Editor's Choice - Radiation Dose Reduction During Contralateral Limb Cannulation Using Fiber Optic RealShape Technology in Endovascular Aneurysm Repair.

OBJECTIVE: The increasing number of endovascular procedures has resulted in an increasing radiation burden, particularly for the treatment team. Fiber Optic RealShape (FORS) technology uses laser light instead of fluoroscopy to visualise the endovascular guidewire and catheters. These devices can be used during the navigational part of procedures, such as cannulation of the contralateral limb (CL) in endovascular aneurysm repair (EVAR). The aim of this study was to describe the effect of using FORS on radiation dose during CL cannulation in standard EVAR. METHODS: This was a non-randomised, retrospective comparison study of prospectively collected, single centre data from FORS guided EVAR compared with a conventional fluoroscopy only guided EVAR cohort. A total of 27 FORS guided cases were matched 1:1 based on sex, age, and body mass index (BMI) with 27 regular (fluoroscopy only) EVARs. This study primarily focused on (1) technical success of FORS and (2) navigation time and radiation dose (cumulative air kerma [CAK], air kerma area product [KAP], and fluoroscopy time [FT]) during cannulation of the CL. In addition, overall procedure time and radiation dose of the complete EVAR procedure were studied. RESULTS: In 22 (81%) of the 27 FORS guided cases the CL was successfully cannulated using FORS. All radiation dose parameters were significantly lower in the FORS group (CAK, p < .001; KAP, p = .009; and FT, p < .001) for an equal navigation time (p = .95). No significant differences were found when comparing outcomes of the complete procedure. CONCLUSION: Use of FORS technology significantly reduces radiation doses during cannulation of the CL in standard EVAR.

Sex Differences in Mortality Risk after the First Hospitalisation with Lower Extremity Peripheral Arterial Disease.

OBJECTIVE: Lower extremity peripheral arterial disease (PAD) is a severe condition that increases the risk of major adverse cardiovascular events, major adverse limb events, and all cause mortality. This study aimed to investigate the mortality risk among females and males hospitalised for the first time with lower extremity PAD. METHODS: Three cohorts of patients who were admitted for the first time with lower extremity PAD in 2007 - 2010, 2011 - 2014, and 2015 - 2018 were constructed. For the 2007 - 2010 and 2011 - 2014 cohorts, the 28 day, one year, and five year mortality rates were calculated, assessing survival time from date of hospital admission until date of death, end of study period, or censoring. For the 2015 - 2018 cohort, only 28 day and one year mortality were investigated due to lack of follow up data. Mortality rates of these cohorts were compared with the general population using standardised mortality rates (SMRs), and the risk of death between sexes was evaluated using Cox proportional hazards models. Cox models were adjusted for age, cardiovascular disease, and diabetes mellitus to account for potential confounding factors. RESULTS: In total, 7 950, 9 670, and 13 522 patients were included in the 2007 - 2010, 2011 - 2014, and 2015 - 2018 cohorts, respectively. Over 60% of individuals in each cohort were males. Mortality rates at 28 day and one year remained stable across all cohorts, while the five year mortality rate increased for both males and females in the 2011 - 2014 cohort. The SMRs both of females and males with PAD were significantly higher than in the general population. Multivariable regression analyses found no significant differences in mortality risk between sexes at 28 day and one year. However, the five year mortality risk was lower in females, with a hazard ratio of 0.89 (95% confidence interval [CI] 0.83 - 0.97) in the 2007 - 2010 cohort and 0.88 (95% CI 0.82 - 0.94) in the 2011 - 2014 cohort. CONCLUSION: The five year mortality risk has increased, and females face a lower mortality risk than males. Lower extremity PAD still carries unfavourable long term consequences compared with the general population.

Prognostic Factors and Models to Predict Mortality Outcomes in Patients with Peripheral Arterial Disease: A Systematic Review.

OBJECTIVE: Predicting adverse outcomes in patients with peripheral arterial disease (PAD) is a complex task owing to the heterogeneity in patient and disease characteristics. This systematic review aimed to identify prognostic factors and prognostic models to predict mortality outcomes in patients with PAD Fontaine stage I - III or Rutherford category 0 - 4. DATA SOURCES: PubMed, Embase, and Cochrane Database of Systematic Reviews were searched to identify studies examining individual prognostic factors or studies aiming to develop or validate a prognostic model for mortality outcomes in patients with PAD. REVIEW METHODS: Information on study design, patient population, prognostic factors, and prognostic model characteristics was extracted, and risk of bias was evaluated. RESULTS: Sixty nine studies investigated prognostic factors for mortality outcomes in PAD. Over 80 single prognostic factors were identified, with age as a predictor of death in most of the studies. Other common factors included sex, diabetes, and smoking status. Six studies had low risk of bias in all domains, and the remainder had an unclear or high risk of bias in at least one domain. Eight studies developed or validated a prognostic model. All models included age in their primary model, but not sex. All studies had similar discrimination levels of > 70%. Five of the studies on prognostic models had an overall high risk of bias, whereas two studies had an overall unclear risk of bias. CONCLUSION: This systematic review shows that a large number of prognostic studies have been published, with heterogeneity in patient populations, outcomes, and risk of bias. Factors such as sex, age, diabetes, hypertension, and smoking are significant in predicting mortality risk among patients with PAD Fontaine stage I - III or Rutherford category 0 - 4.

External validation of bleeding risk models for the prediction of long-term bleeding risk in patients with established cardiovascular disease.

OBJECTIVE: The long-term predictive performance of existing bleeding risk models in patients with various manifestations of cardiovascular disease (CVD) is not well known. This study aims to assess and compare the performance of relevant existing bleeding risk models in estimating the long-term risk of major bleeding in a cohort of patients with established CVD. METHODS: Seven existing bleeding risk models (PRECISE-DAPT, DAPT, Ducrocq et al, de Vries et al, S2TOP-BLEED, Intracranial B2LEED3S and HAS-BLED) were identified and externally validated in 7,249 patients with established CVD included in the Utrecht Cardiovascular Cohort-second manifestations of arterial disease study. Predictive performance was assessed in terms of discrimination and calibration, both at 10 years and the original prediction horizon of the models. Major bleeding was defined as Bleeding Academic Research Consortium type 3 or 5. RESULTS: After a median follow-up of 8.4 years (interquartile range 4.5-12.5), a total of 233 (3.2%) major bleeding events occurred. C-statistics for discrimination at 10 years ranged from 0.53 (95%CI 0.49-0.57) to 0.64 (95%CI 0.60-0.68). Calibration plots after recalibration to 10 years showed best agreement between predicted and observed bleeding risk for De Vries et al, S2TOP-BLEED, DAPT and PRECISE-DAPT. CONCLUSIONS: The performance of existing bleeding risk models to predict long-term bleeding in patients with CVD varied. Discrimination and calibration were best for the models of de Vries et al, S2TOP-BLEED, DAPT and PRECISE-DAPT. Of these, recalibrated models requiring the least predictors may be preferred for use to personalize prevention with antithrombotic therapy.

Differences in Symptom Presentation in Women and Men with Confirmed Lower Limb Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the differences in symptoms between men and women that present with lower limb peripheral artery disease (PAD). DATA SOURCES: Systematic review and meta-analysis using PubMed, EMBASE, and the Cochrane Library. REVIEW METHODS: A systematic search of the literature to identify studies that examined PAD and its symptoms using PubMed, EMBASE, and the Cochrane Library, which were screened in duplicate by two reviewers. Information on study design, source of data, population characteristics, and outcomes of interest was extracted and used the Newcastle-Ottawa Scale and Cochrane risk of bias tool. Quality of evidence was rated using the GRADE methodology. Estimates of relative effects were pooled to generate pooled odds ratios (OR) and their 95% confidence interval (CI) using a random effects model. RESULTS: Thirteen cross sectional studies, six cohorts, one case control, and one randomised clinical trial, reporting on 1 929 966 patients with confirmed PAD (established by clinical history, clinical examination, and/or ankle brachial index, or further tests) were included. Women presented less often with intermittent claudication than men (25.9% vs. 30.2%) OR 0.78 (95% CI 0.72 - 0.84, very low quality of evidence), while rest pain and atypical leg symptoms were more prevalent in women (12.8% vs. 9.2%) OR 1.40 (95% CI 1.22 - 1.60, very low quality of evidence) and (22.8% vs. 19.8%) OR 1.18 (95% CI 0.96 - 1.45, very low quality of evidence), respectively. CONCLUSION: Women with PAD more often present with rest pain, while their prevalence of intermittent claudication is lower. They also tend to present more often with atypical leg symptoms. This study underlines that PAD symptom presentation differs between the sexes. Therefore, clinicians and researchers should not consider men and women as a single population and report their data separately.

Mid-Term Outcomes of Chimney Endovascular Aortic Aneurysm Repair: A Systematic Review and Meta-analysis.

BACKGROUND: To provide an overview of the literature on the mid-term outcomes of chimney EVAR (ChEVAR) for the treatment of juxtarenal abdominal aortic aneurysms (JAAA). METHODS: Different electronic databases were searched for published articles up to January 2020. The eligibility criteria were studies describing mid- or long-term outcomes of chimney EVAR (mean follow-up at least 1 year) for treatment of JAAA, including more than 10 cases, published in English, and with full text available. The outcomes measure were overall survival rate, target vessel patency, and freedom from reintervention at 3 years. Quality of the included studies was analyzed using the MINORS criteria. Pooled effect estimates were analyzed using random-effect models and heterogeneity was tested using I2 statistics. RESULTS: Thirteen articles met the inclusion criteria. The included studies described 1,019 patients. According to the quality assessment, methodological quality was moderate to poor. The pooled overall survival, freedom from reintervention, and target vessel patency at 3 year was 81.4 % (95%CI 73.8-87.9), 85.7% (95%CI 75.6-93.5), and 95.1% (95%CI 89.3-98.7) respectively. CONCLUSIONS: The results of this review show good to acceptable short and mid-term survival and good mid-term durability, which supports that ChEVAR as a suitable alternative in high-risk JAAA. However, proper patient selection for ChEVAR seems essential to attain good mid-term outcomes, and further large prospective and good quality studies are required to demonstrate its long-term results and enable conclusions on specific determinants for outcome.

Superficial Femoral Artery Recanalization Using Fiber Optic RealShape Technology.

PURPOSE: Report of a successful case of endovascular recanalization of an occluded superficial femoral artery (SFA) using Fiber Optic RealShape (FORS) technology. CASE REPORT: A 79-year-old male was referred for evaluation of multiple ischemic pretibial ulcers of the right lower extremity. Computed tomography-angiography (CTA) imaging confirmed significant stenosis of the right common femoral artery (CFA) and an occlusion of the SFA from its origin to the Hunter's canal. The patient was treated with a hybrid surgical procedure: an endarterectomy of the CFA and SFA origin was performed combined with an endovascular recanalization of the occluded SFA using FORS technology. During recanalization, the FORS guidewire slowly twisted subintimally around the occluded lumen of the SFA, maintaining the created corkscrew shape after pre-dilation with the percutaneous transluminal angioplasty (PTA) balloon and subsequent stenting. CONCLUSIONS: FORS technology can be successfully used during recanalization of an occluded SFA without the use of fluoroscopy. The corkscrew shape formed during recanalization in this case was retained during PTA balloon pre-dilation and stenting; this potentially improves hemodynamics and thereby reduces the risk of in-stent restenosis. However, expanding patient series and longer follow-up data are needed to increase the understanding of the feasibility and effectiveness of using FORS in the treatment of peripheral arterial occlusive disease.

Long Term Survival and Limb Salvage in Patients With Non-Revascularisable Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to provide long term survival and limb salvage rates for patients with non-revascularisable (NR) chronic limb threatening ischaemia (CLTI). METHODS: This was a retrospective review of prospectively collected data, derived from a randomised controlled trial (JUVENTAS) investigating the use of a regenerative cell therapy. Survival and limb salvage of the index limb in CLTI patients without viable options for revascularisation at inclusion were analysed retrospectively. The primary outcome was amputation free survival, a composite of survival and limb salvage, at five years after inclusion in the original trial. RESULTS: In 150 patients with NR-CLTI, amputation free survival was 43% five years after inclusion. This outcome was driven by an equal rate of all cause mortality (35%) and amputation (33%). Amputation occurred predominantly in the first year. Furthermore, 33% of those with amputation subsequently died within the investigated period, with a median interval of 291 days. CONCLUSION: Five years after the initial need for revascularisation, about half of the CLTI patients who were deemed non-revascularisable survived with salvage of the index limb. Although the prospects for these high risk patients are still poor, under optimal medical care, amputation free survival seems comparable with that of revascularisable CLTI patients, while the major amputation rate within one year, especially among NR-CLTI patients with ischaemic tissue loss, is very high.

External validation of the Vascular Quality Initiative prediction model for survival in no-option chronic limb-threatening ischemia patients.

OBJECTIVE: Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortality rates. More than 50% of all CLTI patients die within 5 years after presentation. Patient-specific survival prediction is critical for informing treatment strategies, even for those without a clear option for revascularization. We validated a survival prediction model, developed in a revascularized Vascular Quality Initiative (VQI) cohort, in a Western European no-option CLTI cohort. METHODS: The VQI survival prediction model was applied to the validation cohort (N = 150) to compare estimated mortality and observed mortality at 2 years after baseline. Performance of the VQI model was tested by evaluating discrimination using the receiver operating characteristic area under the curve and calibration using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The 2-year survival rate was 79% in the validation cohort compared with 83% in the VQI cohort. Baseline characteristics were significantly different for 13 of 17 variables. The C statistic was 0.86 (95% confidence interval, 0.78-0.95), which indicates good discrimination. The Hosmer-Lemeshow goodness-of-fit test had a P value of .30, which indicates good fit. CONCLUSIONS: This is the first external validation of the VQI survival prediction model. The good model performance suggests that this model can be used in different CLTI populations, including no-option CLTI, and underlines its contributory role in this challenging population.

Validation of randomized controlled trial-derived models for the prediction of postintervention outcomes in chronic limb-threatening ischemia.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. METHODS: This study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. RESULTS: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. CONCLUSIONS: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice.

Exhaustion of the bone marrow progenitor cell reserve is associated with major events in severe limb ischemia.

Lower numbers of progenitor cells (PCs) in peripheral blood (PB) have been associated with cardiovascular events in high-risk populations. Therapies aiming to increase the numbers of PCs in circulation have been developed, but clinical trials did not result in better outcomes. It is currently unknown what causes the reduction in PB PC numbers: whether it is primary depletion of the progenitor cell reserve, or a reduced mobilization of PCs from the bone marrow (BM). In this study, we examine if PB and BM PC numbers predict Amputation-Free Survival (AFS) in patients with Severe Limb Ischemia (SLI). We obtained PB and BM from 160 patients enrolled in a clinical trial investigating BM cell therapy for SLI. Samples were incubated with antibodies against CD34, KDR, CD133, CD184, CD14, CD105, CD140b, and CD31; PC populations were enumerated by flow cytometry. Higher PB CD34+ and CD133+ PC numbers were related to AFS (Both Hazard Ratio [HRevent] = 0.56, p = 0.003 and p = 0.0007, respectively). AFS was not associated with the other cell populations in PB. BM PC numbers correlated with PB PC numbers and showed similar HRs for AFS. A further subdivision based on relative BM and PB PC numbers showed that BM PC numbers, rather than mobilization, associated with AFS. Both PB and BM PC numbers are associated with AFS independently from traditional risk factor and show very similar risk profiles. Our data suggest that depletion of the progenitor cell reserve, rather than decreased PC mobilization, underlies the association between PB PC numbers and cardiovascular risk.

Prognostic value of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification in patients with no-option chronic limb-threatening ischemia.

OBJECTIVE: The Wound, Ischemia, and foot Infection (WIfI) classification was developed to assess amputation risk and hence to aid in clinical decision-making in patients with chronic limb-threatening ischemia (CLTI). WIfI has been validated in multiple CLTI cohorts worldwide. In this study, we examined the relationship between WIfI stage and clinical outcomes in a well-defined subpopulation of CLTI patients considered not eligible for conventional revascularization. The aim of this study was to assess the prognostic value of the WIfI classification for clinical outcomes in a "no-option" CLTI population. METHODS: The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial was a single-center, double-blinded, randomized placebo-controlled trial studying the effects of autologous bone marrow mononuclear cells in no-option CLTI patients (N = 160). We conducted a retrospective analysis incorporating baseline and follow-up data from the JUVENTAS trial. All wounds were photographed and described at the start and end of the trial to allow WIfI staging. Two independent researchers retrospectively classified all limbs according to the WIfI scheme, which was then related to prospectively collected trial data. Outcomes including wound healing, clinical improvement, minor and major amputation rate, amputation-free survival, and mortality were assessed using Kaplan-Meier analyses. RESULTS: Of the 160 patients, 150 could be included in this study. Most patients had been classified as Rutherford stage 4 (34%) and stage 5 (61%), with corresponding WIfI stage 2 (33%), stage 3 (21%), or stage 4 (35%). Diabetes, impaired renal function, and ankle-brachial index were independently associated with WIfI stage. On univariate analysis, WIfI stage was strongly associated with wound healing (P = .001), improvement of Rutherford stage (P = .009), amputation rate (P < .001), and long-term mortality (median follow-up, 21.1 months; P = .025). Of note, WIfI stage 2 patients had a worse 6-month major amputation rate compared with stage 3. Of the seven amputated stage 2 patients, six were in WIfI category W0-I3-fI0 and scored a maximum grade 3 on ischemia. Reclassification of ischemic rest pain (W0-I3-fI0) to stage 3 improved and reordered the discrimination of outcomes by WIfI stage in this cohort. CONCLUSIONS: This is the first study to demonstrate that WIfI classification is associated with important clinical outcomes in a no-option CLTI population. Our data suggest that limb prognosis is poor in patients with classic ischemic rest pain, without wounds or infection (W0-I3-fI0), when they lack revascularization options. Further studies are needed to determine whether reassignment of this population from WIfI stage 2 to WIfI stage 3 may be appropriate to reflect amputation risk in the absence of successful revascularization for patients suffering from ischemic rest pain in general.

Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia.

BACKGROUND: Critical limb ischemia (CLI) represents the most severe form of peripheral artery disease and has an immense impact on quality of life, morbidity, and mortality. A considerable proportion of CLI patients are ineligible for revascularization, leaving amputation as the only option. Mesenchymal stromal cells (MSCs), because of their vasculoregenerative and immunomodulatory characteristics, have emerged as a potential new treatment. METHODS: The primary objective of this trial is to investigate whether intramuscular administration of allogeneic bone marrow (BM)-derived MSCs is safe and potentially effective. The SAIL (allogeneic mesenchymal Stromal cells for Angiogenesis and neovascularization in no-option Ischemic Limbs) trial is a double-blind, placebo-controlled randomized clinical trial to investigate the effect of allogeneic BM-MSCs in patients with CLI who are not eligible for conventional revascularization. A total of 66 patients will be included and randomized (1:1) to undergo 30 intramuscular injections with either BM-MSCs (5 × 106 MSCs per injection) or placebo in the ischemic lower extremity. Primary outcome, that is, therapy success, a composite outcome consisting of mortality, limb status, clinical status, and changes in pain score, will be assessed at 6 months. All study-related procedures will take place in the University Medical Center Utrecht in The Netherlands. CONCLUSIONS: If our results indicate that intramuscular allogeneic BM-MSC therapy for CLI is safe and potentially effective, this will have important consequences for treatment of patients with CLI. A large multicenter clinical trial with longer follow-up focusing on hard end points should then be initiated to confirm these findings.

High and immeasurable ankle-brachial index as predictor of poor amputation-free survival in critical limb ischemia.

OBJECTIVE: The objective of this study was to assess the prognostic value of a high or immeasurable ankle-brachial index (ABI) at baseline for major amputation and amputation-free survival (AFS) in patients with critical limb ischemia (CLI). METHODS: Data from two recent trials in patients with CLI and proven infrapopliteal arterial obstructive disease were pooled. Patients were allocated to the low (<0.7), intermediate (0.7-1.4), or high (>1.4)/immeasurable ABI subgroup. Major amputation and AFS rates were compared. Hazard ratios for major amputation and death were calculated. The net reclassification improvement of incorporating high/immeasurable ABI in the Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) prediction model was derived. RESULTS: There were 146 patients (56.2%) who had a low ABI, 81 patients (31.2%) who had an intermediate ABI, and 33 patients (12.7%) who had a high/immeasurable ABI at baseline. Patients with high/immeasurable ABI showed higher 5-year major amputation (52.1%) and lower 5-year AFS (5.0%) rates than the intermediate (25.5% and 41.6%, respectively) and low ABI patients (23.5% and 46.9%, respectively; both P < .001). This same trend was observed in subgroup analysis of diabetics and nondiabetics. Adjusted hazard ratio of high/immeasurable ABI for major amputation/death risk was 2.93 (P < .001). Adding a high/immeasurable ABI as model factor to the PREVENT III model yielded a net reclassification index of 0.38 (P < .0001). CONCLUSIONS: A high/immeasurable ABI in patients with CLI and infrapopliteal arterial obstructive disease is an independent risk factor of major amputation and of poor AFS, in both diabetics and nondiabetics. Incorporating high/immeasurable ABI in the PREVENT III prediction model improves its performance.