Improving footwear to prevent ulcer recurrence in diabetes: Analysis of adherence and pressure reduction Waaijman, R.

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1 UvA-DARE (Digital Academic Repository) Improving footwear to prevent ulcer recurrence in diabetes: Analysis of adherence and pressure reduction Waaijman, R. Link to publication Citation for published version (APA): Waaijman, R. (2013). Improving footwear to prevent ulcer recurrence in diabetes: Analysis of adherence and pressure reduction General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 04 Dec 2018

2 Improving footwear to prevent ulcer recurrence in diabetes Analysis of adherence and pressure reduction Roelof Waaijman

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4 IMPROVING FOOTWEAR TO PREVENT ULCER RECURRENCE IN DIABETES ANALYSIS OF ADHERENCE AND PRESSURE REDUCTION Roelof Waaijman

5 Waaijman, R. Improving footwear to prevent ulcer recurrence in diabetes. Analysis of adherence and pressure reduction. Academisch proefschrift, Universiteit van Amsterdam. ISBN/EAN Cover design and lay-out by Roelof Waaijman. Printed by Gildeprint Drukkerijen, Enschede. 2013, Roelof Waaijman, The Netherlands. No parts of this thesis may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage and retrieval system, without prior permission from the author.

6 IMPROVING FOOTWEAR TO PREVENT ULCER RECURRENCE IN DIABETES ANALYSIS OF ADHERENCE AND PRESSURE REDUCTION ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op vrijdag 5 juli 2013, te 13:00 uur door Roelof Waaijman geboren te Hengelo

7 Promotiecommissie: Promotor: prof. dr. F. Nollet Co-promotores: dr. S.A. Bus dr. M. de Haart Overige leden: prof. dr. P.M.M. Bossuyt prof. dr. R.W.M. van Deursen prof. dr. C.N. van Dijk prof. dr. K. Postema prof. dr. N.C. Schaper dr. J.G. van Baal Faculteit der Geneeskunde

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9 The DIAbetic Foot Orthopedic Shoe (DIAFOS) trial was financially supported by: The Dutch Diabetes Research Foundation (Diabetes Fonds) The Dutch Foundation for the Development of Orthopedic Footwear Technology (OFOM) The Dutch Organization for Health Research and Development (ZonMW) Department of Rehabilitation, Academic Medical Center Amsterdam Printing of this thesis was financially supported by: Academic Medical Center Amsterdam Roessingh Revalidatie Techniek Anna Fonds George In der Maur orthopedische schoentechniek Penders Voetzorg Biometrics Buchrnhornen Tomorrow Options OIM Orthopedie Livit Orthopedie Novo Nordisk Hanssen footcare

10 CONTENTS Chapter 1 General introduction 9 Chapter 2 The interdependency of peak pressure and pressure-time 23 integral in pressure studies on diabetic footwear: no need to report both parameters. Gait and Posture 2012; 35: 1-5 Chapter 3 New monitoring technology to objectively assess 35 adherence to prescribed footwear and assistive devices during ambulatory activity. Archives of Physical Medicine and Rehabilitation 2012; 93: Chapter 4 Adherence to wearing prescription custom-made footwear 47 in patients with diabetes at high risk for plantar foot ulceration. Diabetes Care 2013; 36: Chapter 5 Pressure-reduction and preservation in custom-made 63 footwear of patients with diabetes and a history of plantar ulceration. Diabetic Medicine 2012; 29: Chapter 6 Effect of custom-made footwear on foot ulcer recurrence 79 in diabetes: a multicenter randomized controlled trial. Submitted Chapter 7 Prognostic factors of plantar foot ulcer recurrence in 97 neuropathic diabetic patients. In preparation Chapter 8 General discussion 115 Summary / Nederlandse samenvatting 129 Dankwoord 137 List of Publications 143 Curriculum vitae / Portfolio 147

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12 1 Chapter 1 GENERAL INTRODUCTION 9

13 Chapter 1 Diabetes mellitus affects more than 366 million people worldwide and its prevalence is expected to rise substantially in the next decade 1. The lifetime incidence of developing an ulcer is as high as 25% in patients with diabetes 2. Ulcers can cause infections, amputations and emotional and physical loss 2, 3. It is believed that every 30 seconds a lower limb is lost somewhere in the world 4 due to diabetes of which 85% is preceded by a foot ulcer 5. Ulcers are a costly complication of diabetes, accounting for approximately one third of the direct healthcare costs associated with diabetes 6. Therefore, diabetic foot ulcers are a major problem in patients with diabetes and the prevention of foot ulcers has a great potential in the individual well-being and public health gain. Patients with a previous plantar foot ulcer often develop a recurrent ulcer It is suggested that the development of a foot ulcer reflects the presence of underlying pathologic conditions, such as micro- and macro-vascular dysfunction, and peripheral nerve damage. Therefore patients with previous ulcers are at high risk for ulcer recurrence 7, 9. One of the strategies used to prevent ulcer recurrence is providing custommade footwear. There are many studies on the effectiveness of custom-made footwear to prevent ulcer recurrence, but the evidence to support this approach is still meagre 13. Since ulcer recurrence is found to be multi-factorial 14, the effectiveness of custom-made footwear needs to be studied in a broader perspective of factors to determine prognostic factors of plantar foot ulcer recurrence. In this introduction, the causes of ulceration are described, followed by a description of the existing evidence on the effectiveness of custom-made footwear and a description of a broad range of possible risk factors for plantar foot ulcer recurrence. Thereafter the approach we took to study the effectiveness of custom-made footwear and prognostic factors of plantar foot ulcer recurrence is described and this chapter will be finalized with the aims and outline of this thesis. CAUSES OF ULCER RECURRENCE The current theory of foot ulcer pathogenesis is that ulcers are caused by a combination of interacting risk factors, the three most relevant being: 1) a previous ulcer; 2) peripheral neuropathy; and 3) increased plantar foot pressures 15. Several studies found an association between having previous ulcers and ulcer recurrence with relative risks between 1.6 and 5.3 in patients with diabetes 7-9, 11. Especially a previous ulcer on the plantar side of the foot increases the risk for ulcer recurrence 12. Peripheral neuropathy is also associated with ulcer occurrence. Odds ratio s of 18 were found in diabetic patients with the inability to sense a 10-gram SWF monofilament 11, 16. Peripheral neuropathy results in loss of protective sensation and is present in half of the diabetic patients with an age above 60 years 17. Due to this inability to sense pressure and pain, high pressures may not be detected and patients continue to walk, which could lead to damage of the skin 18. Also, a more than twofold risk on ulcer recurrence was found in patients with high plantar pressures 11, 19, which could account for the fact that half of the ulcers occur on the plantar side of the foot 20. Thus, high plantar pressures to a neuropathic foot play an important contributing role in ulcer recurrence 11, Furthermore, foot deformities, limited joint mobility and reduced plantar soft tissue thickness result in higher plantar peak pressures 25, 26. Since patients with diabetes and neuropathy often have these abnormalities, their feet often show high peak pressures and are therefore at high risk for ulcer recurrence. 10

14 Introduction 1 PRESSURE, CUSTOM-MADE FOOTWEAR AND ULCER OCCURRENCE Elevated plantar peak pressures are associated with ulcer recurrence 11, 19, 24, 27. To date, the association between plantar peak pressure and ulcer recurrence has only been assessed in barefoot studies. These peak pressures do not fully reflect the biomechanical stress that the patient experiences during the day, because patients do not walk barefoot all day but use footwear most of the time. Therefore, in-shoe peak pressures are also necessary to determine the biomechanical stress on the foot. For that reason, footwear that reduces biomechanical stress on the foot might prevent ulcer recurrence. Custom-made footwear aims to reduce in-shoe plantar peak pressures as compared to confection footwear. Based on this assumption, diabetic foot care-providers currently prescribe patients at high risk for ulceration with custom-made footwear to prevent foot ulceration 15, Despite custom-made footwear, a recent study showed that still 40% of the patients with neuropathy and a previous ulcer developed a recurrent ulcer, in a median 126 days 31. This high recurrence rate indicates that besides foot care, footwear might not (sufficiently) target the relevant risk factors. Possible explanations for this high recurrence rate might be that relieving pressure (offloading) in custom-made footwear is variable 32 or that the prescribed footwear is not worn sufficiently 33. In this regard the quality of the custom-made footwear and patient s adherence to wearing the prescribed footwear are thought to be important prognostic factors. The offloading effect of custom-made footwear is achieved by accommodating the insoles to the foot and the use of special materials and corrective elements in such a way that load from high pressure locations is redistributed to low pressure locations 34. Cross-sectional studies found that in-shoe plantar peak pressures is reduced in custommade footwear and a longitudinal study demonstrated that the initial pressure reduction can be maintained in the first 6 months, but these studies did not follow-up the patients to evaluate ulcer outcome Prospective studies show conflicting results regarding the effectiveness of custom-made footwear to prevent ulcer recurrence. Several non-randomized longitudinal studies have found that ulcer recurrence rates were much lower in patients wearing custom-made footwear compared to patients wearing their own shoes 33, However, a randomized controlled trial found no beneficial effect of specialized footwear on foot ulcer recurrence rate 44. In none of these longitudinal studies on ulcer recurrence the in-shoe plantar pressures were measured, and therefore, the effectiveness of footwear in pressure relief is unknown. Therefore, it remains unclear if the conflicting results of these studies can be explained by differences in pressurerelieving quality of the different footwear used or by other factors. Furthermore, these longitudinal studies had several other limitations: 1) patients were not always representative of the appropriate high risk population: not all patients had neuropathy and often patients with amputations and major foot deformities were excluded; 2) not all studies randomized the patients to an intervention group, or there was cross-over between study groups; 3) the definition of the primary ulcer outcome was often unclear, unreliable or very conservative and only one study assessed adherence to wearing the studied footwear subjectively. In view of this, two systematic reviews concluded that there is still no compelling evidence on the effectiveness of therapeutic footwear in preventing ulcer recurrence 13,

15 Chapter 1 PROGNOSTIC RISK FACTORS OF ULCER RECURRENCE Elevated dynamic barefoot plantar pressure during walking is, in the presence of neuropathy, an important predictor of diabetic foot ulceration. One biomechanical study found the most optimal barefoot peak pressure cut-off level, 700kPa, to be 70% sensitive and 65% specific for ulceration 46, while another study found a barefoot peak pressure of 875kPa to be 64% sensitive and 46% specific 27. These findings indicate that a significant number of patients develop a recurrent ulcer despite lower pressure than threshold and patients do not develop an ulcer despite higher pressures than threshold. These results suggest that ulcer recurrence can not be predicted solely based on barefoot pressure and predictions may be improved by taking other prognostic factors into account. Possible prognostic factors can be divided biomechanical, behavioural, and disease-related factors 14. The main factors of interest in this thesis are discussed below. Biomechanical factors Biomechanical stress parameter One of the risk factors of ulcer recurrence is biomechanical stress on the plantar side of the foot. Often used indicators of biomechanical stress are plantar pressure and peak pressure-time integral. Maximum peak pressure represents the maximum measured pressure of a defined region during one step cycle. Peak pressure-time integral integrates the peak pressure to the time duration of one step cycle. Although both parameters are often reported, specific conclusions per parameter are not usually reported, suggesting that these parameters may be interchangeable 47. A study that explores the association between maximum peak pressure and pressure-time integral in the diabetic foot is needed to further explore whether or not these parameters are interchangeable. Barefoot pressure Foot deformities, minor amputation, limited joint mobility, major callus and reduced plantar soft tissue thickness frequently occur in diabetic patients and all result in increased plantar foot pressures 25, 26, Several studies assessed the association between barefoot plantar peak pressure and ulcer occurrence and found that elevated barefoot plantar peak pressure is predictive for ulcer occurrence in diabetic patients with neuropathy 11, 19, 24, 27. As mentioned before, the defined pressure thresholds in these studies showed a low sensitivity and specificity. It is unlikely that these patients walk barefoot all day. Adherence determines the amount of steps the patient wears (protective) footwear. Furthermore, these patients show variation in the level of ambulant activity 51. Therefore, an approximation of the true biomechanical stress on the plantar side of the foot might be improved when in-shoe pressures, adherence and ambulant activity are taken into account in combination with barefoot pressures. This suggests that the prediction of plantar foot ulceration can be more precise when more factors are included to estimate the biomechanical stress. In-shoe plantar pressure in custom-made footwear Inappropriate footwear has been reported to be the root cause of 21-76% of diabetic foot ulcers and/or amputations 52. It is said, for example, that inappropriate footwear is too tight or that the insole is too stiff. With these facts in mind, many care-providers 12

16 Introduction 1 in clinical practise prescribe custom-made footwear in the belief that such footwear reduces plantar peak pressures and thereby reduce the incidence of foot ulceration. However, the evidence base for such a view is unclear. Currently, prescription of custom-made footwear is primarily based on clinical expertise and the effectiveness of this footwear is most often evaluated on whether the patient remains free of ulceration. Regular objective evaluation of peak pressures in custom-made footwear is not being done. Due to the presence of peripheral neuropathy, the patient s feedback on pressure, pain and comfort is limited. Therefore, variability exists in the offloading properties of this footwear 32, 34. This variability in offloading may explain the high recurrence rates of ulceration 31. Offloading may be improved by modifying footwear after it has been delivered to the patient, using objective measurement tools. In-shoe plantar pressure analysis is such a tool that can efficiently guide footwear modification to create better offloading properties, although studied in a relatively small and heterogeneous group of patients 53. Furthermore, wear and tear of footwear or progress of foot deformities may alter the pressure offloading over time, requiring repeated footwear modifications over time. Therefore a study that explores the effect of improving offloading guided by in-shoe pressure analyses and the course of peak pressure over time in a large homogenous group of high-risk patients and footwear conditions is needed. Behavioural factors Adherence to footwear use To effectively contribute to the prevention of ulcer recurrence, custom-made footwear should be worn by the patient, in particular when being ambulant 54. An observational study reported that half of the ulcer recurrence can be prevented when therapeutic footwear was worn more than 60% of the daytime 33. But, studies in which footwear use was self-reported have shown that only 22-36% of patients with diabetes wear their prescribed footwear regularly (>80% of the day) 55, 56. This indicates that many patients do not wear their therapeutic footwear as intended, elevating the risk of ulcer recurrence. Furthermore, to date, footwear adherence has been measured subjectively and might therefore be less accurate and reliable than objective methods. Therefore, data on footwear adherence in patients who have diabetes and are at high risk for ulceration should be measured objectively, but these methods have until recently been unavailable. Having these data and knowing what determines footwear use is valuable in addressing issues of footwear effectiveness. Ambulant activity Apart from plantar foot pressure and adherence, other factors such as the type and intensity of daily ambulant activity might determine clinical outcome, since the amount of weight-bearing activity is likely to influence the amount of mechanical stress accumulated by plantar tissues 57. So far, evidence for the relation between ambulant activity and ulcer recurrence is unclear. Several studies assessed daily weight-bearing activity, but none found that increased activity was associated with ulcer occurrence 51, However, increased intra-individual day to day variability in activity was associated with ulcer recurrence 51. Furthermore, weight-bearing activity in combination with plantar pressures is suggested to predict ulcer recurrence 60. The number of steps taken during the day and the applied biomechanical stress during each step determines the accumu- 13

17 Chapter 1 lated stress on the foot. This accumulated stress was surprisingly lower in patients who had previous ulcers 60, 61. In these previous studies on accumulated stress, adherence to wearing footwear was not taken into account and accumulated stress was calculated as if the patients wore the footwear in each step, which seems unlikely. Therefore, as mentioned before, information on ambulant activity in relation to footwear adherence, barefoot peak pressures, and in-shoe peak pressures might result in an improved estimate of the accumulated stress, with improved prediction of ulcer recurrence. Patient and disease-related factors Besides the above mentioned biomechanical and behavioural factors, several studies have identified many significant patient and disease-related risk factors for diabetic foot ulceration 7-12, 62, 63. These factors include age, gender, BMI, degree of peripheral neuropathy, peripheral arterial disease, diabetes type and duration, history of ulceration, Hb1Ac, deformities and minor lesions (callus, hematoma, blisters). These patient and disease-related factors might mediate or moderate the relation between biomechanical and behavioural factors and ulcer outcome, and therefore they are important to examine. For that reason these parameters should be integrated in a broader perspective to study their influence on ulcer recurrence in relation to other risk factors. THE DIABETIC FOOT ORTHOPAEDIC SHOE TRIAL To increase knowledge on the effect of plantar foot pressure and custom-made footwear on plantar foot ulcer recurrence, the DIAFOS trial was conducted. DIAFOS (the DIAbetic Foot Orthopaedic Shoe trial; Dutch trial register NTR1091) is a multicenter randomized controlled trial, in which the effectiveness of offloading-improved custom-made footwear in comparison with non-improved custom-made footwear on plantar foot ulcer recurrence in diabetic patients with neuropathy and a previous ulcer was studied. In this study, the Academic Medical Centre in Amsterdam collaborated with 9 other multidisciplinary diabetic foot centres and 9 orthopaedic footwear companies in the Netherlands. Patients in the intervention group were provided with custom-made footwear that was improved in its offloading capacity using in-shoe plantar pressure measurements as guidance tool for footwear modifications. Since the offloading properties of this footwear might be affected over time due to wear and tear or an altered foot shape, each 3 months a follow-up visit was scheduled so that adjustments could be made to ensure improved offloading. In the control group, patients received custom-made footwear that was prescribed following normal clinical practice, in which in-shoe pressure measurements were not used to improve offloading of the footwear. This footwear was also monitored for pressure each 3 months. Additionally, we measured many other parameters in addition to foot pressure to gain further insight in prognostic risk factors of ulcer recurrence. These data provided us with more insight in the biomechanical stress applied to the foot in combination with adherence to wearing prescribed footwear use and ambulatory weight-bearing activity (e.g. walking) 14. In summary, the review of the literature shows that ulcer recurrence is a major problem in patients with a diabetic foot. Several studies have explored causal pathways and elaborated on prognostic factors of ulcer recurrence. These studies led to screening tools to identify patients at risk and interventions with the goal to prevent ulcer recurrence. One of the interventions that is often used is prescription of custom-made footwear, 14

18 Introduction 1 because there is an almost universal clinical opinion that this intervention is effective 52. However, intervention studies show conflicting results in this matter. None of the prospective studies on ulcer recurrence measured the offloading properties of prescribed footwear and none of the studies measured adherence to wearing this footwear objectively. With the use of in-shoe pressure analysis we can evaluate, improve, and preserve pressure offloading of prescribed footwear. Furthermore, by applying new quantitative technologies, adherence to footwear use and ambulant activity can be measured in an objective way. With these technologies, a wide range of biomechanical, behavioural, and patient- and disease-related prognostic factors of ulcer recurrence can be assessed which so far have remained underexposed. Therefore, the goal of the DIAFOS project was to study the effectiveness of offloading-improved custom-made footwear in a longitudinal multicenter randomized controlled trial that includes objectively measured peak pressures, adherence to wearing custom-made footwear and ambulant activity. AIMS OF THIS THESIS The aims of this thesis were to select the most appropriate biomechanical stress parameter to use in pressure studies on the diabetic foot, to evaluate the use of foot pressure analysis to modify footwear, to develop a method to measure adherence and to assess adherence to wearing custom-made footwear objectively in these patients. These studies will form the basis of the main aims of this thesis, which are: assessing the effectiveness of pressure-improved custom-made footwear on plantar foot ulcer recurrence and to expand the body of knowledge on the predictive value of a broad range of biomechanical, behavioural, and patient and disease-related factors on plantar foot ulcer recurrence in diabetic patients with neuropathy and a previously healed plantar foot ulcer. More specifically, the objectives of this thesis are: 1. To explore the interdependency of maximal peak pressure and pressure-time integral in diabetic patients wearing different types of footwear. 2. To assess the validity and feasibility of a new temperature-based adherence monitor to measure adherence of wearing different types of footwear. 3. To assess objectively measured adherence to wearing prescribed custom-made footwear during ambulant activity. 4. To assess the value of using in-shoe plantar pressure analysis for evaluating, improving and maintaining the offloading properties of newly prescribed custom-made footwear. 5. To assess if offloading-improved custom-made footwear reduces recurrence of plantar ulcers. 6. To assess the prognostic value of biomechanical, behavioural, and patient and disease-related factors on plantar foot ulcer recurrence. OUTLINE OF THIS THESIS Chapter 2 presents a study that explores the association between maximum peak pressure and pressure time integral. The results of this study guided us to select the most appropriate parameter to be used for the subsequent studies. 15

19 Chapter 1 In chapter 3 a study in which the validity and feasibility of a new sensor that measures adherence to wearing footwear in an objective way, was tested. With this technology we assessed adherence to wearing prescribed custom-made footwear in diabetic patients with neuropathy and a previous ulcer. The study results are described in chapter 4. Chapter 5 assesses the value of using in-shoe plantar pressure analysis to evaluate, improve and preserve the offloading properties of newly prescribed custom-made footwear. Whether this approach was effective in preventing plantar foot ulcer recurrence in diabetic patients was studied in a multicenter randomized controlled trail of which the results are described in chapter 6. In chapter 7 a study is described in which the prognostic value of a broad range of biomechanical, behavioural, and patient- and disease-related factors on plantar diabetic foot ulcer recurrence was assessed in order to explore risk factors for ulcer recurrence. Finally, in chapter 8 the main findings of this thesis are presented and some methodological considerations are discussed. Additionally, the clinical implications of these studies and some recommendations for further research together with an overall conclusion is described. 16

20 Introduction 1 REFERENCES 1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and Diabetes Res Clin Pract 2011; 94: Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA. Risk factors for foot infections in individuals with diabetes. Diabetes Care 2006; 29: Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2005; 366: Reiber GE. The epidemiology of diabetic foot problems. Diabet Med 1996; 13 Suppl 1: S Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Vasc Surg 2010; 52: 17S-22S. 7. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ER, Whalley AM, Widdows P, Williamson S, Boulton AJ. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 2002; 19: Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG. A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care 1999; 22: Boyko EJ, Ahroni JH, Cohen V, Nelson KM, Heagerty PJ. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care 2006; 29: Muller IS, de Grauw WJ, van Gerwen WH, Bartelink ML, van Den Hoogen HJ, Rutten GE. Foot ulceration and lower limb amputation in type 2 diabetic patients in dutch primary health care. Diabetes Care 2002; 25: Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23: Dubsky M, Jirkovska A, Bem R, Fejfarova V, Skibova J, Schaper NC, Lipsky BA. Risk factors for recurrence of diabetic foot ulcers: prospective follow-up analysis of a Eurodiale subgroup. Int Wound J Maciejewski ML, Reiber GE, Smith DG, Wallace C, Hayes S, Boyko EJ. Effectiveness of diabetic therapeutic footwear in preventing reulceration. Diabetes Care 2004; 27: Bus SA. Priorities in offloading the diabetic foot. Diabetes Metab Res Rev 2012; 28 Suppl 1: Bakker K, Apelqvist J, Schaper NC. Practical guidelines on the management and prevention of the diabetic foot Diabetes Metab Res Rev 2012; 28 Suppl 1: McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, Pecoraro RF. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care 1995; 18: Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. 17

21 Chapter 1 18 Diabetologia 1993; 36: Apelqvist J, Bakker K, van Houtum WH, Schaper NC. Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot. Diabetes Metab Res Rev 2008; 24 Suppl 1: S181-S Frykberg RG, Lavery LA, Pham H, Harvey C, Harkless L, Veves A. Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care 1998; 21: Reiber GE, Vileikyte L, Boyko EJ, del AM, Smith DG, Lavery LA, Boulton AJ. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999; 22: Cowley MS, Boyko EJ, Shofer JB, Ahroni JH, Ledoux WR. Foot ulcer risk and location in relation to prospective clinical assessment of foot shape and mobility among persons with diabetes. Diabetes Res Clin Pract 2008; 82: Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, Edmonds M, Holstein P, Jirkovska A, Mauricio D, Ragnarson TG, Reike H, Spraul M, Uccioli L, Urbancic V, Van AK, Van BJ, Van MF, Schaper N. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 2007; 50: Boulton AJ, Hardisty CA, Betts RP, Franks CI, Worth RC, Ward JD, Duckworth T. Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy. Diabetes Care 1983; 6: Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992; 35: Abouaesha F, van Schie CH, Griffths GD, Young RJ, Boulton AJ. Plantar tissue thickness is related to peak plantar pressure in the high-risk diabetic foot. Diabetes Care 2001; 24: Bus SA, Maas M, de LA, Michels RP, Levi M. Elevated plantar pressures in neuropathic diabetic patients with claw/hammer toe deformity. J Biomech 2005; 38: Lavery LA, Armstrong DG, Wunderlich RP, Tredwell J, Boulton AJ. Predictive value of foot pressure assessment as part of a population-based diabetes disease management program. Diabetes Care 2003; 26: Cavanagh PR, Ulbrecht JS, Caputo GM. Biomechanical aspects of diabetic foot disease: aetiology, treatment, and prevention. Diabet Med 1996; 13 Suppl 1: S17-S Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med 2004; 351: Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev 2000; 16 Suppl 1: S75-S Pound N, Chipchase S, Treece K, Game F, Jeffcoate W. Ulcer-free survival following management of foot ulcers in diabetes. Diabet Med 2005; 22: Guldemond NA, Leffers P, Schaper NC, Sanders AP, Nieman FH, Walenkamp GH. Comparison of foot orthoses made by podiatrists, pedorthists and orthotists regarding plantar pressure reduction in The Netherlands. BMC Musculoskelet Disord 2005; 6: Chantelau E, Haage P. An audit of cushioned diabetic footwear: relation to patient compliance. Diabet Med 1994; 11:

22 Introduction Bus SA, Ulbrecht JS, Cavanagh PR. Pressure relief and load redistribution by custom-made insoles in diabetic patients with neuropathy and foot deformity. Clin Biomech 2004; 19: Guldemond NA, Leffers P, Schaper NC, Sanders AP, Nieman F, Willems P, Walenkamp GH. The effects of insole configurations on forefoot plantar pressure and walking convenience in diabetic patients with neuropathic feet. Clin Biomech 2007; 22: Mueller MJ, Lott DJ, Hastings MK, Commean PK, Smith KE, Pilgram TK. Efficacy and mechanism of orthotic devices to unload metatarsal heads in people with diabetes and a history of plantar ulcers. Phys Ther 2006; 86: Praet SF, Louwerens JW. The influence of shoe design on plantar pressures in neuropathic feet. Diabetes Care 2003; 26: Tsung BY, Zhang M, Mak AF, Wong MW. Effectiveness of insoles on plantar pressure redistribution. J Rehabil Res Dev 2004; 41: Bus SA, Valk GD, van Deursen RW, Armstrong DG, Caravaggi C, Hlavacek P, Bakker K, Cavanagh PR. The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Diabetes Metab Res Rev 2008; 24 Suppl 1: S162-S Lobmann R, Kayser R, Kasten G, Kasten U, Kluge K, Neumann W, Lehnert H. Effects of preventative footwear on foot pressure as determined by pedobarography in diabetic patients: a prospective study. Diabet Med 2001; 18: Busch K, Chantelau E. Effectiveness of a new brand of stock diabetic shoes to protect against diabetic foot ulcer relapse. A prospective cohort study. Diabet Med 2003; 20: Uccioli L, Faglia E, Monticone G, Favales F, Durola L, Aldeghi A, Quarantiello A, Calia P, Menzinger G. Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 1995; 18: Dargis V, Pantelejeva O, Jonushaite A, Vileikyte L, Boulton AJ. Benefits of a multidisciplinary approach in the management of recurrent diabetic foot ulceration in Lithuania: a prospective study. Diabetes Care 1999; 22: Reiber GE, Smith DG, Wallace C, Sullivan K, Hayes S, Vath C, Maciejewski ML, Yu O, Heagerty PJ, Lemaster J. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA 2002; 287: Spencer S. Pressure relieving interventions for preventing and treating diabetic foot ulcers. Cochrane Database Syst Rev 2000: CD Armstrong DG, Peters EJ, Athanasiou KA, Lavery LA. Is there a critical level of plantar foot pressure to identify patients at risk for neuropathic foot ulceration? J Foot Ankle Surg 1998; 37: Bus SA, Waaijman R. The value of reporting pressure-time integral data in addition to peak pressure data in studies on the diabetic foot: A systematic review. Clin Biomech 2013; 28: Mueller MJ, Hastings M, Commean PK, Smith KE, Pilgram TK, Robertson D, Johnson J. Forefoot structural predictors of plantar pressures during walking in people with diabetes and peripheral neuropathy. J Biomech 2003; 36: Payne C, Turner D, Miller K. Determinants of plantar pressures in the diabetic foot. J Diabetes Complications 2002; 16:

23 Chapter Pataky Z, Golay A, Faravel L, Da SJ, Makoundou V, Peter-Riesch B, Assal JP. The impact of callosities on the magnitude and duration of plantar pressure in patients with diabetes mellitus. A callus may cause 18,600 kilograms of excess plantar pressure per day. Diabetes Metab 2002; 28: Armstrong DG, Lavery LA, Holtz-Neiderer K, Mohler MJ, Wendel CS, Nixon BP, Boulton AJ. Variability in activity may precede diabetic foot ulceration. Diabetes Care 2004; 27: Cavanagh PR. Therapeutic footwear for people with diabetes. Diabetes Metab Res Rev 2004; 20 Suppl 1: S51-S Bus SA, Haspels R, Busch-Westbroek TE. Evaluation and optimization of therapeutic footwear for neuropathic diabetic foot patients using in-shoe plantar pressure analysis. Diabetes Care 2011; 34: Connor H, Mahdi OZ. Repetitive ulceration in neuropathic patients. Diabetes Metab Res Rev 2004; 20 Suppl 1: S23-S Knowles EA, Boulton AJ. Do people with diabetes wear their prescribed footwear? Diabet Med 1996; 13: McCabe CJ, Stevenson RC, Dolan AM. Evaluation of a diabetic foot screening and protection programme. Diabet Med 1998; 15: Cavanagh PR, Ulbrecht JS, Caputo GM. Biomechanical aspects of diabetic foot disease: aetiology, treatment, and prevention. Diabet Med 1996; 13 Suppl 1: S17-S Lemaster JW, Reiber GE, Smith DG, Heagerty PJ, Wallace C. Daily weight-bearing activity does not increase the risk of diabetic foot ulcers. Med Sci Sports Exerc 2003; 35: Lemaster JW, Mueller MJ, Reiber GE, Mehr DR, Madsen RW, Conn VS. Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Phys Ther 2008; 88: Maluf KS, Mueller MJ. Novel Award Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers. Clin Biomech 2003; 18: Lott DJ, Maluf KS, Sinacore DR, Mueller MJ. Relationship between changes in activity and plantar ulcer recurrence in a patient with diabetes mellitus. Phys Ther 2005; 85: Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic patients with foot ulcers. J Intern Med 1993; 233: Monteiro-Soares M, Boyko E, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Predictive factors for diabetic foot ulceration: a systematic review. Diabetes Metab Res Rev

24 Introduction 1 21

25 2 22

26 Chapter 2 2 THE INTERDEPENDENCY OF PEAK PRESSURE AND PRES- SURE-TIME INTEGRAL IN PRESSURE STUDIES ON DIABE- TIC FOOTWEAR: NO NEED TO REPORT BOTH PARAMETERS Gait and Posture 2012; 35: 1-5 Reprinted with permission from Elsevier Roelof Waaijman Sicco A. Bus 23

27 Chapter 2 ABSTRACT Background: In plantar pressure studies on diabetic footwear, both the maximum peak pressure (MPP) and peak pressure-time integral (PTI) are often reported. However, specific conclusions for each parameter are not commonly reported, suggesting these parameters may be interchangeable. The aim was to explore the interdependency of MPP and PTI in diabetic patients wearing different types of footwear. Methods: In-shoe plantar pressure was measured in 69 neuropathic diabetic patients who walked in custom made footwear, forefoot offloading shoes, cast shoes, and/or standard footwear. For each of six anatomical foot regions, correlation coefficients were calculated between MPP and PTI. To assess parameter congruency, the percentage of patients showing correlation coefficients > 0.7 or coefficients of variation for both MPP and PTI < 10%, was calculated. Results: Across all footwear conditions, MPP and PTI were highly correlated in the forefoot and midfoot (r > 0.78 in all but one foot region in one footwear condition). Lower correlations coefficients were found in the rearfoot (r = ). Across regions, between 46% and 87% of patients (mean 72%) showed parameter congruency in the forefoot and midfoot. Conclusions: The results showed that the MPP and PTI are highly interdependent in those foot regions most at risk for plantar ulceration in patients wearing commonly prescribed footwear. Since MPP has been shown to date to be the clinically more relevant parameter of the two, these results suggest that the value of reporting PTI in addition to MPP in the same diabetic footwear study is small. 24

28 Interdependency of peak pressure and pressure-time integral INTRODUCTION In-shoe plantar pressure assessment is becoming increasingly popular in both research and clinical practice to evaluate the effects of prescribed footwear in diabetic patients who have a foot ulcer or who are at risk for ulceration. Foot ulcers are a serious problem, with a life-time prevalence of 15-25% in the diabetic population 1. These ulcers can lead to infection and lower limb amputation, with 85% of all non-traumatic amputations in diabetes being preceded by a foot ulcer 2. In the presence of loss of protective sensation due to peripheral neuropathy, the majority of plantar foot ulcers develop as a result of the repetitive action of increased mechanical stress (i.e. pressure) on the foot during ambulation 3. The goal of prescribed footwear is to lower these pressures in order to heal a plantar foot ulcer or to prevent it from (re)occurring. 2 In pressure studies on diabetic footwear, often multiple pressure parameters are reported. The maximum peak pressure (MPP) is almost always reported, likely because both in retrospective and prospective studies, diabetic foot ulceration has been associated with the presence of elevated MPP 3-6. A significant odds ratio of 3.2 has been found 7. The peak pressure-time integral (PTI) is also often reported. The PTI has also been associated with foot ulceration, but this association has not yet been demonstrated in a prospective analysis Recently, a systematic review of the diabetic foot literature from our group showed that in the majority of studies collecting both MPP and PTI data, differences in outcomes between these two parameters were generally small and conclusion were non-specific 11. Also recently, Keijsers et al. 12 found that MPP and PTI were highly interdependent in healthy subjects walking barefoot across a pressure platform. The findings in these studies suggest that these parameters may be interchangeable and the value of reporting both parameters in the same study may be limited. Because of their suggested relevance in diabetic foot ulceration and their suggested interdependency in previous studies, we chose to further explore the association between MPP and PTI in the diabetic foot. The aim of this study was to assess the degree of interdependency of MPP and PTI in foot pressure analyses of neuropathic diabetic patients wearing different types of offloading footwear. We hypothesized that a strong association between these two pressure parameters would suggest that there is no need to report both parameters in the same footwear study. METHODS Subjects A total 69 diabetic patients at risk for foot ulceration were included in this study (60 males, mean (SD) age 60.7 (8.9) years, mean (SD) diabetes duration 17.7 (14.4) years). All patients had loss of protective sensation due to peripheral neuropathy. This was confirmed by the inability to sense the pressure of a 10g monofilament on the plantar hallux, first or fifth metatarsal head or a 25V vibration on the dorsal hallux from a Bio-thesiometer (Bio-Medical Instrument Company, New-bury, OH, USA) 7. Patients had one or more foot deformities, including claw/hammer toes, hallux valgus or rigidus, prominent metatarsal heads, pes cavus, pes planus or Charcot osteoarthropathy, or had 25

29 Chapter 2 experienced a partial foot amputation. Patients were excluded if they had a current foot ulcer, lower-leg amputation, or if they were unable to walk repeatedly unaided over a distance of 12 m. All patients gave their written informed consent for participation in the study, which was approved by the Local Research Ethics Committee. Footwear conditions Patients were measured in four different types of footwear, all ankle-high modalities commonly prescribed for treatment or prevention of plantar foot ulcers in diabetes. The footwear included custom made therapeutic footwear, a cast shoe (Mabal, Almelo, Netherlands), a forefoot offloading shoe (FOS, Rattenhuber Talus, and a standard shoe (Pulman, with flexible outsole and flat insert (Figure 1). Patients wore their therapeutic footwear on both feet. The other footwear conditions were tested on the right foot only (patients wore their own shoe on the left). Not all patients were tested in each footwear condition. A total of 30 patients were tested in the custom made footwear, 24 in the cast shoe, 38 in the forefoot offloading shoe, and 39 in the standard shoe. Figure 1. The four different types of footwear tested in this study: (A) custom made therapeutic footwear, (B) a cast shoe, (C) a forefoot offloading shoe, and (D) a standard shoe. Procedures After a baseline assessment, in which data on health history, neuropathy, and foot deformities was collected, patients were tested in one or more footwear conditions in a laboratory setting. Patients were asked to walk at their comfortable speed along a 12 m long walkway. For each footwear condition, several practice trials were used for the patient to familiarize with the procedures and the footwear tested. The walking speed 26

30 Interdependency of peak pressure and pressure-time integral was measured using a photocell system and was standardized between walking trials within a footwear condition (maximum variation 10%). In-shoe dynamic plantar pressures were measured at 50 Hz sampling rate using the Pedar-X system (Novel, Munich, Germany). This system comprised a matrix of 99 sensors in 2-mm thick capacitance based flexible insoles which were placed between the foot and the insole of the shoe. Six pairs of wide Pedar insoles were available to accommodate each foot size. All insoles were calibrated following guidelines from the manufacturer. A minimum of 20 midgait steps per foot in multiple walking trials were collected in each footwear condition. 2 Figure 2. Peak pressure-time curves shown in the left panes and scatter plots of maximum peak pressure (MPP) versus peak pressure-time integral (PTI) shown in the right panes for two foot regions in one subject: the midfoot and metatarsals 2-5. These figures clarify the two different criteria of congruence used for the individual analysis. The midfoot region shows a high correlation coefficient between MPP and PTI (r > 0.7). The metatarsals 2-5 region shows a low correlation coefficient (r < 0.7), but small coefficients of variation (CV < 10%) for both parameters, indicating a high congruence of peak pressure-time curves from subsequent foot steps. Data analysis In-shoe pressure data was analyzed using Novel software. The first and last step of each trial was automatically excluded by the software to eliminate acceleration and deceleration effects. Only the right foot was analyzed. The foot was divided into six anatomical regions using an automated masking procedure: the rearfoot, midfoot, metatarsal 1, metatarsals 2-5, hallux, and lesser toes. For each foot region the maximum peak pressure (MPP) and the peak pressure-time integral (PTI) were calculated. The MPP is the highest measured pressure in any sensor within a region in one foot step. This is the highest value in the peak pressure-time curve of a particular region. The PTI is the time integral of the peak pressure measured in any sensor within the region during one foot 27

31 Chapter 2 step. This is the area under the peak pressure-time curve of a particular region. Statistical analysis All statistical analyses were performed using SPSS, version 18.0 and Matlab, version R2010b. Data was analyzed at a patient group level and at an individual patient level. For group level analysis, correlation coefficients were calculated between mean MPP and mean PTI. For normally distributed data, Pearson correlations coefficients were computed. For skewed data, Spearman correlations coefficients were calculated. At the individual patient level, correlation coefficients between MPP and PTI were obtained using the values of each single foot step in a pressure measurement. Higher coefficients reflect more interdependency between parameters. However, low correlation coefficients may incorrectly imply that MPP and PTI are not interdependent (i.e. congruent). This may be the case when the MPP versus PTI scatter plot is concentrated within a small value range, something that is expected from in-shoe pressure measurements in which multiple footsteps are taken by a patient and between-step variability is known to be small (Figure 2) 13. To take this into account, the coefficient of variation (= SD / Mean * 100%) over all footsteps was calculated for both the MPP and PTI. If the coefficient of variation was < 10% in both MPP and PTI, these parameters were considered congruent. If the correlation coefficient between MPP and PTI was > 0.7 the parameters were considered interdependent. These two criteria were named the criteria of congruence. Table 1. Mean ± SD results for MPP and PTI expressed for each of the six foot regions and four footwear conditions. MPP Therapeutic footwear Rearfoot Midfoot Metatarsal 1 Metatarsals 2-5 Hallux Lesser toes 193 ± ± ± ± ± ± 76 Cast shoe 168 ± ± ± ± ± ± 71 Forefoot offloading shoe 248 ± ± ± ± ± ± 54 Standard shoe 275 ± ± ± ± ± ± 90 PTI Therapeutic footwear 76 ± ± ± ± ± ± 23 Cast shoe 40 ± 8 39 ± ± ± ± ± 15 Forefoot offloading shoe 61 ± ± ± ± ± ± 17 Standard shoe 66 ± ± ± ± ± ± 32 MPP, maximum peak pressure; PTI, peak pressure-time integral. RESULTS Mean outcomes for MPP and PTI at group level are shown in Table 1. The correlation 28

32 Interdependency of peak pressure and pressure-time integral coefficient between MPP and PTI across all regions and footwear conditions was r = 0.78 (P < 0.01). For each region and condition, significant correlation coefficients were found (Table 2). The highest coefficients were found in the forefoot and midfoot (r = ), the lowest in the rearfoot (r = ). Between footwear conditions, the variation in correlation coefficients was small. 2 Table 2. Correlation coefficients between MPP and PTI for each of the six foot regions and four footwear conditions. Rearfoot Midfoot Metatarsal 1 Metatarsals 2-5 Hallux Lesser toes Therapeutic footwear 0.44* 0.80** 0.85** 0.92** 0.86** 0.82** Cast shoe 0.43* 0.93** 0.82** 0.92** 0.90** 0.92** Forefoot offloading shoe 0.45** 0.82** 0.64** 0.80** 0.81** 0.78** Standard shoe 0.44** 0.90** 0.78** 0.85** 0.81** 0.92** MPP, maximum peak pressure; PTI, peak pressure-time integral. * Significantly correlated at P<0.05. ** Significantly correlated at P<0.01. Table 3. Percentage of patients that reached the criteria of congruence for MPP and PTI expressed in each of the six foot regions and four footwear conditions. Criterion 1* Rearfoot Midfoot Metatarsal 1 Metatarsals 2-5 Hallux Lesser toes Therapeutic footwear 63% 13% 17% 30% 3% 30% Cast shoe 29% 4% 0% 0% 0% 4% Forefoot offloading shoe 37% 32% 16% 42% 3% 8% Standard shoe 28% 5% 21% 41% 5% 21% Criterion 2** Therapeutic footwear 20% 77% 73% 47% 67% 43% Cast shoe 8% 71% 79% 46% 75% 54% Forefoot offloading shoe 21% 58% 74% 29% 84% 74% Standard shoe 18% 62% 54% 31% 67% 44% Criterion 1 or 2 Therapeutic footwear 83% 83% 87% 70% 67% 63% Cast shoe 38% 75% 79% 46% 75% 58% Forefoot offloading shoe 55% 79% 84% 66% 87% 76% Standard shoe 44% 67% 69% 69% 69% 62% MPP, maximum peak pressure; PTI, peak pressure-time integral. * Criterion 1: coefficients of variation in both MPP and PTI < 10%. ** Criterion 2: correlation coefficient between MPP and PTI > 0.7. Results from the individual patient analysis are shown in Table 3. The percentage of 29

33 Chapter 2 patients fulfilling the criteria of congruence ranged from 38% to 87% across regions and conditions. Higher percentages were found in the forefoot and midfoot than in the rearfoot. For the forefoot and midfoot, most patients fulfilled the criteria of congruence based on a calculated correlation coefficient between MPP and PTI of >0.7. For the rearfoot, more patients fulfilled the criteria based on small coefficients of variation (<10%) found in both parameters. DISCUSSION The in-shoe pressure results show that the MPP and PTI are highly interdependent in the four different types of footwear tested in these high-risk diabetic patients. Strong interdependency was found, both at the group and individual patient level, in those regions that are most at risk for plantar ulceration (forefoot and midfoot). At group level, correlation coefficients between MPP and PTI ranged from 0.64 to 0.93 across foot regions and conditions (from 0.78 to 0.93 if the metatarsal 1 region in the forefoot offloading shoe was left out). At the individual patient level, parameter congruency varied across the same regions and conditions between 46% and 83% (mean 72%). Between subjects, these data suggest a high degree of similarity in the shape of the peak pressure-time curves, which may differ only in amplitude and time of contact. Within subjects, the results suggest a high reproducibility of the peak pressure-time curves. These findings suggest that the MPP and PTI are interchangeable parameters and therefore do not seem to have a mutual additional value in the same footwear study. The interdependency of MPP and PTI found in this study is in agreement with findings from recent reports. Our own systematic review of the diabetic foot literature showed that the majority of studies found no or only minimal differences in the pattern and significance of outcomes between reported MPP and PTI data 11. Specific conclusions for each parameter were drawn in a minority of papers. A recent study on dynamic barefoot pressures measured in healthy subjects also showed a strong interdependency between measured MPP and PTI (r = 0.78; same value as in current study) 12. The findings in these previous studies add to the conclusion that the value of reporting one parameter in addition to the other is small. The lowest correlation coefficients were found in the rearfoot. Also the percentage of subjects showing high parameter congruence was lowest in the rearfoot. Similar findings were reported by Keijsers et al. for measured barefoot pressure in healthy subjects 12. Lower correlation coefficients in the rearfoot may be explained by a smaller variability in measured MPP and PTI found between subjects in the rearfoot than in other regions (Table 1). Less scattered data generally leads to lower correlation coefficients. Also, differences in the shape of the normalized peak pressure-time curves may explain these results. Visual inspection of these curves showed more variability in shape for the rearfoot than for the other regions, particularly during mid stance and terminal stance, suggesting that the rollover dynamics of the foot may play a role. Nevertheless, the clinical relevance of finding lower correlation coefficients in the rearfoot is not very high, because pressure related plantar ulcers are rare in this region 2. In cases where the measurement of rearfoot pressures is important, calculating both the MPP and PTI may give a more valuable description. 30

34 Interdependency of peak pressure and pressure-time integral Four different types of footwear were tested in this study to be representative of the range of footwear conditions commonly prescribed to diabetic patients. Two types of custom made and two types of prefabricated shoes were included. Small differences for calculated correlation coefficients and percentages of parameter congruency were found between footwear conditions. This suggests that the interdependency of MPP and PTI is not affected by the type of footwear. Based on these results, we may further speculate that the different design principles incorporated in the tested footwear, such as custom molding, total contact, rocker bottom, and negative heel outsole, do not influence MPP or PTI in such a different way that specific conclusions would be expected. Future pressure studies on the effects of footwear modifications are needed to confirm or refute these hypotheses. 2 Based on the current and previous findings, it seems difficult to determine in which way the PTI may be mediated differently than the MPP. Some factors such as the size of a masked foot region or the speed of walking may play a role. Within one masked region, more than one anatomical structure (e.g. multiple metatarsal heads) can be loaded. This could affect PTI more than MPP, because only for the calculation of PTI multiple sensors within one mask may contribute. With smaller masks, the interdependency between MPP and PTI has been shown to be stronger 12. Speed of walking affects MPP and PTI differently, in particular at low speeds 14, 15. With decreased walking speed, the MPP decreases in a linear fashion, whereas the PTI increases in a non-linear fashion 15. This is not an issue when walking speed is controlled or standardized between tested conditions. However, it may be important when treatment methods enforce a significant decrease in walking speed, such as with the use of a total contact cast for treating plantar foot ulcers in diabetes. In such cases, different conclusions may be drawn based on the PTI data than on the MPP data. More research is needed to determine how these parameters may be influenced differently and how such a difference should be interpreted. The MPP has been shown in both retrospective and prospective studies to be predictive of foot ulceration in diabetes 3-6. Although the PTI has been suggested by several authors to be associated with diabetic foot ulceration, its clinical value has not been proven in prospective analyses. Therefore, we may consider the PTI as the redundant parameter of the two. More practical reasons for preferring the MPP instead of the PTI is that the MPP is more comprehensible, and it is directly interpretable on-screen during measurement. Therefore, until studies demonstrate that the PTI is similarly or more predictive of ulceration than the MPP, it seems sufficient to report only MPP data in diabetic footwear studies. A limitation of the study was that the cut-off levels to define a high correlation coefficient or a good congruency between MPP and PTI were arbitrarily chosen. We considered a correlation coefficient above 0.7 as high because ~50% or more of the variance in one parameter would be explained by the other. The cut-off level of 10% to define small coefficients of variations was based on common sense rather than scientific deduction. Such a percentage indicates a concentrated cloud of dots in the MPP versus PTI scatter plot that may illustrate the congruency between parameters. With a different cut-off level chosen, outcomes may have been different, but conclusions likely would have been similar. Another limitation of the study may be that the results are specific 31

35 Chapter 2 for the calculation method for PTI as defined by the measurement system used in this study (i.e. area under the peak pressure-time curve). Different calculation methods may lead to different results and potentially to different conclusions on the added value of using the PTI. Also as part of a composite parameter, such as in the calculation of daily cumulative tissue stress 16, the value of PTI may be interpreted differently. Additionally, the shape of the peak pressure-time curve that determines the PTI has been shown to distinguish patients with different levels of foot impairment 17. Despite the presence of these different calculation methods and uses of the PTI, the way it is used and analyzed in the current study is the most commonly reported and, therefore, the most representative method to include. CONCLUSION This foot pressure study showed a high interdependency and congruency between the two most reported pressure parameters, the MPP and the PTI, when measured in neuropathic diabetic patients wearing commonly prescribed diabetic footwear. This interdependency was strongest in the foot regions most prone to pressure-related ulcers and was independent of type of footwear tested. These results suggest that the MPP and PTI are interchangeable and that outcomes on each parameter will likely lead to similar conclusions. Until the moment that prospective studies show that the PTI is a better or equally good predictor of diabetic foot ulceration as the MPP, the value of reporting the PTI in addition to the MPP in the same diabetic footwear study seems small. 32

36 Interdependency of peak pressure and pressure-time integral REFERENCES 1. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: Reiber GE, Vileikyte L, Boyko EJ, del AM, Smith DG, Lavery LA, Boulton AJ. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999; 22: Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992; 35: Boulton AJ, Hardisty CA, Betts RP, Franks CI, Worth RC, Ward JD, Duckworth T. Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy. Diabetes Care 1983; 6: Frykberg RG, Lavery LA, Pham H, Harvey C, Harkless L, Veves A. Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care 1998; 21: Kastenbauer T, Sauseng S, Sokol G, Auinger M, Irsigler K. A prospective study of predictors for foot ulceration in type 2 diabetes. J Am Podiatr Med Assoc 2001; 91: Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23: Sauseng S, Kastenbauer T, Sokol G, Irsigler K. Estimation of risk for plantar foot ulceration in diabetic patients with neuropathy. Diabetes Nutr Metab 1999; 12: Shaw JE, Boulton AJM. Pressure time integrals may be more important than peak pressures in diabetic foot ulceration (Abstract). Diabet Med 1996; 13: S Stess RM, Jensen SR, Mirmiran R. The role of dynamic plantar pressures in diabetic foot ulcers. Diabetes Care 1997; 20: Bus SA, Waaijman R. The additional value of reporting pressure-time integral results in foot pressure studies on the diabetic foot. In: Proceedings of the EMED Scientific Meeting 2008, July 2008, Dundee, Scotland, UK; p. 36 [Abstract]. 12. Keijsers NL, Stolwijk NM, Pataky TC. Linear dependence of peak, mean, and pressure-time integral values in plantar pressure images. Gait Posture 2010; 31: Arts ML, Bus SA. Twelve steps per foot are recommended for valid and reliable in-shoe plantar pressure data in neuropathic diabetic patients wearing custom made footwear. Clin Biomech 2011; 26: Hsi WL, Chai HM, Lai JS. Comparison of pressure and time parameters in evaluating diabetic footwear. Am J Phys Med Rehabil 2002; 81: Melai T, Lange de T. Foot loading during different walking speeds: is there a balance between peak pressures and pressure-time integrals? In: Proceedings of the 17 th IVO World Congress for Orthopedic Shoe Technicians, November 2009, The Hague, The Netherlands; p. 67 [Abstract]. 16. Maluf KS, Mueller MJ. Novel Award Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers. Clin Biomech 2003; 18: Giacomozzi C, Martelli F. Peak pressure curve: an effective parameter for early detection of foot functional impairments in diabetic patients. Gait Posture 2006; 23:

37 3 34

38 Chapter 3 NEW MONITORING TECHNOLOGY TO OBJECTIVELY ASSESS ADHERENCE TO PRESCRIBED FOOTWEAR AND ASSISTIVE DEVICES DURING AMBULATORY ACTIVITY 3 Archives of Physical Medicine and Rehabilitation 2012; 93: Reprinted with permission from Elsevier Sicco A. Bus Roelof Waaijman Frans Nollet 35

39 Chapter 3 ABSTRACT Objective: To assess the validity and feasibility of a new temperature-based adherence monitor to measure footwear use. Design: Observational study. Setting: University medical center and participants homes. Participants: Convenience sample of healthy subjects (n = 11) and neuropathic diabetic patients at high risk for foot ulceration (n = 14). Interventions: In healthy subjects, the validity of the in-shoe attached adherence monitor was investigated by comparing its registrations of donning and doffing of footwear during 7 days to an accurately kept log registration. In diabetic patients, the feasibility of using the adherence monitor for seven days in conjunction with a time-synchronized ankle-worn step activity monitor to register prescribed footwear use during walking was assessed. Furthermore, a usability questionnaire was completed. Main Outcome Measures: For validity, the mean time difference and 95% confidence interval (CI) between moments of donning/doffing footwear recorded with the adherence monitor and in the log were calculated. For feasibility, technical performance, usability, and the percentage of steps that the footwear was worn (adherence) were assessed. Results: The mean time difference between the adherence monitor and log recordings was 0.4 minutes (95% CI, min). One erroneous and 2 incomplete recordings were obtained in diabetic patients. Three patients reported discomfort with the step activity monitor, and 4 patients would not favor repeated testing. Patients used their footwear for between 9% and 99% of their walking steps. Conclusions: The adherence monitor shows good validity in measuring when footwear is used or not, and is, together with instrumented monitoring of walking activity, a feasible and objective method to assess treatment adherence. This method can have wide application in clinical practice and research regarding prescribed footwear and other body-worn assistive devices. 36

40 Objective monitoring of footwear use INTRODUCTION In different fields of medicine, patient adherence to prescribed treatment is important to assure treatment efficacy. This includes the use of assistive devices in rehabilitation, such as prescription footwear, removable offloading devices, and upper and lower limb orthoses. In patients with diabetic foot disease, studies have shown that only 22% to 28% of these patients wear their prescribed footwear more than 80% of the daytime 1, 2. Also, in cases of active foot ulceration, diabetic patients may wear their prescribed cast walker only 28% of the steps taken during the day 3. Possibly, this reduced adherence explains the lower efficacy of these devices to heal foot ulcers when compared to nonremovable offloading devices 3, 4. Clearly, nonadherence is a problem in patients with diabetic foot disease. 3 Adherence is traditionally assessed through patient reporting, diary recordings, or by observing wear and tear of the worn device. These subjective or semiquantitative methods, however, lack sensitivity and increase the risk of reporting bias and missing data 5-7. Several objective methods, mostly based on temperature or pressure readings, have previously been developed, in particular for assessment of spine orthosis use in scoliosis patients 5, In offloading treatment of the diabetic foot, accelerometer-based activity monitors have been used for this purpose 3, 11. However, because to their weight and size, these monitors were not intended for use inside footwear. The Department of Medical Technological Innovation and Development of the Academic Medical Centre in Amsterdam developed and manufactured an adherence to treatment monitor, which is small enough to fit inside the patients shoe and potentially can be used with almost any other body worn assistive device. The system incorporates 2 temperature sensors, a data logger, and a battery in the same plastic housing. The adherence monitor can be combined with existing methods of activity monitoring to determine adherence to treatment during weight-bearing ambulatory activity. For the adherence monitor to have wide application in research and clinical practice, it must accurately discriminate between time periods of use and nonuse of the assistive device. This requires sensitive sensors, sufficiently high sample frequencies, multiple day measurements, and protection against loads from the body. Furthermore, the adherence monitor should be safe and easy to use and should measure what it intends to measure, namely treatment adherence. The goal of this study was to assess the validity of the adherence monitor to measure footwear use in healthy subjects and to assess the feasibility of using the adherence monitor together with a step activity monitor in diabetic patients at high-risk for plantar ulceration who wear prescribed footwear. METHODS Study design This proof of principle study was an observational study with a maximum of 7-day follow-up of subjects. 37

41 Chapter 3 Subjects The validity of the adherence monitor was assessed in a convenience sample of wellinstructed healthy subjects to assure accurate log recordings of footwear use. Feasibility was assessed in a convenience sample of diabetic patients at high risk for ulceration, one of the intended groups of users of the system. The diabetic patients were measured in a patient care setting. After examination of the study description, the local ethics committee waived the requirement for ethical review of the study under the Medical Research Involving Human Subjects Act in the Netherlands. However, informed consent was still obtained from participating subjects. Adherence monitor The adherence to treatment monitor (@monitor) is a temperature-based monitoring system and is shown in Figure 1. measures 35x15x5 mm (length x width x height). It consists of a plastic housing integrating a digital-to-digital temperature sensors on each of the largest flat sides of a battery, and a data logger. The temperature sensors measure ambient temperature with a resolution of C. Sample frequency can be set at a maximum of 1 sample per minute and a minimum of 1 sample per 30 minutes. The data logger stores data from 14 to 300 days of recording, dependent on sample frequency. The life of the 2.5-V battery varies between 40 and 150 days, dependent on sample frequency and ambient temperature. is attached to the inner surface of the body-worn assistive device (footwear, upper limb or lower limb orthosis), which means that 1 of the 2 sensors of is close to the skin. By measuring the temperature difference across the 2 sensors, with DT non-use DT use, the use of the assistive device is determined. Using a docking station and custom software, start date and time, number of days of data collection, and sample frequency are defined. At readout after data collection, the temperatures from both temperature sensors for each time sample are exported to a text file for further analysis. can be used as a stand-alone monitor to assess the duration of use of the assistive device, or combined with a step activity monitor to specifically determine use during ambulation, which is of primary interest in diabetic patients who wear prescribed footwear in order to reduce risk of ulceration caused by repetitive loading of the foot. Testing protocol Healthy subjects wore low-cut or bottine shoes (Oxford style, canvas, sport) or high boots; patients wore fully or semicustomized footwear with a low, bottine or high shaft. Eight prototypes of were used and set to the maximum frequency of 1 sample per minute. was placed in a plastazote foam pad with trimmed edges to avoid excessive pressure on the skin or (see Figure 1). One thin layer of adhesive tape was placed over and pad to avoid it dropping into the shoe. The pad was taped to the inner surface of the lateral shoe border using adhesive athletic tape, at a level just distal to the lateral malleolus. One of the shoes was fitted with was initialized to start recording before it was inserted in the shoe to help event recognition (shoe on/off) in data analysis. 38

42 Objective monitoring of footwear use 3 Figure 1. (A) (B) which is fitted inside a plastazote foam pad, (C) covered with a thin layer of cellophane tape to prevent it from falling out, and (D) then taped to the inner surface of the shoe using adhesive athletic tape, at a level just distal to the lateral malleolus. The healthy subjects were instructed to don/doff their shoes several times while wearing for 1 day in a climate controlled hospital setting. Subjects kept a record of the exact time moments (1-minute resolution) of these events in a log using a digital clock that was time synchronized with the internal clock of the PC from which was initialized. A subset of healthy subjects were instructed to wear between 4 and 7 days, again recording the exact time moments of donning/ doffing their shoes in a log. The diabetic patients were tested with in their prescription footwear for a 7-day period. Patients additionally wore a step activity monitor (Stepwatch) a around the ankle to assess walking activity. The step activity monitor was initialized on the same PC as and measurement accuracy was optimized by personalizing body height, body mass and type of gait (normal, fast, slow). These personal settings were confirmed to be correct by a light on the step activity monitor that flashed with each of the first 40 steps taken by the subject. Patients were instructed to wear the activity monitor at all times except when taking a bath or shower but including time spent in bed to catch any ambulatory activity at night. They were also instructed to complete a daily diary for periods of sleeping, riding a bicycle, being away from home and for not wearing the step activity monitor, if this occurred. After testing, patients returned step activity monitor, and diary via postal mail or at their next clinic visit, 39

43 Chapter 3 whichever came first. To assess usability with and step activity monitor, patients completed a short questionnaire after data collection addressing complications or practical issues encountered during the 7 days of monitoring. Data analysis Using custom MATLAB software b, the data were checked for completeness and errors. The readouts from the 2 temperature sensors of were normalized to each other using the temperature offset measured in the first few samples of registration (shoe off). To assess the cutoff point for shoes being on or off, first the average temperature difference between both temperature sensors was calculated in all samples that showed a 0.3 C difference. Subsequently, the shoes were classified as being worn when the temperature difference between sensors in a sample was >25% of this average temperature difference, and not worn when the difference was <25%. This 25% cutoff level was defined based on pilot tests. Validity of was assessed for 1-day and multiple-day recordings in the healthy subjects. For this purpose, the time instances for donning and doffing the shoes were compared to the log recorded time instances using descriptive analyses in SPSS (version 16.0) c. The mean difference and log readings and the 95% confidence interval (CI) of this mean difference was calculated to assess the limits of agreement between the 2 methods 12. These mean time differences were compared between donning and doffing using independent sample t tests with a significance level of P = Using the same tests, mean temperature differences from were compared between study groups. If in the diabetic patients less than 4 days were recorded by either or step activity monitor, data collection was considered a failure. Readouts of and step activity monitor were matched on date and time using MATLAB software. Periods of reported cycling (7% of total number of steps in the study) were filtered in the data, because we were only interested in weight-bearing ambulatory activity. Periods of reported nonuse of the step activity monitor were also filtered. For each day of data collection, the number of steps taken and the total time in hours that the footwear was worn were calculated. Adherence was calculated as the percentage of daily steps that the prescribed footwear was worn by the patient and averaged over the number of data collection days (range, 0%-100%). RESULTS Eleven healthy subjects (8 men, 3 women, mean age ± SD, 42.0±9.4y) and 14 diabetic patients (11 men, 3 women, mean age ± SD 56.2±12.9y) with peripheral neuropathy, foot deformity, and a history of plantar foot ulceration were tested. A total 62 events (donning and doffing of shoes) were registered in the 1-day recordings of the 11 healthy subjects. The mean time difference in minutes between and log recordings was 0.0 minutes (95% CI, -0.2 to 0.3min). For donning alone, this was -0.3 minutes (95% CI, -0.6 to 0.0min). For doffing, this was 0.3 minutes (95% CI, -0.1 to 0.7min). Mean time differences were significantly different between donning and 40

44 Objective monitoring of footwear use doffing (P < 0.05). In 30 of 62 events, the time difference and log recordings was 0 minutes, in 24 events plus or minus 1 minute, in 7 events plus or minus 2 minutes, and in one event 3 minutes. Multiple-day recordings in a subset of 7 healthy subjects lasted on average 6.3±1.1 days. A total 108 events (donning and doffing of shoes) were registered. The mean time difference in minutes and log recordings was 0.4 minutes (95% CI, 0.2 to 0.6min), for donning alone, this was 0.1 (95% CI, -0.1 to 0.3min). For doffing alone, this was 0.8 (95% CI, 0.5 to 1.0min). Mean time differences were significantly different between donning and doffing (P<.001). In 56 of the 108 events, the time difference and log recordings was 0 minutes, in 40 events plus or minus 1 minute, in 9 events plus or minus 2 minutes, and in one event each 3, 4, and 5 minutes. 3 The average temperature difference measured from while wearing footwear was a mean ± SD 1.5 C±0.3 C (range, ) in the healthy subjects, and a mean ± SD of 1.8 C±0.6 C (range, ) in the diabetic patients. This difference was not significantly different between groups (P=.30). Figure 2. Example readout of temperature and activity data for 1 subject during 1 day of recording. On the horizontal axis is time of day. Dotted and dashed line curves show the raw temperature data from both temperature sensors of Continued line curve shows the temperature difference between sensors after offset correction. The vertical spikes show the weight-bearing activity data from the step activity monitor expressed in number of steps per minute. The straight horizontal lines show the periods that the shoes were on and off after data analysis. In this subject, shoes were worn between and hours and between and hours, but not during activity between 8.00 and hours. 41

45 Chapter 3 Data from 3 diabetic subjects were excluded from analysis. One recording in a patient with showed an error, and from 2 patients less than 4 days of step activity monitor data were collected because these patients removed the step activity monitor and forgot to put it back on. Figure 2 shows a graphical presentation of temperature and activity data in 1 patient. The mean number of daily steps ± SD in the group of diabetic patients was 8294±4794. Patients wore their prescribed footwear on average 8.5 hours per day. Adherence ranged from 9% to 99% across patients. Eleven out of 14 patients documented time spent away from home. Figure 3 shows an example report of adherence constructed from step activity monitor, and diary data. None of the healthy subjects reported any irritation or discomfort from wearing monitor in the shoe. Eleven of the diabetic patients did not encounter any discomfort from wearing or step activity monitor; 3 patients reported discomfort with wearing the step activity monitor. Skin complications were not encountered. Two patients reported difficulty with removing the foam pad with from the inner shoe, 2 others reported glue remains after removal. Two patients forgot to return and step activity monitor to the clinic. When asked about willingness to wear the monitors for repeated testing in the future, 10 patients had no objection. Four patients did not favor repeated testing; in 3 this concerned wearing the step activity monitor. Figure 3. Example data showing adherence over a 7-day period for 1 of the diabetic patients in the study. Adherence data are expressed as percentage of steps that the patient wears the prescribed footwear. Data are shown for overall adherence, adherence at home, and adherence away from home. The dashed horizontal line represents the average adherence over 7 days. Shown are also the average number of steps per day and the at-home activity ratio (= number of steps at home/ total number of steps). DISCUSSION Adherence to treatment is an important factor that affects the efficacy of treatment. The results of this study show that as an objective monitoring tool, provided valid and feasible data on adherence to wearing footwear. showed no under- or overestimation for instances of donning/doffing for the 1-day recordings, and only 0.4 minutes overestimation for the multiple-day recordings. Instances of doffing shoes were overestimated with respect to donning shoes, which can be corrected by adjusting the cutoff level in the calculation algorithm. In any case, all 95% CIs were small (within 1 minute). The recordings with and step activity monitor in the 42

46 Objective monitoring of footwear use diabetic patient group were of good quality (only 1 error) and mostly complete (only 2 < 4-day recordings). Data on treatment adherence could be obtained. There were few issues with usability, and the majority of patients had no objection to repeated testing. These valid and feasible data suggest that is a valuable system for obtaining objective data on footwear adherence. is the first documented objective adherence monitoring system for use with footwear. Hunter et al. 9 tested temperature and pressure sensors for monitoring spinal orthoses use and found a weak association between monitor and log recordings (r = ) together with a large over- or underestimation of total wearing time (4-38min). Validity can be greatly improved when multiple pressure sensors are used at once 10. The use of off-the-shelf accelerometer-based activity monitors showed good correspondence with log recordings (intraclass correlation coefficient =.93) for assessing the use of removable cast walkers 3, 11. The highly accurate outcomes in the current study may be explained by the fact that not just temperature, but temperature difference between the 2 temperature sensors of was measured. This may improve sensitivity to temperature change when the device comes in contact with the body and limits the influence of normal variation in ambient temperature. monitor validity was not assessed in the diabetic patients, the measured temperature differences between the temperature sensors during recording (mean 1.8 C) were comparable to the healthy subject group (mean 1.5 C), which suggests a high sensitivity for defining shoes on/off in diabetic patients. A practical advantage of is that it is small and lightweight. This supports the use of not only in prescribed footwear, but also in upper and lower limb orthoses that often allow only limited space between the device and the skin. 3 One of showed an error resulting in loss of data that we have encountered occasionally (~5% of cases) in other measurements that we have performed to date with (unpublished data, patient care data and Netherlands Trial Register 1091 study data, ). Presumably, the failure is due to contact loss of the battery because of above-threshold mechanical pressure on which depletes battery energy. Strengthening the plastic housing of or improving the absorbing properties of the foam pad in which is placed may solve this issue. A more common issue that can cause incomplete data for treatment adherence is the removal or incorrect placement of the step activity monitor by the patient. This may be avoided by making the step activity monitor nonremovable (the StepWatch is waterproof), or by sending text message alerts during data collection. Another aspect that may bias data is that cycling activity can not be automatically filtered from ambulatory activity in the StepWatch data, necessitating its recording in a diary, which is more prone to errors or missing data. Three patients reported discomfort from wearing the step activity monitor by stating: uncomfortable at night in bed or feels like a detention monitor. Four of the 14 diabetic patients were not in favor of repeated testing, but in only 1 patient this concerned showing that this is a user-friendly system that does not limit the patient in daily life activities. Assessing the validity and feasibility of was important for its future application in research and clinical practice. We are currently assessing treatment adher- 43

47 Chapter 3 ence to prescribed footwear in a large group of high-risk diabetic patients (Netherlands Trial Register 1091), which may provide important insight into the role of adherence in ulcer development. Furthermore, determinants of poor adherence can be studied. For these purposes, objective data recording is much more valuable than subjective data recording. For clinical practice, objective recording of adherence could be used to (1) help explain (lack of) treatment efficacy in a given patient, (2) explore reasons for non-adherence, (3) individualize type and frequency of footwear prescriptions, and (4) evaluate educational interventions aimed at improving adherence. It could also be used as a quality assurance method for hospitals and for footwear and insurance companies. Further development may include an adherence reminder system to notify patients when they are active and not wearing the prescribed treatment 13. Crews et al. 13 proposed some potential ethical dilemmas related to who has access to who has access to patient adherence data and for what purpose: Can this be considered an invasion of privacy? Should adherence be factored into determining reimbursement for assistive devices? These dilemmas should be discussed and resolved before implementation. Nevertheless, the potential for the use of objective adherence monitoring is high. Study limitations The study was limited in that validity of was not tested under challenging climate conditions. Therefore, we do not have full knowledge of system performance in all possible environments. We, however, performed measurements in July (summer) and in November (autumn, in The Netherlands), with no difference in performance found between these two months. Furthermore, the highest sample frequency of monitor is 1 sample per minute, which means that when footwear is donned and doffed within a 1-minute interval, this change may not be registered. Such rapid donning and doffing seems, however, unlikely, even when patients get out of bed at night to visit the bathroom. Finally, we only tested in footwear and not in other assistive devices. Space to fit in a total contact device may be a challenge. However, when close contact of with the skin is assured, valid measurements in other assistive devices are expected to be as likely as in footwear. CONCLUSIONS The study showed that valid data can be acquired when using to assess footwear use in healthy subjects, and that together with step activity monitoring, its use is feasible in neuropathic diabetic subjects. Therefore, is a valuable system for objective assessment of treatment adherence to prescribed footwear that can benefit both research and clinical practice. Besides footwear, may have wider application in settings where patients wear removable body worn assistive devices. Suppliers a Orthocare Innovations, 840 Research Pkwy, Ste 200, Oklahoma City, OK b The MathWorks Inc., 3 Apple Hill Dr, Natick, MA c IBM Corp, 1 New Orchard Rd, Armonk, NY

48 Objective monitoring of footwear use REFERENCES 1. Knowles EA, Boulton AJ. Do people with diabetes wear their prescribed footwear? Diabet Med 1996; 13: Macfarlane DJ, Jensen JL. Factors in diabetic footwear compliance. J Am Podiatr Med Assoc 2003; 93: Armstrong DG, Lavery LA, Kimbriel HR, Nixon BP, Boulton AJ. Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure off-loading regimen. Diabetes Care 2003; 26: Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB. Off-loading the diabetic foot wound: a randomized clinical trial. Diabetes Care 2001; 24: Helfenstein A, Lankes M, Ohlert K, Varoga D, Hahne HJ, Ulrich HW, Hassenpflug J. The objective determination of compliance in treatment of adolescent idiopathic scoliosis with spinal orthoses. Spine (Phila Pa 1976) 2006; 31: Hommel KA, Davis CM, Baldassano RN. Objective versus subjective assessment of oral medication adherence in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: LaFleur J, Oderda GM. Methods to measure patient compliance with medication regimens. J Pain Palliat Care Pharmacother 2004; 18: Takemitsu M, Bowen JR, Rahman T, Glutting JJ, Scott CB. Compliance monitoring of brace treatment for patients with idiopathic scoliosis. Spine 2004; 29: Hunter LN, Sison-Williamson M, Mendoza MM, McDonald CM, Molitor F, Mulcahey MJ, Betz RR, Vogel LC, Bagley A. The validity of compliance monitors to assess wearing time of thoracic-lumbar-sacral orthoses in children with spinal cord injury. Spine 2008; 33: Havey R, Gavin T, Patwardhan A, Pawelczak S, Ibrahim K, Andersson GB, Lavender S. A reliable and accurate method for measuring orthosis wearing time. Spine 2002; 27: Crews RT, Armstrong DG, Boulton AJ. A method for assessing off-loading compliance. J Am Podiatr Med Assoc 2009; 99: Altman DG. Practical statistics for medical research. London, UK: Chapman and Hall, Crews RT, Bowling FL, Boulton AJ. Controversies in off-loading: should big brother be watching? Curr Diab Rep 2009; 9:

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50 Chapter 4 ADHERENCE TO WEARING PRESCRIPTION CUSTOM-MADE FOOTWEAR IN PATIENTS WITH DIABETES AT HIGH RISK FOR PLANTAR FOOT ULCERATION Diabetes Care 2013; 36: Reprinted with permission from The American Diabetes Association 4 Roelof Waaijman Renske Keukenkamp Mirjam de Haart Wojtek P. Polomski Frans Nollet Sicco A. Bus 47

51 Chapter 4 ABSTRACT Objective: Prescription custom-made footwear can only be effective in preventing diabetic foot ulcers if worn by the patient. Particularly the high prevalence of recurrent foot ulcers focuses the attention on adherence, for which objective data is non-existing. We objectively assessed adherence in patients with high ulcer recurrence risk and evaluated what determines adherence. Research Design and Methods: In 107 patients with diabetes, neuropathy, a recently healed plantar foot ulcer, and custom-made footwear, footwear use was measured during 7 consecutive days using a shoe-worn temperature-based monitor while simultaneously daily step count was measured using an ankle-worn activity monitor. Patients logged time away from home. Adherence was calculated as the percentage of steps that prescription footwear was worn. Determinants of adherence were evaluated in multivariate linear regression analysis. Results: Adherence was 71 ± 25% (mean ± SD). Adherence at home was 61 ± 32%, over 3959 ± 2594 steps, and away from home 87 ± 26%, over 2604 ± 2507 steps. In 35 patients with low adherence (<60%), adherence at home was 28 ± 24%. Lower BMI, more severe foot deformity, and more appealing footwear were significantly associated with higher adherence. Conclusions: The results show that adherence to wearing custom-made footwear is insufficient, in particular at home where patients exhibit their largest walking activity. This low adherence is a major threat for re-ulceration. These objective findings provide directions for improvement in adherence, which could include prescribing specific offloading footwear for indoors, and set a reference for future comparative research on footwear adherence in diabetes. 48

52 Footwear adherence in diabetic foot patients INTRODUCTION Custom-made footwear is recommended and often prescribed to patients with diabetes, peripheral neuropathy, and foot deformity, to prevent foot ulceration and further complications such as infection and amputation 1. Elevated plantar pressures and illfitting footwear are important risk factors of ulceration 2, 3. Custom-made footwear aims to reduce ulcer risk by reducing foot pressures and providing proper fit 4-6. It is clear that to be effective in ulcer prevention, prescription footwear should be worn by the patient, in particular when being ambulant 7. Because annual ulcer recurrence rates are high, up to 40% found in one study 8-10, poor adherence may be a factor in this outcome. Patient self-report studies show that only 22-36% of diabetic patients with peripheral neuropathy, vascular disease, and/or foot deformity wear their prescription footwear regularly (>80% of the day) 11, 12. This is unfortunate, since it has been shown that ulcer recurrence rate can be substantially reduced when patients adhere to wearing pressure-relieving footwear 13. Non-adherence is therefore a major issue in high-risk diabetic patients that determines clinical outcome. 4 To date, adherence to footwear use has been assessed using subjective methods, including questionnaires, face-to-face interviews, or diaries Subjective methods are known to have issues with accuracy and reliability, and may lead to a response bias or to missing data Furthermore, these methods do not accurately distinguish between active and non-active periods. In removable below-the-knee walkers used for offloading diabetic foot ulcers, adherence was measured objectively 18, but the accelerometerbased sensors used were not developed to fit inside a shoe. Therefore, we use a new adherence to treatment monitoring system developed at the Academic Medical Center in Amsterdam), which is small enough to fit inside the patients shoe and has been proven to be valid and reliable in determining moments of donning/doffing and feasible in use in diabetic foot patients 19. Objective data on footwear adherence in patients who have diabetes and are at high risk for ulceration is not available. Adherence is most appropriately obtained during ambulation, when pressures on the foot are highest. Furthermore, adherence may vary according to where the patient is (at home or away from home) 14, or according to what day of the week or time of day it is. Knowledge about adherence and what determines adherence is valuable in addressing issues of footwear effectiveness and can direct or even reform footwear prescription practice. Therefore, the aim of this study was to objectively assess adherence to wearing prescribed custom-made footwear during ambulation in patients with diabetes at high risk for ulceration, and to assess the determinants of adherence in this patient group. RESEARCH DESIGN AND METHODS Subjects Patients were selected from the database of a randomized controlled trial on custom footwear effectiveness (DIAbetic Foot Orthopedic Shoe [DIAFOS], clinical trial reg. no. NTR1091) in which patients were consecutively recruited from the outpatient multi- 49

53 Chapter 4 disciplinary foot clinics of 10 Dutch hospitals. The first 120 patients in this trial who were assessed for adherence were included in the current study. Inclusion criteria were diagnosed diabetes mellitus, loss of protective sensation as confirmed by 10-g Semmes Weinstein monofilament and vibration perception threshold testing 20, a prior plantar forefoot or midfoot ulcer that healed in the 18 months before inclusion in the trial, and prescription custom-made footwear. Exclusion criteria were bilateral amputation proximal to the tarso-metatarsal joint, non-ambulatory status, unlikelihood to survive 18 months follow-up, and inability to follow the study instructions. Written informed consent was obtained from each patient prior to inclusion in the trial, which was approved by all involved local Research Ethics Committees. Footwear Patients wore fully custom-made footwear (i.e. custom insoles in custom shoes) or semi custom-made footwear (i.e. custom insoles in off-the-shelf extra depth shoes). The footwear was prescribed by a rehabilitation medicine specialist and manufactured by a shoe technician, both experienced in treating diabetic foot patients. Shoes were mostly ankle high or bottine, in some cases tibia high. The footwear generally had a stiffened rubber outsole with roller configuration and multi-density insoles. Instrumentation Data on footwear use was collected using a temperature-based adherence to treatment monitor, which is described in detail elsewhere 19. In short, measures 35x15x5 mm (LxWxH) and integrates two digital-to-digital temperature sensors, one on each flat side of the monitor, a battery, and a data logger. samples temperatures at a maximum 1-minute interval giving a 14-day collection period. is placed in a plastazote foam pad and taped to the inner lateral shoe border, just below ankle level. Only thin adhesive tape (covering and the patient s sock separate from the leg. Because the temperature difference across when wearing the footwear is unequal to the temperature difference when not wearing the footwear, footwear use can be determined. Response of to donning and doffing footwear is immediate, with temperature change present at the next measurement sample. has been shown accurate in determining moments of donning and doffing of footwear (mean 0.4 minutes difference with accurately kept log, 95% CI: 0.2 to 0.6]) and feasible in use by high-risk diabetic patients 19. Using a docking station and custom software, start date and time, number of days of data collection, and sample frequency are defined. Temperature readouts are exported to a text file after data collection. Ambulatory activity was recorded using a step activity monitor (Stepwatch TM, Orthocare Innovations LLC, Oklahoma, United States), which was strapped to the lateral side of the leg above the ankle. The step activity monitor stores the number of steps per minute over a maximum period of 14 days. Measurement accuracy is optimized by personalizing body height and type of gait of the patient (normal, fast, slow) in the settings of the monitor and verified by a light on the monitor that blinks at each of the first 40 steps taken by the patient after initialization. The error between counted steps and measured steps with the StepWatch TM is 0.3%

54 Procedures Footwear adherence in diabetic foot patients At baseline, demographic, socio-economic, disease-related, and foot complication history data were collected and a foot examination was performed. Each patient received brochures and standard verbal information from the researcher on diabetic foot care and the need to wear prescribed footwear as mush as possible, preferably with each step taken. Because of the break-in period of footwear, data on adherence was collected minimally 3 months after footwear delivery. Three months after footwear delivery, perceived footwear aesthetics and comfort were scored on a visual analogue scale using the Questionnaire of Usability Evaluation 22. To avoid change in behavior of the patient during the measurement, patients were informed that foot temperature (not adherence) would be measured. The sample frequency of was set at the maximum 1 sample per minute. Both and the step activity monitor were synchronized to local time on the same personal computer before each measurement. Shoes were equipped with and the step activity monitor was strapped to the ankle. If the patients had more than one pair of prescription custom-made shoes, a second pair was also equipped with If a patient had more than two pair of prescription shoes, the patient was asked to wear only those two pair equipped with Each patient was asked to wear the step activity monitor for seven consecutive full days, at all times, except when taking a shower or bath or when discomfort was felt. Patients were also instructed not to remove from the shoes. Additionally, they were asked to write down in a daily log the time periods (from [hh:mm] to [hh:mm]) that they were away from home, were cycling, or did not wear the step activity monitor. Patients returned the monitors and log after the measurement through postal mail. 4 Data analysis Recordings with less than 4 days of step activity or without a weekend day included were considered incomplete and were excluded from analysis. and step activity monitor data were analyzed using Matlab R2011a software (The MathWorks, Inc., Natick, United States) 19. For patients with two pair of custom-made shoes in the study, data were accumulated. For each measurement day, step count and total wearing time were calculated. Adherence was calculated from the cumulative number of steps over the full measurement period as: Adherence = steps wearing prescribed footwear steps When step activity was recorded during periods that did not record footwear use, it was assumed that the patient walked either barefoot or in non-prescription footwear. The reported time periods in the daily log for cycling were used to filter the step count data to keep walking-only data. Reported time in the daily log for being away from home was used to separate step count, wearing time, and adherence data for periods at home and for periods away from home. Subgroup analyses were done for patients with adherence 80% (adherence high ) and adherence <60% (adherence low ). To compare outcomes with previous studies that used subjective methods, we also calcu- 51

55 Chapter 4 lated adherence as percentage of daytime, that the prescription footwear was worn. We assumed out-of-bed daytime to be 16 hours. Determinants of adherence As potential determinants of adherence, the following factors were taken into account: age, gender, education level (low, medium, high), living status, employement, diabetes type, diabetes duration, cumulative months of past ulceration, history of amputation, presence of peripheral arterial disease, body mass index, glycated hemoglobin, severity of foot deformity, daily step count, variation in daily step count over the measurement period, type of footwear, and perceived footwear aesthetics and footwear comfort. Statistical analysis All statistical analyses were performed using IBM SPSS Statistics version 19 (SPSS Inc., Chicago, United States). Mann-Whitney U-tests assessed baseline differences between included and excluded patients. Descriptive analyses were done on baseline patient characteristics and on outcomes for wearing time, adherence, and step activity. Paired t-tests assessed differences in adherence between being at home and away from home and between weekdays and weekend days. One-way analysis of variance tested for differences in adherence between participating centers and between patient subgroups (adherence high versus adherence low ). Pearson correlation coefficients were calculated between adherence and wearing time and between adherence and daily step count. For all above tests, a significance level of P < 0.05 was used. Univariate regression analysis (P < 0.10) was used to assess the association between variation in step count and time away from home and to assess factors significantly associated with adherence. Significant univariate factors were entered in a multivariate regression analysis of adherence (with backward selection, P < 0.10). RESULTS Thirteen of the 120 included patients were excluded from analysis because of incomplete (< 4 days) step activity data (N = 10), technical failure (N = 2), or refusal to wear the step activity monitor (N = 1). Baseline characteristics did not differ significantly between excluded and analyzed patients, except for gender (relatively more women were excluded, P = 0.018). Of the remaining 107 patients, 93 (=87%) were men, 103 (=96%) were Caucasian, 76 (=71%) had diabetes type 2, and 89 (=83%) wore fully custom-made footwear. Mean ± SD age was 63.8 ± 9.6 years and diabetes duration 17.3 ± 11.9 years, Thirty-five patients had one pair of prescription custom-made shoes, 72 had two pair. Footwear age at assessment was 1.4 ± 0.9 years. We had 6.5 ± 0.9 days of analyzed data per patient. Seventy-nine patients (74% of total group) had complete reports of time spent away from home. The step activity monitor was not worn during 3.5 ± 9.6% of the day, and non-use occurred mostly at night. Patients donned and doffed their footwear 1.3 ± 0.9 times/day. Outcome data for step count and adherence are shown in Table 1. Footwear adherence 52

56 Footwear adherence in diabetic foot patients was 71% ± 25% (range %). When patients were at home, adherence was significantly lower than when away from home (P < 0.001), while daily step count was significantly higher at home (P < 0.001). Adherence was below 60% between 8pm and 10am, and below 40% between midnight and 8am (Figure 1). Both adherence and step count were significantly lower during weekend days than weekdays (P < 0.001). Adherence and daily step count were not significantly correlated (r = 0.14, P = 0.16). Correcting for cycling had a negligible effect on adherence while walking. 4 Figure 1. Mean adherence, total step count, and the number of steps taken without wearing prescribed footwear during 2-h time slots over the day. Patients wore their prescribed footwear 9.4 ± 4.4 hours per day, at home 6.4 ± 4.6 hours, and away from home 3.5 ± 2.7 hours. Wearing time was 59 ± 27% of daytime. Twenty-nine percent of patients wore their prescription footwear >80% of daytime. Wearing time was significantly correlated with adherence (r = 0.87, P < 0.001). Adherence was not significantly different between participating centers (P = 0.16), nor was daily step count (P = 0.35), or wearing time (P = 0.59). Day-to-day variation in step count increased significantly when patients were more away from home (β = 181 steps/hour; 95% CI: 80 to 282, P < 0.001). Thirty-three percent of the patients had adherence <60% (Figure 2). In this adherencelow group, adherence was 40 ± 15% and was 2.5 times higher for away from home than for at home (Table 1). In the adherencehigh group, adherence was 85 ± 12%, and was 1.1 times higher for away from home than for at home. Daily step count was not significantly different between the adherence subgroups ( P = 0.19) (Table 1). 53

57 Chapter 4 Table 1. Data on daily step count and adherence. Total group Adherence low group Daily step count Adherence (%) Adherence high group Total group Adherence low group Adherence high group Full measurement period (N=107) 6397 ± ± ± ± ± ± 6* Walking only (N=107) 5967 ± ± ± ± ± ± 7* Cycling only (N=28) 1642 ± ± ± ± ± ± 24* At home (N=79) 3959 ± ± ± ± ± ± 17* Away from home (N= (79) 2604 ± ± ± ± ± ± 22* Weekday (N=107) 6686 ± ± ± ± ± ± 6* Weekend day (N=107) 5734 ± 3628 # 5542 ± ± 3545 # 66 ± 30 # 34 ± ± 11#* Data are means ± SD. Adherence high group, adherence 80%; adherence low group, adherence < 60%. * P<0.001,significantly different from the adherence low group. P < P < 0.01, significantly different from away from home. # P < 0.05, significantly different from weekday. 54

58 Footwear adherence in diabetic foot patients 4 Figure 2. Distribution of patients across five subgroups of adherence. Also shown is the mean daily step count for each subgroup. In the univariate regression analysis, a lower BMI, a history of amputation, more severe foot deformity, more variation in daily step count, and a better perception of footwear aesthetics were significantly associated with higher adherence (Table 2). In the multivariate analysis, all these factors except history of amputation remained significant (R , P < 0.10; Table 2). 55

59 Chapter 4 Table 2. Outcomes for the univariate and multivariate regression analysis on determinants of adherence. Univariate regression Multivariate regression Variable N or Mean ± SD ß (95% CI) P value ß (95% CI) P value Age (years) 63.8 ± (-0.380; 0.620) Gender (M / F) 93 / (-9.833; ) Diabetes type (1 / 2) 31 / ( ; 5.039) Diabetes duration (years) 17.3 ± (-0.324; 0.484) BMI (kg/m 2 ) 31.1 ± (-1.717; ) 0.020* (-1.544; 0.051) 0.066* PAD grade (I / II) a 60 / (-2.288; ) HbA1c (%) 7.4 ± (-3.284; 3.878) Cumulative past ulcer months (log(months)) 2.00 ± (-3.639; 4.621) History of amputations (No / Yes) 69 / (1.291; ) 0.029* Severity of deformity (No/Mild/Moderate/Severe) b 4 / 37 / 50 / (2.464; ) 0.006* (0.545; ) 0.034* Education level (Low/Medium/High) 63 / 21 / (-7.629; 4.037) Living with others (No/Yes) 29 / (-6.524; ) Employed (No/Yes) 82 / ( ; 7.923) Daily step count (per 1000 steps) 6397 ± (-0.901; 2.870) Variation in daily step count (per 1000 steps) ± (0.651; 7.261) 0.021* (0.307; 7.003) 0.033* Type of footwear (fully custom-made / semi custommade) 89 / ( ; ) Perceived footwear aesthetics (VAS score) 6.8 ± (-0.025; 3.747) 0.056* (0.176; 3.775) 0.032* Perceived footwear comfort (VAS score) 8.1 ± (-2.988; 2.536) Data are N or means ± SD for descriptive data and unstandardized linear regression coefficients (95% confidence intervals) for regression analysis. PAD, peripheral arterial disease; VAS, visual analogue scale. *Significant association (P<0.10). a Presence of peripheral arterial disease was classified according to a diabetic foot ulcer classification system for research purposes 23. b Severity of deformity was classified as no, mild (i.e., presence of pes planus, pes cavus, hallux valgus, hammer toes, or lesser toe amputation), moderate (i.e., hallux or ray amputation, prominent metatarsal heads, or claw toes), or severe (i.e., Charcot deformity or [fore]foot amputation). The most severe deformity present determined classification. 56

60 Footwear adherence in diabetic foot patients CONCLUSIONS Adherence to wearing prescription custom-made footwear is important to prevent ulceration in high risk patients with diabetes. Using objective methods to measure adherence, the study results showed that 71% of the steps taken were in prescription custom-made footwear, while inter-individual differences in adherence were large (10-100%). Adherence was much lower at home than away from home, which substantiates earlier studies that use subjective data 14. In particular in the patient group with low adherence (<60%), adherence at home was poor (28% compared to 69% away from home). Patients were significantly more active at home than away from home, which corresponds with previous data 24. This further amplifies the problem of footwear use at home, increasing the cumulative stress on a not adequately protected foot. Therefore, interventions aimed to increase adherence should primarily target the home situation, for example through the prescription of special offloading footwear for indoors. When calculating adherence in similar units to what most previous studies did, our results show that 29% of the patients wore their prescribed footwear more than 80% of the daytime. This is comparable to these earlier studies that used mailed questionnaires (with a less-than-optimal response rate) and face-to-face interviews and showed that 22-36% of diabetic patients at risk for ulceration wear their prescription footwear all day 11, 12 or at least >80% of daytime 14. These consistent outcomes across studies reinforce the problem of non-adherence in this patient group. Furthermore, it shows that interpretations may vary based on which method is chosen to report adherence (percentage of daytime versus percentage of steps). A major disadvantage of subjective methods is that they lack the sensitivity, accuracy, and reliability to measure adherence during ambulant and non-ambulant periods added with the risk of reporting bias. Therefore, these methods lack the ability to accurately assess adherence when it is most important, namely when the foot is loaded most. This strongly supports the use of objective methods to assess true adherence in a patient. Using these methods, our study still showed that on average 29% of steps were taken without wearing custom-made footwear. Non-adherence was largest during the late evening, night, and early morning hours when patients may walk more on a hard bathroom or kitchen floor. This further increases the risk for ulcer recurrence. 4 The multivariate regression analysis showed that patients with more severe deformity had higher adherence to prescribed footwear, maybe because these patients have no other choice than to wear custom-made footwear or because they are more aware of its benefits. Patients with higher body mass index were less adherent, which may reflect overall difficulty with adhering to a healthy life style in overweight or obese patients. More day-to-day variation in activity was positively associated with adherence, probably because patients who spent more time away from home (higher adherence) were the ones more variable in activity. Finally, patients who perceived their footwear as more attractive were more adherent, which seems intuitive although previous studies are inconclusive on this association 14, 25. Despite these significant associations, overall explained variance in adherence was only 18%, which implies that optimizing any of these predicting factors may have a limited effect on adherence. More research is needed to further elucidate why patients are adherent or not. 57

61 Chapter 4 The objective data collected on adherence provide an excellent basis to further explore predictors of adherence, and have great value in guiding footwear prescription practice and diabetic foot treatment. In many chronic diseases, adherence to treatment is a major problem and influenced by social and economical factors, the health care team, disease characteristics, therapy, and patient-related factors 26. Therefore, objective footwear adherence data could be used to assess patient groups with different social-economic or cultural backgrounds, ethnicity, or past experiences with foot complications. Assessment of adherence in different regions or at different centers may provide information on more or less successful prescription and health care practices. Effects of patient education and other interventions can be accurately determined. Finally, objective adherence data could be used to explore reasons for non-adherence and to individualize type and frequency of footwear prescription 19. Effectively, these analyses could shape and potentially reform the prescription and utilization of specialist diabetic footwear. Some limitations apply. First, we did not measure adherence while standing, even though patients spend twice as much time standing than walking 27, and forces equal to body weight are applied to the foot. Custom-made footwear was worn 9.4 hours per day and was strongly associated with adherence. We therefore suggest that adherence may be as high in standing as in walking. Second, we measured adherence objectively, but we were still dependent on daily kept logs to determine periods of cycling, being away from home, and non-use of the step activity monitor. This increases the chance for missing data or unreliable data. More objective ways to evaluate these events should be further explored, as well as methods to assure that patients do not take off the step activity monitor during measurement. Non-use of the step activity monitor may underor overestimate adherence. We verified from the daily kept logs that non-use occurred only during 3.5% of the day, suggesting a negligible impact on the adherence values. Third, we attempted to avoid a conscious change in behavior by blinding the patient for the goal of the measurement, but we have no confirmation if we succeeded. Finally, we did not measure adherence to wearing non-prescription footwear (e.g. off-the-shelf shoes, sandals, slippers), and therefore we lack information on the amount of barefoot walking, which is the most hazardous walking condition. In conclusion, the results show that adherence to wearing prescribed custom-made footwear is insufficient in neuropathic diabetic patients with prior foot ulceration, in particular at home where they exhibit their largest walking activity. This low adherence is a major threat for re-ulceration in this high-risk patient group. Improvement of adherence could therefore include the prescription of specific protective footwear for indoors, while the importance of wearing prescription footwear should be further promoted. The objective data collected on adherence have great value in guiding clinical practice and provide an excellent basis to further explore predictive factors of adherence, to perform comparative research, and to investigate interventions that aim to improve adherence. 58

62 Acknowledgements Footwear adherence in diabetic foot patients The DIAFOS trial was supported by project grants from the Dutch Diabetes Research Foundation (project no ), the Dutch Foundation for the Development of Orthopedic Footwear Technology (OFOM), and the Dutch Organization for Health Research and Development (project no ). The Academic Medical Center (Amsterdam, the Netherlands) collaborates with nine other multidisciplinary diabetic foot centers and nine orthopedic footwear companies in the Netherlands in the DIAFOS trial on the effectiveness of custom-made footwear to prevent foot ulcer recurrence. The authors gratefully acknowledge the contribution of Mark Arts (Academic Medical Center) in collecting data for the study and also acknowledge the following persons for their contribution in patient recruitment and footwear prescription: T.E. Busch-Westbroek, MD; P.J.A. Mooren (Academic Medical Center); J.W.E. Verlouw, MD; I. Ruijs and H. van Wessel (Maxima Medical Center, Veldhoven, the Netherlands); J.P.J. Bakker, MD, PhD; C. van den Eijnde (Medical Center Alkmaar); D. Wever, MD; H. Wessendorf (Medisch Spectrum Twente, Enschede, the Netherlands); R. Dahmen, MD; B. Koomen (Slotervaart Hospital, Amsterdam, the Netherlands); J.G. van Baal, MD, PhD; R. Haspels (Ziekenhuisgroep Twente, Almelo, the Netherlands); J. Harlaar, PhD; V. de Groot, MD, PhD; J. Pulles (VU Medical Center, Amsterdam, the Netherlands); R. Lever; G. du Mont (Spaarne Hospital, Hoofddorp, the Netherlands); H.G.A. Hacking, MD; J. de Bruin (St. Antonius Hospital, Nieuwegein, the Netherlands); H. Berendsen, MD; and W. Custers (Reinier de Graaf Gasthuis, Delft, the Netherlands). 4 59

63 Chapter 4 REFERENCES 1. Bakker K, Apelqvist J, Schaper NC. Practical guidelines on the management and prevention of the diabetic foot Diabetes Metab Res Rev 2012; 28 Suppl 1: Macfarlane RM, Jeffcoate WJ. Factors contributing to the presentation of diabetic foot ulcers. Diabet Med 1997; 14: Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992; 35: Cavanagh PR. Therapeutic footwear for people with diabetes. Diabetes Metab Res Rev 2004; 20 Suppl 1: S51-S Praet SF, Louwerens JW. The influence of shoe design on plantar pressures in neuropathic feet. Diabetes Care 2003; 26: Waaijman R, Arts ML, Haspels R, Busch-Westbroek TE, Nollet F, Bus SA. Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a history of plantar ulceration. Diabet Med 2012; 29: Connor H, Mahdi OZ. Repetitive ulceration in neuropathic patients. Diabetes Metab Res Rev 2004; 20 Suppl 1: S23-S Chantelau E, Kushner T, Spraul M. How effective is cushioned therapeutic footwear in protecting diabetic feet? A clinical study. Diabet Med 1990; 7: Uccioli L, Faglia E, Monticone G, Favales F, Durola L, Aldeghi A, Quarantiello A, Calia P, Menzinger G. Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 1995; 18: Pound N, Chipchase S, Treece K, Game F, Jeffcoate W. Ulcer-free survival following management of foot ulcers in diabetes. Diabet Med 2005; 22: Knowles EA, Boulton AJ. Do people with diabetes wear their prescribed footwear? Diabet Med 1996; 13: McCabe CJ, Stevenson RC, Dolan AM. Evaluation of a diabetic foot screening and protection programme. Diabet Med 1998; 15: Chantelau E, Haage P. An audit of cushioned diabetic footwear: relation to patient compliance. Diabet Med 1994; 11: Macfarlane DJ, Jensen JL. Factors in diabetic footwear compliance. J Am Podiatr Med Assoc 2003; 93: Hommel KA, Davis CM, Baldassano RN. Objective versus subjective assessment of oral medication adherence in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2009; 15: Adams AS, Soumerai SB, Lomas J, Ross-Degnan D. Evidence of self-report bias in assessing adherence to guidelines. Int J Qual Health Care 1999; 11: Garber MC, Nau DP, Erickson SR, Aikens JE, Lawrence JB. The concordance of self-report with other measures of medication adherence: a summary of the literature. Med Care 2004; 42: Armstrong DG, Lavery LA, Kimbriel HR, Nixon BP, Boulton AJ. Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure off-loading regimen. Diabetes Care 2003; 26:

64 Footwear adherence in diabetic foot patients 19. Bus SA, Waaijman R, Nollet F. New Monitoring Technology to Objectively Assess Adherence to Prescribed Footwear and Assistive Devices During Ambulatory Activity. Arch Phys Med Rehabil 2012; 93: Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23: Coleman KL, Smith DG, Boone DA, Joseph AW, Del Aguila MA. Step activity monitor: longterm, continuous recording of ambulatory function. J Rehabil Res Dev 1999; 36: Jannink MJ, de VJ, Stewart RE, Groothoff JW, Lankhorst GJ. Questionnaire for usability evaluation of orthopaedic shoes: construction and reliability in patients with degenerative disorders of the foot. J Rehabil Med 2004; 36: Schaper NC. Diabetic foot ulcer classification system for research purposes: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev 2004; 20 Suppl 1: S90-S Armstrong DG, Abu-Rumman PL, Nixon BP, Boulton AJ. Continuous activity monitoring in persons at high risk for diabetes-related lower-extremity amputation. J Am Podiatr Med Assoc 2001; 91: Williams AE, Nester CJ. Patient perceptions of stock footwear design features. Prosthet Orthot Int 2006; 30: Yach, D. WHO report. Adherence to long-term therapies. Evidence for action World Health Organisation. 27. Najafi B, Crews RT, Wrobel JS. Importance of time spent standing for those at risk of diabetic foot ulceration. Diabetes Care 2010; 33:

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66 Chapter 5 PRESSURE-REDUCTION AND PRESERVATION IN CUSTOM- MADE FOOTWEAR OF PATIENTS WITH DIABETES AND A HISTORY OF PLANTAR ULCERATION Diabetic Medicine 2012; 29: Reprinted with permission from Wiley-Blackwell 5 Roelof Waaijman Mark L.J. Arts Rob Haspels Tessa E. Busch-Westbroek Frans Nollet Sicco A. Bus 63

67 Chapter 5 ABSTRACT Aims: To assess the value of using in-shoe plantar pressure analysis to improve and preserve the offloading properties of custom-made footwear in patients with diabetes. Methods: Dynamic in-shoe plantar pressures were measured in new custom-made footwear of 117 patients with diabetes, neuropathy and a healed plantar foot ulcer. In 85 of these patients, high peak pressure locations (peak pressure >200kPa) were targeted for pressure reduction (goal: >25% relief or below an absolute level of 200 kpa) by modifying the footwear. After each of a maximum three rounds of modifications pressures were measured. In a subgroup of 32 patients, pressures were measured and, if needed, footwear was modified at 3-monthly visits for 1 year. Pressures were compared to those measured in 32 control patients who had no footwear modifications based on pressure analysis. Results: At the previous ulcer location and the highest and second highest pressure locations, peak pressures were significantly reduced with 23%, 21%, and 15%, respectively, after footwear modification. These lowered pressures were maintained or further reduced over time and were significantly lower, by 24-28%, compared with pressures in the control group. Conclusion: The offloading capacity of custom-made footwear for high-risk patients can be effectively improved and preserved using in-shoe plantar pressure analysis as guidance tool for footwear modification. This provides a useful approach to obtain better offloading footwear that may reduce the risk for pressure-related diabetic foot ulcers. 64

68 Pressure-reduction and preservation in custom-made footwear INTRODUCTION Foot ulceration is a serious long term complication in patients with diabetes mellitus and polyneuropathy, which significantly increases the risk of infection and lower limb amputation 1-3. The lifetime risk of developing an ulcer is 15-25% 4. About half of all ulcers occur on the plantar foot surface 5. Loss of protective sensation and high levels of plantar foot pressure during ambulation are the main causative factors 6-9. To prevent ulceration, custom-made footwear is often prescribed to patients at high-risk for ulceration, and acts primarily by redistributing and relieving high plantar pressure levels. Despite this goal, objective evaluation of the pressure-relieving properties of custommade footwear is still not common in diabetic foot practice. Footwear is mostly evaluated based on clinical experience and a trial-and-error approach. Feedback from the patient is limited due to the presence of neuropathy. Therefore, variability may exist in the offloading properties of this footwear, which several biomechanical studies show to be the case 10, 11. Consequently, the offloading capacity of this footwear may often be insufficient, which could be one of the factors that may explain the high recurrence rates of ulceration 1. Offloading may be improved by modifying the patients footwear after delivery using objective measurement tools. A recent proof-of-principle study showed that in-shoe plantar pressure analysis is a valuable and efficient tool to guide footwear modification and achieve better offloading footwear 12. This study was, however, conducted in a relatively small and heterogeneous sample of patients, different footwear conditions, and in a setting where time was not constrained. Confirmation of these results in a large homogenous group of high-risk patients and footwear conditions, and in a time-constrained clinical setting is required. 5 Another important aspect in footwear evaluation is the preservation of offloading properties over time since only then a sustained reduction in the risk for ulceration may be assured. Wear and tear of the footwear or changes in foot shape could influence the pressure-relieving effects of custom-made footwear over time Therefore, to maintain proper offloading, repeated in-shoe pressure assessments and (if needed) additional footwear modifications may be required. For these reasons, we aimed to assess (1) the value of using in-shoe plantar pressure analysis for evaluating and improving the offloading properties of newly prescribed custom-made footwear in patients with diabetes, neuropathy and a recently healed plantar ulcer, and (2) to determine in these patients whether improved offloading results can be maintained over a 1-year period when compared to a control group of patients wearing custom-made footwear that is not modified based on in-shoe pressure analysis. PATIENTS AND METHODS Subjects Thirty-four patients with Type 1 diabetes and 83 patients with Type 2 diabetes (mean 65

69 Chapter 5 ± SD age of 63.3 ± 10.1 years) with duration of 17.7 ± 14.1 years were included. All patients were consecutively recruited from the outpatient foot clinics of 10 hospitals in the Netherlands, which all participated in a trial on the effectiveness of custom-made footwear in preventing diabetic foot ulcer recurrence (DIAbetic Foot Orthopaedic Shoe (DIAFOS) trial, trial register: NTR1091). All patients had loss of protective sensation as confirmed by the inability to sense the pressure of a 10-g Semmes Weinstein monofilament at one or more of three plantar foot sites, or a vibration perception threshold at the hallux >25V 7. Most patients had one or more foot deformities, including claw/hammer toes, hallux valgus, Charcot midfoot deformity, prominent metatarsal heads, and partial foot amputation. Each patient had a healed plantar ulcer during the previous 18 months. For the first study objective (improving offloading), data were collected in 85 of the total 117 patients. For the second study objective (preserving offloading), data were collected in the first 32 of these 85 patients who had completed one year follow-up (experimental group) and in 32 patients who were measured for in-shoe plantar pressure in their custom-made footwear, but had no modifications to the footwear based on these pressures (control group). Written informed consent was obtained from each patient before inclusion in the study, which was approved by the Local Research Ethics Committee. Footwear Patients wore newly prescribed fully custom-made footwear (i.e. custom-made insoles in custom-made shoes, also referred to as orthopaedic footwear in some countries, N = 95) or semi custom-made footwear (i.e. custom-made insoles in off-the-shelf extra depth shoes, also referred to as semi-orthopaedic footwear, N = 22). The footwear was prescribed by a rehabilitation specialist and manufactured by a shoe technician working in each of the centres. Each team had a minimum of 4 years experience in diabetic foot practice. Although not enforced by any protocol, footwear design mostly followed the Delphi-based algorithm published by Dahmen and colleagues 17. The footwear was generally manufactured from a plaster cast or foam mould of the foot. Blueprints were commonly used to identify target regions of high pressure for footwear design. The footwear generally had a stiffened rubber outsole with roller configuration. Custom-made insoles consisted of multi-density layered materials, with mouldable cork or multiform base and an open or closed-cell material top cover. Instrumentation In-shoe plantar pressures were measured using the Pedar-X system (Novel, Munich, Germany). This system consists of flexible 2-mm-thick insoles with 99 sensors which independently measure the normal pressure at a sample frequency of 50 Hz. The insoles were placed between the sock and the insole of the shoe. Multiple insole sizes were available to accommodate different foot sizes. Each pair of Pedar insoles was calibrated each 3 months using a calibration device and guidelines from the manufacturer. Protocol In-shoe plantar pressures were measured while walking at a self-chosen comfortable speed along a minimum 10-m long walkway. Walking speed was measured using a stopwatch and kept constant during subsequent measurements in the same session or 66

70 Pressure-reduction and preservation in custom-made footwear during follow-up measurements (maximum 5% deviation in average walking speed). A minimum of 20 midgait steps per foot were collected per measurement 18. Patients were provided with thin seamless socks during the measurement sessions. The protocol used for evaluating and modifying the footwear is shown in Figure 1. Inshoe plantar pressures were measured in the footwear as delivered (entry visit, baseline assessment). Based on the average peak pressure pictures obtained over multiple foot steps, regions of interest were selected (peak pressure was the parameter used throughout the study) 19. These included the previous ulcer location and, if present, per foot the two highest peak pressure locations in the midfoot and forefoot with peak pressure >200 kpa. In the 85 patients assessed for offloading improvement, the footwear was subsequently modified by the shoe technician with the goal to reduce peak pressure at the regions of interest. Choice of modification to the shoes or insoles was left to the shoe technician and/or rehabilitation specialist. Multiple modifications were allowed at once. Criteria for successful improvement in offloading were defined. These were a peak pressure reduction at the region of interest of 25% compared to baseline levels or a reduction to an absolute level below 200 kpa. Using in-shoe pressure within this context as a surrogate indicator for risk of foot ulceration, both criteria were considered to be indicative of a relevant reduction in risk of ulceration 12, 20. If the criteria were not met, a maximum of two subsequent rounds of footwear modifications and in-shoe pressure measurements were applied. If the criteria were eventually not met, offloading improvement was considered as a failure. 5 Follow-up in-shoe pressures were measured at 3-monthly intervals (Figure 1). The regions of interest that were defined at baseline were also the regions of interest during follow-up. In the 32 experimental group patients in-shoe pressure was measured and the footwear was modified if the criteria for successful offloading were not yet achieved at entry visit (0 months) or when, compared to the final pressure measured at entry, peak pressure at the region of interest had increased with 5% or more. After each round of footwear modifications, in-shoe pressures were measured, similar to how this occurred at entry. Footwear modifications in the control group between study visits based on normal practice were identified by asking the patient about visits to the shoe technician. If confirmed, the shoe technician was asked about modifications made and details were recorded. Data analysis and statistics During the testing sessions, data analysis was done on-screen from the peak pressure distribution pictures of the foot. After the testing session, formal data analysis was conducted by masking the regions of interest in the pressure pictures and calculating mean peak pressures for each mask using Novel multimask software (Novel, Munich, Germany). 67

71 Chapter 5 Figure 1. Flow diagram of the footwear modification protocol used at entry and at each follow-up assessment. The regions of interest (ROI) were the previous ulcer location (PUL) and the two highest peak pressure locations in the midfoot and forefoot with peak pressure >200 kpa (HPL1 and HPL2). PP, peak pressure; FU, follow-up; wrt, with respect to. High-pressure locations may shift from the region of interest to neighbouring (anatomical) regions as a result of modifying the footwear. To assess this possible effect, change in peak pressure after all rounds of footwear modifications was calculated in each of 10 masked foot regions: lateral and medial heel, medial and lateral midfoot, metatarsal 1, metatarsals 2-3, metatarsals 4-5, hallux, toes 2-3, and toes 4-5. These transfer pressure effects were considered excessive when peak pressure increase was more than 25 kpa, more than 25%, and when peak pressures reached a level >200 kpa Descriptive analyses were done using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). Outcomes for offloading at entry and follow-up pressure measurement were modelled by multilevel linear regression analysis using MLwiN software, version 2.23 (Institute 68

72 Pressure-reduction and preservation in custom-made footwear of Education, University of London, London, UK). The foot pressure data were nested at four levels - participating centre (fourth level), patient (third), foot (second), and time (first) - to determine and (if needed) account for dependency of the data on these factors 21. To analyse footwear modification effects, in-shoe peak pressure was regressed on the variable time (pre-modification, post-modification), and on the covariate type of footwear (fully custom-made or semi custom-made). To analyse follow-up effects, in-shoe peak pressure was regressed on the variables study group (experimental, control), time (each 3-month visit), and their interaction. RESULTS The previous ulcer location and the two highest peak pressure locations are shown in Table 1. A peak pressure >200 kpa at the previous ulcer location was found in 27 patients, a peak pressure <200 kpa in 49 patients of 85 patients assessed for offloading improvement. These groups were analysed separately. In nine patients, the previous ulcer location was amputated. Table 1. Anatomical locations of the previous ulcer and, the two highest peak pressures per foot in the 85 patients assessed for offloading improvement. Region Previous ulcer location Highest and second highest peak pressure location Hallux 15 (1) 33 Toes (4) 1 Toes (1) 0 Metatarsal 1 23 (2) 53 Metatarsal (1) 90 Metatarsal (0) 19 Midfoot medial 1 (0) 4 Midfoot lateral 1 (0) 2 Total 85 (9) 202 Data are expressed as n with the number of amputations of that region in between brackets. 5 Table 2 shows the outcomes for offloading improvement at entry. In-shoe peak pressure was reduced significantly after modifying the footwear with 23% at the previous ulcer location with peak pressure >200 kpa, with 21% at the highest peak pressure location, and with 15% at the second highest peak pressure location (P < 0.01). To achieve these results, on average 1.4 (SD 0.7) rounds of footwear modifications were needed. In 64% of the cases, one round of footwear modifications was used. In both footwear types, modifications were made to the shoes and insoles. The modifications applied most were the removal of material in the insole at the region of interest (33% of all modifications), replacement of the insole top cover (20%), softening of material in the insole at the region of interest (16%), placement of a metatarsal pad or bar (16%), and the adjustment of the pivot point in the outsole roller (6%). Successful offloading was achieved in 51-59% of these regions, dependent on location. At the previous ulcer location with peak pressure <200 kpa, peak pressures could not be further reduced by modifying the footwear (in 60% of cases one round of modification was applied, in 40% the footwear 69

73 Chapter 5 was not modified). None of the outcomes was dependent on type of footwear or participating centre. Excessive build-up of peak pressure in neighbouring regions was present in 2% of cases. Table 3 shows the outcomes for the follow-up pressure analysis. No significant differences were present between the two study groups in patient characteristics and baseline in-shoe pressures. Figure 2 shows the course of peak pressure over one year for the two study groups. For this analysis, all regions of interest with a peak pressure >200 kpa were pooled. After modification at entry, the difference between study groups for these pooled regions was significant, and this difference increased over time. Peak pressure reduced significantly over time in the experimental group (β time = -5 kpa/follow-up; 95% CI, -8.6 to -0.7; P < 0.01), but not in the control group (β time = -1 kpa/follow-up; 95% CI, -6.6 to 3.9; non-significant). For the previous ulcer location with baseline peak pressure <200 kpa, mean peak pressure did not change significantly over time in either study group. At 3 months follow-up, in 58% of the cases one round of footwear modifications was applied and in 28% of cases no modifications were made. At 12 months follow-up, these percentages were 20% and 78%, respectively. Successful offloading was achieved in 64% of the regions of interest with baseline peak pressure >200 kpa after 3 months follow-up and in 81% after 12 months follow-up. In four of the 32 control group patients, the footwear was modified between visits at a single occasion during follow-up. None of the outcomes in either group during follow-up was dependent on participating centre. Figure 2. Mean in-shoe peak pressure measured at entry and at 3-monthly intervals over the course of 1 year follow-up in the experimental group (E, closed symbols) and the control group (C, open symbols) for all regions of interest with peak pressure >200kPa (ROI >200 ) and the previous ulcer location with peak pressure <200kPa (PUL <200 ). 70

74 Pressure-reduction and preservation in custom-made footwear Table 2. Results for in-shoe pressure offloading at entry in 85 patients. Modelled in-shoe peak pressure (kpa) Measured in-shoe peak pressure (kpa) No. of rounds of modifications β 0 β 1 Successful optimization n Baseline After footwear modification Region of interest Mean (SD) Mean (SD) Mean (SE) Mean (SE) % Mean (SD) PUL < (43) 127 (46) 123 (6.3)** ns (0.5) PUL > (79) 221 (49) 287 (12.5)** -66 (12.4)** (0.6) HPL (67) 220 (61) 276 (6.3)** -57 (3.9)** (0.8) HPL (44) 210 (44) 246 (5.8)** -38 (3.9)** (0.8) Measured in-shoe peak pressures are shown for baseline and for final in-shoe pressure assessment (after all rounds of modifications). Abbreviations: PUL <200, PUL >200, all previous ulcer locations with measured peak pressures below and above 200kPa, respectively; HPL1 and HPL2, highest and second -highest peak pressure location with peak pressure >200 kpa, respectively; SD, standard deviation; SE, standard error. Regression model: outcome variable = β 0 + β opt * time, in which β 0 = intercept; β 1 = regression slope; time = before (0) and after (1) footwear modification. Significance: ns, not significant, ** P<

75 Chapter 5 Table 3. Results for in-shoe pressure offloading during follow-up assessments. Region of interest Study group Before footwear modification Measured in-shoe peak pressure (kpa) Successful improvement Rounds of modifications (n) After footwear modification 0 months 3 months 1 year 0 months 3 months 1 year n Mean (SD) Mean (SD) % % % Mean (SD) PUL <200 Control (40) ROI > (55) PUL <200 Experimental (41) 133 (42) (0.5) 0.1 (0.3) 0.1 (0.2) ROI > (51) 213 (45) (0.8) 1.0 (0.8) 0.3 (0.5) Mean (SD) Mean (SD) Results of multilevel linear regression model. β 0 β study group β time kpa (SE) kpa (SE) kpa/follow-up (SE) PUL < (5.9)** ns ns No Interaction ROI > (8.2)** -64 (10.8)** -3 (1.4)* Interaction effect Measured in-shoe peak pressures for are shown both study groups before any modification and for the experimental group after all rounds of modifications. PUL <200, all previous ulcer locations with measured peak pressures below 200kPa; ROI >200, all regions of interest with measured peak pressure above 200 kpa; SD, standard deviation; SE, standard error. Regression model: outcome variable = β 0 + β study group * study group + β time * time, in which β 0 = intercept; β study group and, β time = regression slope; study group = control group (0) or experimental group (1); time = follow-up visit (0, 3, 6, 9 and 12 months). Significance: ns, not significant, * P<0.05 ** P<

76 Pressure-reduction and preservation in custom-made footwear DISCUSSION This study shows that plantar pressures at high-pressure regions can be reduced to substantial degrees after modifying custom-made footwear based on in-shoe pressure analysis. At the most at-risk foot location, the previous ulcer location, peak pressures above 200kPa were reduced with a mean 23%. However, when peak pressures at the previous ulcer location were below 200 kpa, further pressure reduction proved elusive, suggesting that sufficiently offloaded conditions were already present. Improved offloading was maintained and even further improved over a 12-month follow-up period, and was significantly better that footwear that was not modified based on in-shoe pressure analysis. In only 2% of regions neighbouring the regions of interest, excessive build of pressure was found. In the majority of high-pressure regions (53%), successful offloading was achieved according to the set criteria, and this improved to 64% after 3 months and to 81% after 1 year. This provides a valuable objective approach to achieve and preserve better offloading custom-made footwear. Whether this will reduce the risk for pressure-related plantar foot ulcers in patients with diabetes remains to be investigated. The offloading results at entry confirm recent findings from a similar but smaller study 12. This study reported a mean 30% peak pressure relief after footwear modification and a 100% success rate using similar criteria. The lower current success rates may be because more regions of interest per foot were selected. This may have reduced the chance for success in each region of interest, because of pressure redistribution effects or because a certain region was given priority for clinical reasons. In 63% of the failed offloading attempts, the maximum three rounds of modifications were not used. This may have been caused by time constraints in busy outpatient clinic or by the fear for increasing pressure in an already offloaded region. This adds to the lower success rate in the current study. These factors may also explain the lower mean number of modification rounds in the current study (1.4) compared to the previous study (1.8). Nevertheless, both studies lead to the conclusion that in-shoe pressure analysis is a valuable tool to achieve better offloading footwear. 5 During follow-up, in-shoe peak pressures were further reduced by modifying the footwear. Fewer rounds of modifications were needed at each subsequent follow-up visit. The saw tooth pattern of peak pressure change in the first 6 months (Figure 2), showed that improved results could not be preserved in the short run without further modification of the footwear. These results support the long-term pressure monitoring at 3-monthly intervals. At each follow-up stage, in-shoe peak pressures were significantly lower in the experimental group than in the control group, in which peak pressures did not change over 12 months time. Wear and tear of the footwear was expected to increase peak pressures over time in the control group 22, 23, despite that results on this aspect are still inconclusive 14, 24. Clearly, more research on the mechanisms of in-shoe pressure change, or the lack thereof, over time is required to better clarify the follow-up pressure results in this study. The majority of previous ulcer locations (64%) showed baseline peak pressures below 200 kpa and further pressure relief was not possible by modification of the footwear. The mean measured in-shoe peak pressure of 127 kpa in these cases was low. This sug- 73

77 Chapter 5 gests that, for the previous ulcer location, the footwear was already sufficiently offloaded, maybe because this location is an important and clear target in footwear design. In contrast, in 85 patients, 229 regions of interest with peak pressures >200 kpa were identified. Among these regions were many less clear targets, supporting the use of objective evaluation tools. Risk for ulceration may be increased at these high-pressure locations 20, 25. Therefore, offloading was considered insufficient in these cases and in need for improvement. The lack of a structured and evidence-based protocol for footwear design and manufacturing may be an underlying cause. Footwear prescription and evaluation is in many ways still more an art than a science, and this may introduce variability in design and in offloading efficacy of footwear prescriptions 10, 26. Better offloading can be achieved with the use of quantitative computer-assisted approaches in footwear design and manufacturing, which may reduce variability 27. However, an individual-based approach in footwear evaluation seems necessary. The current approach can be helpful in this regard, and seems to be independent of the clinical team (albeit having ample experience) and type of custom-made footwear used, which improves external validity. This study was limited in some aspects. First, data on ulcer recurrence rates were not available for this study. Therefore offloading success could not be associated with ulcer recurrence data. Success criteria were based on common sense and indications of clinically relevant pressure reduction that may prevent ulcer recurrence 20, 28. Future studies, such as our DIAFOS trial, should confirm if using such criteria can prevent plantar foot ulcer recurrence. Second, successful offloading did not necessarily imply optimal footwear. Further modification or other footwear designs may have further reduced pressure. However, our goal was to test a clinically feasible approach and, therefore, the number of modification rounds was limited to three. Finally, we did not use standardized protocols for modifying the footwear because of a lack of guidelines. This could affect the reproducibility of the results. Future investigations should focus on developing evidence-based guidelines for effective footwear designs and modifications. In conclusion, we found that the majority of high-risk regions, whether predictable or not from foot screening, can be offloaded to a substantial degree using in-shoe plantar pressure analysis as guidance tool for modifying custom-made footwear. These improved conditions could be maintained and even further improved over time using the same approach. This provides a useful objective approach for clinical practice to achieve and preserve better offloading footwear that may reduce the risk for pressure-related plantar foot ulcers in patients with diabetic. 74

78 Acknowledgements Pressure-reduction and preservation in custom-made footwear In the DIAFOS trial, the Academic Medical Center collaborates with 9 other multidisciplinary diabetic foot centres and 9 orthopaedic footwear companies in the Netherlands. The authors like to acknowledge the contribution of M. de Haart in project management and R. Keukenkamp in data collection (both Academic Medical Centre, Amsterdam) as welll as the following persons in recruitment of patients and prescription, manufacturing, and modification of custom-made footwear: P. J. A. Mooren (AcademicMedical Centre, Amsterdam), J. W. E. Verlouw, I. Ruijs and H. van Wessel (Maxima Medical Centre, Veldhoven), J. P. J. Bakker and C. van den Eijnde (Medical Centre Alkmaar), D. Wever and H. Wessendorf (Medisch Spectrum Twente, Enschede), R. Dahmen and B. Koomen (Slotervaart Hospital, Amsterdam), J. G. van Baal (Ziekenhuisgroep Twente, Almelo), J. Harlaar, V. de Groot and J. Pulles (VU Medical Centre, Amsterdam), W. P. Polomski, R. Lever and G. du Mont (Spaarne Hospital, Hoofddorp), H. G. A. Hacking and J. de Bruin (St Antonius Hospital, Nieuwegein), and H. Berendsen and W. Custers (Reinier de Graaf Gasthuis, Delft). The DIAFOS trial was supported by project grants from the Dutch Diabetes Research Foundation (project ), the Dutch Foundation for the Development of Orthopedic Footwear Technology (OFOM), and the Dutch Organization for Health Research and Development (ZonMw, project ). 5 75

79 Chapter 5 REFERENCES 1. Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med 2004; 351: Pound N, Chipchase S, Treece K, Game F, Jeffcoate W. Ulcer-free survival following management of foot ulcers in diabetes. Diabet Med 2005; 22: Reiber GE, Vileikyte L, Boyko EJ, del AM, Smith DG, Lavery LA, Boulton AJ. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999; 22: Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, Edmonds M, Holstein P, Jirkovska A, Mauricio D, Ragnarson TG, Reike H, Spraul M, Uccioli L, Urbancic V, Van AK, Van BJ, Van MF, Schaper N. High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study. Diabetologia 2007; 50: Frykberg RG, Lavery LA, Pham H, Harvey C, Harkless L, Veves. A Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care 1998; 21: Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23: Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992; 35: Boulton AJ, Hardisty CA, Betts RP, Franks CI, Worth RC, Ward JD, Duckworth T. Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy. Diabetes Care 1983; 6: Bus SA, Ulbrecht JS, Cavanagh PR. Pressure relief and load redistribution by custom-made insoles in diabetic patients with neuropathy and foot deformity. Clin Biomech (Bristol, Avon) 2004; 19: Guldemond NA, Leffers P, Schaper NC, Sanders AP, Nieman FH, Walenkamp GH. Comparison of foot orthoses made by podiatrists, pedorthists and orthotists regarding plantar pressure reduction in The Netherlands. BMC Musculoskelet Disord 2005; 6: Bus SA, Haspels R, Busch-Westbroek TE. Evaluation and optimization of therapeutic footwear for neuropathic diabetic foot patients using in-shoe plantar pressure analysis. Diabetes Care 2011; 34: Brodsky JW, Pollo FE, Cheleuitte D, Baum BS. Physical properties, durability, and energydissipation function of dual-density orthotic materials used in insoles for diabetic patients. Foot Ankle Int 2007; 28: Lobmann R, Kayser R, Kasten G, Kasten U, Kluge K, Neumann W, Lehnert H. Effects of preventative footwear on foot pressure as determined by pedobarography in diabetic patients: a prospective study. Diabet Med 2001; 18: Grimm A, Kastenbauer T, Sauseng S, Sokol G, Irsigler K. Progression and distribution of plantar pressure in Type 2 diabetic patients. Diabetes Nutr Metab 2004; 17: Boulton AJ, Betts RP, Franks CI, Ward JD, Duckworth T. The natural history of foot pressure 76

80 Pressure-reduction and preservation in custom-made footwear abnormalities in neuropathic diabetic subjects. Diabetes Res 1987; 5: Dahmen R, van der Wilden GJ, Lankhorst GJ, Boers M. Delphi process yielded consensus on terminology and research agenda for therapeutic footwear for neuropathic foot. J Clin Epidemiol 2008; 61: Arts ML, Bus SA. Twelve steps per foot are recommended for valid and reliable in-shoe plantar pressure data in neuropathic diabetic patients wearing custom made footwear. Clin Biomech 2011; 26: Waaijman R, Bus SA. The interdependency of peak pressure and pressure-time integral in pressure studies on diabetic footwear: no need to report both parameters. Gait Posture 2012; 35: Owings TM, Apelqvist J, Stenstrom A, Becker M, Bus SA, Kalpen A, Ulbrecht JS, Cavanagh PR. Plantar pressures in diabetic patients with foot ulcers which have remained healed. Diabet Med 2009; 26: Goldstein H. Multilivel Statistical Models. London: Edward Arnold, Foto JG, Birke JA. Evaluation of multidensity orthotic materials used in footwear for patients with diabetes. Foot Ankle Int 1998; 19: Paton J, Bruce G, Jones R, Stenhouse E. Effectiveness of insoles used for the prevention of ulceration in the neuropathic diabetic foot: a systematic review. J Diabetes Complications 2011; 25: Donaghue VM, Sarnow MR, Giurini JM, Chrzan JS, Habershaw GM, Veves A. Longitudinal inshoe foot pressure relief achieved by specially designed footwear in high risk diabetic patients. Diabetes Res Clin Pract 1996; 31: Cavanagh PR. Therapeutic footwear for people with diabetes. Diabetes Metab Res Rev 2004; 20 Suppl 1: S51-S Mueller MJ. Application of plantar pressure assessment in footwear and insert design. J Orthop Sports Phys Ther 1999; 29: Owings TM, Woerner JL, Frampton JD, Cavanagh PR, Botek G. Custom therapeutic insoles based on both foot shape and plantar pressure measurement provide enhanced pressure relief. Diabetes Care 2008; 31: Mueller MJ, Smith KE, Commean PK, Robertson DD, Johnson JE. Use of computed tomography and plantar pressure measurement for management of neuropathic ulcers in patients with diabetes. Phys Ther 1999; 79:

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82 Chapter 6 EFFECT OF CUSTOM-MADE FOOTWEAR ON FOOT ULCER RECURRENCE IN DIABETES: A MULTICENTER RANDOMI- ZED CONTROLLED TRIAL Submitted Sicco A. Bus Roelof Waaijman Mark L.J. Arts Mirjam de Haart Tessa E. Busch-Westbroek Jeff G. van Baal Frans Nollet 6 79

83 Chapter 6 ABSTRACT Objective: Custom-made footwear is the treatment of choice to prevent foot ulcer recurrence in diabetes, and primarily aims to offload plantar regions at high ulcer risk. However, ulcer recurrence rates are high. We assessed the effect of offloading-improved custom-made footwear and the role of footwear adherence on plantar foot ulcer recurrence. Research design and methods: We randomly assigned 171 neuropathic diabetic patients with a recently healed plantar foot ulcer to custom-made footwear with improved and subsequently preserved offloading ( 20% peak-pressure relief by modifying the footwear) or to usual care (i.e. non-improved custom-made footwear). Primary outcome was plantar foot ulcer recurrence in 18 months. Secondary outcome was ulcer recurrence in patients with an objectively measured adherence 80% of steps taken. Results: Based on intention-to-treat, 33 of 85 patients (38.8%) with improved footwear and 38 of 86 patients (44.2%) with usual care had a recurrent ulcer (effect size 11%, P =.48, odds ratio 0.80, 95% confidence interval [0.44; 1.47]). Ulcer-free survival curves were not significantly different between groups (P =.40). In the 79 patients (46% of total group) with high adherence, 9 of 35 patients (25.7%) with improved footwear and 21 of 44 patients (47.8%) with usual care had a recurrent ulcer (effect size 46%, P =.045; odds ratio 0.38, 95% confidence interval [0.15; 0.99]). Conclusions: Offloading-improved custom-made footwear does not significantly reduce the incidence of plantar foot ulcer recurrence in diabetes. However, the results suggest that this footwear can be effective when adherence is assured, which needs confirmation in future trials. 80

84 Prevention of foot ulcer recurrence in diabetes INTRODUCTION Every 30 seconds a limb is lost somewhere in the world due to diabetes 1. These amputations are nearly always preceded by a foot ulcer, which has a lifetime risk of 15-25% in patients with diabetes 2, 3. Foot disorders, including ulcers, are a leading cause of hospitalization and high treatment costs in patients with diabetes 4. Therefore, prevention of ulceration is important to decrease the large patient and economic burden of diabetic foot disease. About half of all diabetic foot ulcers occur on the plantar foot surface and are mainly caused by elevated levels of mechanical pressure acting on the foot during ambulation in the presence of loss of protective foot sensation due to peripheral neuropathy 5, 6. Therefore, to reduce risk of ulceration, relief of mechanical pressure (also called offloading ) is indicated. For this purpose, custom-made therapeutic footwear is recommended and the treatment of choice, in particular for patients with foot deformity and a history of ulceration 7. Despite widespread prescription of custom-made footwear, foot ulcers often recur 8. A limited number of randomized trials with moderate to high probability for bias have shown inconsistent results on custom-made footwear efficacy to prevent ulcer recurrence in diabetes 7, These studies varied considerably in used prescription methods and shoe designs, and foot pressure was not measured. To explain clinical outcome in footwear studies, an indication for effective pressure-relief seems important as well as an accurate estimate of patient adherence to wearing prescription footwear, which we know is low in these patients 12. High quality randomized trials on this matter are needed to better inform clinical practice 13. Within this context, the lack of existing evidence-based prescription guidelines and the proven variation in the offloading effect of custom-made footwear designs suggests that prescription footwear is sub-optimal in relieving pressure, and should be improved to increase clinical benefit We recently showed that evaluation of footwear using in-shoe plantar pressure measurements can effectively guide footwear modifications to improve pressure relief in each individual patient 17. Significant reductions in peak pressure between 17% and 52% were achieved across patients. We hypothesized that with this approach ulcer recurrence can be reduced significantly, provided that pressure reduction is maintained over time. Therefore, the objective was to examine in an intention-to-treat analysis the effect of pressure-improved custom-made footwear in comparison with usual care (i.e. non-improved custom-made footwear) on plantar foot ulcer recurrence incidence in 18 months. In addition, we evaluated whether adherence to wearing custom-made footwear influences the outcomes on ulcer recurrence. 6 RESEARCH DESIGN AND METHODS Study participants We enrolled patients from the multidisciplinary outpatient diabetic foot clinics of two academic and eight large general public hospitals across the Netherlands. Inclusion cri- 81

85 Chapter 6 teria were: age 18 or above, confirmed type 1 of type 2 diabetes mellitus, loss of protective foot sensation due to peripheral neuropathy, a healed plantar foot ulcer (i.e. full epithelialization without exudate) in the 18 months preceding randomization, and a new prescription of custom-made footwear. Exclusion criteria were bilateral amputation proximal to the tarso-metatarsal joint, the use of walking aids that offload the foot, unlikelihood to survive 18 months follow-up, and inability to follow the study instructions. Each subject provided written informed consent before inclusion. Study design and randomization In this investigator-initiated parallel-group study, we randomly assigned subjects between November 2007 and October 2010 in a balanced design to custom-made footwear of which the offloading properties were improved and subsequently preserved based on in-shoe plantar pressure measurement and analysis or custom-made footwear that were not improved based on in-shoe pressure measurement (i.e. usual care). At footwear delivery, subjects were randomly assigned by the study investigator using an online accessible computer-generated allocation sequence a that used the non-deterministic minimization method. The allocation sequence was prepared and managed by a noninvolved investigator. Participating centre and gender were used as factors for stratification. Primary outcome assessors were blinded to group assignment. Care givers and investigators were not blinded to group assignment and were instructed not to communicate treatment allocation with patients. We attempted to blind patients by measuring in-shoe plantar pressures in both study groups at equal intervals and by evaluating and modifying the footwear outside the view of patients. The study was registered in the Dutch Trial Register (Study ID NTR1091) and was approved by the medical ethical committees of all ten participating centers. Custom-made footwear Footwear consisted of custom-made insoles worn in custom-made shoes or in off-theshelf (extra depth) shoes. Additional custom-made footwear, that patients already possessed at study entry or were prescribed with during follow-up, was included in the study. All footwear was prescribed by a specialist in physical and rehabilitation medicine and manufactured by an orthopedic shoe technician, both experienced in diabetic foot care. Although not enforced by any protocol, footwear design generally resembled design recommendations from a previously published algorithm 18. Shoe lasts were created based on plaster cast molding of the foot or on foam impressions including geometrical foot measures. Blueprints of the foot were used to specify at-risk regions to be targeted. Insoles consisted of multi-layered materials, with a cork base added with micro-cork and a mid layer of multiform (mix of ethylene vinyl acetate and polyethylene). The insoles were finished with a leather, PPT b, or Plastazote c top cover. Local softening, metatarsal pads, or bars could be incorporated in the insoles. The stiffened rubber or Poron b shoe outsole had a roller configuration. Assessments All study data were collected, post-processed, and entered into a database by three trained researchers to minimize variation between assessments and centers. At baseline, data on demographics, diabetes, and foot complication history were collected. Loss 82

86 Prevention of foot ulcer recurrence in diabetes of protective sensation was assessed using 10g Semmes-Weinstein monofilament and Biothesiometer e testing 5. Peripheral arterial status was assessed based on the PEDIS classification 19. Presence of foot deformity was assessed from standardized digital photographs of the foot. Barefoot dynamic plantar pressure distribution was measured at 100Hz sampling rate using an Emed-X pressure platform d, 20. Regional mean peak pressures over 5 steps per foot were calculated and used for analysis. Each patient received written and verbal instructions on foot care and on proper use of footwear. All footwear in both study groups was evaluated at delivery and at three-monthly follow-up visits using the Pedar-X in-shoe pressure measurement system d that measured peak pressure distribution at 50Hz sampling rate at the sock-insole interface during comfortable walking 21. In the improved-footwear group, the measured in-shoe plantar pressures guided the modification of footwear, according to a previously described algorithm 22. In short, the previous ulcer location and, per foot, the two highest forefoot or midfoot peak pressure locations above 200kPa were identified. The footwear was modified by the shoe technician with the goal to reduce peak pressure at these regions of interest with 25%, or below an absolute level of 200kPa 17, 23. If these criteria were not met directly, a maximum of two further rounds of modifications and pressure evaluations were applied. The choice of footwear modifications was left to the shoe technician and multiple modifications were allowed at once. At each 3-month follow-up visit, the same protocol was applied when the offloading criteria were not yet met at footwear delivery or when peak pressure at the region of interest had increased 5% over time. Footwear use was measured objectively during 7 consecutive days at least three months after randomization with a temperature-based monitor f placed inside the shoe 12, 24. Walking activity was measured simultaneously using a step activity monitor g worn around the ankle. Both monitors produced valid and reliable data 24, 25. Average daily step count and adherence, defined as the percentage of steps over seven days that custom-made footwear was worn, were calculated. 6 Subjects were followed for 18 months or until plantar foot ulcer recurrence. The primary outcome was the percentage of patients with a plantar foot ulcer in 18 months. Ulcers were defined as cutaneous erosions through the dermis without reference to time present 19, 26. Ulcers were diagnosed by three (or by five in case of disagreement) blinded and independent foot care specialists, not directly involved in the study, from digital photographs taken at or in-between follow-up visits, added with descriptions of the lesion. These specialists classified ulcers using the University of Texas system 27. Non-ulcerative plantar lesions (i.e. hemorrhage, blister, abundant callus, or erythema) were scored from the photographs by two teams of two blinded observers who reached consensus on outcome. Statistical analysis Statistical analysis was performed after the last follow-up measurement in April 2012 using SPSS h, if not otherwise mentioned. All tests assessed group effects, were two-sided, using P < 0.05 for significance. Baseline patient characteristics, in-shoe peak pressures at delivery, daily step count, and adherence were assessed using independent sample t-tests when data was normally distributed and Mann-Whitney U tests when 83

87 Chapter 6 data was not-normally distributed. In-shoe peak pressures over time were modeled by multilevel linear regression analysis using MLwiN software i and nested at three levels: time, patient, and centre, to account for any dependency on these factors. Fixed factors were group, time, and group-time interaction. To analyze study group effects, pressures were corrected for baseline values at study entry. In an intention-to-treat analysis, the primary outcome was assessed using Pearson χ 2 tests. Outcome data from patients who died during the study was based on outcome at moment of death. From patients who withdrew participation, 18-month outcome data was obtained with their consent from patient files. Survival of ulcer recurrence was assessed using Kaplan-Meier plots and log-rank testing using censored data for death. χ 2 tests were conducted to test for the percentage of patients who had ulcer recurrence at the previous ulcer location and the percentage of patients with non-ulcerative lesions. Fisher s exact test was conducted for the percentage of patients with complicated foot ulcers. To assess the influence of footwear adherence on ulcer recurrence, χ 2 tests compared the primary outcome between study groups in the subgroups of patients with high adherence and with low adherence. These subgroups were determined based on a pre-statistical-analysis defined cut-off point of 80% indicated from previous studies as being an appropriate cut-off point to create similar-sized groups of high and low adherent patients 12, 28. We anticipated an 18-month ulcer recurrence rate of 30% in the usual-care group based on estimates from the literature 8-10, 29 and 15% in the improved-footwear group based on what we considered a relevant risk reduction compared to usual care. Based on a 0.05 (one-sided), power 0.80, χ 2 analysis, and anticipated loss to follow-up of 20%, we intended to include 240 patients. Due to a lower recruitment rate in the time available, actual sample size was 171. Based on the initially anticipated recurrence rates and intention-to-treat analysis, this sample size yielded a power of 0.76 (one-sided) and 0.65 (two-sided). RESULTS Study participants A study flow diagram is shown in Figure 1. The number of included subjects varied between six and 32 across participating centers. Loss to follow-up was 6%. Causes of death and reasons given to withdraw were not related to the study intervention. Of all planned 3-monthly follow-up visits, 97% took place. Of the 77 patients who were surveyed at final visit for success in patient blinding, 74 did not know the existence of two study groups or to which study group they were assigned. Baseline patient characteristics are shown in Table 1. There was no effect of sex or ethnicity on the primary and secondary outcome. 84

88 Prevention of foot ulcer recurrence in diabetes Table 1. Baseline characteristics of the subjects. Characteristic Improved footwear Usual care No. of subjects Age (years) 62.6± ±10.1 Male gender (%) Caucasian ethnicity (%) Diabetes type 2 (%) Diabetes duration (years) (n=169) 19.9± ±11.2* Glycated haemoglobin (mmol/mol) (n=162) 58.9± ±16.1 Body mass index (kg/m 2 ) 30.9± ±4.9 Loss of protective sensation (%), based on: Abnormal SW monofilament Vibration perception threshold >25V Vibration perception threshold (V) 50.0 (11.1) 50.0 (9.0) Peripheral arterial disease (%) (n=160) Foot deformity (%) Absent Mild Moderate Severe Fully custom-made footwear (%)ǁ Barefoot peak pressure at baseline (kpa) At the previous ulcer location (n=147) 675± ±396 At the highest pressure location (n=167) 934± ±286* In-shoe peak pressure at footwear delivery (kpa)# At all regions of interest >200 kpa (n=564) 269±62 273±56 Previous ulcer location > 200 kpa (n=90) 281±68 316±87* Previous ulcer location < 200 kpa (n=139) 124±44 126±40 Data are expressed as N, percentage (%), mean ± standard deviation for normally distributed data, or median (inter-quartile range) for not-normally distributed data, for the 171 analyzed patients if not specified differently. Loss of protective sensation was confirmed present in both feet by the inability to sense the pressure of a 10g Semmes Weinstein monofilament at any of three plantar foot sites (hallux, first and third metatarsal head) or a vibration of 25 Volts at the hallux from a Biothesiometer (maximum measurable value 50 Volts). In 12 patients the vibration perception threshold could only be measured in one foot due to hallux amputation. Peripheral arterial disease was confirmed present when pedal pulses were non-palpable and ankle-brachial index was <0.9 in the foot with the most recent episode of ulceration, according to the PEDIS classification 19. In five cases, peripheral arterial disease could not be assessed and in six other cases data was missing. Foot deformity was classified as absent, mild (i.e. pes planus, pes cavus, hallux valgus or limitus, hammer toes, and lesser toe amputation), moderate (i.e. hallux rigidus, hallux or ray amputation, prominent metatarsal heads, claw toes), or severe (i.e. Charcot deformity, (fore)foot amputation and pes equines). The foot with the most severe deformity classification determined classification per patient. ǁ Fully custom-made footwear was custom-made insoles worn in custom-made shoes. All other subjects wore custom-made insoles in off-the-shelf (extra-depth) shoes. Barefoot pressure could not be measured in four patients. In 20 more patients, the previous ulcer location was not present due to amputation. # Cumulative numbers for the previous ulcer location (90 and 139) add up to more than 171 because many patients had more than one pair of custom-made shoes. * Significantly different between groups, P <

89 Chapter 6 Figure 1. Study flow diagram. In-shoe pressures and footwear modifications At footwear delivery and over time, in-shoe peak pressures were significantly lower after modifying the footwear in the improved-footwear group when compared to the usual-care group in regions with peak pressure >200 kpa (Figure 2, Table 2). No time or group-time interaction effects were found. A total of 1183 footwear modifications in a mean 1.2 rounds of modifications per shoe pair per visit per patient were made in the improved-footwear group. In-between visits, no footwear modifications were made in the improved-footwear group. In 20 of 86 subjects from the usual-care group, a total of 33 footwear modifications were made in-between follow-up visits following usual care. Ulcer recurrence Of the 171 randomized patients, 71 had a recurrent plantar foot ulcer in 18 months (Table 2). In the improved-footwear group, 38.8% of patients had a recurrent ulcer, 86

90 Prevention of foot ulcer recurrence in diabetes which was not significantly different compared to the 44.2% recurrence in the usualcare group (relative risk reduction 11%, odds ratio 0.80, 95% confidence interval 0.44 to 1.47, P = 0.48). Ulcer survival curves were also not significantly different between study groups (Figure 3; P = 0.40). The improved-footwear group showed significantly less complicated foot ulcers (i.e. depth 3 or grade C, D ulcers according to Texas classification system) than the usual-care group. Seventy-nine patients (=46% of the total group) were adherent to wearing their custommade footwear, of which 35 were in the improved-offloading group and 44 in the usualcare group. No significant differences were found between the two study groups on baseline patient characteristics. In this subgroup of 79 adherent patients, 25.7% of patients with improved footwear had a recurrent ulcer. This was significantly lower than the 47.8% recurrence in with usual care (relative risk reduction 46%, odds ratio 0.38, 95% confidence interval 0.15 to 0.99, P = 0.045). Ulcer survival curves were also significantly different between study groups, in favor of the improved-footwear group (Figure 3; P = 0.046). 6 Figure 2. Mean in-shoe peak pressures over 18 months follow-up for all previous ulcer locations (PUL) with peak pressure at footwear delivery >200 kpa in black, all previous ulcer locations with peak pressure <200 kpa in dark grey, and all regions of interest (ROI) with peak pressure >200 kpa in light grey for both the improvedfootwear group (IF, closed symbols) and usual-care group (UC, open symbols). Changes in peak pressure at each follow-up in the improved-footwear group are pressure changes after footwear modification. Error bars represent standard errors (SE) of the mean. 87

91 Chapter 6 Table 2. Clinical and biomechanical outcomes. Outcome parameter Improved footwear Usual care P-value; Effect; [95%CI] In-shoe peak pressure at follow-up (kpa) All regions of interest >200 kpa (n=2648) 221±51 274±66 P < 0.001; b: -53; [-65; -42] Previous ulcer locations >200 kpa (n=473) 200±47 304±101 P < 0.001; b: -69; [-89; -49] Previous ulcer locations < 200 kpa (n=767) 127±44 133±42 P = 0.17; b: -6; [-14; 2] Daily step count (n=157) 7287± ±3175 P = Adherence (% of steps) (n=150) 70.2± ±23.4 P = 0.18 Ulcer recurrence No. of patients with ulcer (%) 33 (38.8) 38 (44.2) P = 0.48; OR: 0.80; [0.44; 1.47] At previous ulcer location (%) P = 0.63; OR: 0.79; [0.31; 2.07] Complicated foot ulcers (%) P = 0.027; OR: 0.07; [0.00; 1.38] Ulcer recurrence according to adherence No. of adherent patients No. of adherent patients with ulcer (%) 9 (25.7) 21 (47.8) P = 0.045; OR: 0.38; [0.15; 0.99] No. of non-adherent patients No. of non-adherent patients with ulcer (%) 16 (41.0) 11 (34.4) P = 0.57; OR: 1.33; [0.50; 3.50] Non-ulcerative lesions at follow-up No. of patients with a non-ulcerative lesion (%) 31 (36.5) 39 (45.3) P = 0.24; OR: 0.69; [0.38; 1.28] No. of non-ulcerative lesions Data are expressed as N, percentage (%), mean ± standard deviation for normally distributed data, or median (inter-quartile range) for not-normally distributed data. Effect size from multi-level analysis; OR: odds ratio; CI: confidence interval. Footwear use was not measured in 21 patients because these patients dropped-out of the study before measurement (n=4), had a foot ulcer before measurement (n=5), refused measurement (n=7), or for other reasons (n=5). High adherence was a priori defined as 80% of steps in custom-made footwear, low adherence as <80% of steps in custom-made footwear. University of Texas classification with complicated ulcers represented as depth 3 (i.e. bone contact) or grade C or D ulcers (ischemia with or without infection) 27. Two patients were not classified, one in each study group. 88

92 Prevention of foot ulcer recurrence in diabetes 6 Figure 3. Kaplan-Meier plots of cumulative survival on plantar foot ulcer recurrence over 18 months follow-up with censored data for patients who died. Top diagram: intention-to-treat (N=171). Bottom diagram: the group of 79 patients (=46% of total) who were adherent to wearing custom-made footwear (i.e. 80% of steps taken in custom-made footwear). 89

93 Chapter 6 Adverse events and non-ulcerative lesions Thirty serious adverse events occurred during follow-up (four deaths, 26 hospital admissions), equally divided between groups, and none could be related to the intervention. No significant group differences were present for non-ulcerative lesions (Table 2). Of the 71 patients who reulcerated, 29 (=41%) had a non-ulcerative plantar lesion at study entry against 17 of the 100 patients (=17%) who did not reulcerate (odds ratio 3.4, 95% confidence interval 1.7 to 6.8, P < 0.001). CONCLUSIONS Among patients with diabetes, peripheral neuropathy, and a recently healed plantar foot ulcer, offloading-improved custom-made footwear showed no statistically significant protective effect against plantar foot ulcer recurrence over usual care. This unexpected outcome shows that better offloading in protective footwear is by itself not clinically beneficial. The intention-to-treat analysis was slightly underpowered, but we do not expect that inclusion of the originally anticipated number of patients would have given different outcomes. To understand (lack of) clinical success, we assessed the influence of footwear adherence, which was accurately measured using objective methods. Offloading-improved custom-made footwear significantly reduced plantar foot ulcer recurrence risk with 46% compared to usual care in the subgroup of 79 adherent patients. This suggests that improved offloading can be clinically beneficial when continuous pressure relief is guaranteed by assuring that custom-made footwear is worn. Although such a positive effect should be confirmed in future trials, for patient care this would imply a reduced risk for infection and amputation, reduced treatment costs, and preserved patient quality of life 4. The incidence of plantar foot ulcer recurrence was higher than found in other footwear studies, confirming that we included high-risk patients who are prone to develop recurrent ulcers. Reiber et al. 10 showed 15% recurrence in two years in patients wearing custom-made footwear. However, many of their patients had foot sensation, they used a more conservative classification for ulceration, and they excluded moderate to severe foot deformity, which may explain the difference with our study. Rizzo et al. 11 reported 12% ulcer occurrence in 12 months, including patients with severe deformity, but only 20% of their studied patients had a prior foot ulcer. All patients in our study had a recently healed foot ulcer, which could leave the tissue more vulnerable for subsequent breakdown, as indicated by the high prevalence of non-ulcerative lesions at footwear delivery in patients who developed ulcer recurrence, and the quick drop in ulcer-free survival (Figure 3). Uccioli et al. 9 found comparable recurrence percentages to our study, but we assessed only plantar foot ulcers, whereas others including Uccioli et al. assessed all foot ulcers, regardless of location. The primary goal of custom-made footwear is to protect the foot by reducing pressure at high-risk foot locations. Previous footwear trials did not identify whether intervention footwear relieved pressure more than control footwear and, therefore, what role pressure relief plays in ulcer prevention. The non-significant relative risk reduction of 11% found in our study suggests that ~20% improvement in offloading at selected regions of interest is insufficient to reduce ulcer recurrence risk. As comparison, devices found to 90

94 Prevention of foot ulcer recurrence in diabetes be successful in healing plantar diabetic foot ulcers can reduce peak pressure with more than 50% compared to a control condition 30. Also the effect of the many repetitive cycles produced while walking unprotected on a deformed foot at high levels of barefoot pressure (see table 1 and 2 for data) may play a role. This combination of biomechanical and behavioral factors may counteract any beneficial effect that the footwear had and explain the high ulcer recurrence percentages and small effect size found. Identifying the exact cause of ulceration may shed more light on the relative role of these factors. This is difficult though. We collected data on ulcer cause from patient self-reports, but this data was not reliable enough to present and draw conclusions from. The relative reduction of 46% in ulcer recurrence risk with using offloading-improved custom-made footwear in the group of adherent patients suggests that diabetic foot care should focus on the combined improvement of offloading and adherence. Footwear offloading can be improved under guidance of in-shoe pressure measurements or by using specific insole design methods 14, 15, 17, 22. To improve adherence, the provision of offloading footwear specifically for indoor use may be effective since recent data shows that adherence in high-risk diabetic patients is much lower at home than away from home 12. To date, patient education programs have failed to assess, let alone improve, footwear adherence and require further investigation 31. The relatively high prevalence of non-ulcerative lesions found at footwear delivery in patients who re-ulcerated suggests that, additionally, the early recognition and treatment of these lesions could be an important contributor to prevention of ulcer recurrence. In conclusion, our findings do not support the use of offloading-improved custom-made footwear as a single intervention to reduce the incidence of plantar foot ulcer recurrence in diabetic patients with high foot ulcer risk. However, the data suggests that a favorable and important clinical effect of offloading-improved custom-made footwear can be achieved when adherence to wearing this footwear is assured. Although future trials should confirm the positive effect of continuously worn offloading-improved footwear, based on the current findings we recommend the combined improvement of footwear offloading and adherence to reduce the risk of plantar foot ulcer recurrence in high-risk diabetic patients. 6 Suppliers a TENALEA Clinical Trial Data Management System, National Cancer Institute, Amsterdam, the Netherlands b PPT; Professional Protective Technology, Langer, Inc., Deer Park, New York, USA c Zotefoams plc, Croydon, UK d Novel, Munich, Germany e Biomedical Instruments, Newbury, Ohio, USA f Department of Medical Technology and Innovation, Academic Medical Center, Amsterdam, the Netherlands g Orthocare Innovations LLC, Oklahoma City, OK, USA h SPSS Inc., version 19.0, an IBM company, Armonk, NY, USA i MLwiN software, version 2.23, Institute of Education, University of London, London, UK. 91

95 Chapter 6 Acknowledgements The DIAbetic Foot Orthopedic Shoe (DIAFOS) trial was supported by project grants from the Dutch Diabetes Research Foundation (project ), the Dutch Foundation for the Development of Orthopedic Footwear Technology (OFOM), and the Dutch Organization for Health Research and Development (project ). In the DIAFOS trial, the Academic Medical Center in Amsterdam collaborated with nine other hospitals and nine orthopedic footwear companies in the Netherlands. The authors acknowledge the contribution of Ms. R. Keukenkamp (Academic Medical Center, Amsterdam) in collecting data for the study, and the following persons in recruiting patients and modifying footwear: PJA Mooren (Academic Medical Center, Amsterdam); JWE Verlouw, MD, I Ruijs, H van Wessel (Maxima Medical Centre, Veldhoven); JPJ Bakker, MD, PhD, C van den Eijnde (Medical Center Alkmaar); D Wever, MD, H Wessendorf (Medisch Spectrum Twente, Enschede); R Dahmen, MD, B Koomen (Slotervaart Hospital, Amsterdam); R Haspels (Hospital group Twente, Almelo); J Harlaar, PhD, V de Groot, MD, PhD, J Pulles (VU Medical Center, Amsterdam); WP Polomski, MD, R Lever, G du Mont (Spaarne Hospital, Hoofddorp); HGA Hacking, MD, J de Bruin (St. Antonius Hospital, Nieuwegein); H Berendsen, MD, W Custers, and I Paardekoper (Reinier de Graaf Gasthuis, Delft). Furthermore, we acknowledge the contribution of RP Michels, MD, PhD, HA Manning, CEVB Hazenberg, MD, EJ Peters, MD, PhD, and NC Schaper, MD, PhD in assessing the primary outcome in the study, and members of the Trial Steering Committee (NC Schaper, MD, PhD, F Elferink, and AL de Lange, PhD) for their valuable advice. 92

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