Impact of diabetes on outcome in critical limb ischemia with tissue loss: a large-scaled routine data analysis

Critical limb ischemia (CLI), the chronic end-stage condition of lower extremity peripheral artery disease (PAD), is defined by clinical symptoms such as rest pain and/or ischemic lesions (ulcer or gangrene) objectively attributable to PAD [1, 2]. Patients with CLI are at high risk of limb loss: recent German nationwide data report an annual major amputation rate of 10% and a minor amputation rate of 15.5% per year in patients with ischemic lesions present (Rutherford grade 5 and 6) [3]. Further, CLI is an independent risk factor for cardiovascular events and death [4‐6].

Diabetes mellitus is an important risk factor of arteriosclerotic diseases and has been reported to increase the risk of PAD by an Odds Ratio 1.68 (95% CI 1.53–1.84; p < 0.0001) in a global meta-analysis [7] and the relative risk for PAD has been shown to further increase with increasing duration of the diabetic status [8]. Accordingly, diabetes is frequently prevalent in patients with PAD and has been co-diagnosed in ∼35% of all in-patient PAD cases in Germany [3]. PAD patients with concurrent diabetes mellitus represent a subgroup at particular high risk for adverse outcome [9]. Co-morbidity with diabetes is particularly associated with (Mönckeberg’s) medial sclerosis to become manifest in the arteries below-the-knee [10‐12]. Thus, diabetes ratio has been reported ∼80% in CLI patient with infrainguinal TransAtlantic Inter-Society Consensus (TASC) II C/D lesions [13], compared to ∼40% in overall CLI [3]. These often complex and highly calcified infrainguinal lesions are difficult to approach for both, surgical and endovascular revascularization procedures. Therefore, these are associated with restricted long-term patency and unfavorable outcome and the choice of the right treatment strategy in these patients remains challenging [4, 7]. Furthermore, diabetes and therewith attended conditions, such as polyneuropathy, foot malformation, or immunosuppression promote the development of ulcers and impaired wound healing [11], which again increase the risk of limb loss [6, 14‐16]. Moreover, the presence of a diabetic foot syndrome is associated with a notable increase of minor amputations [17]. As a consequence, high rates of primary amputations are common in patients with CLI, particularly in those with diabetes [18, 19].

However, hitherto existing data on the impact of diabetes on patients with CLI are mainly small-sized sub-analyses of pre-selected patient populations. By reason of a lack of large-sized data on rather non-selected patients, conclusions on diabetic CLI patients with tissue loss are drawn from extrapolations of small-sized highly selected patient cohorts, leading to conflicting results [20].

Objective of our large-scaled routine data analysis is to investigate the recent health care situation of CLI patients with diabetes in terms of treatment strategies, complications and impact on outcome parameters as well as health expenditures in a real-world scenario.

We obtained data on 15,332 patients hospitalized with the primary diagnosis of lower limb PAD at the stage of critical limb ischemia with tissue loss (CLI; ICD-10 codes I70.23–I70.24) in the time period between January 1st, 2009 and December 31st, 2011, including a follow-up until 2013 (median follow-up 677 days in Rutherford grade 5, and 577 days in Rutherford grade 6). Data were provided by the BARMER GEK as the largest public health insurance in Germany, comprising >8 million insured respective ∼10% of the German population.

Briefly, all in- and outpatient diagnostic and procedural data are encoded conformable to the diagnosis and procedure- related reimbursement system (German Diagnosis Related Groups, G-DRG system) as required by the mandatory coding guidelines and transferred to the health insurance for remuneration (in detail see [4]). These data are electronically verified and inspected by the personnel of the German Health Insurance Medical Service (MDK; Medizinischer Dienst der Krankenversicherung) in about 20% of cases.

We performed a retrospective analysis on all in- and outpatient diagnostic and procedural data of CLI patients classified in the Rutherford grades 5 (Rutherford grade 5; ICD-10 I70.23; n = 6916) and 6 (Rutherford grade 6; ICD-10 I70.24; n = 8416) (Additional file 1: Table S1). Patients with ischemic rest pain (Rutherford grade 4), that are also commonly recognized as CLI, were not included in the analysis, since particularly in diabetic patients rest pain may not be dependably ascertainable due to diabetic polyneuropathy. In contrast, tissue loss (Rutherford grades 5 and 6) is a much better objectifiable parameter. Within these Rutherford grades, we identified the patient subgroup with the co-diagnosis of diabetes mellitus (IDC-10 E10*, E11*) to be compared with the subgroup without encoded diabetes mellitus. We analyzed these in-hospital cases with respect to baseline characteristics such as age, sex, and the further co-diagnoses hypertension (ICD-10 I10-15*), obesity (ICD-10 E66), dyslipidemia (ICD-10 E78*), smoking (ICD-10 F17*), chronic kidney disease (ICD-10 N18*; CKD), coronary artery disease (ICD-10 I25*; CAD), chronic heart failure (ICD-10 I50*; CHF), and malignancies (ICD-10 C*). Further, we analyzed the encoded procedures during the index hospitalization: angiography (OPS 3-605, 3-607), any revascularization (OPS 5-380*, 5-381*, 5-383*, 5-386*, 5-388*, 5-393*, 5-395*, 8-836*, 8-84*), endovascular revascularization (EVR; OPS 8-836*, 8-84*), surgical revascularization (OPS 5-380*, 5-381*, 5-383*, 5-386*, 5-388*, 5-393*, 5-395*), thrombendartherectomy (TEA; OPS 5-381*), peripheral bypass surgery (OPS 5-393*). We evaluated the in-hospital complications acute renal failure (ICD-10 N17*), acute myocardial infarction (ICD-10 I21*), ischemic stroke (ICD-10 I63*), infection (ICD-10 A30-49*), and sepsis (ICD-10 B95-99*) as well as the in-hospital amputation (OPS 5-864*, 5-865*, 5-866*) and in-hospital mortality. A detailed listing on the diagnosis and procedural defining codes is presented in Additional file 1: Table S1.

We found concomitant diabetes in CLI patients with tissue loss to be associated with lower revascularization procedures and increased amputation rate during in-hospital and follow-up period. However, mortality rate was not further increased subject to diabetes status in this end-stage PAD patient subset.

Patients with CLI and concomitant diabetes receive less revascularization procedures compared to non-diabetic patients despite being at particular high risk for amputation. This reflects in increased subsequent in-hospital costs. However, diabetes was not associated with increased mortality of CLI patients with tissue loss. Further research is needed to identify the underlying reasons for the under-usage of revascularization procedures in diabetic CLI patients to improve limb salvage and reduce health expenditure.