Peripheral Arterial Disease and the Diabetic Foot Syndrome: Neuropathy Makes the Difference! A Narrative Review.

Background: In vascular medicine, peripheral arterial disease (PAD) and diabetic foot syndrome (DFS) are often considered synonymous with respect to the need for revascularization. In PAD patients, clinical symptoms reflect the degree of atherosclerotic disease, since peripheral innervation, including pain sensation, is not usually compromised. In DFS patients, however, symptoms of relevant foot ischemia are often absent and progression of ischemia goes unnoticed owing to diabetic polyneuropathy, the loss of nociception being the main trigger for foot ulcers. This review analyzes the fundamental differences between PAD and DFS against the background of polyneuropathy. Methods: The literature research for the 2014 revision of the German evidence-based S3-PAD-guidelines was extended to 2023. Results: Vascular examination is imperative for both, PAD and DFS. Stage-dependent revascularization is of utmost importance in PAD patients, especially those suffering from critical limb-threatening ischemia (CLTI). Successful therapy of DFS goes further, including infection and metabolic control, wound management, offloading the foot and lifelong prophylaxis in the course of a multidisciplinary treatment concept. Revascularization is not needed in all cases of DFS. Conclusions: There are fundamental differences between PAD and DFS with respect to pathophysiology, the anatomical distribution of arterial occlusive processes, the clinical symptoms, the value of diagnostic tools such as the ankle-brachial index, and classification. Also, therapeutic concepts differ substantially between the two patient populations.

Hospitalisation rate and mortality among people with and without diabetes during the COVID-19 pandemic year 2020.

Most studies reported reduced health care use among people with diabetes during the COVID-19 pandemic. This may be due to restricted medical services or people avoiding health care services because they fear being infected with COVID-19 in health care facilities. The aim of our study was to analyse hospitalisation and mortality in people with and without diabetes in Germany during the COVID-19 pandemic year 2020 compared to 2017-2019. The data were sourced from a German statutory health insurance company covering 3.2 million people. We estimated age-sex standardised rates of mortality, all-cause hospitalisation, hospitalisation due to coronary heart disease (CHD), acute myocardial infarction (AMI), stroke, diabetic foot syndrome (DFS), and major and minor amputations in people with and without diabetes. We predicted rates for 2020 using Poisson regression based on results from 2017-2019 and compared these with the observed rates.In people with diabetes, the hospitalisation rate for major amputation was significantly increased, while all-cause hospitalisation rate and hospitalisation due to CHD, AMI and DFS were significantly decreased compared to the previous period. Moreover, we found a significantly increased mortality and hospitalisation rate for minor amputation in people without diabetes while all-cause hospitalisation and hospitalisation due to CHD and AMI was significantly lower during the COVID-19 pandemic year 2020.We observed changes in health care utilisation and outcomes during the COVID-19 pandemic compared to previous years in people with and without diabetes. Concerning diabetes care, the increase of hospitalisations due to amputation in people with diabetes with a simultaneous reduction in DFS needs special attention.

Therapeutic Alternatives in Diabetic Foot Patients without an Option for Revascularization: A Narrative Review.

BACKGROUND: The healing of foot wounds in patients with diabetes mellitus is frequently complicated by critical limb threatening ischemia (neuro-ischemic diabetic foot syndrome, DFS). In this situation, imminent arterial revascularization is imperative in order to avoid amputation. However, in many patients this is no longer possible ("too late", "too sick", "no technical option"). Besides conservative treatment or major amputation, many alternative methods supposed to decrease pain, promote wound healing, and avoid amputations are employed. We performed a narrative review in order to stress their efficiency and evidence. METHODS: The literature research for the 2014 revision of the German evidenced-based S3-PAD-guidelines was extended to 2020. RESULTS: If revascularization is impossible, there is not enough evidence for gene- and stem-cell therapy, hyperbaric oxygen, sympathectomy, spinal cord stimulation, prostanoids etc. to be able to recommend them. Risk factor management is recommended for all CLTI patients. With appropriate wound care and strict offloading, conservative treatment may be an effective alternative. Timely amputation can accelerate mobilization and improve the quality of life. CONCLUSIONS: Alternative treatments said to decrease the amputation rate by improving arterial perfusion and wound healing in case revascularization is impossible and lack both efficiency and evidence. Conservative therapy can yield acceptable results, but early amputation may be a beneficial alternative. Patients unfit for revascularization or major amputation should receive palliative wound care and pain therapy. New treatment strategies for no-option CLTI are urgently needed.

Cumulative long-term recurrence of diabetic foot ulcers in two cohorts from centres in Germany and the Czech Republic.

AIMS: Our aim was to comprehensively estimate the incidence of diabetic foot ulcer (DFU) recurrence and corresponding risk factors in two cohorts. METHODS: Prospective data from patients with active DFU from two diabetes centres in Germany (GER, n = 222) and the Czech Republic (CZ, n = 99) were analysed. Crude cumulative incidences were obtained. Additionally, time to recurrence and risk factors were investigated using multivariate Cox models. RESULTS: 69%(154) of patients in GER and 70%(69) in CZ experienced at least one DFU recurrence; 25%(56) in DEU and 15%(15) in CZ died; 5%(11) and 9%(9) were lost to follow-up. The crude cumulative incidence in the first year was 28% in GER and 25% in CZ; 68%/70% within ten years, and 69%/70% in 15 years. In GER, renal replacement therapy was associated with shorter time to recurrence (HR = 3.71, 95%CI:1.26-10.87); no history of DFU before the index lesion with longer time to recurrence (HR = 0.62, 0.42-0.92). In CZ, type 2 diabetes (HR = 2.57, 1.18-5.62) and index ulcer treatment by minor amputation (HR = 2.11, 1.03-4.33) were associated with shorter time to recurrence. CONCLUSIONS: Cumulative DFU recurrence was approximately 70% in 15 years in both cohorts. We found a significantly higher risk of future recurrence in patients having a consecutive ulcer compared with the first ever ulcer.

Impact of wound duration on diabetic foot ulcer healing: evaluation of a new sucrose octasulfate wound dressing.

OBJECTIVE: A common and frequent complication of diabetes is diabetic foot ulcers (DFU), which can have high treatment costs and severe adverse events. This study aims to evaluate the effects of wound duration on wound healing and the impact on costs, including treatment with a new sucrose octasulfate dressing compared with a control dressing. METHOD: Based on the Explorer study (a two-armed randomised double-blind clinical trial), a cost-effectiveness analysis compared four different patient groups distinguished by their wound duration and additionally two DFU treatment options: a sucrose octasulfate dressing and a neutral dressing (as control). Clinical outcomes and total direct costs of wound dressings were evaluated over 20 weeks from the perspective of the Social Health Insurance in Germany. Simulation of long-term outcomes and costs were demonstrated by a five cycle Markov model. RESULTS: The results show total wound healing rates between 71% and 14.8%, and direct treatment costs for DFU in the range of €2482-3278 (sucrose octasulfate dressing) and €2768-3194 (control dressing). Patients with a wound duration of ≤2 months revealed the highest wound healing rates for both the sucrose octasulfate dressing and control dressing (71% and 41%, respectively) and had the lowest direct treatment costs of €2482 and €2768, respectively. The 100-week Markov model amplified the results. Patients with ≤2 months' wound duration achieved wound healing rates of 98% and 88%, respectively and costs of €3450 and €6054, respectively (CE=€3520, €6864). Sensitivity analysis revealed that the dressing changes per week were the most significant uncertainty factor. CONCLUSION: Based on the findings of this study, early treatment of DFU with a sucrose octasulfate dressing is recommended from a health economic view due to lower treatment costs, greater cost-effectiveness and higher wound healing rates.

Intermittent Claudication and Asymptomatic Peripheral Arterial Disease.

BACKGROUND: The conservative treatment of peripheral arterial disease (PAD), as recommended in current guidelines, encompasses measures such as lifestyle modification and risk-factor management. In addition, in patients with vasogenic intermittent claudication (IC), it is recommended that patients first be given drugs to improve perfusion and undergo supervised gait training. Revascularization is not recommended for asymptomatic persons, but it is considered mandatory for patients with critical ischemia. In this article on conservative and revascularizing treatment strategies for IC, we address the following questions: whether all treatment options are available, how effective they are, and whether the reality of treatment for IC in Germany corresponds to what is recommended in the guidelines. METHODS: In 2014, the German Society for Angiology carried out a comprehensive literature search in order to prepare a new version of the S3 guideline on PAD. This literature search was updated up to 2018, with identical methods, for the present review. RESULTS: The benefit of lifestyle modification and risk factor treatment is supported by high-level evidence ( evidence level I, recommendation grade A ). The distance patients are able to walk without pain is increased by drug therapy as well (evidence level IIb), but the therapeutic effect is only moderate. Supervised exercise training (SET), though supported by high-level evidence (I, A), is of limited efficacy, availability, and applicability, and patient compliance with it is also limited. In patients with IC, revascularization leads to complete relief of symptoms more rapidly than gait training, and its long-term benefit is steadily improving owing to advances in medical technology. A combination of arterial revascularization and gait training yields the best results. In a clinical trial, patients with IC who underwent combined therapy increased the distance they could walk without pain by 954 m in six months, compared to 407 m in a group that underwent gait training alone. CONCLUSION: In the treatment of vasogenic IC, SET and drugs to increase perfusion are now giving way to revascularization, which is more effective. As far as can be determined, SET is not currently implemented at all in the German health care system. It would be desirable for SET to be more available and more widely used, both to sustain the benefit of revascularization over the long term and to lower the general cardiovascular risk.

Guidelines on the classification of diabetic foot ulcers (IWGDF 2019).

The International Working Group on the Diabetic Foot (IWGDF) has been publishing evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This publication represents a new guideline addressing the use of classifications of diabetic foot ulcers in routine clinical practice and reviews those which have been published. We only consider systems of classification used for active diabetic foot ulcers and do not include those that might be used to define risk of future ulceration. The guidelines are based on a review of the available literature and on expert opinion leading to the identification of eight key factors judged to contribute most to clinical outcomes. Classifications are graded on the number of key factors included as well as on internal and external validation and the use for which a classification is intended. Key factors judged to contribute to the scoring of classifications are of three types: patient related (end-stage renal failure), limb-related (peripheral artery disease and loss of protective sensation), and ulcer-related (area, depth, site, single, or multiple and infection). Particular systems considered for each of the following five clinical situations: (a) communication among health professionals, (b) predicting the outcome of an individual ulcer, (c) as an aid to clinical decision-making for an individual case, (d) assessment of a wound, with/without infection, and peripheral artery disease (assessment of perfusion and potential benefit from revascularisation), and (d) audit of outcome in local, regional, or national populations. We recommend: (a) for communication among health professionals the use of the SINBAD system (that includes Site, Ischaemia, Neuropathy, Bacterial Infection and Depth); (b) no existing classification for predicting outcome of an individual ulcer; (c) the Infectious Diseases Society of America/IWGDF (IDSA/IWGDF) classification for assessment of infection; (d) the WIfI (Wound, Ischemia, and foot Infection) system for the assessment of perfusion and the likely benefit of revascularisation; and (e) the SINBAD classification for the audit of outcome of populations.

Diabetic foot ulcer classifications: A critical review.

Classification and scoring systems can help both clinical management and audit outcomes of routine care. The aim of this study was to assess published systems of diabetic foot ulcers (DFUs) to determine which should be recommended for a given clinical purpose. Published classifications had to have been validated in populations of > 75% people with diabetes and a foot ulcer. Each study was assessed for internal and external validity and reliability. Eight key factors associated with failure to heal were identified from large clinical series and each classification was scored on the number of these key factors included. Classifications were then arranged according to their proposed purpose into one or more of four groups: (a) aid communication between health professionals, (b) predict clinical outcome of individual ulcers, (c) aid clinical management decision making for an individual case, and (d) audit to compare outcome in different populations. Thirty-seven classification systems were identified of which 18 were excluded for not being validated in a population of >75% DFUs. The included 19 classifications had different purposes and were derived from different populations. Only six were developed in multicentre studies, just 13 were externally validated, and very few had evaluated reliability.Classifications varied in the number (4 - 30), and definition of individual items and the diagnostic tools required. Clinical outcomes were not standardized but included ulcer-free survival, ulcer healing, hospitalization, limb amputation, mortality, and cost. Despite the limitations, there was sufficient evidence to make recommendations on the use of particular classifications for the indications listed above.

Outcomes of severe limb ischemia with tissue loss and impact of revascularization in haemodialysis patients with wound, ischemia, and foot infection (WIfI) stage 3 or 4.

Background: With growing prevalence, end-stage renal disease (ESRD) as well as critical limb ischemia (CLI) are both conditions associated with high morbidity and mortality rates. Patients and methods: A retrospective single-centre study provided data of a German interdisciplinary vascular centre. Seventy-seven consecutive haemodialysis (HD) inpatients (median age, 73.6 years) with 91 threatened limbs with Wound, Ischemia, and foot Infection (WIfI) clinical stage 3 or 4 were evaluated for in-hospital treatment of peripheral arterial disease, limb salvage rates, major amputation (MA)-free and overall survival. Results: The 1-year MA-free limb salvage rate was 82 %. On multivariate analysis, a higher WIfI clinical stage (hazard ratio [HR], 7.54; p = 0.008) indicated a higher risk of MA, while at least one-vessel run-off to the foot after revascularization of any kind was associated with a lower risk of MA (HR, 0.17; p = 0.001). In the composite endpoint analysis, the 1-year MA-free overall survival rate was 65 %. Patients with limbs in WIfI clinical stage 4 versus stage 3 carried a more than two-fold increased hazard of death or MA (HR, 2.63; p = 0.028), while revascularization was associated with reduced risk (HR, 0.40; p = 0.021). One-year overall survival (78 %) was not associated with WIfI stage or revascularization but was worse in patients with previous symptomatic coronary artery disease (HR, 3.25; p = 0.039). During long-term follow-up over 12 years, MA-free survival probability was significantly lower in the WIfI stage 4 versus WIfI stage 3 group (HR, 1.58; p = 0.048) without significant differences in overall survival (HR, 1.10; p = 0.696). Conclusions: Lower-extremity CLI with tissue loss in HD patients is associated with high morbidity and mortality rates. WIfI clinical stage was predictive of 1-year MA-free survival, while revascularization significantly reduced MA risk but did not influence overall survival.

Decreasing rates of major lower-extremity amputation in people with diabetes but not in those without: a nationwide study in Belgium.

AIMS/HYPOTHESIS: The reduction of major lower-extremity amputations (LEAs) is one of the main goals in diabetes care. Our aim was to estimate annual LEA rates in individuals with and without diabetes in Belgium, and corresponding time trends. METHODS: Data for 2009-2013 were provided by the Belgian national health insurance funds, covering more than 99% of the Belgian population (about 11 million people). We estimated the age-sex standardised annual amputation rate (first per year) in the populations with and without diabetes for major and minor LEAs, and the corresponding relative risks. To test for time trends, Poisson regression models were fitted. RESULTS: A total of 5438 individuals (52.1% with diabetes) underwent a major LEA, 2884 people with above- and 3070 with below-the-knee major amputations. A significant decline in the major amputation rate was observed in people with diabetes (2009: 42.3; 2013: 29.9 per 100,000 person-years, 8% annual reduction, p < 0.001), which was particularly evident for major amputations above the knee. The annual major amputation rate remained stable in individuals without diabetes (2009: 6.1 per 100,000 person-years; 2013: 6.0 per 100,000 person-years, p = 0.324) and thus the relative risk reduced from 6.9 to 5.0 (p < 0.001). A significant but weaker decrease was observed for minor amputation in individuals with and without diabetes (5% and 3% annual reduction, respectively, p < 0.001). CONCLUSIONS/INTERPRETATION: In this nationwide study, the risk of undergoing a major LEA in Belgium gradually declined for individuals with diabetes between 2009 and 2013. However, continued efforts should be made to further reduce the number of unnecessary amputations.

Lower-extremity amputations in people with and without diabetes in Germany, 2008-2012 - an analysis of more than 30 million inhabitants.

BACKGROUND AND PURPOSE: Lower-extremity amputations (LEAs) in people with diabetes are associated with reduced quality of life and increased health care costs. Detailed knowledge on amputation rates (ARs) is of utmost importance for future health care and economics strategies. We conducted the present cohort study in order to estimate the incidences of LEA as well as relative and attributable risk due to diabetes and to investigate time trends for the period 2008-2012. METHODS: On the basis of the administrative data from three large branches of German statutory health insurers, covering ~34 million insured people nationwide (about 40% of the German population), we estimated age-sex-standardized AR (first amputation per year) in the populations with and without diabetes for any, major, and minor LEAs. Time trends were analyzed using Poisson regression. RESULTS: A total of 108,208 individuals (diabetes: 67.3%; mean age 72.6 years) had at least one amputation. Among people with diabetes, we observed a significant reduction in major and minor ARs during 2008-2012 from 81.2 (95% CI 77.5-84.9) to 58.4 (55.0-61.7), and from 206.1 (197.3-214.8) to 177.0 (169.7-184.4) per 100,000 person-years, respectively. Among people without diabetes, the major AR decreased significantly from 14.3 (13.9-14.8) to 11.6 ([11.2-12.0], 12.0), whereas the minor AR increased from 15.8 (15.3-16.3) to 17.0 (16.5-17.5) per 100,000 person-years. The relative risk (RR) comparing the diabetic with the nondiabetic populations decreased significantly for both major and minor LEAs (4% and 5% annual reduction, respectively). CONCLUSION: In this large nationwide population, we still found higher major and minor ARs among people with diabetes compared with those without diabetes. However, AR and RR of major and minor LEAs in the diabetic compared with the nondiabetic population decreased significantly during the study period, confirming a positive trend that has been observed in smaller and regional studies in recent years.

Incidence of lower extremity amputations in the diabetic compared with the non-diabetic population: A systematic review.

SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD4201501780.

Study of Disease Progression and Relevant Risk Factors in Diabetic Foot Patients Using a Multistate Continuous-Time Markov Chain Model.

The diabetic foot is a lifelong disease. The longer patients with diabetes and foot ulcers are observed, the higher the likelihood that they will develop comorbidities that adversely influence ulcer recurrence, amputation and survival (for example peripheral arterial disease, renal failure or ischaemic heart disease). The purpose of our study was to quantify person and limb-related disease progression and the time-dependent influence of any associated factors (present at baseline or appearing during observation) based on which effective prevention and/or treatment strategies could be developed. Using a nine-state continuous-time Markov chain model with time-dependent risk factors, all living patients were divided into eight groups based on their ulceration (previous or current) and previous amputation (none, minor or major) status. State nine is an absorbing state (death). If all transitions are fully observable, this model can be decomposed into eight submodels, which can be analyzed using the methods of survival analysis for competing risks. The dependencies of the risk factors (covariates) were included in the submodels using Cox-like regression. The transition intensities and relative risks for covariates were calculated from long-term data of patients with diabetic foot ulcers collected in a single specialized center in North-Rhine Westphalia (Germany). The detected estimates were in line with previously published, but scarce, data. Together with the interesting new results obtained, this indicates that the proposed model may be useful for studying disease progression in larger samples of patients with diabetic foot ulcers.

Bayesian evidence synthesis for exploring generalizability of treatment effects: a case study of combining randomized and non-randomized results in diabetes.

In this paper, we present a unified modeling framework to combine aggregated data from randomized controlled trials (RCTs) with individual participant data (IPD) from observational studies. Rather than simply pooling the available evidence into an overall treatment effect, adjusted for potential confounding, the intention of this work is to explore treatment effects in specific patient populations reflected by the IPD. In this way, by collecting IPD, we can potentially gain new insights from RCTs' results, which cannot be seen using only a meta-analysis of RCTs. We present a new Bayesian hierarchical meta-regression model, which combines submodels, representing different types of data into a coherent analysis. Predictors of baseline risk are estimated from the individual data. Simultaneously, a bivariate random effects distribution of baseline risk and treatment effects is estimated from the combined individual and aggregate data. Therefore, given a subgroup of interest, the estimated treatment effect can be calculated through its correlation with baseline risk. We highlight different types of model parameters: those that are the focus of inference (e.g., treatment effect in a subgroup of patients) and those that are used to adjust for biases introduced by data collection processes (e.g., internal or external validity). The model is applied to a case study where RCTs' results, investigating efficacy in the treatment of diabetic foot problems, are extrapolated to groups of patients treated in medical routine and who were enrolled in a prospective cohort study.