Review article| Volume 45, ISSUE 1, SUPPLEMENT , S5-S67, January 01, 2007

# Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)

Open Archive

## Introduction

The Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC) was published in January 2000
• TASC
Management of peripheral arterial disease (PAD). TransAtlantic Inter-Society Consensus (TASC).
• TASC
Management of Peripheral Arterial Disease (PAD) TransAtlantic Intersociety Consensus (TASC).
• TASC
Management of peripheral arterial disease (PAD). TransAtlantic Inter-Society Consensus (TASC).
as a result of cooperation between fourteen medical and surgical vascular, cardiovascular, vascular radiology and cardiology societies in Europe and North America. This comprehensive document had a major impact on vascular care amongst specialists. In subsequent years, the field has progressed with the publication of the CoCaLis document
• Clement D.L.
• Boccalon H.
• Dormandy J.
• Durand-Zaleski I.
• Fowkes G.
• Brown T.
A clinical approach to the management of the patient with coronary (Co) and/or carotid (Ca) artery disease who presents with leg ischaemia (Lis).
and the American College of Cardiology/American Heart Association Guidelines for the Management of Peripheral Arterial Disease.

Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extermity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interverntions, Society for Vascular Medicine and Biology, Society of Interventional Raidology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239-312.

Aiming to continue to reach a readership of vascular specialists, but also physicians in primary health care who see patients with peripheral arterial disease (PAD), another consensus process was initiated during 2004. This new consensus document has been developed with a broader international representation, including Europe, North America, Asia, Africa and Australia, and with a much larger distribution and dissemination of the information. The goals of this new consensus are to provide an abbreviated document (compared with the publication in 2000), to focus on key aspects of diagnosis and management, and to update the information based on new publications and the newer guidelines, but not to add an extensive list of references. Unreferenced statements are, therefore, to be found, provided they are recognized as common practice by the authors, with existing evidence. The recommendations are graded according to levels of evidence. It should also be emphasized that good practice is based on a combination of the scientific evidence described below, patients' preferences, and local availability of facilities and trained professionals. Good practice also includes appropriate specialist referral.

### Process

Representatives of sixteen societies from Europe, North America, Australia, South Africa and Japan were elected from their respective society and were called together in 2004 to form the new Working Group. Specialists in health economics, health outcomes and evidence-based medicine were also included to elaborate on the text for the following sections: history, epidemiology and risk factors; management of risk factors; intermittent claudication; critical limb ischemia; acute limb ischemia; and technologies (intervention/revascularization and imaging).
The Working Group reviewed the literature and, after extensive correspondence and meetings, proposed a series of draft documents with clear recommendations for the diagnosis and treatment of PAD. Each participating society reviewed and commented on these draft consensus documents. The liaison member from each society then took these views back to the Working Group, where all of the amendments, additions and alterations suggested by each participating society were discussed, and the final Consensus Document was agreed upon.
The participating societies were then again invited to review the final document and endorse it if they agreed with its contents. If an individual participating society did not accept any specific recommendation, this is clearly indicated in the final document. Therefore, except where such specific exclusions are indicated, this Consensus Document represents the views of all of the participating societies.
Compared with the original TASC, more emphasis has been put on diabetes and PAD. The text is presented in such a way that vascular specialists will still find most of the information they require, while general practitioners and primary health physicians will easily find guidance for diagnosis and diagnostic procedures, referral of patients and expected outcome of various treatment options.

Recommendations and selected statements are rated according to guidance issued by the former US Agency for Health Care Policy and Research,
• AHCPR. United States Department of Health and Human Services
Agency for Health Care Policy and Research. Acute pain management: operative on medical procedures and trauma. [107].
now renamed the Agency for Healthcare Research and Quality:
Tabled 1
ABased on the criterion of at least one randomized, controlled clinical trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation
BBased on well-conducted clinical studies but no good quality randomized clinical trials on the topic of recommendation
CBased on evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities (i.e. no applicable studies of good quality)
Note that the grade of recommendation is based on the level of available evidence and does not necessarily relate to the clinical importance.

### Acknowledgements

The development of this document was supported by an unrestricted educational grant from sanofi-aventis. Additional support for publication of the document was also provided by Bristol-Myers Squibb .
The TASC Working Group also acknowledges Otsuka Pharmaceuticals for defraying some travel costs and, together with Mitsubishi Pharma, supplying additional support for the future dissemination of these guidelines.
The sponsors did not participate in any of the discussions or provide recommendations as to the preparation of these guidelines. The TASC Steering Committee acknowledges the administrative and logistic assistance from Medicus International, with great appreciation of the work performed by Dr Barbara Byth.
SECTION A – EPIDEMIOLOGY OF PERIPHERAL ARTERIAL DISEASE

## A1 Epidemiology

The management of the patient with peripheral arterial disease (PAD) has to be planned in the context of the epidemiology of the disease, its natural history and, in particular, the modifiable risk factors for the systemic disease as well as those that predict deterioration of the circulation to the limb.

### A1.1 Incidence and prevalence of asymptomatic peripheral arterial disease

Total disease prevalence based on objective testing has been evaluated in several epidemiologic studies and is in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years.
• Criqui M.H.
• Fronek A.
• Barrett-Connor E.
• Klauber M.R.
• Gabriel S.
• Goodman D.
The prevalence of peripheral arterial disease in a defined population.
• Hiatt W.R.
• Hoag S.
• Hamman R.F.
Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study.
• Selvin E.
• Erlinger T.P.
Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000.
The prevalence of asymptomatic PAD in the leg can only be estimated by using non-invasive measurements in a general population. The most widely used test is the measurement of the ankle-brachial systolic pressure index (ABI). (For detailed discussion of the ABI, see Section C2.1.) A resting ABI of ≤0.90 is caused by hemodynamically-significant arterial stenosis and is most often used as a hemodynamic definition of PAD. In symptomatic individuals, an ABI ≤0.90 is approximately 95% sensitive in detecting arteriogram-positive PAD and almost 100% specific in identifying healthy individuals. Using this criterion, several studies have looked at symptomatic and asymptomatic PAD patients in the same population. The ratio of the two is independent of age and is usually in the range of 1:3 to 1:4. The Edinburgh Artery Study found that, using duplex scanning, a third of the patients with asymptomatic PAD had a complete occlusion of a major artery to the leg.
• Fowkes F.G.
• Housley E.
• Cawood E.H.
• Macintyre C.C.
• Ruckley C.V.
• Prescott R.J.
Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population.
The PARTNERS (PAD Awareness, Risk, and Treatment: New Resources for Survival) study screened 6979 subjects for PAD using the ABI (with PAD defined as an ABI of ≤0.90 or a prior history of lower extremity revascularization). Subjects were evaluated if they were aged ≥70 years or aged 50–69 years with a risk factor for vascular disease (smoking, diabetes) in 320 primary care practices in the United States.
• Hirsch A.
• Criqui M.
• Treat-Jacobson D.
• Regensteiner J.
• Creager M.
• Olin J.
• et al.
Peripheral arterial disease detection, awareness, and treatment in primary care.
PAD was detected in 1865 patients which was 29% of the total population. Classic claudication was present in 5.5% of the newly diagnosed patients with PAD and 12.6% of the patients with a prior diagnosis of PAD had claudication. The National Health and Nutritional Examination Survey recently reported on an unselected population of 2174 subjects aged ≥40 years.
• Selvin E.
• Erlinger T.P.
Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000.
The prevalence of PAD, as defined by an ABI of ≤0.90, ranged from 2.5% in the age group 50–59 years to 14.5% in subjects >70 years (there was no information about the proportion of subjects with an ABI of ≤0.90 who had symptoms in the legs). In autopsies of unselected adults, 15% of men and 5% of women who were asymptomatic, had a 50% or greater stenosis of an artery to the leg. It is interesting to compare this with the finding that 20% to 30% of subjects with complete occlusion of at least one coronary artery on autopsy are asymptomatic. Some of the apparent inconsistency regarding data on the prevalence of symptomatic PAD is due to methodology, but in summary it can be concluded that for every patient with symptomatic PAD there are another three to four subjects with PAD who do not meet the clinical criteria for intermittent claudication.

### A1.2 Incidence and prevalence of symptomatic peripheral arterial disease

Intermittent claudication (IC) (see section C1.1 for definition) is usually diagnosed by a history of muscular leg pain on exercise that is relieved by a short rest. Several questionnaires have been developed for epidemiological use. In looking at methods for identifying IC in the population, it must be remembered that while it is the main symptom of PAD, the measurement of this symptom does not always predict the presence or absence of PAD. A patient with quite severe PAD may not have the symptom of IC because some other condition limits exercise or they are sedentary. In contrast, some patients with what seems to be IC may not have PAD (for example, spinal stenosis can produce symptoms like IC in the absence of vascular disease). Likewise, patients with very mild PAD may develop symptoms of IC only when they become very physically active.
The annual incidence of IC is more difficult to measure and probably less important than its prevalence (unlike the case of the relatively very much smaller number of patients with critical limb ischemia [CLI]). The prevalence of IC would appear to increase from about 3% in patients aged 40 to 6% in patients aged 60 years. Several large population studies have looked at the prevalence of IC and Fig. A1 shows a calculated mean prevalence weighted by study sample size. In the relatively younger age groups, claudication is more common in men but at older ages there is little difference between men and women. A surprising finding in population screening studies is that between 10% and 50% of patients with IC have never consulted a doctor about their symptoms.

### A1.3 Epidemiology of peripheral arterial disease in different ethnic groups

Non-white ethnicity is a risk factor for PAD. Black ethnicity increases the risk of PAD by over two-fold, and this risk is not explained by higher levels of other risk factors such as diabetes, hypertension or obesity.
• Criqui M.H.
• Vargas V.
• Denenberg J.O.
• Ho E.
• Allison M.
• Langer R.D.
• et al.
Ethnicity and peripheral arterial disease: the San Diego Population Study.
A high prevalence of arteritis affecting the distal arteries of young black South Africans has also been described.

## A2 Risk Factors for Peripheral Arterial Disease

Although the various factors described in this section are usually referred to as risk factors, in most cases the evidence is only for an association. The criteria used to support a risk factor require a prospective, controlled study showing that altering the factor alters the development or course of the PAD, such as has been shown for smoking cessation or treatment of dyslipidemia. Risk may be conferred by other metabolic or circulatory abnormalities associated with diabetes.

### A2.1 Race

The National Health and Nutrition Examination Survey in the United States found that an ABI ≤0.90 was more common in non-Hispanic Blacks (7.8%) than in Whites (4.4%). Such a difference in the prevalence of PAD was confirmed by the recent GENOA (Genetic Epidemiology Network of Arteriopathy) study,
• Kullo I.J.
• Bailey K.R.
• Kardia S.L.
• Mosley Jr, T.H.
• Boerwinkle E.
• Turner S.T.
Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study.
which also showed that the difference was not explained by a difference in classical risk factors for atherosclerosis.

### A2.2 Gender

The prevalence of PAD, symptomatic or asymptomatic, is slightly greater in men than women, particularly in the younger age groups. In patients with IC, the ratio of men to women is between 1:1 and 2:1. This ratio increases in some studies to at least 3:1 in more severe stages of the disease, such as chronic CLI. Other studies have, however, shown a more equal distribution of PAD between genders and even a predominance of women with CLI.

### A2.3 Age

The striking increase in both the incidence and prevalence of PAD with increasing age is apparent from the earlier discussion of epidemiology (Fig. A1).

### A2.4 Smoking

The relationship between smoking and PAD has been recognized since 1911, when Erb reported that IC was three-times more common among smokers than among non-smokers. Interventions to decrease or eliminate cigarette smoking have, therefore, long been advocated for patients with IC. It has been suggested that the association between smoking and PAD may be even stronger than that between smoking and coronary artery disease (CAD). Furthermore, a diagnosis of PAD is made approximately a decade earlier in smokers than in non-smokers. The severity of PAD tends to increase with the number of cigarettes smoked. Heavy smokers have a four-fold higher risk of developing IC compared with non-smokers. Smoking cessation is associated with a decline in the incidence of IC. Results from the Edinburgh Artery Study
• Fowkes F.G.
• Housley E.
• Cawood E.H.
• Macintyre C.C.
• Ruckley C.V.
• Prescott R.J.
Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population.
found that the relative risk of IC was 3.7 in smokers compared with 3.0 in ex-smokers (who had discontinued smoking for less than 5 years).

### A2.5 Diabetes mellitus

Many studies have shown an association between diabetes mellitus and the development of PAD. Overall, IC is about twice as common among diabetic patients than among non-diabetic patients. In patients with diabetes, for every 1% increase in hemoglobin A1c there is a corresponding 26% increased risk of PAD.
• Selvin E.
• Marinopoulos S.
• Berkenblit G.
• Rami T.
• Brancati F.L.
• Powe N.R.
• et al.
Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.
Over the last decade, mounting evidence has suggested that insulin resistance plays a key role in a clustering of cardiometabolic risk factors which include hyperglycemia, dyslipidemia, hypertension and obesity. Insulin resistance is a risk factor for PAD even in subjects without diabetes, raising the risk approximately 40% to 50%.
• Muntner P.
• Wildman R.P.
• Reynolds K.
• Desalvo K.B.
• Chen J.
• Fonseca V.
Relationship between HbA1c level and peripheral arterial disease.
PAD in patients with diabetes is more aggressive compared to non-diabetics, with early large vessel involvement coupled with distal symmetrical neuropathy. The need for a major amputation is five- to ten-times higher in diabetics than non-diabetics. This is contributed to by sensory neuropathy and decreased resistance to infection. Based on these observations, a consensus statement from the American Diabetes Association recommends PAD screening with an ABI every 5 years in patients with diabetes.
Peripheral arterial disease in people with diabetes.

### A2.6 Hypertension

Hypertension is associated with all forms of cardiovascular disease, including PAD. However, the relative risk for developing PAD is less for hypertension than diabetes or smoking.

### A2.7 Dyslipidemia

In the Framingham study, a fasting cholesterol level greater than 7 mmol/L (270 mg/dL) was associated with a doubling of the incidence of IC but the ratio of total to high-density lipoprotein (HDL) cholesterol was the best predictor of occurrence of PAD. In another study, patients with PAD had significantly higher levels of serum triglycerides, very low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, intermediate density lipoprotein (IDL) cholesterol, and IDL triglycerides and lower levels of HDL than controls.
• Senti M.
• Nogues X.
• Pedro-Botet J.
• Rubies-Prat J.
• Vidal-Barraquer F.
Lipoprotein profile in men with peripheral vascular disease. Role of intermediate density lipoproteins and apoprotein E phenotypes.
Although some studies have also shown that total cholesterol is a powerful independent risk factor for PAD, others have failed to confirm this association. It has been suggested that cigarette smoking may enhance the effect of hypercholesterolemia. There is evidence that treatment of hyperlipidemia reduces both the progression of PAD and the incidence of IC. An association between PAD and hypertriglyceridemia has also been reported and has been shown to be associated with the progression and systemic complications of PAD. Lipoprotein(a) is a significant independent risk factor for PAD.

### A2.8 Inflammatory markers

Some recent studies have shown that C-reactive protein (CRP) was raised in asymptomatic subjects who in the subsequent five years developed PAD compared to an age-matched control group who remained asymptomatic. The risk of developing PAD in the highest quartile of baseline CRP was more than twice that in the lowest quartile.
• Ridker P.M.
• Stampfer M.J.
• Rifai N.
Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.

### A2.9 Hyperviscosity and hypercoagulable states

Raised hematocrit levels and hyperviscosity have been reported in patients with PAD, possibly as a consequence of smoking. Increased plasma levels of fibrinogen, which is also a risk factor for thrombosis, have been associated with PAD in several studies. Both hyperviscosity and hypercoagulability have also been shown to be markers or risk factors for a poor prognosis.

### A2.10 Hyperhomocysteinemia

The prevalence of hyperhomocysteinemia is high in the vascular disease population, compared with 1% in the general population. It is reported that hyperhomocysteinemia is detected in about 30% of young patients with PAD. The suggestion that hyperhomocysteinemia may be an independent risk factor for atherosclerosis has now been substantiated by several studies. It may be a stronger risk factor for PAD than for CAD.

### A2.11 Chronic renal insufficiency

There is an association of renal insufficiency with PAD, with some recent evidence suggesting it may be causal. In the HERS study (Heart and Estrogen/Progestin Replacement Study), renal insufficiency was independently associated with future PAD events in postmenopausal women.
• O'Hare A.M.
• Vittinghoff E.
• Hsia J.
• Shlipak M.G.
Renal insufficiency and the risk of lower extremity peripheral arterial disease: results from the Heart and Estrogen/Progestin Replacement Study (HERS).

### A2.12 Summary

Fig. A2 summarizes graphically the approximate influence or association between some of the above factors and PAD, taking a global view of the existing evidence.

## A3 Fate of the Leg

### A3.1 Asymptomatic

Evidence suggests that the progression of the underlying PAD is identical whether or not the subject has symptoms in the leg. There is nothing to suggest that the risk of local deterioration, with progression to CLI, is dependent on the presence or absence of symptoms of intermittent claudication. Whether symptoms develop or not depends largely on the level of activity of the subject. This is one of the reasons why some patients' initial presentation is with CLI, in the absence of any earlier IC. For example, a patient who has a reduction in their ABI just above the ischemic rest pain level but who is too sedentary to claudicate, may develop CLI because of wounds resulting from relatively minor (often self inflicted) trauma that can not heal at this level of perfusion. It is important to detect this subgroup of patients at a time when protective foot care and risk factor control have their greatest potential to ameliorate outcomes. Functional decline over two years is related to baseline ABI and the nature of the presenting limb symptoms.
• McDermott M.M.
• Criqui M.H.
• Greenland P.
• Guralnik J.M.
• Liu K.
• Pearce W.H.
• et al.
Leg strength in peripheral arterial disease: associations with disease severity and lower-extremity performance.
A lower ABI was associated with a more rapid decline in, for example, 6-minute walk distance.

### A3.2 Intermittent claudication

Although PAD is progressive in the pathological sense, its clinical course as far as the leg is concerned is surprisingly stable in most cases. However, the symptomatic PAD patient continues to have significant functional disability. Large population studies provide the most reliable figures. All of the evidence over the last 40 years since the classic study by Bloor has not materially altered the impression that only about a quarter of patients with IC will ever significantly deteriorate. This symptomatic stabilization may be due to the development of collaterals, metabolic adaptation of ischemic muscle, or the patient altering his or her gait to favor non-ischemic muscle groups. The remaining 25% of patients with IC deteriorate in terms of clinical stage; this is most frequent during the first year after diagnosis (7%–9%) compared with 2% to 3% per year thereafter. This clinical stability is relevant to the patient's perception of their severity of claudication. When these patients have a comprehensive assessment of their actual functional status, measured walking distance does progressively deteriorate over time.
• McDermott M.M.
• Criqui M.H.
• Greenland P.
• Guralnik J.M.
• Liu K.
• Pearce W.H.
• et al.
Leg strength in peripheral arterial disease: associations with disease severity and lower-extremity performance.
More recent reviews also highlight that major amputation is a relatively rare outcome of claudication, with only 1% to 3.3% of patients with IC needing major amputation over a 5-year period. The Basle and Framingham studies,
• Widmer L.
• Biland L.
Risk profile and occlusive peripheral arterial disease.
• Kannel W.B.
• Skinner Jr., J.J.
• Schwartz M.J.
• Shurtleff D.
Intermittent claudication. Incidence in the Framingham Study.
which are the two large-scale studies that have looked at unselected patients, found that less than 2% of PAD patients required major amputation. Although amputation is the major fear of patients told that they have circulatory disease of the legs, they can be assured that this is an unlikely outcome, except in diabetes patients (Fig. A3).
It is difficult to predict the risk of deterioration in a recent claudicant. The various risk factors mentioned in section A2 (above) probably all contribute to the progression of PAD. A changing ABI is possibly the best individual predictor, because if a patient's ABI rapidly deteriorates it is most likely to continue to do so in the absence of successful treatment. It has been shown that in patients with IC, the best predictor of deterioration of PAD (e.g. need for arterial surgery or major amputation), is an ABI of <0.50 with a hazard ratio of more than 2 compared to patients with an ABI >0.50. Studies have also indicated that in those patients with IC in the lowest strata of ankle pressure (i.e. 40–60 mmHg), the risk of progression to severe ischemia or actual limb loss is 8.5% per year.

### A3.3 Critical limb ischemia

The only reliable large prospective population studies on the incidence of CLI showed a figure of 220 new cases every year per million population.
• Rothwell P.M.
• Eliasziw M.
• Gutnikov S.A.
• Warlow C.P.
• Barnett H.J.
Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.
However, there is indirect evidence from studies looking at the progression of IC, population surveys on prevalence and assumptions based on the major amputation rates. Surprisingly, the incidence calculated using these different methodologies is very similar. There will be approximately between 500 and 1000 new cases of CLI every year in a European or North American population of 1 million.
A number of studies have allowed an analysis of the risk factors that seem to be associated with the development of CLI. These are summarized in Fig. A4. These factors appear to be independent and are, therefore, probably additive.
It is no longer possible to describe the natural history of patients with CLI because the majority of these patients now receive some form of active treatment. Treatment very much depends on the center to which the patient is referred. Large surveys suggest that approximately half the patients with CLI will undergo some type of revascularization, although in some, particularly active, interventional centers an attempt at reconstruction is reported in as many as 90% of CLI patients. Fig. A5 provides an estimate of the primary treatment of these patients globally and their status a year later.
There are some good-quality data from multicenter, closely monitored trials of pharmacotherapy for CLI. These only relate to a subgroup of patients who are unreconstructable or in whom attempts at reconstruction have failed. (It is only such patients who are entered into randomized, placebo-controlled, clinical pharmacotherapy trials.) The results for this subgroup reveal the appalling prospect that approximately 40% will lose their leg within 6 months, and up to 20% will die (note that these data refer to 6 months' follow-up and cannot be directly compared with the 1-year data in Fig. A5).

### A3.4 Acute leg ischemia

Acute limb ischemia denotes a quickly developing or sudden decrease in limb perfusion, usually producing new or worsening symptoms and signs, and often threatening limb viability. Progression of PAD from claudication to rest pain to ischemic ulcers or gangrene may be gradual or progress rapidly reflecting sudden worsening of limb perfusion. Acute limb ischemia may also occur as the result of an embolic event or a local thrombosis in a previously asymptomatic patient.
There is little information on the incidence of acute leg ischemia, but a few national registries and regional surveys suggest that the incidence is around 140/million/year. Acute leg ischemia due to emboli has decreased over the years, possibly as a consequence of less cardiac valvular disease from rheumatic fever and also better monitoring and anticoagulant management of atrial fibrillation. Meanwhile the incidence of thrombotic acute leg ischemia has increased. Even with the extensive use of newer endovascular techniques including thrombolysis, most published series report a 10% to 30% 30-day amputation rate.

### A3.5 Amputation

There is an ongoing controversy, often fuelled by unverified retrospective audit data from large and changing populations, as to whether there is a significant reduction in amputations as a result of more revascularization procedures in patients with CLI. Careful, independent studies from Sweden, Denmark and Finland all suggest that increased availability and use of endovascular and surgical interventions have resulted in a significant decrease in amputation for CLI. In the United Kingdom, the number of major amputations has reached a plateau, possibly reflecting increasingly successful limb salvage, but older studies in the United States have not shown benefit of revascularization on amputation rates.
• Tunis S.R.
• Bass E.B.
• Steinberg E.P.
The use of angioplasty, bypass surgery, and amputation in the management of peripheral vascular disease.
The concept that all patients who require an amputation have steadily progressed through increasingly severe claudication to rest pain, ulcers and, ultimately, amputation, is incorrect. It has been shown that more than half of patients having a below-knee major amputation for ischemic disease had no symptoms of leg ischemia whatsoever as recently as 6 months previously.
• Dormandy J.
• Belcher G.
• Broos P.
• Eikelboom B.
• Laszlo G.
• et al.
Prospective study of 713 below-knee amputations for ischaemia and the effect of a prostacyclin analogue on healing. Hawaii Study Group.
The incidence of major amputations from large population or nation-wide data varies from 120 to 500/million/year. The ratio of below-knee to above-knee amputations in large surveys is around 1:1. Only about 60% of below-knee amputations heal by primary intention, 15% heal after secondary procedures and 15% need to be converted to an above-knee level. 10% die in the peri-operative period. The dismal 1- to 2-year prognosis is summarized in Fig. A6.

## A4 Co-existing Vascular Disease

Because PAD, CAD and cerebral artery disease are all manifestations of atherosclerosis, it is not surprising that the three conditions commonly occur together.

### A4.1 Coronary

Studies on the prevalence of cardiovascular disease in patients with PAD show that the history, clinical examination and electrocardiogram identify a prevalence of CAD and cerebral artery disease in 40% to 60% of such patients. In the PARTNERS study, 13% of subjects screened had an ABI of ≤0.90 and no symptomatic CAD or cerebral artery disease, 16% had both PAD and symptomatic CAD or cerebral artery disease, and 24% had symptomatic CAD and cerebral artery disease and a normal ABI.
• Hirsch A.
• Criqui M.
• Treat-Jacobson D.
• Regensteiner J.
• Creager M.
• Olin J.
• et al.
Peripheral arterial disease detection, awareness, and treatment in primary care.
As with asymptomatic PAD, the diagnosis of CAD depends on the sensitivity of the methods used. In the primary care setting, approximately half of those patients diagnosed with PAD also have CAD and cerebral artery disease; in PAD patients referred to hospital, the prevalence of CAD is likely to be higher. The extent of the CAD, both by angiography and by computed tomography (CT) measured coronary calcium, correlates with the ABI. Not surprisingly, patients with documented CAD are more likely to have PAD. The prevalence of PAD in patients with ischemic heart disease varies in different series from around 10% to 30%. Autopsy studies have shown that patients who die from a myocardial infarction are twice as likely to have a significant stenosis in the iliac and carotid arteries as compared to patients dying from other causes.

### A4.2 Cerebral artery disease

The link between PAD and cerebral artery disease seems to be weaker than that with CAD. By duplex examination, carotid artery disease occurs in 26% to 50% of patients with IC, but only about 5% of patients with PAD will have a history of any cerebrovascular event. There is also a good correlation between carotid intimal thickness and the ABI. There is a range of overlap in disease in the cerebral, coronary and peripheral circulations reported in the literature, represented semi-quantitatively in Fig. A7. In the REACH (Reduction of Atherothrombosis for Continued Health) survey
• Bhatt D.
• Steg P.
• Ohman E.
• Hirsch A.
• Ikeda Y.
• Mas J.
• et al.
International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.
of those patients identified with symptomatic PAD, 4.7% had concomitant CAD, 1.2% had concomitant cerebral artery disease and 1.6% had both. Thus in this survey, about 65% of patients with PAD had clinical evidence of other vascular disease. However, in one prospective study of 1886 patients aged 62 or over only 37% of subjects had no evidence of disease in any of the three territories.
• Aronow W.S.
• Ahn C.
Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women > or = 62 years of age.

### A4.3 Renal

Studies have also looked at the prevalence of renal artery stenosis in patients with PAD. The prevalence of renal artery stenosis of 50% or over ranges from 23% to 42% (compare this to the prevalence of renal artery stenosis in the hypertensive general population, which is around 3%). Although it has not been studied specifically it is very likely that renal artery stenosis is also a partly independent risk factor for mortality in patients with PAD since renal artery stenosis of 50% or over is associated with a 3.3-fold higher mortality rate than in the general population.

## A5 Fate of the Patient

### A5.1 Asymptomatic and claudicating peripheral arterial disease patients

The increased risk of cardiovascular events in patients with PAD is related to the severity of the disease in the legs as defined by an ABI measurement. The annual overall major cardiovascular event rate (myocardial infarction, ischemic stroke and vascular death) is approximately 5%–7%.
Excluding those with CLI, patients with PAD have a 2% to 3% annual incidence of non-fatal myocardial infarction and their risk of angina is about two- to three- times higher than that of an age-matched population. The 5-, 10- and 15-year morbidity and mortality rates from all causes are approximately 30%, 50% and 70%, respectively (Fig. A3). CAD is by far the most common cause of death among patients with PAD (40%–60%), with cerebral artery disease accounting for 10% to 20% of deaths. Other vascular events, mostly ruptured aortic aneurysm, cause approximately 10% of deaths. Thus, only 20% to 30% of patients with PAD die of non-cardiovascular causes.
Of particular interest are the studies in which the difference in mortality rates between patients with IC and an age-matched control population was largely unchanged despite the adjustment for risk factors such as smoking, hyperlipidemia and hypertension. These surprising, but consistent, results suggest that the presence of PAD indicates an extensive and severe degree of systemic atherosclerosis that is responsible for mortality, independent of the presence of risk factors. Fig. A8 summarizes the results from all studies comparing mortality rates of claudicating patients with those of an age-matched control population. As expected, the two lines diverge, indicating that, on average, the mortality rate of claudicant patients is 2.5-times higher than that of non-claudicant patients.

### A5.2 Severity of peripheral arterial disease and survival

Patients with chronic CLI have a 20% mortality in the first year after presentation, and the little long-term data that exists suggests that mortality continues at the same rate (Fig. A8). The short-term mortality of patients presenting with acute ischemia is 15% to 20%. Once they have survived the acute episode, their pattern of mortality will follow that of the claudicant or patient with chronic CLI, depending on the outcome of the acute episode.
There is a strong correlation between ABI, as a measure of the severity of the PAD, and mortality. A number of studies, using different ABI ‘cut-off’ points have demonstrated this relationship. For instance, in a study of nearly 2000 claudicants, patients with an ABI <0.50 had twice the mortality of claudicants with an entry ABI of >0.50.
• Dormandy J.A.
• Murray G.D.
The fate of the claudicant–a prospective study of 1969 claudicants.
The Edinburgh Artery Study
• Fowkes F.G.
• Housley E.
• Cawood E.H.
• Macintyre C.C.
• Ruckley C.V.
• Prescott R.J.
Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population.
has also shown that the ABI is a good predictor of non-fatal and fatal cardiovascular events as well as total mortality, in an unselected general population. It has also been suggested that there is an almost linear relationship between ABI and fatal and non-fatal cardiovascular events; each decrease in ABI of 0.10 being associated with a 10% increase in relative risk for a major vascular event. In a study of patients with type 2 diabetes (Fig. A9), the lower the ABI the higher the 5-year risk of a cardiovascular event.
• Mehler P.S.
• Coll J.R.
• Estacio R.
• Esler A.
• Schrier R.W.
• Hiatt W.R.
Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes.
SECTION B – MANAGEMENT OF CARDIOVASCULAR RISK FACTORS AND CO-EXISTING DISEASE

## B1 Risk Factors

### B1.1 Identifying the peripheral arterial disease patient in the population

Patients with peripheral arterial disease (PAD) have multiple atherosclerosis risk factors and extensive atherosclerotic disease, which puts them at markedly increased risk for cardiovascular events, similar to patients with established coronary artery disease (CAD).
• Criqui M.
• Langer R.
• Fronek A.
• Feigelson H.
• Klauber M.
• McCann T.
• et al.
Mortality over a period of 10 years in patients with peripheral arterial disease.
A reduced blood pressure in the ankle relative to the arm pressure indicates the presence of peripheral atherosclerosis, and is an independent risk factor for cardiovascular events. This has been most recently studied in a meta-analysis of 15 population studies and showed that an ankle-brachial index (ABI) ≤0.90 was strongly correlated with all-cause mortality independent of the Framingham Risk Score.
• Fowkes F.
• Lee A.
• Murray G.
On behalf of the ABI collaboration. Ankle-brachial index as an independent indicator of mortality in fifteen international population cohort studies.
Thus, current recommendations from numerous consensus documents, including the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD, identify patients with PAD as a high-risk population who require intensive risk factor modification and need antithrombotic therapy.

Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extermity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interverntions, Society for Vascular Medicine and Biology, Society of Interventional Raidology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239-312.

This section will discuss an approach to identification of PAD as a means to define a high-risk population and the management of each of the major risk factors to reduce the incidence of cardiovascular events.
Over two-thirds of the patients with PAD are asymptomatic or have atypical leg symptoms and thus may not be recognized as having a systemic cardiovascular disease. Also, approximately half of the patients with PAD have not yet suffered a major cardiovascular event. Therefore, many patients with PAD are not identified, resulting in inadequate identification and treatment of their atherosclerosis risk factors.
• Hirsch A.
• Criqui M.
• Treat-Jacobson D.
• Regensteiner J.
• Creager M.
• Olin J.
• et al.
Peripheral arterial disease detection, awareness, and treatment in primary care.
The initial clinical assessment for PAD is a history and physical examination. A history of intermittent claudication is useful in raising the suspicion of PAD, but significantly underestimates the true prevalence of PAD. In contrast, palpable pedal pulses on examination have a negative predictive value of over 90% that may rule out the diagnosis in many cases. In contrast, a pulse abnormality (absent or diminished) significantly overestimates the true prevalence of PAD. Thus, objective testing is warranted in all patients suspected of having PAD. The primary non-invasive screening test for PAD is the ABI (see section C2 for further discussion of the ABI and ABI screening criteria). In the context of identifying a high-risk population, persons who should be considered for ABI screening in the primary care or community setting include: (1) subjects with exertional leg symptoms, (2) subjects aged 50–69 years who also have cardiovascular risk factors and all patients over the age of 70 years,
• Hirsch A.
• Criqui M.
• Treat-Jacobson D.
• Regensteiner J.
• Creager M.
• Olin J.
• et al.
Peripheral arterial disease detection, awareness, and treatment in primary care.
and (3) subjects with a 10-year risk of a cardiovascular event between 10% and 20% in whom further risk stratification is warranted. Cardiovascular risk calculators are readily available in the public domain, such as the SCORE for use in Europe (www.escardio.org) and the Framingham for the US (www.nhlbi.nih.gov/guidelines/cholesterol).
Patients with PAD, defined as an ABI ≤0.90, are known to be at high risk for cardiovascular events (Fig. B1). As discussed in section A, mortality rates in patients with PAD average 2% per year and the rates of non-fatal myocardial infarction, stroke and vascular death are 5% to 7% per year.
• CAPRIE
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
• HPSCG
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
In addition, the lower the ABI, the higher the risk of cardiovascular events, as shown in Fig. B2.
• Resnick H.E.
• Lindsay R.S.
• McDermott M.M.
• Devereux R.B.
• Jones K.L.
• Fabsitz R.R.
• et al.
Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study.
A similar increased mortality risk has also been observed in patients with an increased ABI as shown in Fig. B2. Therefore, an abnormal ABI identifies a high-risk population that needs aggressive risk factor modification and antiplatelet therapy.

### B1.2 Modification of atherosclerotic risk factors

As highlighted above, patients with PAD typically have multiple cardiovascular risk factors, which puts them at markedly increased risk for cardiovascular events. This section will discuss an approach to each of the major risk factors of this disorder.

#### B1.2.1 Smoking cessation

Smoking is associated with a marked increased risk for peripheral atherosclerosis. The number of pack years is associated with disease severity, an increased risk of amputation, peripheral graft occlusion and mortality. Given these associations, smoking cessation has been a cornerstone of the management of PAD as is the case for CAD.
• Critchley J.A.
• Capewell S.
Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review.
Other drugs for smoking cessation are becoming available.
In middle-aged smokers with reduced pulmonary function, physician advice to stop smoking, coupled with a formal cessation program and nicotine replacement is associated with a 22% cessation rate at 5 years compared with only a 5% cessation rate in the usual care group.
• Anthonisen N.R.
• Skeans M.A.
• Wise R.A.
• Manfreda J.
• Kanner R.E.
• Connett J.E.
The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial.
By 14 years, the intervention group had a significant survival advantage. A number of randomized studies have supported the use of bupropion in patients with cardiovascular disease, with 3-, 6- and 12-month abstinence rates of 34%, 27% and 22%, respectively, compared with 15%, 11% and 9%, respectively, with placebo treatment.
• Farsang C.
• Klaene G.
• Lewis K.
• Manolis A.
• Perruchoud A.P.
• et al.
Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study.
Combining bupropion and nicotine replacement therapy has been shown to be more effective than either therapy alone (Fig. B3).
• Jorenby D.E.
• Leischow S.J.
• Nides M.A.
• Rennard S.I.
• Johnston J.A.
• Hughes A.R.
• et al.
A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.
Thus, a practical approach would be to encourage physician advice at every patient visit, combined with behavior modification, nicotine replacement therapy and the antidepressant bupropion to achieve the best cessation rates.
The role of smoking cessation in treating the symptoms of claudication is not as clear; studies have shown that smoking cessation is associated with improved walking distance in some, but not all patients. Therefore, patients should be encouraged to stop smoking primarily to reduce their risk of cardiovascular events, as well as their risk of progression to amputation and progression of disease, but should not be promised improved symptoms immediately upon cessation. Recent studies have shown a three-fold increased risk of graft failure after bypass surgery with continued smoking with a reduction in that risk to that of non-smokers with smoking cessation.
• Willigendael E.M.
• Teijink J.A.
• Peters R.J.
• Buller H.R.
• Prins M.H.
Smoking and the patency of lower extremity bypass grafts: a meta-analysis.
Smoking cessation in peripheral arterial disease
• All patients who smoke should be strongly and repeatedly advised to stop smoking [B].
• All patients who smoke should receive a program of physician advice, group counseling sessions, and nicotine replacement [A].
• Cessation rates can be enhanced by the addition of antidepressant drug therapy (bupropion) and nicotine replacement [A].

#### B1.2.2 Weight reduction

Patients who are overweight (body mass index [BMI] 25–30) or who are obese (BMI>30) should receive counseling for weight reduction by inducing negative caloric balance with reduction of calorie intake, carbohydrate restriction and increased exercise.

#### B1.2.3 Hyperlipidemia

Independent risk factors for PAD include elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein(a). Factors that are protective for the development of PAD are elevated high-density lipoprotein (HDL) cholesterol and apolipoprotein (a-1) levels.
Direct evidence supporting the use of statins to lower LDL cholesterol levels in PAD comes from the Heart Protection Study (HPS).
• HPSCG
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
The HPS enrolled over 20,500 subjects at high risk for cardiovascular events including 6748 patients with PAD, many of whom had no prior history of heart disease or stroke. Patients were randomized to simvastatin 40 mg, antioxidant vitamins, a combination of treatments, or placebo using a 2×2 factorial design, with a 5-year follow up. Simvastatin 40 mg was associated with a 12% reduction in total mortality, 17% reduction in vascular mortality, 24% reduction in coronary heart disease events, 27% reduction in all strokes and a 16% reduction in non-coronary revascularizations. Similar results were obtained in the PAD subgroup, whether they had evidence of coronary disease at baseline or not. Furthermore, there was no threshold cholesterol value below which statin therapy was not associated with benefit. Thus, the HPS demonstrated that in patients with PAD (even in the absence of a prior myocardial infarction or stroke), aggressive LDL lowering was associated with a marked reduction in cardiovascular events (myocardial infarction, stroke and vascular death). A limitation of the HPS was that the evidence in PAD was derived from a subgroup analysis in patients with symptomatic PAD. Despite these limitations, all patients with PAD should have their LDL cholesterol levels lowered to <2.59 mmol/L (<100 mg/dL). To achieve these lipid levels, diet modification should be the initial approach, however, in most cases, diet alone will be unable to decrease the lipids levels to the values mentioned above; therefore, pharmacological treatment will be necessary.
A more recent meta-analysis of statin therapy concluded that in a broad spectrum of patients, a 1 mmol/L (38.6 mg/dL) reduction in LDL cholesterol level was associated with a 20% decrease in the risk of major cardiovascular events.
• Baigent C.
• Keech A.
• Kearney P.M.
• Blackwell L.
• Buck G.
• Pollicino C.
• et al.
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
This benefit was not dependent on the initial lipid levels (even patients with lipids in the “normal” range responded), but did depend on the baseline assessment of cardiovascular risk. Since patients with PAD are at high risk, and were included as a subgroup in this meta analysis, the majority of these patients would be considered candidates for statin therapy.
Current recommendations for the management of lipid disorders in PAD are to achieve an LDL cholesterol level of <2.59 mmol/L (<100 mg/dL) and to treat the increased triglyceride and low HDL pattern.
• De Backer G.
• Ambrosioni E.
• Borch-Johnsen K.
• Brotons C.
• Cifkova R.
• Dallongeville J.
• et al.
European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies and by invited experts).
• Grundy S.M.
• Cleeman J.I.
• Merz C.N.
• Brewer Jr., H.B.
• Clark L.T.
• Hunninghake D.B.
• et al.
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
The recent ACC/AHA guidelines recommend as a general treatment goal achieving an LDL cholesterol level <2.59 mmol/L (<100 mg/dL) in all patients with PAD and in those at high risk (defined as patients with vascular disease in multiple beds) the goal should be an LDL cholesterol level <1.81 mmol/L (<70 mg/dL).

Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extermity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interverntions, Society for Vascular Medicine and Biology, Society of Interventional Raidology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol 2006;47:1239-312.

In patients with PAD who have elevated triglyceride levels where the LDL cholesterol cannot be accurately calculated, the recommendation is to achieve a non-HDL-cholesterol level <3.36 mmol/L (<130 mg/dL),
• Smith Jr, S.C.
• Blair S.N.
• Bonow R.O.
• Brass L.M.
• Cerqueira M.D.
• Dracup K.
• et al.
AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology.
and in the highest risk patients (with vascular disease in multiple beds) the non-HDL-cholesterol goal should be <2.56 mmol/L (<100 mg/dL).
Patients with PAD commonly have disorders of HDL cholesterol and triglyceride metabolism. The use of fibrates in patients with coronary artery disease who had an HDL cholesterol level <1.04 mmol/L (<40 mg/dL) and an LDL cholesterol level <3.63 mmol/L (>140 mg/dL) was associated with a reduction in the risk of non-fatal myocardial infarction and cardiovascular death.
• Rubins H.B.
• Robins S.J.
• Collins D.
• Fye C.L.
• Anderson J.W.
• Elam M.B.
• et al.
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
Niacin is a potent drug used to increase HDL cholesterol levels, with the extended-release formulation providing the lowest risk of flushing and liver toxicity. In patients with PAD, niacin has been associated with regression of femoral atherosclerosis and reduced progression of coronary atherosclerosis.
• Blankenhorn D.H.
• Azen S.P.
• Crawford D.W.
• Nessim S.A.
• Sanmarco M.E.
• Selzer R.H.
• et al.
Effects of colestipol-niacin therapy on human femoral atherosclerosis.
• Taylor A.J.
• Sullenberger L.E.
• Lee H.J.
• Lee J.K.
• Grace K.A.
Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
Whether fibrates and/or niacin will reduce the progression of peripheral atherosclerosis or reduce the risk of systemic cardiovascular events in patients with PAD is not yet known.
Lipid control in patients with peripheral arterial disease (PAD)
• All symptomatic PAD patients should have their low-density lipoprotein (LDL)-cholesterol lowered to <2.59 mmol/L (<100 mg/dL) [A].
• In patients with PAD and a history of vascular disease in other beds (e.g. coronary artery disease) it is reasonable to lower LDL cholesterol levels to <1.81 mmol/L (<70 mg/dL) [B].
• All asymptomatic patients with PAD and no other clinical evidence of cardiovascular disease should also have their LDL-cholesterol level lowered to <2.59 mmol/L (<100 mg/dL) [C].
• In patients with elevated triglyceride levels where the LDL cannot be accurately calculated, the LDL level should be directly measured and treated to values listed above. Alternatively, the non-HDL (high-density lipoprotein) cholesterol level can be calculated with a goal of <3.36 mmol/L (<130 mg/dL), and in high-risk patients the level should be <2.59 mmol/L (<100 mg/dL).
• Dietary modification should be the initial intervention to control abnormal lipid levels [B].
• In symptomatic PAD patients, statins should be the primary agents to lower LDL cholesterol levels to reduce the risk of cardiovascular events [A].
• Fibrates and/or niacin to raise HDL-cholesterol levels and lower triglyceride levels should be considered in patients with PAD who have abnormalities of those lipid fractions [B].

#### B1.2.4 Hypertension

Hypertension is associated with a two- to three-fold increased risk for PAD. Hypertension guidelines support the aggressive treatment of blood pressure in patients with atherosclerosis, indicating PAD. In this high-risk group the current recommendation is a goal of <140/90 mmHg, and <130/80 mmHg if the patient also has diabetes or renal insufficiency.
• Chobanian A.V.
• Bakris G.L.
• Black H.R.
• Cushman W.C.
• Green L.A.
• Izzo Jr, J.L.
• et al.
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
• ESH/ESC
2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.
Regarding drug choice, all drugs that lower blood pressure are effective at reducing the risk of cardiovascular events. Thiazide diuretics are first-line agents, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers should be used in patients with diabetic renal disease or in congestive heart failure, and calcium channel blockers for difficult to control hypertension. Most patients will require multiple agents to achieve desired blood pressure goals. The ACE inhibitor drugs have also shown benefit in PAD, possibly beyond blood-pressure lowering in high-risk groups. This was documented by specific results from the HOPE (Heart Outcomes Prevention Evaluation) study in 4046 patients with PAD.
• Yusuf S.
• Sleight P.
• Pogue J.
• Bosch J.
• Davies R.
• Dagenais G.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
In this subgroup, there was a 22% risk reduction in patients randomized to ramipril compared with placebo, which was independent of lowering of blood pressure. Based on this finding, the United States Federal Drug Administration has now approved ramipril for its cardioprotective benefits in patients at high risk, including those with PAD. Thus, in terms of a drug class, the ACE inhibitors would be recommended in patients with PAD.
Beta-adrenergic blocking drugs have previously been discouraged in PAD because of the possibility of worsening claudication symptoms. However, this concern has not been borne out by randomized trials; therefore, beta-adrenergic-blocking drugs can be safely utilized in patients with claudication.
• Deck C.
Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials.
In particular, patients with PAD who also have concomitant coronary disease may have additional cardio-protection with beta-adrenergic-blocking agents. Therefore, beta-adrenergic-blocking agents may be considered when treating hypertension in patients with PAD.
Control of hypertension in peripheral arterial disease (PAD) patients
• All patients with hypertension should have blood pressure controlled to <140/90 mmHg or <130/80 mmHg if they also have diabetes or renal insufficiency [A].
• JNC VII and European guidelines for the management of hypertension in PAD should be followed [A].
• Thiazides and ACE inhibitors should be considered as initial blood-pressure lowering drugs in PAD to reduce the risk of cardiovascular events [B].

Diabetes increases the risk of PAD approximately three- to four-fold, and the risk of claudication two-fold. Most patients with diabetes have other cardiovascular risk factors (smoking, hypertension and dyslipidemia) that contribute to the development of PAD. Diabetes is also associated with peripheral neuropathy and decreased resistance to infection, which leads to an increased risk of foot ulcers and foot infections.
Several studies of both type 1 and type 2 diabetes have shown that aggressive blood-glucose lowering can prevent microvascular complications (particularly retinopathy and nephropathy); this has not been demonstrated for PAD, primarily because the studies conducted to date examining glycemic control in diabetes were neither designed nor powered to examine PAD endpoints.
• UKPDS
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
• DCCT
Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial.
The current American Diabetes Association guidance recommends hemoglobin A1C of <7.0% as the goal for treatment of diabetes “in general”, but points out that for “the individual patient,” the A1C should be “as close to normal (<6%) as possible without significant hypoglycemia.” However, it is unclear whether achieving this goal will effectively protect the peripheral circulation or prevent amputation.
Standards of medical care in diabetes–2006.
A single study in patients with type 2 diabetes and a history of cardiovascular disease did not show a benefit of lowering blood glucose levels with the insulin-sensitizing agent pioglitazone on the primary endpoint of the study (cardiovascular morbidity and mortality) but did show a reduction in the risk of a secondary endpoint of myocardial infarction, stroke and vascular death.
• UKPDS
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
• Dormandy J.A.
• Charbonnel B.
• Eckland D.J.
• Erdmann E.
• Massi-Benedetti M.
• Moules I.K.
• et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
Additional studies will be necessary to define the role of insulin sensitizing agents in the management of cardiovascular complication of diabetes in patients with PAD.
Control of diabetes in peripheral arterial disease (PAD)
• Patients with diabetes and PAD should have aggressive control of blood glucose levels with a hemoglobin A1c goal of <7.0% or as close to 6% as possible [C].

#### B1.2.6 Homocysteine

An elevated plasma homocysteine level is an independent risk factor for PAD. While supplement with B-vitamins and/or folate can lower homocysteine levels, high-level evidence for the benefits in terms of preventing cardiovascular events is lacking. Two studies of supplemental B vitamins and folic acid in patients with CAD demonstrated no benefit and even a suggestion of harm, so this therapy cannot be recommended.
• Bonaa K.
• Ueland P.
• Schirmer H.
• Tverdal A.
• Steigen T.
• et al.
Homocysteine lowering and cardiovascular events after acute myocardial infarction.
• Lonn E.
• Yusuf S.
• Arnold M.J.
• Sheridan P.
• Pogue J.
• Micks M.
• et al.
Homocysteine lowering with folic acid and B vitamins in vascular disease.
Use of folate supplementation in peripheral arterial disease (PAD)
• Patients with PAD and other evidence of cardiovascular disease should not be given folate supplements to reduce their risk of cardiovascular events [B].

#### B1.2.7 Inflammation

Markers of inflammation have been associated with the development of atherosclerosis and cardiovascular events. In particular, C-reactive protein is independently associated with PAD.

#### B1.2.8 Antiplatelet drug therapy

Aspirin/acetylsalicylic acid (ASA) is a well-recognized antiplatelet drug for secondary prevention that has clear benefits in patients with cardiovascular diseases. Numerous publications from the Antithrombotic Trialists' Collaboration have concluded that patients with cardiovascular disease will realize a 25% odds reduction in subsequent cardiovascular events with the use of aspirin/ASA.
• ATC
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
These findings particularly apply to patients with coronary artery and cerebral artery diseases. This most recent meta-analysis has also clearly demonstrated that low-dose aspirin/ASA (75–160 mg) is protective, and probably safer in terms of gastrointestinal bleeding than higher doses of aspirin/ASA. Thus, current recommendations would strongly favor the use of low-dose aspirin/ASA in patients with cardiovascular diseases. However, the initial Antithrombotic Trialists' Collaboration meta-analysis did not find a statistically significant reduction in cardiovascular events in PAD patients treated with aspirin/ASA who did not have other evidence of vascular disease in other territories.
• ATC
Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration.
However, in the more recent meta-analysis, when the PAD data were combined from trials using not only aspirin/ASA but also clopidogrel, ticlopidine, dipyridamole and picotamide, there was a significant 23% odds reduction in ischemic events in all subgroups of patients with PAD. Antiplatelet drugs are clearly indicated in the overall management of PAD, although the efficacy of aspirin/ASA is uniformly shown only when PAD and cardiovascular disease coexist.
• Clagett P.
• Sobel M.
• Jackson M.
• Lip G.
• Tangelder M.
• Verhaeghe R.
Antithrombotic therapy in peripheral arterial disease: The Seventh ACCP Conference on antithrombotic and thrombolytic therapy.
Picotamide is an antiplatelet drug that inhibits platelet thromboxane A2 synthase and antagonizes thromboxane receptors that has a mortality benefit in the subgroup of patients with PAD who also have diabetes.
• Neri Serneri G.G.
• Coccheri S.
• Marubini E.
• Violi F.
Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.
In that study, the drug significantly reduced 2-year, all-cause mortality, but not the incidence of non-fatal cardiovascular events. Based on these data, further study is warranted before a recommendation can be made in regards to picotamide.
In addition to aspirin/ASA, the thienopyridines are a class of antiplatelet agents that have been studied in patients with cardiovascular disease. Ticlopidine has been evaluated in several trials in patients with PAD, and has been reported to reduce the risk of myocardial infarction, stroke and vascular death.
• Janzon L.
• Bergqvist D.
• Boberg J.
• Boberg M.
• Eriksson I.
• Lindgarde F.
• et al.
Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study.
However, the clinical usefulness of ticlopidine is limited by side effects such as neutropenia and thrombocytopenia. Clopidogrel was studied in the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial and shown to be effective in the symptomatic PAD population to reduce the risk of myocardial infarction, stroke and vascular death. The overall benefit in this particular group was a 24% relative risk reduction over the use of aspirin/ASA.
• CAPRIE
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
This represents a number needed to treat with clopidogrel compared with aspirin/ASA of 87 patients to prevent an event. Clopidogrel has a safety profile similar to aspirin/ASA, with only rare reports of thrombocytopenia. Patients undergoing surgical procedures are at increased risk of bleeding when taking anti-thrombotics including heparins, aspirin/ASA or clopidogrel. Thus, temporary cessation of these drugs should be individualized based on the type of surgery and/or endovascular intervention/revascularization to reduce bleeding risks.
Recent publications in patients with acute coronary syndromes suggest that combination therapy with aspirin/ASA and clopidogrel is more effective than with aspirin/ASA alone, but at a higher risk of major bleeding.
• Yusuf S.
• Zhao F.
• Mehta S.R.
• Chrolavicius S.
• Tognoni G.
• Fox K.K.
Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
A recent study of clopidogrel combined with aspirin/ASA (versus aspirin/ASA alone) was performed in a high-risk population consisting of patients with established cardiovascular disease (including PAD) and patients without a history of cardiovascular disease but who had multiple risk factors. This study showed no overall benefit of the combination of antiplatelet drugs as compared with aspirin/ASA alone on the outcome of myocardial infarction, stroke and vascular death.
• Bhatt D.
• Fox K.
• Hacke W.
• Berger P.
• Black H.
• Boden W.
• et al.
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
Thus, combination therapy cannot be recommended in patients with stable PAD, and if clopidogrel is considered it should be used as monotherapy.
Antiplatelet therapy in peripheral arterial disease (PAD)
• All symptomatic patients with or without a history of other cardiovascular disease should be prescribed an antiplatelet drug long term to reduce the risk of cardiovascular morbidity and mortality [A].
• Aspirin/ASA is effective in patients with PAD who also have clinical evidence of other forms of cardiovascular disease (coronary or carotid) [A].
• The use of aspirin/ASA in patients with PAD who do not have clinical evidence of other forms of cardiovascular disease can be considered [C].
• Clopidogrel is effective in reducing cardiovascular events in a subgroup of patients with symptomatic PAD, with or without other clinical evidence of cardiovascular disease [B].

## B2 Health Economics of Risk-factor Management

For all cardiovascular risk factors, including smoking cessation, the most effective and cost-effective interventions are those that combine a government-led action with individual prevention interventions. In other words, laws that reduce the amount of added salt in processed foods and that increase taxes on tobacco are more cost effective than individual prevention alone, but a combination of both is best.
• Murray C.J.
• Lauer J.A.
• Hutubessy R.C.
• Niessen L.
• Tomijima N.
• Rodgers A.
• et al.
Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk.
The issue in dealing with risk factors is the overall budgetary impact of enforcing compliance to published guidelines. This is due to the large size of the population at risk and the difficulty of organizing the follow up of chronic patients treated by numerous health professionals. An additional difficulty for payers is that the health and economic benefits are delayed while resources for treatment have to be expended at once. Studies on dyslipidemia, diabetes and hypertension have shown that compliance with guidelines is usually cost effective, within the range of $20–30,000 per added year of life. This holds true when several risk factors are associated. • Fischer M.A. • Avorn J. Economic implications of evidence-based prescribing for hypertension: can better care cost less?. • Gaspoz J.M. • Coxson P.G. • Goldman P.A. • Williams L.W. • Kuntz K.M. • Hunink M.G. • et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. The effectiveness and cost-effectiveness of a number of lifestyle interventions, including smoking cessation, exercise and diet, have been assessed by the Cochrane Collaboration. ### B2.1 Cost-effectiveness of smoking cessation interventions For smoking cessation, the performance of professionals in detection and interventions (including follow-up appointments, self-help materials and nicotine gum) is improved by training, although the overall effect on quit rates is modest. However, “training can be expensive, and simply providing programs for health care professionals, without addressing the constraints imposed by the conditions in which they practice, is unlikely to be a wise use of health care resources”. • Lancaster T. • Silagy C. • Fowler G. Training health professionals in smoking cessation. Advising patients to use the telephone services is an effective strategy. • Lancaster T. • Silagy C. • Fowler G. Training health professionals in smoking cessation. The unit cost of advice alone is estimated$5 per patient, while counseling costs $51 per patient. Adding pharmacologic agents to counseling increases the quit rate and is cost effective: assuming that a long-term quitter increases his life expectancy by an average 2 years, the cost-effectiveness ratio of added pharmacological intervention ranges from$1 to $3,000 per life-year gained. • Song F. • Raftery J. • Aveyard P. • Hyde C. • Barton P. • Woolacott N. Cost-effectiveness of pharmacological interventions for smoking cessation: a literature review and a decision analytic analysis. ### B2.2 Cost-effectiveness of exercise interventions Exercise interventions are heterogenic, including one-to-one counseling/advice or group counseling/advice; self-directed or prescribed physical activity; supervised or unsupervised physical activity; home-based or facility-based physical activity; ongoing face-to-face support; telephone support; written education/motivation material; and self monitoring. The intervention can be delivered by one or a number of practitioners including physicians, nurses, health educators, counselors, exercise leaders, and peers. Interventions “have a positive moderate sized effect on increasing self-reported physical activity and measured cardio-respiratory fitness, at least in the short to mid-term”. • Hillsdon M. • Foster C. • Thorogood M. Interventions for promoting physical activity. Assuming an adherence of 50% in the first year and 30% in subsequent years, the cost-effectiveness ratio of unsupervised exercise is less than$12,000 per life year gained. Supervised exercise has a cost-effectiveness ratio ranging from $20,000–$40,000 per life year gained (the strategies are more efficient in elderly males with multiple risk factors).
• Lowensteyn I.
• Coupal L.
• Zowall H.
• Grover S.A.
The cost-effectiveness of exercise training for the primary and secondary prevention of cardiovascular disease.

### B2.3 Cost-effectiveness of pharmacologic interventions

It is difficult to recommend one drug over another for risk factor modification on cost-effectiveness considerations because drug prices are subject to variations between countries and over time. Although this is true for all interventions, the case of a newer drug used in prevention of cardiac risk factors is particular in that the medical benefits of one treatment over another are usually small and, therefore, the cost-effectiveness ratio is highly dependent on drug prices. The global cost-effectiveness analysis on the reduction of cardiovascular disease risk
• Bhatt D.
• Fox K.
• Hacke W.
• Berger P.
• Black H.
• Boden W.
• et al.
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
found that treatment by a combination of statin, beta blocker, diuretic and aspirin was most efficient in avoiding death and disability. When oral anti-platelet agents are considered, assuming a threshold of up to £20,000–40,000 per additional quality-adjusted life year (QALY), clopidogrel would be considered cost effective for treatment duration of 2 years in patients with peripheral arterial disease. For a lifetime treatment duration, clopidogrel would be considered more cost effective than aspirin as long as treatment effects on non-vascular deaths are not considered.
• Jones L.
• Griffin S.
• Palmer S.
• Main C.
• Orton V.
• Sculpher M.
• et al.
Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.
Because recent studies have often failed to demonstrate a benefit on mortality, the efficiency of drug treatments has been measured in ‘cost per major event averted’ and is, therefore, not comparable to ‘cost per life year gained’, although there is a relationship between the two. For example, the cost effectiveness of 40 mg/day simvastatin in high-risk patients is £4,500 (95% CI: 2,300–7,400) per major vascular event averted, but the result is highly sensitive to the statin cost. In this context, it is likely that the use of an off-patent statin would prove more efficient.
• Mihaylova B.
• Briggs A.
• Armitage J.
• Parish S.
• Gray A.
• Collins R.
Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20,536 individuals.

## D9 Future Aspects of Treatment of Critical Limb Ischemia

The most striking feature of CLI is the dismal prognosis for both life and limb outcomes no matter what treatment is employed. This is because most patients have generalized atherosclerosis. One may, therefore, consider what magnitude of treatment options is realistic for the single patient. A successful revascularization may reduce pain and improve quality of life for a limited period of time, but frequently this goal is not achieved. Amputation may be a good alternative to reduce pain, though amputees may have an even more reduced life expectancy. Medical treatment that favorably modifies cardiovascular risk is recommended for all patients, while symptomatic treatment of the limb has to be individualized.
Preliminary trials of intramuscular gene transfer utilizing naked plasmid DNA encoding phVEGF165 have given promising results on symptoms of CLI
• Baumgartner I.
• Pieczek A.
• Manor O.
• Blair R.
• Kearney M.
• Walsh K.
• et al.
Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia.
while others have been negative. Several trials are using viral vectors to increase gene transfer efficiency. Besides vascular endothelial growth factor (VEGF), fibroblast growth factor, angiopoietin and other growth factors are under investigation.
• Yla-Herttuala S.
• Alitalo K.
Gene transfer as a tool to induce therapeutic vascular growth.
Preliminary trials of intramuscular injection of autologous bone-marrow mononuclear cells to stimulate vascular growth
• Tateishi-Yuyama E.
• Matsubara H.
• Murohara T.
• Ikeda U.
• Shintani S.
• Masaki H.
• et al.
Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.
have been promising. Most trials are in Phase I or II and the appropriate use of gene therapy in vascular practice remains to be proven.
In conclusion, there is low-level evidence for spinal cord stimulation to improve outcome of patients with CLI, should revascularization not be possible. Prostanoid treatment may also be of value; however, only a limited proportion of patients will respond to this treatment, as mentioned. Results of other pharmacotherapies are far from good.
• Norgren L.
Pharmacotherapy for critical limb ischaemia.
• Collinson D.J.
• Donnelly R.
Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation?.
Gene therapy has shown promising early efficacy but further trials are warranted.
SECTION E – ACUTE LIMB ISCHEMIA

## E1 Definition and Nomenclature for Acute Limb Ischemia

### E1.1 Definition/etiology of acute limb ischemia

Acute limb ischemia (ALI) is any sudden decrease in limb perfusion causing a potential threat to limb viability. Presentation is normally up to 2 weeks following the acute event. Fig. E1 shows the frequency of different etiologies for ALI.
Timing of presentation is related to severity of ischemia and access to healthcare. Patients with embolism, trauma, peripheral aneurysms with emboli and reconstruction occlusions tend to present early (hours) due to lack of collaterals, extension of thrombus to arterial outflow, or a combination of both. On the other hand, later presentations – within days – tend to be restricted to those with a native thrombosis or reconstruction occlusions (Fig. E2).

## E2 Evaluation

### E2.1 Clinical evaluation of acute limb ischemia

#### E2.1.1 History

The history should have two primary aims: querying leg symptoms relative to the presence and severity of limb ischemia (present illness) and obtaining background information (e.g. history of claudication, recent intervention on the proximal arteries or diagnostic cardiac catheterization), pertaining to etiology, differential diagnosis and the presence of significant concurrent disease.
Present illness
Leg symptoms in ALI relate primarily to pain or function. The abruptness and time of onset of the pain, its location and intensity, as well as change in severity over time, should all be explored. The duration and intensity of the pain and presence of motor or sensory changes are very important in clinical decision-making and urgency of revascularization. For example, thrombolysis may be less effective for thrombosis of >2 weeks duration compared with more acute thrombosis (post hoc analysis of the STILE data
Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
).
Past history
It is important to ask whether the patient has had leg pain before (e.g. a history of claudication), whether there have been interventions for ‘poor circulation’ in the past, and whether the patient has been diagnosed as having heart disease (e.g. atrial fibrillation) or aneurysms (i.e. possible embolic sources). The patient should also be asked about serious concurrent disease or atherosclerotic risk factors (hypertension, diabetes, tobacco abuse, hyperlipidemia, family history of cardiovascular disease, strokes, blood clots or amputations). A more complete discussion of risk factors can be found in section A.

#### E2.1.2 Physical examination

The findings of ALI may include “5 P's”:
• Pain: time of onset, location and intensity, change over time
• Pulselessness: the accuracy of pedal pulse palpation is highly variable and, therefore, absent pulse findings are suggestive but not diagnostic of ALI and palpable pulses alone do not rule it out. Bedside measurement of ankle blood pressure should be performed immediately (technique see section C). Usually, very low pressure is obtained or the Doppler signal may be absent. If performed correctly, the finding of absent flow signals in the foot arteries is highly consistent with a diagnosis of ALI
• Pallor: change in color and temperature is a common finding in ALI (although temperature may be subject to environmental conditions); the finding is most important when different from the contralateral limb. Venous filling may be slow or absent
• Paresthesia: numbness occurs in more than half of patients
• Paralysis: is a poor prognostic sign.
Assessment of acute limb ischemia (ALI)
• Due to inaccuracy of pulse palpation and the physical examination, all patients with suspected ALI should have Doppler assessment of peripheral pulses immediately at presentation to determine if a flow signal is present [C].

#### E2.1.3 Clinical classification of acute limb ischemia

The main question to be answered by the history and physical examination is the severity of the ALI, which is the major consideration in early management decisions. Is the limb viable (if there is no further progression in the severity of ischemia), is its viability immediately threatened (if perfusion is not restored quickly), or are there already irreversible changes that preclude foot salvage?
The three findings that help separate ‘threatened’ from ‘viable’ extremities (Table E1) are:
• Presence of rest pain,
• Sensory loss, or
• Muscle weakness
Table E1Separation of threatened from viable extremities
• Rutherford R.B.
• Baker J.D.
• Ernst C.
• Johnston K.W.
• Porter J.M.
• Ahn S.
• et al.
Recommended standards for reports dealing with lower extremity ischemia: revised version.
CategoryDescription/prognosisFindingsDoppler signals
Obtaining an ankle pressure is very important. However, in severe ALI, blood flow velocity in the affected arteries may be so low that Doppler signals are absent (see section C for technical description of method). Differentiating between arterial and venous flow signals is vital: arterial flow signals will have a rhythmic sound (synchronous with cardiac rhythm) whereas venous signals are more constant and may be affected by respiratory movements or be augmented by distal compression (caution needs to be taken not to compress the vessels with the transducer). Reproduced with permission from Rutherford RB et al. J Vasc Surg 1997;26(3):517–538.
Sensory lossMuscle weaknessArterialVenous
I. ViableNot immediately threatenedNoneNoneAudibleAudible
II. Threatened
a. MarginalSalvageable if promptly treatedMinimal (toes) or noneNone(Often) inaudibleAudible
b. ImmediateSalvageable with immediate revascularizationMore than toes, associated with rest painMild, moderate(Usually) inaudibleAudible
III. IrreversibleMajor tissue loss or permanent nerve damage inevitableProfound, anestheticProfound, paralysis (rigor)InaudibleInaudible
Obtaining an ankle pressure is very important. However, in severe ALI, blood flow velocity in the affected arteries may be so low that Doppler signals are absent (see section C for technical description of method). Differentiating between arterial and venous flow signals is vital: arterial flow signals will have a rhythmic sound (synchronous with cardiac rhythm) whereas venous signals are more constant and may be affected by respiratory movements or be augmented by distal compression (caution needs to be taken not to compress the vessels with the transducer). Reproduced with permission from Rutherford RB et al. J Vasc Surg 1997;26(3):517–538.
Muscle rigor, tenderness, or findings of pain with passive movement are late signs of advanced ischemia and probable tissue loss.
Cases of suspected acute limb ischemia (ALI)
• All patients with suspected ALI should be evaluated immediately by a vascular specialist who should direct immediate decision making and perform revascularization because irreversible nerve and muscle damage may occur within hours [C].
Data presented summarize both registry and clinical trial data and show the frequency of different categories of acute limb ischemia on presentation (Fig. E3).
• Category III: all patients from registries who undergo primary amputation
• Category II: all patients from randomized trials who present with sensory loss
• Category I: all patients from randomized trials who present without sensory loss

#### E2.1.4 Differential diagnosis of acute limb ischemia

There are three levels of differential diagnosis in ALI:
• 1.
Is there a condition mimicking arterial occlusion?
• 2.
Are there other non-atherosclerotic causes of arterial occlusion present and, if not,
• 3.
Is the ischemia caused by an arterial thrombosis or embolus?
The conditions that can cause or mimic acute arterial occlusion are listed in Table E2.
Table E2Differential diagnosis of acute limb ischemia
 ⁎Two of the three conditions (deep vein thrombosis, neuropathy) that may mimic arterial occlusion should be expected to have arterial pulses, except if occult chronic peripheral arterial disease existed prior to the acute event. Low cardiac output makes the chronic arterial ischemia more manifest in terms of symptoms and physical findings.Conditions mimicking acute limb ischemia■Systemic shock (especially if associated with chronic occlusive disease)■Phlegmasia cerulea dolens■Acute compressive neuropathy Differential diagnosis for acute limb ischemia (other than acute PAD)■Arterial trauma■Aortic/arterial dissection■Arteritis with thrombosis (e.g. giant cell arteritis, thromboangiitis obliterans)■HIV arteriopathy■Spontaneous thrombosis associated with a hypercoagulable state■Popliteal adventitial cyst with thrombosis■Popliteal entrapment with thrombosis■Vasospasm with thrombosis (e.g. ergotism)■Compartment syndrome Acute PAD■Thrombosis of an atherosclerotic stenosed artery■Thrombosis of an arterial bypass graft■Embolism from heart, aneurysm, plaque or critical stenosis upstream (including cholesterol or atherothrombotic emboli secondary to endovascular procedures)■Thrombosed aneurysm with or without embolization
Two of the three conditions (deep vein thrombosis, neuropathy) that may mimic arterial occlusion should be expected to have arterial pulses, except if occult chronic peripheral arterial disease existed prior to the acute event. Low cardiac output makes the chronic arterial ischemia more manifest in terms of symptoms and physical findings.
Arterial trauma or dissection
Overt arterial trauma is not difficult to diagnose, but iatrogenic trauma, especially as a result of recent arterial catheterization, is often overlooked. It should be considered in all hospitalized patients undergoing invasive diagnosis and treatment who present with femoral artery occlusion.
Thoracic aortic dissections may progress distally to involve the abdominal aorta and also an iliac artery. Tearing interscapular or back pain associated with hypertension would obviously point to such a thoracic aortic dissection, but these may be obscured by other events and the patient's inability to give a good history. It should be considered when faced with acute unilateral or bilateral iliac occlusion.
Ergotism
Ergotism is rare. It may affect almost any artery and may progress to thrombosis but rarely presents as an immediately threatened limb.
HIV arteriopathy
HIV patients with severe immune compromise and CD4 counts less than 250/cm3 can develop acute ischemia of upper or lower extremities. This entity involves the distal arteries with an acute and chronic cellular infiltrate in the vasa vasorum and viral protein in the lymphocytes. Occasionally, a hypercoaguable focus is found, but primarily the occlusion appears due to the underlying vasculopathy. Standard therapies including thrombectomy, bypass and thrombolysis have been used, with relatively high reocclusion and amputation rates.
Popliteal adventitial cysts and popliteal entrapment
Popliteal adventitial cysts and popliteal entrapment may be discovered before they induce thrombosis if they cause claudication, but they sometimes first present with thrombosis. Like a thrombosed popliteal aneurysm, the degree of ischemia is often severe. Popliteal entrapment affects younger patients, but popliteal adventitial cysts can present at an older age and may be indistinguishable from peripheral arterial disease (PAD). The absence of atherosclerotic risk factors and the location of the obstruction, best ascertained by duplex scan, should suggest the etiology.
Thrombosed popliteal artery aneurysm
Thrombosed popliteal artery aneurysms are commonly mistaken for acute arterial embolism. The popliteal artery is the sole axial artery traversing the knee. Severe ischemia results either because thrombosis occurs in the absence of previous arterial narrowing and the lack of collateral vessels or because prior asymptomatic or symptomatic embolization has occluded the majority of the tibial outflow. As popliteal aneurysms are bilateral in approximately 50% of cases, detecting a prominent popliteal pulse in the opposite leg may help to identify the cause. These patients also tend to have dilated femoral arteries and may have abdominal aortic aneurysms. Once suspected, duplex ultrasound is the quickest way to confirm the diagnosis.
Thromboembolism
Arterial embolism is suspected in patients with atrial arrhythmia (flutter/fibrillation), congestive heart failure, or valvular heart disease. A rare cause can be paradoxical embolization in a patient with venous thromboembolism and a cardiac septal defect. The contralateral limb is often normal. Patients usually do not have any antecedent claudication symptoms. Arteriographic findings include multiple areas with arterial filling defects (particularly at bifurcations), morphology (meniscus sign) consistent with embolus, lack of collaterals and absence of atherosclerotic disease in unaffected segments. Echocardiography (often transesophageal) is useful to locate the source of thromboemboli.
Atheroembolism
Embolism of cholesterol crystals and other debris from friable atherosclerotic plaques in proximal arteries may lodge in the distal circulation and infarct tissue. Although also called “blue toe syndrome” for the appearance of painful cyanotic lesions on the toes of affected patients, more proximal organs such as the kidneys, bowel and pancreas may also be affected by atheroemboli.
Thrombosed arterial segment
Patients with thrombosed arterial segments often have atherosclerotic disease at the site of thrombosis. They may have an antecedent history of claudication and the contralateral limb often has abnormal circulation. Some hypercoagulable states, such as antiphospholipid antibody syndrome or heparin-induced thrombocytopenia can also cause thrombosis in situ, and these should be considered in patients without other overt risk factors for arterial disease.
Thrombosed arterial bypass graft
Patients with thrombosed arterial bypass grafts have a prior history of vascular disease, limb incisions from previous surgery and a thrombosed graft that can be visualized on duplex imaging.
Compartment syndrome
See section E3.7.1.

### E2.2 Investigations for acute limb ischemia

Patients with ALI should be evaluated in the same fashion as those with chronic symptoms (see section G) but the severity and duration of ischemia at the time of presentation rarely allow this to be done at the outset. Ideally, all patients with acute ischemia should be investigated with imaging, however, the clinical condition and access to appropriate medical resources may preclude such investigations.

#### E2.2.1 Other routine laboratory studies

The following laboratory studies should be obtained in patients with ALI: electrocardiogram, standard chemistry, complete blood count, prothrombin time, partial thromboplastin time and creatinine phosphokinase level. Patients with a suspected hypercoagulable state will need additional studies seeking anticardiolipin antibodies, elevated homocysteine concentration and antibody to platelet factor IV.

#### E2.2.2 Imaging – arteriography

Arteriography is of major value in localizing an obstruction and visualizing the distal arterial tree. It also assists in distinguishing patients who will benefit more from percutaneous treatment than from embolectomy or open revascularization procedures.
In limb-threatening ischemia, an important consideration is whether the delay in performing formal angiography in an angiographic suite can be tolerated. Angiography makes the most sense when catheter-based treatment is an option.

#### E2.2.3 Other imaging techniques

Computed tomographic angiography/Magnetic resonance angiography
Computed tomographic angiography (CTA) and magnetic resonance (MR) angiography may also be used in the setting of ALI to diagnose and delineate the extent of disease. MR imaging of the vasculature can be cumbersome and time-consuming which may delay treatment. The advantages of CTA include its speed, convenience and ability for cross-sectional imaging of the vessel. The main disadvantage of CTA is its dependence on iodinated contrast media. In patients with ALI who may also require catheter angiography and intervention, this added load of contrast might increase the risk of renal injury to the patient.
Anticoagulant therapy in acute limb ischemia (ALI)
• Immediate parenteral anticoagulant therapy is indicated in all patients with ALI. In patients expected to undergo imminent imaging/therapy on arrival, heparin should be given [C].

## E3 Treatment of Acute Limb Ischemia

The initial goal of treatment for ALI is to prevent thrombus propagation and worsening ischemia. Therefore, immediate anticoagulation with heparin is indicated. The standard therapy (except in cases of heparin antibodies) is unfractionated heparin intravenously (Fig. E4). Based on the results of randomized trials,
• Berridge D.
• Kessel D.
• Robertson I.
Surgery versus thrombolysis for initial management of acute limb ischaemia.
there is no clear superiority for thrombolysis versus surgery on 30 day limb salvage or mortality. Access to each is a major issue, as time is often critical. National registry data from Europe
• Kuukasjarvi P.
• Salenius J.
Perioperative outcome of acute lower limb ischaemia on the basis of the national vascular registry. The Finnvasc Study Group.
and the United States
• Eliason J.L.
• Wainess R.M.
• Proctor M.C.
• Dimick J.B.
• Cowan Jr, J.A.
• Upchurch Jr, G.R.
• et al.
A national and single institutional experience in the contemporary treatment of acute lower extremity ischemia.
indicate that surgery is used three- to five-fold more frequently than thrombolysis.

### E3.1 Endovascular procedures for acute limb ischemia

#### E3.1.1 Pharmacologic thrombolysis

Three randomized studies have confirmed the important role of catheter-directed thrombolytic therapy in the treatment of ALI.
Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
• Ouriel K.
• Shortell C.
• DeWeese J.
• Green R.
• Francis C.
• Azodo M.
• et al.
A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
• Ouriel K.
• Veith F.
• Sasahara A.
A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
The less invasive nature of a catheter-based approach to this patient population can result in reduced mortality and morbidity compared with open surgery. Thrombolytic therapy is, therefore, the initial treatment of choice in patients in whom the degree of severity allows time (i.e. severity levels I and IIa). More recent advances in endovascular devices and techniques, however, allow for more rapid clot removal and may permit treatment of patients with more advanced degree of ischemia. Advantages of thrombolytic therapy over balloon embolectomy include the reduced risk of endothelial trauma and clot lysis in branch vessels too small for embolectomy balloons. Gradual low-pressure reperfusion, may be advantageous to the sudden, high-pressure reperfusion associated with balloon embolectomy. Systemic thrombolysis has no role in the treatment of patients with ALI.
The choice of lytic therapy depends on many factors such as location and anatomy of lesions, duration of the occlusion, patient risk factors (co-morbidities) and risks of procedure. Because emboli newly arrived in the leg may have previously resided for some time at their site of origin, these ‘old’ emboli may be more resistant to pharmacological thrombolysis than ‘recent’ in-situ thrombus. Contraindications to pharmacologic thrombolysis must be taken into consideration.

#### E3.1.2 Contraindications to thrombolysis.

Table E3Contraindications to thrombolysis
 Absolute contraindications 1. Established cerebrovascular event (excluding TIA within previous 2 months) 2. Active bleeding diathesis 3. Recent gastrointestinal bleeding (within previous 10 days) 4. Neurosurgery (intracranial, spinal) within previous 3 months 5. Intracranial trauma within previous 3 months Relative contraindications 1. Cardiopulmonary resuscitation within previous 10 days 2. Major nonvascular surgery or trauma within previous 10 days 3. Uncontrolled hypertension (systolic >180 mmHg or diastolic >110 mmHg) 4. Puncture of noncompressible vessel 5. Intracranial tumor 6. Recent eye surgery Minor contraindications 1. Hepatic failure, particularly those with coagulopathy 2. Bacterial endocarditis 3. Pregnancy 4. Active diabetic proliferative retinopathy
These contraindications were established for systemic thrombolysis. The markedly improved safety profile of regional thrombolysis is well recognized, and the risk benefit of regional thrombolysis in various above conditions is highly dependent on individual physician practice/experience. The only contraindication in the TOPAS trial was pregnancy.

#### E3.1.3 Other endovascular techniques

When thrombolysis reveals underlying localized arterial disease, catheter-based revascularization becomes an attractive option. Stenoses and occlusions are rarely the sole cause of ALI or even severe chronic symptoms but these commonly lead to superimposed thrombosis and, therefore, should be treated to avoid recurrent thrombosis.
Percutaneous aspiration thrombectomy (PAT) and percutaneous mechanical thrombectomy (PMT) provide alternative non-surgical modalities for the treatment of ALI without the use of pharmacologic thrombolytic agents. Combination of these techniques with pharmacologic thrombolysis may substantially speed up clot lysis, which is important in more advanced ALI where time to revascularization is critical. In practice, the combination is almost always used.
Percutaneous aspiration thrombectomy (PAT)
PAT is a technique that uses thin-wall, large-lumen catheters and suction with a 50-mL syringe to remove embolus or thrombus from native arteries, bypass grafts and run-off vessels. It has been used together with fibrinolysis to reduce time and dose of the fibrinolytic agent or as a stand-alone procedure.
Percutaneous mechanical thrombectomy (PMT)
Most PMT devices operate on the basis of hydrodynamic recirculation. According to this concept, dissolution of the thrombus occurs within an area of continuous mixing referred to as the “hydrodynamic vortex.” This selectively traps, dissolves, and evacuates the thrombus. Non-recirculation devices, which function primarily by direct mechanical thrombus fragmentation, have been used less frequently for peripheral arterial disease because of the higher risk of peripheral embolization and higher potential for vascular injury. The efficiency of PMT depends mainly on the age of the thrombus; fresh thrombus responds better than older organized clot. Small clinical series have demonstrated short-term (30 day) limb salvage of 80%–90%.

### E3.2 Surgery

#### E3.2.1 Indications

Immediate revascularization is indicated for the profoundly ischemic limb (class IIb) (Table E1). It may also be considered in those with profound sensory and motor deficits of very short duration, as revascularization completed within a few hours of onset of severe symptoms may produce remarkable recovery. Beyond this short window, major neuromuscular damage is inevitable. The method of revascularization (open surgical or endovascular) may differ depending on anatomic location of occlusion, etiology of ALI, contraindications to open or endovascular treatment and local practice patterns. Previously, urgency of treatment made surgery the treatment of choice in many cases. However, recent methodological advances within endovascular management, and recognition that improved circulation significantly precedes patency with this approach, have made the time factor less important if endovascular service is readily available.
In considering operative versus percutaneous revascularization, it must be recognized that the time from the decision to operate until reperfusion may be substantially longer than anticipated because of factors outside of the surgeons' control (e.g. operating theater availability, anesthesia preparation, technical details of the operation).
Anatomic location of the acute occlusion
In cases of suprainguinal occlusion (no femoral pulse) open surgery may be the preferred choice of treatment. For instance, a large embolus in the common proximal iliac artery or distal aorta may most effectively be treated with catheter embolectomy. Also, suprainguinal graft occlusion may best be treated with surgery in most cases. Endovascular management with femoral access of a proximal lesion (often involving thrombosis) may not be possible/appropriate or available (see below).
Infrainguinal causes of ALI, such as embolism or thrombosis, are often treated with endovascular methods. Initial therapy with catheter-based thrombolysis should be considered in cases of acute thrombosis due to vulnerable atherosclerotic lesions or late bypass graft failures. In this manner, the underlying occlusive disease is revealed and appropriate adjunctive management may be chosen.
In cases of trauma, for many reasons, surgery will be the treatment of choice in the majority of cases. Infrainguinal grafts often occlude due to obstructive lesions proximal to, within and distal to the graft, thus, simple thrombectomy will not solve the underlying lesion. Catheter-based thrombolysis, on the other hand, will dissolve clot and identify the responsible underlying lesion. Endovascular treatment of these lesions may then be employed. If the lesion is discrete this may suffice, and even if the underlying disease is diffuse and extensive, it may serve as a temporizing measure, a bridge to a later bypass.

#### E3.2.2 Surgical technique

Emboli are preferentially removed surgically if they are lodged proximally in the limb or above the inguinal ligament. Surgery may also be considered if the involved limb has no underlying atherosclerosis. When no further clot can be retrieved, some form of intraoperative assessment of the adequacy of clot removal is required. The most common of these is ‘completion’ angiography; alternatively, ultrasound-based methods may be used.
Distal clot may be treated by intraoperative thrombolysis with instillation of high doses of thrombolytic agents for a brief period followed by irrigation or additional passages of the balloon catheter. Repeat angiography followed by clinical and Doppler examination of the patient should be performed on the operating table. However, as described in section E3.2.1, catheter-directed thrombolysis may have advantages if conditions allow its use.
In patients with arterial thrombosis, an underlying local lesion and residual thrombus must be sought after clot extraction. Often this may be suspected from the tactile sensations and need for deflation at points during the withdrawal of the inflated balloon catheter. Here completion angiography will help decide between proceeding with a bypass or PTA. Fortunately, arterial thrombosis superimposed on an already narrowed artery will ordinarily cause a less severe degree of ischemia because of predeveloped collaterals. Under these circumstances, patients may not be operated on initially but rather undergo catheter-directed lytic therapy.
In patients with suprainguinal occlusion extra-anatomic bypass surgery may be required.
Completion arteriography
• Unless there is good evidence that adequate circulation has been restored, intraoperative angiography should be performed to identify any residual occlusion or critical arterial lesions requiring further treatment [C].

### E3.3 Results of surgical and endovascular procedures for acute limb ischemia

Catheter-directed thrombolysis (CDT) has become a commonly employed technique in the treatment of ALI. Between 1994 and 1996, three large, prospective, randomized trials
Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
• Ouriel K.
• Shortell C.
• DeWeese J.
• Green R.
• Francis C.
• Azodo M.
• et al.
A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
• Ouriel K.
• Veith F.
• Sasahara A.
A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
were reported that focused on the comparison of CDT and surgical revascularization for treatment of ALI. Limb salvage and mortality rates are recognized as the most important outcome, and the 1-year data are summarized in Table E4.
• Berridge D.
• Kessel D.
• Robertson I.
Surgery versus thrombolysis for initial management of acute limb ischaemia.
Comparison of these studies is limited by certain differences in protocol and case mix (e.g. acute vs. subacute or chronic limb ischemia; thrombotic vs. embolic occlusion; native vs. bypass graft occlusion; proximal vs. distal occlusions). End points in each of the studies also vary: the Rochester study used “event free survival”; the STILE trial used “composite clinical outcome”; and the TOPAS study used “arterial recanalization and extent of lysis.” Only the Rochester trial showed any advantage for CDT by primary end points. However, the late end point of limb salvage, required in these trials, may have favored surgery, as CDT was naturally linked with endovascular treatment of the underlying lesions (the patient being in a radiology suite at the time). Except for discrete lesions, PTA is not as durable as bypass, the inevitable result of being randomized to surgery. Such linkage may be inevitable in randomized trials, but in practice the underlying lesion(s) should be treated by the method giving the most durable results.
Table E4Comparison of catheter-directed thrombolysis and surgical revascularization in treatment of limb ischemia
Results atCatheter-Directed Thrombolysis (CDT)Surgical Revascularization
PatientsLimb salvageMortalityPatientsLimb salvageMortality
Rochester
• Ouriel K.
• Shortell C.
• DeWeese J.
• Green R.
• Francis C.
• Azodo M.
• et al.
A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
12 months5782%16%5782%42%
STILE
Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
6 months24688.2%6.5%14189.4%8.5%
TOPAS
• Ouriel K.
• Veith F.
• Sasahara A.
A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
12 months14482.7%13.3%5481.1%15.7%
The data from the randomized, prospective studies in ALI, suggest that CDT may offer advantages when compared with surgical revascularization. These advantages include reduced mortality rates and a less complex surgical procedure in exchange for a higher rate of failure to avoid persistent or recurrent ischemia, major complications and ultimate risk of amputation. In addition, it appears that reperfusion with CDT is achieved at a lower pressure and may reduce the risk of reperfusion injury compared to open surgery. Thus, if the limb is not immediately or irreversibly threatened, CDT offers a lower-risk opportunity for arterial revascularization. Using this approach, the underlying lesions can be further defined by angiography, and the appropriate percutaneous or surgical revascularization procedure can be performed. Therefore, it seems reasonable to recommend CDT as initial therapy in these particular settings, to be potentially followed by surgical revascularization as needed.

### E3.4 Management of graft thrombosis

In general, at least one attempt to salvage a graft should be done, although individual considerations may apply. When treating late graft thrombosis, the main goals are to remove the clot and correct the underlying lesion that caused the thrombosis. Alteration in the inflow and outflow arteries is usually caused by the progression of atherosclerosis and should be treated with either PTA/stent or bypass grafting, as detailed elsewhere. Lesions intrinsic to the graft are dependent on the type of conduit. Venous bypass grafts may develop stenoses, typically at the site of a valve. After thrombolysis and identification of the lesion, it may be treated with either PTA/stent or surgical revision, the latter usually being favored for its superior long-term results. Prosthetic grafts develop intimal hyperplasia, typically at the distal anastomosis. These rubbery lesions respond differently to PTA than do the typical eccentric atherosclerotic plaque and do not yield as durable results. Many surgeons have suggested that treatment should be exposure of the involved anastomosis, with graft thrombectomy and patch angioplasty of the narrowed graft/artery anastomosis or replacement of the graft. However, in case of the latter, the expected patency using another type of graft should be considered (i.e. replacing a failing vein graft).

### E3.5 Management of a thrombosed popliteal aneurysm

Patients with thrombosed popliteal artery aneurysms initially undergo arteriography. If a distal tibial target is present, then they are treated as a critical limb ischemia case with tibial bypass. If no tibial targets are identified on arteriography, regional thrombolysis is the treatment of choice providing the limb is viable. Small series demonstrate successful identification of tibial targets in over 90% and successful surgical revascularization.

### E3.6 Amputation

Amputation in ALI may be complicated by bleeding due to an increased prevalence of concomitant anticoagulation. In addition, the site of amputation is more often proximal, as the calf muscle is usually compromised. The ratio of above-knee to below-knee amputation is 4:1 compared to the usual 1:1 for critical limb ischemia. The incidence of major amputation is up to 25%. When further evaluated, 10%–15% of patients thought to be salvageable undergo therapy and ultimately require major amputation, and 10% of patients with ALI present unsalvageable.

### E3.7 Immediate post-procedural issues

#### E3.7.1 Reperfusion injury

Compartment syndrome
Fasciotomy following successful revascularization for ALI was required in 5.3% of cases in the United States from 1992–2000. Fasciotomy for presumably more severe cases in tertiary referral hospitals is 25%.
• Eliason J.L.
• Wainess R.M.
• Proctor M.C.
• Dimick J.B.
• Cowan Jr, J.A.
• Upchurch Jr, G.R.
• et al.
A national and single institutional experience in the contemporary treatment of acute lower extremity ischemia.
With extremity reperfusion, there is increased capillary permeability, resulting in local edema and compartment hypertension. This leads to regional venule obstruction, nerve dysfunction and, eventually, capillary and arteriolar obstruction and muscle and nerve infarction. Clinical presentation includes pain out of proportion to physical signs, paresthesia and edema. Compartment pressures can be measured, and pressures of ≥20 mmHg are a clear indication for fasciotomy. The anterior compartment is most commonly involved, but the deep posterior compartment (in which the tibial nerve is located) is the most functionally devastating if affected.
Treatment of choice for compartment syndrome
• In case of clinical suspicion of compartment syndrome, the treatment of choice is a four-compartment fasciotomy [C].
Rhabdomyolysis
Laboratory evidence for myoglobinuria is observed in up to 20%. Half of patients with creatine kinase levels >5000 units/L will develop acute renal failure. Urine myoglobin >1142 nmol/L (>20 mg/dL) is also predictive of acute renal failure. The pathophysiology involves tubular necrosis by myoglobin precipitates (favored in a acidic urine), tubular necrosis due to lipid peroxidation and renal vasoconstriction (exacerbated by fluid shifts into the damage muscle compartment). Clinical features include tea colored urine, elevated serum creatine kinase and positive urine myoglobin assay. Therapy is primarily hydration, alkalinizing the urine and eliminating the source of myoglobin. Mannitol and plasmapheresis have not been found to be beneficial.

## E4 Clinical Outcomes

### E4.1 Systemic/limb

Mortality rates for ALI range from 15%–20%. The cause of death is not provided in most series and randomized trials. Major morbidities include major bleeding requiring transfusion/and or operative intervention in 10%–15%, major amputation in up to 25%, fasciotomy in 5%–25% and renal insufficiency in up to 20%. Functional outcomes have at present not been studied.
Improvement in arterial circulation is relatively simple to assess in that the vast majority of patients with ALI have no pedal Doppler signals at presentation or they have an ankle-brachial index (ABI) ≤0.20. Therefore, any improvement in these parameters postoperatively is considered successful.

### E4.2 Follow-up care

All patients should be treated with heparin in the immediate postoperative period. This should be followed by warfarin often for 3–6 months or longer. Patients with thromboembolism will need long-term anticoagulation, from years or life long. However, there are no clear guidelines regarding duration of therapy. The risk of recurrent limb ischemia in the randomized trials was high during the follow-up interval.
Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial.
• Ouriel K.
• Shortell C.
• DeWeese J.
• Green R.
• Francis C.
• Azodo M.
• et al.
A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia.
• Ouriel K.
• Veith F.
• Sasahara A.
A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators.
Therefore, prolonged warfarin therapy is an appropriate strategy, despite the cumulative bleeding risk. It is important to seek the source of embolism after revascularization, whether cardiac or arterial; however, in many cases no source is identified.
Certainly, if long-term anticoagulation is contraindicated, due to bleeding risk factors, platelet inhibition therapy should be considered. Appropriate systemic therapies as outlined above (see section B) should be provided.

## E5 Economic Aspects of Acute Limb Ischemia

The recent literature has added very little to the findings presented in the first TASC document. When thrombolysis is used in association with angioplasty, the costs are identical to those of surgical revascularization at roughly \$20,000. The relative benefits of surgery have been discussed above. The choice of strategy is based on availability and outcome rather than on cost considerations.
• Korn P.
• Khilnani N.M.
• Fellers J.C.
• Lee T.Y.
• Winchester P.A.
• Bush H.L.
• et al.
Thrombolysis for native arterial occlusions of the lower extremities: clinical outcome and cost.

## E6 Future Management

The increased use of percutaneous therapies with or without surgical revascularization is the trend for future therapy in ALI. The use of protection devices to prevent embolization, as in the carotid circulation, will also become part of therapy. Alternative oral therapies for anticoagulation may hold promise.
SECTION F – REVASCULARIZATION

## F1 Localization of Disease

The determination of the best method of revascularization for treatment of symptomatic peripheral arterial disease (PAD) is based upon the balance between risk of a specific intervention and the degree and durability of the improvement that can be expected from this intervention. Adequate inflow and appropriate outflow are required to keep the revascularized segment functioning. The location and morphology of the disease must be characterized prior to carrying out any revascularization to determine the most appropriate intervention. A variety of methods yielding both anatomic and physiologic information are available to assess the arterial circulation. (Refer to section G for preferred imaging techniques.)
In a situation where a proximal stenosis is of questionable hemodynamic significance, pressure measurements across it to determine its significance (criteria: threshold peak systolic difference 5–10 mmHg pre-vasodilatation and 10–15 mmHg post-vasodilatation) may be made. A recent development, that is yet to be validated, is direct flow measurements using a thermodilution catheter rather than pressure gradients. Hyperemic duplex scanning has also been suggested.
Intra-arterial pressure measurements for assessment of stenosis
• If there is doubt about the hemodynamic significance of partially occlusive aortoiliac disease, it should be assessed by intra-arterial pressure measurements across the stenosis at rest and with induced hyperemia [C].
In general, the outcomes of revascularization depend upon the extent of the disease in the subjacent arterial tree (inflow, outflow and the size and length of the diseased segment), the degree of systemic disease (co-morbid conditions that may affect life expectancy and influence graft patency) and the type of procedure performed. Results of large-scale clinical trials must be considered within the context of the individual patient's situation, considering all co-morbidities when deciding upon a recommended treatment course for that individual.
The endovascular techniques for the treatment of patients with lower extremity ischemia include balloon angioplasty, stents, stent-grafts and plaque debulking procedures. Thrombolysis and percutaneous thrombectomy have been described in the section on acute limb ischemia. Surgical options include autogenous or synthetic bypass, endarterectomy or an intra-operative hybrid procedure.
Outcomes of revascularization procedures depend on anatomic as well as clinical factors. Patency following percutaneous transluminal angioplasty (PTA) is highest for lesions in the common iliac artery and progressively decreases for lesions in more distal vessels. Anatomic factors that affect the patency include severity of disease in run off arteries, length of the stenosis/occlusion and the number of lesions treated. Clinical variables impacting the outcome also include diabetes, renal failure, smoking and the severity of ischemia.
Choosing between techniques with equivalent short- and long-term clinical outcomes
• In a situation where endovascular revascularization and open repair/bypass of a specific lesion causing symptoms of peripheral arterial disease give equivalent short-term and long-term symptomatic improvement, endovascular techniques should be used first [B].

### F1.1 Classification of lesions

While the specific lesions stratified in the following TASC classification schemes have been modified from the original TASC guidelines to reflect inevitable technological advances, the principles behind the classification remain unchanged. Thus ‘A’ lesions represent those which yield excellent results from, and should be treated by, endovascular means; ‘B’ lesions offer sufficiently good results with endovascular methods that this approach is still preferred first, unless an open revascularization is required for other associated lesions in the same anatomic area; ‘C’ lesions produce superior enough long-term results with open revascularization that endovascular methods should be used only in patients at high risk for open repair; and ‘D’ lesions do not yield good enough results with endovascular methods to justify them as primary treatment. Finally it must be understood that most PAD requiring intervention is characterized by more than one lesion, at more than one level, so these schemes are limited by the necessity to focus on individual lesions.

### F1.2 Classification of inflow (aorto-iliac) disease (Fig. F1, Table F1)

Treatment of aortoiliac lesions
• TASC A and D lesions: Endovascular therapy is the treatment of choice for type A lesions and surgery is the treatment of choice for type D lesions [C].
• TASC B and C lesions: Endovascular treatment is the preferred treatment for type B lesions and surgery is the preferred treatment for good-risk patients with type C lesions. The patient's co-morbidities, fully informed patient preference and the local operator's long-term success rates must be considered when making treatment recommendations for type B and type C lesions [C].
Table F1TASC classification of aorto-iliac lesions
 Type A lesions ■Unilateral or bilateral stenoses of CIA■Unilateral or bilateral single short (≤3 cm) stenosis of EIA Type B lesions ■Short (≤3 cm) stenosis of infrarenal aorta■Unilateral CIA occlusion■Single or multiple stenosis totaling 3–10 cm involving the EIA not extending into the CFA■Unilateral EIA occlusion not involving the origins of internal iliac or CFA Type C lesions ■Bilateral CIA occlusions■Bilateral EIA stenoses 3–10 cm long not extending into the CFA■Unilateral EIA stenosis extending into the CFA■Unilateral EIA occlusion that involves the origins of internal iliac and/or CFA■Heavily calcified unilateral EIA occlusion with or without involvement of origins of internal iliac and/or CFA Type D lesions ■Infra-renal aortoiliac occlusion■Diffuse disease involving the aorta and both iliac arteries requiring treatment■Diffuse multiple stenoses involving the unilateral CIA, EIA and CFA■Unilateral occlusions of both CIA and EIA■Bilateral occlusions of EIA■Iliac stenoses in patients with AAA requiring treatment and not amenable to endograft placement or other lesions requiring open aortic or iliac surgery
CIA – common iliac artery; EIA – external iliac artery; CFA – common femoral artery; AAA – abdominal aortic aneurysm.

### F1.3 Classification of femoral popliteal disease (Fig. F2, Table F2)

Treatment of femoral popliteal lesions
• TASC A and D lesions: Endovascular therapy is the treatment of choice for type A lesions and surgery is the treatment of choice for type D lesions [C].
• TASC B and C lesions: Endovascular treatment is the preferred treatment for type B lesions and surgery is the preferred treatment for good-risk patients with type C lesions. The patient's co-morbidities, fully informed patient preference and the local operator's long-term success rates must be considered when making treatment recommendations for type B and type C lesions [C].
Table F2TASC classification of femoral popliteal lesions
 Type A lesions ■Single stenosis ≤10 cm in length■Single occlusion ≤5 cm in length Type B lesions ■Multiple lesions (stenoses or occlusions), each ≤5 cm■Single stenosis or occlusion ≤15 cm not involving the infra geniculate popliteal artery■Single or multiple lesions in the absence of continuous tibial vessels to improve inflow for a distal bypass■Heavily calcified occlusion ≤5 cm in length■Single popliteal stenosis Type C lesions ■Multiple stenoses or occlusions totaling >15 cm with or without heavy calcification■Recurrent stenoses or occlusions that need treatment after two endovascular interventions Type D lesions ■Chronic total occlusions of CFA or SFA (>20 cm, involving the popliteal artery)■Chronic total occlusion of popliteal artery and proximal trifurcation vessels
CFA – common femoral artery; SFA – superficial femoral artery.

## F2 Aortoiliac (Supra Inguinal) Revascularization

### F2.1 Endovascular treatment of aorto-iliac occlusive disease

Although aortobifemoral bypass appears to have better long-term patency than the currently available endovascular strategies for diffuse aortoiliac occlusive disease, the risks of surgery are significantly greater than the risks of an endovascular approach, in terms of not only mortality but also major morbidity and delay in return to normal activities. Therefore, the assessment of the patient's general condition and anatomy of the diseased segment(s) become central in deciding which approach is warranted.
The technical and initial clinical success of PTA of iliac stenoses exceeds 90% in all reports in the literature. This figure approaches 100% for focal iliac lesions. The technical success rate of recanalization of long segment iliac occlusions is 80%–85% with or without additional fibrinolysis. Recent device developments geared towards treatment of total occlusions, however, have substantially improved the technical success rate of recanalization.
• Saket R.R.
• Razavi M.K.
• Kee S.T.
• Sze D.Y.
• Dake M.D.
Novel intravascular ultrasound-guided method to create transintimal arterial communications: initial experience in peripheral occlusive disease and aortic dissection.
Becker et al. found 5-year patency rate of 72% in an analysis of 2697 cases from the literature, noting a better patency of 79% in claudicants.
• Becker G.J.
• Katzen B.T.
• Dake M.D.
Noncoronary angioplasty.
Rutherford and Durham found a similar 5-year patency of 70%.
• Rutherford R.
• Durham J.
Percutaneous ballon angioplasty for arteriosclerosis obliterans: long term results.
A recent study reported a primary patency of 74% (primary assisted patency of 81%) 8 years after stent placement suggesting durability of patency of iliac artery stenting.
• Murphy T.P.
• Ariaratnam N.S.
• Carney Jr., W.I.
• Marcaccio E.J.
• Slaiby J.M.
• Soares G.M.
• et al.
Aortoiliac insufficiency: long-term experience with stent placement for treatment.
Factors negatively affecting the patency of such interventions include quality of run off vessels, severity of ischemia and length of diseased segments. Female gender has also been suggested to decrease patency of external iliac artery stents.
• Timaran C.H.
• Stevens S.L.
• Freeman M.B.
• Goldman M.H.
External iliac and common iliac artery angioplasty and stenting in men and women.
Table F3 presents the estimated success rate of iliac artery angioplasty from weighted averages (range) from reports of 2222 limbs.
Table F3Estimated success rate of iliac artery angioplasty from weighted averages (range) from reports of 2222 limbs
% ClaudicationTechnical successPrimary patency
1 yr3 yr5 yr
76% (81–94)96% (90–99)86% (81–94)82% (72–90)71% (64–75)
Choice of stent versus PTA with provisional stenting was addressed in a prospective randomized, multicenter study.
• Tetteroo E.
• van der Graaf Y.
• Bosch J.L.
• van Engelen A.D.
• Hunink M.G.
• Eikelboom B.C.
• et al.
Randomised comparison of primary stent placement versus primary angioplasty followed by selective stent placement in patients with iliac-artery occlusive disease. Dutch Iliac Stent Trial Study Group.