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Evidence-based Management of PAD & the Diabetic Foot

Open ArchivePublished:March 28, 2013DOI:https://doi.org/10.1016/j.ejvs.2013.02.014
      Diabetic foot ulceration (DFU) is associated with high morbidity and mortality, and represents the leading cause of hospitalization in patients with diabetes. Peripheral arterial disease (PAD), present in half of patients with DFU, is an independent predictor of limb loss and can be difficult to diagnose in a diabetic population. This review focuses on the evidence for therapeutic strategies in the management of patients with DFU. We highlight the importance of timely referral of patients presenting with a new foot ulcer to a multidisciplinary team, which includes vascular surgeons and interventional radiologists.

      Keywords

      Despite their widespread use, the evidence to support many interventions in the diabetic foot derives from studies of poor quality. We highlight the need for separate reporting of outcomes in patients with diabetes undergoing revascularisation for critical limb ischaemia and challenge current classification systems for peripheral arterial disease in this cohort. The review focuses on evidence-based strategies for diabetic foot ulceration (DFU) to promote healing and preserve life and limb. We emphasize the importance of referring all patients presenting with DFU to a multidisciplinary team involving vascular surgeons and interventional radiologists.

      Introduction/Epidemiology

      The dramatic increase in the worldwide prevalence of diabetes mellitus (DM) has resulted in an inevitable rise in diabetes-related complications. In 2011, there were an estimated 366 million adults with diabetes worldwide and projections indicate this figure will rise to 552 million by 2030.
      Amputation is a largely preventable complication of diabetes and >85% of major amputations in patients with diabetes are preceded by foot ulceration.
      • Pecoraro R.
      • Reiber G.
      • Burgess E.
      Pathways to diabetic limb amputation: a basis for prevention.
      Despite evidence to suggest that targeted interventions resulting from multidisciplinary care can reduce limb loss, progress to date has been slow.
      • Krishnan S.
      • Nash F.
      • Baker N.
      • Fowler D.
      • Rayman G.
      Reduction in diabetic amputations over 11 years in a defined UK population: benefits of multidisciplinary work and continuous prospective audit.
      Whilst the number and incidence of amputations have fallen in an ageing population without diabetes, those in patients with type 2 diabetes have risen in some countries.
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      • Bottle A.
      • Edmonds M.E.
      • Valabhji J.
      • Majeed A.
      • Millett C.
      Changes in incidence of lower extremity amputations in individuals with and without diabetes in England between 2004 and 2008.
      Twenty years on from the St Vincent's Declaration,
      Diabetes care and research in Europe: the Saint Vincent declaration.
      attempts to achieve 5-year targets to halve the number of lower limb amputations in patients with diabetes have failed. It is therefore timely to review the evidence for the management of peripheral arterial disease (PAD) and the diabetic foot, highlighting recent guidelines produced by the International Working Group on the Diabetic Foot (IWGDF) and the European Society of Vascular Surgery (ESVS).
      • Schaper N.C.
      • Andros G.
      • Apelqvist J.
      • Bakker K.
      • Lammer J.
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      • et al.
      Specific guidelines for the diagnosis and treatment of peripheral arterial disease in a patient with diabetes and ulceration of the foot, 2011.
      • Lepantalo M.
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      • Setacci C.
      • Ricco J.B.
      • de Donato G.
      • Becker F.
      Management of critical limb ischaemia and diabetic foot. Clinical practice guidelines of the European Society for Vascular Surgery.
      Foot lesions carry high morbidity and mortality and represent the most common cause of hospitalization in patients with diabetes. The lifetime risk of foot ulceration in patients with diabetes lies between 15% and 25%,
      • Singh N.
      • Armstrong D.G.
      • Lipsky B.A.
      Preventing foot ulcers in patients with diabetes.
      • Wild S.
      • Roglic G.
      • Green A.
      • Sicree R.
      • King H.
      Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030.
      with an annual incidence of around 2%.
      • Abbott C.A.
      • Carrington A.L.
      • Ashe H.
      • Bath S.
      • Every L.C.
      • Griffiths J.
      • et al.
      The north-west diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based cohort.
      The risk of a person with diabetes undergoing a lower extremity amputation is estimated to be 23 times that of a person without diabetes,
      and the National Diabetes Audit estimates that every 7 out of 10 000 people with diabetes in England and Wales underwent a major amputation in 2008–2009. In 2010–2011 there were 72 459 hospital admissions for diabetes-related foot complications,
      • Holman N.
      • Young R.J.
      • Jeffcoate W.J.
      Variation in the recorded incidence of amputation of the lower limb in England.
      at an estimated cost of between £639 million and £662 million to the National Health Service in England and Wales.

      Kerr M. Foot care in diabetes: the economic case for change. http://www.diabetes.nhs.uk/document.php%3fo%3d3400.

      PAD is an independent risk factor for subsequent ulceration and limb loss in diabetes. It is present in 50% of patients with diabetic foot ulceration (DFU), a proportion which may be increasing.
      • Prompers L.
      • Huijberts M.
      • Apelqvist J.
      • Jude E.
      • Piaggesi A.
      • Bakker K.
      • et al.
      High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study.
      • Jeffcoate W.J.
      • Chipchase S.Y.
      • Ince P.
      • Game F.L.
      Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures.
      Those with DFU and PAD are less likely to heal and more likely to require amputation compared to patients without PAD. It is therefore essential that PAD is identified in all patients with diabetes.

      Pathology in DFU

      The aetiology of DFU is multifactorial and involves a complex interplay between distal polyneuropathy (motor, sensory and autonomic), abnormal foot anatomy, functional changes in the microcirculation and PAD. The pathway to ulceration typically follows abnormal loading or trauma of the painless neuropathic foot, which may be poorly perfused due to PAD, rendering it less able to heal. Both ulceration and infection in the foot will increase the demand for oxygen and, as such, vascular intervention may be required to achieve healing in cases where objective measures of perfusion suggest that PAD is only of mild severity. The wound repair process may be further impaired by virtue of various biological factors inherent to diabetes, including impaired humoral immunity and abnormal inflammatory responses.
      • Martin J.M.
      • Zenilman J.M.
      • Lazarus G.S.
      Molecular microbiology: new dimensions for cutaneous biology and wound healing.
      • Blakytny R.
      • Jude E.
      The molecular biology of chronic wounds and delayed healing in diabetes.
      Early descriptions of diabetes as an occlusive small vessel disease were disproven by histological staining of amputated limbs,
      • Logerfo F.W.
      • Coffman J.D.
      Vascular and microvascular disease of the foot in diabetes – implications for foot care.
      and subsequently by arterial casting studies. This led to the identification of several functional abnormalities of the microvasculature including an increase in arterio-venous shunting and impaired vasoreactivity.
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      • Aidinian G.
      • Singh N.
      • Weiswasser J.M.
      • Arora S.
      Evaluation of the microcirculation in vascular disease.
      In patients with type 2 diabetes these changes lead to capillary hypoperfusion, probably further impairing wound healing.
      • Nabuurs-Franssen M.H.
      • Houben A.J.H.M.
      • Tooke J.E.
      • Schaper N.C.
      The effect of polyneuropathy on foot microcirculation in type 2 diabetes.
      Furthermore, the development of collateral vessels is impaired in patients with diabetes.
      • Abaci A.
      • Oguzhan A.
      • Kahraman S.
      • Eryol N.K.
      • Unal S.
      • Arinc H.
      • et al.
      Effect of diabetes mellitus on formation of coronary collateral vessels.
      Consequently arterial occlusions may result in more severe perfusion deficits in those with diabetes compared to those without diabetes. The distribution of PAD in patients with diabetes is characteristically distal and diffuse, with a greater prevalence of crural disease and long arterial occlusions.
      • LoGerfo F.W.
      • Conrad M.C.
      Large and small artery occlusion in diabetics and nondiabetics with severe vascular disease.
      • Faglia E.
      • Favales F.
      • Quarantiello A.
      • Calia P.
      • Clelia P.
      • Brambilla G.
      • et al.
      Angiographic evaluation of peripheral arterial occlusive disease and its role as a prognostic determinant for major amputation in diabetic subjects with foot ulcers.
      • Jude E.B.
      • Oyibo S.O.
      • Chalmers N.
      • Boulton A.J.
      Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome.
      The distribution of PAD in diabetes may relate to the presence of somatic neuropathy, which has been implicated in the development of medial arterial calcification.
      • Jeffcoate W.J.
      • Rasmussen L.M.
      • Hofbauer L.C.
      • Game F.L.
      Medial arterial calcification in diabetes and its relationship to neuropathy.

      Diagnosis of PAD

      Identification of PAD in patients with diabetes may be difficult because symptoms and signs are frequently masked by co-existing distal symmetrical polyneuropathy. Furthermore, most patients with DFU present to primary care, podiatry or internal medicine clinicians who are not experts in the diagnosis of PAD. IWGDF guidelines suggest that, in addition to a thorough history for symptoms of arterial insufficiency, all patients with a diabetic foot ulcer should undergo hand-held Doppler evaluation of both pedal pulses, measurement of ABI and, in cases of diagnostic uncertainty, measurement of toe-brachial index (TBI) or transcutaneous pressure of oxygen (TcPO2).
      • Schaper N.C.
      • Andros G.
      • Apelqvist J.
      • Bakker K.
      • Lammer J.
      • Lepantalo M.
      • et al.
      Specific guidelines for the diagnosis and treatment of peripheral arterial disease in a patient with diabetes and ulceration of the foot, 2011.
      Importantly these screening tools, whilst highly sensitive in the non-diabetic population, may be less efficacious in diabetes, especially in the presence of peripheral and autonomic neuropathy.
      • Williams D.T.
      • Harding K.G.
      • Price P.
      An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes.
      • Uccioli L.
      • Monticone G.
      • Durola L.
      • Russo F.
      • Mormile F.
      • Mennuni G.
      • et al.
      Autonomic neuropathy influences great toe blood pressure.
      Those patients with signs and symptoms of PAD, including claudication, rest pain, absent foot pulses, monophasic Doppler signals, ABI <0.9 or TBI <0.7 should be referred to a vascular surgeon for imaging of the vascular tree and to consider revascularisation options as part of an interdisciplinary approach. However, vascular specialists might wish to be involved in the diagnosis and management of any new patient presenting with DFU given that the majority will have PAD.
      Once a diagnosis of PAD is established, it is important to assess the severity of the perfusion deficit and what impact this may have on ulcer healing. With respect to ankle pressures, an ABI of <0.6 corresponds to a significant impairment in wound healing (Fig. 1).
      • Bakker K.
      • Apelqvist J.
      • Schaper N.C.
      Practical guidelines on the management and prevention of the diabetic foot 2011.
      A low probability of wound healing due to poor perfusion should prompt further investigations to establish the distribution of PAD.
      Figure thumbnail gr1
      Figure 1Schematic estimate of the probability of healing of foot ulcers and minor amputations in relation to ankle blood pressure, toe blood pressure, and transcutaneous oxygen pressure (TcPo2) based on selected reports. From Bakker K, Apelqvist J, Schaper NC. Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metab Res Rev, 2012;28 Suppl 1:225–31.
      Guidelines published by the National Institute for Clinical Excellence (NICE) in the UK recommend offering duplex ultrasound as first-line imaging to all people with PAD where revascularisation is being considered.
      • National Institute for Health and Clinical Excellence
      Lower limb peripheral arterial disease: diagnosis and management.
      Evaluation of the below-knee vessels is particularly important in patients with diabetes and the sensitivity of DUS for detecting a high-grade stenosis (≥50%) are 90% for the anterior and posterior tibial arteries and 82% for the peroneal artery.
      • Moneta G.L.
      • Yeager R.A.
      • Lee R.W.
      • Porter J.M.
      Noninvasive localization of arterial occlusive disease: a comparison of segmental Doppler pressures and arterial duplex mapping.
      Although DUS is non-invasive and relatively inexpensive compared with other imaging modalities, its reliability is dependent on operator expertise. The evaluation of below-knee vessels with haemodynamic parameters alone does not provide adequate information for preoperative planning, but may serve as a useful and intermediate adjunct to other, more invasive modalities.
      • Schaper N.C.
      • Andros G.
      • Apelqvist J.
      • Bakker K.
      • Lammer J.
      • Lepantalo M.
      • et al.
      Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report from the International Working Group on the diabetic foot.
      Digital subtraction angiography (DSA) remains the gold standard imaging modality for evaluating the distribution of PAD when revascularisation is planned and has the advantage of allowing simultaneous endovascular intervention. Its main drawback in patients with diabetes and a high prevalence of renal insufficiency is the risk of contrast-induced nephropathy. As a precaution, patients with renal impairment should receive peri-procedural intravenous volume expansion and metformin should be stopped prior to DSA as it may cause a lactic acidosis.
      • Heikkinen M.
      • Salmenpera M.
      • Lepantalo A.
      • Lepantalo M.
      Diabetes care for patients with peripheral arterial disease.
      The visualization of pedal vessels with DSA may be limited in patients with severe occlusive disease, where the concentration of contrast falls short of the sensitivity threshold. In such instances, a hand-held Doppler probe can be useful in unmasking pedal target arteries not visible on DSA.
      Contrast-enhanced magnetic resonance angiography (CE-MRA) is a low-invasive modality capable of imaging calcified vessels without artifact and avoids the need for nephrotoxic iodinated contrast. Temporally resolved hybrid CE-MRA using an aortoiliac and femoral bolus-chase achieves the best diagnostic performance. In a study of patients with diabetes, the sensitivity and specificity for time-resolved CE-MRA of crural vessels was 79% and 90% respectively.
      • Andreisek G.
      • Pfammatter T.
      • Goepfert K.
      • Nanz D.
      • Hervo P.
      • Koppensteiner R.
      • et al.
      Peripheral arteries in diabetic patients: standard bolus-chase and time-resolved MR angiography.
      Disadvantages of MRA include limited spatial resolution and a relative contraindication for the use of gadolinium in patients with severe renal insufficiency (creatinine clearance <30 ml/min), which has been linked to the development of nephrogenic systemic fibrosis.

      US Food and Drug Administration, Center for Drug Evaluation and Research, Public Health Advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm.

      In addition, the occurrence of stent artefacts in MRA limit its use for the detection of in-stent stenosis.
      Computed tomography angiography (CTA) should be offered where MRA is contraindicated,
      • National Institute for Health and Clinical Excellence
      Lower limb peripheral arterial disease: diagnosis and management.
      and has several advantages over MRA with respect to the speed of examination and spatial resolution. It is limited by image interference from calcified arteries, which can make interpretation difficult. A systematic review comparing sensitivity and specificity of DUS, contrast enhanced MRA and multidetector-row CTA reported similar accuracies across these modalities for detecting high-grade stenoses above and below the knee.
      • Collins R.
      • Burch J.
      • Cranny G.
      • Aguiar-Ibáñez R.
      • Craig D.
      • Wright K.
      • et al.
      Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: a systematic review.

      Revascularisation

      Data from the EURODIALE Study (a prospective study of newly presenting patients with DFU to 14 experienced European diabetic foot centres) would seem to suggest that many patients are not having vascular imaging nor being considered for revascularisation.
      • Prompers L.
      • Huijberts M.
      • Apelqvist J.
      • Jude E.
      • Piaggesi A.
      • Bakker K.
      • et al.
      Delivery of care to diabetic patients with foot ulcers in daily practice: results of the Eurodiale study, a prospective cohort study.
      Of those patients with severe ischaemia (ABPI <0.5) appropriate vascular imaging was performed in just 56%, and only 43% of those imaged were revascularised. It is quite possible that the picture is even bleaker for patients outside specialist centres. Retrospective review of the Eurodiale data suggests there are various reasons why revascularisation was not performed, including spontaneous wound healing, poor clinical condition of the patient or surgeon preference.
      The decision to revascularise the ulcerated foot is complex. Multiple factors influence wound healing in diabetes in addition to PAD. Patients with mild PAD and adequate perfusion measurements (ABI ≥0.6, TcPO2 >50 mmHg) should be initially managed with optimal wound care (debridement, treatment of infection and off-loading) and a 6-week period of observation. There is level II evidence to suggest the healing response to ‘best medical therapy’ during this period gives a good indication as to the adequacy of perfusion.
      • Sheehan P.
      • Jones P.
      • Caselli A.
      • Giurini J.M.
      • Veves A.
      Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial.
      In large ulcers and in those with the combination of PAD and infection, the expected outcome of conservative treatment is poor (level I evidence) and earlier vascular intervention may be required. If it is felt that PAD is contributing towards impaired wound healing then patients, if ambulatory, should be considered for revascularisation with the exception of the severely frail or functionally impaired and those with an unsalvageable foot. Importantly, where PAD is likely to compromise healing of a major amputation wound, interventions to optimize inflow should be considered.
      Revascularisation in patients with diabetes can be technically difficult by virtue of the distal distribution of disease, impaired collateral formation and vessel calcification. Data pooled by the IWGDF from 19 studies of patients with DFU and PAD showed a median limb salvage rate of 85% at 1-year.
      • Hinchliffe R.J.
      • Andros G.
      • Apelqvist J.
      • Bakker K.
      • Fiedrischs S.
      • Lammer J.
      • et al.
      A systematic review of the effectiveness of revascularisation of the ulcerated foot in patients with diabetes and peripheral arterial disease.
      Half of patients with DFU and PAD can expect to be alive at 5-years and mortality rises to 50% in 2-years following a major amputation.
      • Moulik P.K.
      • Mtonga R.
      • Gill G.V.
      Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology.
      Patients with co-existing chronic kidney disease (CKD) fare worse and the severity of CKD has been shown to correspond with poor outcomes and mortality following revascularisation.
      • Owens C.D.
      • Ho K.J.
      • Kim S.
      • Schanzer A.
      • Lin J.
      • Matros E.
      Refinement of survival prediction in patients undergoing lower extremity bypass surgery: stratification by chronic kidney disease classification.
      There are no randomized trial data comparing surgical bypass and endovascular interventions in selected patients with diabetes or infrageniculate disease, however, in patients with diabetes and an ischaemic foot ulcer, these techniques appear to offer equivalent outcomes where revascularisation is successful.
      • Albers M.
      • Romiti M.
      • Brochado-Neto F.C.
      • De Luccia N.
      • Braganca Pereira C.A.
      Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischaemia.
      • Romiti M.
      • Albers M.
      • Brochado-Neto F.C.
      • Durazzo A.E.S.
      • Braganca Pereira C.A.
      • De Luccia N.
      Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischaemia.
      The BASIL trial,
      • Adam D.J.
      • Berad J.D.
      • Cleveland T.
      • Bell J.
      • Bradbury A.W.
      • Forbes J.F.
      • et al.
      Bypass or angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomized controlled trial.
      which randomized patients with severe limb ischaemia (rest pain or tissue loss for >2 weeks) to bypass or balloon-angioplasty, demonstrated similar outcomes in terms of health-related quality of life and amputation-free survival, although less than half of randomized patients had diabetes and no sub-group analyses were performed. Endovascular techniques performed under local anaesthesia are lower-risk than bypass surgery and cost considerably less; however, an increased re-intervention rate following angioplasty in the BASIL trial reduced any overall cost difference.
      • Forbes J.F.
      • Adam D.J.
      • Bell J.
      • Fowkes F.G.
      • Gillespie I.
      • Raab G.M.
      • et al.
      Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis.
      Data from the BASIL trial suggest they are also associated with lower short-term morbidity and, as such, endovascular therapy is probably justified as the initial approach to restoring perfusion. Surgical bypass has the advantage of increased durability when autologous vein is used but patients with multiple comorbidities and a short life expectancy (6–12 months) are unlikely to realize this benefit.
      The distal distribution of PAD in diabetes has brought about innovation and development in both endovascular techniques and open bypass surgery. Distal endovascular interventions and distal origin bypass grafts arising from the SFA, popliteal or crural vessels show good outcomes in selected patients. Identifying the optimal artery for angioplasty or run-off vessel for bypass requires careful scrutiny of anatomic and haemodynamic factors and some authors advocate revascularisation based on the angiosome model of perfusion, where the target artery corresponds to the area of tissue loss.
      • Neville R.F.
      • Attringer C.E.
      • Bulan E.J.
      • Ducic I.
      • Thomassen M.
      • Sidawy A.N.
      Revascularization of a specific angiosome for limb salvage: does the target artery matter?.
      It is important to note that angiosomes are a representation of normal anatomy and changes to the collateral circulation that result from PAD mean the success of this technique in reconstructive surgery will not necessarily extrapolate to revascularization in cases of DFU. The available evidence for the angiosome concept is limited, but it does seem a logical step to achieve healing in diabetic foot ulcers. In a series of patients with DFU treated by angiosome-guided endovascular techniques, rates of limb salvage and healing at 1-year were encouraging, at 91% and 85% respectively.
      • Alexandrescu V.
      • Hubermont G.
      • Philips Y.
      • Guillaumie B.
      • Ngongang C.
      • Vandenbossche P.
      • et al.
      Selective angioplasty following an angiosome model of reperfusion in the treatment of Wagner 1–4 diabetic foot lesions: practice in a multidisciplinary diabetic limb service.
      Interestingly, a meta-analysis of 31 studies reporting results of popliteal to distal vein bypasses has demonstrated greater limb salvage rates than corresponding patency data.
      • Albers M.
      • Romiti M.
      • Brochado-Neto F.C.
      • De Luccia N.
      • Braganca Pereira C.A.
      Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischaemia.
      Primary patency at 1 and 5-years was 82% and 63% respectively with corresponding foot salvage rates of 89% and 78%. This observation suggests that long-term graft patency is not always necessary for a successful outcome in patients with diabetes, providing that wound healing precedes graft failure.
      A meta-analysis of crural angioplasty performed by the same group reported comparable limb salvage rates of 93% and 82% at 1 and 36 months respectively.
      • Romiti M.
      • Albers M.
      • Brochado-Neto F.C.
      • Durazzo A.E.S.
      • Braganca Pereira C.A.
      • De Luccia N.
      Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischaemia.
      As with surgical bypass, long term patency is less relevant, providing wound healing is achieved following an intervention. The development of drug-eluting stents and balloons offers the potential to reduce rates of re-stenosis following endovascular therapy, however, there is currently insufficient evidence to support the use of these devices in patients with DFU. Some contemporary series report a combined surgical and endovascular approach to the problem of inflow disease
      • Schneider P.A.
      • Caps M.T.
      • Ogawa D.Y.
      • Hayman E.S.
      Intraoperative superficial femoral artery balloon angioplasty and popliteal to distal bypass graft: an option for combined open and endovascular treatment of diabetic gangrene.
      which may be most useful in patients with concomitant SFA and distal arterial occlusive disease. A hybrid approach is particularly attractive in patients with limited availability of vein conduit, which may otherwise necessitate the use of prosthetic grafts. We expect that both endovascular and bypass techniques will remain widely used and complementary in the foreseeable future.

      Prevention of Ulceration/Screening

      Foot examination focussing on the presence of peripheral neuropathy, PAD and abnormal foot anatomy can predict risk of developing a diabetic foot ulcer.
      • Abbott C.A.
      • Carrington A.L.
      • Ashe H.
      • Bath S.
      • Every L.C.
      • Griffiths J.
      • et al.
      The north-west diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based cohort.
      • Monteiro-Soares M.
      • Boyko E.J.
      • Ribiero J.
      • Ribiero I.
      • Dinis-Ribiero M.
      Risk stratification systems for diabetic foot ulcers: a systematic review.
      Diverse risk stratification systems exist incorporating these and additional risk factors, although none has been universally adopted (Table 1). In a Scottish study which stratified foot ulcer risk in 3526 patients with diabetes, foot ulceration was 83 times more common in high-risk patients, compared with low-risk patients.
      • Leese G.P.
      • Reid F.
      • Green V.
      • McAlpine R.
      • Cunningham S.
      • Emslie-Smith A.M.
      • et al.
      Stratification of foot ulcer risk in patients with diabetes: a population-based study.
      During a mean follow-up duration of 1.7 years, the risk of foot ulceration was 0.36% in low-risk patients (64% of the population), 2.3% in moderate-risk patients and 29.4% in high-risk patients. The negative predictive value of a low-risk score may be useful in directing the resources of specialized foot clinics towards the minority of patients at medium- or high-risk.
      Table 1Variables included in the diverse stratification systems.
      Adapted from Monteiro-Soares M, Boyko EJ, Ribeiro J, Ribeiro I, Dinis-Ribeiro M. Risk stratification systems for diabetic foot ulcers: a systematic review. Diabetologia 2011;54:1190–1199.
      StratificationVariables
      DNPADFoot deformityPrevious ulcerPrevious amputationVisual impairment
      UTFRS
      • Nabuurs-Franssen M.H.
      • Huijberts M.S.
      • Nieuwenhuijzen Kruseman A.C.
      • Willems J.
      • Schaper N.C.
      Health-related-quality-of-life of diabetic foot ulcer patients and their caregivers.
      IWGDF
      • Jeffcoate W.J.
      • Chipchase S.Y.
      • Ince P.
      • Game F.L.
      Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures.
      SIGN
      • Abbott C.A.
      • Carrington A.L.
      • Ashe H.
      • Bath S.
      • Every L.C.
      • Griffiths J.
      • et al.
      The north-west diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based cohort.
      ADA
      • Lawall H.
      • Bramlage P.
      • Amann B.
      Stem cell and progenitor cell therapy in peripheral arterial disease.
      Boyko et al.
      • Lu D.
      • Chen B.
      • Liang Z.
      • Deng W.
      • Jiang Y.
      • Li S.
      • et al.
      Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischaemia and foot ulcer: a double blind, randomized, controlled trial.
      UTFRS: University of Texas Foot Risk Stratification; IWGDF: International Working Group on the Diabetic Foot; SIGN: Scottish Intercollegiate Guideline Network; ADA: American Diabetes Association; DN: diabetic neuropathy; PAD: peripheral arterial disease.
      Primary care physicians in the UK undertake annual foot checks and stratify patients with diabetes according to their risk of ulceration, however, the effectiveness of screening programmes and complex interventions (education, podiatry, orthoses) in reducing both the risk of foot ulceration and mortality is difficult to confirm.
      • Jeffcoate W.J.
      Stratification of foot risk predicts the incidence of new foot disease, but do we yet know that the adoption of routine screening reduces it?.
      • Dorresteijn J.A.N.
      • Kriegsman D.M.W.
      • Valk G.D.
      Complex interventions for preventing diabetic foot ulceration.
      While the evidence for specific interventions is sparse, it is clear that patients with an established diabetic foot ulcer benefit from prompt recognition and early referral to a limb salvage team. Following the introduction of a multidisciplinary foot team at Ipswich hospital, UK, Krishnan et al. observed a 62% reduction in major amputations in a catchment general population.
      • Krishnan S.
      • Nash F.
      • Baker N.
      • Fowler D.
      • Rayman G.
      Reduction in diabetic amputations over 11 years in a defined UK population: benefits of multidisciplinary work and continuous prospective audit.
      Larger ulcers are more difficult to manage hence the need for early identification and intervention; data from another established foot clinic demonstrated a direct relationship between cross-sectional area (and ulcer duration) at first assessment and time to healing.
      • Ince P.
      • Game F.L.
      • Jeffcoate W.J.
      Rate of healing of neuropathic ulcers of the foot in diabetes and its relationship to ulcer duration and ulcer area.
      Despite the prognostic performance of neuropathy and PAD in predicting ulceration, a risk stratification tool that uses routinely available demographic and clinical data would be more practical on a population level. The training required for accurate clinical assessment of PAD and neuropathy may not be feasible outside well-resourced settings. Reallocating resources towards evidence based multidisciplinary foot clinics may offer a better alternative to primary care-led screening.

      Medical Optimization

      DM is recognized as a key risk factor for the development of cardiovascular disease (CVD) and mortality from CVD causes is ≈2-fold higher compared with individuals without DM.
      • Preis S.R.
      • Hwang S.J.
      • Coady S.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      • Savage P.J.
      • et al.
      Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham heart study, 1950 to 2005.
      Recent evidence suggests that a history of foot ulceration may increase this risk further still, showing excess all-cause mortality in patients with DFU, compared with patients with diabetes without a history of DFU.
      • Brownrigg J.R.W.
      • Davey J.
      • Holt P.J.
      • Davis W.A.
      • Thompson M.M.
      • Ray K.K.
      • et al.
      The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis..
      Accordingly, the benefits of CVD risk modification in reducing morbidity and mortality have been shown in populations with diabetes and DFU.
      The Steno-2 study randomized patients with type 2 diabetes and persistent microalbuminaemia to intensive CV risk management, which corresponded to an absolute risk reduction for all-cause mortality of 20% after a mean follow up of 13.3 years (7.8 years of multifactorial intervention and an additional 5.5 years of follow-up).
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of multifactorial intervention on mortality in type 2 diabetics.
      Participants were selected for the presence of microalbuminuria which is associated with microvascular disease and therefore neuropathy and ulceration, and is itself a strong predictor of CV events.
      • Dinneen S.F.
      • Gerstein H.C.
      The association of microalbuminuria and mortality in non-insulin dependent diabetes mellitus.
      • Agewall S.
      • Wikstrand J.
      • Ljungman S.
      • Fagerberg B.
      for the Risk Factor Intervention Study Group
      Usefulness of microalbuminuria in predicting cardiovascular mortality in treated hypertensive men with and without diabetes mellitus.
      In the setting of patients with DFU, Young et al. reported improved survival of patients treated with intensive CV risk modification.

      Young MJ, McCardle JE, Randall LE, Barclay JI. Improved survival of diabetic foot ulcer patients 1995–2008. Possible impact of aggressive cardiovascular risk management. 2008;31:2143–7.

      In a foot clinic population, 5-year mortality fell from 48% to 27% following introduction of a protocol incorporating CV risk screening and administration of an antiplatelet agent, statin and antihypertensive where indicated (level II evidence).
      No direct evidence supports a role for tight glycaemic control in preventing ulceration, although epidemiological data suggests that optimizing blood glucose levels can prevent peripheral neuropathy and PAD in patients with diabetes. In the UK Prospective Diabetes Study, a reduction in HbA1C of 1% was associated with a reduction in risk of 43% for amputation or death from PAD.
      • Stratton I.M.
      • Adler A.I.
      • Neil H.A.W.
      • Matthews D.R.
      • Manley S.E.
      • Cull C.A.
      • et al.
      Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
      Similarly, there are no data to support aggressive glycaemic control to aid healing in active ulceration; however this is also likely to be important, not least because raised blood glucose encourages infection. Strict glycaemic control will increase the risk of hypoglycaemic attacks and weight gain in some patients. In the majority of frail and elderly patients with DFU, less intensive glycaemic goals are probably indicated, with target blood glucose levels between 6 and 10 mmol/l.

      Ulcer/Wound Management and Dressings

      The quality of published reports supporting the use of local interventions in DFU is poor but some principles guiding foot care can be derived from the available literature.
      • Hinchliffe R.J.
      • Valk G.D.
      • Apelqvist J.
      • Armstrong D.G.
      • Bakker K.
      • Game F.L.
      • et al.
      A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
      • Game F.L.
      • Hinchliffe R.J.
      • Apelqvist J.
      • Armstrong D.G.
      • Bakker K.
      • Hartemann A.
      • et al.
      A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
      The cornerstone of early management in neuropathic ulcers is offloading pressure with appropriate footwear, removable devices or total contact casts (TCCs). The efficacy of prescribed footwear and removable devices is dependent on patient compliance and, probably for this reason, the TCC has demonstrated superior results in randomized trials,
      • Armstrong D.G.
      • Nguyen H.C.
      • Lavery L.A.
      • van Schie C.H.M.
      • Boulton A.J.M.
      • Harkless L.B.
      Offloading the diabetic foot: a randomized clinical trial.
      and is recommended by the IWGDF as first-choice treatment.
      • Bus S.A.
      • Valk G.D.
      • van Deursen R.W.
      • Armstrong D.G.
      • Caravaggi C.
      • Hlaváček P
      • et al.
      The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review.
      A perception of increased risk of falls with TCCs appears to be unfounded.
      • Armstrong D.G.
      • Nguyen H.C.
      • Lavery L.A.
      • van Schie C.H.M.
      • Boulton A.J.M.
      • Harkless L.B.
      Off-loading the diabetic foot wound. A randomized clinical trial.
      • Armstrong D.G.
      • Lavery L.A.
      • Wu S.
      • Boulton A.J.M.
      Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds. A randomized controlled trial.
      Despite all this, only 18% of approximately 600 patients with a plantar foot ulcer in the Eurodiale study were treated with TCCs.
      • Prompers L.
      • Huijberts M.
      • Apelqvist J.
      • Jude E.
      • Piaggesi A.
      • Bakker K.
      • et al.
      Delivery of care to diabetic patients with foot ulcers in daily practice: results of the Eurodiale study, a prospective cohort study.
      Callus formation contributes to abnormal loading and failure to heal, and debridement should be routinely provided by trained podiatrists. Evidence suggests that removal of calluses is beneficial for reducing plantar pressures,
      • Pitei D.L.
      • Foster A.
      • Edmonds M.
      The effect of regular callus removal on foot pressures.
      • Young M.J.
      • Cavanagh P.R.
      • Thomas G.
      • Johnson M.M.
      • Murray H.
      • Boulton A.J.
      The effect of callus removal on dynamic plantar foot pressures in diabetic patients.
      although this has yet to be confirmed in randomized trials.
      Despite their widespread use there is a paucity of evidence to support the use of topical therapies for diabetic foot ulcers. In agreement with the conclusions of an earlier Cochrane review,
      • Bergin S.
      • Wraight P.
      Silver based wound dressings and topical agents for treating diabetic foot ulcers.
      the IWGDF identified no good quality randomized controlled trials (RCTs) reporting healing rate or infection outcomes from which to produce clinical guidelines.
      • Hinchliffe R.J.
      • Valk G.D.
      • Apelqvist J.
      • Armstrong D.G.
      • Bakker K.
      • Game F.L.
      • et al.
      A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.
      The application of factors which aim to promote healing by altering cell biology have failed to demonstrate consistent efficacy and there is insufficient evidence to justify the use of these expensive agents in routine practice. Bioengineered skin grafts have demonstrated favourable results in a prospective RCT involving more than 300 patients receiving a dermal fibroblast culture
      • Marston W.A.
      • Hanft J.
      • Norwood P.
      • Pollak R.
      The efficacy and safety of dermagraft in improving the healing of chronic diabetic foot ulcers. Results of a prospective randomized trial.
      A greater proportion of patients receiving the bioengineered skin achieved complete healing at 12 weeks (30% vs 18%) compared with conventional therapy (dressings, offloading footwear and debridements), however the healing rates in the control group were lower than expected. Although negative pressure wound therapy (NPWT) is widely used in the treatment of chronic wounds, much of the supporting evidence is based on industry funded trials and unpublished data are largely inaccessible.

      Pienemann F, McGauran N, Sauerland S, Lange S. Negative pressure wound therapy: potential publication bias caused by lack of access to unpublished study results data. BMC Med Res Methodol;8:4.

      One well-designed, industry supported RCT of 342 patients with an ulcer >2 cm2 reported promising outcomes.
      • Blume P.A.
      • Walters J.
      • Payne W.
      • Ayala J.
      • Lantis J.
      Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers.
      NPWT was associated with reduced time to wound closure, increased incidence of healing by 16 weeks and reduced incidence of minor amputation. Further study is, however, needed to justify the use of NPWT in routine clinical practice. The evidence to support the use of a particular dressing or topical therapy for the ulcer bed is thin. Providing a comprehensive environment to improve healing with antibiotics, debridement and offloading is superior to the use of a novel, and often expensive, dressing. It is what you take off the wound and not what you put on it that counts.

      Infection/Antibiotics

      The risk of infection in the diabetic foot increases with the presence of PAD, recurrent or chronic wounds and those penetrating to bone.
      • Lavery L.A.
      • Armstrong D.G.
      • Wunderlich R.P.
      • Mohler J.
      • Wendel C.S.
      • Lipsky B.A.
      Risk factors for foot infections in individuals with diabetes.
      The majority of infections are contained within the soft tissue, but around a fifth involve underlying bone (osteomyelitis) which is associated with a worse outcome. The diagnosis of diabetic foot infection is based on clinical findings; superficial wound cultures are not useful and should not be treated, as bacterial colonization appears to be ubiquitous in diabetic foot ulcers. Bone biopsy for histopathology and culture remains the “gold standard” for diagnosing osteomyelitis, yet unfortunately this procedure is not routinely performed in clinical practice.
      • Lipsky B.A.
      • Peters E.J.G.
      • Senneville E.
      • Berendt
      • Embil J.M.
      • Lavery L.A.
      • et al.
      Expert opinion on the management of infections in the diabetic foot.
      Infection of a foot ulcer can be a major threat to limb and life and should be treated promptly. The IWGDF has produced guidelines for the treatment of diabetic foot infections based on the severity of infection,
      • Bakker K.
      • Apelqvist J.
      • Schaper N.C.
      Practical guidelines on the management and prevention of the diabetic foot 2011.
      which predicts amputation. Ulcers with superficial infection should be treated with debridement and oral antibiotics aimed at Staphylococcus aureus and streptococci. Targeted therapy against gram positive cocci has been shown to be equally effective as broader spectrum regimens (level I evidence),
      • Lipsky B.A.
      • Itani K.
      • Norden C.
      Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin sulbactam/amoxicillin-clavulanate.
      even in the presence of osteomyelitis which will respond to antimicrobial therapy in most cases. Deep infection, characterized by purulent discharge or fullness in the plantar space,
      • Boulton A.J.
      • Meneses P.
      • Ennis W.J.
      Diabetic foot ulcers: a framework for prevention and care.
      necessitates urgent debridement of necrotic tissue including infected bone, and revascularisation if indicated. Intravenous broad-spectrum antibiotics should target Gram-positive and negative micro-organisms, including anaerobes. Signs of life and limb threatening infection include bullae, ecchymoses, soft tissue crepitus and rapid spread of infection.
      • Eneroth M.
      • Larsson J.
      • Apelqvist J.
      Deep foot infections in patients with diabetes and foot ulcer: an entity with different characteristics, treatments, and prognosis.
      In the Eurodiale cohort, investigators observed a markedly negative impact of infection on ulcer healing that was confined to patients with PAD. These findings emphasize the need for studies comparing different antibiotic regimens in PAD and for those investigating the effects of early revascularisation on control of infection.
      • Prompers L.
      • Schaper N.
      • Apelqvist J.
      • Edmonds M.
      • Jude E.
      • Mauricio D.
      • et al.
      Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The Eurodiale study.

      Classification and Outcomes (Reporting)

      In studies of outcome following lower limb revascularisation for critical limb ischaemia (CLI), patients with and without diabetes are typically reported as one group. The unique characteristics of PAD in diabetes, in its distribution and presentation, make it difficult to extrapolate clinical significance from data on unselected patients. Additionally, CLI remains a problematic definition in patients with diabetes as symptoms of ischaemic pain (claudication, rest pain) may be masked by the presence of distal symmetric polyneuropathy, and ulceration may develop with very mild PAD of little haemodynamic significance. In contrast, patients without diabetes are unlikely to develop tissue loss in the absence of a severe perfusion deficit. A haemodynamic classification of PAD using ankle brachial index (ABI), toe pressures or transcutaneous oxygen tension is more useful in patients with diabetes with the caveat that ABIs may be falsely elevated due to arterial calcification and have a poor predictive value. Patients with diabetes need to be identified as an important subgroup in the PAD literature to allow pooling of results for systematic review and meta-analysis.
      Several angiographic classification schemes exist to describe the anatomical distribution of disease in patients with PAD. The limitations of the currently available schemes may, in part, explain the poor reporting of PAD distribution in the literature. The Trans-Atlantic Inter-Society Consensus (TASC) guidelines classify femoral popliteal lesions based on their anatomical distribution,
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.R.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      however, the classification of infrapopliteal lesions is not specifically addressed. This is significant given that the patency of the outflow artery is critical in determining the success of arterial bypass, and this is especially true in diabetes where run-off is more likely to be poor. The Bollinger score,
      • Bollinger A.
      • Breddin K.
      • Hess H.
      • Heystraten F.M.
      • Kollath J.
      • Konttila A.
      • et al.
      Semi-quantitative assessment of lower limb atherosclerosis from routine angiographic images.
      • Bradbury A.W.
      • Adam D.J.
      • Bell J.
      • Forbes J.F.
      • Fowkes F.G.
      • Gillespie I.
      • et al.
      Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: a description of the severity and extent of disease using the Bollinger angiogram scoring method and the TransAtlantic inter-society consensus II classification.
      albeit more cumbersome clinically, describes the infrapopliteal arterial segments in some detail and is advantageous in this respect. In the BASIL trial, below knee Bollinger scores were significantly greater in patients presenting with tissue loss; however the same difference in above knee scores was not significant. Interestingly there was a negative correlation between mean above and below knee Bollinger scores, suggesting that the TASC score, in its current form, may underestimate disease severity in a cohort of patients with diabetes and relative sparing of the above knee arterial segments.
      Several validated scoring systems have been developed for use in diabetic foot ulcers. These include the University of Texas Wound Classification system and the Size (Area and Depth), Sepsis, Arteriopathy, and Denervation (S(AD)SAD) score,
      • Armstrong D.G.
      • Lavery L.A.
      • Harkless L.B.
      Validation of a diabetic wound classification system: the contribution of depth, infection, ischemia to risk of amputation.
      • Macfarlane R.M.
      • Jeffcoate W.J.
      Classification of diabetic foot ulcers. The S(AD) SAD system.
      the latter of which has been prospectively validated in different ethnic groups and is a reliable predictor of healing.
      • Ince P.
      • Abbas Z.G.
      • Lutale J.K.
      • Basit A.
      • Ali S.M.
      • Chohan F.
      • et al.
      Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents.
      The PEDIS score of the International Working Group on the Diabetic Foot (IWDGF) was developed for research purposes,
      • Schaper N.C.
      Classification of diabetic foot ulcers for research purposes.
      but the grading of infection in this system according to its severity is also advocated for clinical use as it predicts outcome.
      • Lavery L.A.
      • Armstrong D.G.
      • Murdoch D.P.
      • Peters E.J.
      • Lipsky B.A.
      Validation of the infectious diseases society of America's diabetic foot infection classification system.
      A universal classification system of diabetic foot ulcers would enable consistent reporting among studies in DFU to guide the development of novel therapies while increasing the external validity of research in this field and allowing fair comparison between centres.
      • Karthikesalingham A.
      • Holt P.J.E.
      • Moxey P.
      • Jones K.G.
      • Thompson M.M.
      • Hinchliffe R.J.
      A systematic review of scoring systems for diabetic foot ulcers.
      To this end the European Wound Management Association (EMWA) has produced a set of recommendations for standardized reporting of outcomes in studies of wound management.
      • Gottrup F.
      • Apelqvist J.
      • Price P.
      Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management.
      Clearly there will be some overlap with the Society for Vascular Surgery standard reporting criteria for the lower limb ischaemia,
      • Rutherford R.B.
      • Baker J.D.
      • Ernst C.
      • Johnston K.W.
      • Porter J.M.
      • Ahn S.
      • et al.
      Recommended standards for reports dealing with lower extremity ischaemia: revised version.
      although some important outcomes may be distinct. Ulcer healing has been shown to be of particular importance to patients with diabetes and is associated with improvements in health-related quality of life (HRQOL).
      • Hogg F.R.A.
      • Peach G.
      • Price P.
      • Thompson M.M.
      • Hinchliffe R.J.
      Measures of health-related quality of life in diabetes-related foot disease: a systematic review.
      One study demonstrated improvements in QOL in both the patient and caregiver following ulcer healing.
      • Nabuurs-Franssen M.H.
      • Huijberts M.S.
      • Nieuwenhuijzen Kruseman A.C.
      • Willems J.
      • Schaper N.C.
      Health-related-quality-of-life of diabetic foot ulcer patients and their caregivers.
      In a study of 449 patients with an index diabetic foot ulcer, Jeffcoate et al. demonstrated how the use of ulcer-related endpoints may underestimate morbidity and mortality in this cohort.
      • Jeffcoate W.J.
      • Chipchase S.Y.
      • Ince P.
      • Game F.L.
      Assessing the outcome of the management of diabetic foot ulcers using ulcer-related and person-related measures.
      At 12 months, ulcer healing without amputation was achieved in 65.7% whereas only 45% of patients were alive, without amputation and ulcer free. The authors suggest that ulceration free survival may merit further exploration as an outcome measure in diabetic foot disease. The balance of risk and benefit for interventions in diabetic foot disease is probably best assessed through a combination of defined clinical endpoints including mortality, amputation-free survival, healing and re-ulceration with patient-reported outcome measures.

      Future Perspectives

      Better selection of patients for revascularisation procedures will rely on improvements in the reporting of outcome in diabetic foot disease. Whilst new data on the impact of revascularisation are awaited, there are encouraging developments in other treatment modalities, including stem cell and progenitor cell therapy. As discussed previously, PAD is present in around half of patients with DFU. The impact of PAD on wound healing is compounded by impaired formation of new capillaries (angiogenesis) and proliferation of pre-existing micro-vessels into collateral arteries (arteriogenesis) in patients with diabetes. Stimulation of angiogenesis and arteriogenesis represent attractive approaches in DFU and there is accumulating evidence to confirm their efficacy in the treatment of critical limb ischaemia.
      • Lawall H.
      • Bramlage P.
      • Amann B.
      Stem cell and progenitor cell therapy in peripheral arterial disease.
      Pooled data from studies of autologous bone marrow mononuclear cell (BMMNC) therapy in patients with PAD show increases in ABI values between 0.1 and 0.2 points, TcPO2 increases between 10 and 20 mmHg O2 and improvements in walking distances. Although data in selected populations with DFU are limited, one study in China demonstrated improved ulcer healing rates with BMMNCs and bone marrow mesenchymal stem cells compared with controls.
      • Lu D.
      • Chen B.
      • Liang Z.
      • Deng W.
      • Jiang Y.
      • Li S.
      • et al.
      Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischaemia and foot ulcer: a double blind, randomized, controlled trial.
      Further research should clarify the role of cell therapies in DFU.

      Conclusions

      The present review underlines the difficulty in diagnosing PAD in patients with diabetes and the importance of referring those presenting with a new foot ulcer to a multidisciplinary team, which includes vascular surgeons and interventional radiologists. Interventions should aim not only to preserve limb, but also attenuate the excess mortality observed in patients with diabetic foot disease; there is likely an unmet potential for CVD prevention in this cohort.
      The role of population based screening to identify those at risk of developing ulceration remains unclear and the evidence for interventions in this high risk population derives from studies of poor methodological quality. The development of future clinical guidelines will rely on selective reporting of relevant outcomes in patients with diabetes following lower limb revascularisation. Patients with diabetes represent a distinct and important sub-group because they behave differently to non-diabetics in almost all respects.

      Conflict of Interest/Funding

      None.

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