Prediction of outcomes in subjects with type 2 diabetes and diabetic foot ulcers in Catalonian primary care centers: a multicenter observational study

The aim of the current study was to assess the clinical progression of DFU during a 12-month follow-up period in people with type 2 diabetes (T2DM) with a diagnosis of a new DFU. We conducted a prospective single-cohort observational study in 36 primary care healthcare centers in Catalonia. The health care system in Catalonia is public and universal to all residents. In each primary care center, the health care user (patient) is allocated a medical doctor and a nurse. The primary healthcare centers act as gatekeepers to access other healthcare levels (secondary and tertiary care). In our study, people with T2DM with a new DFU who attended one of the participating centers were included between February 1^st, 2018 and July 31^st, 2019. The follow-up period was up to 12 months or until premature discontinuation (death or loss to follow-up). The detailed methodology has been previously published [15].

During the first month after the inclusion, weekly follow-up visits for each participant were performed. After the first month, in case of active foot ulcers, follow-up visits were scheduled monthly or more frequently when deemed necessary by the treating team. Upon foot ulcer healing, follow-up visits were scheduled every three months or until the end of the follow-up period. All of the study procedures, data collection check-ups and fulfilment of good clinical practice were externally monitored to ensure correct study practices.

We defined a foot ulcer as a full-thickness lesion below the ankle, regardless of the presence of neuropathy and/or peripheral artery disease. In individuals with more than one ulcer at baseline, the most clinically relevant lesion was selected as the index DFU.

At the inclusion, for each participant in the study, we collected the following demographic and clinical information (variables): socio-demographic characteristics (age, gender, and self-reported ethnicity), toxic habits (smoking, alcohol intake), cardiovascular risk factors and concomitant disease (hypertension, hyperlipidemia, previous history of stroke, ischemic heart disease, peripheral artery disease, and heart failure), and data on diabetes (disease duration, antidiabetic treatment, and previous diagnosis of diabetic microvascular complications such as retinopathy, nephropathy, and peripheral neuropathy), and previous history of amputation or foot ulcers. In addition, for all participants, laboratory parameters were requested at inclusion for HbA1c, lipid profile, kidney function, and clinical parameters such as body mass index (BMI) and blood pressure were measured. We also collected information related to visual acuity, degree of mobility, caregiver access, and any podiatrist visits.

At all study visits, the site researchers also collected information related to the DFU, such as duration, location, the extension of ulcer after surgical debridement (longest diameter multiplied by the second longest diameter of the ulcer), ulcer´s depth (superficial ulcer: loss of superficial substance which does not penetrate beyond the dermis; deep ulcer: loss of substance below the dermis to subcutaneous structures or joint or bone exposure), presence or absence of infection, and infection severity.

The primary study outcomes were: mortality, amputation, recurrence and healing of DFU. Mortality was considered as death for any reason. The amputation event included both minor and major amputations. We defined a minor amputation as any surgical procedure resulting in an amputation of any part of the limb below the foot ankle, and major amputation was defined as any amputation above the foot ankle. DFU recurrence was considered if a new ulcer appeared during the follow-up period once the index ulcer had healed entirely. The healed DFU was defined as a fully epithelialized lesion (with or without amputation).

We used two DFU classification systems: the PEDIS classification [16], which evaluates variables such as Perfusion, Extent, Depth, Infection and Sensation, and the SINBAD classification [17] which includes variables related to the ulcer Site, Ischemia, Neuropathy, Bacterial Infection and Depth based on a scale of 0 to 6. For the PEDIS we used a scoring system (0 to 12) developed by Chuan et al. [18] to facilitate the use of the PEDIS in clinical practice. A PEDIS score of at least seven was considered clinically important, based on the study by Chuan et al. that found that patients with a PEDIS score of at least seven had an increased risk for the composite endpoint of non-healing amputation and death [18]. For the SINBAD classification, we used a scoring system (between 0 and 6) that was created by Ince et al. [17]; we considered a SINBAD score of at least three to be clinically important based on the study by Ince et al. [17] reporting that patients with a score of at least three had a higher risk of non-healing of the ulcer (including amputation and death).

Initially we carried out a descriptive analysis of the participants. The qualitative variables were described for number and frequency, and the quantitative variables were summarized by measures of central tendency and dispersion (mean, median, standard deviation, interquartile range). Subsequently we estimated the incidence (cumulative and event rates) for different study outcomes (mortality, amputations, recurrence and healing of DFU) during the follow-up to determine the evolution of the ulcers and the prognosis. Each event rate was estimated as the number of new cases of the event divided by the total person-time at risk during the follow-up period, stratified by type of the DFU (ischemic, neuro-ischemic or neuropathic). After this, we performed a univariate and multivariable proportional hazards analysis to assess the association of the main study outcomes and risk factors, considering the follow-up time. The variables included in the multivariable models were selected based on the clinical criteria. A complete case-analysis was performed. Estimated measures of association were expressed as crude and adjusted hazards ratios (HRs) and their 95% confidence intervals (95%CI). HRs are a measure of how often a particular event happens in one group compared to how often it happens in another group over time. A HR of 1 indicates a lack of an association between the variable (e.g. age) and the event happening (e.g. mortality), a HR greater than 1 indicates an increased risk of the event happening, and a HR below 1 suggests a lower risk of the event happening. To prevent variable collinearity, two different multivariable models were performed for the PEDIS and SIMBAD variables. We used the cox.zph function from the survival package in R (R statistical software) to check the proportional hazards assumption of the Cox models [19]. Furthermore, we included R2 Nagelkerke as an appropriate measure of goodness of fit for each model. Additionally, assumptions of PH Cox model were checked for each parameter [20, 21]. Thereafter, additional reduced models were done removing statistical non-significant variables. For this analysis we used the function cox.zph from {survival} R package (Version 3.3–1). The statistical analyses were performed using R3.6.1 (https://​www.​r-project.​org).