Peripheral arterial disease and diabetes

General introduction

In 2007 the IWDGF produced a consensus document on peripheral arterial disease (PAD) in diabetes. In recent years new techniques and technologies have been introduced in treating PAD, which might be relevant for the patient with diabetes and a poorly healing ischemic foot ulcer. The editorial board of International Working Group on the Diabetic Foot (IWDGF) therefore established in 2009 a multidisciplinary working group. This working group included specialists in vascular surgery, interventional radiology, cardiology, internal medicine and epidemiology on the diagnosis and treatment of PAD in diabetic patients with a foot ulcer. The aims of this multidisciplinary working group was to produce a systematic review on the efficacy of revascularization procedures in diabetic patients with a foot ulcer and PAD. This document was approved by all representatives of the IWDGF in 2011. Moreover a short progress report on diagnosis and prognosis was produced by the working group. Based on these documents the working group formulated specific guidelines. In this electronic document of the IWDGF the following texts on diabetes and PAD can be found:

    Peripheral arterial disease and diabetes: International Consensus 2007 A Systematic Review of the Effectiveness of Revascularization of the Ulcerated Foot in Patients with Diabetes and Peripheral Arterial Disease (2011). Diagnosis and treatment of PAD in the diabetic patient with a foot ulcer. A progress report (2011).
    In this document the IWDGF working group on PAD and diabetes gives an updated overview on the management of a patient with diabetes and a foot ulcer, based on the above described systematic review and supplemented with expert opinions.
    Specific guidelines on diagnosis and treatment of PAD in the diabetic patient with a foot ulcer (2011).

I. Peripheral arterial disease and diabetes: International Consensus 2007

Contents

    Key messages Introduction Characteristics Pathophysiology Symptoms Identifying PAD Chronic critical ischaemia Non-invasive vascular investigation Treatment Further reading Peripheral vascular disease Angioplasty Bypass surgery

1. Key messages

  • Peripheral arterial disease (PAD) is the most important factor relating to the outcome of a diabetic foot ulcer.
  • PAD often can be recognized by simple clinical examination: colour and temperature of the skin, palpation of pedal pulses, ankle blood pressure measurement.
  • The probability of a diabetic foot ulcer healing can be estimated using non-invasive vascular tests. Ankle, and occasionally, toe blood pressure readings may be falsely elevated due to medial sclerosis.
  • Rest pain due to ischaemia may be absent in people with diabetes - probably due to peripheral neuropathy.
  • Micro-angiopathy should never be accepted as the primary cause of an ulcer.
  • Conservative approaches should involve a walking programme (if no ulcer or gangrene is present), appropriate footwear, cessation of smoking, and aggressive treatment of hypertension and dyslipidaemia.
  • Patency rates and limb-salvage rates after revascularization do not differ between people with or without diabetes. Therefore, diabetes is not a reason to withhold this treatment.

The management of foot disease in diabetes remains a major therapeutic challenge throughout the world. The International Working Group of the Diabetic Foot (IWGDF) has issued guidelines on management since 1999, but good evidence is still required to substantiate the roles of particular interventions.

It is for this reason that from 2005 the IWGDF established working groups to undertake a series of systematic reviews into aspects of prevention and management of foot disease, including off-loading [1], osteomyelitis [2] and chronic ulceration [3]. At the invitation of the IWGDF Editorial Board the IWGDF working group on wound healing has already started six years ago therefore to undertake a systematic review of the evidence in order to inform protocols for routine care and to highlight areas which should be considered for further study. This evidence-based guideline was developed by a multidisciplinary group of clinicians and scientists working in the field of wound healing for the diabetic foot. The working group had worked on it between November 2005 and May 2007 to select the interventions of interest, discuss the methodology of literature search and grading, carry out the methodological assessment of the literature, agree on the results, and wrote the guideline, which was approved by the IWGDF Editorial board and launched at the 5th International Symposium on the Diabetic Foot in 2007. The documents were published in 2008[3]. The same working group reports now on papers published since 2006 on the interventions to improve the healing of chronic ulcers.

2. Introduction

Peripheral arterial disease (PAD) causing arterial insufficiency is the most important factor relating to the outcome of a diabetic foot ulcer. In people with diabetes, atherosclerosis and medial sclerosis are the most common arterial diseases. Atherosclerosis causes ischaemia by arterial narrowing and blockage. Medial sclerosis (Moenckeberg sclerosis) is calcification of the tunica media producing rigid conduit arteries - without encroachment on the arterial lumen. Thus medial sclerosis, which is frequently associated with neuropathy, does not cause ischaemia, but the rigid arterial tube may severely interfere with indirect measurement of arterial blood pressure. Finally, micro-angiopathy should not be accepted as the primary cause of a skin lesion.

3. Characteristics

The prevalence of PAD in people with diabetes is probably high, and ranges from 10% to 40% depending on the definition used; in patients with foot ulcers 50% have signs of PAD. There are no peripheral arterial lesions specific to diabetes, but the pattern of atherosclerosis is somewhat different. The characteristics of these lesions, according to expert opinion, are listed in Table 1.

Table 1:

Characteristics of atherosclerosis in people with diabetes as opposed to people without diabetes
  • More common
  • Affects younger individuals
  • No sex difference
  • Faster progress
  • Multi-segmental
  • More distal (aorto-iliac arteries less frequently involved)
  • More aggressive

4. Pathophysiology

The presence of PAD in people with diabetes is related to older age, HbA1c, smoking, and hypertension. Based on studies in people without diabetes, dyslipidaemia and end-stage renal disease are also probably risk factors. In patients with diabetes, for every 1% increase in HbA1c, there is a corresponding 26% increase risk of PAD. Accumulation of cholesterol within the vessel wall is the cardinal step in atherogenesis. During this process, intimal plaques are formed, which can ulcerate with subsequent thrombosis. This narrows and occludes the arteries, reducing blood flow and perfusion pressure in the peripheral tissues. The process is mostly segmental, leaving distal segments, for instance, of the crural or pedal arteries - open and accessible for vascular reconstruction. Following arterial obstruction, local microcirculatory changes occur unless the obstruction is compensated by collateral vessels.

PAD can be regarded as a sign of general atherosclerotic disease. Therefore, the heart and carotid arteries should also be examined in patients with PAD. Precisely why people with diabetes are more prone to develop atherosclerotic vascular disease is still unclear, but it is likely that changes in circulating lipoproteins result in a more atherogenic lipid profile, with low HDL-cholesterol and elevated triglycerides. The role of hyperglycaemia in atherogenesis is less clear, however, and still open to debate. Within the diabetic population, nephropathy is a marker for generalized vascular disease, and it is likely - but not proven - that these people are more prone to develop PAD.

5. Symptoms

When adequate collateral vessels compensate for arterial occlusion, there may be no symptoms at rest, but when the demand for blood-flow increases, for example during walking, intermittent claudication may occur. However, less than 25% of individuals with PAD and diabetes report intermittent claudication, which means that 75% of people with diabetes have so-called 'asymptomatic' disease. End-stage symptoms are rest pain - particularly at night - and ulceration/gangrene. Also, many of these patients have few symptoms, despite extensive tissue loss - probably due to peripheral neuropathy.

6. Identifying PAD

Experts recommend that the vascular status in people with diabetes should be examined on an annual basis, with particular attention to:

  1. A history of intermittent claudication or ischaemic rest pain, to be distinguished from pain caused by peripheral neuropathy.
  2. Palpation of pulses in the posterior tibial and dorsalis pedis arteries is mandatory. Detection of foot pulses by palpation is affected by room temperature and the skill of the examiner. If a pulse is absent, popliteal and femoral pulsations should be examined. The dorsalis pedis artery may be congenitally absent. If foot pulses are present, significant vascular disease is unlikely. Some experts advise that when pedal pulses are absent in an asymptomatic patient, ankle blood pressure should be measured with a hand-held ultrasound Doppler device. An ankle brachial pressure index (ABI - systolic ankle blood pressure divided by systolic arm blood pressure, both measured with the patient in the supine position) of below 0.9 indicates occlusive arterial disease. If pedal pulses are absent in a patient with a foot ulcer, further non-invasive investigation is mandatory.
  3. Potential signs of critical ischaemia are: blanching of the feet on elevation, dependent rubor, ulceration, skin necrosis or gangrene. However, due to peripheral neuropathy, the critically ischaemic foot maybe relatively warm, with little discoloration. Finally, critical ischaemia can sometimes be confused with infection, as local erythema may be observed in the ischaemic foot.

7. Chronic critical ischaemia

Critical ischaemia indicates risk of amputation of a major part of the limb, unless reversed by a revascularization procedure. Definition and guidelines for the treatment of acute ischaemia are beyond the scope of this document. Chronic critical ischaemia has been defined by either of the two following criteria: persistent ischaemic rest pain requiring regular analgesia for more than two weeks; ulceration or gangrene of the foot or toes - both associated with an ankle systolic pressure of <50 mmHg or a toe systolic pressure of <30-50 mmHg.

These criteria are based on the assumption that there are no differences between people with or without diabetes concerning critical ischaemia. However, studies in patients with diabetes with foot ulcers suggest that these cut-off pressure levels are either too low or inaccurate, as described below.

8. Non-invasive vascular investigation

Given the uncertainties of history and clinical examination, more objective measurements of skin perfusion are frequently needed. Commonly used techniques include ankle pressure, toe pressure and (less frequently) transcutaneous oxygen pressure (TcPO2) measurements. These non-invasive vascular tests can be used for:

  • diagnosis and quantification of PAD
  • predicting wound healing of a diabetic foot ulcer
  • follow-up and control of treatment.

The most widely used method for the diagnosis and quantification of PAD is the measurement of ankle pressure, as described above. Ankle pressures may be falsely high (due to medial sclerosis), and an ABI above 1.3 is unreliable. It has been suggested that in this situation ankle perfusion pressure can be estimated with the 'pole-test', which records the disappearance of the ultrasound signal as the leg is elevated. However, ankle pressures are not accurate predictors of wound healing. Therefore, experts suggest that in a patient with a foot ulcer, these measurements should, if possible, be supplemented with a more peripheral measurement.

Several studies have been published on the ability of these techniques to predict the probability of wound healing. A schematic estimate of probability of healing for foot ulcers and minor amputations in relation to ankle blood pressure, toe blood pressure and transcutaneous oxygen pressure measurements (TcPo2), based on selected reports, is given in Figure 1. It should be noted that diagnostic specificity can not be ascertained from these curves.


Figure 1: Non-invasive evaluation and an estimate of probability of healing

In a recent study comparing different methods for PAD screening in people with diabetes, the sensitivity of ABI in neuropathic patients was only 53%; in a patient with a non-healing ulcer, significant peripheral vascular disease should always be considered - even if clinical signs of PAD are absent and non-invasive testing is not clearly abnormal. In these patients, repeated evaluation may be necessary, and, according to experts, angiography should be considered in a chronic non-healing ulcer after 6 weeks of optimal treatment.

9. Treatment

Revascularization

In a patient with a foot ulcer, an estimate of the probability of wound healing should be based on clinical examination and, if possible, the non-invasive vascular tests described above. If the probability of healing is deemed to be too low (see Figure 1), or if the patient has persistent ischaemic rest pain, revascularization should always be considered. A second indication for revascularization can be intermittent claudication. In all of these cases, the arterial tree of the lower extremity, including the pedal arteries, must be visualized. Several techniques can be used. Arteriography of the lower extremity can be performed using the Seldinger technique - with or without digital subtraction angiography. If there are no signs of more proximal vascular disease, the examination can be restricted to one leg, with puncture of the femoral artery to limit the amount of contrast medium. This technique can be replaced or supplemented by magnetic resonance angiography (MRA), CT-angiography, or duplex (echo-Doppler) examinations. To avoid contrast nephropathy, adequate hydration and blood glucose control are mandatory before, during, and after angiography.

Arterial reconstruction can be performed through open procedures such as a bypass or, more rarely, via a thromboendarterectomy or an endovascular procedure - such as a balloon dilatation (percutaneous transluminal angioplasty, PTA) or an endovascular (subintimal) recanalization. In general, when endovascular revascularization and open repair or bypass of a specific lesion give equivalent results, endovascular techniques should be used first, given their lower risks and costs. Traditionally, endovascular procedures were reserved for short proximal arterial lesions, and bypass surgery was usually required for long and distal occlusions. However, based on recent reports, and according to the experience of experts, endovascular techniques can also be used in long lesions in the lower leg, with good healing rates of (neuro-)ischaemic ulcers. If bypass surgery is performed, the great saphenous vein is superior to synthetic graft material. Most recent reports suggest that durability is of the same order of magnitude in people with or without diabetes.

A revascularization procedure is technically possible in most patients suffering from critical ischaemia. Because excellent results have been published on distal reconstructions in patients with diabetes, a more aggressive approach to revascularization procedures should be promoted. Whenever a major amputation is under consideration, the option of revascularization should always be considered first. Pharmacological therapy to maintain patency after vascular reconstruction is controversial, although aspirin is used by the majority of vascular surgeons.

According to the recent TASC II Guidelines, patients should participate in a clinical surveillance programme after bypass surgery, which should be performed in the immediate post-operative period and at regular intervals (usually every 6 months) for at least 2 years.

Risk-factor modification

Cardiovascular morbidity and morality are markedly increased in patients with PAD. Treatment of neuro-ischaemic ulcers should therefore not be solely focused at the foot, but should also aim to reduce this poor survival. In patients without diabetes, cessation of smoking has been shown to decrease the risk of developing intermittent claudication and decrease the subsequent risk of amputation. Moreover, patency rates for vascular reconstruction are higher, and the risk of death is lower, if the patient stops smoking. Although there are no studies which demonstrate that treating hypertension and dyslipidaemia has any beneficial effect on ischaemic foot problems, experts strongly advise that these factors be treated aggressively. In addition, patients with PAD should be treated with low-dose aspirin to reduce vascular co-morbidity.

Placebo-controlled trials have demonstrated that pharmacological treatment can be of some value in improving peripheral perfusion in patients with critical ischaemia. However, at present, there is not sufficient evidence of efficacy to advocate the routine use of any drug for this purpose.

Walking programmes have been shown to improve intermittent claudication in people with diabetes. Proper footwear is essential, and cardiac function should be assessed before a walking programme is initiated. Expert opinion is that walking programmes should not be initiated in case of ulceration or gangrene.

Lumbar sympathectomy is an obsolete procedure for the treatment of intermittent claudication and critical ischaemia in patients with diabetes.

10. Further reading

  • Beks PJ, Mackaay AJ, de Neeling JN, de Vries H, Bouter LM, Heine RJ. Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study. Diabetologia 1995; 38: 86-96.
  • Ubels FL, Links TP, Sluiter WJ, Reitsma WD, Smit AJ. Walking training for intermittent claudication in diabetes. Diabetes Care 1999; 22: 198-201.
  • Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes 2002; 25: 894-9.
  • Faglia E, Mantero M, Caminiti M, Caravaggi C, De Giglio R, Pritelli C, Clerici G, Fratino P, De Cata P, Dalla Paola L, Mariani G, Poli M, Settembrini PG, Sciangula L, Morabito A, Graziani L. Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects. J Intern Med 2002; 252: 225-32.
  • Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005; 366: 1925-34.
  • Williams DT, Harding KG, Price P. An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes. Diabetes Care 2005; 28: 2206-10.
  • Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR. HbA1c and peripheral arterial disease in diabetes: the Atherosclerosis Risk in Communities study. Diabetes Care 2006; 29: 877-82.
  • Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG: on behalf of the TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 (Suppl S): S5-S67

11. Peripheral vascular disease

Peripheral vascular disease
Mediasclerosis of the artery leading to incompressible crural vessels.
Pre-gangrenous fourth toe due to ischemia.
(Minor) gangrene of the fourth toe.
(Major) gangrene of the forefoot.

12. Angioplasty

Angioplasty
69-year old male with a history of a resection of the second through fourth toe with subplantar abscess underwent angiography.
Angiography showed short segment occlusion of the superficial femoral artery and multiple crural occlusions.
Percutaneous transluminal angioplasty (PTA) of the distal superficial femoral artery was performed.
Wound healing after successful PTA.

13. Bypass surgery

Angioplasty
Bypass surgery

1) Angiography showed multiple crural occlusions.

2) Because of the non-healing defect a popliteal-pedal bypass from the infragenual popliteal artery to the pedal artery was performed.

Secondarily healed defect after successful reconstructive revascularisation.

I. Abbreviations

ABIankle:brachial pressure index
AHAAmerical Heart Association
AKAabove knee amputation
ARFacute renal failure
ATanterior tibial artery
BKAbelow knee amputation
CADcoronary artery disease
CBAcontrol before and after (study)
CFAcommon femoral artery
CIAcommon iliac artery
CKDchronic kidney disease
CLIcritical limb ischaemia
CVDcerebrovascular disease
DFUdiabetic foot ulcer
DMdiabetes mellitus
DPdorsalis pedis artery
IQRinterquartile range
ITSinterrupted time series (study)
ITTintention to treat (analysis)
IWGDFInternational Working Group on the Diabetic Foot
MImyocardial infarction
MRAMagnetic Resonance Angiography
NAnot available
NPWTnegative pressure wound therapy
NRnot reported
PADperipheral artery disease
PTposterior tibial artery
PTApecutaneous transluminal angioplasty
RCTrandomised controlled trial
SDstandard deviation
SFAsuperficial femoral artery
SIGNScottish Intercollegiate Guidelines Network
TASCThe Inter-Society Consensus for the Management of Peripheral Arterial Disease
TBItoe-brachial pressure index
TcpO2transcutaneous oxygen tension
UTUniversity of Texas (wound classification system)

II. Introduction

An amputation of the leg or foot is one of the most feared complications of diabetes mellitus and it is has been calculated that at this moment every 20 seconds a leg is lost in our world due to diabetes 1, 2. Peripheral artery disease (PAD) and infection are the major causes of lower leg amputation in diabetes and >80% of these amputations are preceded by a foot ulcer 3, 4. Diabetes is a risk factor for PAD and depending on the definitions used, prevalence rates of 10 to 40% in the general population of patients with diabetes have been reported 5, 6, 7. Moreover, in comparison to subjects without diabetes, PAD is more likely to progress in patients with diabetes8. A substantial number of individuals with a foot ulcer will therefore have PAD, ranging from relatively mild disease with limited effect on wound healing to severe limb ischemia with delayed wound healing and a high risk of amputation. In several large observational studies PAD was present in recent series in up to 50% of the patients with a diabetic foot ulcer and was an independent risk factor for amputation 9, 10, 11. The relatively poor outcome of ischaemic foot ulcers in diabetes is probably related to a combination of factors, such as the anatomic distribution of the vascular lesions rendering them more difficult to treat, the association with other abnormalities like infection, neuropathy and renal failure and the presence of abnormalities in other vascular territories, such as the coronary or cerebral arteries7, 9, 12, 13, 14 The mortality of patients with PAD and a diabetic foot ulcer is high with 50% of patients dead at 5 years15; the results are worse after major amputation with a 50% mortality after 2 years. In addition, wound healing can be further disturbed by a complex interplay of several other factors such as poor glycaemic control, microvascular dysfunction, impaired collateral formation, abnormal mechanical loading of the ulcer and co-morbidities. The effect of PAD on wound healing in diabetic patients with a foot ulcer will therefore relate in part to its severity and extent but also to these other factors16.

Clearly, early recognition of PAD, an accurate estimation of its severity and prompt institution of effective treatment in cases of severe disease would seem to be a logical approach to reduce the high number of amputations. However, as shown in the Eurodiale cohort, less than 50% of the diabetic patients with ABI<0.5 underwent adequate vascular evaluation and subsequent revascularisation, suggesting that there is ample room for improvement in the delivery of care14. PAD in patients with diabetes has a number of important characteristics which renders it more difficult to treat. The atherosclerotic lesions are multilevel and particularly severe in tibial arteries, with a high prevalence of long occlusions17. The predilection for multiple crural vessel involvement combined with extensive arterial calcification increases the technical challenges associated with revascularisation using either open bypass or endovascular techniques.

The term critical limb ischaemia (CLI) is frequently used in the PAD literature but may not be particularly relevant for patients with diabetes. The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) document suggests that the term "should be used for all patients with chronic ischemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive disease"18. However, in diabetic patients ulceration or gangrene are usually the result of several interacting factors, with neuropathy playing a central role in most patients in combination with varying degrees of PAD and therefore confusion may exist in reporting outcomes in the literature.

Updated guidelines on the diagnosis and treatment of PAD have been provided in 2007 by TASC II, but evidence based guidelines on the treatment of PAD in patients with diabetes and ischaemic foot ulcers are currently lacking18. In recent decades new techniques and technologies have been introduced in treating PAD, which might be relevant for the patient with diabetes and a poorly healing ischemic foot ulcer. In particular interesting results have been reported on endovascular approaches in the leg and the field is rapidly evolving19, 20. The International Working Group on the Diabetic Foot (IWDGF) therefore established a multidisciplinary working group, including specialists in vascular surgery, interventional radiology, cardiology, internal medicine and epidemiology to evaluate the effectiveness of revascularisation of the ulcerated foot in patients with diabetes and PAD. The aims of this multidisciplinary working group was to produce a systematic review on the efficacy of (endovascular and surgical) revascularisation procedures and medical therapies in diabetic patients with a foot ulcer and PAD. Based on this review and supplemented with expert opinion if necessary, practical guidelines were formulated These documents were commented upon and subsequently approved by all members (n=xx) of the IWDGF and in this article we report the results of the systematic review on revascularisation techniques and the consensus practical guidelines.

III. Materials and methods

The Medline and Embase databases were searched for therapies to revascularise the ulcerated foot in patients with diabetes and PAD from 1980 - June 2010 respectively (Appendix 1). Searches excluded studies pre-1980 due to the changing nature of interventions for PAD and improving technology. PAD was defined for the purpose of this systematic review as any flow limiting atherosclerotic lesion of the arteries below the inguinal ligament. All patients included had to have objective evidence of PAD (eg angiography or MRA).

It was felt that studies on patients with less severe PAD (resulting in claudication, rest pain or unspecified 'critical ischaemia') were not really of great importance as the aim was to determine the effects of vascular intervention in patients with PAD, diabetes and a foot ulcer. We therefore restricted the studies to those with patients with tissue loss and studies were only included if greater than 80% of patients had evidence of tissue loss (defined as any lesion of the skin breaching the epithelium / ulceration / gangrene). The diagnosis of diabetes was made according to the individual publication. Because many studies in PAD are not exclusively on patients with diabetes and because the outcome of the patient with diabetes and PAD and a foot ulcer can not be assumed to behave in a similar way to patients without diabetes. We reported studies where >80% of patients of the population studied had diabetes were compromised of more than 40 patients. If a smaller proportion of patients had diabetes we included them only if the outcomes of that cohort were specifically reported as a separate sub-group and the results of at least 30 patients were reported. We excluded studies solely reporting interventions on aortic and iliac arterial disease, studies that had only data on health related quality of life or costs and studies examining the diagnosis and prognosis of PAD in diabetes. Studies reporting medical therapy or local / topical therapy to improve tissue perfusion or to increase oxygen delivery were excluded (for example prostaglandin or hyperbaric oxygen therapy) as well as studies comparing one form of revascularisation technology with another (for example various atherectomy devices).

Only studies reporting ulcer healing, limb salvage, major amputation and survival as the primary outcome measures were included in the review. Early morbidity or mortality was considered within 30 days or within the first hospital admission. A major complication was defined as any which resulted in a systemic disturbance of the patient or prolonged hospitalisation (or as defined by the reporting study). Target lesion revascularisation was not considered.

Patient demographics that were assessed included patient age, gender, ethnicity and co-morbidities (cardiovascular, renal and cerebrovascular). The specifics of the foot lesions were reported where possible, such as site on the foot, depth, presence of infection and stratified when possible according to any previously reported / validated diabetic foot ulcer scoring system. The anatomical distribution of PAD was extracted according to the site of the disease; standard reporting systems were included where possible (eg TASC / Bollinger systems18, 21). Objective assessment of perfusion was reported when possible, which included ankle-brachial pressure index (ABI), toe pressure and transcutaneous oxygen concentration (TcpO2). We made no distinction between various endovascular techniques (eg angioplasty, stenting, subintimal angioplasty, atherectomy), all being referred to as 'endovascular therapy' and similarly no distinction was made between various bypass techniques (eg in situ versus reversed venous bypass).

The systematic search was performed according to PRISMA guidelines22. Two reviewers assessed studies for inclusion based on titles; two reviewers then excluded studies based on review of the abstract; and then finally, a full text review was performed of selected articles. Studies were assessed for methodological robustness. To do this the Scottish Intercollegiate Guidelines Network (SIGN) instrument was used as follows: Level 1 includes meta-analyses and RCTs, Level 2 includes studies with case-control, cohort, controlled-before-after (CBA) or interrupted time series (ITS) design. Studies were rated as: ++ (high quality with low risk of bias), + (well conducted with low risk of bias) and - (low quality with higher risk of bias), according to the SIGN methodological quality score23. Level 3 studies were studies without a control group (eg case series), these studies were not rated. Data were extracted into evidence tables by pairs of reviewers and then reviewed by the whole group. Pooling of data (and therefore weighting of studies) was not possible due to study heterogeneity and the generally low quality of evidence (see below). When several studies reported on a specific item we have summarised the data of these separate studies as inter-quartile ranges and median. It should be noted that these figures are not weighed means.

IV. Results

After the identification and screening phase 866 articles were assessed for eligibility and total of 49 papers described revascularisation of the ulcerated foot in 8,290 patients with diabetes and PAD (PRISMA diagram). These 49 studies were selected for full text review and are summarised in table 1. There were no randomised controlled trials but there were three non-randomised studies with an intervention and control group31, 47, 57. These were all of low quality and potentially subject to significant bias (SIGN 2-). The remaining 46 papers were case series (SIGN 3). Studies reported bypass surgery, endovascular therapy or both techniques used in combination. Although most reports adequately presented patient demographics and comorbidities, a major limitation was that few studies adequately reported or categorized either baseline foot lesions or PAD severity. A number of studies were reported from the same institution and it is likely that some patients were reported more than once.

1. Co-morbidity and patient demographics

Overall the proportion of males in each study varied from 37% - 96% with mean or median ages of individual studies varying from 36 - 74 years. Patient with diabetes, PAD and foot ulcers had significant comorbidity with a relative large proportion of patients having cardiovascular, cerebrovascular or renal disease. The prevalence of coronary artery disease was reported as 40 - 60% (interquartile ranges) with a median of 50%, of cerebrovascular disease as 18 - 24% with a median of 20% and of end-stage renal disease as 11 - 48% with a median of 20% (although the definition varied form study to study and in some studies was only reported as renal impairment). Eight studies did not report any data on co-morbidity and data on severity of co-morbidities was sparse (eg NYHA classifications).

2. Early complications

Methods for reporting early complications were varied. Major systemic complications were frequent in both patients undergoing bypass surgery and endovascular procedures with the majority of studies reporting major systemic complications in the region of 10% with similar rates for endovascular and bypass surgery.

3. Peri-operative mortality

30-day or in-hospital mortality was described in 30 studies. The peri-operative mortality following open surgery was reported in 20 studies and had an interquartile range of 0.8-3.7%, with a median of 1.4% and was comparable in endovascular procedures: 0 - 4.3% with a median of 0.5%. In both open and endovascular series there were several outlying studies with either no mortality or a mortality rate of 9% or greater. It was not clear why these results were so different. As the severity of co-morbidities frequently was not stated it was difficult to infer the effect of co-morbidity on outcomes.

4. Mortality

Mortality at one year or longer following intervention was reported more frequently in studies describing open surgery. Morality at one year follow-up reported in these studies had an inter-quartile range of 11.3 - 21.8%, with a median of 13.5% and at five years: 36 - 52.3% with a median of 46.5%. There was a paucity of long-term follow-up data in patients having undergone endovascular procedures. Three studies reported on one-year follow-up of patients undergoing endovascular procedures with mortality rates of 10% in two studies and 29% in another; five year follow-up mortality rate was reported in two studies and varied widely (5% and 74%).

5. Limb salvage and wound healing

Limb salvage data were reported in the majority of studies, however in almost all studies it was not clearly defined. Following open surgery, the one-year limb salvage rates had an inter-quartile range of 80 - 90% with a median of 85% in the 19 studies with one year data. Following endovascular revascularisation these rates were 70.5 - 85.5% (inter-quartile ranges) with a median of 78%. At three and five years following open surgery these figures were 79.5 - 90% with a median of 82% and 74 - 78% with a median of 78%, respectively. At three years following endovascular procedures the limb salvage rate was 72 - 78.5% (inter-quartile ranges) with a median of 76% in four studies. At five years limb salvage was 56% and 77% in the two studies which reported it. Wound healing was reported in seven studies25, 30, 33, 35, 59, 65, 66. Only one defined wound healing at a pre-defined time point of 12 months59. However, overall the seven studies following endovascular and two following bypass surgery demonstrated an ulcer healing rate of 60% or more at 12 months follow-up.

6. Amputation

Major amputation was reported by 30 studies. The definition of major amputation was not always specified and sometimes differed between studies. Major amputations within 30 days were reported in three studies and varied from 2.1%, 3.5% and 5%. Only two studies reported amputations at 12 months29, 63. The amputation rates within 24 months following open surgery had an inter-quartile range of 12.8 - 22.8%, with a median of 17.3% and following an endovascular procedure these figures were 5.4 - 12.5% and 8.9%, respectively. The study by Malmstedt was an interpretation of the Swedish national vascular registry, Swedvasc and therefore represents the results of a number of different vascular centres rather than those simply focussed on distal bypass procedures44. A composite outcome of amputation and death (median follow-up 2.2 years) was given in the registry. The rate of ipsilateral amputation or death per 100 person years was 30.2 (95% CI 26.6 - 34.2). The median time to reach this end-point in patients with diabetes and PAD undergoing bypass surgery (82% for ulceration) was 2.3 years.

Minor amputation rates varied widely in the 11 studies reporting on this complication24, 28, 29, 30, 32, 39, 41, 43, 49, 65, 66. Over the study periods minor amputation was reported a median of 38% (inter-quartile range 23 - 59%). However there was great variation with studies reporting a range of 12% to 91.7%. It was not clear whether patients received one or more minor amputations in any particular study. The rates of minor amputations varied between open surgery studies 26% (inter-quartile range 19 - 70%) and angioplasty studies 43% (inter-quartile range 38 - 53%), however the numbers of studies was small and the demographics heterogeneous.

7. Infection

Only two studies specifically reported the outcomes of patients presenting with foot infection, PAD and diabetes62, 61. Mortality at one year was 5% and 19%. Limb outcomes were poorly described but limb salvage was 98% in one study at one year61.

8. End-stage renal disease

Patients with end-stage renal disease (ESRD) were identified in six studies40, 43, 47, 52, 58, 67. The definition of ESRD varied and included patients both prior to and on dialysis and those with functioning renal transplants. Thirty day mortality was 4.6% (inter-quartile range 2.6 - 8.8%) but one year mortality was high with 38% (interquartile range 25.5 - 41.5%) of patients perishing. One year limb salvage rates were 70% (inter-quartile range 65 - 75%) in survivors. Long-term outcomes were also poor. Reported mortalities at 2 years were 48%43 and 72%40, at 3 years 56%58 and at 5 years 91%47.

9. Angioplasty first strategy

Three studies, with a mean follow-up of 20, 25 and 26 months reported on an angioplasty first strategy, where angioplasty was the preferred fist-line option for revascularisation (scoring of anatomical distribution was not given)65, 30, 39. In one of these studies, a large series of 993 consecutive patients with diabetes hospitalised with foot ulcer or ischemic rest pain and PAD. PTA was technically not feasible in 16% of the patients due the complete calcified occlusion of the vessel which did not permit balloon catheter passage30. PTA did not establish in line flow to the foot in only 1%. The second study was a consecutive series of 100 patients considered suitable for an infra-inguinal PTA first approach and 11% of the patients required bypass surgery for a failed PTA39. In the third study, a consecutive series of 534 patients were recruited from a tertiary referral hospital. Of these, data was available on 510. Angioplasty was attempted in 456 (89.4%). Angioplasty was a technical failure in 11%65. Mortality and limb salvage rates were comparable to the other series.

10. Crural vessel angioplasty

Crural PTA employed as a revascularisation technique in isolation was reported in four studies27, 32, 35, 67, 69. Outcomes were variously on limb salvage, all of which exceeded 63% at 18 months (up to 93% at 35 months).

11. Pedal bypass grafts

Ten studies reported the results of pedal bypass grafting (one of which focused on outcomes in patients with ESRD). Studies reported limb salvage rates following pedal bypass grafting with an inter-quartile range of 85 - 98%, with a median of 86% at one year, 88.5 (81.3 - 82.3%) at three years and 78% (78 - 82.3%) at five years. However, the numbers available for follow-up at three and five years were low; the distribution / severity of PAD and the type of foot lesion were poorly reported.

V. Discussion

This systematic review examines the evidence to support the effectiveness of revascularisation of the ulcerated foot in patients with diabetes and PAD. This is timely because the proportion of patients with diabetes and an ischaemic component to their ulcer is increasing. Recent reports suggest that up to 50% of the diabetic patients with a foot ulcer have signs of PAD, which had a major impact on ulcer healing and the risk for lower leg amputation3, 72, 73. Early reports on the effectiveness of revascularisation in patients with diabetes and PAD were not encouraging and led some to suggest that diabetes was associated with a characteristic occlusive small vessel arteriopathy, consequently leading to a nihilistic attitude toward revascularisation. Subsequent laboratory studies and clinical results well summarised by the Beth Israel-Deaconess group suggested that revascularisation was possible74. It has become increasingly recognised that patients with diabetes and an ischemic foot ulcer represent a unique problem among patients with PAD. Consequently the numbers of studies reporting a population or sub-group of patients with PAD, diabetes and ulceration is increasing and more than 50% of the studies included in this systematic review were published after 2001. We specifically did not include studies reporting either outcomes which were not clinically relevant (eg target lesion revascularisation) or that compared specific techniques (such as atherectomy versus transluminal versus subintimal angioplasty).

Whilst the quality of studies included in the review was frequently low there were a surprising number reporting on the effectiveness of revascularisation in diabetic patients with PAD and tissue loss. The interpretation of the effectiveness of revascularisation on outcomes in these studies is difficult as none of the studies included a matched control group receiving non-interventional therapy and the natural history of patients with PAD and an ulcerated foot remains poorly defined. Data on the natural history of patients with PAD, diabetes and critical limb ischaemia (CLI (though not necessarily limited to those patients with tissue loss or ulceration) do, however, exist. In one study that reported the outcomes of diabetic patients with CLI who were not revascularised, the limb salvage rate was 54% at one year75. This rate would appear much lower than in the series presented here where limb salvage rates were the majority of studies reported limb salvage rates between 78% and 85%. In a study by Marston in which patients with PAD and ulceration of the foot were treated without revascularisation (70% diabetes) amputation was required in 23% at 12 months but complete wound closure was achieved in 52% in the same time period. ABI at presentation (<0.5) predicted limb loss and the only factor associated with healing was size of ulcer.76

We defined peri-procedural mortality and morbidity as any event occurring during a 30-day hospitalisation period. Although peri-operative mortality rates in this review were generally low given associated comorbidities, peri-operative major systemic complications were significant, in the region of 10%. It is possible that part of these major complications were not related to the revascularisation procedure per se, but were more related to the poor general health status of the patients. These major systemic complications were usually poorly defined and are therefore not reported separately in this systematic review. However, our review does indicate that patients with diabetes and a foot ulcer undergoing revascularisation for PAD should be optimised if possible prior to revascularisation. There did not appear to be major differences in morbidity or mortality between open and endovascular techniques, although the studies are difficult to compare as discussed above and we cannot exclude that there were major differences in patient characteristics and severity of disease. Intermediate and long-term mortality rates during follow-up of studies in this systematic review were high. Over 10% of patients were dead at one year and almost half were dead at five years. These results are similar to those reported in patients presenting with a foot ulcer of any origin, with five year mortality rates around 44%15. It was difficult to establish whether early aggressive and successful revascularisation reduced mortality in the long-term. Lepantalo also found that patients with diabetes and CLI appear to be at particularly high risk of death compared to the others with CLI75. However, patients in whom successful revascularisation is performed appear to do better than those who undergo major amputation, half of whom are dead within three years 77, 78. These findings underscore the importance of the severity and systemic nature of vascular disease in patients with diabetes. Diabetic patients with an ischaemic foot ulcer should therefore receive aggressive and appropriate medical management of risk factors to reduce their high long-term mortality.

Ulceration of the foot in diabetes is often a complex interplay of many aetiologic factors, and the situation is compounded by the presence and severity of PAD. In any diabetic patient with ulceration of the foot the pathways to ulceration may differ (eg neuropathy, altered biomechanics) as well as the predominant factors affecting outcome (eg PAD, infection, co-morbidities). Although the current data indicate that revascularisation should always be considered in a patient with diabetes, foot ulceration and severe ischemia, it remains still unclear if such procedures have an added value in cases of mild-moderate perfusion deficits. There are little data to inform on the indications or timing for either diagnostic angiography or intervention among the studies, which should be one of the important topics of future studies. These studies should probably revolve around the influence of patient co-morbidity, the severity of PAD (distribution and level of perfusion) and the characteristics of the foot wound itself.

End-stage renal disease (ESRD) is a strong risk factor for both foot ulceration and amputation in diabetic patients79. These patients are frequently difficult to treat and long-term mortality is high, as also exemplified in this systematic review, which might negatively influence the decision to perform a revascularisation procedure. However, our data indicate that even in these patients favourable results can be obtained, the majority of studies reported 1-year limb salvage rates of 65-75% after revascularisation.

Attempts have been made to categorize the distribution of PAD in patients with diabetes and correlate this with perfusion17. However, the severity of PAD was not well described in most studies. Results of ABI, toe-pressure or tcPO2 measurements and the anatomical distribution pattern of the PAD were usually not reported and our review indicates that all future reports on revascularisation in diabetic patients with an ischemic ulcer should include objective measurements of the severity of PAD, including both anatomical and functional measurements, such as toe-pressure and/ or TcpO2 measurements. Also wound characteristics were reported poorly, although prospective studies have shown the impact of factors such as size, depth or the presence of infection on healing and amputation rate. Clearly, a standardised wound classification system should be part of all future studies80. Moreover, there is a clear need for studies on the role of early revascularisation in diabetic patients with PAD and infected foot ulcers, as these patients are in particular at risk for a major amputation3.

Standard reporting criteria exist for dealing with lower extremity ischaemia (Rutherford 1997) but are 15 years old and do not focus on factors that are specific to patients with diabetes81. Interestingly outcome measures such as major amputation and wound healing were less frequently reported and if reported variously defined in the studies reviewed. Given the difficulty in strictly defining limb salvage, we suggest that major amputation and wound healing should be used as the major endpoints in future reports on revascularisation in diabetic patients with PAD. A separate document on endpoints in studies reporting outcomes of patients with PAD, diabetes and ulceration of the foot will be published from the IWGDF.

There are currently no RCTs directly comparing open vs endovascular revascularisation techniques in diabetic patients with an ischemic foot ulcer. Therefore, there were insufficient data to demonstrate whether open bypass surgery or endovascular interventions were more effective in these patients. However, broadly speaking the major outcomes appeared similar across all studies where revascularisation of the foot was successful. Two meta-analyses on the outcomes of pedal bypass grafting and crural angioplasty have been performed by the same group and the majority of patients in these two meta-analyses had diabetes82, 83. Although the inclusion criteria were different (many of the studies included did not specifically report on patients with diabetes or tissue loss) from our systematic review, limb salvage rates of pedal bypass grafting and crural angioplasty appeared to be equivalent to the results of our systematic review and no major differences were reported between the two techniques. In contrast, primary and secondary patency rates were better after bypass surgery. In two studies of consecutive diabetic patients where angioplasty was the preferred first-line option for revascularisation favourable results were obtained and bypass surgery was only required in a minority of these patients31, 40. It is not possible to infer data from the BASIL trial that compared endovascular and bypass surgery in PAD, because it only included 42% of patients with diabetes and no sub-group analysis was performed84. However, the results of both open and endovascular procedures will greatly depend upon the expertise in a given center. Clearly further data are required to establish specifically which technique should be preferred taking patient characteristics, severity and distribution of PAD, and wound characteristics into account. Many of the studies reported herein were from well recognised expert centres in revascularisation techniques for patients with diabetes, which bias the results towards more favourable outcomes. Moreover, in some instances there was probably significant overlap in the larger series of patients from certain centres. The data from the Swedvasc registry would suggest that it is possible to attain good outcomes when revascularisation techniques are applied outside centres of expertise44. However, such a procedure should not be performed in isolation but should always be part of an integrated multifactorial approach that should include aggressive treatment of infection, debridement and off-loading to protect the wound from repetitive biomechanical stress.

There were significant variations in the proportion of patients undergoing minor amputations. It is difficult to speculate why these rates may vary especially because few studies reported validated foot ulcer scoring systems and the indications for amputation were rarely reported. As discussed above, healing of an ulcer with an intact foot should be one of the primary endpoints of future studies but healing was, if reported, poorly defined in almost all studies. Where healing is only defined as intact skin, an apparently high proportion of patients with healed wounds can be reported if many patients undergo a minor amputation combined with primary wound closure. Clearly this is also an area for future reporting standards.

Almost all studies were cases series with high risk of selection and publication bias. Moreover, cases series comparing bypass surgery and endovascular treatment are difficult to compare because of indication bias. Several studies included in this review were retrospective analyses of small number of patients. Due to heterogeneity we could not pool the data. For ease of data presentation we could only provide the median and (interquartile) ranges of the results of the studies we selected, but this did not correct for number of patients, severity of disease and comorbidities. Due to these limitations we cannot give reliable estimates of expected outcome. Clearly, there is an urgent need for properly controlled studies with a well described population and outcomes which are relevant to patients with diabetes.

In conclusion, studies reported herein appear to demonstrate improved rates of limb salvage associated with revascularisation compared to the results of medically treated patients with diabetes, PAD and ulceration previously reported in the literature. High peri-operative morbidity and long-term mortality rates underline the importance of peri-operative optimisation and long-term medical management of patients' diabetes and co-morbidities. Overall, there were insufficient data to recommend one method of revascularisation over another. There is a real need for standardised reporting of baseline demographic data, severity of disease and outcome reporting in this group of patients. These standards should take into account both the specific characteristics of the PAD and of the wound in these patients. Further efforts are also required to standardise and improve outcome reporting, which should include wound healing, and it is important to move away from procedure specific outcomes to disease specific outcomes in this cohort of patients.

VI. PRISMA Flow Diagram

Open in new window Fig 1

VII. References

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  68. Woelfle KD, Lange G, Mayer H, Bruijnen H, Loeprecht H. Distal vein graft reconstruction for isolated tibioperoneal vessel occlusive disease in diabetics with critical foot ischaemia--does it work? Eur J Vasc Surg. 1993 Jul;7(4):409-13.
  69. Wölfle KD, Bruijnen H, Reeps C, Reutemann S, Wack C, Campbell P, Loeprecht H, Häuser H, Bohndorf K. Tibioperoneal arterial lesions and critical foot ischaemia: successful management by the use of short vein grafts and percutaneous transluminal angioplasty. Vasa. 2000 Aug;29(3):207-14.
  70. Woelfle KD, Bruijnen H, Loeprecht H. Infrapopliteal arterial occlusive disease in diabetics with critical foot ischaemia: The role of distal origin bypass grafts. Vasa 2001; Suppl.58:40-43
  71. Zayed H, Halawa M, Maillardet L, Sidhu PS, Edmonds M, Rashid H. Improving limb salvage rate in diabetic patients with critical leg ischaemia using a multidisciplinary approach. Int J Clin Pract. 2009 Jun;63(6):855-8
  72. Gershater MA, Löndahl M, Nyberg P, Larsson J, Thörne J, Eneroth M, Apelqvist J. Complexity of factors related to outcome of neuropathic and neuroischaemic/ ischaemic diabetic foot ulcers: a cohort study. Diabetologia. 2009 Mar;52(3):398-407
  73. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care. 1998 May;21(5):855-9.
  74. LoGerfo FW, Coffman JD. Current concepts. Vascular and microvascular disease of the foot in diabetes. Implications for foot care. N Engl J Med. 1984 Dec 20;311(25):1615-9
  75. Lepäntalo M, Mätzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg. 1996 Feb;11(2):153-7
  76. Marston WA, Davies SW, Armstrong B, Farber MA, Mendes RC, Fulton JJ, Keagy BA. Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. J Vasc Surg. 2006 Jul;44(1):108-114
  77. Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care. 1983 Jan-Feb;6(1):87-91
  78. Waugh NR. Amputations in diabetic patients--a review of rates, relative risks and resource use. Community Med. 1988 Nov;10(4):279-88
  79. Ndip A, Lavery LA, Boulton AJ. Diabetic foot disease in people with advanced nephropathy and those on renal dialysis. Curr Diab Rep. 2010 Aug;10(4):283-90
  80. Karthikesalingam A, Holt PJ, Moxey P, Jones KG, Thompson MM, Hinchliffe RJ. A systematic review of scoring systems for diabetic foot ulcers. Diabet Med. 2010 May;27(5):544-9
  81. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997 Sep;26(3):517-38
  82. Albers M, Romiti M, Brochado-Neto FC, De Luccia N, Pereira CA. Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischemia. J Vasc Surg. 2006 Mar;43(3):498-503
  83. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008 May;47(5):975-981
  84. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366:1925-34

Appendix

A. Medline and Embase search strings

Medline Diabetes Treatments Final Search
Date of search: 2nd June 2010
Search Platform: OvidSp,
File searched: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to Present

  1. diabet*.ti,ab.
  2. exp Diabetes Mellitus/
  3. 1 or 2
  4. (lower adj1 extremit*).ti,ab.
  5. (lower adj5 limb*).ti,ab.
  6. limb*.ti,ab.
  7. leg*.ti,ab.
  8. (foot or feet).ti,ab.
  9. toe*.ti,ab.
  10. Lower Extremity/
  11. Leg/
  12. Foot/
  13. Toes/
  14. Extremities/
  15. 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14
  16. 3 and 15
  17. peripheral vascular disease*.ti,ab.
  18. peripheral arterial disease*.ti,ab.
  19. (pvd or povd).ti,ab.
  20. (pad or paod or poad).ti,ab.
  21. exp Peripheral Vascular Diseases/
  22. (claudication or claudicant*).ti,ab.
  23. exp Intermittent Claudication/
  24. exp Arterial Occlusive Diseases/
  25. exp Graft Occlusion, Vascular/
  26. exp Saphenous Vein/
  27. exp Femoral Artery/
  28. exp Popliteal Artery/
  29. 26 or 27 or 28
  30. occlus*.ti,ab.
  31. stenosis.ti,ab.
  32. 30 or 31
  33. 29 and 32
  34. 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 33
  35. 15 and 34
  36. 16 or 35
  37. perfusion.ti,ab.
  38. reperfusion.ti,ab.
  39. exp Reperfusion/
  40. (odema or edema or oedema).ti,ab.
  41. exp Edema/
  42. (swelling* or swollen).ti,ab.
  43. inflamed.ti,ab.
  44. inflammation.ti,ab.
  45. (flow or flux).ti,ab.
  46. exp Blood Flow Velocity/
  47. capillar*.ti,ab.
  48. exp Capillaries/
  49. (ischem* or ischaem*).ti,ab.
  50. exp Ischemia/
  51. (by-pass or by-pass).ti,ab.
  52. percutaneous.ti,ab.
  53. angioplast*.ti,ab.
  54. exp Angioplasty/
  55. (ballon adj1 dilation).ti,ab.
  56. (ballon adj1 dilatation).ti,ab.
  57. exp Balloon Dilatation/
  58. endotherapy.ti,ab.
  59. endovascular.ti,ab.
  60. evt.ti,ab.
  61. (revascularization or revascularisation).ti,ab.
  62. (endoscopic adj1 therapy).ti,ab.
  63. exp Endoscopy/
  64. atherectom*.ti,ab.
  65. endarterectom*.ti,ab.
  66. artherosclerosis.ti,ab.
  67. exp Atherectomy/
  68. stent*.ti,ab.
  69. exp Stents/
  70. patency.ti,ab.
  71. exp Vascular Patency/
  72. (limb adj1 salvage).ti,ab.
  73. exp Limb Salvage/
  74. subintimal.ti,ab.
  75. surg*.ti,ab.
  76. su.fs.
  77. pta.ti,ab.
  78. 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50
  79. 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77
  80. 36 and 78 and 79
  81. (letter or comment or editorial or case reports).pt.
  82. 80 not 81
  83. limit 82 to humans

Embase Diabetes Treatments Final Search
Date of search: 30th June 2010
Platform: OvidSP
Database file searched: Embase 1980 to present 30th June

  1. diabet*.ti,ab.
  2. exp Diabetes Mellitus/
  3. exp Diabetic Foot/
  4. 1 or 3
  5. (lower adj1 extremit*).ti,ab.
  6. (lower adj1 limb*).ti,ab.
  7. limb*.ti,ab.
  8. leg.ti,ab.
  9. (foot or feet).ti,ab.
  10. exp Lower Extremity/
  11. Leg/
  12. Foot/
  13. Toes/
  14. toe*.ti,ab.
  15. Extremities/
  16. or/5-15
  17. 4 and 16
  18. peripheral vascular disease*.ti,ab.
  19. peripheral arterial disease*.ti,ab.
  20. (pvd or povd).ti,ab.
  21. (pad or paod or poad).ti,ab.
  22. exp peripheral vascular disease/
  23. (claudication or claudicant).ti,ab.
  24. exp intermittent claudication/
  25. exp peripheral occlusive artery disease/
  26. exp graft occlusion/
  27. exp saphenous vein/
  28. exp femoral artery/
  29. exp popliteal artery/
  30. 27 or 28 or 29
  31. occlu*.ti,ab.
  32. stenosis.ti,ab.
  33. 31 or 32
  34. 30 and 33
  35. 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 34
  36. 16 and 35
  37. 17 or 36
  38. perfusion.ti,ab.
  39. reperfusion.ti,ab.
  40. exp reperfusion/
  41. (odema or edema or oedema).ti,ab.
  42. exp edema/
  43. (swelling* or swollen).ti,ab.
  44. inflamed.ti,ab.
  45. inflammation.ti,ab.
  46. (flow or flux).ti,ab.
  47. exp blood flow velocity/
  48. capillar*.ti,ab.
  49. exp capillaries/
  50. (ischemi* or ischaemi*).ti,ab.
  51. exp ischemia/
  52. or/38-51
  53. (by-pass or bypass or by pass).ti,ab.
  54. percutaneous.ti,ab.
  55. angioplast*.ti,ab.
  56. exp angioplasty/
  57. (ballon adj1 dilation).ti,ab.
  58. (balllon adj1 dilatation).ti,ab.
  59. exp balloon dilatation/
  60. endotherapy.ti,ab.
  61. endovascular.ti,ab.
  62. revasculari#ation.ti,ab.
  63. (endoscopic adj1 therapy).ti,ab.
  64. exp endoscopy/
  65. artherosclerosis.ti,ab.
  66. exp atherectomy/
  67. stent*.ti,ab.
  68. patency/
  69. exp vascular patency/
  70. exp stents/
  71. patency.ti,ab.
  72. (limb adj1 salvage).ti,ab.
  73. exp limb salvage/
  74. subintimal.ti,ab.
  75. surg*.ti,ab.
  76. su.fs.
  77. pta.ti,ab.
  78. or/53-77
  79. 37 and 52 and 78
  80. (Letter or Editorial).pt.
  81. 79 not 80
  82. limit 81 to human
Open in new window

B. Evidence tables

Reference Study design Population (age, sex, comorbidity, number with diabetes) PAD (distribution and severity) Foot Lesion Comorbidity Intervention and control management Outcomes Comment Opinion
AhChong 2004 24 Case series

265 consecutive infrainguinal bypasses with outcomes described diabetes versus no diabetes
DM patients 176

No DM 89

Age median 74 (45-94) yrs versus 75 (29-94) no DM

gender: 50% (88) male DM, 45 (51%) no DM (P=NS)
Distribution: NR

Severity: ABI 0.43 Median toe pressure 26mm Hg (0-57) No scoring system used
Tissue loss 158 (90%) DM

No DM 70 (79%) tissue loss (P=0.014)

Ulcer score: NR

Infection: NR
CAD 48%

CVD 26%

ESRD NR
Bypass graft to DM patients Fem-pop 44% Crural 40% Pedal 16%

Autogenous vein 66%

No DM Fem-pop 56% Crural 35% Pedal 9% (P=NS)

Autogenous vein 63%
Median f/u 19months

Mortality 30days 8% DM versus 1% No DM (P=0.04)

Cardiovascular complications 9% v 4% (P=NS)

Overall graft patency 1yr 63%

Graft patency 4yrs 46% DM versus 34% no DM (P=0.19)

Survival rate at 1,3,5 yrs 80%, 57%, 33%

Ulcer healing: NR

Limb salvage overall at 1 yr 83% for both groups and 5yrs 78% DM v 81% no DM (P=0.79)

Major amputation: NR

Minor amputation: NR

Complications: 8% mortality peri-op
Chinese population may differ from Western world

Limited information about patient management
Early graft failure 6%

65 grafts failed overall during total study
Alexandrescu 2009 25 Case series

A retrospective case series of subintimal PTA and PTA in 161 patients with diabetes and ischaemic wound, PTA first approach
161 DM patients

age: > 70 years 41%

gender
Distribution: majority multilevel disease

Severity: NR

TASC classificaion reported
Wagner classification grade 2-4 in 104 limbs (59%) or as isolated calf ulcers in 42 cases (24%). In 30 (17%) limbs, complex below-theknee trophic lesions were noted.

Infection: NR
CVD 40 (22%)

CAD 122 (69%)

ESRD 33 (18%)

dialysis
161 procedures majority multilevel with 124 subintimal PTA (26 had single subintimal Ulcer healing: 129 (73%) before end of study, mean f/u 22 (1) months

Limb salvage: 12, 24, 36 and 48 month limb-salvage proportions: 89%, 83%, 80% and 80%. In a intention- to-treat analysis, the cumulative primary and secondary patency at 12, 24, 36 and 48 months were 62%, 45%, 41% and 38%, together with 80%, 69%, 66% and 66%, respectively.

Major amputation: 24 (13%) during f/u

Minor amputation: 67 (38%)

30-day mortality: 1% 2

year mortality: 19%

Major complication: 4
Level of intervention not described in all patients. Approximately 50% infrapopliteal or crural

70% neuropathy
Bargellini 2008 26 Prospective case series of multilevel subintimal PTA in patients deemed not fit for surgical bypass DM patients: 60

age: 69,4 (SD 9,4)

gender: 41 males
Distribution: NR

Severity: NR
Fontaine: 100% Fontaine IV

Infection: NR
CAD 42%

CVD 25%
Subintimal PTA in patients not suitable for surgical bypass:

Fem-pop level 56.7% (34)

Infrapopliteal level 25% (15)

Both levels combined 18,3% (11)
Mean follow-up 23 months (range, 0-48 months)

Ulcer healing: 75% (45/60)

Limb salvage: 93.3% (56/60)

Major amputation: 3 within 30 days and 4 within 16 months

Minor amputation:

Complications: Peri-procedural mortality was 5% (3/60)

Mortality at 1yr, 3yr 10%, 17%
How followup was performed, was not defined

Long term mortality low for a 'high risk' population medically unfit for bypass surgery
Davidson 1993 27 Retrospective case series

Bypass below knee case series
54 DM patients (total wpopulation 70) age 55-95; 38 men (total population) Distribution: majority infra-popliteal

severity: no information

No score of distribution
gangrene 56%, ulcer 28% (of total population)

Infection: NR

Ulcer score: NR
CAD 55%, CVD 27%, hemodialysis 7% (total population) Vein graft below knee (57% to foot) Limb salvage 90% at 12months and 86% at 24 months

Major complications: 9/70

Early graft failure n=3 (4.2%)

Patency 93% 1yr and 85% 2yrs

Mortality: NR
Follow-up duration was variable and after 1 year 29 limbs out of 58 limbs were available for evaluation and after 3 years 6 limbs out of 58. Strengths
Dosluoglu 2008 28 Case series

A comparison of peroneal to other run-off vessels after PTA
80 DM patients out of 111

age: NR

gender: NR
Distribution: infrapopliteal

Severity: NR

TASC classification provided
All tissue loss

Infection: NR
NR Infrapopliteal PTA Ulcer healing: NR

Limb salvage rate 75% in 24 months in diabetic patients with peroneal run-off and in run-off in other vessels 76%

No other data on the diabetes sub-group divided
Strengths and weaknesses: No data on patient, leg or ulcer characteristics in DM patients provided.

Study with less than 80% with diabetes but limb salvage was reported separately for the diabetes patients in both groups
Dorweiler 2002 29 Case series of pedal bypass grafts DM patients 46

age: median 69yrs

gender: 36/46 (78%) male
Distribution: crural occlusions

Severity: NR
All (100%) tissue loss

Ulcer score: NR

Infection: NR
CAD 46%

ESRD 13%
Pedal bypass with vein graft F/U median 28 (1-70) months

Ulcer healing:

Limb salvage: 30 days 98%, 87% at 2 years

Major amputation: 4 (3 within 30 days)

Minor amputation: 32/46

Complications: peri-operative mortality 2%

One patient failed graft within 30days

Mortality at end of study 21/46 (47%)
No data on severity of PAD.

No specific data on foot lesions

Drop out and loss to f/u NR

Well defined study
Faglia 2002 19 Case series

Mixed series of PTA
All DM patients 221

age: NR

gender: NR
Distribution: 11 patients ilio/ femoral/popliteal axis

81 exclusively infrapopliteal 127 femoropopliteal and infrapopliteal

Severity: TcpO2 21 (30 SD) mm Hg in 180 cases. ABI in 128 cases 0.53 (0.15)
Wagner grade ulceration

I - 19%

II - 25%

III - 17%

IV - 38%

V - 1%
CAD 55%

ESRD 4%
PTA of stenoses greater than 50% diameter infrainguinal Median f/u 12 (5-30) months

Ulcer healing:

Limb salvage:

Major amputation: 10 (5%)

Minor amputation: 83 (38%)

Mortality 30days: 0%

Mortality 5.3% at f/u

Complications: n=1 (transient renal failure)
Probably significant (> 80%??) of the data is a duplication of Pdf 117, data reported in DE 117

221 had angio but 2 had no significant stenoses therefore 219 reported

28 subjects PTA not possible (9 surgery and 19 no candidate for any revasc)

All ulcers healed with medical dressings of the 190 patients - nothing more specific
Faglia 2005 30 Retrospective case series

Consecutive series of diabetic foot patients hospitalised.

PTA as first choice revascularisation
DM patients 993

age: 65.5 (9.4)

gender: 663 (67%) male
7% ilio-femoral 61% femoropopliteal /crural 32% crural

Severity: tcpO2 17,0 (11,9)
88% tissue loss

Texas classification
0 - 12%

I - 16%

II - 19%

III- 53%
CAD 62%

ESRD 5%
PTA 68% procedures in crural arteries Mean f/u 26 (15.1) months

Ulcer healing: 862/868 wounds healed

Limb salvage: NR NR 21/993 major amputations

Minor amputation: 478

Complications: NR 3.4%

Mortality 30-day 1/993

Primary patency at 5yrs 88% (SD 9%)

Mortality at 1 yr 5% (extrapolated from Kaplan-Meier curve)
good wound description at presentation, level of disease : treated was well described some f/u data was obtained by treating physician telephone interview Possibly some patients reported elsewhere

Of the 993 treated with PTA only 10 did not manage to successfully get one vessel in line flow to the foot
Faglia 2009 31 Cohort with follow up 5,9 year (SD 1,28)

Follow up study of 564 diabetic patients with 'CLI' referred for angiography, patients with obstruction more than 50% underwent PTA, when possible as first choice
PTA: 413 DM patients age:69,7 (SD 9,5) gender: 146 (35,4%) females

Bypass group: 114 DM patients age: 69.9 (SD 9.4) gender: 35 (30.7%) females

No revasc group: 27 DM patients age: 76.7 (SD 10.4) gender: 13 (48,1%) females
Distribution:

PTA: Iliac -femoral- popliteal axis in 28 patients (6,8%)

Infra-popliteal in 137 patients (32,2%)

Combination of both in 248 patients (60%)

Bypass: NR No revasc: NR

Severity: PTA: tcpO2 15,3 (11,9)

Bypass: tcpO2 10,2 (10,3)

No revasc: tcpO2: 7,0 (8,1)

Scoring: NR
PTA: No lesion 62 (16%), rest Wagner 1-4
Infection: 65%

Bypass: No lesion 16 (14%), rest Wagner 1-4
Infection 63%

No revasc: No lesion 3 (11%), rest Wagner 1-4
Infection: 63%
PTA: Dialysis 24 (5,7%) CAD 225 (54,8%), CVD 53 (19%)

Bypass: Dialysis 8 (7%); CAD 64 (59%), CVD 18 (15,8%)

No revasc: Dialysis NR, CAD 24 (88,9%), CVD 9 (33,3%)
PTA:
Ulcer healing: NR
Limb salvage: NR
Major amputation: 1 month 6 (2,3%); 34 (8%) at end of follow up
Minor amputation: NR
Complications: NR

Bypass:
Ulcer healing: NR
Limb salvage: NR
Major amputation: 1 month 3 (5,4%); 24 (21%) at end of follow up
Minor amputation:
Complications: NR 36 (32%) primary bypass failures

No revascularisation:
Ulcer healing: NR
Limb salvage: NR
Major amputation: 16 at end of follow up
Minor amputation: NR
Complications: NR
PTA vs. bypass p < 0,001 SIGN 2-
In addition authors analyzed their datya as a a case control study No data on severity of PAD.

No specific data on foot lesions

Drop out and loss to f/u NR

Well defined study
The groups are the result of a stepwise treatment approach Statistical analyses do not seem systematically performed and analyses are missing. In particular, Kaplan-Meijer data are incomplete: number at risk at time points are missing. The study cannot used as a cohort study comparing PTA vs bypass, it does however give information about the results of PTA and information of the revascularised vs nonrevascularised patients

Baseline characteristics of the groups are different and therefore confounding was induced.
Ferraresi 2009 32 101 DM patients and 107 legs

age: 66 (SD 9,4)

gender: 16 females
Distribution: Infrapopliteal

Severity: tcpO2 18.1 (SD 11,2)

Infection: NR
34 ulcers, 74 gangrene

Rutherford classification
CAD 28%
CVD 4%
ESRD 3% (dialysis)
PTA infrapopliteal Ulcer healing: NR

Limb salvage: 93% during mean f/u 2.9yrs

Major amputation: 8/107 (7%) during mean f/u 2.9yrs

Minor amputation: 64%

Complications: NR

Mortality 30 day: NR

Mortality during f/u 9%
This case series is a sub analysis of a larger study Strengths: Treated lesions clearly defined and standardised Patients with marked tissue loss

Weaknesses: 1 and 3 year leg salvage and survival data are not provided, hindering interpretation.
Gargiulo 2008 33 Prospective case series

Outcome of successful tibial PTA in 'CLI'
74 DM patients out of 87 total population

age: 72 (SD 8,8)

gender: 44% female
Distribution: NR

Severity: NR
92% Fontaine IV

Ulcer classification: University of Texas

Infection: NR 237/318
CAD 53%
ESRD 28%
infrapopliteal PTA's (100%) combined with fem-pop angiopolasty in 63% and in 3 (3,4%) patients combined with open revascularisation Ulcer healing: 74,9% at 1 year

Limb salvage: 92,7% at 1 year

Major amputation: NR

Minor amputation: NR

Complications: No early perioperative complications
Only technically successful PTA included in the analysis Strengths and weaknesses: Strengths: well performed prospective study with complete data set, provides relevant information on wound healing Weakness: the shortest followup data was 2 days, a Kaplan Meijer that includes duration of follow-up is missing, hampering interpretation
Gibbons 1995 34 Retrospective case series

Infrainguinal bypass series
259 DM patients (total population 318)

age: mean age 66years

gender: 62.3% males
Distribution: Multilevel disease

Severity: no information

No score anatomical distribution Distribution:
(74.8%) ulcer or gangrene

Infection: NR

Ulcer score: NR
No information infra-inguinal open revascularisation

fempop 84 (26.4%) femtibial / peroneal 132 (41.5%) fempedal / plantar 100 (31.4%)
Ulcer healing: NA

Limb salvage: 97% at 6 months

Major amputation: n/a

Minor amputation: NA

93% primary graft patency at 6months and secondary 97%

Complications: morbidity peri-op 21%
Walking devices used at start of study 63% and at end of 6months 74%

38% more active at f/u 32.5% about the same and 29.5% worse. Less than half back to normal at 6months (47.4%)
primarily HRQOL study
Hering 2010 35 Prospective case series

Case series of crural PTA
All diabetics 44

Gender 33 male

Age 72 (42-88yrs)
Distribution: NR

Severity: NR
Wagner grade
I - 0
II - 6 (14%)
III (30 (68%)
IV - 8 (18%)

Infection: NR
CAD 77%
CVD 52%
ESRD 16%
Peroneal PTA Mean F/u 23 (5-45) months

Ulcer healing: 26/44

Limb salvage: 81%, 6, 71% 12, and 63% at 18 months

Mortality 30days: 9.1%

Major amputation: 5 (11%)

Minor amputation: NR

Complications: 1 renal failure
Really a prognostic study of doppler waveform patterns predicting outcome of peroneal PTA

Overall 50% had a restenosis or occlusion of peroneal artery
Hertzer 2007 36 Case series

Mixed case series of bypass grafts
312 DM patients out of 650 (48%)

age: NR

gender: 62 males
Distribution: NR

Severity: NR
71% ulceration or gangrene

Ulcer score: NR

Infection: NR
NR infrainguinal bypass grafts for occlusive disease Median follow-up 4yrs

Ulcer healing: NR

Limb salvage: 73% (95% CI 67 - 78) at 5 years, 15 years 51% (38 - 64)

Major amputation: 29 amputations in 201 diabetic patients

Minor amputation: NR

Mortality 6.7% 30 days
Strengths and weaknesses: very long follow up time limited specific data on diabetics
Hughes 2004 37 Retrospective case series

Series of pedal bypasses
DM patients 82 (84%), total 98

age: 68 (SD12)

gender: 81/98 (83%) male
Distribution: Crural

Severity: NR

No scoring
93 (95%) tissue loss

Infection: NR

Ulcer classification: NR
CAD 40%
ESRD 4%
Bypass to plantar and tarsal arteries with vein graft (one prosthetic)

Popliteal inflow 72% Pedal bypass
Mortality at end of study 83% at median 4yrs

Complications: not reported separately for diabetes

Duration of f/u median 9 (1-112)months

Ulcer healing: NR Mortality 30 days 1/98 total

Complications: 124 peri-op complications

Mortality at 1yr 9%, 5yrs 37%

Limb salvage 75% 1yr, 69% 5yr

Secondary patency 70% 1yr
Primary patency 41% and secondary patency of 50% at 5yrs

Consecutive series of all revascularisations

Excluded lost to f/u cases from analysis (n=26)
No differences in outcome between tarsal/ plantar and dorsalis pedis bypass
Isaksson 2000 38 Retrospective case series

Pedal bypass graft case series
DM patients 43 (48 legs)

age: 74 (40-84)

gender: females 27 (63%)
Distribution: NR

Severity: ABPI median 0.47 (0 - 2.14)

Score: NR
7 (15%) rest pain

All others (85%) tissue loss

Ulcer score: NR

Infection: NR
Prev MI 11 (26%), angina 6 (14%) with vein

(proximal anastomosis femoral artery 20 (42%) and popliteal artery or below 28 (58%))
F/U up to 1yr

Ulcer healing:

Limb salvage: 1yr 85%

Major amputation: NR

Minor amputation: NR

Complications at 30 days 2 died (4%), 1 patient MI

Mortality rate at 1yr 14%

Patency at 1yr 83%
Short followup - early results only
Jamsen 2002 39 Retrospective case series

Outcome of consecutive series of 100 infrainguinal PTA considered suitable for PTA first approach
100 patients (116 limbs) 76 (76%) DM patients

age: 72 (38-90)yr total population

gender: 40 (40%) total population males
Distribution: NR

Severity: ankle systolic pressure <50mm Hg

Scoring system not used
Rest pain 23 (20%), ulcer 50 (43%), gangrene 43 (37%)

Wound classification: NR

Infection: NR
CAD 47%,
CVD 28%
Angioplasty

Femoropopliteal 54%

Crural 17%

Multilevel 29%
Intention to treat analysis 1yr 67%, 3yr 63%, 5yr 56%, 8yr 45% limb salvage

Ulcer healing: NR

Limb salvage for endovascular treatments at 3, 5, and 8 years was 65%, 60%, and 60%,

Major amputation: 37 (32%) major amp during total f/u

Minor amputation: 14 (12%)

Major complications: 11%

The survival rates of the present study 7 2%, 26%, and 14% at 1, 5, and 10 years
11 required bypass for PTA failure.

Median f/u 25months. Validity of 5 and 10 year questionable - very small numbers available after 3 years

Pre selected to PTA first approach
Johnson 1995 40 Restrospective case series

Retrospective review of popliteal distal bypass grafts in patients with ESRD
43 DM patients In total population 53

age: 59 (total population)

gender: 27 males (total population)
Distribution: NR

Severity: in general toe pressures <40, ABI <0.5 (or incompressable)

Scoring NR
69 limbs (53 with tissue loss)

Ulcer score: NR
43 ESRD (kidney transplant 10)
CAD 38%
CVD 15%
Total population 69 venous bypasses:
Fem-pop 19
Crural 50
Ulcer healing: NR

Limb salvage: 1yr 65% and 62% at 18 months

Major amputation: 22 ('foot amputations')

Minor amputation: NR

Major complications: NR

Peri-op mortality 10% 1yr mortality 42%, 2yr mortality 72%
59% 'foot amputations' performed with patent graft Amputation can be related not only to occlusion but also to other factors like infection.
Kalra 2001 41 Retrospectivecase series

Series of pedal bypass grafting using vein
DM patients 191 (75%), total population 256, 280 procedures

age: median 70 (30-91)yrs total population

gender: 174 (68%) male total population

Long grafts (prox anastomosis above popliteal) 130 (46%) of total population

Short grafts (prox anastomosis at or below popliteal) 150 (54%) of total population
Distribution: NR

Severity: tcpO2 < 20mmHg in 88% and ABI =0.44 (38% incompressible) in 150 limbs

Scoring system: NR
90% tissue loss total population

Infection: NR

Wound classification: NR
(52%), CVD 54 (21%), ESRD 19 (7%) All vein bypass grafts to pedal vessels Ulcer healing:

Cumulative limb salvage rates at 1, 3, and 5 years were 85% (95% CI, 80.3-89.5), 79% (95% CI, 73.9-85.1), and 78% (95% CI, 71.7-83.7), respectively

Ulcer helaing: NR

Major amputation: 15% at 2.7years mean f/u

Minor amputation: 12.4%

Complications: 1.6% peri-op mortality

Long-term mortality 1,3,5 yr = 13%, 24%, 40%

Secondary patency at 1yr 78%, 3yr 72%, 5yr 71%
Survival rate was 65% if had patent graft at 5 yrs versus 26% if leg off

57% of patients had one or more secondary interventions for pedal graft
Kandzari 2006 42 Case series

Endovascular revascularisation using catheter based plaque excision
52 DM patients out of total pop of 69

age: 70 (SD 12) (total pop)

gender: 49% males
Distribution: 154/160 lesions infrainguinal 43% crural

Severity: ankle pressure < 50 mmHg
93% Ruth 5 7% Ruth 6 (total pop)

No ulcer lassififcation
CAD 57%
CVD 23%

Infection: NR
endo-vascular plaque excision Ulcer healing: NR

Limb salvage: NR

Major amputation: 20% diabetes versus 18% no diabetes (p=0.86) at 6 months

Minor amputation: NR

Complications: major adverse events (26.7% diabetes versus 22.2% no diabetes, p=0.72).
Data reported comparing patients with and without diabetes however very little information given
Leers 1998 43 Retrospective case series

Pedal bypass grafts in ESRD
DM patients 31 (91%) 34 total

age: 64 (39-85)yrs total population

gender: male 59% total population
Distribution: infrapopliteal in 23 legs and infrainguinal in 13 legs of total population

Severity (only in 16 patients): ABI 0.48 (0-0.95) mean, toe pressure 18 (0-78)
probably > 90% had tissue loss although this was not explicitly stated in the article

Wound classification: NR

Infection: NR
CAD: 28 (82%)
ESRD: 100% (29 haemodialysis and 2 transplants)
Pedal venous bypass 88% total population Average followup 13.5 (1-84) months

Ulcer healing: NR

Cumulative assisted primary patency at 1yr, 2ys = 62%, 62%

Limb salvage: 56% at 1yr total pop and at 2yrs 50%

Major amputation: 16 (39%) at 13.5months average f/u

Minor amputation: 51 (26%) total population at 1yr

Complications: Survival 64% at 1yr

1 periop death (2%)

Mortality 36% at 1yr and 48% at 2yrs
Survival rate was 65% if had patent graft at 5 yrs versus 26% if leg off

57% of patients had one or more secondary interventions for pedal graft
Malmstedt 2008 44 part of country wide observational data base (Swedvasc)

Outcome after bypass surgery in diabetics
742 DM patients

age: 74 (SD 9,8)

gender: 42% female
Distribution: NR

Severity: NR

Infection: NR
82% tissue loss

Ulcer classification: NR
CAD 65%

CVD 19%

ESRD defined as creatinine 150 umol/L 20%
261 femeralpopliteal bypasses 481 infrapopliteal bypasses Ulcer healing: NR

Limb salvage: NR

Major amputation: NR

Minor amputation: NR

Complications: NR
Composite primary endpoint was: amputation or death With a median follow-up of 2,2 years the rate of ipsilateral amputation or death per 100 person years 30,2 (95% CI 26,6-34,2) Median time to life or limb loss was 2,3 years (CI 1,9-2,8)

The use of the composite end-point renders interpretation very difficult.
Mills 1994 45 Retrospective case series of patients with popliteal distal vein bypass grafts 46 DM patients (total population 53)

age: 62,4 (total population)

gender: 37 men (total population)
Distribution: infra-popliteal

Severity: NR

Scoring distribution: NR
52 tissue loss

Infection: NR

Ulcer score: NR
ESRD 28%;
CAD 57%;
Infrapoplitea lvein bypass

All crural bypass
Ulcer healing:

Limb salvage: 85% after 1 year (22 limbs out of 56 legs available at 1 year).

Major amputation: NR

Minor amputation: NR

Complications: Peri-operative mortality: 2 out 53 (3,6%) Within 30 days 2 graft occlusions with subsequent 2 major amputations

Mortality 1yr, 13%, 2yr
Strength: well defined cohort

Weaknesses: high rate withdrawal rate, probably combination of short duration and lost-tofollow- up (not reported separately)

Paper is an example of the confusion between the total population, number of diabetics, number of extremities and number of procedures.
Mohan 1996 46 Case series

Pedal bypass graft case series
All DM patients 32

Mean age: 60 (range 42-84) yrs

gender: 50% males
Distribution: popliteal artery inflow AK pop 9 BK pop 26

Severity: NR
NR 18 (51%) ulcers 15 (43%) gangrene 2 (6%) patients rest pain

Ulcer score: NR

Infection: NR
CAD 47%
Chronic renal failure 28%
Popliteal to distal artery bypass
PT
9 AT 8
DP 10
Peroneal 8

All vein grafts
Mean followup 24 (1-72) months

Ulcer healing: NR

30day mortality 0%

Limb salvage: 90% at 1yr, 82% at 3 years

Major amputation: 5 within 20 months

Minor amputation: NR

Patency 1, 3yr 95%, 89%

Complications: 4 failing grafts surgery revised. 3 bypass occlusions of which 2 resulted in major amputation 3 additional amp due to infection

Mortality (longterm): NR
Small study population and no information regarding drop-out rate
Owen 2007 47 Cohort study
According to 4 different levels of kidney disease
CKD 4 (eGRF 15-29): 25 DM patients out of 32 (total cohort)
age: 67,5 (SD 11,5)
gender: 19 males (59%)

CKD 5 (eGRF < 15 and HD): 60 DM patients out of 72 (total cohort)
age: 65 (SD 11)
gender: 38 males (53%)
Distribution: infra-inguinal, no further data given

Severity: NR
CKD 4 (eGRF 15-29): 84% foot lesions

CKD 5 (eGRF < 15 and HD): 90% foot lesions

Ulcer score: NR

Infection: NR
CKD 4 (eGRF 15-29): CAD: 23 (71,9%)

CKD 5 (eGRF < 15 and HD): CAD: 44 (61,1%)
Infra-inguinal bypass CKD 4 (eGRF 15-29):
Ulcer healing: NR
Limb salvage: at 5 year 77 (Sd14)
Major amputation: NR
Minor amputation: NR
Complications: 30 day mortality 3,1%

CKD 5 (eGRF < 15 and HD):
Ulcer healing: NR
Limb salvage: at 5 year 50 (Sd 12)
Major amputation: NR
Minor amputation: NR
Complications: 30 day mortality 4,2%

CKD 5 mortality at 1yr 46%, 91% at 5yr

SIGN 2-
A study that provides relevant data on CKD in severe forms as a prognostic factor.

Infra-inguinal bypass, outflow data not provided

This study was reported as a case series

Probably only sufficient data on CKD 5 patients

Difficult to use patency data because mortality very high
Panneton 2000 48 Retrospective case series

Pedal bypass graft series
DM patients 157

age: 66 (30- 78)yrs

gender: 111 males
Distribution:

NR Severity: NR

Scoring system: NR
93% tissue loss 53% gangrene

Wound classification: NR

Infection: 27%
CAD 80 (51%),
ESRD 41 (26%)
Pedal bypass graft with vein Mean follow-up 2.7yrs

Ulcer healing: NR

Limb salvage: 1yr 86%, 5yr 78%

Major amputation: NR

Minor amputation: NR

Complications: 30-day mortality 1.3%, MI 11 (7%), ARF 5 (3.2%), major amp 3 (1.8%)
A sub group of a series comparing diabetics versus no diabetics in which no differences were observed between the two groups Comparison of diabetes and no diabetes
Pomposelli 1995 49 Case series

Retrospective review of 367 consecutive patients undergoing 384 distal bypasses
350 DM patients, total population 367

age: 58 mean

gender: 352 male; 114 female
Distribution: NR

Severity: NR

Scoring: NR
219 (72%) with ulcer; 47 (12%) of gangrene; 16% other indications

Infection: 222 (55%)

Ulcer classification: NR
Prior myocardial infarction 29%, CVD 12%, ESRD 5% (dialysis) of total population Dorsalis pedis arterial bypass Sub group analysis of 1032 DP artery bypass

All except 2 with vein
Ulcer healing: NR

Limb salvage: cumulative limb salvage rate 87% at 5 years. 1yr and 2yr estimated from K-M 90% and 85%

Secondary patency rates 82% at 5yrs

Major amputation: 13 (3,5%) within 30 days. Total number of major amputations 30 (8,1%) within the 5 year follow up.

Minor amputation: 75 (19%)

Complications: 30-day mortality 1.8% myocardial infarction 5.4%. graft failures 7.5% at 30 days,

Mortality 43% after 5yrs
Comorbidity subdivided in various kinds of cardiovascular disease. 43 (4.2%) failed within 30 days Large case series, long follow up period (5 years). Outcome is rather thoroughly described.

Retrospective evaluation; not based on predifend problem; there is no drop out rate reported. Outcome lim salvage wasn't defined any further. Sub-group analysis of a large 3731 bypasses to 1032 to DP arteries of which some were diabetic (865)
Pomposelli 2003 50 Retrospecitve case series

Pedal bypass graft series
865 total population 92% diabetes

age: 67

gender: 69% male
Distribution: inflow vessel 41% BK pop 29% CFA 12% AK pop 11% SFA

Severity: NR

No scoring
78% ulcer

Infection: NR

Ulcer score: NR
CAD 47%
ESRD 11%
Of the total population
Ulcer healing: NR

Limb salvage: 78% at 5 yrs and 10yrs 58%

Graft patency 85% 1yr

Secondary patency at 5yrs 66% DM versus 56% no DM

51% and 76% mortality at 5 and 10yrs

Major amputation: NR

Minor amputation: NR

Complications: 10 (1%) deaths within 30days 3% MI
Pua 2008 51 Case series

Consecutive patients receiving PTA for limb slavage
91% DM patients out of 46 total

age: NR

gender: NR
Distribution: NR

Severity: NR

No Score
37/46 patients with foot lesions

Ulcer score: NR

Infection: NR
33% CAD
20% CVD
Mixed 25
5 crural
16 fem-pop
3 aortoiliac
Ulcer healing: at 13months 66% patients with gangrene healed

Limb salvage: 78% at 1 year.

Mortality: NR

Major amputation: NR

Minor amputation: NR
5 technical failures Limited information regarding patient characteristics, comorbidity and selection procedures.

Foot ulcers / gangrene are not specified any further
Ramdey 2002 52 Prospective case series (registry)

Infrainguinal revascularisation
DM patients; 92% out of a total population of 146

age: 63 (SD 13) (total population)

gender:65 % (Total population)
Distribution: NR

Severity: NR
Tissue loss: 91% (total population)

Ulcer score: NR

Infection: 48%
CAD 115 (65%)
MI 64 (36%)
CVD 27 (15%)
ESRD: all patients
Artery Inflow Iliac or femoral 123 (70%) Suprageniculate popliteal 20 (11%) Infrageniculate popliteal 34 (19%)

Outflow Iliac/femoral 1 (0.6%) Suprageniculate popliteal 17 (10%) Infrageniculate popliteal 28 (16%) Tibial 50 (28%) Dorsalis pedis 80 (45%) Tarsal 1 (0.6%)
Follow-up: no data provided

Complications: 30 day morbidity 23%

30 day mortality 5%

Ulcer healing: NR

Patency 1,3yr: 85, 68%

Limb salvage: 1 yr 80% and 3yrs 80%

Major amputation: 21

Minor amputation: NR
Follow-up not specified Follow-up not specified
Reed 2002 53 Retrospective case series

Case series of bypass grafts originating distal to the groin
DM patients 140, total population 217, 249 procedures

age: 65 (30-90)

gender: 79 female
Distribution: NR

Severity: NR

Scoring system: NR
Necrosis 127 (80%), rest pain 27 (17%)

Infection: NR

Wound classification: NR
CAD 95 (60%),
ESRD 53 (33%) with 35 (23%) on dialysis
Infrainguinal vein bypass graft Pedal (35%), Crural (60%) Femoropopliteal (4%), Survival 60% 1 year, 3yrs 18% and only 5% alive at 5yrs 30 day mortality 0.6%

Complications: major post-op morbidity 16 (10%)

Ulcer healing: NR

Limb salvage rate was 84% (SD +/-4) at 5years

Major amputation:

Minor amputation:

5yr patient survival was 44 (+/-5)%
Data extracted out of a cohort study comparing diabetics with non diabetics

21% secondary procedures

Mean 27months f/u
Rosenbaum 1994 54 Retrospective case series

Case series of infrapopliteal bypass grafts
DM patients: 39

age:62.3 (45-78)

gender:33 (85%) males
Distribution: NR

Severity: NR

Score: NR
100% tissue loss

Ulcer score: Gibbons classification

Infection: NR
NR Peripheral bypass: 79% infrapopliteal

Popliteal 19%
Tibial/ peroneal: 48%
Dorsalis pedis/plantar artery: 31%
Aotobifemoral 2%
Follow-up: Mean 21,2 (2-64) months

Ulcer healing: 40 limbs (of total 42 limbs) with or without foot surgery

Limb salvage:

Major amputation: 1

Minor amputation: NR

Complications:
Data of this study may be included in other reports of this group No life-table analysis, no information about healing time, small series; follow-up procedures unclear
Saltzberg 2003 55 Retrospective case series

Case series of mixed bypass grafts
DM patients: 96% of total population in 51 patients all younger than 40 years

age: 36 (27-40 yrs)

gender:49% male

All data in this table as reported on total population
Distribution: 76 bypass procedures with inflow:
Common Iliac 2.6%
Femoral 67%
Above knee popliteal 7,9%
Below knee popliteal 21.1 %
Tibial artery 1.3%

Severity: NR
86% tissue loss

Ulcer score: NR

Infection: NR
CAD 37% ESRD (creat > 2 mg/dl, dialysis or transplant) 53% (of which dialysis 29%) Venous (95%) or prosthetic (5%) bypass with outflow:
Dorsalis Pedis: 30,3%
Tibial artery: 18.4%
Peroneal atery 3.9%
Below knee popliteal: 23,7%
Above knee popliteal: 11.8%
Femoral artery: 3.9%
Other: 7.9%
How follow-up was performed not described; no data on follow-up reported NR

Patency 1yr, 5yr 82,63%

Ulcer healing: NR

Limb salvage: 87% at 1 year and 77% at 5yrs

Major amputation: 23.5% required amp level unspecified (12/51)

Minor amputation: see above

Complications: 30 days mortality rate: 0%; postoperative heart failure: 1.32%

Overall motrality 88%, 73% at 1yr, 5yrs
Unspecified follow-up
Schneider 1993 56 Case series of pedal bypass extracted from an intital cohort study of diabetes versus non diabetes but this study compares tibial with pedal DM patients 45 of total population n=53

age: 67 (42-78)yrs total population

gender: 33males of total population
Distribution: NR

Severity: ABI 0.53 total population
77% tissue loss

Ulcer score: NR

Infection: NR
CVD NR
CAD NR
ESRD NR
All pedal bypass graft with vein Follow-up: 22.5months (SD 3.4)

Ulcer healing: NR

Patency 1yr,3, 5yr 70, 58, 58%

Limb salvage at 1,3,5yr: 98%, 98%,95%

Major amputation: NR

Minor amputation: NR

Complications: Peri-op 9% mortalty

Mortality 27,39,50 at 1yr,3,5yr
Major amputation defined as amputation proximal to metatarsals

Low numbers of patients (6) at 5yrs
Schneider 2001 57 Retrospective cohort

Revascularisation using either fem-distal bypass, combined SFA PTA and distal bypass grafting or short distal bypass graft
SFA PTA plus short distal bypass DM patients 12

age: 70 (13) yrs

gender: 83% male

Long distal bypass DM patients 46

age: 68 (11) yrs

gender: 50% male

Short distal bypass DM patients 52

age: 69 (11) yrs

gender: 65% male
Distribution: Combined:
Below knee disease plus focal SFA disease (<3cm length)
Severity ABPI 0.52 (0.19)

Long distal bypass:
Extensive infrainguinal disease involving fempop and infrageniculate arteries
Severity ABPI 0.42 (0.17)

Short distal bypass:
Severe infra-geniculate occlusive disease and patent fempop arteries
Severity: ABPI 0.46 (SD 0.15)

Scoring system: NR
All gangrene

Infection: NR

Wound classification: NR
Combined CAD 33%,
ESRD 58%

Long distal
CAD 38%
ESRD 74%

Short distal
CAD 49%
ESRD 67%
Distal target vessels

Combined
Tibial - 25%
Pedal 75%

Long distal
Tibial 57%
Pedal 43%

Short distal
Tibial 35%
Pedal 65%
Mean f/u 23 months

Ulcer healing: NR

Limb salvage at 2 years
Combined 90 (9)%
Long distal 78 (9)%
Short distal 98 (2)%

Patency all procedures 78 (+/-5)% at 2yrs, 63 (8)% 5 yrs

Major amputation: NR

Minor amputation: NR

Complications: NR

Mortality: NR

No differences between groups

SIGN 2-
Small sample

Heterogeneous populations - different distribution of PAD

Confounding by indication

Drop out and loss to f/u not reported
Sigala 2006 58 Case series

Mixed bypass graft plus 50 PTA
All diabetics 97 with 121 procedures

66% male

Mean age 68 (range 41 - 85)yrs
Distribution: Large variation

Severity: NR
49 necrosis 32 gangrene, 24 ulcers, 16 rest pain,

Ulcer score: NR

Infection: NR
CAD 78%
CVD 20%
100% ESRD
Infra-inguinal revascularisations

Endovascular - 36% only

5% combination endo and open

Bypass only 59%

Crural artery 55% 10% crural artery only 28% femoropopliteal 18% ext iliac to femoropopliteal
Ulcer healing: NR

Limb salvage: 86% at 6 mo, 75% at 12, 56% 3 yrs

Major amputation: NR

Minor amputation: NR

Complications 12/97 patients

Mortality 30day 10%, 1yr 22%, 3yr 56%
Heterogeneous population of patients with wide variation of PAD distribution and revascularisation procedures

All patients had ESRD

Number of infections not stated in study but outcomes reported in K-M relative to infection
Sigala 2006

PDF 845
Soderstrom 2008 59 Prospective case series

Healing of ischaemic ulcers after infrainguinal bypass surgery
74 DM patients out of 148 total population

age: NR

gender: NR
Distribution: NR

Severity: ABI < 0,5, systolic toe pressure < 30 mmHg. Fontaine 4

Classification: NR
Classification provided: All Fontaine IV ulcers

Infection: NR
NR Infra-inguinal bypass in all subjects, with 13 PTA inflow procedures (total population) Ulcer healing: 63% in 12 months in the diabetic patients

Limb salvage: NR

Major amputation: NR

Minor amputation: NR

Complications: NR

Mortality: NR
Median time to achieve healing 213 days

Diabetes was the only risk factor which delayed tissue healing (HR 0.5 95%CI 0.3-0.8 in multivariate analysis)
Arterial run-off for patients with diabetes not specified.

No specific data on diabetic patients reported other than healing
Stonebridge 1991 60 Case series

Retrospective review of 117 diabetic patients with a popliteal artery (or below) to distal bypass
All DM patients (117)

age: 64 (27-92)

gender: Male:female 5:1
Distribution: tibial

Severity: NR

Scoring: NR
non-healing 65 (52%), gangrene 20 (16%)

infection: 40 (32%) foot abscess 2 (1.6%) osteomyelitis 6 (5%)

Ulcer score: NR
CAD 37/117
ESRD 17/117
pop-distal by-pass graft (129 procedures) Ulcer healing: NR

Limb salvage: NR

Major amputation: 8 during mean f/u 13months: minor amputation: 34

Complications: operative mortality 0.8 %,

1yr and 3yr secondary patency rates 92% and 89%
Non data about inclusion criteria according to PAD severity.
Tannenbaum 1992 61 Retrospective case series

Case series of pedal bypass
DM patients 53

age: NR

gender: 34 male
Distribution: NR

Severity: NR

Score: NR
73% ulcers,

Infection: 45% cellulitis, 29% osteomyelitis, 20% gangrene, 2% abscess

11 minor amps performed pre bypass
NR DP bypass with vein Follow-up: average 25 (SD 14) months 10 patients lost to f/u

Limb salvage 1,2,3yr 98%, 98%, 95%

Major amputation: NR

Minor amputation: NR

Patency 1,2,3yr 95%, 95%, 95%

Complications: NR

Mortality rate 1,2,3yr 5%,16%,16%

In the patients who didnt die or major amp all ulcers healed during f/u
Study of acute sepsis in ischaemic diabetic feet

Excellent limb survival and patient survival and healing

No report on severity of PAD

Wound infection 13%
Taylor 1987 62 Retrospective case series

Case series of 114 patients with infection, 43 of whom revascularised
DM patients 114 patients with a foot infection (138 limbs):

43 (48 limbs) with ischaemia and 71 without ischaemia

age: NR

gender: NR
Distribution: NR

Severity: NR But ischemia was defined as absent pulses + ABI < 0.6 or TBI < 0,4 and abnormal wave forms

Score: NR
All infected ulcers

Ulcer score: NR
NR Peripheral bypass undefined Mean f/u 3yrs (1-11yrs)

Ulcer healing: NR

Limb salvage: 2yrs 87%, 4yrs 73%

Major amputation: 9 (19%) at 3yr mean f/u

Minor amputation: NR

Complications: NR

Motality rate at 1,3,5yr 19, 62, 84%
17 lost to follow-up

No data on lost to follow up on revasc patients

Much important data missing

4/9 amputations due to infection
Toursarkissian 2002 64 Primarily a prognostic study of the use of duplex as a predictor of bypass graft failure in diabetics DM patients 65

age: 61yrs

gender: 40/64 (63%) males
Distribution: NR

Severity: toe brachial index 0.2

Score: NR
61 (94%) tissue loss

Infection: NR Ulcer

score: NR
CAD 38%,
ESRD 16%
68 limbs

Femoral to distal bypass 42
BK pop distal 16
Fem pop 10

All vein bypass
Duration of f/u 12months (SD 6months)

Ulcer healing: NR

Limb salvage: whole group 80% at 1 yr

Major amputation: 8/68 limbs at 12months (SD 6months)

Minor amputation: NR

Graft patency assisted primary 75% at 1 yr (estimate of K-M)

Complications: nil

Mortality: NR
86% Hispanic population
Uccioli 2010 65 Case series of pedal bypass 135 patients 144 procedures all DM patients

age: 62 (SD 11)yrs

gender: 78% males
Distribution: NR

Severity: NR
96% tissue loss

Ulcer score: NR

Infection: NR
CAD 62%
ESRD 20%
Dorsalis pedis bypass grafts Median f/u 8 (1-62) months

Ulcer healing: NR

Limb salvage: 83% at 30 months

Major amputation: 19% at total f/u (mean 8 months)

Minor amputation: 36%

Patency : 70% 1yr, 68% 30months

Complications: 25 peri-op complications

Mortality 30day 1.5%

Mortality at end of study 10%
82% hispanics

Study comparing outcome in various ethnic groups (hispanics versus no hispanics). Higher amp rate in hispanics
Verhelst 1997 66 Retrospective case series

Case study of pedal and crural bypass graft
DM patients: 33 (92% of total population n=36)

age:62 (29-78)

gender: 29 males

All data in this table as reported on total population
Distribution: NR

Severity: tcpO2 18 mmHg +/- 7

Score: NR
89% tissue loss

Ulcer score: NR

Infection: NR
CAD 44%
Dialysis 4
Popliteal-to- Distal venous Bypass Grafts (n=44):
Posterior tibial: 13
Anterior tibial: 10
Peroneal: 6
Dorsalis pedis/ plantar: 23
Meal follow-up 27 months (1-65)

Ulcer healing: in 33/36 patients complete healing of skin lesions and that includes minor amputations.

Limb salvage: 90, 82, 77% at 1, 3 and 5 years.

Major amputation: major amputations occurred in follow up period of 27 months

Minor amputation: 35

Patency 1,3yr 87%, 74%

Complications: MI 1
Heart failure 1
Post-operative bypass occlusion and major amputation 3

Mortality 30days 0%

Deaths: 4 during following follow-up
Confusion between patients/ extremities. Small study. Mixture of vascular interventions.

Started treating 33 patients - No standard error in curve and therefore high likelihood of significantly small numbers during follow-up
Werneck 2009 67 Case series

Tibial PTA in patients with 'CLI' at 'high risk' restrospective case series
40 DM patients (total population 49)

age:70

gender: 71% males
Distribution: All had 'severe' tibial disease, "some also had femoropopliteal PAD"

Severity: NR

TASC reported:
Classification: 20% Ruth 4 80% Ruth 5*

Infection: NR
CAD 69%
ESRD 73%
of the total population
Tibial angioplasty in all and in 45% multilevel (fempop segment) Ulcer healing: NR

Limb salvage: 76% after mean f/u 8months
Cumulative limb salvage rate in tibial PTA only after 1yr: approx 70% estimated from K-M

Major amputation: NR

Minor amputation: NR

Complications: major complications occurred in 6.1% 30day mortality 2%

Mortality after 1yr 10%
Angiographic success rate was 84%. Number of pts with surgery vs. PTA not given. There are 10 amputations in diabetics. However, it is unclear how many vases were in the PTA group.
Woefle 1993 68 Retrospective case series Case study of mixed bypass grafts DM patients: 72

age: 70.5

gender: NR
Distribution: Isolated Tibioperoneal Vessel Occlusive

Disease Severity: NR
Bypass
All with minor tissue loss

Ulcer score: NR

Infection: NR
CAD 41
ESRD (creat > 2 mg/dl): 18
Symptomatic carotid disease: 15
Distal Vein Graft Reconstruction:
Proximal anastomosis:
Below knee popliteal: 56
Anteriot tibial: 18

Distal anastomosis:
ATA 10
DPA 37
PTA 13
Peroneal: 12
Plantar 3
Follow-up: no information provided how this was performed or data reported Ulcer healing:

Limb salvage: at 30 days 93%, at 1 year 81%, 5yr 72%

Patency: 30days 97%, 1yr 86%, 5yr 75%

Major amputation: NR

Minor amputation: NR

Complications: mortality within 30 days 1,3%

23 patients died during follow-up (including postop mortalty)
ulcer healing not reported; total number of BK amputations not reported. No data on follow-up
Woefle 2000 69 Retrospective case series of two different procedures
Bypass crural versus PTA crural
Bypass DM patients 125 (130 grafts)

age: 70 (50-87)yrs

gender: NR

Distal PTA DM patients 74 (89 limbs), 84 total

age: 68 (48-89)

gender: NR
Distribution: Crural

Severity: NR

PTA Distribution: Crural

Severity: tcpO2 6.7 (0-29)

Score: AHA
Bypass 127 tissue loss

PTA 84 tissue loss

Ulcer score: NR

Infection: NR
Bypass
CAD 57%
CVD 18%
ESRD 25%

PTA
CAD 48%
CVD 17%
ESRD 42%
Vein to DP in 63 or ant tibial artery in 20 and PT in 28 and in peroneal in 19

Angioplasty crural arteries AHA classification (1994)
1 - 8
2 - 28
3 - 26
4 - 27
Average followup probably 24months

Bypass
Limb salvage 80% 1yr, 73% at 3yrs and 69% at 6yrs

2.3% 30day mortality

Patency 1,3,5yr = 76%, 70%, 60%

30 major amputation at 24months

Minor amputations: NR

64 died during f/u

PTA
Limb salvage 1yr 82%, 77% at 3yrs and 77% at 5 years

30day mortality 6%

17 major amputations during 24 months

Minor amputations: NR

26 deaths died during f/u

Complications: Major haematoma 3 patients
Poor information on loss to follow-up and drop out.

Retrospective case series of two different procedures and not a controlled study
Woefle 2001 70 Retrospective case series

Case studies infrappopliteal bypass graft
DM patients: 135 (143 procedures)

age:70 (50-89)

gender: NR
Distribution: extensive intra-popliteal occlusions

Severity:NR
Tissue loss in 140 limbs

Ulcer score: NR

Infection: NR
CAD 82 (61%),
ESRD 43 (16%),
CVD 29 (20%),
All venous bypass with proximal anastomosis:
BK popliteal 113
ATA 29
PA 1

Distal anastomosis:
ATA 21
DPA 71
PTA 29
Peroneal 22

PTA of SFA prior to surgery in 37
Follow-up duration not reported

Ulcer healing: NR

Patency 1yr 83%, 5yr 60%, 7yr 51%

Limb salvage: Limb salvage rates 30 days 94%, 1 yr 80%, 5 yrs 74%, 7 yrs 64%

Major amputation: 35 during follow-up

Minor amputation: NR

Complications: 30 day mortality 8%

Mortality 1yr 27%, 5yr 70%, 7yr 82%
No data on mean duration of followup or on severity of PAD
No data on
Zayed 2009 71 Retrospective series

Series of combined PTA and bypass surgery
DM patients: 312

age: 188 males (40%)

gender:188 males (60%)
Distribution: NR

Severity: NR

Classififcation: NR
93% tissue loss

Ulcer score: NR

Infection: NR
CAD 107 (34%)

Dialysis: 33 (10.5%)
257 (82%) PTA,

55 (18%) surgical bypass open surgery

20 had combination of both procedures
Follow-up not defined and no data reported

Ulcer healing: NR

Limb salvage: NR

Major amputation: 13 cases (4,1%), of these 7 had PTA, 6 had reconstructive vasc surgery

Minor amputation: NR

Complications: NR
follow-up

PTA not specified, severity of PAD not described

All amputations above or through knee

III. Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report.

Contents

    Introduction Diagnosis of PAD Assessing severity of PAD and estimating wound healing potential Imaging modalities for PAD in diabetes
      Colour Doppler ultrasound Multi-detector-row computed tomography angiography Contrast enhanced magnetic resonance angiography Intra-arterial digital subtraction angiography
    Treatment References

I. Introduction

Peripheral arterial disease (PAD) causing arterial insufficiency is an important predictor of outcome of ulceration of the foot in patients with diabetes. The clinician examining a patient with diabetes and an ulcer of the foot should therefore always evaluate the vascular status of the lower extremity, specifically looking for signs of ischaemia, as up to 50% of these patients have signs of PAD1-3. Whenever a major amputation is under consideration, the option of revascularization should always be considered first.

In people with diabetes, atherosclerosis and medial sclerosis are the most common arterial diseases of the peripheral arteries. PAD is characterised by obstructive atherosclerotic disease reducing distal blood flow and perfusion pressure. Peripheral vascular involvement is diffuse and particularly severe in the tibial arteries, with a high prevalence of long occlusions. Moreover, collateral formation - a normal response to blockade of a large artery - is impaired in patients with diabetes rendering the tissue downstream more susceptible to severe ischaemia. Medial sclerosis (Mönckeberg sclerosis) is calcification of the tunica media producing rigid arteries - without encroachment on the arterial lumen. Thus medial sclerosis, which is frequently associated with neuropathy, does not cause ischaemia, but the rigid arterial tube may severely interfere with indirect measurement of arterial blood pressure, as discussed below4. In the past diabetic microangiopathy was thought to be an important cause of poor healing of a diabetic foot ulcer. However, there is currently is no evidence to support this notion and PAD is the most important cause of impaired perfusion on the foot of a diabetic patient5.

II. Diagnosis of PAD

In all patients with a foot ulcer, evaluation should include at least a history and palpation of foot pulses. A history of intermittent claudication or ischaemic rest pain should be obtained. However, many patients with diabetes and PAD have few or atypical symptoms Severe lower extremity ischaemia and extensive tissue loss may occur without pain, frequently due to the concomitant neuropathy. In addition, the foot should be observed while elevated above the heart in a supine position and subsequently lowered in a sitting position; pallor of the foot with elevation and rubor on dependency suggest severe ischemia. The presence of a femoral bruit is also a reliable sign of PAD6.

Palpation of pulses in the posterior tibial and dorsalis pedis arteries is mandatory. Detection of foot pulses by palpation is affected by room temperature and the skill of the examiner and pedal pulse palpation has moderate reproducibility7. Therefore in all patents with a foot ulcer a more objective evaluation should also be performed. This should include hand-held Doppler evaluation of the flow signals from both foot arteries (dorsalis pedis and posterior tibial). An absent or monophasic signal is an indicator of severe PAD. The ankle brachial index (ABI) should also be obtained by measuring the systolic blood pressure from both brachial arteries and from both the dorsalis pedis and posterior tibial arteries using a Doppler device and appropriately sized pneumatic cuffs. The higher ankle pressure on each side and the highest brachial pressure are used to calculate the ABI. The leg arteries in diabetic patients with a foot ulcer can be calcified, resulting in partially-compressible or non-compressible arteries and pressures are measured during limb cuff inflation that are above true systolic values. An ABI above 1.3 indicates non-compressible leg arteries, a finding in up to 1/3 of the diabetic patients with a foot ulcer1. While an ABI value greater than 1.3 does not provide an accurate assessment of lower extremity ischaemia, this is associated with increased cardiovascular event rates and other risk factors for PAD. Less severe calcification may result in a normal ABI (0.9-1.3) despite clinically significant PAD. An ABI < 0.9, however, is highly suggestive of PAD. Toe-pressure measurements are probably more reliable in assessing forefoot circulation in patients with diabetes, since the digital arteries are less frequently affected by calcification. A toe pressure <55 mm Hg or a toe-brachial index <0.7 strongly suggests PAD in a foot acclimatised in a warm surrounding8.

III. Assessing severity of PAD and estimating wound healing potential

Once the diagnosis of PAD is established, attempts should be made to assess the severity of the perfusion deficit. An ABI <0.6 indicates significant ischaemia with respect to wound healing potential. As discussed above, the ABI is a gross measurement and is often unreliable in patients with ulceration of the foot and diabetes; other methods such as toe-pressures and tcpO2 are often more useful. Multiple factors influence wound healing in diabetes, one of which is perfusion. Prediction of wound healing based on perfusion testing, regardless of method, follows a sigmoidal curve. Ulceration of the foot in diabetes will generally heal if the toe pressure is >55 mmHg and the tcpO2 >50. Healing is usually severely impaired when toe-pressure is <30 mmHg and tcpO2 <30 mmHg. When inadequate perfusion is identified, revascularisation should always considered (see below).

In patients without clinical signs of ischaemia or with perfusion measurements suggesting only mild PAD, the effect of 6 weeks optimal wound care should be evaluated. If the wound healing response is poor, perfusion should be reassessed. Duplex ultrasound or angiography of the arteries of the lower limb should be strongly considered to assess the presence, severity, and distribution of arterial stenoses or occlusions. Detailed angiograms of belowknee and pedal arteries, especially with a dedicated assessment of the pedal circulation, are critically important in patients with diabetes.

Efforts should be made to objectively diagnose and quantify PAD in all patients with ulceration of the foot in diabetes. If PAD of sufficient severity to impair wound healing is identified, revascularisation (endovascular or bypass) should be considered in all ambulatory patients. Exceptions to this general rule may include: severely frail, elderly (or short life expectancy, <6-12 months), patients; patients with pre-existing severe functional impairment unlikely to be significantly worsened by an amputation; and patients who have such a large volume of tissue necrosis that the foot is functionally unsalvageable.

IV. Imaging modalities for PAD in diabetes

1. Colour Doppler ultrasound

Colour Doppler ultrasound (CDUS) combines real-time B-mode imaging and pulsed Doppler flow detection to provide both anatomic details and a physiologic assessment of blood flow at specific arterial sites. Most current instruments can display the Doppler flow information as either spectral waveforms or a color-flow map. By scanning sequentially from the abdominal aorta through the iliac, femoral, popliteal, and tibial arteries, the entire lower extremity arterial circulation can be directly evaluated. Classification of disease severity is based primarily on focal velocity changes derived from spectral waveforms9. The sensitivity of CDUS for detecting a hemodynamically significant lesion (≥50% diameter reduction) ran ges from 89% in the iliac segment to 68% at the popliteal artery. Sensitivities for predicting interruption of patency are 90% for the anterior and posterior tibial arteries and 82% for the peroneal artery9. The ability to evaluate the arteries below the knee is particularly important in diabetic patients. However, diffuse multisegmental involvement and calcifications may hamper the examination.

Although CDUS is noninvasive and relatively inexpensive compared to the other anatomical imaging modalities, it requires sophisticated equipment and specialized expertise and is not appropriate as a routine screening test. The best role for CDUS is as an "intermediate" diagnostic test when simple physiologic screening such as ankle-brachial indices or TcpO2 indicate the presence of disease but more invasive and expensive anatomic imaging is not yet needed. In this setting, CDUS can be used to assess the location and severity of arterial lesions throughout the lower extremity and serve as the basis for initial clinical decisions, including the need for intervention and also to guide intervention when the decision to revascularise has been taken 10-12.

2. Multi-detector-row computed tomography angiography

Multi-detector-row computed tomography angiography (MD-CTA) is a low invasive imaging modality for PAD. It can be performed with any MD-CTA, however, currently 32 to 128 row scanners are used for peripheral MD-CTA and iodinated contrast media are injected intravenously. For lower extremity PAD the scan range is from the renal arteries to the foot. After data acquisition 3D reconstructions are performed. The sensitivity and specificity in comparison to the reference examination digital subtraction angiography (DSA) has been evaluated extensively. In two meta-analyses the pooled sensitivity and specificity for detecting a stenosis of at least 50% per segment were 92 -95% and 93-96%, respectively13,14. The advantage of MD-CTA is high image resolution for better evaluation of the small vessels in the calves. However, severe calcifications with blooming artifacts may cause difficulties to estimate the degree of stenosis in small arteries. The disadvantages of MD-CTA are the use of ionizing radiation and potentially nephrotoxic contrast agents.

3. Contrast enhanced magnetic resonance angiography

Contrast enhanced magnetic resonance angiography (CE-MRA) is also a low invasive imaging modality for PAD. Unenhanced mask images of the aortoiliac, femoropopliteal and popliteocrural area are acquired first. After injection of gadolinium as paramagnetic contrast material, contrast enhanced images are acquired. In patients with tibial artery disease hybrid CE-MRA protocols are used. The first stage is high-spatial-resolution CE-MRA of the calf and foot. The second stage (i.e., after the second injection) is aortoiliac and femoral bolus-chase CE-MRA. Hybrid techniques are more accurate for evaluating the trifurcation and foot vessels than single-injection multistation CE-MRA which may have venous contamination of the calf arteries. Alternatively, temporally resolved MRA techniques can be used15,16. The sensitivity and specificity of CE-MRA of peripheral arteries were both in one meta-analysis 94%17. However, in diabetic patients with a foot ulcer and tibial artery disease such a high accuracy can be achieved only when using hybrid techniques18. The advantage of CE-MRA is the use of paramagnetic contrast agents with limited nephrotoxicity and no radiation. However, disadvantages are the limited special resolution, artefacts due to flow and previous stent placement, and the limitation due implants (i.e. pacemakers) and claustrophobia.

One study reviewed and compared CE-MRA, MD-CTA and CDUS. CE-MRA had median sensitivity 94% and median specificity 99%. MD-CTA had median sensitivity 97% and median specificity 99%. CDUS had median sensitivity 90%, and median specificity 99%. The accuracy of the different techniques was similar for the detection of stenosis of 50% or more above and below the knee19.

4. Intra-arterial digital subtraction angiography

Intra-arterial digital subtraction angiography (DSA) is still regarded as the gold standard for arterial imaging, because of its highest spatial resolution. It has the advantage of endovascular therapy during the same procedure. Disadvantage is the arterial puncture with the risk of local complications (i.e. hematoma)20.

V. Treatment21

Cardiovascular morbidity and morality are markedly increased in patients with PAD, these patients have an overall mortality at 5 years of 50%21. In patients who had a major amputation these figures are even more dismal, with a 50% mortality at 2 years21. Treatment of neuro-ischaemic ulcers should therefore not be solely focused at the foot, but should also aim to reduce this poor survival. This cardiovascular risk management should include support for cessation of smoking, treatment of hypertension and prescription of a statin as well as clopidogel or low-dose aspirin.

In a patient with a foot ulcer and signs of PAD, an estimate of the probability of wound healing should be based on clinical examination and the non-invasive vascular tests described above. In addition to PAD, wound healing may be further disturbed by a complex interplay of several other factors such as poor glycaemic control, impaired collateral formation, abnormal mechanical loading of the ulcer and co-morbidities. The effect of PAD on wound healing in patients with diabetes and a foot ulcer will therefore relate in part to its severity and extent but also to these other factors. If due to the PAD the probability of healing is deemed to be too low, or if the patient has persistent ischemic rest pain, revascularization should always be considered.

Arterial revascularization can be performed through open procedures such as a bypass or more rarely via thromboendarterectomy, or in many cases an endovascular procedure - such as a balloon dilatation (percutaneous transluminal angioplasty, PTA) or an endovascular (subintimal) recanalisation. Bypass grafting using autologous vein and balloon angioplasty represent the most commonly used techniques. The aim of revascularisation is to restore direct pulsatile flow to at least one of the foot arteries, preferably the one feeding the wound or to the peroneal artery but only in case of sufficient collateral blood flow to the foot arteries, as the peroneal artery ends above the ankle. However, the common involvement of the arteries in the lower leg and the foot in combination with the impaired collateral formation render a revascularization a challenging procedure in patients with diabetes, severe PAD and ulceration of the foot22. Feasibility, effectiveness, repeatability, safety and costs, are the five parameters to evaluate in selecting the proper technique to be adopted.

Not all patients with diabetes, PAD and ulceration of the foot require revascularisation. Leg salvage is an indirect measure of the success of revascularisation and actually should only refer to improvement over natural limb survival. The key question is what the limb outcome would be if treated only conservatively. There are no randomized controlled clinical trials directly comparing conservative treatment with a revascularisation procedure in patients with diabetes, PAD and a foot ulcer. In patients with diabetes and critical limb ischaemia who were not revascularised, a limb salvage rate at one year of 54% was reported21. This rate is much lower than the limb salvage rates between 78% and 85% at one year after open and endovascular revascularisation techniques rates, as reported in the majority of the published studies21. Moreover, ulcer healing can be achieved in more than 60% of the patients at 12 months21. In contrast, minor amputation rates (and indications for minor amputation) varies considerably in the literature21. Peri-operative mortality rates of revascularisation procedures in patients with diabetes and an ischaemic foot ulcer is low (in most studies < 5%), but major systemic in-hospital complications were observed in about 10% of the patients in both open and endovascular series, probably reflecting the poor general health state of these patients21. The outcomes in diabetic patients with end stage renal disease (ESRD) is worse with a 5% peri-operative mortality and one year mortality of 40%21. However, even in these patients favourable results can be obtained. The majority of studies report 1-year limb salvage rates of approximately 70%21. In addition to ESRD, old age and preoperative functional status were strongly associated with complication rate in an extended series of infrainguinal bypass surgery in a series of diabetic and non-diabetic patients23.

In recent decades new techniques and technologies have been introduced in treating PAD and in particular interesting results have been reported on endovascular approaches in the lower limb. The field is rapidly evolving. In general, when endovascular revascularisation and open repair or bypass of a specific lesion give equivalent short- and long-term results, endovascular techniques may probably be used first, given their lower risks and costs. There are currently no randomised controlled clinical trials comparing open with endovascular revascularisation techniques in diabetic patients with an ischemic foot ulcer. Based on the current literature, broadly speaking the major outcomes of both techniques appear similar across all studies where revascularisation of the foot was successful21. In the cases series where angioplasty was the preferred first-line option for revascularisation, this approach appeared feasible in most patients and favourable results were obtained; bypass surgery was only required in a minority of these patients21. However, the results of both open and endovascular procedures will greatly depend upon the local availability and expertise in a given center as well as the morphological distribution of PAD23. The local complications of PTA are understood to be scarce and minor and not to prevent bypass in the later phase, if necessary. Yet, crural interventions may have severe non-correctable outcomes24. Subintimal angioplasty to attempt to open up infra-popliteal occlusions is associated with technical failure rates of 20% and procedural complication rates of PTA were between 7-17% in series of patients with and without diabetes25,26,27.

"Time is tissue" in particular in infected ischemic diabetic foot ulcers. Patients with signs of PAD and a foot infection are at particularly high risk for major limb amputation and should be treated with medical urgency, to include aggressive debridement, (intravenous) antibiotics, and rapid vascular evaluation. However, in case of severe infection in the ischemic foot, especially in patients with systemic signs of sepsis (e.g. haemodynamic instability) immediate amputation may be the only option to save life.

With the advent of less invasive endovascular revascularisation techniques, some would consider revascularisation in patients with slow to heal DFUs of <6 weeks duration who have intermediate perfusion abnormalities such as toe-pressures between 50-70 mmHg or tcpO2 values between 30-50 mmHg, but this still remains controversial. In these patients the potential beneficial effects of a revascularisation should be weighed against its associated risks and costs. Clinical trials are currently lacking in this area, and the role of early revascularisation should be one of the important topics of future clinical trials.

Performing a distal revascularization procedure in patients with diabetes is frequently a challenge for the vascular specialist involved. The nature and morphology of the local pathology, usually involving the vessels below the knee (BTK), is different compared to plain atherosclerotic disease. Patients require expert assessment and BKT procedures, both open and endovascular, require specific knowledge and technical procedural skills. Moreover, a sufficient number of such procedures should be performed annually to maintain skill and emergency treatment should be possible The vascular specialists performing open and endovascular treatments should be part of a team who can deliver comprehensive multidisciplinary care to the patient with diabetes, PAD and ulceration of the foot. These procedures are no stand-alone treatment and should be part of a comprehensive care plan which should also include aggressive treatment of infection, frequent debridement, biomechanical off-loading, blood glucose control and treatment of co-morbidities.

VI. References

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  5. LoGerfo FW, Coffman JD. Current concepts. Vascular and microvascular disease of the foot in diabetes. Implications for foot care. N Engl J Med 1984; 311:1615-9.
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  15. Dinter DJ, Neff KW, Visciani G, Lachmann R, Weiss C, Schoenberg SO, Michaely HJ. Peripheral bolus-chase MR angiography: analysis of risk factors for nondiagnostic image quality of the calf vessels--a combined retrospective and prospective study. AJR Am J Roentgenol. 2009; 193:234-40.
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  17. Koelemay MJ, Lijmer JG, Stoker J, Legemate DA, Bossuyt PM. Magnetic resonance angiography for the evaluation of lower extremity arterial disease: a meta-analysis. JAMA. 2001; 285:1338-45.
  18. Andreisek G, Pfammatter T, Goepfert K, Nanz D, Hervo P, Koppensteiner R, Weishaupt D. Peripheral arteries in diabetic patients: standard bolus-chase and time-resolved MR angiography. Radiology 2007; 242:610-20.
  19. Collins R, Burch J, Cranny G, Aguiar-Ibáñez R, Craig D, Wright K, Berry E, Gough M, Kleijnen J, Westwood M. Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review. BMJ 2007; 334:1257.
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  21. Hinchliffe RJ, Andros G, Apelqvist J, Bakker K, Fiedrichs S, Graziani L, Lammer J, Lepantalo M, Mills JL, Reekers J, Shearman CP, Valk G, Zierler RE, Schaper NC.A Systematic Review of the Effectiveness of Revascularisation of the Ulcerated Foot in Patients with Diabetes and Peripheral Arterial Disease (this chapter).
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  23. Crawford RS, Cambria RP, Abularrage CJ, Conrad MF, Lancaster RT, Watkins MT, et al. Preoperative functional status predicts perioperative outcomes after infrainguinal bypass surgery. J Vasc Surg 2010; 51: 351-8.
  24. Beard JD. Which is the best revascularization for critical limb ischemia: Endovascular or open surgery? J Vasc Surg 2008; 48(6 Suppl):11S-16S.
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