Treatment Of Critical Limb Ischemia Research Articles

John Adam Dormandy: championed new approaches to tackling peripheral arterial disease

John Dormandy was a consultant vascular surgeon, researcher, and medical educator best known for innovative work on the diagnosis and management of peripheral arterial disease. He had a leading role...

IP185. Novel Technique for Lower Extremity Reverse Saphenous Vein Bypass—Use of Fistula Formation During Great Saphenous Vein Harvest

Infrainguinal arterial bypass remains a mainstay in treatment of critical limb ischemia and significant peripheral artery disease. Our report describes a novel technique that uses fistula formation between native saphenous vein and the femoral artery. We present the case of a 64-year-old man with symptoms of tissue loss of the right lower extremity. Arterial duplex ultrasound demonstrated a >75% superficial femoral artery stenosis with occlusion of proximal popliteal with reconstitution into distal popliteal artery. With the inability to revascularize the artery endovascularly, the decision was made to bypass this femoral-popliteal lesion. The patient was taken to the operating room. The procedure began with dissection of the arterial supply at the common femoral artery suitable for bypass, which is identified and isolated, gaining proximal and distal control. Attention was then turned to dissection of the presumed distal arterial landing for the bypass, also gaining proximal and distal control. This distance between the two sites was measured to give approximate length of venous conduit required. Based on those measurements, the distal half of the great saphenous vein was then dissected out. Once completed, the distal end of the vein was transected and immediately taken up to the common femoral, spatulated, and anastomosed, creating a femoral artery to great saphenous vein fistula. The remaining vein was dissected under distention, allowing easier identification of branch points as well as any stenotic segments. The vein was transected proximally, the proximal end was brought down to the distal artery and spatulated, and the anastomosis was performed, completing the bypass. At 3-month follow-up, duplex ultrasound examination of the bypass demonstrated a patent bypass; with repeated noninvasive studies, ankle-brachial index improved to 1.02. The patient has not required any further intervention for the bypass. This technique minimizes intimal manipulation, which theoretically will improve long-term patency rates of infrainguinal bypasses. During the second portion of dissection of our venous conduit, the vein is under distention from the arterial supply. This has the additional benefit of allowing completion of the bypass to be performed without artificial dilation or manual irrigation, reducing insult to the intima and vasospasm. In addition, there is visualization of any potential stenotic segments of conduit that may require resection with end-to-end anastomosis. The vein is kept superficial, reducing the chance of kinking and allowing easier surveillance. Further study and long-term patency follow-up are required to determine the long-term feasibility of this technique.Fig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

PLX-PAD Cell Treatment of Critical Limb Ischaemia: Rationale and Design of the PACE Trial

PLX-PAD Cell Treatment of Critical Limb Ischaemia: Rationale and Design of the PACE Trial

PC084. Outcomes of Peripheral Vascular Intervention for Critical Limb Ischemia by Retrograde Pedal Access

PC084. Outcomes of Peripheral Vascular Intervention for Critical Limb Ischemia by Retrograde Pedal Access

A promising blood-derived novel treatment for critical limb ischemia and beyond

Background & Aim Peripheral vascular disease in people with diabetes and the elderly affects principally medium and small caliber vessels which are less amenable to surgical intervention. Stem/progenitor cell (SPCs) treatments with bone-marrow-derived cells show promising outcomes in treating vascular diseases, albeit not without adverse events related to cell mobilization and collection. A unique patented treatment product of enriched endothelial progenitor cells (EnEPCs) generated from peripheral blood was developed, that utilizes novel one-day technology employing dendritic cells (DCs) to specifically direct potentially therapeutic stem/progenitor cell (SPC) activity in-vitro. Previous animal studies have shown promising results in reversing induced limb ischemia. We describe a first in human study of the product for treating patients with severe peripheral vascular disease with no available surgical option. Methods, Results & Conclusion We performed pilot open-label study of treatment with the product in patients with critical limb ischemia (CLI) characterized by rest pain and/or ulceration, and with no surgical option for revascularization. The product was prepared from 250—350 ml of standard blood draw. Co-culture of activated DCs with SPCs from the same patient sample yielded 97% viability. Treatment consisted of single treatment session with intramuscular injections into the gastrocnemius muscle of the diseased leg. Acute safety follow-up was conducted during the initial 48±6 hours in the hospital and long-term follow-up at 1 week and at 1, 3, 6 and 12 months. Results revealed that the treatment is well tolerated and safe. The therapy showed promising therapeutic effects in objective outcomes including limb salvage, increased leg blood flow and wound healing, as well as, subjective outcomes including walking ability, reduction of pain, decreased usage of narcotic medications and improved quality of life (QoL). Conclusion These observations indicate that the cell product, derived from standard peripheral blood draw of EPC-enriched SPCs, generated by novel culture process taking less than one day, shows promising preliminary results in the treatment of CLI and may also be therapeutic in other vascular conditions.

Comparison of specialties participating in the BEST-CLI trial to specialists treating peripheral arterial disease nationally

BackgroundThe Best Endovascular vs Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial compares open surgery and endovascular therapy for the treatment of critical limb ischemia (CLI). This report describes the types and proportion of investigators participating in BEST-CLI and determines how these compare with those specialists treating peripheral artery disease (PAD) outside of the trial. MethodsTo be credentialed to enroll in BEST-CLI, investigators must be approved by the Surgical and Interventional Management Committee to have sufficient experience and skill in the management of patients with CLI. Investigators must attest to having completed at least 12 below-knee interventions in the last 2 years on CLI patients for endovascular approval and 10 lower extremity below-knee bypass procedures in the last 2 years for open surgical treatment. Investigators who met these criteria but were within their first year of practice were conditionally approved to do procedures under the oversight of a fully approved investigator. The type and proportion of specialists credentialed in BEST-CLI were compared with those treating PAD on a national basis by auditing 10% of Medicare claims for PAD. ResultsAs of September 2017, a total of 865 physicians were credentialed to enroll in the BEST-CLI trial. Of these, 596 (69%) are vascular surgeons, 128 (15%) are interventional cardiologists, 123 (14%) are interventional radiologists, 7 (1%) are vascular medicine specialists, and 11 (1%) are other. Of the 596 vascular surgeons enrolling in the trial, 113 (19%) are credentialed for open surgery only, 409 (69%) are credentialed for both open surgery and endovascular therapy, and 3 (1%) are credentialed for only endovascular therapy. The remaining 71 participating vascular surgeons were conditionally approved. Of the 136 centers enrolling patients, multispecialty involvement is present in 98 (72%). In 38 (28%), vascular surgery alone is the service enrolling CLI patients. Endovascular treatment by specialty in BEST-CLI vs national Medicare claims is as follows: vascular surgery, 55% vs 51%; interventional cardiology, 17% vs 13%; interventional radiology, 16% vs 25%; and other, 2% vs 10%. ConclusionsBEST-CLI contains a diverse group of specialists enrolling and treating patients with CLI. Whereas a majority of the participating practitioners are vascular surgeons who do both open and endovascular procedures, a broad variety of specialists are represented in BEST-CLI in a pattern that represents national treatment patterns outside of the BEST-CLI trial. These treatment patterns will help ensure that findings from BEST-CLI are applicable to the real-world practice of treatments for PAD.

Below-the-ankle Angioplasty: Current Evidence and Future Perspectives

Over 20 million adults in Europe suffer from peripheral arterial disease (PAD). The annual incidence of PAD is approximately 2.4%, while the annual incidence of critical limb ischaemia (CLI), the last and most severe stage of PAD, has been reported to be 0.4%. Endovascular angioplasty and/or stenting of infrapopliteal disease is, today, an established treatment for critical limb ischaemia. The main technical advantages of endovascular treatment over open bypass surgery include the possibility to revascularise more than one infrapopliteal vessels and, most importantly, to treat outflow pedal vessel disease or even reconstitute the pedal arch. Data of below-the-ankle angioplasty are beginning to sum up and the contribution of pedal arch angioplasty in limb salvage and wound healing are currently under investigation. In this review, currently available data and the future perspectives on below-the-ankle and pedal arch endovascular treatment will be presented.

Cell therapy of critical limb ischemia-problems and prospects.

Cell therapy is proposed for indirect revascularization for the patient's incurable by endovascular or surgical revascularization. The therapy with stem cells (SCs) or progenitor cells is assumed to be more efficient as compared with protein or gene therapy not only because of their direct vasculogenic properties, but also thanks to their paracrine effect via secretion of manifold biologically active substances. This review gives an overview of the potential of SC-based therapy for critical limb ischemia (CLI), putative mechanism underlying cell therapy, and comparison of cell therapy to angiogenesis gene therapy in CLI treatment. Human trial data and meta-analysis, as well as some problems of clinical trials and considerations for future SC-based therapy in CLI are also discussed.

Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes

We first compared long-term clinical outcomes in treating critical limb ischemia (CLI) and foot ulcer in patients with diabetes between autologous bone marrow mesenchymal stem cell (BMMSC) and bone-marrow-derived mononuclear cell (BMMNC) transplants. Forty-one patients were enrolled and followed up for 3 years. They received an 18-day standard treatment before stem cell transplantation. Patients with bilateral CLI and foot ulcer were injected intramuscularly or basally with BMMSC, BMMNC, or normal saline (NS). Cox model analysis showed significant differences in the hazard ratio (HR) for amputation with treatment by BMMSC (HR 0.21 [95% CI (0.05, 0.95)], P = 0.043), infection of foot (HR 5.30 [95% CI (1.89, 14.92)], P = 0.002), and age ≥64 (HR 3.01 [95% CI (1.11, 8.15)], P = 0.030), but no significant differences by BMMNC at 9 months after transplantation. Regarding ulcer healing and recurrence rate, the BMMSC group demonstrated a significant difference from the NS group during the 3–6 months after transplantation or healing, but the BMMNC group did not. This trial suggests that, compared with BMMNC treatment, BMMSC treatment leads to a longer time of limb salvage and blood flow improvement, and, when compared with conventional therapy, it can promote limb blood flow and ulcerative healing, and reduce ulcer recurrence and amputation within 9 months.

Cost-effectiveness of the treatments for critical limb ischemia in the elderly population

ObjectiveThe treatment of critical limb ischemia (CLI), with the intention to prevent limb loss, is often an intensive and expensive therapy. The aim of this study was to examine the cost-effectiveness of endovascular and conservative treatment of elderly CLI patients unsuitable for surgery. MethodsIn this prospective observational cohort study, data were gathered in two Dutch peripheral hospitals. CLI patients aged 70 years or older were included in the outpatient clinic. Exclusion criteria were malignant disease, lack of language skills, and cognitive impairment; 195 patients were included and 192 patients were excluded. After a multidisciplinary vascular conference, patients were divided into three treatment groups (endovascular revascularization, surgical revascularization, or conservative therapy). Subanalyses based on age were made (70-79 years and ≥80 years). The follow-up period was 2 years. Cost-effectiveness of endovascular and conservative treatment was quantified using incremental cost-effectiveness ratios (ICERs) in euros per quality-adjusted life-years (QALYs). ResultsAt baseline, patients allocated to surgical revascularization had better health states, but the health states of endovascular revascularization and conservative therapy patients were comparable. With an ICER of €38,247.41/QALY (∼$50,869/QALY), endovascular revascularization was cost-effective compared with conservative therapy. This is favorable compared with the Dutch applicable threshold of €80,000/QALY (∼$106,400/QALY). The subanalyses also established that endovascular revascularization is a cost-effective alternative for conservative treatment both in patients aged 70 to 79 years (ICER €29,898.36/QALY; ∼$39,765/QALY) and in octogenarians (ICER €56,810.14/QALY; ∼$75,557/QALY). ConclusionsOur study has shown that endovascular revascularization is cost-effective compared with conservative treatment of CLI patients older than 70 years and also in octogenarians. Given the small absolute differences in costs and effects, physicians should also consider individual circumstances that can alter the outcome of the intervention. Cost-effectiveness remains one of the aspects to take into consideration in making a clinical decision.

PLX-PAD Treatment of Critical Limb Ischaemia: A Clinically Effective Cell Therapy at Long Last?

PLX-PAD Treatment of Critical Limb Ischaemia: A Clinically Effective Cell Therapy at Long Last?

PLX-PAD Cell Treatment of Critical Limb Ischaemia: Rationale and Design of the PACE Trial

Critical limb ischaemia (CLI) is a life threatening condition with a considerable risk of major amputation and death. Besides revascularisation, no treatment has been proven to reduce the risks. Therapeutic angiogenesis by gene or cell therapy has not demonstrated definitive evidence in randomised controlled trials. PLX-PAD is an "off the shelf" allogeneic placental derived, mesenchymal like cell therapy, which, in preclinical studies, has shown pro-angiogenic, anti-inflammatory, and regenerative properties. Favourable one year amputation free survival (AFS), and trends in reduction of pain scores and increase of tissue perfusion have been shown in two small, open label, phase I trials. The PACE study is a phase III randomised, double blind, multicentre, multinational placebo controlled, parallel group study to evaluate the efficacy, tolerability, and safety of intramuscular injections of PLX-PAD cells to treat patients with atherosclerotic CLI with minor tissue loss (Rutherford Category 5) up to the ankle level, who are unsuitable for revascularisation or carry an unfavourable risk benefit for that treatment. The study will enroll 246 patients, who after screening are randomised in a ratio of 2:1 to treatment with intramuscular injections of PLX-PAD 300×106cells or placebo on two occasions, eight weeks apart. The primary efficacy endpoint is time to major amputation or death (amputation free survival), which will be assessed in follow up of at least 12 months and up to 36 months. Based on favourable pre-clinical and initial clinical study results, the PACE phase III randomised controlled trial will evaluate placenta derived PLX-PAD cell treatment in patients with critical limb ischaemia, with an unfavourable risk benefit for revascularisation. Clinicaltrials.gov: NCT03006770.

Critical limb ischemia: Current and novel therapeutic strategies.

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell-based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.

Ultrasound-guided popliteal sciatic nerve block: an effective alternative technique to control ischaemic severe rest pain during endovascular treatment of critical limb ischaemia.

PurposeThere are challenges with pain management related to a severely ischaemic limb. Although opioid-based treatment has been the cornerstone of pain relief, the use of these drugs should be limited because of their side effects in such vulnerable patients. We evaluated the utility and efficiency of sciatic nerve block as an alternative method to relieve severe rest pain during endovascular treatment of critical limb ischaemia.Material and methodsWe retrospectively investigated 10 patients who received ultrasound-guided popliteal sciatic nerve block for the relief of severe rest pain during endovascular treatment of critical limb ischaemia. The degree of pain relief was evaluated by using subjective criteria, from no relief of pain (= 1) to complete relief of pain (= 4). Details of endovascular treatment, time to perform the block, amount of local anaesthetics, duration of the block, need for supplemental analgesia, patient and operator satisfaction, and complications were recorded.ResultsAll blocks were technically successful, and all of the patients had complete resolution of the pain within five minutes. The degree of pain relief was 3 in two patients and 4 in eight patients. All patients were satisfied with the block anaesthesia, and no patient required additional analgesia during this period. Operator satisfaction was very good in all cases. Complications secondary to block did not occur in any patient.ConclusionsUltrasound-guided popliteal sciatic nerve block provides effective pain control, which results in excellent patient and operator satisfaction during endovascular treatment of critical limb ischaemia with severe rest pain.

Multidisciplinary treatment for critical limb ischemia in high age patients with end stage renal disease

高齢維持透析患者は徐々に増加しており，2016年現在で透析患者の3人に1人が後期高齢者となっている．糖尿病性腎症による末期腎不全患者が多いため，血管合併症による心血管イベントやCLIが増加している．高齢維持透析患者は，出血リスクも高いため，抗血栓療法にも注意が必要である．高齢腎不全CLI患者に対する切断回避ならびに生命予後を優先した治療は，治療の長期化によりかえってADLの低下を招く危険性もあり，注意が必要である．個々の症例によって，目標とすべき治療ゴールの設定は異なるので，理学療法士やソーシャルワーカーなど，多職種を巻き込んだアプローチが不可欠であると思われる．

Treatment of Atherosclerotic Disease of the Femoral Artery: Randomized Controlled Trials and Meta-Analyses. Should You Be Sceptical?

A narrative review of the data provided by Randomised Controlled clinical trials and meta-analyses was undertaken to assess how much reliance a clinician could place on these in selecting a treatment for patients with disease of the Femoral artery. An attempt was made to detect and review every clinical trial and meta-analysis published on treatments relating to disease of the femoral artery but not relating to drug treatment. Disease of the femoral artery in >65 years age group occurs in approximately 20% of the population but symptomatology was present in 40%. In almost all trials the predominant (>90%) indication for treatment was intermittent claudication. In this setting, clinical benefit was limited and did not extend beyond 12 months. Mortality, from co-morbidities was high. The Basil Trial was the only one to examine intervention for critical limb ischemia. The results for Bypass surgery and Percutaneous transarterial balloon angioplasty (PTA) were equivalent. There is little evidence to support the use of PTA or stenting other than in the treatment of patients with critical limb ischemia.

Plasma NAP-2 levels are associated with critical limb ischemia in peripheral arterial disease patients.

Critical limb ischemia (CLI) is a serious arterial obstruction, resulting in serious reduction of blood flow to the extremities. CLI is a symptomatic disorder and is frequently not diagnosed in time. This results in a high mortality and elevated risk of limb amputation. Serum or plasma biomarkers play important roles in disease prevention, diagnosis, and prognosis. Elevated plasma neutrophil-activating peptide-2 (NAP-2) was found independently associated with CLI, but not with T2DM. Plasma NAP-2 levels might be an early CLI diagnostic biomarker and might provide a novel target for CLI treatment.

Self-assembled GFFYK peptide hydrogel enhances the therapeutic efficacy of mesenchymal stem cells in a mouse hindlimb ischemia model

Mesenchymal stem cell (MSC) transplantation has emerged as a very promising strategy for the treatments of peripheral artery disease (PAD). However, MSC-based therapies are limited by low cell retention and survival rate in the ischemic zone. Small molecular (SM) hydrogels have shown attractive abilities to enhance the therapeutic effects of human MSCs via promoting their proliferation or maintaining their differentiation potential. Here, we designed and synthesized a new bioactive and biocompatible hydrogel, Nap-GFFYK-Thiol, using disulfide bonds as cleavable linkers to control the molecular self-assembly and we hypothesized this hydrogel could enhance the retention and engraftment of human placenta-derived MSCs (hP-MSCs) in a mouse ischemic hindlimb model. In vitro results demonstrated that the Nap-GFFYK-Thiol hydrogel increased cell viability through paracrine effects. Moreover, it enhanced the proangiogenic and anti-apoptotic effects of hP-MSCs. In vivo, Nap-GFFYK-Thiol hydrogel improved the hP-MSC retention in the murine ischemic hindlimb model as visualized by bioluminescence imaging. Furthermore, cotransplantation of hP-MSCs with hydrogel improved blood perfusion, leading to superior limb salvage. These therapeutic effects may attribute to reduced inflammatory cell infiltration, enhanced angiogenesis as well as suppressed collagen deposition. In conclusion, the Nap-GFFYK-Thiol hydrogel fabricated using disulfide bonds as cleavable linkers serves as an artificial niche for promoting hP-MSC survival and proangiogenic factor secretion in PAD therapy and thereby provide an alternative strategy for PAD therapy. Statement of significanceAlthough several phase I/II clinical trials of MSC-based treatments for critical limb ischemia (CLI) are ongoing, MSC-based therapies are still challenged by the low quality and quantity of cells in the ischemic zone, especially in cases of extensive or irreversible damage. Hydrogels have favorable biocompatibility and safety records in the medical field. In the current study, we engineered a new bioactive and biocompatible hydrogel, Nap-GFFYK-Thiol, using disulfide bonds as cleavable linkers to enhance the therapeutic efficacy of human placenta-derived MSCs (hP-MSCs) in mouse limb ischemia model. Notably, Nap-GFFYK-Thiol hydrogel acts as an artificial niche for promoting hP-MSC survival and proangiogenic factor secretion in PAD therapy, which further promoted the restoration of blood perfusion and regeneration of muscle cells. Considering the proangiogenic effect of Nap-GFFYK-Thiol on hP-MSCs, our results may provide a new strategy for the treatment of PAD.

Role of CXCR2 in the Ac-PGP-Induced Mobilization of Circulating Angiogenic Cells and its Therapeutic Implications.

Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N‐acetylated proline‐glycine‐proline (Ac‐PGP; a collagen‐derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac‐PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac‐PGP on blood perfusion and CAC mobilization (Sca1+Flk1+ cells) into peripheral blood were assessed. Intramuscular administration of Ac‐PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac‐PGP‐induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2‐knockout mice. In addition, Ac‐PGP‐induced CAC mobilization was found to occur in wild‐type mice but not in CXCR2‐knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild‐type mice showed bone marrow‐derived cells homed to ischemic limbs after Ac‐PGP administration and that GFP‐positive cells contributed to the formation of ILB4‐positive capillaries and α smooth muscle actin (α‐SMA)‐positive arteries. These results suggest CXCR2 activation in bone marrow after Ac‐PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. stem cells translational medicine 2019;8:236&246

5-Year Outcomes After Salvage Tibial Angioplasty for Critical Limb Ischaemia

Introduction: Distal bypass surgery for critical limb ischaemia (CLI) is technically challenging and risky in the ageing frail population. Data from BASIL trial have shown that endovascular revascularization is a viable option for CLI however long-term outcome studies are lacking. Aims: To evaluate technical success and primary patency rates after salvage tibial angioplasty, mortality and amputation-free survival as well as long term outcome. Methods: A retrospective study included consecutive tibial angioplasties performed from December 2009 to May 2014 at single tertiary center. Disease severity was classified according to Graziani classification from digital subtraction imaging. Primary outcomes were technical success, major and minor amputation rate, patient’s survival and long-term outcome. Results: Sixty two angioplasties were performed in 54 patients (M:F=42:12). The mean age was 70±11 years, 83% diabetics, 50% hypertensives and 64% were current or ex-smokers. Multivessel disease was present in 52% of cases. Overall mean follow-up was 3.96±2.7 years and 6.15±1.5 years amongst patients still alive. Technical success, as defined at ≥ 1 patent vessel with improved completion pedal flow, was achieved in 81%. Wound healing was 69% and was significantly associated with technical success (p<0.001). Five year survival was 49%. Only 16% required major amputations and 46% minor amputations. Patients required re-angioplasty in 9.5%. Chronic kidney disease (CKD) was a strong predictor of poor wound healing and major amputation (p=0.02). Disease severity was not associated with a poorer outcome. Conclusion: Tibial angioplasty is an effective treatment for CLI. Technical success and CKD are predictors of wound healing and major amputation.