Critical limb-threatening ischaemia and microvascular transformation: clinical implications.

BACKGROUND AND AIMS: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology. METHODS: Clinical high-resolution imaging of CLTI patients (n = 50) and muscle samples from amputated CLTI limbs (n = 40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischaemia model in rabbits (n = 24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome. RESULTS: Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P < .01) in CLTI muscles. Critical limb-threatening ischaemia muscle microvasculature also exhibited capillary enlargement (P < .001) and further arterialization along worsening of myofibre atrophy and detaching of capillaries from myofibres. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P < .05) and tissue outcome (P < .01) under chronic ischaemia in rabbits and in healthy, normal rabbit muscle. CONCLUSIONS: These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.

The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer.

Diabetes related foot complications have become a major cause of morbidity and are implicated in most major and minor amputations globally. Approximately 50% of people with diabetes and a foot ulcer have peripheral artery disease (PAD) and the presence of PAD significantly increases the risk of adverse limb and cardiovascular events. The International Working Group on the Diabetic Foot (IWGDF) has published evidence based guidelines on the management and prevention of diabetes related foot complications since 1999. This guideline is an update of the 2019 IWGDF guideline on the diagnosis, prognosis and management of peripheral artery disease in people with diabetes mellitus and a foot ulcer. For this guideline the IWGDF, the European Society for Vascular Surgery and the Society for Vascular Surgery decided to collaborate to develop a consistent suite of recommendations relevant to clinicians in all countries. This guideline is based on three new systematic reviews. Using the Grading of Recommendations, Assessment, Development, and Evaluation framework clinically relevant questions were formulated, and the literature was systematically reviewed. After assessing the certainty of the evidence, recommendations were formulated which were weighed against the balance of benefits and harms, patient values, feasibility, acceptability, equity, resources required, and when available, costs. Through this process five recommendations were developed for diagnosing PAD in a person with diabetes, with and without a foot ulcer or gangrene. Five recommendations were developed for prognosis relating to estimating likelihood of healing and amputation outcomes in a person with diabetes and a foot ulcer or gangrene. Fifteen recommendations were developed related to PAD treatment encompassing prioritisation of people for revascularisation, the choice of a procedure and post-surgical care. In addition, the Writing Committee has highlighted key research questions where current evidence is lacking. The Writing Committee believes that following these recommendations will help healthcare professionals to provide better care and will reduce the burden of diabetes related foot complications.

Editor's Choice - Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL) Prospective Cohort Study and the Generalisability of the BASIL-2 Randomised Controlled Trial.

OBJECTIVE: The Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2) randomised controlled trial has shown that, for patients with chronic limb threatening ischaemia (CLTI) who require an infrapopliteal (IP) revascularisation a vein bypass (VB) first revascularisation strategy led to a 35% increased risk of major amputation or death when compared with a best endovascular treatment (BET) first revascularisation strategy. The study aims are to place the BASIL-2 trial within the context of the CLTI patient population as a whole and to investigate the generalisability of the BASIL-2 outcome data. METHODS: This was an observational, single centre prospective cohort study. Between 24 June 2014 and 31 July 2018, the BASIL Prospective Cohort Study (PCS) was performed which used BASIL-2 trial case record forms to document the characteristics, initial and subsequent management, and outcomes of 471 consecutive CLTI patients admitted to an academic vascular centre. Ethical approval was obtained, and all patients provided fully informed written consent. Follow up data were censored on 14 December 2022. RESULTS: Of the 238 patients who required an infrainguinal revascularisation, 75 (32%) had either IP bypass (39 patients) or IP BET (36 patients) outside BASIL-2. Seventeen patients were initially randomised to BASIL-2. A further three patients who did not have an IP revascularisation as their initial management were later randomised in BASIL-2. Therefore, 95/471 (20%) of patients had IP revascularisation (16% outside, 4% inside BASIL-2). Differences in amputation free survival, overall survival, and limb salvage between IP bypass and IP BET performed outside BASIL-2 were not subject to hypothesis testing due to the small sample size. Reasons for non-randomisation into the trial were numerous, but often due to anatomical and technical considerations. CONCLUSION: CLTI patients who required an IP revascularisation procedure and were subsequently randomised into BASIL-2 accounted for a small subset of the CLTI population as a whole. For a wide range of patient, limb, anatomical and operational reasons, most patients in this cohort were deemed unsuitable for randomisation in BASIL-2. The results of BASIL-2 should be interpreted in this context.

Reduction of Major Amputations after Surgery Versus Endovascular Intervention: The BEST-CLI Randomised Trial.

OBJECTIVE: BEST-CLI, an international randomised trial, compared bypass surgery with endovascular treatment in chronic limb threatening ischaemia (CLTI). In this substudy, overall amputation rates and risk of major amputation as an initial or subsequent outcome were evaluated. METHODS: A total of 1 830 patients were randomised to receive surgical or endovascular treatment:(1) patients with adequate single segment great saphenous vein (SSGSV) (n = 1 434); and (2) patients without adequate SSGSV (n = 396). Differences in time to first event and number of amputations were evaluated. RESULTS: In cohort 1, 410 (45.6%) total amputation events occurred in the surgical group vs. 490 (54.4%) in the endovascular group (p = .001) during mean follow up of 2.7 years. Every third patient underwent minor amputation after index revascularisation: 31.5% of the surgical group vs. 34.9% in the endovascular group (p = .17). Subsequent major amputation was required significantly less often in the surgical group compared with the endovascular group (15.0% vs. 25.6%; p = .002). The first amputation was major in 5.6% of patients in the surgical and 6.0% in the endovascular group (p = .72). Major amputation was required in 10.3% (n = 74/718) of patients in the surgical group and 14.9% (n = 107/716) in the endovascular group (p = .008). In cohort 2, 199 amputation events occurred in 132 (33.3%) patients during mean follow up of 1.6 years: 95 (47.7%) in the surgical vs. 104 (52.3%) in the endovascular group (p = .49). Major amputation was required in 15.2% (n = 30/197) of the patients in the surgical and 14.1% (n = 28/199) in the endovascular group (p = .74). CONCLUSION: In patients with CLTI, surgical bypass with SSGSV was more effective than endovascular treatment in preventing major amputations because of a decrease in major amputations subsequent to minor amputations.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-2 Trial: Analysis of the Timing and Causes of Death in Participants Randomised to an Infrapopliteal Vein Bypass or Best Endovascular Treatment First Revascularisation Strategy.

OBJECTIVE: The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL)-2 trial enrolled participants with chronic limb threatening ischaemia who required an infrapopliteal, with or without a femoropopliteal, revascularisation procedure to restore limb perfusion. Participants randomised to a vein bypass (VB) first revascularisation strategy were over one third more likely than those randomised to a best endovascular treatment (BET) first revascularisation strategy to die from any cause during a median follow up of 40.0 (interquartile range 20.9, 60.6) months. The aim was to describe the timing and causes of death in BASIL-2 as a first step towards trying to better understand why randomisation to a VB first revascularisation strategy was associated with this excess mortality. METHODS: A 10 person international panel comprising vascular and endovascular surgeons as well as vascular interventional radiologists, who had all been principal investigators in BASIL-2, took part in a modified Delphi consensus exercise to adjudicate the primary cause of death and, in particular, whether the cause was primarily cardiac or non-cardiac. RESULTS: In 151/168 deaths (89.9%) the Delphi panel achieved a consensus regarding the cause of death being probably cardiac or non-cardiac. In the BET group, 16/77 deaths (21%) were classified as probably cardiac compared with 32/91 (35%) in the VB group (unadjusted subdistribution hazard ratio 2.16, 95% confidence interval [CI] 1.20 - 3.87; unadjusted cause specific hazard ratio 2.15, 95% CI 1.19 - 3.90). At the point of randomisation, 64/344 (18.6%), 37/344 (10.8%), and 40/342 (9%) participants had a previous myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG), respectively. There was no evidence of varying treatment effects for cause of death in subgroup analyses of previous PCI, CABG, or MI. CONCLUSION: The excess mortality observed in the VB first revascularisation strategy group in BASIL-2 was largely due to deaths that were adjudicated by the Delphi panel as probably primarily cardiac. These excess cardiac deaths were observed throughout follow up and there was no evidence of non-proportional hazards. Further work is ongoing to try to better understand the reasons for these findings.

Biomimetic Stents for Infrainguinal Peripheral Arterial Disease: Systematic Review and Meta-Analysis.

OBJECTIVE: Biomimetic stents are peripheral infrainguinal self expanding stents that mimic the anatomy of the vasculature and artery movement. They are indicated for use in infrainguinal arteries. This research aimed to synthesise all current evidence on the use of biomimetic stents as adjuncts for endovascular treatment of infrainguinal peripheral arterial disease (PAD), helping to guide clinical decision making. DATA SOURCES: MEDLINE, Embase, CINAHL and Cochrane databases. REVIEW METHODS: Random effects meta-analysis following PRISMA guidelines (PROSPERO registration CRD42022385256). Study quality was assessed using the Joanna Briggs Institute critical appraisal tools checklist, and certainty assessment through the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Endpoints included primary patency, target lesion revascularisation, stent fracture, secondary patency, and Death at one year. RESULTS: In total, 37 studies were included in the meta-analysis (33 cohort studies, two case series, and two randomised controlled trials [RCTs]), representing 4 480 participants. Of these, 34 studies included data on the Supera (81.5% of participants) and three studies reported data on the BioMimics 3D (18.5% of participants) stents. The pooled primary patency rate of 33 studies at one year follow up was 81.4% (95% confidence interval [CI] 78.7 - 83.9%), and the pooled target lesion revascularisation rate of 18 studies at one year was 12.2% (95% CI 9.6 - 15.0%). The certainty of evidence outcome rating as qualified by GRADE was very low for both. Only one study reported a positive stent fracture rate at one year follow up of 0.4% with a certainty of evidence outcome of low. CONCLUSION: Using biomimetic stents for infrainguinal PAD may be associated with acceptable one year primary patency and target lesion revascularisation rates, with a near negligible one year stent fracture rate. Their use should be considered in those presenting with infrainguinal PAD undergoing endovascular revascularisation. A RCT is necessary to determine their clinical and cost effectiveness.

Network Meta-analysis of Randomised Controlled Trials Comparing the Outcomes of Different Endovascular Revascularisation Treatments for Infra-inguinal Peripheral Arterial Disease Causing Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to compare the efficacy of different endovascular revascularisation procedures for treating chronic limb threatening ischaemia (CLTI) using network meta-analysis (NMA). DATA SOURCES: The databases PubMed and Cochrane Central Register for Controlled Trials were searched on 14 March 2023. REVIEW METHODS: A NMA of randomised controlled trials (RCTs) reporting the efficacy of different endovascular revascularisation techniques for treating CLTI was performed according to PRISMA guidelines. The primary and secondary outcomes were major amputation and death, respectively. Random effects models were developed and the results were presented using surface under the cumulative ranking curve plots and forest plots. A p value of ≤ .050 was considered statistically significant. The Cochrane collaborative tool was used to assess risk of bias. RESULTS: A total of 2 655 participants of whom 94.8% had CLTI were included. Eleven trials compared plain balloon angioplasty (PBA) vs. drug coated balloon (DCB) angioplasty (n = 1 771), five trials compared bare metal stent (BMS) vs. drug coated stent (DCS) (n = 466), three trials compared atherectomy vs. DCB (n = 194), two trials compared PBA vs. BMS (n = 70), one trial compared PBA vs. atherectomy (n = 50), and one trial compared BMS vs. DCB (n = 104). None of the revascularisation strategies significantly reduced the risk of major amputation or death compared with PBA. Using the network estimates, GRADE certainty of evidence for improvement in major amputation outcomes for DCB was moderate, for atherectomy and BMS was low, and for DCS was very low compared with PBA. Risk of bias was low in 16 trials, of some concerns in six trials, and high in one trial, respectively. CONCLUSION: There is no current evidence from RCTs to reliably conclude that BMS, DCB, DCS, or atherectomy are superior to PBA in preventing major amputation and death in patients with CLTI. Larger comparative RCTs are needed to identify the best endovascular revascularisation strategy.

Short and Mid Term Outcomes of Percutaneous Deep Venous Arterialisation for No-option Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Percutaneous deep venous arterialisation (pDVA) is a state of the art technique for treating patients with chronic limb threatening ischaemia (CLTI) with no conventional option for revascularisation. There are limited large scale data examining the clinical effectiveness of pDVA for patients with end stage CLTI. DATA SOURCES: MEDLINE, Embase, Google Scholar, and Cochrane databases. REVIEW METHODS: Four databases were searched from January 2018 to June 2024 to identify studies investigating the feasibility and clinical outcomes of pDVA for patients with CLTI with no conventional revascularisation options. Meta-analysis of time to event outcomes (mean ± standard deviation) was performed for amputation free survival as the primary outcome, and freedom from amputation and overall survival as secondary outcomes. Other secondary outcomes (mean and 95% confidence interval [CI]) were procedural success rate, patency, re-intervention, and complete wound healing. RESULTS: Ten non-randomised studies were included with 351 patients. Mean patient age was 70.3 years, and 67.6% were male. Most procedures utilised the posterior tibial artery. The aggregated rate of amputation free survival at six and 12 months (five studies, 260 patients) was 72.6 ± 2.8% and 66.0 ± 3.1%, respectively, while the overall survival at six and 12 months (five studies, 260 patients) was 85.0 ± 2.3% and 77.7 ± 2.9%, respectively. The procedural success rate (nine studies, 330 patients) was 95.5% (95% CI 92.4 - 98.7%). Primary and secondary patency at six months (four studies, 241 patients) was 23.4% (95% CI 13.6 - 33.2%) and 54.9% (95% CI 34.3 - 75.5%), respectively. The rates of re-intervention (four studies, 190 patients) and complete wound healing (seven studies, 266 patients) at six and 12 months were 15.5% (95% CI 1.4 - 29.6%) and 41.7% (95% CI 25.7 - 57.7%), respectively, for re-intervention, and 19.3% (95% CI 9.6 - 29.0%) and 46.0% (95% CI 31.7 - 60.3%) for wound healing. CONCLUSION: This meta-analysis demonstrated acceptable feasibility for no-option CLTI at highly specialised institutions for patients undergoing pDVA. Meta-analysis of time to event outcomes revealed that pDVA provides reasonable amputation free survival for up to 12 months, albeit with a overall low certainty of evidence. Wider adoption of pDVA may be considered in selective patients with CLTI, although its clinical impact and cost effectiveness require further evaluation.

The BioMimics 3D Helical Centreline Nitinol Stent in Chronic Limb Threatening Ischaemia and Complex Lesions: Three Year Outcomes of the MIMICS-3D Registry.

OBJECTIVE: There is a need for improved outcomes in the endovascular treatment of patients suffering from chronic limb threatening ischaemia (CLTI), highly calcified lesions, and chronic total occlusions (CTOs). The helical centreline self expanding BioMimics 3D stent might be particularly useful in these high risk subsets, combining flexibility and fracture resistance with radial strength. Herein, the performance of the BioMimics 3D stent was assessed in these high risk subsets. METHODS: MIMICS-3D is a prospective, multicentre, European real world registry. This was a post hoc analysis, comparing patients with CLTI vs. intermittent claudication (IC), lesions with bilateral calcification vs. those without (peripheral arterial calcium scoring system [PACSS] 3,4 vs. PACSS 0 - 2), and CTO vs. no CTO. Propensity score matching was performed to reduce the impact of baseline variables. The 36 month endpoints were clinically driven target lesion revascularisation (CD-TLR), death, major target limb amputation, and stent patency. RESULTS: A total of 507 patients were enrolled. At 36 months, patients with CLTI had lower freedom from major amputation than patients with IC (92.6% vs. 100%, p < .001). In terms of primary patency, patients with CTO had lower patency rates than those without (63.9% vs. 77.8%, p = .003), but the difference reduced after propensity score matching (70.5% vs. 76.8%, p = .43). Primary patency was not impaired for patients with PACSS 3,4 or patients with CLTI. Freedom from CD-TLR was not significantly different among the groups and was 73.8% for CLTI vs. 78.9% for IC (p = .15), 77.6% for PACSS 3,4 vs. 78.7% for PACSS 0 - 2 (p = .55), and 75.6% for CTO vs. 81.0% for no CTO (p = .11). CONCLUSIONS: The outcome of the MIMICS-3D registry suggests that the BioMimics 3D stent is effective in the endovascular treatment of complex femoropopliteal lesions and in CLTI. Future randomised controlled trials should confirm its non-inferiority or superiority compared with existing alternatives.

Recombinant Human Hepatocyte Growth Factor Plasmids for Treating Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-analysis.

OBJECTIVE: Recombinant human hepatocyte growth factor (HGF) plasmids are novel alternatives to salvage limbs in patients with chronic limb threatening ischaemia (CLTI). A systematic review and meta-analysis of data were conducted to assess the therapeutic efficacy of HGF plasmids in patients with CLTI. DATA SOURCES: Randomised controlled studies evaluating HGF plasmid efficacy in patients with CLTI were identified using Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases. REVIEW METHODS: Meta-analyses of the reported relative risks (RR) or mean differences (MD) were conducted. Subgroup analyses determined the efficacy of HGF plasmids in cohorts excluding Buerger's disease. Certainty of evidence for each outcome was assessed. RESULTS: Seven studies (n = 655) were included. Based on low certainty evidence, patients treated with HGF had a significantly higher complete ulcer healing rate (RR 1.99, 95% CI 1.30 - 3.04; p = .015) than patients treated with placebo. The HGF treatment was associated with reduced visual analogue scale (VAS) scores of pain severity (MD -1.56, 95% CI -2.12 - -1.00; p < .001) vs. placebo in patients with CLTI assessed at the 3 month follow up (low certainty evidence); no significant differences were observed in major amputation (RR 0.91, 95% CI 0.48 - 1.73; p = .77) (low certainty evidence), or all-cause mortality (RR 0.93, 95% CI 0.38 - 2.27; p = .87) (low certainty evidence) between patients treated with HGF and placebo. Low certainty evidence suggested no significant differences in change in ankle-brachial index at 6 months (MD 0.00, 95% CI -0.09 - 0.09; p = 1.0) between patients treated with HGF and placebo. The complete ulcer healing rate and improved 3 month VAS scores of pain severity benefits persisted in subgroup analyses (low certainty evidence). CONCLUSION: Hepatocyte growth factor treatment is associated with an increased complete ulcer healing rate and reduced ischaemic pain in patients with CLTI.

Association of Pedal Acceleration Time With Healing and Amputation Free Survival in Patients With Ulceration and Gangrene.

OBJECTIVE: Pedal acceleration time (PAT) is a novel non-invasive perfusion measurement that may be useful in the management of patients with ulceration and gangrene. The objective of this study was to report the association between PAT and wound healing, amputation free survival (AFS), and mortality at one year. METHODS: This prospective observational study reviewed all patients who underwent PAT after presentation with ulceration or gangrene from 1 January 2020 to 30 June 2022. PAT was defined as the time (in milliseconds) from the onset of systole to the peak of systole in the mid artery. The final PAT of a limb was used to assess outcomes (presenting PAT if no revascularisation, or post-revascularisation PAT). Wound healing, major limb amputation, and death at one year were collected. Healing was assessed with Fine-Gray competing risks model, AFS via logistic regression, and survival using Cox proportional hazards model. RESULTS: Overall, 265 patients (307 limbs) were included. The median patient age was 71 years and 74.0% (196/265) had diabetes mellitus. Patient demographics were similar among the final PAT category cohorts. Compared with a final PAT category 1, analysis of one year outcomes showed that the final PAT categories 2 - 4 had lower wound healing (category 2, hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43 - 0.9, p = .012; category 3, HR 0.21, 95% CI 0.08 - 0.58, p = .002; category 4, HR 0.12, 95% CI 0.04 - 0.34, p < .001), lower AFS (category 2, odds ratio [OR] 2.86, 95% CI 1.64 - 5.0, p < .001; category 3, OR 5.1, 95% CI 1.71 - 15.22, p = .003; category 4, OR 12.59, 95% CI 4.34 - 36.56, p < .001), and lower survival (category 2, HR 1.89, 95% CI 1.17 - 3.03, p =.009; category 3, HR 2.37, 95% CI 1.05 - 5.36, p = .039; category 4, HR 4.52, 95% CI 2.48 - 8.21, p < .001). CONCLUSION: The final PAT measurement is associated with wound healing, AFS, and death at one year. PAT may be a valuable tool to assess perfusion of the foot.

Validation of JCLIMB, SPINACH, and VQI Calculators for Prediction of Two Year Survival in Patients With Chronic Limb Threatening Ischaemia After Infra-Inguinal Surgical or Endovascular Revascularisation.

OBJECTIVE: This study aimed to evaluate three survival prediction models: the JAPAN Critical Limb Ischaemia Database (JCLIMB), Surgical Reconstruction Versus Peripheral Intervention in Patients With Critical Limb Ischaemia (SPINACH), and Vascular Quality Initiative (VQI) calculators. METHODS: Multicentre data of patients who underwent infrainguinal revascularisation for chronic limb threatening ischaemia between 2018 and 2021 were analysed retrospectively. The prediction models were validated using a calibration plot analysis with the intercept and slope. The discrimination was evaluated using area under the curve (AUC) analysis. The observed two year overall survival (OS) was evaluated by the Kaplan - Meier method. The two year OS predicted by each model at < 50%, 50 - 70%, and > 70% was defined as high, medium, and low risk, respectively. RESULTS: A total of 491 patients who underwent infra-inguinal revascularisation were analysed. The rates of surgical revascularisation, endovascular therapy, and hybrid therapy were 26.5%, 70.1%, and 5.5%, respectively. The average age was 75.6 years, and the percentages of patients with diabetes mellitus and dialysis dependent end stage renal disease were 66.6% and 44.6%, respectively. The tissue loss rate was 85.7%. The intercept and slope were -0.13 and 1.18 for the JCLIMB, 0.11 and 0.82 for the SPINACH, and -0.15 and 1.10 for the VQI. The AUC for the two year OS of JCLIMB, SPINACH, and VQI were 0.758, 0.756, and 0.740, respectively. The observed two year OS rates of low, medium, and high risk using the JCLIMB calculator were 80.1%, 61.1%, and 28.5%, respectively (p < .001), using the SPINACH calculator were 81.0%, 57.0%, and 38.1%, respectively (p < .001), and using the VQI calculator were 77.8%, 45.8%, and 49.6%, respectively (p < .001). CONCLUSION: The JCLIMB, SPINACH, and VQI survival calculation models were useful, although the OS predicted by the VQI model appeared to be lower than the observed OS.

Impact of Infrapopliteal Revascularisation Establishing In Line Flow to the Wound in Patients with Chronic Limb Threatening Ischaemia.

OBJECTIVE: This study aimed to determine the impact of infrapopliteal (IP) revascularisation establishing in line flow to the wound (IFW) on wound healing in chronic limb threatening ischaemia (CLTI), using a core laboratory assessment for wounds and in line flow. METHODS: The Wound directed Angiosome RevasculaRIsation apprOach to patients with cRitical limb iSchaemia (WARRIORS) multicentre observational study enrolled patients with CLTI with tissue loss undergoing IP revascularisation in Japan, with scheduled two year follow up. The primary outcome measure was complete wound healing, defined as achievement of complete epithelialisation of all wounds without major amputation. IP revascularisation establishing IFW was defined as revascularisation after which a tibiopedal artery that actually fed an injured pedal unit was patent. The incidence of wound healing was compared between the IFW and non-IFW groups using inverse probability of treatment weighting based on the propensity score. RESULTS: A total of 440 patients with CLTI (median age, 75 years; male, 64.1%; diabetes mellitus, 72.0%; dialysis, 57.7%) with tissue loss (Wound, Ischaemia, and foot Infection stage 4, 66.4%) who underwent IP revascularisation (endovascular procedure, n = 304; bypass grafting, n = 136) between October 2017 and June 2020 were registered. During a median follow up of 23.6 months, 51.1% achieved wound healing. Successful IP revascularisation with IFW was achieved in 68.2%. After analysis, the IFW group had a higher rate of wound healing than the non-IFW group (34.5 vs. 16.1 per 100 person years; p = .030). The association between IFW and wound healing was not statistically different between patients undergoing bypass grafting and those undergoing an endovascular procedure (p for interaction = .38). There was no statistically significant interaction effect between IFW and direct revascularisation for wound healing (p for interaction = .51). CONCLUSION: IP revascularisation establishing IFW was statistically significantly associated with a higher wound healing rate in patients with CLTI.

Major Adverse Limb Events in Patients Undergoing Revascularisation for Lower Limb Peripheral Arterial Disease: A Nationwide Observational Study☠.

OBJECTIVE: Major adverse limb events (MALEs) are frequent in patients with lower extremity peripheral arterial disease (PAD). However, routine care MALE rate estimations after revascularisation are scarce. This study aimed to determine post-procedural MALE rates in revascularised patients with PAD and identify predictors for post-procedural MALEs. METHODS: This was a population based observational study on merged national registry data. Patients with PAD undergoing lower limb revascularisation between 2008 and 2016 were retrieved from the Swedish National Registry for Vascular Surgery. Information on comorbidities, medications, and post-procedural MALE endpoints were identified in national healthcare registries. Primary outcomes of interest were categorised as 2 - 4 point MALE composites that included limb amputation, acute lower limb ischaemia, progression to or relapse of chronic limb threatening ischaemia (CLTI), and ipsilateral re-interventions regardless of indication. Patients with intermittent claudication (IC) and CLTI were analysed separately using Kaplan-Meier estimates. Stepwise Cox proportional hazard models were used for predictor candidate analysis. RESULTS: Overall, 28 021 revascularised patients with PAD were analysed (IC, n = 10 506, 37.5%; CLTI, n = 17 515, 62.5%). During a mean follow up ± standard deviation of 3.2 ± 2.4 years, 5 226 (18.7%), 9 423 (33.6%), and 12 696 (45.3%) patients experienced a 2, 3, and 4 point MALE, respectively. The estimated one year 4 point MALE rates were 21.4% (95% confidence interval [CI] 20.6 - 22.2%) in IC and 46.9% (95% CI 46.1 - 47.7%) in CLTI. Adjusted predictors for experiencing a 4 point MALE in IC were chronic kidney disease (CKD) (hazard ratio [HR] 1.33, 95% CI 1.12 - 1.59) and previous lower limb revascularisation (HR 1.29, 95% CI 1.19 - 1.40). In CLTI, previous contralateral lower limb amputation (HR 1.60, 95% CI 1.47 - 1.73) and CKD (HR 1.25, 95% CI 1.17 - 1.34) were adjusted predictors. CONCLUSION: This study emphasises the very high MALE rates in revascularised patients with lower limb PAD, especially in CLTI. Prior lower limb revascularisation correlated with increased MALE rates in IC patients, while prior lower limb amputation was linked to subsequent MALEs in CLTI. In both IC and CLTI, CKD was associated with poorer outcomes, regardless of applied MALE definition.

New Horizons in Peripheral Artery Disease.

Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent claudication, whilst chronic limb-threatening ischaemia (CLTI), the end stage of PAD, presents with rest pain and/or tissue loss. PAD is an age-related condition present in over 10% of those aged ≥65 in high-income countries. Guidelines regarding definition, diagnosis and staging of PAD and CLTI have been updated to reflect the changing patterns and presentations of disease given the increasing prevalence of diabetes. Recent research has changed guidelines on optimal medical therapy, with low-dose anticoagulant plus aspirin recommended in some patients. Recently published randomised trials highlight where bypass-first or endovascular-first approaches may be optimal in infra-inguinal disease. New techniques in endovascular surgery have increased minimally invasive options for ever more complex disease. Increasing recognition has been given to the complexity of patients with CLTI where a high prevalence of both frailty and cognitive impairment are present and a significant burden of multi-morbidity and polypharmacy. Despite advances in minimally invasive revascularisation techniques and reduction in amputation incidence, survival remains poor for many with CLTI. Shared decision-making is essential, and conservative management is often appropriate for older patients. There is emerging evidence of the benefit of specialist geriatric team input in the perioperative management of older patients undergoing surgery for CLTI. Recent UK guidelines now recommend screening for frailty, cognitive impairment and delirium in older vascular surgery patients as well as recommending all vascular surgery services have support and input from specialist geriatrics teams.

Antimicrobial resistance is not increasing in subsequent cases of ischaemic foot infections, a single-centre cohort from 2012 to 2021.

Patients with chronic limb-threatening ischaemia (CLTI) are at risk of foot infections, which is associated with an increase in amputation rates. The use of antibiotics may lead to a higher incidence of antimicrobial resistance (AMR) in subsequent episodes of ischaemic foot infections (IFI). This retrospective single-centre cohort study included 130 patients with IFI undergoing endovascular revascularisation. Staphylococcus aureus and Pseudomonas aeruginosa were the two most common pathogens, accounting for 20.5% and 10.8% of cases, respectively. The prevalence of antimicrobial resistance (AMR) and multi-drug resistance did not significantly increase between episodes (10.2% vs. 13.4%, p = 0.42). In 59% of subsequent episodes, the identified pathogens were unrelated to the previous episode. However, the partial concordance of identified pathogens significantly increased to 66.7% when S. aureus was identified (p = 0.027). Subsequent episodes of IFI in the same patient are likely to differ in causative pathogens. However, in the case of S. aureus, the risk of reinfection, particularly with S. aureus, is increased. Multi-drug resistance does not appear to change between IFI episodes. Therefore, recommendations for empirical antimicrobial therapy should be based on local pathogen and resistance statistics without the need to broaden the spectrum of antibiotics in subsequent episodes.

The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes mellitus and a foot ulcer.

Diabetes related foot complications have become a major cause of morbidity and are implicated in most major and minor amputations globally. Approximately 50% of people with diabetes and a foot ulcer have peripheral artery disease (PAD) and the presence of PAD significantly increases the risk of adverse limb and cardiovascular events. The International Working Group on the Diabetic Foot (IWGDF) has published evidence based guidelines on the management and prevention of diabetes related foot complications since 1999. This guideline is an update of the 2019 IWGDF guideline on the diagnosis, prognosis, and management of peripheral artery disease in people with diabetes mellitus and a foot ulcer. For this updated guideline, the IWGDF, the European Society for Vascular Surgery, and the Society for Vascular Surgery decided to collaborate to develop a consistent suite of recommendations relevant to clinicians in all countries. This guideline is based on three new systematic reviews. Using the Grading of Recommendations, Assessment, Development and Evaluation framework clinically relevant questions were formulated, and the literature was systematically reviewed. After assessing the certainty of the evidence, recommendations were formulated which were weighed against the balance of benefits and harms, patient values, feasibility, acceptability, equity, resources required, and when available, costs. Through this process five recommendations were developed for diagnosing PAD in a person with diabetes, with and without a foot ulcer or gangrene. Five recommendations were developed for prognosis relating to estimating likelihood of healing and amputation outcomes in a person with diabetes and a foot ulcer or gangrene. Fifteen recommendations were developed related to PAD treatment encompassing prioritisation of people for revascularisation, the choice of a procedure and post-surgical care. In addition, the Writing Committee has highlighted key research questions where current evidence is lacking. The Writing Committee believes that following these recommendations will help healthcare professionals to provide better care and will reduce the burden of diabetes related foot complications.

A substantial number of patients with rest pain, ulceration or gangrene are unable to undergo current non-invasive perfusion testing-Could another modality be utilised?

Rest pain, ulceration and gangrene are hallmark features of chronic limb-threatening ischaemia (CLTI). Wound healing can be challenging, and this is compounded by an inability to measure lower limb perfusion via non-invasive tools such as toe pressure (TP). Novel perfusion tests, such as pedal acceleration time (PAT), may overcome some limitations. This study aimed to quantify the proportion of patients with CLTI that were unable to undergo TP measurement. Over a three-year duration, 344 consecutive patients with CLTI underwent PAT assessment (403 limbs). Overall, 32% of limbs were unable to undergo first toe TP, and 12.9% were unable to undergo first and second toe TP due to forefoot/digit amputation or tissue loss. Inability to measure first toe TP disproportionately impacted CLTI patients with diabetes compared to patients without diabetes (39.6% limbs (106/268); vs. 17% limbs (23/135); p < 0.001). Novel modalities may provide a useful tool for assessing perfusion in CLTI.

Limb Related Outcomes of Endovascular vs. Open Surgical Revascularisation in Patients with Peripheral Arterial Occlusive Disease: A Report from the Prospective GermanVasc Cohort Study.

OBJECTIVE: The goal of this study was to compare clinical outcomes in patients with peripheral arterial occlusive disease undergoing revascularisation by peripheral endovascular intervention (EVI), bypass surgery, endarterectomy (EA), and hybrid surgery in an unselected real world setting. METHODS: This was a German, prospective, multicentre, comparative cohort study, enrolling patients at hospital admission for revascularisation at 35 vascular centres with 12 months of follow up. Primary composite endpoints were major amputation or death, major adverse limb events, and any minor or major amputation. Twelve month incidences and hazard ratios (HRs) for the four subgroups and 95% confidence intervals (CIs) were estimated using Kaplan-Meier functions and Cox proportional hazard models. Sociodemographic and clinical characteristics, pharmacological treatment, and comorbidities were used to adjust for patient differentials (unique identifier ClinicalTrials.gov: NCT03098290). RESULTS: In total, 4 475 patients were analysed (mean age 69 years, 69.4% males, and 31.5% suffering from chronic limb threatening ischaemia). After 12 months of follow up, 5.3% (95% CI 3.6 - 6.9%) of the patients experienced either death or major amputation, 7.2% (95% CI 4.8 - 9.6%) major adverse limb event, and 6.6% (95% CI 5.0 - 8.2%) any minor or major amputation. Compared with EVI, bypass surgery was associated with an increased risk of amputation or death (HR 2.59, 95% CI 1.75 - 3.85), major adverse limb event (HR 1.93, 95% CI 1.11 - 3.36), and any minor or major amputation (HR 2.12, 95% CI 1.42 - 3.16), and hybrid surgery with an increased risk of amputation or death (HR 2.29, 95% CI 1.27 - 4.13) and major adverse limb event (HR 1.62, 95% CI 1.03 - 2.54). After adjusting for patient differentials, no significant differences among study groups remained. CONCLUSION: More favourable outcomes after EVI were completely attributed to differentials in patient characteristics and not procedure type. The current study emphasised that all competing approaches performed similarly in a real world setting.

Disease Specific Health Related Quality of Life in Patients With Chronic Limb Threatening Ischaemia Undergoing Revascularisation of Femoropopliteal Lesions.

OBJECTIVE: Patients with chronic limb threatening ischaemia (CLTI) suffer from pain and non-healing ulcers, which impact negatively on both their physical and mental health. While maintaining and improving quality of life is a principal aim with all treatments, little is known about the health related quality of life (HRQoL) of CLTI patients and how revascularisation procedures impact on HRQoL endpoints. The aim of this study was to investigate disease specific HRQoL before and after revascularisation in patients with CLTI undergoing femoropopliteal revascularisation. METHODS: HRQoL was prospectively analysed in 190 CLTI patients with main atherosclerotic target lesions in the femoropopliteal segment, who were planned for endovascular or open revascularisation. The choice of revascularisation method was made by the vascular team, represented by both open and endovascular expertise. The Vascular Quality of Life (VascuQoL) questionnaire was used to assess disease specific HRQoL before revascularisation and one month, one year, and two years after the procedure. Main endpoints were mean VascuQoL score changes, effect sizes of observed changes and the proportion reaching a minimally important difference (half a standard deviation change from baseline) during two years after revascularisation. RESULTS: Patient reported VascuQoL scores were low at baseline (mean 2.68, 95% CI 1.18 - 4.17). After revascularisation, the mean VascuQoL score improved statistically significantly over time, with the largest improvement observed after one year (difference from baseline 2.02, 95% CI 1.75 - 2.29; p < .001). No differences in HRQoL change over time were observed between patients treated with endovascular approaches compared with bypass surgery. Approximately half the patients reached the minimally important threshold at one year (53%), which was largely maintained also at two years (41%). CONCLUSION: While CLTI profoundly affected HRQoL, a large and clinically meaningful HRQoL increase was observed after revascularisation. This confirms the value of CLTI revascularisation on HRQoL and underlines the importance of including patient reported outcomes when evaluating revascularisation procedures in CLTI patients.