Safety and efficacy of an iBTA-induced autologous Biotube vascular graft and its preparation device BTM1 in below-the-knee bypass surgery for chronic limb threatening ischemia: A protocol for an open-label, single-arm, multicenter clinical trial.

PurposeChronic limb-threatening ischemia (CLTI) increases the risk of lower limb amputation if revascularization is not performed. The use of autologous venous conduits is the only option for patients requiring below-the-knee bypass surgery, but it is limited by a lack of usable veins. The Biotube Maker (BTM1), based on in-Body Tissue Architecture (iBTA) technology, is a mold for the in vivo production of the Biotube® regenerative artificial vascular grafts. This clinical trial is designed to evaluate the safety and efficacy of subcutaneous embedding of the BTM1 for Biotube preparation and arterial bypass surgery using Biotube.MethodsPatients with CLTI who lack suitable veins for bypass surgery will be enrolled. This exploratory, investigator-initiated clinical trial will include 12 subjects. The primary endpoint is successful formation of an implantable Biotube following subcutaneous embedding of the BTM1. Secondary endpoints include intraoperative usability, patency and biocompatibility of the Biotube, wound healing, relief of rest pain, limb salvage, and procedure-related mortality, assessed up to 12 weeks after surgery. These outcomes are expected to provide essential feasibility and safety data to guide future pivotal studies.DiscussionThis study may offer a new treatment option for CLTI patients who otherwise face major amputation. If feasibility and safety are confirmed, the findings will support planning of a pivotal trial aimed at regulatory approval.Trial registrationjRCT2072220062. Registered on October 19, 2022.

In recent years, life expectancy has increased in many societies consequent to better health conditions. Although the trends of decreasing mortality rates from ischemic heart disease and stroke have continued into the 21st century, both causes continue to be the biggest killers in the Western societies. No change is predicted in the foreseeable future and consequently both these conditions contribute significantly to the burden of disease. 1 Diabetes is considered a cardiovascular disease equivalent and with diabetes patients share the benefits of the improved approach to the treatment of cardiovascular disease. However, because of the longer life span and disease duration, other chronic complications such as peripheral arterial disease (PAD) may well become more evident. In a recent survey, PAD was present in 21% of newly diagnosed type 2 diabetic patients 2 and in about 50% of the patients admitted to a diabetic foot clinic on account of a new foot ulcer. It is interesting to emphasize that half of those patients had concomitant peripheral neuropathy. 3 Neuropathy can mask the classic PAD symptoms as claudication, thereby delaying a diagnosis. On the other hand, the presence of PAD may limit the use of total contact cast that is considered the “gold standard” treatment for neuropathic ulcerations. PAD alone is responsible for the increased risk of lower limb amputation observed in patients with diabetes. 4,5 In type 1 diabetes, the overall 25-year cumulative incidence of lower extremity amputation (LEA) is 10.1%. History of heavy smoking, high HbA1c, presence of hypertension are all factors related to PAD and major determinants associated with LEA. 6 In addition, major complex gender differences exist in diabetes-related LEA: Men are more likely to undergo LEA. 7 The presence of a foot infection increases the risk of LEA. A multidisciplinary approach to diabetic foot problems is mandatory to reduce the frequency of LEA, particularly when PAD is complicated by the presence of infected foot ulcers. 8 Today significantly better outcomes are expected for patients with diabetes affected by critical limb ischemia (CLI) based on improved technical options in peripheral revascularization, new options in antibiotic therapy, and aggressive wound debridement and wound care. Until recently, open peripheral arterial bypass has been the firstline surgical treatment option for PAD. Although open bypass is associated with successful results, the invasive nature of the surgery can limit optimal overall outcome. Endovascular procedure is less invasive; however, it reaches similar limb salvage rates in patients with CLI, 9 with the added benefits of fewer wound complications and a shorter hospital stay. As expected, endovascular therapy is increasingly being considered as a first-line treatment option in carefully selected PAD diabetic patients. With the widespread adoption of endovascular therapy, there has been a profound shift in practice patterns for lower extremity PAD. In the past decade, there has been a consistent increase in the number of patients treated by peripheral transluminal angioplasty because of CLI. 10 Hong et al 10 reported that in the general population the average annual number of endovascular interventions is increased by 78% while there is a concomitant decrease in open bypass by 20%. The same authors found that the trends in amputation were consistent with the increase in endovascular therapy. The number of major amputations (ankle to above-the-knee level) decreased by 21% and the number of minor amputations, defined as involving the toe and forefoot, showed a moderate decrease of 5%. Although better outcomes for CLI have been observed in the general population, the LEA observed in patients with diabetes are reportedly reduced, unchanged, or even increased. A recent survey conducted in England reported that the number and incidence of amputations decreased in the aging nondiabetic population whereas the overall population

The use of endovascular therapy (EVT) for lower extremity atherosclerosis is markedly increasing while open surgical bypass is in decline. The results of EVT for critical limb ischaemia (CLI) are difficult to evaluate, especially for patients with diabetes. To date, only one randomized, prospective trial has been published comparing EVT with open bypass for CLI. Although early costs and outcomes were equivalent or superior for EVT, after 2 years, surgery was associated with a significantly reduced risk of future amputation and death.Approximately, 40-50% of diabetic patients with CLI can be initially treated with EVT. Patients with Trans-Atlantic Inter-Society Consensus (TASC) A and B lesions should be treated endoluminally. EVT should be used with caution in patients with TASC C and D lesions; however, in selected patients, particularly if vein conduit is lacking and life expectancy is short, EVT is not unreasonable. For low-to-moderate risk patients with TASC C or D lesions, extensive tibial disease, and suitable vein conduit, surgical bypass remains the best limb preservation option. The primary therapeutic goals are relief of rest pain, healing of ischaemic lesions, and maintenance of functional status. Haemodynamic assessment is critical following both open and EVT for CLI and aids in determining the need for further revascularization; additional interventions are required in 20-30% of CLI patients depending on the degree of ischaemia, anatomical disease extent, and mode of initial therapy. At the University of Arizona, we currently recommend that TASC A and B CLI patients undergo EVT first. TASC C and D patients should undergo bypass unless available conduit is poor, surgical risk is prohibitive, or life expectancy is limited. CLI is a serious end-of-life condition given the sobering realization that only 50-55% of CLI patients are alive with an intact limb 5 years after initial presentation.

Tibial Angioplasty as an Alternative Strategy in Patients with Limb-Threatening Ischemia

Limb Salvage in Octogenarians With Critical Limb Ischemia After Lower Extremity Bypass Surgery

Wound Healing Society 2014 update on guidelines for arterial ulcers.

The objective of this study was to use instrumental variable (IV) analyses to evaluate the clinical effectiveness of percutaneous stent revascularization versus bypass surgery in the treatment of peripheral artery disease (PAD) among type 2 diabetic patients. Type 2 diabetic patients who received peripheral artery bypass surgery (n = 5,652) or stent revascularization (n = 659) for lower extremity arterial stenosis between 2000 and 2007 were identified from the Taiwan National Health Insurance claims database. Patients were followed from the date of index hospitalization for 2 years for lower-extremity amputation, revascularization, and hospitalization for medical treatment. Analysis using treatment year, patients’ monthly income level, and regional difference as IVs were conducted to reduce unobserved treatment selection bias. The crude analysis showed a statistically significant risk reduction in favor of stent placement in lower extremity amputation and in the composite endpoint of amputation, revascularization, or hospitalization for medical treatment. However, peripheral artery stent revascularization and bypass surgery had similar risk of lower limb amputation and composite endpoints in the analyses using calendar year or patients’ monthly income level as IVs. These two treatment modalities had similar risk of lower limb amputation among DM patients with PAD.

Influence of inframalleolar modifier P0/P1 on wound healing in bypass surgery vs endovascular therapy in patients with chronic limb-threatening ischemia

Comparison of limb outcomes between bypass surgery and endovascular therapy in dialysis-dependent and -independent patients with chronic limb-threatening ischemia

Background Peripheral artery disease (PAD) is the leading cause of non-traumatic lower limb amputation. Microvascular disease (peripheral neuropathy, nephropathy, or retinopathy) increases the risk of lower limb amputation in patients with established PAD. Purpose We estimated risk of lower limb amputation associated with microvascular disease and PAD in a Danish cohort. Methods We conducted a population-based cohort study of every person living in Western Denmark aged 50–75 years on January 1, 2012 and followed them for 7 years. People with previous lower limb amputation were excluded. People were stratified by the presence of microvascular disease (peripheral neuropathy, nephropathy, or retinopathy) and PAD (peripheral atherosclerosis including intermittent claudication, or previous lower limb revascularization). We estimated the 7-year cumulative incidence and hazard ratio (HR) of lower limb amputation using individuals with neither microvascular disease nor PAD as reference. We also provide a sex-specific analyses and estimated the population attributable fraction of amputation associated with male sex. Results We included 933,597 individuals, of whom 16,007 had microvascular disease, 18,400 had PAD, and 1,789 had both microvascular disease and PAD. Patients with either microvascular disease (3.7%) or PAD (3.9%) had similar unadjusted 7-year risks of lower limb amputation (Figure). Microvascular disease (adjusted HR 3.21, 95% CI 2.86–3.59) and PAD (adjusted HR 7.37, 95% CI 6.68–8.14) increased the risk of lower limb amputation separately in adjusted analysis. Individuals with both microvascular disease and PAD had the highest risk of amputation (adjusted HR 11.82, 95% CI 10.11–13.80). While the relative impact of microvascular disease and PAD were similar in men and women, men had increased risk of amputation compared to women, in absolute terms. The population attributable fraction of amputations associated with male sex was 31%. Conclusion Microvascular disease and PAD are independently associated with a 3-fold and 7-fold increase of amputation rate, respectively. Combined, microvascular disease and PAD had an additive effect constituting a 12-fold amputation risk. Amputation risk was higher in men than in women, with 3 in 10 lower limb amputations in Western Denmark attributable to male sex. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Department of Cardiology, Aarhus University Hospital

Background Diabetes patients are at greater risk of lower limb amputation due to a higher risk of peripheral artery disease (PAD) and peripheral neuropathy. The effect of concomitant coronary artery disease (CAD) is less explored. Purpose We examined the risk of PAD, lower limb revascularization, and lower limb amputation in diabetes and non-diabetes patients with and without CAD examined by coronary angiography. Methods We included all patients who underwent coronary angiography between 2003–2016 in Western Denmark. Patients with a history of PAD or previous lower limb revascularization or amputation were excluded. Patients were stratified by diabetes and CAD status and followed in prospective registries for a maximum of 10 years. Outcomes were PAD, lower limb revascularization, and lower limb amputation. We estimated 10-year cumulative incidence and adjusted hazard ratios (aHR) using patients with neither diabetes nor CAD as reference. We also examined the effect of CAD extent, insulin treatment, and duration of diabetes in the diabetes group. Results A total of 118,787 coronary angiography patients were included of whom 17,482 (14.7%) had diabetes. Median follow-up was 6.8 years. Patients with both diabetes and CAD had the highest risk of PAD (aHR 3.90, 95% CI 3.55–4.28), lower limb revascularization (aHR 4.61, 95% CI 3.85–5.52), and lower limb amputation (aHR 9.49, 95% CI 7.27–12.39), compared with patients with neither diabetes nor CAD. Extent of CAD, insulin treatment, and duration of diabetes were all associated with increased risks of PAD and amputation in the diabetes group. CAD only patients had higher 10-year risk of PAD compared to diabetes only patients (7.9% versus 6.9%), but had lower risk of amputation (0.6% versus 2.4%, Figure). CAD only patients were most often amputated at hip/femur level, while diabetes only patients most often were amputated at ankle/foot/toe level. Conclusions Presence of CAD in patients with diabetes was an indicator of high risk of PAD and lower limb amputation, and the risk depended on severity of both CAD and diabetes. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Department of Cardiology, Aarhus University Hospital

Surgical Revascularization Versus Endovascular Therapy to Treat Chronic Limb-Threatening Ischemia: Perhaps Less Invasive Is Not Always Better

Subintimal angioplasty for the treatment of claudication and critical limb ischemia: 3-year results

Peripheral artery disease is the leading cause of nontraumatic lower limb amputation. Microvascular disease (MVD) increases the risk of lower limb amputation in patients with peripheral artery disease (PAD). We estimated the risk of lower limb amputation associated with MVD and PAD in a Danish cohort. We included every resident without previous lower limb amputation in Western Denmark aged 50-75 years on 1 January 2012 and followed them for 7 years. Participants were stratified by MVD and PAD. We estimated adjusted hazard ratios of lower limb amputation using individuals with no MVD and no PAD as reference. We also provide a sex-specific analysis and estimated the population attributable fraction of the male sex. We included 933,597 individuals, of whom 16,741 had MVD only, 18,217 had PAD only and 1,827 had MVD and PAD. Both MVD only (adjusted hazard ratio 3.36, 95% CI 2.98-3.73) and PAD only (adjusted hazard ratio 7.32, 95% CI 6.62-8.08) increased the risk of lower limb amputation separately. Individuals with MVD and PAD had the highest risk of amputation (adjusted hazard ratio 12.27, 95% CI 10.43-14.80). Men had an increased absolute risk of amputation. The population attributable fraction associated with the male sex was 31%. Microvascular disease and PAD are independently associated with a threefold and sevenfold increase of amputation risk, respectively. Combined, they had an additive effect constituting a 12-fold amputation risk. The amputation risk was higher in men than women, and 3 in 10 amputations were attributed to the male sex.

Infra-inguinal bypass surgery vs endovascular revascularization for chronic limb-threatening ischemia in average- and high-risk patients