Introduction 1 2 3 5 6 7 8 9 7 The aim of the present study was therefore: (1) to obtain prospective data on outcome of individuals presenting with a new diabetic foot ulcer, including patients both with and without PAD; (2) to assess clinical characteristics that best predict poor outcome (i.e. non-healing of the foot ulcer) from this large set of patients; and (3) to examine whether such predictors differ between patients with and without PAD. Methods Study design and population 10 Briefly, between 1 September 2003 and 1 October 2004, 1,232 patients with a new foot ulcer were included in 14 diabetic foot centres in ten European countries. The mean (range) number of included patients per centre was 88 (40–125). All participating centres have a longstanding expertise in the field of diabetic foot disease. Patients included were those presenting for the first time with a new foot ulcer within a period of 12 months, either at the outpatient or inpatient clinics of participating centres. Excluded patients were those who had been treated at the participating centres for an ulcer on the ipsilateral foot during the previous 12 months and those with a life expectancy of less than 1 year. Participants attended follow-up visits on a monthly basis. At baseline and during all follow-up visits, data were collected and recorded on standardised case record forms. This was done by dedicated investigators in each centre who were trained during plenary meetings and on-site visits. Recorded data included demographics, data on co-morbidities and foot and ulcer characteristics, as well as management. The local ethics committees of the 14 hospitals approved the study protocol and all patients gave written informed consent. Management of diabetic foot ulcer 11 Potential predictive factors 10 Ulcer characteristics 11 12 2 2 2 Co-morbidities Study main outcome n n n n 1 Table 1 Baseline characteristics of participants included and those excluded (dropouts) from the present study Variable n n p Age (years) 64.7 ± 12.5 68.0 ± 11.6 0.003 n a 703 (64.6) 85 (59.0) 0.189 n a   0.418 <5 years 148 (14.1) 19 (13.5)  5–10 years 169 (16.1) 17 (12.1)  >10 years 731 (69.8) 105 (74.5)  n a 476 (43.8) 80 (55.6) 0.007 n a   0.843 2 403 (37.2) 50 (35.0)  2 563 (52.0) 76 (53.1)  2 117 (10.8) 17 (11.9)  n a   <0.001 <1 week 184 (17.0) 10 (7.0)  1 week–3 months 627 (58.1) 68 (47.6)  >3 months 269 (24.9) 65 (45.5)  n a 493 (48.2) 62 (46.3) 0.675 n a 197 (18.2) 29 (20.3) 0.538 n a 117 (10.9) 23 (16.1) 0.065 n a 70 (6.5) 9 (6.3) 0.918 n a 107 (9.9) 15 (10.4) 0.843 n a 164 (15.3) 19 (13.2) 0.507 n a 63 (5.8) 7 (4.9) 0.639 n a 826 (78.5) 105 (76.1) 0.515 n a 591 (57.2) 82 (61.2) 0.380 n a 505 (47.5) 78 (56.1) 0.056 Unless otherwise stated, data are mean values ± SD. a Statistical analyses χ 2 t Multiple imputation of missing values of predictor variables n n n 13 14 15 16 17 Development of predictive models Results Clinical outcome p p p  2 Table 2 Patients’ baseline characteristics according to their PAD status Variable n n p Age (years) 69.1 ± 11.2 60.5 ± 12.3 <0.001 n a 321 (65.6) 366 (63.6) 0.490 n a   0.265 <5 years 63 (12.9) 80 (14.9)  5–10 years 72 (14.7) 93 (17.4)  >10 years 354 (72.4) 363 (67.7)  n a 266 (52.7) 200 (35.8) <0.001 n a   0.002 2 173 (34.4) 219 (39.5)  2 259 (51.5) 294 (53.0)  2 71 (14.2) 42 (7.5)  n a   <0.001 <1 week 58 (11.5) 120 (21.7)  1 week–3 months 296 (58.0) 318 (57.5)  >3 months 148 (29.5) 115 (20.8)  n a 197 (40.9) 284 (55.0) <0.001 n a 111 (22.0) 83 (14.9) 0.002 n a 64 (12.7) 47 (8.5) 0.027 n a 40 (8.0) 27 (4.9) 0.039 n a 65 (12.9) 36 (6.5) <0.001 n a 89 (17.9) 66 (12.0) 0.007 n a 35 (7.0) 25 (4.5) 0.082 n a 383 (77.2) 424 (79.3) 0.429 n a 293 (60.9) 282 (53.4) 0.016 Unless otherwise stated, data are mean values ± SD a Predictors of healing 3 4 n Table 3 n Predictor variables Outcome: healing OR 95% CI p Age, per 10 year increase 1.32 1.17–1.49 <0.001 Sex, men vs women 1.50 1.07–1.97 0.018 Duration of diabetes   0.712 a 0.96 0.56–1.65  a 1.05 0.69–1.60  Depth of ulcer, deep vs superficial 1.66 1.25–2.20 <0.001 Size of ulcer   <0.001 2a 2.25 1.60–3.17  2a 4.22 2.64–6.72  Duration of ulcer   <0.001 a 1.81 1.15–2.85  a 2.61 1.60–4.27  Location, plantar vs non-plantar 0.73 0.55–0.98 0.035 Pretibial oedema, yes vs no 1.79 1.27–2.51 0.001 Heart failure (NYHA III–IV), yes vs no 2.03 1.35–3.05 0.001 Neurological disorder, yes vs no 1.44 0.85–2.46 0.176 Inability to stand or walk without help, yes vs no 2.50 1.62–3.79 <0.001 Visual impairment, yes vs no 1.36 0.94–1.98 0.105 ESRD, yes vs no 2.20 1.30–3.73 0.004 Polyneuropathy, yes vs no 1.41 0.98–2.04 0.065 Infection, yes vs no 1.47 1.09–2.00 0.012 PAD, yes vs no 2.31 1.72–3.10 <0.001 a Table 4 Multivariable models with independent predictors of non-healing in the whole study population and in patients with and without PAD Variable All patients Patients with PAD Patients without PAD OR 95% CI p OR 95% CI p OR 95% CI p Age, per 10 year increase 1.28 1.11–1.47 0.001 1.42 0.17–1.73 <0.001 1.55 0.91–2.63 0.105 Sex, men vs women 1.72 1.23–2.40 0.002 1.97 1.25–3.11 0.003 – – – Size of ulcer   <0.001   <0.001   0.008 2a 2.26 1.58–3.22  3.22 1.95–5.32  1.25 0.74–2.12  2a 3.88 2.37–6.34  3.84 1.97–7.48  3.48 1.62–7.46  Duration of ulcer   –   –   0.086 a – –  – –  2.14 1.05–4.36  a – –   – –  2.18 0.98–4.84  Heart failure (NYHA III–IV), yes vs no 1.55 0.99–2.43 0.054 1.54 0.87–2.74 0.141 – – – Inability to stand or walk without help, yes vs no 2.00 1.27–3.14 0.003 2.36 1.34–4.17 0.003 1.91 0.86–4.24 0.112 ESRD, yes vs no 2.51 1.41–4.48 0.002 3.04 1.38–6.70 0.006 2.00 0.76–5.25 0.161 Polyneuropathy, yes vs no 1.42 0.96–2.08 0.078 – – – 1.70 0.89–3.25 0.108 Infection, yes vs no – – – 1.63 1.03–2.58 0.036 – – – PAD, yes vs no 1.71 1.23–2.37 0.001 N/A   N/A   a N/A, not applicable 4 9 p 1 p Fig. 1 ORs of healing per PAD and infection (Inf) status  Discussion 7 18 19 20 1 7 21 22 23 24 25 19 26 26 27 25 28 29 31 32 33 34 35 36 37 39 40 In conclusion, the results of this study have several implications. Both ulcer characteristics and several patient-related characteristics affected the outcome of diabetic foot ulcers. Therefore, a holistic approach by healthcare professionals who are familiar with the treatment of complicated diabetic patients is essential in order to identify the high-risk patient and start appropriate treatment. We found that patients with and without PAD differ in clinical characteristics, outcome and predictors of outcome. Taking into account these findings and the different pathophysiology and treatment of PAD and non-PAD ulcers, we feel that that diabetic foot ulcer with and without PAD should be defined as two separate disease states. The prevalent combination of PAD and infection is a unique entity; an important challenge lies in the development of evidence-based strategies to improve the poor outcome of these patients. Both studies comparing different antibiotic regimens in PAD, and studies evaluating the effects of early revascularisation on control of infection are urgently needed.