Risk Factors Associated With Adverse Outcomes in a Population-bgfytyased

lications 21 (2007) 341–349
Journal of Diabetes and Its Comp
Risk factors associated with adverse outcomes in a population-basedprospective cohort study of people with their first diabetic foot ulcer

Kirsty Winkleya,⁎, Daniel Stahlb, Trudie Chaldera, Michael E. Edmondsc, Khalida Ismaila

aDepartment of Psychological Medicine, Institute of Psychiatry, King's College London, Weston Education Centre, SE5 9RJ London, UKbDepartment of Biostatistics, Institute of Psychiatry, King's College London, De Crespigny Park, SE5 8AZ London, UK

cDiabetic Foot Clinic, King's College Hospital, Denmark Hill, SE5 9RS London, UK

Received 13 June 2007; received in revised form 13 August 2007; accepted 6 September 2007

Abstract

Aims/Hypothesis: The aim of this study was to determine which clinic-based measures of diabetes and foot status at baseline wereassociated with adverse outcomes 18 months later in people with diabetes presenting with their first foot ulcer. Subjects and Methods: Thiswas a prospective population-based cohort study of adults with type 1 and type 2 diabetes mellitus presenting with their first foot ulcer(excluding those with severe ischaemia, ankle brachial pressure index b0.5). The main explanatory variables were age, sex, smoking status,ulcer site (dorsal or plantar), size and severity of ulcer, severity of neuropathy, ischaemia, glycosylated haemoglobin, presence of micro- andmacrovascular complications, and depression. The main outcomes recorded were death, amputation and recurrence of ulceration, and thetime taken for each outcome to occur. Results: Two hundred fifty-three people were recruited. There were 40 deaths (15.8%), 36 amputations(15.5%), and 99 recurrences (43.2%) at 18 months. Our main findings were that being older [hazard ratio (HR) 1.07, 95% CI 1.04–1.11],having lower glycosylated haemoglobin (HR 0.73, 95% CI 0.56–0.96), moderate ischaemia (HR 2.74, 95% CI 1.46–5.14), and depression(HR 2.51, 95% CI 1.33–4.73) were associated with mortality. Ulcer severity was the only explanatory factor significantly associated withamputation (HR 3.18, 95% CI 1.53–6.59). Microvascular complications were the only explanatory factor associated with recurrent ulceration(HR 3.34, 95% CI 1.17–9.56). Conclusions/Interpretation: Commonly used primary and secondary care clinic-based measures couldprovide the basis for a risk assessment tool for adverse outcomes following first presentation of diabetic foot ulcers.© 2007 Elsevier Inc. All rights reserved.

Keywords: Diabetic foot; Clinical diabetes; Peripheral arterial disease; Cohort study

1. Introduction

Adverse outcomes are common in people with diabeticfoot ulcers. Survival is reduced (Ramsey et al., 1999), andfoot ulcers precede almost all lower extremity amputations(Wrobel, Mayfield, & Reiber, 2001). Costs of treatingdiabetic foot ulcers increase dramatically if patients requireinpatient care (Harrington, Zagari, Corea, & Klitenic, 2000;Van Acker et al., 2000) and represent a substantial drain on

⁎ Corresponding author. Tel.: +44 20 3299 1739; fax: +44 20 32991730.

E-mail address: [email protected] (K. Winkley).

1056-8727/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.jdiacomp.2007.09.004

health service resources. Sparse qualitative research suggeststhat diabetic foot ulceration has a profound social impactwith patients reporting stigma, social isolation, loss of socialrole, and unemployment (Croxson, 2002; Douglas, 2001;Fox, 2005). Quality of life is also reduced (Nabuurs-Franssen, Huijberts, Nieuwenhuijzen Kruseman, Willems,& Schaper, 2005; Vileikyte, 2001), and recent findingssuggest that depression is more prevalent (Carrington,Mawdsley, Morley, Kincey, Boulton, 1996; Ismail, Winkley,Stahl, Chalder, & Edmonds, 2007) than in general diabetes.There is a general consensus that successful treatment of footulcers involves multidisciplinary management following anagreed protocol, such as education (Barth, Campbell, Allen,Jupp, & Chisholm, 1991), regular debridement, wound

342 K. Winkley et al. / Journal of Diabetes and Its Complications 21 (2007) 341–349

dressing, and pressure relief plus management of factors thatmay compromise healing (Edmonds & Foster, 2000).However, the availability and quality of treatment isdependent on service provision (Edmonds, 2004) and mayvary across regions (Canavan, Connolly, Airey, Burden, &Unwin, 2003). There remains a need to translate risk factorsidentified in studies into simple risk assessment tools whichcan be used by nonspecialist clinicians especially in the earlystages of diabetic foot disease.

Prospective studies have examined risk factors forulceration in people with diabetes (Abbott et al., 2002;Boyko et al., 1999) and also risk factors for and rates of newulceration, amputation, and mortality in people hospitalisedfor diabetic foot ulcer (Faglia, Favales, & Morabito, 2001)and those attending outpatient diabetic foot clinics (Apelq-vist, Larsson, & Agardh, 1993). The multicentre Eurodialecohort study has demonstrated a high prevalence of baselineischaemia, infection, and comorbidity in Europeans withnew-onset diabetic foot ulcers, whether hospitalised or not(Prompers et al., 2007). Psychological factors, such asdepressive disorders, are increasingly being recognised asprognostic factors associated with increased mortality inpeople with diabetes (Katon et al., 2005; Zhang et al., 2005),and in people with their first foot ulcer, we found that there isa threefold increased risk of death (Ismail et al., 2007).However, incorporating psychological risk factors in a riskassessment for adverse outcomes in diabetic foot disease hasnot been studied; there are relatively simple measures forscreening for depression, and it is a treatable condition.Using the same cohort as previously reported (Ismail et al.,2007), the aim of this study is to determine whethercommonly used clinic-based measures of diabetes and thefoot are associated with adverse outcomes at 18 months inpeople with first foot ulcers presenting at hospital foot andcommunity chiropody clinics in south London, UK.Examination of potential clinical risk factors following firstulceration may provide health professionals, who do nothave specialist foot knowledge, with an easy to use riskassessment guide for the diabetic foot.

2. Subjects, materials, and methods

This was a prospective population-based cohort designwith four time points: baseline, 6, 12, and 18 months. Thesetting was all the community chiropody and hospital footclinics within 5 National Health Service health authorities inSouth London, UK (Lambeth, Southwark, Lewisham,Croydon, and Greenwich), which has approximately80000 people with diabetes. Between October 2001 andFebruary 2003, adults with type 1 or type 2 diabetes andpresenting with their first (baseline) diabetic foot ulcer wereidentified through fortnightly contact with each participatingclinic and review of previous fortnight's records using astandardised checklist of case definition and exclusioncriteria for all current and all new patients. Diabetes was

defined according to the World Health Organization (WHO)criteria. Informed consent was obtained for each participant,and ethical approval was obtained through local ethicscommittees of the participating centres. A clinicallysignificant case definition of diabetic foot ulcer was used:(i) the ulceration was in the anatomical foot; (ii) there was afull thickness break in the epithelium with a minimum widthof 5 mm; and (iii) to exclude severely ischaemic feet, theankle:brachial ratio was N0.5 and no greater than 1.5 (toexclude those with potential calcification of the medialarteries) at either the dorsalis pedis or posterior tibial sitesusing Doppler pressure readings. When subjects had morethan one ulcer at first presentation, the largest ulcer wasdefined as the baseline ulcer. Subjects whose first ulcerhealed within 3 months from the start of the study wereincluded. Any first diabetic foot ulcers with duration ofgreater than 1 year at recruitment were excluded to reduceeffects of chronicity on adverse outcome. The exclusioncriteria were (i) not being fluent in English; (ii) currentindependent comorbid medical condition (such as rheuma-toid arthritis); and (iii) severe mental illness, such asschizophrenia, other psychoses, dementia.

2.1. Measures

At baseline, general demographics and diabetes-specificinformation were recorded for all participants. Clinicalfactors such as the severity of the ulcer, including ulcersize, and the degree of neuropathy and ischaemia weremeasured at baseline. Size was determined using digitalimaging (Rajbhandari, Harris, Sutton, Lockett, Eaton, 1999).Images were resized using the AutoCAD R14 software(Microsoft) so that the surface area of the ulcer could becalculated in square centimeters. The severity of the ulcerwas determined using the University of Texas DiabeticWound Classification System (Armstrong, Lavery, Harkless,1998). Wounds extending through the epidermis or dermisonly were coded as superficial. Wounds penetrating tendons,joint capsule, bone, or joint were coded as severe. Twoqualified podiatrists (one community, one hospital-based)independently graded the wounds from the digital photo-graphs. Discussion of the images took place between seniorpodiatrists at the King's College Hospital foot clinic wherethere was disagreement until a consensus was reached.

Duration of ulceration was recorded from first presenta-tion (using medical records) to the date of recruitment. Thedegree of ischaemia was assessed using the ankle brachialpressure index (ABPI). A handheld Doppler was used toidentify the foot pulses (MultiDopplex, Huntleigh Diagnos-tics, Huntleigh Healthcare, Unit 35, Portmanmoor Road,Cardiff, UK) and measure the brachial and ankle systolicpressure together with a sphygmanometer. Assessment ofprotective pain sensation and sensory neuropathy was madeusing a neurosthesiometer (Neurosthesiometer, ScientificLab supplies, Wilford Industrial Estate, Ruddington Lane,Wilford, Nottingham, UK). In this study, we defined

343K. Winkley et al. / Journal of Diabetes and Its Complications 21 (2007) 341–349

participants with a vibration perception threshold (VPT) of≥25 V as neuropathic regardless of their age.

Glycosylated hemoglobin was measured at baseline andat 12 and 18 months, as blood glucose levels may fluctuatemarkedly throughout 18 months and there is likely to be aclose temporal relationship between high blood sugars andadverse outcomes (Jeffcoate, 2004). The mean percentage ofglycosylated haemoglobin values were derived from base-line and 12 and 18 months to capture the assumed closetemporal association between glycaemic control and risk ofulceration. Values were obtained using the Primus Ultra 2,Primus, Kansas City, MO, USA, and were Diabetes Controland Complications Trial-standardised (Colman, Goodall,Garcia-Webb, Williams, & Dunlop, 1997; Little, Rohlfing, &Wiedmeyer, 2001).

Macrovascular complications were defined as priormyocardial infarct, coronary angioplasty, coronary arterybypass, and peripheral angioplasty or cerebrovascularaccident. Microvascular complications were defined asretinopathy (background or proliferative) measured usingdigital fundal examination, nephropathy (macroalbuminuriaor on dialysis) and neuropathy (VPT ≥25 V). The WHO'sSCAN 2.1 (WHO, 1997) was administered to the patients atbaseline to determine the presence or absence of minor andmajor depressive disorder according to the Diagnostic andStatistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria. The SCAN 2.1 is a semistructured comprehen-sive diagnostic interview allowing the interviewer to make aclinical judgement to distinguish between psychiatric andphysical basis of symptoms such as weight loss and fatigue.It is superior to rating scales as it provides a diagnosis ofdepression and other psychiatric disorders, using operationalcriteria based on accepted psychiatric classification systemssuch as the DSM-IV [and/or International Classification ofDiseases, Tenth Revision (ICD-10)] using computerisedalgorithms (APA, 2000; Çelik, 1999). It has acceptablereliability and validity (Rijinders et al., 2000). Interraterreliability of the SCAN 2.1 was acceptable for this study andhas been described previously (Ismail et al., 2007).

The main confounders included were age and sex andsubstance use. The Alcohol Use Disorders Identification Testwas used to classify patients who reported hazardous andharmful alcohol consumption; those scoring above 8 weredefined as having an alcohol problem (Saunders, Aasland,Babor, de la Fuente, & Grant, 1993). Patients were coded asnon- or ex-smoker vs. smokers.

2.2. Outcomes

The three clinical outcomes recorded were death, firstamputation, and first recurrent ulceration. The date and causeof death were obtained through the UK Central RegisterOffice and coded according to ICD-10 codes (WHO, 1992).The podiatrist attending the patient recorded the date of firstamputation, first recurrent ulceration, and date of healing.Amputation was defined as surgical removal of all or part

of lower limb and stratified as above and below theanatomical ankle. Recurrence of foot ulcers was defined asa recurrence of a full thickness break in the epithelium witha minimum width of 5 mm at the same or different site tothe baseline ulcer.

2.3. Statistical analysis

The main baseline characteristics of the sample werecomputed using percentage proportions or means and theirS.D. Patients who refused to participate in the study,exclusions, and withdrawals were compared with the studysample using independent samples t tests to comparemeans and Fisher's Exact test to compare frequencies(Cochran, 1954).

Survival was modelled from time of entry into the studyup until the date of the 18-month follow-up. Those who didnot die (n=213) were censored 18 months from their date ofentry. Log-rank tests were used to compare the distributionof survival times between those who had amputations andrecurrent ulcers with those who did not.

Cox proportional hazards regression was used tomeasure the hazard ratios (HR) of the clinical factors onsurvival and the other adverse outcomes (Cox and Oates,1984). Factors were first investigated with a univariableapproach. Following this, multivariable Cox models wereused to examine the effect of age and sex on adverseoutcome (Model 1) and Model 1 plus relevant clinicalvariables identified from the univariable analysis, includingsmoking and depression (Model 2). Robust standard errorswere used to adjust for potential misspecification of themodels (Cleves, 2004).

3. Results

Two hundred sixty-two people presented with their firstdiabetic foot ulcer during the study period, and all wereinvited to participate in the study. Two were excludedbecause they did not meet the inclusion criteria; one had arecurrent foot ulcer and the other did not speak Englishfluently. Seven people contacted refused to participate, andthree withdrew from the study after completing the baselineinterview and assessments. All three withdrawals agreed thatoutcome data could be collected but did not want to completeany further questionnaires. When refusers (n=7) werecompared with the study sample, they were older thanparticipants [69.8 (S.D. 12.0) vs. 62.0 (S.D. 13.9) years,P=.9], but this was not significant and more likely to befemale (85.7% vs. 36.4%, P=.01), and this was significant.Our follow-up rate was 100% for mortality outcome, 92.0%and 90.5% for amputation (n=233) and recurrence (n=229),respectively. For amputation and recurrence, people withmissing information had, in general, a shorter duration ofdiabetes (P=.02 and P=.05, respectively) and less micro-vascular problems (P=.01 and P=.02, respectively). There


were six patients for whom there was no glycosylatedhaemoglobin measure at any time point.

3.1. Baseline characteristics

The clinical characteristics of the 253 participants whomet the inclusion criteria and agreed to participate in thestudy can be found in Table 1. The majority of the samplewere male and had Type 2 diabetes. The average duration ofdiabetes was more than 14 years. There were equal numbersof participants treated with oral hypoglycaemic agents and

Table 1Characteristics of the sample at baseline and univariable associations with adverse

Explanatory variables

Total population (N=253) M

Mean (S.D.) /no. (%) H

Mean age (years) 62.0 (13.9) 1.SexFemale 92 (36.4) 1Male 161 (63.6) 1.Type of diabetesType 1 43 (17.0) 1Type 2 210 (83) 0.TreatmentInsulin 114 (45.1) 1Tablet 139 (54.9) 0.Current smoking statusNon- or ex-smoker 213 (84.2) 1Smoker 40 (15.8) 1.Alcohol problemsNone 214 (88.1) 1Yes 29 (11.9) 1.Microvascular complicationsNone 32 (12.6) 1≥1 221 (87.4) 6.Macrovascular complicationsNone 185 (73.1) 1≥1 68 (26.9) 2.Mean duration of diabetes (years) 14.7 (13.2) 1.Mean duration of ulcer (months) 3.1 (3.6) 1.Mean glycated haemoglobin (%) 8.2 (1.7) 0.Texas severity of ulcerSuperficial 188 (74.3) 1Deep 65 (25.7) 2.Mean ulcer size (cm2)≤1 123 (48.6) 1N1 130 (51.4) 1.Vibration perception thresholdb25 V 47 (18.6) 1≥25 V 206 (81.4) 3.ABPI≥0.9 193 (76.3) 1≥0.5, b0.9 60 (23.7) 3.Location of ulcerPlantar 111 (43.9) 1Dorsal 142 (56.1) 1.DSM-IV depressionNone 171 (67.6) 1Any 82 (32.4) 2.

Abbreviations: HR=hazard ratio; ABPI=Ankle Brachial Pressure Index; DSM-IV

insulin. Diabetes control of the sample was suboptimal. Mostparticipants had superficial ulcers, i.e., not penetrating to thejoint capsule, tendon, or bone; there were almost equalnumbers of patients with ulcers N1 and≤1 cm2; and just overhalf had dorsal ulcerations compared with plantar ulcera-tions. The majority of the sample had significant sensoryneuropathy of the feet, as determined by neurosthesiometerto estimate the VPT. Almost 90% of the sample had one ormore microvascular complications, and four people were onrenal dialysis. A quarter of the sample had had previouscardiovascular problems documented in their medical notes

outcomes

ortality (n=40) Amputation (n=36) Recurrence (n=99)

R (95% CI) HR (95% CI) HR (95% CI)

07 (1.04–1.09) 0.99 (0.97–1.01) 0.98 (0.96–0.99)

1 120 (0.62–2.32) 1.24 (0.62–2.48) 1.43 (0.93–2.19)

1 151 (0.18–1.40) 1.91 (0.93–3.89) 1.84 (1.14–2.95)

1 193 (0.48–1.79) 0.96 (0.49–1.86) 0.59 (0.39–0.89)

1 110 (0.50–2.43) 1.09 (0.47–2.57) 1.12 (0.66–1.91)

1 105 (0.42–2.62) 0.96 (0.34–2.75) 1.74 (0.99–3.07)

1 121 (0.88–43.86) 2.18 (0.54–8.84) 3.52 (1.28–9.67)

1 135 (1.27–4.37) 1.30 (0.65–2.58) 0.80 (0.51–1.25)01 (0.98–1.03) 0.99 (0.97–1.02) 1.01 (0.99–1.03)05 (0.96–1.14) 1.03 (0.95–1.12) 1.03 (0.98–1.09)67 (0.51–0.88) 0.99 (0.81–1.19) 1.10 (0.99–1.22)

1 136 (1.26–4.41) 3.60 (1.88–6.91) 1.15 (0.74–1.79)

1 146 (0.78–2.75) 1.99 (1.00–3.96) 1.14 (0.77–1.69)

1 110 (0.99–9.72) 1.70 (0.61–4.72) 1.53 (0.82–2.84)

1 181 (2.05–7.08) 1.67 (0.83–3.33) 0.75 (0.45–1.24)

1 111 (0.59–2.06) 1.55 (0.78–3.12) 0.61 (0.41–0.90)

1 124 (1.21–4.17) 1.87 (0.97–3.61) 1.37 (0.90–2.06)

=Diagnostic and Statistical Manual for Mental Disorders Fourth Edition.

Table 2Primary causes of death (n=40) in a cohort of 253 people with their first diabetic foot ulcer

Frequency (%) Male (%) Mean age (S.D.)

Total deaths 40 (15.8) 28 (70.0) 71.80 (8.41)Primary cause of deathCardiovascular diseases 10 (25.0) 5 (50.0) 69.0 (8.74)Cerebrovascular accident 10 (25.0) 6 (60.0) 71.0 (7.99)Infection 14 (35.0) 11 (78.6) 71.93 (8.86)Cancer 4 (10.0) 4 (100.0) 80.75 (4.79)Renal failure 1 (2.5) 1 (100.0) 72.0Complications from liver disease 1 (2.5) 1 (100.0) 70.0

Table 3Multivariable associations of age and sex (Model 1) and clinical explanatory variables, including depression (Model 2), with adverse outcomes

Explanatory variables

Mortality (n=40) Amputation (n=36) Recurrence (n=99)

Model 1

Model 2

Model 1

Model 2

Model 1

Model 2HR (95% CI) HR (95% CI) HR (95% CI)

Mean age (years) 1.07 (1.04–1.09) 1.07 (1.04–1.11) 0.99 (0.97–1.01) 0.99 (0.97–1.02) 0.98 (0.97–1.00) 0.99 (0.97–1.00)SexFemale 1 1 1 1 1 1Male 1.35 (0.67–2.73) 0.88 (0.41–1.89) 1.24 (0.63–2.47) 1.12 (0.56–2.26) 1.43 (0.94–2.20) 1.42 (0.87–2.33)Type of diabetesType 1 1Type 2 0.84 (0.49–1.45)TreatmentInsulin 1Tablet 0.69 (0.44–1.06)Current smoking statusNon- or ex-smoker 1 1 1Smoker 1.36 (0.61–3.06) 0.88 (0.36–2.14) 1.16 (0.64–2.11)Alcohol problemsNoneYesMicrovascular complicationsNone 1≥1 3.34 (1.17–9.56)Macrovascular complicationsNone 1≥1 1.11 (0.51–2.40)Mean duration of diabetes (years)Mean duration of ulcer (months)Mean glycated haemoglobin (%) 0.73 (0.56–0.96)Texas severity of ulcerSuperficial 1 1Deep 1.70 (0.86–3.38) 3.18 (1.53–6.59)Mean ulcer size (cm2)≤1 1N1 1.40 (0.69–2.85)VPTb25 V 1≥25 V 1.80 (0.63–5.12)ABPI≥0.9 1≥0.5, b0.9 2.74 (1.46–5.14)Location of ulcerPlantar 1Dorsal 0.68 (0.45–1.05)DSM-IV depressionNone 1 1 1Any 2.51 (1.33–4.73) 1.38 (0.70–2.72) 1.18 (0.77–1.81)



(prior myocardial infarct, coronary angioplasty, coronaryartery bypass, and peripheral angioplasty or cerebrovascularaccident). Ischaemia was measured with the ABPI, and thisshowed that a quarter had moderate to severe ischaemia, butthe majority were well perfused.

3.2. Mortality data and survival analyses

Survival data were available for the entire sample. Fortyparticipants died of natural causes during the course of thestudy, a survival rate of 84%. Table 2 shows the primarycauses of death. Twenty-seven men (16.8%) died during the18-month follow-up, and 13 women (14.1%) (Fisher's Exacttest=0.14, P=.71).

3.3. Amputation

Thirty-six (15.5%, n=233) participants underwent anamputation over the course of the study. All amputationswere due to diabetic foot disease. Ten underwent majoramputation (amputation above the ankle), and the remainderwere minor amputations (below the ankle), mainly of thetoes. Five (14%) of the 36 participants who underwentamputation died during the follow-up period, compared with35 (18%) of the 197 who did not undergo amputation.Amputation was not significantly associated with survival(unadjusted HR 0.77, P=.58, 95% CI 0.30–1.96).

3.4. Recurrence

Outcome data on recurrence of ulcer was available for229 participants. Ninety-nine (43%) had a recurrence within18 months. Seven (7%) of the 99 participants died after theirfirst recurrence compared with 33 (26%) of the 130participants who died but had no recurrence. Those whodied but had recurrent ulceration survived longer than thosewho died with no recurrence (unadjusted HR 0.23, P=.001,95% CI 0.10–0.53).

3.5. Clinical factors associated with mortality

In a univariable analysis age, macrovascular complica-tions, glycaemic control (% glycosylated haemoglobin),ulcer severity, neuropathy, and ischaemia were found to beassociated with mortality (Table 1). In the first multivariableanalysis (Model 1, Table 3), older age was still significantlyassociated with mortality but not sex. In Model 2 (Table 3),where clinical variables and depression were added,independent associations were found with ischaemia andbetter glycaemic control.

3.6. Clinical factors associated with amputation

In a univariable analysis, ulcer severity and ulcer sizewere found to be associated with amputation (Table 1). In thefirst multivariable analysis (Model 1, Table 3), neither age

nor sex was significantly associated with amputation. Inmultivariable Model 2 (Table 3), where clinical variables anddepression were added, an independent association wasfound with ulcer severity.

3.7. Clinical factors associated with ulcer recurrence

In a univariable analysis age, type of diabetes, diabetestreatment, microvascular complications, and location ofulcer were found to be associated with recurrent ulceration(Table 1). In the first multivariable analysis (Model 1, Table3), neither age nor sex was significantly associated withrecurrent ulceration. In Model 2 (Table 3), where clinicalvariables and depression were added, an independentassociation was found with microvascular complications.

4. Discussion

The aim of this prospective cohort study was to determinerisk factors for adverse outcome in people with their firstdiabetic foot ulcer followed up for 18 months. Our mainfindings demonstrated that being older, having betterglycaemic control, moderate ischaemia, and suffering froma depressive disorder were independent risk factors formortality following first ulceration. Severity of ulcer wasindependently associated with amputation and microvascularcomplications were associated with recurrent ulceration.

The strengths of this study include that it was apopulation-based cohort and had a prospective design,reducing selection bias and allowing for the temporalassociation between exposure and outcome to be deter-mined. The outcomes measured were clinical and objective,and podiatrists were blind to depression status. Limitationsof the study were that housebound patients with first ulcerswould not have been identified, however, as patients wererecruited from hospital and community clinics the resultsare likely to be generalisable to the population of foot ulcersas a whole.

Diabetes control was suboptimal for the entire sample atbaseline, and potential explanations for better control in thegroup who died might include increased surveillance andmedical management of patients who were sicker and,second, that this group may have had more frequenthospitalisations and increased the likelihood of anorexia/poor appetite. Previous cohorts (Boyko et al., 1999) havedemonstrated that poor diabetes control is a risk factor for thedevelopment of foot ulcers, but to date, there have been nopublished data demonstrating a prospective association withadverse outcome following ulceration.

Of greater clinical significance is the 3-fold increased riskof mortality in people with moderate ischaemia or peripheralarterial disease (PAD). In addition to coronary and carotidartery disease and hyperlipidaemia, PAD is considered to bea marker for artherosclerosis and is known to be moreprevalent in people with diabetes (Jager et al., 1999; Pan et


al. 1986). Studies such as the Hoorn population cohort,which examined glucose disturbance in an elderly DutchCaucasian population, have demonstrated independentassociations between PAD and twofold increased risk ofall-cause mortality at 5 years of follow-up (Jager et al.,1999). Hoorn defined PAD as ABPI b0.9, included thosewith absent foot pulses and found it was more prevalentamongst those with known diabetes (Beks et al., 1995).Similarly, in the Strong Heart study, a population cohort ofAmerican Indians investigating risk factors for cardiovas-cular disease (CVD), the relative risk of CVD mortality inpeople with PAD (ABPI b0.9) was 1.69 (Resnick et al.,2004). In our study people with severe PAD were excluded,and we found a 3-fold increased risk of death and in over50% of cases death was due to cardiovascular cause.

Amputation occurred to relatively few of the studyparticipants, and the majority had minor amputations whichmay explain the absence of an association with depressivedisorder (as perhaps minor is perceived as “good” newscompared to having to undergo “major” amputation).Recurrent ulceration was not associated with depressionand this may perhaps relate to how participants perceivereulceration, e.g., that it is not serious, especially as theyalready have impaired functioning from the first one andthey have no or little pain sensation to match the worseningfoot disease.

Severity of ulcer was the only risk factor independentlyassociated with amputation. Deep ulcerations were asso-ciated with a threefold increased risk. The absence of anindependent association between PAD and amputation,found in previous cohort studies (Faglia et al., 2001; Jude,Oyibo, Chalmers, & Boulton, 2001), may be explained bythe fact that this was a population of people with first ulcers,that the majority of amputations recorded were minor, andthat people with severe PAD (ABPI b0.5) were excluded.

A threefold increased risk of recurrent ulceration wasfound in participants with one or more microvascularcomplications. Sensory neuropathy alone, measured in thisstudy with VPT, was not independently associated withrecurrence, although associations with neuropathy (bothsubjective symptoms and VPT N25 V) have been describedin cases with current or recent ulceration compared todiabetes controls without a history of ulceration (Lavery,Armstrong, Vela, Quebedeaux, & Fleischli, 1998). Neuro-pathy, measured by the 10-g monofilament, is a risk factorfor the development of foot ulcers (Boyko et al., 1999).The absence of an independent association with reulcera-tion in this study may have occurred, as only 50% of thispopulation of people with diabetes and first ulcers met thecriteria for neuropathy (VPT N25 V), although anindependent association with any microvascular diseasewas present.

This study may inform strategies to improve diabetic footcare for people with diabetes and their first ulcer. Itdemonstrates that measuring ABPI and monitoring depres-sion status can help identify people at increased risk for

mortality, that the assessment of wound severity candetermine amputation risk, and any microvascular complica-tion can increase risk of recurrent ulceration. Mostly, theseare simple measurements and can be done routinely inprimary care. They depend on the use of low-tech and low-cost equipment, direct observation, and accurate recording ofdiabetes complications. Podiatrists, nurses, or generalpractitioners can therefore identify those at high risk foradverse outcomes in primary care, where the majority ofdiabetes care is delivered, and once high risk patients areidentified, resources to modify their risk status can be moreaccurately targeted.

To reduce mortality, this may involve intensification oftreatment to reduce the impact of PAD (AntiplateletsTrialists' Collaboration, 1994; Beckman, Creager, & Libby,2002) or at least manage associated problems such ascoronary and carotid artery disease and hyperlipidaemia,with platelet antagonists, statins, and angiotensin-convertingenzyme inhibitors, which may reduce vascular deaths(Antiplatelets Trialists' Collaboration, 1994) and strokes(Executive Committee for the Asymptomatic CarotidArtherosclerosis Study 1995; North American SymptomaticCarotid Endarterectomy Trial Collaborators 1991). Further-more, routine monitoring of depression can also beperformed and indeed in the United Kingdom, there is anational programme for screening for depression in allpeople with diabetes in primary care (Gilbody, Sheldon, &Wessely, 2006). We used a highly intensive semistructuredinterview, which is not suitable for diabetes professionals,but there are numerous screening and case findingmeasures available, such as the Patient Health Question-naire 9 (Kroenke, Spitzer, & Williams, 2001). There maybe local or national guidelines for the treatment ofdepression (NICE, 2004). To avoid amputation, thosewith severe first ulcers will require intensive treatment andfollow-up in the foot clinic, and to prevent reulceration,patients with preexisting microvascular disease will requireintensive monitoring.

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