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The utilisation of vascular limb salvage services in the assessment and management of chronic limb‐threatening ischaemia and diabetic foot ulceration: A systematic review

Specialist vascular limb salvage services have gained prominence as a new model of care to help overcome barriers which exist in the management of patients with chronic limb‐threatening ischaemia (CLTI) and/or diabetic foot ulceration (DFU). This systematic review aims to explore the nature of reported services, investigate their outcome in the management of CLTI/DFU, and assess the scope and quality of the evidence base to help make recommendations for future practice and research. A systematic search of MEDLINE, Embase, The Cochrane Library, Scopus and CINAHL, from 1st January 1995 to 18th January 2019, was performed. Specialist vascular limb salvage services were defined as those services conforming to the definition of “centres of excellence” within the 2019 Global Vascular Guidelines. A study protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42019123325). In total, 2260 articles were screened, with 12 articles (describing 11 services) included in a narrative synthesis. All services ran akin to the “toe‐and‐flow” model, with a number of services having additional core input from diabetology, microbiology, allied health professionals and/or internal/vascular medicine. Methodological weaknesses were identified within the design of the included articles and only one was deemed of high quality. The inception of services was associated with improved rates of major amputation; however, no significant changes in minor amputation or mortality rates were identified. Further research should adopt more a standardised study design and outcomes measures in order to improve the quality of evidence within the literature.


| INTRODUCTION
The approach to managing chronic limb-threatening ischaemia (CLTI) and diabetic foot ulceration (DFU) has been transformed over the last 30 years, in part due to two fundamental changes. First, the advent of the endovascular era has radically changed how patients are managed and provides treatment options to those who were once deemed unsuitable for revascularisation. Second, is the recognition of the role that ischaemia plays in the aetiology of DFU. Peripheral arterial disease (PAD) is highly prevalent in patients with diabetic foot disease; the assessment of the peripheral vasculature and subsequent revascularisation are therefore key components of ulcer management. 1,2 This recognition has led to a global shift in how CLTI should be defined, with greater emphasis on a broader and more heterogeneous definition. This new definition highlights the interaction between ischaemia, wound complexity and infection in the natural history of ulceration and aetiology of limb loss. 3 The definition also helps to homogenise care for patients with limb ischaemia and/or DFU.
Many problems, however, still exist within the referral and management pathways for patients, often resulting in lengthy time delays in accessing vascular services. 4 Two recent surveys of healthcare professionals both identified difficulties with accessing specialist vascular consultation and non-invasive imaging as major barriers to care. 5,6 This defies the contemporary trend towards greater multidisciplinary and collaborative working. While vascular surgeons are now established members of the multidisciplinary team (MDT) for managing patients with DFUs, many centres and MDT services (eg, MDT diabetic foot clinics) do not provide direct access to vascular assessment, imaging and revascularisation. 7 In response to this, the idea of a specialist limb salvage service has been gaining prominence as a new model of care, which builds upon the MDT concept to help overcome these barriers. Fitzgerald and colleagues 8 provided the first definition of these services, describing seven essential skills required to deliver a limb salvage service in the context of managing DFUs. These included the ability to assess and manage PAD and neuropathy, and perform debridement and drainage of infection. In order to deliver this, input from specialists in vascular surgery and podiatry (or equivalent speciality) were described as the minimum to form an effective service. 8 This has led to what has been described as the "toe-and-flow" model of conjoined care; comprising a team who can assess and manage ischaemia, and provide complex lower limb wound care and ulcer prevention strategies.
Building upon this, Rogers and colleagues 9 established the idea of tiers of care for the management of DFUs. These range from community-based "basic" providers to "centres of excellence," which provide specialist limb salvage services. "Centres of excellence" usually run within a university/teaching hospital. They offer regional and/or national referrals for complex cases, provide a full spectrum of multidisciplinary specialist input and run educational services. 9 While these limb salvage services have been described principally in the care of patients with DFUs, they are now also being considered within the context of the broader definition of CLTI. Subsequently, the recently published Global Vascular Guidelines (GVG) have further developed the idea and defined criteria for vascular limb salvage "centres of excellence." 3 Unlike traditional MDT services, which may not have provision to manage ischaemia, these vascular limb salvage services provide dedicated access to vascular specialists who manage PAD, in addition to specialities who provide complex wound and medical care. Furthermore, they also provide care to patients without diabetes.
To date, no review has used the GVG criteria to explore limb salvage services within the literature or evaluated the evidence base to support their use. This systematic review therefore aims to: (a) explore the nature of these services within the literature, (b) investigate their outcomes in the management of CLTI/DFU and (c) assess the scope and quality of the evidence base to make recommendations for future research.

| METHODOLOGY
This systematic review was performed in accordance with the "Meta-analysis of Observational Studies in Epidemiology" (MOOSE) specification. 10 A study protocol was designed conforming to the Preferred Reporting Items for Systematic Review of Meta-analysis Protocols (PRISMA-P) 11 and registered at the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019123325).

| Search strategy
A search of MEDLINE, Embase, The Cochrane Library, Scopus and CINAHL was performed on 18th January 2019. A search strategy was employed using combinations of keywords and thesaurus headings, including: "limb ischaemia," "diabetic foot," "foot ulcers," "wound clinic," "perfusion clinic," "toe and flow," "limb preservation," "amputation" and "wound healing." Only English language articles were considered. The search strategy was developed in MEDLINE and adapted accordingly for use with other databases (Appendix S1). From preliminary searches a number of historical articles potentially meeting the inclusion criteria were identified. Therefore, in order to provide a thorough overview of all services meeting the inclusion criteria, articles published from first January 1995 onwards were considered. For each included article, bibliographic lists were screened for additional articles of interest. Additional internet searches were also performed, utilising Google and Google Scholar (Google LLC). The searches were developed and performed by investigator AN. The searches were repeated prior to completion of the study (July 17, 2019).

| Types of studies
All observational studies (except case reports), qualitative research, conference abstract and audits were included. Given the heterogeneous nature of the management of CLTI/DFU across healthcare systems, only articles based within "high-income" countries (annual GDP > $15 000 per capita) were eligible.

| Study participants
Articles involving adult patients (>18 years) with a presumed or confirmed diagnosis of CLTI/DFU were included. Articles which presented data on ulcers of other aetiology were excluded unless data were presented separately from CLTI/DFU results.

| Intervention
This review focussed on services defined as specialist vascular limb salvage "centres of excellence" as defined within the 2019 GVG. 3 These centres were defined by the following four characteristics: Multi-disciplinary team: • Consists of a specialist team who can provide both medical and surgical management of PAD (ie, vascular surgery or interventional radiology) and infection (eg, podiatry, orthopaedics, plastic surgery or other specialty that perform surgical debridement), and provide general and intensive medical care Protocol-drive care: • The service follows evidence-based clinical protocols, procedures and pathways.
Outcome monitoring and improvements: • Have an established process for data collection and reporting data to the literature • Serves as an educational resource for the medical community via mentoring, publishing, teaching or conferences.
For the purposes of this study, services must provide daily patient review plus vascular review more than twice per week. Acknowledging that specific speciality roles (particularly podiatry) vary between healthcare systems, the description of individual responsibilities within the reporting article were used to judge for study inclusion.
Given the potentially novel and developing nature of some services, educational pathways may yet to be established and therefore articles were not excluded solely upon this criterion.

| Outcomes
For individual articles, baseline data were extracted. This included study design, sample size, publication date, inclusion/exclusion criteria and number of patients with CLTI/DFU. Details on individual services were also collected, including core specialities (specialities who function within the service without onward referral), treatment scope and education services.
Individual outcomes of this review are shown in Table 1. For the purposes of this review, major amputation rate (1 year and total) was the primary outcome.

| Data extraction
A process of data extraction was formulated in line with the Cochrane Handbook for Systematic Reviews of Interventions. 12  In cases where two articles describe the same service and outcomes, only the most contemporary article was included. Likewise, where the same cohort is described in different articles (albeit presenting different outcomes), baseline data were only recorded once.
In cases where further detail was required to interpret results, the corresponding author was contacted (where possible) through their published email address.

| Quality assessment
Methodological quality was assessed using the appropriate study type critical appraisal tool published by the Joanne Briggs Institute. 13 For cohort studies (anticipated as the most likely study type), articles meeting fewer than 6 criteria were deemed low, 6 to 9 moderate and greater than 9 high quality. Quality assessment was performed by A.N. with independent assessment provided by A.E.A. and S.N., following data extraction. Disagreements were resolved through discussion. No tools currently exist to assess conference abstract or published audits.

| Data synthesis
From initial searches the observed heterogeneity between articles led to the anticipation that a formal meta-analysis would not be possible and as such was not the basis of this review. A narrative synthesis of results was conducted with amputation-related outcomes being tabulated. Where data were available, the "high-low" amputation rate was calculated,if not presented. 14 Furthermore, Pearson's χ 2 test was utilised to test for statistical significance in situations where categorical data were provided without being tested for statistical significance. Analysis was undertaken using SPSS v25.0 (IBM Corp., Armonk, USA) with P < .05 deemed statistically significant.

| RESULTS
On completion of the search strategy 2260 articles were screened, with 12 articles 15-26 being included in the final synthesis ( Figure 1).
The characteristics of the included articles are shown in Table 2.

| Study quality
Results of the quality assessment process are shown in Appendix S2.
Only one article 26 was deemed of "high" quality. Five articles 15,17,22,23,25 were "moderate" quality with five articles 16,18,20,21,24 deemed of "low" quality. The article by Gottrup 19 could not be quality assessed. and Alexandrescu 15 did not clearly describe the setting of their service.
In line with the GVG guidelines, 3

| Education
Only four services 18

| Rates of minor amputation
Only two articles 17,26 provided comparative rates of minor amputation.  Table 3).
Armstrong 16 reported data on minor amputation as a proportion of total procedures, identifying a significant increase in the proportion of mid−/hindfoot amputation performed since inception of their service (P < .05), with a decrease in the proportion of toe amputations (P < .05). As with major amputations, data were only presented in graphical form from which an exact result could not be deduced.
High-low amputation ratios were also available within two articles. 16,23 Armstrong 16 provided comparative data, identifying a fall in this ratio since inception of their service. however, insufficient data were reported to make this comparison for endovascular procedures.
Driver 17 identified a significant improvement in overall mortality in favour of their limb salvage service (pre-service = 19.5%, service = 7.7%, P < .001); however, only patients with 3 years of followup were included. Alexandrescu 15 reported an overall mortality rate of 9% at 12 months and 21% at 24 months across both cohorts, although no comparative data was provided.

| Wound healing
Vartanian 23 reported complete wound healing was achieved in 59% of patients within their service by the end of their study (median followup 207 days). They reported a median time to healing of 12 (range 1-73) weeks; however, no comparative data was presented.

| DISCUSSION
Patients with CLTI/DFU represent a complex, multi-morbid group who at minimum require input from multiple specialities in order to receive effective care. 27  Based upon this review, it is also recommended that services present data on all patients diagnosed with CLTI/DFU, irrespective of their eventual treatment, as this helps to provide greater context to the operation of the service and minimises selection bias. In line with the recently published GVG, standardised definitions and reporting of outcome measures, including rate of major amputation, time to ulcer healing and mortality are also required, along with time-to-event data. 3 These changes (Table 4) would help not only to reduce bias but allow for greater pooling of data to provide high level evidence to evaluate the effectiveness of these services. 31 Although these standards may be difficult to meet they should serve as an aspiration for future practice and bring about changes in how institutional data are collected.

| Limitations
While this review is the first to examine the evidence for limb salvage service, it is not without limitation.
First, comparing outcomes before and after the inception of a limb salvage service, even on a single institutional level, is inherently difficult and carries potential for bias. As demonstrated in this review, many articles had highly selective inclusion criteria and some provided limited (or even no) baseline demographic data to allow for accurate comparison between groups. It is also possible that performance bias existed in the way patients were managed, with higher thresholds for amputations within limb salvage services. Likewise, publication bias may also exist, with the potential of services failing to publish outcomes which are not favourable. Although judging the exact effect of these biases is challenging, their potential means that the results of this review should be interpreted with some caution.
The heterogeneity between services also means the comparison of outcomes between institutions is unreliable. This issue limits the generalisability of the review's conclusions as any benefits of limb salvage services may be specific to an individual population.
Furthermore, the GVG criteria used to define a vascular limb salvage service "centre of excellence" are broad and open to individual interpretation. While this review used the agreed international definition, in a number of cases it was difficult to establish the true nature of services from a publication alone and in some circumstances differentiating a well-run MDT from a limb salvage services was challenging. In some cases, articles were also excluded as they failed to provide sufficient detail on the nature of the input of vascular surgery.
It is therefore plausible that services were incorrectly included or excluded from the review, although it is not possible to establish how this could have affected the results. Using other criteria could have potentially alleviated this issue; however, the intention of this systematic review was to utilise the most contemporary guidelines, as defined by the GVG.
Lastly, using a search strategy which included all articles from 1995 onwards is controversial and not without limitation. This historical limit was applied following preliminary searches, which identified a number of potentially suitable articles published in the 1990s (although following the full selection process, the earliest included paper in the review was from 1999). However, the GVG criteria used to define services are contemporary and may not be applicable to historical services. This is particularly relevant as the methods and processes of managing CLTI have changed over this period. Using a more recent time limit could have helped to mitigate this; however, as one of the review's aims was to explore the nature of these services within the literature, it was felt the breadth provided by this criterion outweighed any limitation.
In conclusion, a limited number of specialist vascular limb salvage services have been described, all based around the "toe-and-flow" model of care. The results of this review indicate that the inception of these services is associated with a significant reduction in the rate of major amputation for patients with CLTI and/or DFUs; however, no significant changes in minor amputation or mortality rates were identified. Methodological problems exist in many of the included articles and further research should adopt a more standardised approach to study design and outcome reporting in order to improve the quality of evidence within the literature.
Use of medical therapy (rates of anti-platelet and lipid lowering medication use) All patients with chronic limb-threatening ischaemia/ diabetic foot ulceration within service-irrespective of eventual treatment strategy

Service
Referral criteria to service Comparative institutional data-prior to inception of service had no role in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review or approval of the manuscript.

CONFLICT OF INTEREST
RSMD has received personal fees for speaking from Cook Medical and Gore and has received sponsorship to run educational workshops from TerumoAortic. These are outside of the submitted work.