Long-Term Mortality Predictors Using a Machine-Learning Approach in Patients With Chronic Limb-Threatening Ischemia After Peripheral Vascular Intervention.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) face a high long-term mortality risk. Identifying novel mortality predictors and risk profiles would enable individual health care plan design and improved survival. We aimed to leverage a random survival forest machine-learning algorithm to identify long-term all-cause mortality predictors in patients with CLTI undergoing peripheral vascular intervention. METHODS AND RESULTS: Patients with CLTI undergoing peripheral vascular intervention from 2017 to 2018 were derived from the Medicare-linked VQI (Vascular Quality Initiative) registry. We constructed a random survival forest to rank 66 preprocedural variables according to their relative importance and mean minimal depth for 3-year all-cause mortality. A random survival forest of 2000 trees was built using a training sample (80% of the cohort). Accuracy was assessed in a testing sample (20%) using continuous ranked probability score, Harrell C-index, and out-of-bag error rate. A total of 10 114 patients were included (mean±SD age, 72.0±11.0 years; 59% men). The 3-year mortality rate was 39.1%, with a median survival of 1.4 years (interquartile range, 0.7-2.0 years). The most predictive variables were chronic kidney disease, age, congestive heart failure, dementia, arrhythmias, requiring assisted care, living at home, and body mass index. A total of 41 variables spanning all domains of the biopsychosocial model were ranked as mortality predictors. The accuracy of the model was excellent (continuous ranked probability score, 0.172; Harrell C-index, 0.70; out-of-bag error rate, 29.7%). CONCLUSIONS: Our random survival forest accurately predicts long-term CLTI mortality, which is driven by demographic, functional, behavioral, and medical comorbidities. Broadening frameworks of risk and refining health care plans to include multidimensional risk factors could improve individualized care for CLTI.

Alternative vein bypass in octogenarians with chronic limb-threatening ischaemia.

BACKGROUND: Octogenarians are regarded as one of the frailest patient groups among the chronic limb-threatening ischaemia population with high perioperative morbidity and mortality rates. As a result, alternative vein bypass surgery in the absence of sufficient great saphenous vein is often not considered as a potential treatment option. The aim of this study was to compare the results of octogenarians undergoing alternative vein bypass surgery due to chronic limb-threatening ischaemia to younger patients. METHODS: A single-centre retrospective analysis of patients undergoing bypass surgery for chronic limb-threatening ischaemia with alternative autologous vein grafts between 1997 and 2018 was performed. Patients aged over 80 years were compared with those under 80 years. Graft patency rates were assessed and a risk factor analysis for limb loss was performed. RESULTS: In total, 592 patients underwent bypass surgery during the study interval. Twenty-one per cent (n = 126) of patients were 80 years or older. At 4 years, primary, primary-assisted and secondary patency as well as limb salvage rates were not significantly different between the two groups (46% versus 50%, 60% versus 66%, 69% versus 72%, 72% versus 77%, for octogenarians versus non-octogenarians respectively). Major amputations were performed in 27 (21%) octogenarians and 91 (20%) non-octogenarians (P = 0.190). No higher 30-day and long-term mortality rates nor morbidity rates were detected in the octogenarian group with a median follow-up time of 27 (interquartile range 12-56) months. Minor amputation, the reason for alternative vein grafts, as well as the profunda femoris artery as proximal origin of the bypass were risk factors for limb loss in the postoperative course. CONCLUSION: Alternative vein bypass surgery in octogenarians with chronic limb-threatening ischaemia is safe and effective in terms of patency rates, limb salvage and survival compared with younger patients in the absence of sufficient great saphenous vein. Age alone should not be a deterrent from performing bypass surgery.

Documentary analysis of national and international guidance for community clinicians referring patients with suspected chronic limb-threatening ischaemia.

BACKGROUND: Delayed referral of patients with chronic limb-threatening ischaemia (CLTI) from the community to vascular services may increase risk of amputation due to delayed revascularisation. Lack of appropriate guidance for clinicians in the community may contribute to this problem. This documentary analysis investigated referral guidance available to primary care clinicians. METHODS: National and international documents providing guidance on CLTI management were identified by searching sources including Medline, Embase, Guidelines International Network and College/Society websites. Data were extracted on referral recommendations, target audience and author groups. Recommendations were coded according to the Behaviour Change Technique Taxonomy. Clinical practice guideline quality and ease of implementation were assessed independently by two reviewers using the Appraisal of Guidelines Research and Evaluation (AGREE) II and Guideline Implementability Appraisal (GLIA) tools, respectively. RESULTS: 12 documents containing guidance on CLTI referrals were included. Five were clinical practice guidelines. Nine targeted clinicians in the community among their audience, yet only one included a primary care clinician in their author group. Recommendations on identification and referral of CLTI were often in non-specific language and frequently assumed specialist knowledge of vascular disease. Just 4 of the 93 behaviour change techniques were identified in the guidance documents. Three relevant domains of the AGREE II tool were scored for five clinical practice guidelines: stakeholder involvement (range 21.4%-52.4%, mean 42.9%), clarity of presentation (range 71.4%-92.9%, mean 82.9%) and applicability (25.0%-57.1%, mean 36.8%). The GLIA tool identified barriers to ease of implementation for all five clinical practice guidelines. CONCLUSIONS: Most guidance for clinicians in the community on the management of CLTI has been written without their input and assumes knowledge of vascular disease, which may be lacking. Future guidance development should involve community clinicians, consider using additional behaviour change techniques, and improve the applicability and ease of implementation of recommendations.

Association Between Diagnosis-to-Limb Revascularization Time and Clinical Outcomes in Outpatients With Chronic Limb-Threatening Ischemia: Insights From the CLIPPER Cohort.

BACKGROUND: The extent and consequences of ischemia in patients with chronic limb-threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may worsen outcomes. We sought to describe the association between time from diagnosis to endovascular lower extremity revascularization (diagnosis-to-limb revascularization [D2L] time) and clinical outcomes in outpatients with CLTI. METHODS AND RESULTS: In the CLIPPER cohort, comprising patients between 66 and 86 years old diagnosed with CLTI betweeen 2010 and 2019, we used Medicare claims data to identify patients who underwent outpatient endovascular revascularization within 180 days of diagnosis. We described the risk-adjusted association between D2L time and clinical outcomes. Among 1 130 065 patients aged between 66 and 86 years with CLTI, 99 221 (8.8%) underwent outpatient endovascular lower extremity revascularization within 180 days of their CLTI diagnosis. Among patients with D2L time <30 days, there was no association between D2L time and all-cause death or major lower extremity amputation. However, among patients with D2L time >30 days, each additional 10-day increase in D2L time was associated with a 2.5% greater risk of major amputation (hazard ratio, 1.025 [95% CI, 1.014-1.036]). There was no association between D2L time and all-cause death. CONCLUSIONS: A delay of >30 days from CLTI diagnosis to lower extremity endovascular revascularization was associated with an increased risk of major lower extremity amputation among patients undergoing outpatient endovascular revascularization. Improving systems of care to reduce D2L time could reduce amputations.

Quality of Life in Patients With Chronic Limb-Threatening Ischemia Treated With Revascularization.

BACKGROUND: In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of revascularization strategy on health-related quality of life (HRQoL). METHODS: Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression. RESULTS: A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 [95% CI, -0.25 to -0.02]; P=0.02), SF-12 MCS (difference, -1.03 [95% CI, -1.89 to -0.18]; P=0.02), SF-6D R2 (difference, -0.01 [95% CI, -0.02 to -0.001]; P=0.03), numeric rating scale pain at present (difference, 0.26 [95% CI, 0.03 to 0.49]; P=0.03), usual level during previous week (difference, 0.26 [95% CI, 0.04 to 0.48]; P=0.02), and worst level during previous week (difference, 0.29 [95% CI, 0.02 to 0.56]; P=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 [95% CI, -0.03 to 0.004]; P=0.12) or SF-12 PCS (difference, -0.41 [95% CI, -1.2 to 0.37]; P=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure. CONCLUSIONS: Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.

Reversion of the Inflammatory Markers in Patients With Chronic Limb-Threatening Ischemia.

BACKGROUND: Peripheral artery disease is characterized by an intense inflammatory process that can be associated with a higher mortality rate, particularly in chronic limb-threatening ischemia (CLTI). This study aims to compare the evolution of inflammatory markers between patients with claudication with those with CLTI at 3, 6, and 12 months. METHODS AND RESULTS: An observational, single-center, and prospective study was conducted. A total of 119 patients with peripheral artery disease (65 with claudication and 54 with CLTI) were observed and inflammatory markers collected at admission and 3, 6, and 12 months. At admission, patients with CLTI, when compared with patients with claudication, had significantly higher serum levels of C-reactive protein and fibrinogen (positive acute-phase proteins) and lower serum level of albumin, total cholesterol, and high-density lipoprotein (negative acute-phase proteins): C-reactive protein (g/dL), 2.90 (25th-75th percentile, 2.90-4.90) versus 6.80 (25th-75th percentile, 2.90-53.26) (P=0.000); fibrinogen (mg/dL), 293.00 (25th-75th percentile, 269.25-349.00) versus 415.50 (25th-75th percentile, 312.00-615.75) (P=0.000); total cholesterol (mg/dL), 161.79±95% [152.74-170.85] versus 146.42%±95% [135.30-157.53] (P=0.034); high-density lipoprotein (mg/dL), 50.00 (25th-75th percentile, 41.00-60.00) versus 37.00 (25th-75th percentile, 30.00-45.50) (P=0.000); albumin (g/dL): 4.00 (25th-75th percentile, 3.70-4.20) versus 3.60 (25th-75th percentile, 3.10-4.00) (P=0.003). The association between CLTI and total cholesterol was lost after adjusting for confounders. Three months after the resolution of the CLTI, there was an increase in the levels of negative acute-phase proteins and a decrease in positive acute-phase proteins. These inflammatory proteins did not register an evolution in patients with claudication. The differences in the inflammatory proteins between groups disappeared at 6 months. CONCLUSIONS: CLTI has an inflammatory environment that can be partially reverted after resolution of the ischemic process, emphasizing the importance of timely intervention.

Prospective, Multi-center, Single-Arm Study of the Auryon Laser System for Treatment of Below-the-Knee Arteries in Patients With Chronic Limb-Threatening Ischemia: 30-Day Results of the Auryon BTK.

The 355 nm Auryon laser (AngioDynamics, Inc., Latham, New York) has been shown to be effective and safe in treating various morphology lesions in the femoropopliteal arteries. There are limited data on the Auryon laser in treating below-the-knee (BTK) arteries in patients with chronic limb-threatening ischemia. We present the 30-day efficacy and safety findings from the ongoing Auryon BTK study. Patients with chronic limb-threatening ischemia were prospectively enrolled in the Auryon BTK study between March 2022 and February 2023 in 4 US centers after obtaining written informed consent. The primary safety end point included major adverse limb events + postoperative death at 30 days, defined as a composite of all-cause death, major amputation, and target vessel revascularization. Demographic, procedural, angiographic, and outcome data were collected. A total of 60 patients (61 lesions) were treated. The mean age was 74.6 ± 10.3 years, with 65.0% men, 58.3% with diabetes, 43.3% Rutherford Becker (RB) IV, and 56.7% RB V. Of the 61 lesions, 59% had severe calcification, 31.1% were chronic total occlusions, and 90.2% were de novo disease. The baseline diameter stenosis was 80.2 ± 16.4%, after laser 57.4 ± 21.7%, and after final treatment 24.0 ± 23.1% (p <0.0050). The primary performance end point showed a procedure success rate of 37 of 68 (63.8%). Bailout stenting occurred in 1 of 61 lesions (1.6%). The RB category was 100% RB IV or higher at baseline versus 35.3% at 30 days. At 30 days, there was no target vessel revascularization and the patency was 88.9% (Peak Systolic Velocity Ratio (PSVR) ≤2.4). In conclusion, the Auryon laser is safe and relatively effective in treating BTK lesions with minimal complications.

Making decisions about amputation for chronic limb threatening ischaemia.

INTRODUCTION: Chronic limb threatening ischaemia causes pain, loss of function and complex wounds, necessitating urgent interventions. While growing options for minimally invasive revascularisation make operating on frail and older persons safer, the challenge is knowing when to stop this option and offer amputation. Decisions about amputation are difficult for the person, or for the family who act as substitute decision-makers. Timely treatment decisions are important to optimise clinical outcomes but do not always align with outcomes that are acceptable to patients. AIM: To provide a philosophically-based understanding of patient/family experiences of making decisions for chronic limb threatening ischaemia. METHODS: Longitudinal qualitative study using Heideggerian phenomenology. Patient and family participants were recruited from three sites. Semi-structured interviews occurred at two time points: soon after advice to consider major amputation, and for those who experienced amputation, six-months post-operatively. The COnsolidated criteria for REporting Qualitative studies (COREQ) checklist guided this report. FINDINGS: Variable timelines, disease progression, and interventions were encountered prior to confronting the possibility of amputation. Decision-making was interpreted as an initial irresoluteness (neglecting or renouncing decisions). For most, this was eventually followed by a resoluteness where participants either turned away or towards amputation, according to one's preferred mode of suffering, and thus owning the decision to turn. Those who opted for amputation often experienced better-than-anticipated outcomes. CONCLUSION: Patients and families had difficulty making decisions about amputation. Clinicians may have been complicit in the neglecting and renouncing of decisions and have an important role in sharing decision-making through their authentic discourse. IMPLICATIONS: Chronic limb threatening ischaemia requires complex discussions to support decisions and shared decision-making requires clinician presence and engagement in discourse. Patients and family members benefit from more time to experience and process the phenomenon as they move towards owning their decision about amputation.

Impact of hyperuricemia on 5-year clinical outcomes in patients with critical limb ischemia following percutaneous transluminal angioplasty.

BACKGROUND: A growing evidence on the correlation between hyperuricemia and cardiovascular disease (CVD) has been previously reported. However, there have been limited data on the impact of hyperuricemia on long-term clinical outcomes in patients with critical limb ischemia (CLI) who underwent percutaneous transluminal angioplasty (PTA). METHODS: A total of 425 peripheral artery disease patients who underwent PTA for CLI were enrolled. The patients were divided into the hyperuricemia group (n = 101) and the normal group (n = 324). The primary endpoint was major adverse cerebral and cardiovascular event (MACCE), including death, myocardial infarction, any coronary revascularization, and stroke, up to 5 years. The secondary endpoint was a major adverse limb event (MALE), including any repeated PTA, and target extremity surgery. Inverse probability weighting (IPTW) analysis, derived from the logistic regression model, was performed to adjust for potential confounders. RESULTS: After IPTW matching analysis, compared to the normal group, the hyperuricemia group was associated with a higher incidence of MACCE (20.7% vs. 13.6%, hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.15-2.38, P  = 0.006) including non-cardiac death (11.7% vs. 6.3%, HR: 1.95, 95% CI: 1.19-3.19, P  = 0.006) and MALE (47.7% vs. 36.0%, HR: 1.62, 95% CI: 1.23-2.13, P  = 0.001) including non-target extremity revascularization (15.0% vs. 6.8%, HR: 2.42, 95% CI: 1.52-3.84, P  < 0.001). CONCLUSION: In the present study, hyperuricemia was associated with worse clinical outcomes in patients with CLI following PTA during 5-year clinical follow-up. Efficacy of controlling hyperuricemia in improving clinical outcomes should be evaluated in further studies.

Accuracy of maximal acceleration time of pedal arteries to diagnose critical limb-threatening ischemia.

INTRODUCTION: Maximal acceleration time of distal arteries of the foot (ATmax) is correlated to ankle-brachial index (ABI) and toe-brachial index (TBI), and seems very promising in diagnosing severe peripheral artery disease (PAD) and especially critical limb-threatening ischemia (CLTI). Our goal was to confirm the cut-off value of 215 ms to predict a toe pressure (TP) ⩽ 30 mmHg. METHODS: A 4-month retrospective study was conducted on patients addressed for suspicion of PAD. Demographic data, ABI, TBI, and Doppler ultrasound scanning parameters of the dorsal pedis and lateral plantar arteries (DPA and LPA) were recorded. RESULTS: A total of 137 patients with 258 lower limbs were included. ATmax was highly correlated to TBI (r = -0.89, p < 0.001). With the cut-off value of 215 ms, ATmax was effective to diagnose TP ⩽ 30 mmHg with a sensitivity of 93% [95% CI 77-99], a specificity of 96% [95% CI 92-98], a positive predictive value of 73% [95% CI 56-86], a negative predictive value of 99% [95% CI 97-100], and an area under the receiver operating characteristics curve of 0.99 [95% CI 0.98-1.00]. ATmax also showed promising results to rule out PAD in healthy patients. CONCLUSION: ATmax is a reliable diagnostic tool to diagnose low TP and could be a new easily performed hemodynamic criterion for diagnosis of CLTI.

Wound, Ischemia, Foot Infection (Wifi) Classification System And Its Predictive Ability Concerning Amputation-Free Survival, Mortality And Major Limb Amputation In A Portuguese Population: A Single Center Experience.

INTRODUCTION: Commonly used chronic limb-threatening ischemia (CLTI) classifications lack granularity and detail to precisely stratify patients according to risk of limb loss, expected revascularization benefit and mortality. The aim of this study is to evaluate in a Portuguese population the prognostic value of an updated CLTI classification based on Wound, Ischemia, and foot Infection (WIfI) proposed by the Society for Vascular Surgery. MATERIALS AND METHODS: Single-center retrospective evaluation of prospectively collected data of consecutive patients with CLTI submitted to lower limb revascularization from January to December of 2017. All consecutive patients with chronic peripheral artery disease with ischemic rest pain or tissue loss were included. The exclusion criteria were patients with intermittent claudication, vascular trauma, acute ischemia, non-atherosclerotic arterial disease and isolated iliac intervention. The primary end-point was major limb amputation, mortality and amputation-free survival (AFS) at 30 days, 1 year and 2 year follow-up. Secondary end-points were minor amputation, wound healing time (WHT) and rate (WHR). RESULTS: A total of 111 patients with CLTI were submitted to infra-inguinal revascularization: 91 endovascular and 20 open surgery. After categorizing them according to the WIfI: 20 had stage 1 (18.52%), 29 stage 2 (26.85%), 38 stage 3 (35.19%) and 21 stage 4 (19.44%). Overall mortality rate was 1.8%, 17% and 22.3% at 30 days, 1 year and 2 years follow-up. Major amputation rate was 0.9%, 2.7% and 2.7% at 30 days, 1 year and 2 years follow-up. AFS rate was 97.3%, 82.1%, and 76.8% at 30 days, 1 year, 2 years follow-up. In multi-variable analysis, higher WIfI score was the only predictive factor for mortality and AFS. WIfI 3 and 4 were also associated with increased risk of non-healing ulcer. CONCLUSION: This study proved the prognostic value of the WIfI classification in a Portuguese population by showing an association between higher scores and increased mortality, lower AFS and non-healing ulcer.

Poor Limb Prognosis of Patients with Chronic Limb-Threatening Ischemia on Hemodialysis: A Retrospective Observational Study Based on the Global Limb Anatomic Staging System.

BACKGROUND: The Global Limb Anatomic Staging System (GLASS) has been widely used to evaluate patients with chronic limb-threatening ischemia (CLTI). As end-stage kidney disease (ESKD) is a well-known CLTI risk factor, we aimed to determine whether patients on hemodialysis (HD) have a worse limb prognosis than those without ESKD, considering the same GLASS background. METHODS: The data of 445 patients who underwent surgical and/or endovascular revascularization procedures for lower extremity ischemia were retrospectively collected in our division between 2005 and 2018. The major amputation rate and amputation-free survival (AFS) were compared between HD and non-HD patients. RESULTS: Among the 215 (48%) patients receiving HD, 58 limbs required major amputation (27% limb loss rate). Among the non-HD group, the limb loss rate was 13% (P < 0.0001). The overall AFS was significantly worse in patients receiving HD than those not (P < 0.0001). The AFS was significantly worse in HD patients when comparing GLASS-standardized subgroups. CONCLUSIONS: Patients with CLTI who were receiving HD had a worse limb prognosis than those not receiving, even when considering the same GLASS classification. Furthermore, there is a need for an ideal guideline focused on ESKD-directed peripheral artery disease.

Evaluation of short-term mortality in patients with Medicare undergoing endovascular interventions for chronic limb-threatening ischemia.

INTRODUCTION: Patients with chronic limb-threatening ischemia (CLTI) have high mortality rates after revascularization. Risk stratification for short-term outcomes is challenging. We aimed to develop machine-learning models to rank predictive variables for 30-day and 90-day all-cause mortality after peripheral vascular intervention (PVI). METHODS: Patients undergoing PVI for CLTI in the Medicare-linked Vascular Quality Initiative were included. Sixty-six preprocedural variables were included. Random survival forest (RSF) models were constructed for 30-day and 90-day all-cause mortality in the training sample and evaluated in the testing sample. Predictive variables were ranked based on the frequency that they caused branch splitting nearest the root node by importance-weighted relative importance plots. Model performance was assessed by the Brier score, continuous ranked probability score, out-of-bag error rate, and Harrell's C-index. RESULTS: A total of 10,114 patients were included. The crude mortality rate was 4.4% at 30 days and 10.6% at 90 days. RSF models commonly identified stage 5 chronic kidney disease (CKD), dementia, congestive heart failure (CHF), age, urgent procedures, and need for assisted care as the most predictive variables. For both models, eight of the top 10 variables were either medical comorbidities or functional status variables. Models showed good discrimination (C-statistic 0.72 and 0.73) and calibration (Brier score 0.03 and 0.10). CONCLUSION: RSF models for 30-day and 90-day all-cause mortality commonly identified CKD, dementia, CHF, need for assisted care at home, urgent procedures, and age as the most predictive variables as critical factors in CLTI. Results may help guide individualized risk-benefit treatment conversations regarding PVI.

Predictors of amputation-free survival and wound healing after infrainguinal bypass with alternative conduits.

OBJECTIVE: Inadequate vein quality or prior harvest precludes use of autologous single segment greater saphenous vein (ssGSV) in many patients with chronic limb-threatening ischemia (CLTI). Predictors of patient outcome after infrainguinal bypass with alternative (non-ssGSV) conduits are not well-understood. We explored whether limb presentation, bypass target, and conduit type were associated with amputation-free survival (AFS) after infrainguinal bypass using alternative conduits. METHODS: A single-center retrospective study (2013-2020) was conducted of 139 infrainguinal bypasses performed for CLTI with cryopreserved ssGSV (cryovein) (n = 71), polytetrafluoroethylene (PTFE) (n = 23), or arm/spliced vein grafts (n = 45). Characteristics, Wound, Ischemia, and foot Infection (WIfI) stage, and outcomes were recorded. Multivariable Cox proportional hazards and classification and regression tree analysis modeled predictors of AFS. RESULTS: Within 139 cases, the mean age was 71 years, 59% of patients were male, and 51% of cases were nonelective. More patients undergoing bypass with cryovein were WIfI stage 4 (41%) compared with PTFE (13%) or arm/spliced vein (27%) (P = .04). Across groups, AFS at 2 years was 78% for spliced/arm, 79% for PTFE, and 53% for cryovein (adjusted hazard ratio for cryovein, 2.5; P = .02). Among cases using cryovein, classification and regression tree analysis showed that WIfI stage 3 or 4, age >70 years, and prior failed bypass were predictive of the lowest AFS at 2 years of 36% vs AFS of 58% to 76% among subgroups with less than two of these factors. Although secondary patency at 2 years was worse in the cryovein group (26% vs 68% and 89% in arm/spliced and PTFE groups; P < .01), in patients with tissue loss there was no statistically significant difference in wound healing in the cryovein group (72%) compared with other bypass types (72% vs 87%, respectively; P = .12). CONCLUSIONS: In patients with CLTI lacking suitable ssGSV, bypass with autogenous arm/spliced vein or PTFE has superior AFS compared with cryovein, although data were limited for PTFE conduits for distal targets. Despite poor patency with cryovein, wound healing is achieved in a majority of cases, although it should be used with caution in older patients with high WIfI stage and prior failed bypass, given the low rates of AFS.

Secondary interventions following open vs endovascular revascularization for chronic limb threatening ischemia in the BEST-CLI trial.

OBJECTIVES: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints. METHODS: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models. RESULTS: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. CONCLUSIONS: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions.

Relevance of BEST-CLI trial endpoints in a tertiary care limb preservation program.

OBJECTIVE: Major adverse limb event-free survival (MALE-FS) differed significantly by initial revascularization approach in the BEST-CLI randomized trial. The BEST-CLI trial represented a highly selected subgroup of patients seen in clinical practice; thus, we examined the endpoint of MALE-FS in an all-comers tertiary care practice setting. METHODS: This is a single-center retrospective study of consecutive, unique patients who underwent technically successful infrainguinal revascularization for chronic limb-threatening ischemia (2011-2021). MALE was major amputation (transtibial or above) or major reintervention (new bypass, open bypass revision, thrombectomy, or thrombolysis). RESULTS: Among 469 subjects, the mean age was 70 years, and 34% were female. Characteristics included diabetes (68%), end-stage renal disease (ESRD) (16%), Wound, Ischemia, and foot Infection (WIfI) stage 4 (44%), Global Limb Anatomic Staging System (GLASS) stage 3 (62%), and high pedal artery calcium score (pMAC) (22%). Index revascularization was autogenous vein bypass (AVB) (30%), non-autogenous bypass (NAB) (13%), or endovascular (ENDO) (57%). The composite endpoint of MALE or death occurred in 237 patients (51%) at a median time of 189 days from index revascularization. In an adjusted Cox model, factors independently associated with MALE or death included younger age, ESRD, WIfI stage 4, higher GLASS stage, and moderate-severe pMAC, whereas AVB was associated with improved MALE-FS. Freedom from MALE-FS, MALE, and major amputation at 30 days were 90%, 92%, and 95%; and at 1 year were 63%, 70%, and 83%, respectively. MALE occurred in 144 patients (31%) and was associated with ESRD, WIfI stage, GLASS stage, pMAC score, and index revascularization approach. AVB had superior durability, with adjusted 2-year freedom from MALE of 72%, compared with 66% for ENDO and 51% for NAB. Within the AVB group, spliced vein conduit had higher MALE compared with single-segment vein (hazard ratio, 1.8; 95% confidence interval, 0.9-3.7; P = .008 after inverse propensity weighting), but there was no statistically significant difference in major amputation. Of the 144 patients with any MALE, the first MALE was major reintervention in 47% and major amputation in 53%. Major amputation as first MALE was associated with non-AVB index approach. Indications for major reintervention were symptomatic stenosis/occlusion (54%), lack of clinical improvement (28%), asymptomatic graft stenosis (16%), and iatrogenic events (3%). Conversion to bypass occurred after 6% of ENDO cases, two-thirds of which involved distal bypass targets at the ankle or foot. CONCLUSIONS: In this consecutive, all-comers cohort, disease complexity was associated with procedural selection and MALE-FS. AVB independently provided the greatest MALE-FS and freedom from MALE and major amputation. Compared with the BEST-CLI randomized trial, MALE after ENDO in this series was more frequently major amputation, with relatively few conversions to open bypass.

The comparison of adipose-derived stromal cells (ADSCs) delivery method in a murine model of hindlimb ischemia.

BACKGROUND: Adipose-derived stromal cells (ADSCs) demonstrate ability to promote tissue healing and down-regulate excessive inflammation. ADSCs have been used to treat critical limb ischemia in preclinical and clinical trials, but still, there is little known about their optimal delivery strategy. To date, no direct analysis of different methods of ADSCs delivery has been performed in the hindlimb ischemia model. Therefore, in this study we focused on the therapeutic efficacy of different ADSCs delivery methods in a murine model of hindlimb ischemia. METHODS: For the hADSCs isolation, we used the subcutaneous adipose tissue collected during the surgery. The murine hindlimb ischemia was used as a model. The unilateral femoral artery ligation was performed on 10-12-week-old male C57BL/6. ADSCs were delivered directly into ischemic muscle, into the contralateral muscle or intravenously. 7 and 14 days after the surgery, the gastrocnemius and quadriceps muscles were collected for the immunohistochemical analysis. The results were analyzed with relevant tests using the Statistica software. RESULTS: Our research revealed that muscle regeneration, angiogenesis, arteriogenesis and macrophage infiltration in murine model of hindlimb ischemia differ depending on ADSCs delivery method. We have demonstrated that intramuscular method (directly into ischemic limb) of ADSCs delivery is more efficient in functional recovery after critical limb ischemia than intravenous or contralateral route. CONCLUSIONS: We have noticed that injection of ADSCs directly into ischemic limb is the optimal delivery strategy because it increases: (1) muscle fiber regeneration, (2) the number of capillaries and (3) the influx of macrophages F4/80+/CD206+.