Chronic critical limb ischaemia (CLI) affects a defined subgroup of patients with systemic atherosclerosis. Often, these patients exhibit additional cardiovascular risk factors and co-morbidities, which complicate their disease pattern and limit treatment modalities. Therefore, CLI is clearly associated with excessive morbidity and mortality rates and leads to a substantial decline in quality of life.1,2
Clinical symptoms of CLI are either ischaemic rest pain or additional ischaemic tissue loss. To justify the clinical suspicion of CLI, these symptoms need to be accompanied with objective diagnostic criteria such as:
- an absolute ankle-brachial index (ABI) of <0.4;
- an absolute ankle pressure <50mmHg; or
- a great toe pressure of <30mmHg.3
Although ABI is a simple and reliable non-invasive means to assess the severity of peripheral arterial disease (PAD)4 and to estimate its prognosis quod vitam,5 this association might be lost for certain subgroups of patients due to media calcification, which is often prevalent in patients with diabetes or renal insufficiency.6–9 Media calcification reduces arterial compressibility and, thus, leads to systematic overestimation of the true ABI. It was recently shown that such falsely elevated ABI values >1.15, which are an expression of media calcification, independently predict a later need for major amputation.10 This needs to be taken into consideration and implies that in the evaluation of CLI patients especially, haemodynamic observation should be performed by additional oscillometry.
Due to multilevel affection and various serious co-morbidities that influence recovery from operation and quality of life or survival, CLI patients constitute a very challenging subgroup and should be provided with an individually tailored treatment concept. Lepäntalo and colleagues have been showing that CLI patients not undergoing revascularisation face mortality and amputation rates as high as 54 and 46%, respectively, after 12 months.11 In addition, it has been observed that CLI patients, subsequent to successful revascularisation, survive for longer or have an increased quality of life compared to the patients who receive the conservative treatment of primary amputation.12,13
Within an ageing population and improved medical care, physicians are likely to face an increasing number of elderly patients with severe PAD at risk of developing CLI.13 Therefore, it is of great importance to carefully consider the different prevention and treatment options in order to provide patients with the most appropriate therapies.
Contemporary Treatment Options for Critical Limb Ischaemia Patients
Considering the multifaceted problems in CLI patients, a dedicated interdisciplinary approach incorporating the efforts of vascular physicians, endovascular interventionalists, vascular and orthopaedic surgeons as well as internists, wound care specialists and podologists is mandatory in order to bail out all given options.
The benefit of secondary prevention, encountering reduction and therapy of associated cardiovascular risk factors has been established and is widely accepted as the privileged treatment approach. Indeed, risk-factor management might be the most important part of therapy with regard to long-term survival. In fact, many patients are unacceptably undertreated. Thus, important improvements can be made with regard to dedicated risk factor modifications such as smoking cessation advice, medical treatment of diabetes (glycated haemoglobin [HbA1c] <7.0%), reduction of arterial blood pressure (systolic pressure <140/90mmHg in general, <130/80mmHg in patients with diabetes), preferably using angiotensin-converting enzyme inhibitors or angiotensin II antagonists, and statin-based lipid-lowering therapy.14 In addition, all patients with symptomatic PAD should receive an antiplatelet therapy due to high prevalence of concomitant coronary artery disease (CAD).
Considering the fact that ischaemic lesions may be the first manifestation of CLI, local wound management is of pivotal importance. Proper wound care, such as wound debridement of necrotic or fibrous tissue and timely removal of necrotic toes, is of great importance to avoid wound complications and to neutralise other aetiological wound factors. Therefore, interdisciplinary wound care teams should perform an off-loading of the wound region and the surrounding tissue at risk to minimise pressure or shear stress, which is essentially induced by inadequate shoes. In general, a dry wound environment is maintained and disinfection is performed on a daily basis.
In severe cases, vacuum-assisted closure and additional local wound care may be desirable. In case of spreading infection or the development of cellulitis, systemic antibiotics might become mandatory.
Independently of the above-mentioned therapy approaches, arterial revascularisation remains one of the main treatments to achieve adequate wound healing and to salvage a functioning lower extremity in CLI patients with ischaemic rest pain.
Even though endovascular revascularisation has been established as the privileged revascularisation option for PAD for most patients based on findings from a randomised trial, the strategy of revascularisation needs to be evaluated on a case-by-case basis and individually reconsidered for each patient. In certain cases there is not even the option to choose, but a number of factors such as age, the absence of a useful vein for bypass surgery or even the patient’s general condition do not allow for invasive surgical treatment. In addition, it is of great relevance which arterial segment is affected by the flow-limiting lesion. Obstructions at the level of the common femoral artery (CFA) or its bifurcation are still mainly treated using a surgical approach. Similarly, treatment of long and heavily calcified lesions have been reasons to perform surgery in the past.
With regard to surgical treatment strategies, the conventional option of surgical revascularisation is bypass surgery, preferably using autologous vein. This is a well established procedure demonstrating favourable mid- to long-term results and might be the undisputed procedure for younger patients with long life expectancy and in case of long lesions. For younger patients, long-term results suggest patency rates subsequent to bypass surgery outperforming endovascular revascularisation. However, the success of this procedure is dependent on the availability of an autologous vein for surgical bypass and is much more invasive than endoluminal therapy. Moreover, long-term patency might not be relevant to CLI patients in whom excess mortality rates have been described.11 While increased perfusion is required for ulcer healing in CLI, maintenance of lower extremity skin integrity may be observed despite arterial re-obstruction.15,16 Thus, functional lower limb outcomes are substantially better as compared to arterial patency rates in CLI patients undergoing endovascular revascularisation. In addition, the evaluation procedure of patency remains controversial. Angiography is established as the undisputed procedure outperforming duplex-sonography, largely attributed to its observer-variability and the lack of well conducted duplex sonography criteria for below-the-knee (BTK) arteries.17
In comparison with endoluminal therapy, surgical revascularisation modalities are more invasive and therefore accompanied by higher rates of consecutive complications, such as higher risk for infection, haematoma and lymph oedema, and frequently result in more extensive hospitalisation./p>
As a matter of fact, CLI patients often display multilevel PAD; this being a great handicap for surgical treatment options leading to the introduction of hybrid interventions. Thus, a segmental lesion is treated by surgery and subsequent additional obstructions, proximal or distal of the initial lesion, are treated by an endoluminal approach using surgical access to insert a sheath into the artery.
Ever since the first percutaneous transluminal angioplasty (PTA) was carried out in Zürich in 1977, this minimally invasive approach has remained a fascinating treatment modality, although high restenosis rates continue to be a major drawback of the technique. Due to continuous technical improvements and the innovation of adapted devices, enhanced accessibility and treatment options have been implemented. Even distal lower limb lesions (i.e. pedal arteries) have become accessible for treatment by endovascular revascularisation. However, endoluminal therapy in CLI patients continues to be a great technical challenge due to the typically obstructive pattern of femoropopliteal disease with multisegmental lesions, which is mostly associated with very long and heavily calcified occlusions of crural vessels. Subsequent to the performance of plain old balloon angioplasty (POBA) of the femoropopliteal axis, binary restenosis rates of up to 50% after 12 months have been observed. Interestingly, the prevalence of binary restenosis correlates with the length of the treated lesions. This might explain the high rates of restenosis in CLI patients. Meanwhile, improvement of long-term patency subsequent to endovascular revascularisation of long-segment obstructions of the superficial femoral artery has been achieved using Nitinol stents.18 Despite the introduction of novel nitinol stents with increased biomechanical capabilities, restenosis rates after femoropopliteal revascularisation using uncoated nitinol stents still remains in the 30% range.
It has been observed that intima hyperplasia is one of the key issues in the pattern of reobstruction. Therefore, a novel strategy has been invented in order to reduce binary restenosis. The upcoming innovation of drug-eluting devices, balloons and stents which use anti-proliferative drug coats have achieved better outcomes.
Indeed, the (SIROCCO) trial,19 which compares sirolimus-eluting with bare nitinol stents, showed a significantly better outcome in short-/mid-term binary restenosis subsequent to revascularisation. However, in the long-term observation out to 24 months, the application of sirolimus-eluting stents was inferior to the application of bare nitinol stents, mainly due to high rates of stentfractures.
More recent data from Dake and co-workers (presented at the Transcatheter Cardiovascular Therapeutics meeting on 24 September 2010), investigating the efficacy of paclitaxel drug-eluting stents versus PTA and bare metal stents for SFA revascularisation within a randomised trial, have been showing event-free survival of 90.4% for the drug-eluting stent versus 82.6% in the control group after 12 months, which was statistically significant. Similar observations have been made, presenting a significantly better outcome of 83.1% versus 65.3% accounting for primary patency rates; again favouring the paclitaxel-coated stents. In addition, these most dedicated devices revealed a stent-fracture rate of 0.9%, thereby ruling out the main problem that has been observed in the SIROCCO trial.
Moreover, downsizing of catheter material and the introduction of dedicated devices such as long balloons, low profile catheters and dedicated guidewires have substantially facilitated endovascular therapy of BTK arteries. About 40% of patients with CLI and particularly those with ischaemic lesions have associated diabetic disease. These patients constitute a challenging subgroup since diabetes is very frequently associated with isolated or additional crural obstructions. Since crural vessels, similar to coronary arteries, display small-calibre diameter, BTK revascularisation remains a challenge for every interventionalist. In the meantime, there have been concerns arising from the Bypass angioplasty revascularisation investigation (BARI) trial,9 implying that the long-term outcome subsequent to coronary bypass might clearly outperform coronary angioplasty. However, observational studies investigating clinical outcomes subsequent to BTK revascularisation observed that the initial revascularisation success, regardless of the strategy, was generally impaired in diabetic patients.9 Nevertheless, it is thought that ulcer healing is best promoted by a direct flow to the foot, thus, at least one of the cural vessels should be reopened.
Even though high rates of binary restenosis have been reported subsequent to endovascular BTK revascularisation, transient improvement of lower extremity perfusion is often sufficient for ulcer healing in CLI patients, whereas the maintenance of lower extremity skin integrity may be observed despite arterial reobstruction.15,16 Therefore, it seems that revascularisation should be attempted regardless of the risk-factor constellation. However, long-term surveillance is mandatory to perform reinterventions when needed.
To date, there is only one randomised trial presenting level A evidence as to whether either the endovascular or the open surgical revascularisation strategy offers advantages over the other. On the basis of the UK bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial,20 involving 452 CLI patients from 47 vascular centres, which were suitable for both endoluminal and surgical treatment of infrainguinal lesions, the results did not reveal a preferred strategy. After two and a half years of follow-up, outcomes (amputation-free survival, all-cause mortality, health-related quality of life and treatment cost) were very similar. In regard to long-term results and durability, the BASIL trial slightly favoured open surgical revascularisation. However, since many CLI patients have a rather limited life expectancy due to its poly-morbidity and advanced age, this advantage only applies to fit patients and if there is a good vein available for surgical bypass. In addition, endoluminal options have significantly improved since the BASIL trial, reflecting UK practice between 1999 and 2004, when patients were mainly treated with POBA. In the meantime, however, a myriad of endovascular innovations such as stents and devices facilitating endovascular therapy of chronic occlusions has substantially improved technical outcomes.
In CLI patients who are not amendable for surgical or endovascular revascularisation or patients with whom revascularisation attempts have been unsuccessful, prostanoids are currently the only vasoactive drugs with proven clinical efficacy. Several studies have shown that parenteral administration of either prostaglandin-1 or iloprost reduced ischaemic rest pain, ulcer size and the need for amputation.2
In additon, the stimulation of angiogenesis is another very appealing concept for CLI patients. Vascular endothelial growth factors have drawn much attention due to their potential for therapeutic use in cardiac and lower limb ischaemia. The danger of an increased occurrence of retinopathy, cancer, or renal impairment subsequent to intramuscular injection of riferminogene pecaplasmid (NV1FGF) has been ruled out by a multicentre double-blind placebo-controlled trial performed by Nikol and coworkers.21 In contrast, the NV1FGF gene transfer was well tolerated in most patients and significant reduction of amputation rates has been observed. Despite these encouraging preliminary results, the interpretation and application of this procedure has to be performed with utmost caution since the number of treated patients is very limited and gene therapy can so far not be considered as a standardised treatment alternative to the well established revascularisation strategies.
Patients suffering from CLI remain as a very challenging subgroup of patients because of the substantial threat to the limb and even life. In addition, CLI patients demonstrate a most sophisticated lesion morphology which requires multidisciplinary approaches to achieve the most appropriate treatment strategy.
Despite the difficult starting point, CLI patients clearly benefit from this multidisciplinary and individually tailored treatment strategies and especially from revascularisation attempts notwithstanding the high prevalence of binary restenosis. Moreover, CLI patients require regular clinical follow-ups which must be accompanied by standardised surveillance protocols and secondary prevention strategies. Further technical innovations such as the introduction of drug-coated angioplasty balloons will hopefully expand endovascular treatment options.