 16]. A more recently developed compression system is the four-layer compression system (4LB), initially proposed by Blair et al [1]. This system involves the application of a layer of orthopaedic padding to absorb wound exudate and protect bony prominences, followed by a light conformable bandage. A light elastic compression bandage is then applied as the third layer followed by an elastic cohesive bandage to apply additional compression and to hold the other bandages in place. This system has since been evaluated comprehensively in a community clinics setting and excellent efficacy results have been reported [8, 9, 14]. The aim of this study was to compare the efficacy of 4LB with SSB in the treatment of venous leg ulceration. Methods This was a prospective, randomised, open, multicentre, parallel group study to compare the healing rates achieved using 4LB and SS in venous leg ulceration in outpatients. The study was conducted in two centres in Austria (Vienna and Graz) and five centres in The Netherlands (Heerenveen, Sneek, Drachten, Nijmegen and Leiden). Patients with bilateral ulceration were randomised to one treatment only. The study reference limb was taken as the one with the largest area of total ulceration. Randomisation was carried-out separately for each centre and was further stratified according to whether the total reference limb ulcerated area was less than or equal to 10 cm 2, or greater than 10 cm 2. The patient study follow-up duration was for up to 16 weeks or until the reference limb had healed or the patient was withdrawn. In addition to the primary endpoint of complete healing of the reference limb, SF-36 quality of life (QOL) assessments [17] were made at baseline, end of study and at four weeks post-healing for those patients that healed. The analysis of these data is beyond the scope of this publication and will be presented separately in a future paper. Each patient s ankle circumference was measured at baseline and at each subsequent visit, in order to account for a reduction in oedema. 4LB was applied as recommended by Moffatt et al. [9] with ankle circumference measurement used to determine the combination of bandages to apply. Specific details of the Profore system (Smith & Nephew Medical UK) used, are provided in Table I. Shortstretch bandages (Rosidal K, Lohmann-Rauscher, Germany) were applied over a layer of protective orthopaedic padding using the Pütter technique [3]. Two separate bandages were applied, one over the other, in opposite directions. Bandaging took place at weekly intervals unless the patient required more frequent changes. At each follow-up visit the ulcer was cleansed with saline or water and a simple non-adherent dressing was applied (Tricotex, Smith & Nephew Medical UK). If the ulcer was in the hollow behind the malleolus, then a foam pad (Komprex, Lohmann-Rauscher, Germany) could be placed over the ulcer to increase the local pressure [12]. Patients were encouraged to walk as much as possible. No additional physical therapy was performed. Consecutive outpatients presenting at the clinics at the trial centres with a new episode of ulceration were considered for inclusion into the study. Before a patient was recruited into the study he was screened using a standard procedure. Patients of both sexes, aged over 18 years, with confirmed venous ulceration of one or both limbs were recruited into the study. Venous ulceration was diagnosed where venous reflux in the superficial or deep veins could be conformed by hand held Doppler. If venous reflux was not detected but the patient had a documented history of DVT and the appearance of the leg was typical of a postthrombotic limb (chronic oedema and skin changes), then the patient was also eligible for recruitment into the study. Patients with significant arterial disease (ABPI < 0.8) or with rheumatoid, diabetic or malignant ulceration were excluded from the trial. Patients with infected ulcers could be recruited to the study provided that the trial dressings and bandages were still felt to be the appropriate treatment. Written informed consent was obtained from each patient prior to participation in the study. Each ulcer was traced at baseline and the area of ulceration was determined using computerised planimetry. At each follow-up assessment the ulceration was assessed and time to complete healing was recorded, up to a maximum of 16 weeks. Healing was defined as the complete epithelialisation of all areas of ulceration on the reference limb. The hospital ethics committee at each of the participating centres approved the protocol. Table I: PROFORE Bandaging. < 26 cm ankle circumference cm ankle circumference Soffban (Natural padding) Soffban (Natural padding) Soffcrepe (Crepe bandage) Tensopress (High compression Litepress (Light compression bandage) bandage) Co-Plus (Flexible cohesive Co-Plus (Flexible cohesive bandage) bandage) 109

3 Statistics The data were analysed using SAS version The primary study endpoint was the time to complete healing of the reference limb. With a sample size of 112 eligible patients, this confirmatory study had 77% power to detect a 25% difference in the proportion of patients fully healed at week 16 assuming a two-sided test with 5% sigificance level. Cox proportional hazards survival analysis was applied to time to healing [4]. All patients withdrawn prior to complete healing were treated as censored at their last study visit time point. An initial model was fitted including terms for initial ulcer area and duration of ulceration, as these were well-established prognostic factors for ulcer healing [15]. The effect of trial centre was also included in the model. All other baseline parameters were assessed for inclusion in the model using a forward selection procedure with p = 0.05 for parameter entry to the model. The final selected model included terms for treatment, centre, initial ulcer area, duration of ulceration and the SF-36 dimension Mental Health. The Kaplan-Meier estimates presented in Figure 1 correspond to the model with treatment effect only. The 95% confidence interval for the difference in percent of patients fully healed between the bandaging systems at 16 weeks, was calculated. Results A total of 116 patients were recruited into the study with four of these patients being excluded from the statistical analysis: three patients did not provide any post-treatment follow-up data and one patient was recruited in error and subsequently diagnosed as having a basal cell carcinoma. Therefore a total of 112 patients (53 patients treated with 4LB and 59 patients treated with SSB) who completed at least one post-treatment follow-up assessment and had a confirmed venous leg ulcer were included in the statistical analysis. Twelve 4LB patients (23%) and 10 SSB patients (17%) withdrew from the trial prematurely, there being no significant difference in the withdrawal rates between treatments, p = Reasons for withdrawal are given in Table II. The baseline characteristics of the patients entered into the trial are presented in Table III. The two treatment groups were broadly comparable with regards the baseline variables assessed. The median interval between visits was 7 days for both treatment groups. Patient mean intervals between visits were similar for both treatment groups and ranged from 3.0 days to 10.3 days. It can be seen from Table IV that Vienna, Heerenveen, Sneek and Drachten had much higher healing rates than Graz, Nijmegen and Leiden. To support this, the proportional hazards models with terms for treatment and centre gave strong evidence of different levels of healing between centres (p = 0.003). However, baseline imbalances in the prognostic variables initial ulcer area and duration of ulceration were found to explain the differences between centres in healing rates. The centres with the three highest healing rates, Heerenveen, Sneek and Drachten also had the lowest initial ulcer sizes and so the differences between centres in initial ulcer area explain the initial observed difference in healing rates between centres. Similarly the centres with the three lowest healing rates, Graz, Nijmegen, and Leiden had the longest median duration of ulceration. When the proportional hazard models were re-fitted including terms for initial ulcer area and duration of ulceration there was no evidence of the centre effect (p = 0.79). Overall, there was no significant difference between treatments in the primary survival analysis (p = 0.49), with a hazard ratio of 1.19 and a broad 95% confidence interval of (0.73 to 1.91). Here the hazard ratio of 1.19 represents a higher healing rate for SSB as compared with 4LB. 110 Fig. 1: Kaplan-Meier plot: Time to healing by treatment.

4 Table II: Reason for Patient Withdrawal (4LB: four-layer compression, SS: Short stretch bandages). 4LB SS Number of patients Number withdrawn 12 (23%) 10 (17%) Reason Patient s request 7 (13%) 2 (7%) Lost to follow-up 3 (0%) 2 (2%) Lack of response 0 (2%) 1 (7%) Adverse incident 1 (2%) 1 (2%) Other 1 (2%) 1 (2%) Table III: Baseline Characteristics (4LB: four-layer compression, SS: Short stretch bandages). 4LB Number of patients Sex Male 20 (38%) 22 (37%) Female 33 (62%) 37 (63%) Patient age (yrs) Median Range 34 to to 87 Initial ulcer size Median (cm 2 ) Range 0.4 to to 70.1 Initial ulcer size 11 (21%) 13 (23%) > 5cm 2 Number of patients 7 (13%) 9 (16%) with ulcers > 10cm 2 Ulcer duration Median (weeks) Range 1 to to 780 Patient mobility Bed/chair bound 1 (2%) 2 (3%) Walks with aid 3 (6%) 4 (7%) Walks freely 49 (92%) 53 (90%) Previous medical Hypertension 13 (25%) 12 (20%) history or Diabetes 1 (2%) 4 (7%) documentation DVT 14 (26%) 12 (20%) Venous pathology Superficial only 32 (60%) 32 (54%) Superficial and deep 19 (36%) 25 (42%) Deep only 2 (4%) 1 (2%) None 0 (0%) 1* (2%) * previous DVT SS Figure 1 is the survival plot of the Kaplan-Meier estimates of the proportion healed for each treatment through time. By 16 weeks the Kaplan-Meier estimates of healing were 78% for 4LB and 85% for SSB. The median times to healing were similar for the two treatment groups. For 4LB the median time to healing was 57 days (95% confidence interval 47 days to 85 days) and for SSB the median time to healing was 63 days (95% confidence interval 43 days to 70 days). In total, 33/53 (62%) of 4LB patients were healed during the study, compared with 43/59 (73%) of SSB patients. The difference in the proportion healed was 11% in favour of SSB with a corresponding 95% confidence interval of 28% to 7%. Seventy-seven percent of the ulcers with an initial ulcer area less than or equal to 5 cm 2 healed as compared with 33% healed for the ulcers with initial ulcer area greater than 5 cm 2 (Fig. 2). Discussion The systematic review of compression concludes that whilst there is evidence that compression systems improved the healing of venous leg ulcers, insufficient reliable evidence exists to indicate which system is the most effective [7]. A plea was made for more, good quality, randomised controlled trials. In this study we found no significant difference in healing rates between 4LB and SSB (p = 0.49). For the 4LB patients 33/53 (62%) were healed during the study, compared with 43/59 (73%) for SSB. One of the difficulties experienced in conducting multicentre comparative studies of different compression systems is that, inevitably, the centres involved tend to have had extensive experience of one of the systems prior to study commencement, and often a more limited experience with the comparator system. In this study, whilst staff at all participating centres were trained in the application of 4LB prior to the study, they all had many years experience of applying SSB. It is possible that this familiarity with A secondary survival analysis with no adjustment for covariates gave a similar result with no significant difference between treatments (p = 0.54). Table V shows the mean ankle circumference in the two groups at the beginning and at the end of the study. Table V: Mean ankle circumference (cm) 4LB SS Week 0 23,4 23,3 Final assessment 21,8 22,0 Table IV: Number of Patients Fully Healed (4LB: four-layer compression, SS: Short stretch bandages). Median initial ulcer Median ulcer duration 4LB SS (cm 2 ) (weeks) Centre Vienna /5 (80%) 6/9 (67%) Graz /9 (44%) 3/10 (30%) Drachten /15 (80%) 13/15 (87%) Sneek /6 (67%) 7/7 (100%) Heerenveen /10 (90%) 9/10 (90%) Nijmegen /6 (0%) 4/6 (67%) Leiden /2 (0%) 1/2 (50%) Overall /53 (62%) 43/59 (73%) 111

5 Fig. 2: Kaplan-Meier plot: Time to healing by ulcer area. 112 their existing system made it more difficult to demonstrate the advantages of the newly introduced system. This issue could possibly be resolved by conducting a study in centres who routinely used neither (or both) of the bandage systems being compared. The results from randomised controlled trials comparing short stretch and long stretch bandages for ulcer-healing are conflicting. Some centres found superior healing rates with elastic bandages, possibly because of the lacking experience to apply adequate inelastic bandages [2, 5]. (The bandaging technique with short stretch material generally needs more training than with long stretch bandages.) A group from Oxford, UK [6] reported a study of 50 venous leg ulcers and obtained 12 week healing rates of 44% with 4LB and 40% with SSB (p > 0.05). These healing rates are lower than those obtained in the present study but along with the shorter duration of follow-up, the ulcers studied by the Oxford group were considerably larger (mean 13 cm 2 ) than those reported here (mean 5.9 cm 2 ). A study performed in Leicester, UK [13] of 64 venous leg ulcer patients also found no difference between SSB and 4LB reporting 1 year healing rates of 55% for the 4LB group and 57% for the SSB group (p = 1.00). Again, the difference in results may be explained by the relatively large ulcers studied in Leicester (mean 11 cm 2 ). Baseline imbalances in the prognostic variables initial ulcer area and duration of ulceration were found to explain the large differences in healing rates observed between centres. The centres with the highest healing rates had the smallest initial ulcer sizes and similarly the centres with the lowest healing rates had the longest durations of ulceration. Experiments using air-plethysmography have demonstrated that 4LB and SSB have similar effects concerning the reduction of venous volume and venous refluxes. One advantage of four-layer bandaging is that they are able to keep sufficient pressure for a longer time than short-stretch bandages [10]. These experimental findings are in accordance with the results of this present study, which demonstrates the effective performance of both four layer bandaging and short stretch bandaging in the treatment of venous leg ulceration, with no significant difference of healing rates observed. Finally, this study was conducted in outpatient clinics of major referral centres by experienced clinicians, who are used to handle short-stretch bandages with sufficiently high pressure. This is possibly an idealised setting for the comparison of venous leg ulcer treatments as it is generally the case that venous leg ulcer patient are treated in their own home by community nursing staff. It is possible that a community-based study may be a more appropriate comparison of different bandage systems and this is a potential area for future research. Acknowledgements: We thank Peter Cooper for providing statistical input into the design of the study and the statistical analysis. The funding for this study was provided by Smith & Nephew Medical Ltd, UK. References 1 Blair S, Wright D, Blachkouse C, Riddle E, McCollum C. Sustained compression and healing of chronic venous ulcers. Br Med J 1998; 298: Callam MJ, Harper DR, Dale JJ, Brown D. Lothian and Forth Valley leg ulcer healing trial, part 1: elastic versus non-elastic bandaging in the treatment of chronic leg ulceration. Phlebology 1992; 7: Charles H. Short-stretch bandaging in the treatment of venous leg ulcers. J Wound Care 1999; 8: Cox DR. Regression models and life tables (with discussion). J R Stat Soc B 1972; 34: Danielsen L, Madsen SM, Henriksen L. Venous leg ulcer healing: a randomized prospective study of long-stretch versus shortstretch compression bandages. Phlebology 1998;13:

6 6 Duby T, Hoffman D, Cameron C, Doblhoff-Brown D, Cherry G, Ryan TA. Randomized trial in the treatment of venous leg ulcers comparing short stretch bandages, four layer bandage system, and a long stretch-paste bandage system.wounds 1993; 5: Fletcher A, Cullum N, Sheldon TA. A systematic review of compression treatment for venous leg ulcers. Br Med J 1997; 315: Guest M, Smith JJ, Sira MS, Madden P, Greenhalgh RM, Davies AH. Venous ulcer healing by four-layer compression bandages. Phlebology 1998; 13: Moffatt CJ, Franks PJ, Oldroyd M, Bosanquet N, Brown P, Greenhalgh RM, McCollum CN. Community clinics for leg ulcers and impact on wound healing. Br Med J 1992; 305: Partsch H, Menzinger G, Mostbeck A. Inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. Dermatol Surg 1999; 25: Partsch H. Compression therapy of the legs. J Dermatol Surg Oncol 1991; 17: Partsch H. Compression therapy of venous ulcers. Curr Probl Dermatol 1999; 27: Scriven JM, Bell PRF, Taylor LE, Naylor AR, Wood AJ, London NJM. A prospective randomised trial of four-layer versus short-stretch compression bandages for the treatment of venous leg ulcers.ann R Coll Surg Engl 1998; 80: Simon DA, Freak L, Kinsella M, Walsh J, Lane C, Groarke L. Community leg ulcer clinics: a comparative study in two health authorities. Br Med J 1996; 312: Skene AI, Smith JM, Dore CJ, Charlett A, Lewis JD.Venous leg ulcers: a prognostic index to predict time to healing Br Med J 1992; 305: Veraart JCJM, Daamen E, Neumann HAM. Short stretch versus elastic bandages: effect of time and walking. Phlebologie 1997; 26: Ware J. SF-36 Health Survey, Manual and Interpretation Guide, The Health Institute, New England Medical Center, Boston (1993). Professor H. Partsch, Department of Dermatology, Wilhelminenspital der Stadt Wien, Wien 16, Austria 113