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Surgical digest

Chronic limb-threatening ischaemia: current knowledge and future perspectives


Fabio Stocco

The Leeds Vascular Institute, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK.

The Leeds Institute of Cardiovascular Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.

Jing Yi Kwan

The Leeds Vascular Institute, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK.

The Leeds Institute of Cardiovascular Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.

Marc A. Bailey

The Leeds Institute of Cardiovascular Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK.

Patrick A. Coughlin

The Leeds Vascular Institute, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Great George Street, Leeds LS1 3EX, UK.

https://doi.org/10.58974/bjss/azbc036

Fabio Stocco

The incidence of peripheral arterial disease (PAD) has risen dramatically, and it is estimated to affect around 200 million people worldwide. This rise can be explained by an ageing population, persisting high rates of tobacco smoking and the increasing incidence of diabetes mellitus (DM).1,2 Chronic limb-threatening ischaemia (CLTI) is the most severe manifestation of PAD and is characterized by rest pain and/or tissue loss (e.g. ulceration or gangrene).1 It is estimated that CLTI affects about 10% of all patients with PAD.3

Figure 1. Typical critical ischaemia of the left foot.

Patients with CLTI are at high risk of major limb amputation (MLA) and major adverse cardiovascular events (MACE – myocardial infarction and stroke)1 with a significant reduction in life expectancy. Overall mortality rates are similar to that of advanced cancers.3 They also commonly experience poor quality of life.

One in 14 people in the UK have DM. 1 in 5 people over 80 years have PAD. The combination of PAD and DM carries a high risk of minor foot amputations (22.1 per 10000 population /yr). If you have a minor amputation, you are more likely to progress to an MLA. Patients with combination of DM and PAD have a shorter time to MLA compared to PAD or DM alone. Prevention, and aggressive management of DM is vital to reducing the burden of managing CLTI.4

Current guidelines suggest a multimodal approach to management. Wound care to prevent infection/aid healing; targeting risk factors through appropriate optimal medical therapy to reduce MACE; and limb revascularisation, where possible.1 Revascularisation strategies include endovascular or open surgical interventions (or a combination of the two). The choice of revascularisation is dependent on patient and anatomical factors, alongside technical expertise. The results of two recent randomised controlled trials (BEST-CLI and BASIL-2) have helped clinical management decision making.5 Both studies compared open surgical and endovascular revascularisation in patients with CLTI. BEST-CLI enrolled patients with infrainguinal PAD, whereas BASIL-2 focused on patients requiring infrapopliteal (+/- femoropopliteal) revascularisation.6 The results of the studies contrasted but in part this may reflect the differing inclusion criteria. BEST-CLI demonstrated that where a suitable autologous venous conduit is available, open surgery is associated with significantly reduced major adverse limb events or death. BASIL-2 showed that better amputation-free survival rates were achieved by best endovascular treatment first.5,6 Both studies highlighted the high-risk nature of the population, with an overall mortality rate of 40% at 5 years.

Figure 2. Endovascular treatment of left external iliac artery stenosis causing critical ischaemia in Figure 1. (a) and (b) (angios pre 1 and 2) extent of iliac artery Figure 2. Endovascular treatment of left external iliac artery stenosis causing critical ischaemia (same patient as in Figure 1). (a) and (b) extent of iliac artery disease. (c) after angioplasty and stenting. (c) after angioplasty and stenting (angiopost).

“Time to treatment” is important to reduce the risk of MLA in CLTI. Current UK guidance (Vascular Society in the Provision of Vascular Services (POVS) 2018; Peripheral Arterial Disease Quality Improvement Framework (PAD QIF) 2019) is that patients with CLTI should be revascularised within 5 days of presentation for inpatients or within 14 days for out-patients. Such timelines are challenging to achieve. Current UK vascular surgery networks commonly operate in a hub-and-spoke fashion; patients admitted to spoke centres are transferred to the major arterial hub centres only when surgery is required. Recent data suggest that patients in spoke hospitals have longer waits for revascularisation with poorer MLA and mortality rates.7 The vascular community should look to reduce this inequality across services.

But what of the future for CLTI?

Between 20-40% of patients are deemed unsuitable for revascularisation either due to anatomy or co-morbidities, with treatment options limited to palliative wound care or MLA. This cohort are at high risk with 20% mortality rate / 40% MLA at 6 months post diagnosis.2 Finding new therapies for “no-option” patients remains a challenge. Studies have focused on gene/stem-cell therapy to promote angiogenesis and improve limb perfusion but, to date, these have failed to demonstrate any benefit in placebo-controlled trials.2,3 The PACE trial evaluated the effect of PLX-PAD (an off-the-shelf placental-derived mesenchymal stromal cell) on amputation-free survival in “no-option” patients. Benefit was demonstrated in subsets of the cohort investigated, namely patients without DM or in those with well-controlled DM (HbA1c<6.5%). It was postulated that uncontrolled DM is associated with increased chronic inflammation, which may influence the response to PLX-PAD; this is supported by other cell therapy studies.2

Deep vein arterialisation (DVA) is a rekindled revascularisation concept that shows promise. The concept of DVA is shunting blood from arteries to deep veins to “arterialise” such veins. Open surgical DVA was explored in the late 1900’s but never became established. Advancement of endovascular techniques and technology have reinvented the technique. The procedure involves passing a stent from a patent infrapopliteal artery to a parallel deep vein. The PROMISE-II study, a cohort study of 105 patients with “no-option” CLTI, showed an amputation-free survival of 66.1% at 6 months.8 Further studies have compared the PROMISE II cohort to patients from a registry of untreated “no-option” CLTI patients, finding a significant reduction in amputation-free survival in the DVA group.9

Once successfully revascularized, the key is then to achieve long term patency. Rates of graft or stent thrombosis remain high in part due to due to neointimal hyperplasia, pathological vascular remodelling and hypercoagulability. As the ability to assess coagulability improves, personalising antithrombotic strategies has been a focus of research. Such an approach is evident from the work from the group of Dr Anahita Dua in the United States. Their work, hypothesising that increased platelet reactivity (assessed using thromboelastography (TEG)) is associated with subacute postoperative thrombosis, showed that appropriate inhibition of platelet function significantly reduced postoperative graft/stent thrombotic events. They also showed that there is a recognised sex difference in platelet reactivity (which may explain the poorer outcome seen in women) and that the use of point of care testing (e.g., TEG) could help personalise care to achieve optimal platelet inhibition.

Patients with CLTI are the predominant group now treated by vascular surgeons. The evidence base is building on how to treat such high-risk patients optimally, as evidenced in this review. There are still several questions to be answered and there are a large number of high-quality clinical trials about to start that focus on revascularisation strategies and optimising medical therapy. These data will form the basis of how these patients are treated in the future.

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