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Multiple factors predict longer and shorter time-to-ulcer-free in people with diabetes-related foot ulcers: Survival analyses of a large prospective cohort followed-up for 24-months

  • Yuqi Zhang
    Correspondence
    Corresponding author at: School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia, 60 Musk Ave Kelvin Grove, QLD 4059, Australia.
    Affiliations
    Australian Centre for Health Services Innovation & Centre for Healthcare Transformation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia

    Centre for Data Science, Queensland University of Technology, Brisbane, Australia
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  • Susanna Cramb
    Affiliations
    Australian Centre for Health Services Innovation & Centre for Healthcare Transformation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia

    Centre for Data Science, Queensland University of Technology, Brisbane, Australia

    Jamieson Trauma Institute, Royal Brisbane and Women’s Hospital, Metro North Health, Brisbane, Australia
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  • Steven M. McPhail
    Affiliations
    Australian Centre for Health Services Innovation & Centre for Healthcare Transformation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia

    Clinical Informatics Directorate, Metro South Health, Brisbane, Australia
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  • Rosana Pacella
    Affiliations
    Institute for Lifecourse Development, University of Greenwich, Greenwich, London, UK
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  • Jaap J. van Netten
    Affiliations
    Amsterdam UMC, University of Amsterdam, Department of Rehabilitation Medicine, Amsterdam Movement Sciences, Meibergdreef 9, Amsterdam, the Netherlands
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  • Qinglu Cheng
    Affiliations
    Kirby Institute, University of New South Wales, Sydney, Australia
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  • Patrick H. Derhy
    Affiliations
    Clinical Access and Redesign Unit, Queensland Health, Brisbane, Australia
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  • Ewan M. Kinnear
    Affiliations
    Allied Health Research Collaborative, The Prince Charles Hospital, Brisbane, Australia
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  • Peter A. Lazzarini
    Affiliations
    Australian Centre for Health Services Innovation & Centre for Healthcare Transformation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia

    Allied Health Research Collaborative, The Prince Charles Hospital, Brisbane, Australia
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  • on behalf of the Diabetic Foot Working Group, Queensland Statewide Diabetes Clinical Network, Australia
    Author Footnotes
    1 Membership of the Diabetic Foot Working Group, Queensland Statewide Diabetes Clinical Network (Australia) is provided in the Acknowledgments.
  • Author Footnotes
    1 Membership of the Diabetic Foot Working Group, Queensland Statewide Diabetes Clinical Network (Australia) is provided in the Acknowledgments.
Published:February 03, 2022DOI:https://doi.org/10.1016/j.diabres.2022.109239

      Highlights

      • Median time-to-(being)-ulcer-free in 4,709 DFU patients was 112 days and 68.4% were ulcer-free within two years.
      • Each year younger than 60 years was independently associated with longer time-to-ulcer-free.
      • PAD and ulcer size were associated with longer time-to-ulcer-free but only for 6 months.
      • Podiatry and knee-high offloading treatment were associated shorter time-to-ulcer-free.
      • Probability of being ulcer-free was largest for geographical remoteness and PAD factors.

      Abstract

      Aims

      To investigate factors independently associated with time-to-(being)-ulcer-free, time-varying effects and predict adjusted ulcer-free probabilities, in a large prospective cohort with diabetes-related foot ulcers (DFU) followed-up for 24 months.

      Methods

      Patients presenting with DFU(s) to 65 Diabetic Foot Services across Queensland, Australia, between July-2011 and December-2017 were included. Demographic, comorbidity, limb, ulcer, and treatment factors were captured at presentation. Patients were followed-up until ulcer-free (all DFU(s) healed), amputation, death or two years. Factors associated with time-to-ulcer-free were investigated using both Cox proportional hazards and flexible parametric survival models to explore time-varying effects and plot predicted adjusted ulcer-free probability graphs.

      Results

      Of 4,709 included patients (median age 63 years, 69.5% male), median time-to-ulcer-free was 112 days (IQR:40->730), with 68.4% ulcer-free within two years. Factors independently associated with longer time-to-ulcer-free were each year of age younger than 60 years, living in a regional or remote area, smoking, neuropathy, peripheral artery disease (PAD), ulcer size >1 cm2, deep ulcer and mild infection (all p < 0.05). Time-varying effects were found for PAD and ulcer size limiting their association to six months only. Shorter time-to-ulcer-free was associated with recent DFU treatment by a podiatrist and receiving knee-high offloading treatment (both p < 0.05). Predicted adjusted ulcer-free probability graphs reported largest differences in time-to-ulcer-free over 24-months for geographical remoteness and PAD factors.

      Conclusions

      Multiple factors predicted longer and shorter time-to-ulcer-free in people presenting with DFUs. Considering these factors, their time-varying effects and adjusted ulcer-free probability graphs, should aid the prediction of the likely time-to-(being)-ulcer-free for DFU patients.

      Keywords

      Abbreviations:

      DFU (diabetes-related foot ulcer), PAD (peripheral artery disease), QHRFF (Queensland High Risk Foot Form), HR (hazard ratio), IQR (interquartile range), CI (confidence interval)
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      References

        • Zhang Y.
        • Lazzarini P.
        • McPhail S.
        • van Netten J.
        • Armstrong D.
        • Pacella R.
        Global Disability Burdens of Diabetes-Related Lower-Extremity Complications in 1990 and 2016.
        Diabetes Care. 2020; 43: 964-974https://doi.org/10.2337/dc19-1614
        • Armstrong D.G.
        • Boulton A.J.M.
        • Bus S.A.
        Diabetic Foot Ulcers and Their Recurrence.
        N Engl J Med. 2017; 376: 2367-2375
        • Jia L.
        • Parker C.N.
        • Parker T.J.
        • Kinnear E.M.
        • Derhy P.H.
        • Alvarado A.M.
        • et al.
        Incidence and risk factors for developing infection in patients presenting with uninfected diabetic foot ulcers.
        PLoS ONE. 2017; 12: e0177916
        • Pickwell K.
        • Siersma V.
        • Kars M.
        • Apelqvist J.
        • Bakker K.
        • Edmonds M.
        • et al.
        Predictors of Lower-Extremity Amputation in Patients With an Infected Diabetic Foot Ulcer.
        Diabetes Care. 2015; 38: 852-857https://doi.org/10.2337/dc14-1598
        • Lazzarini P.
        • Hurn S.E.
        • Kuys S.S.
        • et al.
        The silent overall burden of foot disease in a representative hospitalised population.
        Int Wound J. 2016; 14: 716-728https://doi.org/10.1111/iwj.12683
        • Lazzarini P.A.
        • Pacella R.E.
        • Armstrong D.G.
        • van Netten J.J.
        Diabetes-related lower-extremity complications are a leading cause of the global burden of disability.
        Diabet Med. 2018; 35: 1297-1299https://doi.org/10.1111/dme.13680
        • Kerr M.
        • Barron E.
        • Chadwick P.
        • Evans T.
        • Kong W.M.
        • Rayman G.
        • et al.
        The cost of diabetic foot ulcers and amputations to the National Health Service in England.
        Diabet Med. 2019; 36: 995-1002https://doi.org/10.1111/dme.13973
        • Prompers L.
        • Schaper N.
        • Apelqvist J.
        • Edmonds M.
        • Jude E.
        • Mauricio D.
        • et al.
        Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease.
        The EURODIALE Study. Diabetologia. 2008; 51: 747-755
        • Pickwell K.M.
        • Siersma V.D.
        • Kars M.
        • Holstein P.E.
        • Schaper N.C.
        Diabetic foot disease: impact of ulcer location on ulcer healing.
        Diabetes Metab Res Rev. 2013; 29: 377-383https://doi.org/10.1002/dmrr.2400
        • Örneholm H.
        • Apelqvist J.
        • Larsson J.
        • Eneroth M.J.W.R.
        • Regeneration
        High probability of healing without amputation of plantar forefoot ulcers in patients with diabetes.
        Wound Repair Regen. 2015; 23: 922-931
      1. National Diabetes Foot Care Audit (2019) National Diabetes Foot Care Audit Fourth Annual Report. Available from https://digital.nhs.uk/data-and-information/publications/statistical/national-diabetes-footcare-audit/2014-2018. Accessed 9 May 2021.

        • Monteiro‐Soares M.
        • Boyko E.J.
        • Jeffcoate W.
        • Mills J.L.
        • Russell D.
        • Morbach S.
        • et al.
        Diabetic foot ulcer classifications: A critical review.
        Diabetes Metab Res Rev. 2020; 36https://doi.org/10.1002/dmrr.3272
        • Leese G.
        • Schofield C.
        • McMurray B.
        • Libby G.
        • Golden J.
        • MacAlpine R.
        • et al.
        Scottish foot ulcer risk score predicts foot ulcer healing in a regional specialist foot clinic.
        Diabetes Care. 2007; 30: 2064-2069
        • Jeffcoate W.J.
        • Chipchase S.Y.
        • Ince P.
        • Game F.L.
        Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures.
        Diabetes Care. 2006; 29: 1784-1787https://doi.org/10.2337/dc06-0306
        • Holman N.
        • Young B.
        • Stephens H.
        • Jeffcoate W.
        Pilot study to assess measures to be used in the prospective audit of the management of foot ulcers in people with diabetes.
        Diabet Med. 2015; 32: 78-84
        • Ha Van G.
        • Amouyal C.
        • Bourron O.
        • Aubert C.
        • Carlier A.
        • Mosbah H.
        • et al.
        Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.
        Journal of Wound Care. 2020; 29: 464-471
        • Gershater M.A.
        • Löndahl M.
        • Nyberg P.
        • Larsson J.
        • Thörne J.
        • Eneroth M.
        • et al.
        Complexity of factors related to outcome of neuropathic and neuroischaemic/ischaemic diabetic foot ulcers: a cohort study.
        Diabetologia. 2009; 52: 398-407https://doi.org/10.1007/s00125-008-1226-2
        • Fife C.E.
        • Horn S.D.
        • Smout R.J.
        • Barrett R.S.
        • Thomson B.
        A Predictive Model for Diabetic Foot Ulcer Outcome: The Wound Healing Index.
        Advances in Wound Care. 2016; 5: 279-287https://doi.org/10.1089/wound.2015.0668
        • Beckert S.
        • Witte M.
        • Wicke C.
        • Königsrainer A.
        • Coerper S.
        A new wound-based severity score for diabetic foot ulcers: a prospective analysis of 1,000 patients.
        Diabetes Care. 2006; 29: 988-992
        • Oyibo S.O.
        • Jude E.B.
        • Tarawneh I.
        • Nguyen H.C.
        • Armstrong D.G.
        • Harkless L.B.
        • et al.
        The effects of ulcer size and site, patient's age, sex and type and duration of diabetes on the outcome of diabetic foot ulcers.
        Diabet Med. 2001; 18: 133-138https://doi.org/10.1046/j.1464-5491.2001.00422.x
        • Margolis D.J.
        • Allen-Taylor L.
        • Hoffstad O.
        • Berlin J.A.
        Diabetic neuropathic foot ulcers: the association of wound size, wound duration, and wound grade on healing.
        Diabetes Care. 2002; 25: 1835-1839https://doi.org/10.2337/diacare.25.10.1835
        • Akturk A.
        • Netten J.J.
        • Scheer R.
        • Vermeer M.
        • Baal J.G.
        Ulcer-free survival days and ulcer healing in patients with diabetic foot ulcers: A prospective cohort study.
        Int Wound J. 2019; 16: 1365-1372https://doi.org/10.1111/iwj.13199
        • Jeffcoate W.J.
        • Bus S.A.
        • Game F.L.
        • Hinchliffe R.J.
        • Price P.E.
        • Schaper N.C.
        Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality.
        Lancet Diabetes Endocrinol. 2016; 4: 781-788https://doi.org/10.1016/s2213-8587(16)30012-2
        • Zhang Y.
        • Cramb S.
        • McPhail S.M.
        • Pacella R.
        • van Netten J.J.
        • Cheng Q.
        • et al.
        Factors associated with healing of diabetes-related foot ulcers: observations from a large prospective real-world cohort.
        Diabetes Care. 2021; 44: e143-e145https://doi.org/10.2337/dc20-3120
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gøtzsche P.C.
        • Vandenbroucke J.P.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies.
        PLoS Med. 2007; 18: 800-804
      2. Australian Bureau of Statistics (2019) Data by region, 2013-18. Available from https://www.abs.gov.au/AUSSTATS/[email protected]/Lookup/1410.0Main+Features12013-18?OpenDocument. Accessed March 1 2020.

      3. National Diabetes Service Scheme (2019) The Australian diabetes map. Available from https://map.ndss.com.au/. Accessed 1 May 2020.

        • van Netten J.J.
        • Bus S.A.
        • Apelqvist J.
        • Lipsky B.A.
        • Hinchliffe R.J.
        • Game F.
        • et al.
        Definitions and criteria for diabetic foot disease.
        Diabetes Metab Res Rev. 2020; 36https://doi.org/10.1002/dmrr.3268
        • Armstrong D.
        • Lavery L.
        • Harkless L.
        Validation of a Diabetic Wound Classification System: The contribution of depth, infection, and ischemia to risk of amputation.
        Diabetes Care. 1998; 21: 855-859https://doi.org/10.2337/diacare.21.5.855
        • Lazzarini P.A.
        • Ng V.
        • Kinnear E.M.
        • Kamp M.C.
        • Kuys S.S.
        • Hurst C.
        • et al.
        The Queensland high risk foot form (QHRFF)–is it a reliable and valid clinical research tool for foot disease?.
        Journal of foot and ankle research. 2014; 7https://doi.org/10.1186/1757-1146-7-7
        • Queensland Health
        Queensland High Risk Foot Form Guideline: Statewide Diabetic Foot Working Group.
        in: Network S.D.C. Brisbane. Australia, 2011
        • Lazzarini P.A.
        • O’Rourke S.R.
        • Russell A.W.
        • Derhy P.H.
        • Kamp M.C.
        • Icks A.
        Reduced Incidence of Foot-Related Hospitalisation and Amputation amongst Persons with Diabetes in Queensland, Australia.
        PLoS ONE. 2015; 10: e0130609https://doi.org/10.1371/journal.pone.0130609
        • Lambert P.C.
        • Royston P.
        Further Development of Flexible Parametric Models for Survival Analysis.
        the Stata Journal. 2009; 9: 265-290https://doi.org/10.1177/1536867x0900900206
        • Hamilton E.J.
        • Davis W.A.
        • Siru R.
        • Baba M.
        • Norman P.E.
        • Davis T.M.E.
        Temporal Trends in Incident Hospitalization for Diabetes-Related Foot Ulcer in Type 2 Diabetes: The Fremantle Diabetes Study.
        Diabetes Care. 2021; 44: 722-730https://doi.org/10.2337/dc20-1743
        • Aan de Stegge W.B.
        • Schut M.C.
        • Abu-Hanna A.
        • van Baal J.G.
        • van Netten J.J.
        • Bus S.A.
        Development of a prediction model for foot ulcer recurrence in people with diabetes using easy-to-obtain clinical variables.
        BMJ Open Diabetes Res Care. 2021; 9: e002257https://doi.org/10.1136/bmjdrc-2021-002257
        • Tan T.-W.
        • Armstrong D.G.
        • Concha-Moore K.C.
        • et al.
        Association between race/ethnicity and the risk of amputation of lower extremities among medicare beneficiaries with diabetic foot ulcers and diabetic foot infections.
        BMJ Open Diabetes Research & Care. 2020; 8e001328https://doi.org/10.1136/bmjdrc-2020-001328
        • Driver V.R.
        • Goodman R.A.
        • Fabbi M.
        • French M.A.
        • Andersen C.A.
        The impact of a podiatric lead limb preservation team on disease outcomes and risk prediction in the diabetic lower extremity: a retrospective cohort study.
        J Am Podiatr Med Assoc. 2010; 100: 235-241https://doi.org/10.7547/1000235
        • Blanchette V.
        • Brousseau-Foley M.
        • Cloutier L.
        Effect of contact with podiatry in a team approach context on diabetic foot ulcer and lower extremity amputation: systematic review and meta-analysis.
        Journal of Foot and Ankle Research. 2020; 13https://doi.org/10.1186/s13047-020-0380-8
        • Ince P.
        • Kendrick D.
        • Game F.
        • Jeffcoate W.
        The association between baseline characteristics and the outcome of foot lesions in a UK population with diabetes.
        Diabet Med. 2007; 24: 977-981https://doi.org/10.1111/j.1464-5491.2007.02189.x
        • Hinchliffe R.J.
        • Forsythe R.O.
        • Apelqvist J.
        • Boyko E.J.
        • Fitridge R.
        • Hong J.P.
        • et al.
        Guidelines on diagnosis, prognosis, and management of peripheral artery disease in patients with foot ulcers and diabetes (IWGDF 2019 update).
        Diabetes Metab Res Rev. 2020; 36https://doi.org/10.1002/dmrr.3276
        • Cramb S.M.
        • Mengersen K.L.
        • Lambert P.C.
        • Ryan L.M.
        • Baade P.D.
        A flexible parametric approach to examining spatial variation in relative survival.
        Stat Med. 2016; 35: 5448-5463https://doi.org/10.1002/sim.7071
        • Lazzarini P.
        • Fitridge R.
        Regional variations in amputation rates: are regional diabetic foot services the reason?.
        ANZ Journal of Surgery. 2019; 89: 796-797https://doi.org/10.1111/ans.15161
        • Margolis D.J.
        • Hoffstad O.
        • Nafash J.
        • Leonard C.E.
        • Freeman C.P.
        • Hennessy S.
        • et al.
        Location, location, location: Geographic clustering of lower-extremity amputation among medicare beneficiaries with diabetes.
        Diabetes Care. 2011; 34: 2363-2367https://doi.org/10.2337/dc11-0807
        • Disler R.
        • Glenister K.
        • Wright J.
        Rural chronic disease research patterns in the United Kingdom, United States, Canada, Australia and New Zealand: a systematic integrative review.
        BMC public health. 2020; 20: 7https://doi.org/10.1186/s12889-020-08912-1
        • Chen P.Y.
        • Elmer S.
        • Callisaya M.
        • Wills K.
        • Greenaway T.M.
        • Winzenberg T.M.
        Associations of health literacy with diabetic foot outcomes: a systematic review and meta-analysis.
        Diabet Med. 2018; 35: 1470-1479https://doi.org/10.1111/dme.13694
        • Lazzarini P.A.
        • Jarl G.
        • Gooday C.
        • Viswanathan V.
        • Caravaggi C.F.
        • Armstrong D.G.
        • et al.
        Effectiveness of offloading interventions to heal foot ulcers in persons with diabetes: a systematic review.
        Diabetes Metab Res Rev. 2020; 36https://doi.org/10.1002/dmrr.3275
        • Bus S.A.
        • Armstrong D.G.
        • Gooday C.
        • Jarl G.
        • Caravaggi C.
        • Viswanathan V.
        • et al.
        Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update).
        Diabetes Metab Res Rev. 2020; 36https://doi.org/10.1002/dmrr.3274
        • Lazzarini P.A.
        • Crews R.T.
        • van Netten J.J.
        • Bus S.A.
        • Fernando M.E.
        • Chadwick P.J.
        • et al.
        Measuring Plantar Tissue Stress in People With Diabetic Peripheral Neuropathy: A Critical Concept in Diabetic Foot Management.
        J Diabetes Sci Technol. 2019; 13: 869-880https://doi.org/10.1177/1932296819849092
        • Fu X.L.
        • Ding H.
        • Miao W.W.
        • Chen H.L.
        Association Between Cigarette Smoking and Diabetic Foot Healing: A Systematic Review and Meta-Analysis.
        Int J Low Extrem Wounds. 2018; 17: 247-257https://doi.org/10.1177/1534734618809583
        • Xia N.
        • Morteza A.
        • Yang F.
        • Cao H.
        • Wang A.
        Review of the role of cigarette smoking in diabetic foot.
        J Diabetes Investig. 2019; 10: 202-215https://doi.org/10.1111/jdi.12952
        • Commons R.J.
        • Raby E.
        • Athan E.
        • Bhally H.
        • Chen S.
        • Guy S.
        • et al.
        Managing diabetic foot infections: a survey of Australasian infectious diseases clinicians.
        Journal of Foot and Ankle Research. 2018; 11https://doi.org/10.1186/s13047-018-0256-3
      4. Fernando ME, Seneviratne RM, Tan YM, et al. (2016) Intensive versus conventional glycaemic control for treating diabetic foot ulcers. The Cochrane database of systematic reviews(1): Cd010764. 10.1002/14651858.CD010764.pub2.

      5. Australian Bureau of Statistics (2016) Australian Standard Geographical Classification (ABS Cat No.1270.0). Available from https://www.abs.gov.au/AUSSTATS/[email protected]/Lookup/1270.0.55.005Explanatory%20Notes1July%202016?OpenDocument. Accessed 23 June 2019.