Eur J Vasc Endovasc Surg 33, S1eS70 (2007)

doi:10.1016/j.ejvs.2006.09.024, available online at http://www.sciencedirect.com on

Inter-Society Consensus for the Management

of Peripheral Arterial Disease (TASC II)
L. Norgren,1* W.R. Hiatt,2* J.A. Dormandy, M.R. Nehler, K.A. Harris and F.G.R. Fowkes
on behalf of the TASC II Working Group
1
Department of Surgery, University Hospital, Övebro, Sweden,
2
University of Colorado School of Medicine and Colorado Prevention Center, Denver, USA

Introduction a combination of the scientific evidence described

below, patients’ preferences, and local availability
The Trans-Atlantic Inter-Society Consensus Document of facilities and trained professionals. Good practice
on Management of Peripheral Arterial Disease (TASC) also includes appropriate specialist referral.
was published in January 20001e3 as a result of coop-
eration between fourteen medical and surgical vascu-
lar, cardiovascular, vascular radiology and cardiology
societies in Europe and North America. This compre- Process
hensive document had a major impact on vascular
care amongst specialists. In subsequent years, the field Representatives of sixteen societies from Europe, North
has progressed with the publication of the CoCaLis America, Australia, South Africa and Japan were elec-
document4 and the American College of Cardiology/ ted from their respective society and were called
American Heart Association Guidelines for the Man- together in 2004 to form the new Working Group. Spe-
agement of Peripheral Arterial Disease.5 Aiming to cialists in health economics, health outcomes and
continue to reach a readership of vascular specialists, evidence-based medicine were also included to elabo-
but also physicians in primary health care who see rate on the text for the following sections: history,
patients with peripheral arterial disease (PAD), an- epidemiology and risk factors; management of
other consensus process was initiated during 2004. risk factors; intermittent claudication; critical limb
This new consensus document has been developed ischemia; acute limb ischemia; and technologies
with a broader international representation, includ- (intervention/revascularization and imaging).
ing Europe, North America, Asia, Africa and The Working Group reviewed the literature and, af-
Australia, and with a much larger distribution and ter extensive correspondence and meetings, proposed
dissemination of the information. The goals of this a series of draft documents with clear recommenda-
new consensus are to provide an abbreviated tions for the diagnosis and treatment of PAD. Each
document (compared with the publication in 2000), participating society reviewed and commented on
to focus on key aspects of diagnosis and manage- these draft consensus documents. The liaison member
ment, and to update the information based on new from each society then took these views back to the
publications and the newer guidelines, but not to Working Group, where all of the amendments, addi-
add an extensive list of references. Unreferenced tions and alterations suggested by each participating
statements are, therefore, to be found, provided society were discussed, and the final Consensus
they are recognized as common practice by the au- Document was agreed upon.
thors, with existing evidence. The recommendations The participating societies were then again invited
are graded according to levels of evidence. It should to review the final document and endorse it if they
also be emphasized that good practice is based on agreed with its contents. If an individual participating
society did not accept any specific recommendation,
this is clearly indicated in the final document.
*Corresponding authors. Therefore, except where such specific exclusions are

1078–5884/000001 + 70 $32.00/0 Ó 2006 Published by Elsevier Ltd.

S2 L. Norgren and W. R. Hyatt et al.

indicated, this Consensus Document represents the SECTION A e EPIDEMIOLOGY OF PERIPHERAL

views of all of the participating societies. ARTERIAL DISEASE
Compared with the original TASC, more emphasis
has been put on diabetes and PAD. The text is pre-
sented in such a way that vascular specialists will still A1 Epidemiology
find most of the information they require, while gen-
eral practitioners and primary health physicians will The management of the patient with peripheral arte-
easily find guidance for diagnosis and diagnostic pro- rial disease (PAD) has to be planned in the context
cedures, referral of patients and expected outcome of of the epidemiology of the disease, its natural history
various treatment options. and, in particular, the modifiable risk factors for the
systemic disease as well as those that predict deteri-
oration of the circulation to the limb.
Grading of recommendations

Recommendations and selected statements are rated A1.1 Incidence and prevalence of asymptomatic
according to guidance issued by the former US peripheral arterial disease
Agency for Health Care Policy and Research,6 now
renamed the Agency for Healthcare Research and Total disease prevalence based on objective testing has
Quality: 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.7e9 The prevalence of asymp-
Grade Recommendation
tomatic PAD in the leg can only be estimated by using
A Based on the criterion of at least non-invasive measurements in a general population.
one randomized, controlled clinical trial as
part of the body of literature of overall The most widely used test is the measurement of
good quality and consistency addressing the ankle-brachial systolic pressure index (ABI).
the specific recommendation (For detailed discussion of the ABI, see Section C2.1.)
B Based on well-conducted clinical studies
but no good quality randomized clinical A resting ABI of 0.90 is caused by hemodynami-
trials on the topic of recommendation cally-significant arterial stenosis and is most often
C Based on evidence obtained from expert used as a hemodynamic definition of PAD. In symp-
committee reports or opinions and/or
clinical experiences of respected authorities tomatic individuals, an ABI 0.90 is approximately
(i.e. no applicable studies of good quality) 95% sensitive in detecting arteriogram-positive PAD
and almost 100% specific in identifying healthy indi-
viduals. Using this criterion, several studies have
Note that the grade of recommendation is based on looked at symptomatic and asymptomatic PAD pa-
the level of available evidence and does not necessa- tients in the same population. The ratio of the two is
rily relate to the clinical importance. independent of age and is usually in the range of 1:3
to 1:4. The Edinburgh Artery Study found that, using
Acknowledgements duplex scanning, a third of the patients with asymp-
tomatic PAD had a complete occlusion of a major ar-
The development of this document was supported by tery to the leg.10 The PARTNERS (PAD Awareness,
an unrestricted educational grant from sanofi-aventis. Risk, and Treatment: New Resources for Survival)
Additional support for publication of the document study screened 6979 subjects for PAD using the ABI
was also provided by Bristol-Myers Squibb.* The (with PAD defined as an ABI of 0.90 or a prior history
sponsors did not participate in any of the discussions of lower extremity revascularization). Subjects were
or provide recommendations as to the preparation of evaluated if they were aged 70 years or aged 50e69
these guidelines. The TASC Steering Committee ac- years with a risk factor for vascular disease (smoking,
knowledges the administrative and logistic assistance diabetes) in 320 primary care practices in the United
from Medicus International, with great appreciation States.11 PAD was detected in 1865 patients which
of the work performed by Dr Barbara Byth. 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 diag-
nosis of PAD had claudication. The National Health
* The TASC Working Group also acknowledges Otsuka Pharma- and Nutritional Examination Survey recently reported
ceuticals for defraying some travel costs and, together with
Mitsubishi Pharma, supplying additional support for the future on an unselected population of 2174 subjects aged 40
dissemination of these guidelines. years.9 The prevalence of PAD, as defined by an ABI of

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S3

0.90, ranged from 2.5% in the age group 50e59 years PAD may develop symptoms of IC only when they
to 14.5% in subjects >70 years (there was no informa- become very physically active.
tion about the proportion of subjects with an ABI of The annual incidence of IC is more difficult to mea-
0.90 who had symptoms in the legs). In autopsies of sure and probably less important than its prevalence
unselected adults, 15% of men and 5% of women (unlike the case of the relatively very much smaller
who were asymptomatic, had a 50% or greater stenosis number of patients with critical limb ischemia
of an artery to the leg. It is interesting to compare this [CLI]). The prevalence of IC would appear to increase
with the finding that 20% to 30% of subjects with from about 3% in patients aged 40 to 6% in patients
complete occlusion of at least one coronary artery on aged 60 years. Several large population studies have
autopsy are asymptomatic. Some of the apparent looked at the prevalence of IC and Fig. A1 shows a cal-
inconsistency regarding data on the prevalence of culated mean prevalence weighted by study sample
symptomatic PAD is due to methodology, but in sum- size. In the relatively younger age groups, claudica-
mary it can be concluded that for every patient with tion is more common in men but at older ages there
symptomatic PAD there are another three to four sub- is little difference between men and women. A sur-
jects with PAD who do not meet the clinical criteria for prising finding in population screening studies is
intermittent claudication. that between 10% and 50% of patients with IC have
never consulted a doctor about their symptoms.

A1.2 Incidence and prevalence of symptomatic

peripheral arterial disease A1.3 Epidemiology of peripheral arterial disease
in different ethnic groups
Intermittent claudication (IC) (see section C1.1 for def-
inition) is usually diagnosed by a history of muscular Non-white ethnicity is a risk factor for PAD. Black eth-
leg pain on exercise that is relieved by a short rest. nicity increases the risk of PAD by over two-fold, and
Several questionnaires have been developed for epi- this risk is not explained by higher levels of other risk
demiological use. In looking at methods for identify- factors such as diabetes, hypertension or obesity.12 A
ing IC in the population, it must be remembered high prevalence of arteritis affecting the distal arteries
that while it is the main symptom of PAD, the mea- of young black South Africans has also been described.
surement 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 A2 Risk Factors for Peripheral Arterial Disease
some other condition limits exercise or they are seden-
tary. In contrast, some patients with what seems to be Although the various factors described in this section
IC may not have PAD (for example, spinal stenosis are usually referred to as risk factors, in most cases
can produce symptoms like IC in the absence of the evidence is only for an association. The criteria
vascular disease). Likewise, patients with very mild used to support a risk factor require a prospective,

Fig. A1. Weighted mean prevalence of intermittent claudication (symptomatic PAD) in large population-based studies.

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S4 L. Norgren and W. R. Hyatt et al.

controlled study showing that altering the factor alters incidence of IC. Results from the Edinburgh Artery
the development or course of the PAD, such as has Study10 found that the relative risk of IC was 3.7 in
been shown for smoking cessation or treatment of dys- smokers compared with 3.0 in ex-smokers (who had
lipidemia. Risk may be conferred by other metabolic or discontinued smoking for less than 5 years).
circulatory abnormalities associated with diabetes.
A2.5 Diabetes mellitus
A2.1 Race
Many studies have shown an association between
The National Health and Nutrition Examination Sur- diabetes mellitus and the development of PAD. Over-
vey in the United States found that an ABI 0.90 all, IC is about twice as common among diabetic
was more common in non-Hispanic Blacks (7.8%) patients than among non-diabetic patients. In patients
than in Whites (4.4%). Such a difference in the preva- with diabetes, for every 1% increase in hemoglobin
lence of PAD was confirmed by the recent GENOA A1c there is a corresponding 26% increased risk of
(Genetic Epidemiology Network of Arteriopathy) PAD.14 Over the last decade, mounting evidence has
study,13 which also showed that the difference was suggested that insulin resistance plays a key role in
not explained by a difference in classical risk factors a clustering of cardiometabolic risk factors which
for atherosclerosis. include hyperglycemia, dyslipidemia, hypertension
and obesity. Insulin resistance is a risk factor for
A2.2 Gender PAD even in subjects without diabetes, raising the
risk approximately 40% to 50%.15 PAD in patients
The prevalence of PAD, symptomatic or asymptom- with diabetes is more aggressive compared to non-
atic, is slightly greater in men than women, particu- diabetics, with early large vessel involvement coupled
larly in the younger age groups. In patients with IC, with distal symmetrical neuropathy. The need for
the ratio of men to women is between 1:1 and 2:1. a major amputation is five- to ten-times higher in
This ratio increases in some studies to at least 3:1 in diabetics than non-diabetics. This is contributed to
more severe stages of the disease, such as chronic by sensory neuropathy and decreased resistance to
CLI. Other studies have, however, shown a more infection. Based on these observations, a consensus
equal distribution of PAD between genders and statement from the American Diabetes Association
even a predominance of women with CLI. recommends PAD screening with an ABI every 5 years
in patients with diabetes.16
A2.3 Age
A2.6 Hypertension
The striking increase in both the incidence and preva-
lence of PAD with increasing age is apparent from the Hypertension is associated with all forms of cardio-
earlier discussion of epidemiology (Fig. A1). vascular disease, including PAD. However, the rela-
tive risk for developing PAD is less for hypertension
A2.4 Smoking than diabetes or smoking.

The relationship between smoking and PAD has been A2.7 Dyslipidemia
recognized since 1911, when Erb reported that IC was
three-times more common among smokers than In the Framingham study, a fasting cholesterol level
among non-smokers. Interventions to decrease or greater than 7 mmol/L (270 mg/dL) was associated
eliminate cigarette smoking have, therefore, long with a doubling of the incidence of IC but the ratio
been advocated for patients with IC. It has been sug- of total to high-density lipoprotein (HDL) cholesterol
gested that the association between smoking and PAD was the best predictor of occurrence of PAD. In an-
may be even stronger than that between smoking other study, patients with PAD had significantly
and coronary artery disease (CAD). Furthermore, a higher levels of serum triglycerides, very low-density
diagnosis of PAD is made approximately a decade lipoprotein (VLDL) cholesterol, VLDL triglycerides,
earlier in smokers than in non-smokers. The severity VLDL proteins, intermediate density lipoprotein
of PAD tends to increase with the number of cigarettes (IDL) cholesterol, and IDL triglycerides and lower
smoked. Heavy smokers have a four-fold higher risk levels of HDL than controls.17 Although some studies
of developing IC compared with non-smokers. have also shown that total cholesterol is a powerful
Smoking cessation is associated with a decline in the independent risk factor for PAD, others have failed

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S5

to confirm this association. It has been suggested that A2.12 Summary

cigarette smoking may enhance the effect of hyper-
cholesterolemia. There is evidence that treatment of Fig. A2 summarizes graphically the approximate influ-
hyperlipidemia reduces both the progression of PAD ence or association between some of the above factors
and the incidence of IC. An association between PAD and PAD, taking a global view of the existing evidence.
and hypertriglyceridemia has also been reported and
has been shown to be associated with the progression
and systemic complications of PAD. Lipoprotein(a) is A3 Fate of the Leg
a significant independent risk factor for PAD.
A3.1 Asymptomatic

A2.8 Inflammatory markers Evidence suggests that the progression of the under-
lying PAD is identical whether or not the subject has
Some recent studies have shown that C-reactive pro- symptoms in the leg. There is nothing to suggest
tein (CRP) was raised in asymptomatic subjects who that the risk of local deterioration, with progression
in the subsequent five years developed PAD com- to CLI, is dependent on the presence or absence of
pared to an age-matched control group who remained symptoms of intermittent claudication. Whether
asymptomatic. The risk of developing PAD in the symptoms develop or not depends largely on the level
highest quartile of baseline CRP was more than twice of activity of the subject. This is one of the reasons
that in the lowest quartile.18 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 ische-
A2.9 Hyperviscosity and hypercoagulable states mic rest pain level but who is too sedentary to claudi-
cate, may develop CLI because of wounds resulting
Raised hematocrit levels and hyperviscosity have been
reported in patients with PAD, possibly as a conse-
quence of smoking. Increased plasma levels of fibrino-
gen, which is also a risk factor for thrombosis, have been
associated with PAD in several studies. Both hypervis-
cosity 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 hyperho-
mocysteinemia is detected in about 30% of young
patients with PAD. The suggestion that hyperhomo-
cysteinemia 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 Fig. A2. Approximate range of odds ratios for risk factors
for symptomatic peripheral arterial disease. Treatment of
was independently associated with future PAD events risk factors and the effect on the outcomes of PAD are
in postmenopausal women.19 described in Chapter B.

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S6 L. Norgren and W. R. Hyatt et al.

from relatively minor (often self inflicted) trauma that groups. The remaining 25% of patients with IC deteri-
can not heal at this level of perfusion. It is important orate in terms of clinical stage; this is most frequent
to detect this subgroup of patients at a time when pro- during the first year after diagnosis (7%e9%) com-
tective foot care and risk factor control have their pared with 2% to 3% per year thereafter. This clinical
greatest potential to ameliorate outcomes. Functional stability is relevant to the patient’s perception of their
decline over two years is related to baseline ABI and severity of claudication. When these patients have
the nature of the presenting limb symptoms.20 A a comprehensive assessment of their actual functional
lower ABI was associated with a more rapid decline status, measured walking distance does progressively
in, for example, 6-minute walk distance. deteriorate over time.20
More recent reviews also highlight that major am-
A3.2 Intermittent claudication putation is a relatively rare outcome of claudication,
with only 1% to 3.3% of patients with IC needing ma-
Although PAD is progressive in the pathological jor amputation over a 5-year period. The Basle and
sense, its clinical course as far as the leg is concerned Framingham studies,21,22 which are the two large-
is surprisingly stable in most cases. However, the scale studies that have looked at unselected patients,
symptomatic PAD patient continues to have signifi- found that less than 2% of PAD patients required ma-
cant functional disability. Large population studies jor amputation. Although amputation is the major
provide the most reliable figures. All of the evidence fear of patients told that they have circulatory disease
over the last 40 years since the classic study by Bloor of the legs, they can be assured that this is an unlikely
has not materially altered the impression that only outcome, except in diabetes patients (Fig. A3).
about a quarter of patients with IC will ever signifi- It is difficult to predict the risk of deterioration in
cantly deteriorate. This symptomatic stabilization a recent claudicant. The various risk factors mentioned
may be due to the development of collaterals, meta- in section A2 (above) probably all contribute to the
bolic adaptation of ischemic muscle, or the patient progression of PAD. A changing ABI is possibly the
altering his or her gait to favor non-ischemic muscle best individual predictor, because if a patient’s ABI

Fig. A3. Fate of the claudicant over 5 years (adapted from ACC/AHA guidelines5). PAD e peripheral arterial disease;
CLI e critical limb ischemia; CV e cardiovascular; MI e myocardial infarction. Reproduced with permission from Hirsch
AT et al. J Am Coll Cardiol 2006;47:1239e1312.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S7

rapidly deteriorates it is most likely to continue to do these patients now receive some form of active treat-
so in the absence of successful treatment. It has been ment. Treatment very much depends on the center
shown that in patients with IC, the best predictor of to which the patient is referred. Large surveys suggest
deterioration of PAD (e.g. need for arterial surgery or that approximately half the patients with CLI will
major amputation), is an ABI of <0.50 with a hazard undergo some type of revascularization, although in
ratio of more than 2 compared to patients with an some, particularly active, interventional centers an at-
ABI >0.50. Studies have also indicated that in those tempt at reconstruction is reported in as many as 90%
patients with IC in the lowest strata of ankle pressure of CLI patients. Fig. A5 provides an estimate of the
(i.e. 40e60 mmHg), the risk of progression to severe primary treatment of these patients globally and their
ischemia or actual limb loss is 8.5% per year. status a year later.
There are some good-quality data from multicenter,
closely monitored trials of pharmacotherapy for CLI.
A3.3 Critical limb ischemia These only relate to a subgroup of patients who are
unreconstructable or in whom attempts at reconstruc-
The only reliable large prospective population tion have failed. (It is only such patients who are
studies on the incidence of CLI showed a figure of entered into randomized, placebo-controlled, clinical
220 new cases every year per million population.23 pharmacotherapy trials.) The results for this subgroup
However, there is indirect evidence from studies reveal the appalling prospect that approximately 40%
looking at the progression of IC, population will lose their leg within 6 months, and up to 20% will
surveys on prevalence and assumptions based on die (note that these data refer to 6 months’ follow-up
the major amputation rates. Surprisingly, the and cannot be directly compared with the 1-year data
incidence calculated using these different methodolo- in Fig. A5).
gies 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 A3.4 Acute leg ischemia
1 million.
A number of studies have allowed an analysis of Acute limb ischemia denotes a quickly developing or
the risk factors that seem to be associated with the de- sudden decrease in limb perfusion, usually producing
velopment of CLI. These are summarized in Fig. A4. new or worsening symptoms and signs, and often
These factors appear to be independent and are, there- threatening limb viability. Progression of PAD from
fore, probably additive. claudication to rest pain to ischemic ulcers or gan-
It is no longer possible to describe the natural grene may be gradual or progress rapidly reflecting
history of patients with CLI because the majority of sudden worsening of limb perfusion. Acute limb

Fig. A4. Approximate magnitude of the effect of risk factors on the development of critical limb ischemia in patients with
peripheral arterial disease. CLI e critical limb ischemia.

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S8 L. Norgren and W. R. Hyatt et al.

Fig. A5. Fate of the patients presenting with chronic critical leg ischemia. CLI e critical limb ischemia.

ischemia may also occur as the result of an embolic amputation, is incorrect. It has been shown that more
event or a local thrombosis in a previously asymptom- than half of patients having a below-knee major am-
atic patient. putation for ischemic disease had no symptoms of
There is little information on the incidence of leg ischemia whatsoever as recently as 6 months pre-
acute leg ischemia, but a few national registries and viously.25 The incidence of major amputations from
regional surveys suggest that the incidence is around large population or nation-wide data varies from
140/million/year. Acute leg ischemia due to emboli 120 to 500/million/year. The ratio of below-knee to
has decreased over the years, possibly as a consequence above-knee amputations in large surveys is around
of less cardiac valvular disease from rheumatic fever 1:1. Only about 60% of below-knee amputations heal
and also better monitoring and anticoagulant manage- by primary intention, 15% heal after secondary proce-
ment of atrial fibrillation. Meanwhile the incidence of dures and 15% need to be converted to an above-knee
thrombotic acute leg ischemia has increased. Even level. 10% die in the peri-operative period. The dismal
with the extensive use of newer endovascular tech- 1- to 2-year prognosis is summarized in Fig. A6.
niques including thrombolysis, most published series
report a 10% to 30% 30-day amputation rate.
A4 Co-existing Vascular Disease

Because PAD, CAD and cerebral artery disease are all

A3.5 Amputation
manifestations of atherosclerosis, it is not surprising
that the three conditions commonly occur together.
There is an ongoing controversy, often fuelled by un-
verified retrospective audit data from large and
changing populations, as to whether there is a signifi- A4.1 Coronary
cant reduction in amputations as a result of more re-
vascularization procedures in patients with CLI. Studies on the prevalence of cardiovascular disease in
Careful, independent studies from Sweden, Denmark patients with PAD show that the history, clinical ex-
and Finland all suggest that increased availability and amination and electrocardiogram identify a preva-
use of endovascular and surgical interventions have lence of CAD and cerebral artery disease in 40% to
resulted in a significant decrease in amputation for 60% of such patients. In the PARTNERS study, 13%
CLI. In the United Kingdom, the number of major of subjects screened had an ABI of 0.90 and no
amputations has reached a plateau, possibly reflecting symptomatic CAD or cerebral artery disease, 16%
increasingly successful limb salvage, but older studies had both PAD and symptomatic CAD or cerebral
in the United States have not shown benefit of revas- artery disease, and 24% had symptomatic CAD and
cularization on amputation rates.24 cerebral artery disease and a normal ABI.11 As with
The concept that all patients who require an ampu- asymptomatic PAD, the diagnosis of CAD depends
tation have steadily progressed through increasingly on the sensitivity of the methods used. In the primary
severe claudication to rest pain, ulcers and, ultimately, care setting, approximately half of those patients

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S9

Fig. A6. Fate of the patient with below-knee amputation.

diagnosed with PAD also have CAD and cerebral ar- A4.3 Renal
tery disease; in PAD patients referred to hospital, the
prevalence of CAD is likely to be higher. The extent of Studies have also looked at the prevalence of renal ar-
the CAD, both by angiography and by computed to- tery stenosis in patients with PAD. The prevalence of
mography (CT) measured coronary calcium, corre- renal artery stenosis of 50% or over ranges from 23%
lates with the ABI. Not surprisingly, patients with to 42% (compare this to the prevalence of renal artery
documented CAD are more likely to have PAD. The stenosis in the hypertensive general population,
prevalence of PAD in patients with ischemic heart which is around 3%). Although it has not been studied
disease varies in different series from around 10% specifically it is very likely that renal artery stenosis
to 30%. Autopsy studies have shown that patients is also a partly independent risk factor for mortality
who die from a myocardial infarction are twice as in patients with PAD since renal artery stenosis of
likely to have a significant stenosis in the iliac and 50% or over is associated with a 3.3-fold higher
carotid arteries as compared to patients dying from mortality rate than in the general population.
other causes.

A5 Fate of the Patient

A4.2 Cerebral artery disease
A5.1 Asymptomatic and claudicating peripheral
The link between PAD and cerebral artery disease arterial disease patients
seems to be weaker than that with CAD. By duplex ex-
amination, carotid artery disease occurs in 26% to 50% The increased risk of cardiovascular events in patients
of patients with IC, but only about 5% of patients with with PAD is related to the severity of the disease in
PAD will have a history of any cerebrovascular event. the legs as defined by an ABI measurement. The an-
There is also a good correlation between carotid inti- nual overall major cardiovascular event rate (myocar-
mal thickness and the ABI. There is a range of overlap dial infarction, ischemic stroke and vascular death) is
in disease in the cerebral, coronary and peripheral cir- approximately 5%e7%.
culations reported in the literature, represented semi- Excluding those with CLI, patients with PAD have
quantitatively in Fig. A7. In the REACH (Reduction a 2% to 3% annual incidence of non-fatal myocardial
of Atherothrombosis for Continued Health) survey26 infarction and their risk of angina is about two- to
of those patients identified with symptomatic PAD, three- times higher than that of an age-matched popu-
4.7% had concomitant CAD, 1.2% had concomitant ce- lation. The 5-, 10- and 15-year morbidity and mortality
rebral artery disease and 1.6% had both. Thus in this rates from all causes are approximately 30%, 50% and
survey, about 65% of patients with PAD had clinical 70%, respectively (Fig. A3). CAD is by far the most
evidence of other vascular disease. However, in one common cause of death among patients with PAD
prospective study of 1886 patients aged 62 or over (40%e60%), with cerebral artery disease accounting
only 37% of subjects had no evidence of disease in for 10% to 20% of deaths. Other vascular events, mostly
any of the three territories.27 ruptured aortic aneurysm, cause approximately 10% of

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S10 L. Norgren and W. R. Hyatt et al.

Fig. A7. Typical overlap in vascular disease affecting different territories.26 Based on REACH data. PAD e peripheral
arterial disease.

deaths. Thus, only 20% to 30% of patients with PAD die have demonstrated this relationship. For instance, in
of non-cardiovascular causes. a study of nearly 2000 claudicants, patients with an
Of particular interest are the studies in which the ABI <0.50 had twice the mortality of claudicants
difference in mortality rates between patients with IC with an entry ABI of >0.50.28 The Edinburgh Artery
and an age-matched control population was largely Study10 has also shown that the ABI is a good predic-
unchanged despite the adjustment for risk factors tor of non-fatal and fatal cardiovascular events as well
such as smoking, hyperlipidemia and hypertension. as total mortality, in an unselected general population.
These surprising, but consistent, results suggest that It has also been suggested that there is an almost lin-
the presence of PAD indicates an extensive and severe ear relationship between ABI and fatal and non-fatal
degree of systemic atherosclerosis that is responsible cardiovascular events; each decrease in ABI of 0.10 be-
for mortality, independent of the presence of risk fac- ing associated with a 10% increase in relative risk for
tors. Fig. A8 summarizes the results from all studies a major vascular event. In a study of patients with
comparing mortality rates of claudicating patients type 2 diabetes (Fig. A9), the lower the ABI the higher
with those of an age-matched control population. As the 5-year risk of a cardiovascular event.29
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 out-
come of the acute episode.
There is a strong correlation between ABI, as a mea-
sure of the severity of the PAD, and mortality. A Fig. A8. Survival of patients with peripheral arterial disease.
number of studies, using different ABI ‘cut-off’ points IC e intermittent claudication; CLI e critical limb ischemia.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S11

Over two-thirds of the patients with PAD are asymp-

tomatic 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.11
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 pre-
Fig. A9. Adjusted odds of a cardiovascular event by valence of PAD. In contrast, palpable pedal pulses
ankle-brachial index.29 Data from the placebo arm of the on examination have a negative predictive value of
Appropriate Blood Pressure Control in Diabetes study29
show an inverse correlation between ABI and odds of a over 90% that may rule out the diagnosis in many
major cardiovascular event. ABI e ankle-brachial index; cases. In contrast, a pulse abnormality (absent or di-
CV e cardiovascular; MI e myocardial infarction. Repro- minished) significantly overestimates the true preva-
duced with permission from Mehler PS et al. Circulation
2003;107:753e756. lence 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 B e MANAGEMENT OF CARDIO- section C2 for further discussion of the ABI and ABI
VASCULAR RISK FACTORS AND screening criteria). In the context of identifying a
CO-EXISTING DISEASE high-risk population, persons who should be consid-
ered for ABI screening in the primary care or commu-
nity setting include: (1) subjects with exertional leg
B1 Risk Factors symptoms, (2) subjects aged 50e69 years who also
have cardiovascular risk factors and all patients over
B1.1 Identifying the peripheral arterial disease patient the age of 70 years,11 and (3) subjects with a 10-year
in the population risk of a cardiovascular event between 10% and 20%
in whom further risk stratification is warranted.
Patients with peripheral arterial disease (PAD) have Cardiovascular risk calculators are readily available
multiple atherosclerosis risk factors and extensive ath- in the public domain, such as the SCORE for use in
erosclerotic disease, which puts them at markedly in- Europe (www.escardio.org) and the Framingham for
creased risk for cardiovascular events, similar to the US (www.nhlbi.nih.gov/guidelines/cholesterol).
patients with established coronary artery disease Patients with PAD, defined as an ABI 0.90, are
(CAD).30 A reduced blood pressure in the ankle rela- known to be at high risk for cardiovascular events
tive to the arm pressure indicates the presence of pe- (Fig. B1). As discussed in section A, mortality rates
ripheral atherosclerosis, and is an independent risk in patients with PAD average 2% per year and the
factor for cardiovascular events. This has been most rates of non-fatal myocardial infarction, stroke and
recently studied in a meta-analysis of 15 population vascular death are 5% to 7% per year.32,33 In addition,
studies and showed that an ankle-brachial index the lower the ABI, the higher the risk of cardiovascu-
(ABI) 0.90 was strongly correlated with all-cause lar events, as shown in Fig. B2.34 A similar increased
mortality independent of the Framingham Risk mortality risk has also been observed in patients
Score.31 Thus, current recommendations from numer- with an increased ABI as shown in Fig. B2. Therefore,
ous consensus documents, including the recent an abnormal ABI identifies a high-risk population that
American College of Cardiology/American Heart needs aggressive risk factor modification and anti-
Association (ACC/AHA) guidelines on PAD, identify platelet therapy.
patients with PAD as a high-risk population who
require intensive risk factor modification and need
antithrombotic therapy.5 This section will discuss an B1.2 Modification of atherosclerotic risk factors
approach to identification of PAD as a means to define
a high-risk population and the management of each of As highlighted above, patients with PAD typically
the major risk factors to reduce the incidence of have multiple cardiovascular risk factors, which puts
cardiovascular events. them at markedly increased risk for cardiovascular

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S12 L. Norgren and W. R. Hyatt et al.

Fig. B1. Algorithm for use of the ABI in the assessment of systemic risk in the population. Primary prevention: No antipla-
telet therapy; LDL (low density lipoprotein) <3.37 mmol/L (<130 mg/dL) except in patients with diabetes where the LDL
goal is <2.59 mmol/L (<100 mg/dL) even in the absence of CVD (cardiovascular disease); appropriate blood pressure
(<140/90 mmHg and <130/80 mmHg in diabetes/renal insufficiency). Secondary prevention: Prescribe antiplatelet
therapy; LDL <2.59 mmol/L (<100 mg/dL) (<1.81 mmol/L [<70 mg/dL] in high risk); appropriate blood pressure
(<140/90 mmHg and <130/80 mmHg in diabetes/renal insufficiency). See section B1.2 and surrounding text for references.
In patients with diabetes, HbA1c <7.0%. See text for references. ABI e ankle-brachial index; PAD e peripheral arterial
disease; CLI e critical limb ischemia.

events. This section will discuss an approach to each that smoking cessation is associated with improved
of the major risk factors of this disorder. walking distance in some, but not all patients. There-
fore, patients should be encouraged to stop smoking
B1.2.1 Smoking cessation primarily to reduce their risk of cardiovascular events,
Smoking is associated with a marked increased risk as well as their risk of progression to amputation and
for peripheral atherosclerosis. The number of pack progression of disease, but should not be promised im-
years is associated with disease severity, an increased proved symptoms immediately upon cessation. Recent
risk of amputation, peripheral graft occlusion and studies have shown a three-fold increased risk of graft
mortality. Given these associations, smoking cessation failure after bypass surgery with continued smoking
has been a cornerstone of the management of PAD with a reduction in that risk to that of non-smokers
as is the case for CAD.35 Other drugs for smoking with smoking cessation.39
cessation are becoming available.
In middle-aged smokers with reduced pulmonary
function, physician advice to stop smoking, coupled Recommendation 1. Smoking cessation in peri-
with a formal cessation program and nicotine replace- pheral arterial disease
ment is associated with a 22% cessation rate at 5 years
compared with only a 5% cessation rate in the usual
 All patients who smoke should be strongly and
care group.36 By 14 years, the intervention group
repeatedly advised to stop smoking [B].
had a significant survival advantage. A number of
 All patients who smoke should receive a pro-
randomized studies have supported the use of bupro-
gram of physician advice, group counseling
pion in patients with cardiovascular disease, with 3-,
sessions, and nicotine replacement [A].
6- and 12-month abstinence rates of 34%, 27% and
 Cessation rates can be enhanced by the addition
22%, respectively, compared with 15%, 11% and 9%,
of antidepressant drug therapy (bupropion)
respectively, with placebo treatment.37 Combining bu-
and nicotine replacement [A].
propion and nicotine replacement therapy has been
shown to be more effective than either therapy alone
(Fig. B3).38 Thus, a practical approach would be to
encourage physician advice at every patient visit, B1.2.2 Weight reduction
combined with behavior modification, nicotine re- Patients who are overweight (body mass index [BMI]
placement therapy and the antidepressant bupropion 25e30) or who are obese (BMI >30) should receive
to achieve the best cessation rates. counseling for weight reduction by inducing negative
The role of smoking cessation in treating the symptoms caloric balance with reduction of calorie intake,
of claudication is not as clear; studies have shown carbohydrate restriction and increased exercise.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S13

Fig. B2. All cause mortality as a function of baseline ABI. Excess mortality was observed at ABI values <1.00 and >1.40.34
ABI e ankle-brachial index. Reproduced with permission from Resnick HE et al. Circulation 2004;109(6):733e739.

B1.2.3 Hyperlipidemia not associated with benefit. Thus, the HPS demon-
Independent risk factors for PAD include elevated strated that in patients with PAD (even in the absence
levels of total cholesterol, low-density lipoprotein of a prior myocardial infarction or stroke), aggressive
(LDL) cholesterol, triglycerides, and lipoprotein(a). LDL lowering was associated with a marked reduc-
Factors that are protective for the development of tion in cardiovascular events (myocardial infarction,
PAD are elevated high-density lipoprotein (HDL) stroke and vascular death). A limitation of the HPS
cholesterol and apolipoprotein (a-1) levels. was that the evidence in PAD was derived from a sub-
Direct evidence supporting the use of statins to group analysis in patients with symptomatic PAD.
lower LDL cholesterol levels in PAD comes from the Despite these limitations, all patients with PAD
Heart Protection Study (HPS).33 The HPS enrolled should have their LDL cholesterol levels lowered to
over 20,500 subjects at high risk for cardiovascular <2.59 mmol/L (<100 mg/dL). To achieve these lipid
events including 6748 patients with PAD, many of levels, diet modification should be the initial
whom had no prior history of heart disease or stroke. approach, however, in most cases, diet alone will be
Patients were randomized to simvastatin 40 mg, anti- unable to decrease the lipids levels to the values men-
oxidant vitamins, a combination of treatments, or pla- tioned above; therefore, pharmacological treatment
cebo using a 2  2 factorial design, with a 5-year will be necessary.
follow up. Simvastatin 40 mg was associated with A more recent meta-analysis of statin therapy
a 12% reduction in total mortality, 17% reduction in concluded that in a broad spectrum of patients,
vascular mortality, 24% reduction in coronary heart a 1 mmol/L (38.6 mg/dL) reduction in LDL choles-
disease events, 27% reduction in all strokes and terol level was associated with a 20% decrease in the
a 16% reduction in non-coronary revascularizations. risk of major cardiovascular events.40 This benefit
Similar results were obtained in the PAD subgroup, was not dependent on the initial lipid levels (even pa-
whether they had evidence of coronary disease at tients with lipids in the ‘‘normal’’ range responded),
baseline or not. Furthermore, there was no threshold but did depend on the baseline assessment of cardio-
cholesterol value below which statin therapy was vascular risk. Since patients with PAD are at high risk,

Fig. B3. Percent abstinence for bupropion SR, nicotine replacement, or both, versus placebo.38 Reproduced with permission
from Jorenby DE et al. N Engl J Med 1999;340(9):685e691.

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S14 L. Norgren and W. R. Hyatt et al.

and were included as a subgroup in this meta analy- multiple agents to achieve desired blood pressure
sis, the majority of these patients would be considered goals. The ACE inhibitor drugs have also shown benefit
candidates for statin therapy. in PAD, possibly beyond blood-pressure lowering in
Current recommendations for the management of high-risk groups. This was documented by specific re-
lipid disorders in PAD are to achieve an LDL choles- sults from the HOPE (Heart Outcomes Prevention
terol level of <2.59 mmol/L (<100 mg/dL) and to treat Evaluation) study in 4046 patients with PAD.49 In this
the increased triglyceride and low HDL pattern.41,42 subgroup, there was a 22% risk reduction in patients
The recent ACC/AHA guidelines recommend as a gen- randomized to ramipril compared with placebo, which
eral treatment goal achieving an LDL cholesterol level was independent of lowering of blood pressure. Based
<2.59 mmol/L (<100 mg/dL) in all patients with PAD on this finding, the United States Federal Drug Admin-
and in those at high risk (defined as patients with vas- istration has now approved ramipril for its cardiopro-
cular disease in multiple beds) the goal should be an tective benefits in patients at high risk, including
LDL cholesterol level <1.81 mmol/L (<70 mg/dL).5 those with PAD. Thus, in terms of a drug class, the
In patients with PAD who have elevated triglyceride ACE inhibitors would be recommended in patients
levels where the LDL cholesterol cannot be accurately with PAD.
calculated, the recommendation is to achieve a non- Beta-adrenergic blocking drugs have previously
HDL-cholesterol level <3.36 mmol/L (<130 mg/dL),43 been discouraged in PAD because of the possibility
and in the highest risk patients (with vascular disease of worsening claudication symptoms. However, this
in multiple beds) the non-HDL-cholesterol goal should concern has not been borne out by randomized
be <2.56 mmol/L (<100 mg/dL). trials; therefore, beta-adrenergic-blocking drugs can
Patients with PAD commonly have disorders of
HDL cholesterol and triglyceride metabolism. The
use of fibrates in patients with coronary artery disease Recommendation 2. Lipid control in patients
who had an HDL cholesterol level <1.04 mmol/L with peripheral arterial disease (PAD)
(<40 mg/dL) and an LDL cholesterol level
<3.63 mmol/L (>140 mg/dL) was associated with a  All symptomatic PAD patients should have
reduction in the risk of non-fatal myocardial infarction their low-density lipoprotein (LDL)-cholesterol
and cardiovascular death.44 Niacin is a potent drug lowered to <2.59 mmol/L (<100 mg/dL) [A].
used to increase HDL cholesterol levels, with the  In patients with PAD and a history of vascular
extended-release formulation providing the lowest disease in other beds (e.g. coronary artery dis-
risk of flushing and liver toxicity. In patients with ease) it is reasonable to lower LDL cholesterol
PAD, niacin has been associated with regression of levels to <1.81 mmol/L (<70 mg/dL) [B].
femoral atherosclerosis and reduced progression of  All asymptomatic patients with PAD and no
coronary atherosclerosis.45,46 Whether fibrates and/or other clinical evidence of cardiovascular disease
niacin will reduce the progression of peripheral ather- should also have their LDL-cholesterol level
osclerosis or reduce the risk of systemic cardiovascular lowered to <2.59 mmol/L (<100 mg/dL) [C].
events in patients with PAD is not yet known.  In patients with elevated triglyceride levels where
the LDL cannot be accurately calculated, the
B1.2.4 Hypertension LDL level should be directly measured or the
Hypertension is associated with a two- to three-fold non-HDL (high-density lipoprotein) cholesterol
increased risk for PAD. Hypertension guidelines level should be <3.36 mmol/L (<130 mg/dL)
support the aggressive treatment of blood pressure and in high-risk patients the level should be
in patients with atherosclerosis, indicating PAD. In <2.59 mmol/L (<100 mg/dL) [C].
this high-risk group the current recommendation is  Dietary modification should be the initial inter-
a goal of <140/90 mmHg, and <130/80 mmHg if vention to control abnormal lipid levels [B].
the patient also has diabetes or renal insufficiency.47,48  In symptomatic PAD patients, statins should be
Regarding drug choice, all drugs that lower blood the primary agents to lower LDL cholesterol
pressure are effective at reducing the risk of cardiovas- levels to reduce the risk of cardiovascular
cular events. Thiazide diuretics are first-line agents, events [A].
angiotensin converting enzyme (ACE) inhibitors or an-  Fibrates and/or niacin to raise HDL-cholesterol
giotensin receptor blockers should be used in patients levels and lower triglyceride levels should be
with diabetic renal disease or in congestive heart considered in patients with PAD who have
failure, and calcium channel blockers for difficult to abnormalities of those lipid fractions [B].
control hypertension. Most patients will require

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S15

be safely utilized in patients with claudication.50 In par- insulin-sensitizing agent pioglitazone on the primary
ticular, patients with PAD who also have concomitant endpoint of the study (cardiovascular morbidity and
coronary disease may have additional cardio- mortality) but did show a reduction in the risk of a
protection with beta-adrenergic-blocking agents. secondary endpoint of myocardial infarction, stroke
Therefore, beta-adrenergic-blocking agents may be and vascular death.51,54 Additional studies will be
considered when treating hypertension in patients necessary to define the role of insulin sensitizing
with PAD. agents in the management of cardiovascular comp-
lication of diabetes in patients with PAD.
Recommendation 3. Control of hypertension in
peripheral arterial disease (PAD) patients
Recommendation 4. Control of diabetes in
peripheral arterial disease (PAD)
 All patients with hypertension should have
blood pressure controlled to <140/90 mmHg
 Patients with diabetes and PAD should have
or <130/80 mmHg if they also have diabetes
aggressive control of blood glucose levels
or renal insufficiency [A].
with a hemoglobin A1c goal of <7.0% or as
 JNC VII and European guidelines for the
close to 6% as possible [C].
management of hypertension in PAD should
be followed [A].
 Thiazides and ACE inhibitors should be con-
B1.2.6 Homocysteine
sidered as initial blood-pressure lowering An elevated plasma homocysteine level is an indepen-
drugs in PAD to reduce the risk of cardiovascu- dent risk factor for PAD. While supplement with
lar events [B]. B-vitamins and/or folate can lower homocysteine
 Beta-adrenergic-blocking drugs are not contra-
levels, high-level evidence for the benefits in terms
indicated in PAD [A]. of preventing cardiovascular events is lacking. Two
studies of supplemental B vitamins and folic acid in
patients with CAD demonstrated no benefit and
B1.2.5 Diabetes [see also section D2.4] even a suggestion of harm, so this therapy cannot
Diabetes increases the risk of PAD approximately three- be recommended.55,56
to four-fold, and the risk of claudication two-fold. Most
patients with diabetes have other cardiovascular risk
factors (smoking, hypertension and dyslipidemia) Recommendation 5. Use of folate supplementa-
that contribute to the development of PAD. Diabetes tion in peripheral arterial disease (PAD)
is also associated with peripheral neuropathy and
decreased resistance to infection, which leads to an  Patients with PAD and other evidence of car-
increased risk of foot ulcers and foot infections. diovascular disease should not be given folate
Several studies of both type 1 and type 2 diabetes supplements to reduce their risk of cardiovas-
have shown that aggressive blood-glucose lowering cular events [B].
can prevent microvascular complications (particularly
retinopathy and nephropathy); this has not been dem-
onstrated for PAD, primarily because the studies con- B1.2.7 Inflammation
ducted to date examining glycemic control in diabetes Markers of inflammation have been associated with
were neither designed nor powered to examine PAD the development of atherosclerosis and cardiovascu-
endpoints.51,52 The current American Diabetes Associ- lar events. In particular, C-reactive protein is indepe-
ation guidance recommends hemoglobin A1C of ndently associated with PAD.
<7.0% as the goal for treatment of diabetes ‘‘in gen-
eral’’, but points out that for ‘‘the individual patient,’’ B1.2.8 Antiplatelet drug therapy
the A1C should be ‘‘as close to normal (<6%) as pos- Aspirin/acetylsalicylic acid (ASA) is a well-recognized
sible without significant hypoglycemia.’’ However, it antiplatelet drug for secondary prevention that has
is unclear whether achieving this goal will effectively clear benefits in patients with cardiovascular diseases.
protect the peripheral circulation or prevent amputa- Numerous publications from the Antithrombotic
tion.53 A single study in patients with type 2 diabetes Trialists’ Collaboration have concluded that patients
and a history of cardiovascular disease did not show with cardiovascular disease will realize a 25% odds
a benefit of lowering blood glucose levels with the reduction in subsequent cardiovascular events with

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S16 L. Norgren and W. R. Hyatt et al.

the use of aspirin/ASA.57 These findings particularly taking anti-thrombotics including heparins, aspirin/
apply to patients with coronary artery and cerebral ASA or clopidogrel. Thus, temporary cessation of these
artery diseases. This most recent meta-analysis has drugs should be individualized based on the type of sur-
also clearly demonstrated that low-dose aspirin/ASA gery and/or endovascular intervention/revasculariza-
(75e160 mg) is protective, and probably safer in terms tion to reduce bleeding risks.
of gastrointestinal bleeding than higher doses of aspi- Recent publications in patients with acute coronary
rin/ASA. Thus, current recommendations would syndromes suggest that combination therapy with
strongly favor the use of low-dose aspirin/ASA in aspirin/ASA and clopidogrel is more effective than
patients with cardiovascular diseases. However, the with aspirin/ASA alone, but at a higher risk of major
initial Antithrombotic Trialists’ Collaboration meta- bleeding.62 A recent study of clopidogrel combined
analysis did not find a statistically significant with aspirin/ASA (versus aspirin/ASA alone) was
reduction in cardiovascular events in PAD patients performed in a high-risk population consisting of
treated with aspirin/ASA who did not have other patients with established cardiovascular disease (in-
evidence of vascular disease in other territories.58 cluding PAD) and patients without a history of cardio-
However, in the more recent meta-analysis, when the vascular disease but who had multiple risk factors. This
PAD data were combined from trials using not only study showed no overall benefit of the combination of
aspirin/ASA but also clopidogrel, ticlopidine, dipyri- antiplatelet drugs as compared with aspirin/ASA
damole and picotamide, there was a significant 23% alone on the outcome of myocardial infarction, stroke
odds reduction in ischemic events in all subgroups and vascular death.63 Thus, combination therapy
of patients with PAD. Antiplatelet drugs are cannot be recommended in patients with stable PAD,
clearly indicated in the overall management of and if clopidogrel is considered it should be used
PAD, although the efficacy of aspirin/ASA is as monotherapy.
uniformly shown only when PAD and cardiovascular
disease coexist.59
Recommendation 6. Antiplatelet therapy in
Picotamide is an antiplatelet drug that inhibits
peripheral arterial disease (PAD)
platelet thromboxane A2 synthase and antagonizes
thromboxane receptors that has a mortality benefit
 All symptomatic patients with or without
in the subgroup of patients with PAD who also have
diabetes.60 In that study, the drug significantly a history of other cardiovascular disease should
reduced 2-year, all-cause mortality, but not the be prescribed an antiplatelet drug long term to
incidence of non-fatal cardiovascular events. Based reduce the risk of cardiovascular morbidity and
mortality [A].
on these data, further study is warranted before a
 Aspirin/ASA is effective in patients with PAD
recommendation can be made in regards to picotamide.
who also have clinical evidence of other forms
In addition to aspirin/ASA, the thienopyridines
of cardiovascular disease (coronary or carotid)
are a class of antiplatelet agents that have been stud-
[A].
ied in patients with cardiovascular disease. Ticlopi-
 The use of aspirin/ASA in patients with PAD
dine has been evaluated in several trials in patients
with PAD, and has been reported to reduce the risk who do not have clinical evidence of other forms
of myocardial infarction, stroke and vascular death.61 of cardiovascular disease can be considered [C].
 Clopidogrel is effective in reducing cardiovas-
However, the clinical usefulness of ticlopidine is lim-
cular events in a subgroup of patients with
ited by side effects such as neutropenia and thrombo-
symptomatic PAD, with or without other clini-
cytopenia. Clopidogrel was studied in the CAPRIE
cal evidence of cardiovascular disease [B].
(Clopidogrel versus Aspirin in Patients at Risk of
Ischemic Events) trial and shown to be effective
in the symptomatic PAD population to reduce the B2 Health Economics of Risk-factor Management
risk of myocardial infarction, stroke and vascular
death. The overall benefit in this particular group For all cardiovascular risk factors, including smoking
was a 24% relative risk reduction over the use of cessation, the most effective and cost-effective inter-
aspirin/ASA.32 This represents a number needed to ventions are those that combine a government-led
treat with clopidogrel compared with aspirin/ASA of action with individual prevention interventions. In
87 patients to prevent an event. Clopidogrel has a safety other words, laws that reduce the amount of added
profile similar to aspirin/ASA, with only rare reports salt in processed foods and that increase taxes on to-
of thrombocytopenia. Patients undergoing surgical bacco are more cost effective than individual prevention
procedures are at increased risk of bleeding when alone, but a combination of both is best.64

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S17

The issue in dealing with risk factors is the overall on increasing self-reported physical activity and
budgetary impact of enforcing compliance to pub- measured cardio-respiratory fitness, at least in the
lished guidelines. This is due to the large size of the short to mid-term’’.69 Assuming an adherence of
population at risk and the difficulty of organizing 50% in the first year and 30% in subsequent years,
the follow up of chronic patients treated by numerous the cost-effectiveness ratio of unsupervised exercise
health professionals. An additional difficulty for is less than $12,000 per life year gained. Supervised
payers is that the health and economic benefits are de- exercise has a cost-effectiveness ratio ranging from
layed while resources for treatment have to be ex- $20,000e$40,000 per life year gained (the strategies
pended at once. Studies on dyslipidemia, diabetes are more efficient in elderly males with multiple
and hypertension have shown that compliance with risk factors).70
guidelines is usually cost effective, within the range
of $20e30,000 per added year of life. This holds true B2.3 Cost-effectiveness of pharmacologic interventions
when several risk factors are associated.65,66
The effectiveness and cost-effectiveness of a num- It is difficult to recommend one drug over another
ber of lifestyle interventions, including smoking ces- for risk factor modification on cost-effectiveness con-
sation, exercise and diet, have been assessed by the siderations because drug prices are subject to varia-
Cochrane Collaboration. tions 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
B2.1 Cost-effectiveness of smoking cessation interventions
in that the medical benefits of one treatment over
another are usually small and, therefore, the cost-
For smoking cessation, the performance of profes-
effectiveness ratio is highly dependent on drug prices.
sionals in detection and interventions (including
The global cost-effectiveness analysis on the reduction
follow-up appointments, self-help materials and nico-
of cardiovascular disease risk63 found that treatment
tine gum) is improved by training, although the over-
by a combination of statin, beta blocker, diuretic and
all effect on quit rates is modest. However, ‘‘training
aspirin was most efficient in avoiding death and dis-
can be expensive, and simply providing programs
ability. When oral anti-platelet agents are considered,
for health care professionals, without addressing the
assuming a threshold of up to £20,000e40,000 per ad-
constraints imposed by the conditions in which they
ditional quality-adjusted life year (QALY), clopidogrel
practice, is unlikely to be a wise use of health care
would be considered cost effective for treatment dura-
resources’’.67 Advising patients to use the telephone
tion of 2 years in patients with peripheral arterial
services is an effective strategy.67
disease. For a lifetime treatment duration, clopidogrel
The unit cost of advice alone is estimated $5 per
would be considered more cost effective than aspirin
patient, while counseling costs $51 per patient. Adding
as long as treatment effects on non-vascular deaths
pharmacologic agents to counseling increases the quit
are not considered.71
rate and is cost effective: assuming that a long-term
Because recent studies have often failed to demon-
quitter increases his life expectancy by an average
strate a benefit on mortality, the efficiency of drug
2 years, the cost-effectiveness ratio of added pharmaco-
treatments has been measured in ‘cost per major event
logical intervention ranges from $1 to $3,000 per
averted’ and is, therefore, not comparable to ‘cost per
life-year gained.68
life year gained’, although there is a relationship
between the two. For example, the cost effectiveness
B2.2 Cost-effectiveness of exercise interventions of 40 mg/day simvastatin in high-risk patients is
£4,500 (95% CI: 2,300e7,400) per major vascular event
Exercise interventions are heterogenic, including one- averted, but the result is highly sensitive to the statin
to-one counseling/advice or group counseling/ cost. In this context, it is likely that the use of an off-
advice; self-directed or prescribed physical activity; patent statin would prove more efficient.72 For pa-
supervised or unsupervised physical activity; home- tients with high cardiovascular risk, the use of ACE
based or facility-based physical activity; ongoing inhibitors appears very cost effective in most coun-
face-to-face support; telephone support; written tries, as shown by the results of the HOPE study:
education/motivation material; and self monitoring. less than $10,000 per event averted in the various
The intervention can be delivered by one or a number developed countries where the economic analyses
of practitioners including physicians, nurses, health were undertaken.73
educators, counselors, exercise leaders, and peers. In conclusion, the risk-management strategy chosen
Interventions ‘‘have a positive moderate sized effect may differ depending on whether the individual or

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S18 L. Norgren and W. R. Hyatt et al.

population perspectives are considered. In a population and morbidity in these patients (see section A4.1).4,26
perspective with an objective of sustainability and Therefore, all PAD patients should be considered at
access, public interventions to reduce smoking, salt high risk for clinically significant CAD, for which sev-
and fat intake, combined with the prescription of cheap eral guidelines exist.74,75 Patients should be evaluated
and off-patent drugs, are preferred. If the individual for evidence of CAD.
perspective is considered, however, newer and more Treatment decisions for coexisting CAD should
expensive drugs offer additional health benefits at be based on current practice standards, and patients
reasonable cost-effectiveness ratios. who have unstable symptoms (acute coronary
syndrome, decompensated heart failure) should be
referred to a cardiovascular physician for appropri-
B3 Future Aspects of Controlling Ischemic ate diagnosis and treatment. For patients with stable
Risk Factors CAD, management should be guided by the sever-
ity of the symptoms and co-morbid conditions.
It is clear that decreasing the level of any risk factor, Most patients with severe cardiac symptoms will
such as blood pressure and LDL cholesterol, can require coronary angiography to determine the
help improve prognosis. However, it is not clear appropriate means for revascularization. All patients
what the optimal values are in the general popula- should be given appropriate medical therapy to
tion and in individual disease states. Future studies treat symptoms and atherosclerotic risk factors (see
are also needed to define guidelines for different section B1).
clinical presentations: should blood pressure be Cardiac assessment scores may be useful in the
lowered to 140/90 mmHg in patients with PAD, or context of patients being considered for peripheral
should it be lower? Should these values also revascularization.76 In patients with a high cardiac
be usable in critical leg ischemia? Is there a risk assessment score, current guidelines recommend
J-shaped curve (an increased risk at very low blood further evaluation of the patient for possible coronary
pressure values)? revascularization.76 However in the recent Coronary
Modifying several risk factors is at least as Artery Revascularization Prophylaxis (CARP) trial of
beneficial as changing only one. Combination therapy patients with peripheral vascular disease who were
with several drugs will become inevitable. However, considered high risk for perioperative complications
what is the compliance of the patients who are faced and had significant CAD, coronary revascularization
with such combination therapy? Future studies did not reduce overall mortality or perioperative
should clarify whether the ‘polypill’ (several drugs myocardial infarction.77 In addition, patients who un-
in one pill) could help in achieving the goals of im- derwent coronary revascularization had a significantly
proved risk factor modification. Calculations should longer time to vascular surgery compared with
be made on the costs of such combination therapy patients who did not. Therefore, this strategy of
versus the change in long-term prognosis. a pre-emptive coronary revascularization prior to
Diabetes sharply increases total cardiovascular peripheral vascular surgery should not normally
risk; are the current goals for blood pressure and be pursued.
lipids strict enough to control this risk? Studies are In most patients, perioperative use of beta-
needed to show whether the choice of antihyperten- adrenergic-blocking agents is associated with
sive drugs should be guided by their influence on reduced cardiovascular risks of surgery. Recent stud-
insulin resistance or other metabolic parameters. ies have shown that beta-adrenergic blockade with
It is becoming evident that inflammatory processes bisoprolol significantly decreased the risk for cardio-
play an important role in the atherosclerotic process. vascular events during vascular surgery and
It is not yet clear if drugs that target chronic inflam- afterwards.78,79 Besides controlling symptoms of
mation (e.g. antibiotics) would add to usual risk factor myocardial ischemia, treatment with beta-blocking
management in controlling the progress of the ather- agents also has the benefit of favorably influencing
osclerotic process. prognosis in these patients.80

B4 Co-existing Coronary Artery Disease B5 Co-existing Carotid Artery Disease

The prevalence of CAD in patients with PAD is high, The prevalence of carotid artery disease in PAD
which strongly increases the risk for cardiac mortality patients is also high (see section A4.2); and patients

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S19

Recommendation 7. Management of coronary Recommendation 10. Management of renal ar-

artery disease (CAD) in peripheral arterial disease tery disease in peripheral arterial disease (PAD)
patients patients

 Patients with clinical evidence of CAD (angina,  When renal artery disease is suspected in PAD
ischemic congestive heart failure) should be patients, as evidenced by poorly controlled hy-
evaluated and managed according to current pertension or renal insufficiency, patients
guidelines [C]. should be treated according to current guide-
 Patients with PAD considered for vascular sur- lines and consider referral to a cardiovascular
gery may undergo further risk stratification physician [C].
and those found to be at very high risk man-
aged according to current guidelines for coro-
nary revascularization [C]. SECTION C e INTERMITTENT CLAUDICATION
 Routine coronary revascularization in prepara-
tion for vascular surgery is not recommended C1 Characterization of Patients
[A].
C1.1 Definition of intermittent claudication and limb
symptoms in peripheral arterial disease
Recommendation 8. Use of beta-blocking agents
The majority of patients with peripheral arterial dis-
before vascular surgery
ease (PAD) have limited exercise performance and
walking ability. As a consequence, PAD is associated
 When there are no contraindications, beta- with reduced physical functioning and quality of life.
adrenergic blockers should be given periopera- In patients with PAD, the classical symptom is inter-
tively to patients with peripheral arterial mittent claudication (which means to limp), which is
disease undergoing vascular surgery in order muscle discomfort in the lower limb reproducibly
to decrease cardiac morbidity and mortality [A]. produced by exercise and relieved by rest within
10 minutes. Patients may describe muscle fatigue, ach-
with PAD are at an increased risk for cerebrovascular ing or cramping on exertion that is relieved by rest. The
events. Evaluation of the carotid circulation should symptoms are most commonly localized to the calf, but
be based on a history of transient ischemic attack or may also affect the thigh or buttocks. Typical claudica-
stroke. Further evaluation and consideration for revas- tion occurs in up to one-third of all patients with PAD.
cularization should be based on current guidelines.81,82 Importantly, patients without classical claudication
also have walking limitations that may be associated
Recommendation 9. Management of carotid ar- with atypical or no limb symptoms.85 Typical claudica-
tery disease in peripheral arterial disease (PAD) tion symptoms may not occur in patients who have co-
patients morbidities that prevent sufficient activity to produce
limb symptoms (i.e. congestive heart failure, severe
pulmonary disease, musculoskeletal disease) or in
 The management of symptomatic carotid ar-
patients who are so deconditioned that exercise is not
tery disease in patients with PAD should be
performed. Therefore, patients suspected of having
based on current guidelines [C].
PAD should be questioned about any limitations they
experience during exercise of the lower extremities
B6 Co-existing Renal Artery Disease that limits their walking ability.
PAD is caused by atherosclerosis that leads to
Patients with PAD are at an increased risk for reno- arterial stenosis and occlusions in the major vessels
vascular hypertension. The management of patients supplying the lower extremities. Patients with inter-
with PAD and atherosclerotic renal artery disease is mittent claudication have normal blood flow at rest
focused on control of hypertension and preservation (and, therefore, have no limb symptoms at rest).
of renal function. In such cases, evaluation and treat- With exercise, occlusive lesions in the arterial supply
ment should be based on current guidelines.5,83,84 of the leg muscles limits the increase in blood flow,
These patients should be referred to an appropriate resulting in a mismatch between oxygen supply and
cardiovascular physician. muscle metabolic demand that is associated with

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S20 L. Norgren and W. R. Hyatt et al.

the symptom of claudication. Acquired metabolic aneurysm (does not exclude the presence of an an-
abnormalities in the muscle of the lower extremity eurysm). Less specific aspects of the physical examina-
also contribute to the reduced exercise performance tion for PAD include changes in color and temperature
in PAD. of the skin of the feet, muscle atrophy from inability to
exercise, decreased hair growth and hypertrophied,
slow-growing nails. The presence of a bruit in the
C1.2 Differential diagnosis
region of the carotid, aorta or femoral arteries may
arise from turbulence and suggest significant arterial
Table C1 shows the differential diagnosis of intermit-
disease. However, the absence of a bruit does not
tent claudication (IC); Table C2 shows potential causes
exclude arterial disease.
of occlusive arterial lesions in the lower extremity
The specific peripheral vascular examination re-
arteries potentially causing claudication.
quires palpation of the radial, ulnar, brachial, carotid,
femoral, popliteal, dorsalis pedis and posterior tibial
C1.3 Physical examination artery pulses. The posterior tibial artery is palpated
at the medial malleolus. In a small number of
The physical examination should assess the circula- healthy adults, the dorsalis pedis pulse on the dor-
tory system as a whole. Key components of the general sum of the foot may be absent due to branching of
examination include measurement of blood pressure the anterior tibial artery at the level of the ankle. In
in both arms, assessment of cardiac murmurs, gallops this situation, the distal aspect of the anterior tibial
or arrhythmias, and palpation for an abdominal aortic artery may be detected and assessed at the ankle.

Table C1. Differential diagnosis of intermittent claudication (IC)

Condition Location Prevalence Characteristic Effect of Effect of Effect of Other

exercise rest position characteristics
Calf IC Calf muscles 3e5% of Cramping, Reproducible Quickly None May have atypical
adult aching onset relieved limb symptoms on
population discomfort exercise
Thigh and Buttocks, hip, Rare Cramping, Reproducible Quickly None Impotence
buttock IC thigh aching discomfort onset relieved May have normal
pedal pulses with
isolated iliac artery
disease
Foot IC Foot arch Rare Severe pain on Reproducible Quickly None Also may present
exercise onset relieved as numbness
Chronic Calf muscles Rare Tight, bursting After much Subsides Relief with Typically heavy
compartment pain exercise very slowly elevation muscled athletes
syndrome (jogging)
Venous Entire leg, Rare Tight, bursting After walking Subsides Relief speeded History of
claudication worse in calf pain slowly by elevation iliofemoral deep
vein thrombosis,
signs of venous
congestion, edema
Nerve root Radiates Common Sharp lancinating Induced by Often present Improved by History of back
compression down leg pain sitting, standing at rest change in problems
or walking position Worse with sitting
Relief when supine
or sitting
Symptomatic Behind knee, Rare Swelling, With exercise Present None Not intermittent
Bakers cyst down calf tenderness at rest
Hip arthritis Lateral hip, Common Aching discomfort After variable Not quickly Improved Symptoms variable
thigh, degree of relieved when not History of
exercise weight bearing degenerative
arthritis
Spinal Often bilateral Common Pain and weakness May mimic IC Variable relief Relief by Worse with
stenosis buttocks, but can take a lumbar spine standing and
posterior leg long time to flexion extending spine
recover
Foot/ankle Ankle, foot, Common Aching pain After variable Not quickly May be relieved Variable, may relate
arthritis arch degree of relieved by not bearing to activity level and
exercise weight present at rest

IC e intermittent claudication.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S21

Also, a terminal branch of the peroneal artery may C2 Diagnostic Evaluation of Patients with
be palpated at the lateral malleolus. For simplicity, Peripheral Arterial Disease
pulses may be graded from 0 (absent), 1 (dimin-
ished) and 2 (normal). An especially prominent pulse C2.1 Ankle pressure measurements
at the femoral and/or popliteal location should raise (ankle-brachial index)
the suspicion of an aneurysm. A diminished or
absent femoral pulse suggests aorto-iliac artery Measuring the pressure in the ankle arteries has be-
occlusive disease, which reduces inflow to the limb. come a standard part of the initial evaluation of
In contrast, a normal femoral, but absent pedal, patients with suspected PAD. A common method of
pulse suggests significant arterial disease in the leg measurement uses a 10e12 cm sphygmomanometer
with preserved inflow. Pulses should be assessed in cuff placed just above the ankle and a Doppler instru-
both legs and pulse abnormalities correlated with ment used to measure the systolic pressure of the
leg symptoms to determine the lateralization of posterior tibial and dorsalis pedis arteries of each
the disease. leg (Fig. C1). These pressures are then normalized to
Patients with an isolated occlusion of an internal the higher brachial pressure of either arm to form
iliac (hypogastric) artery may have normal femoral the ankle-brachial index (ABI). The index leg is often
and pedal pulses at rest and after exercise, but buttocks defined as the leg with the lower ABI.
claudication (and impotence in males). Similar symp- The ABI provides considerable information. A
toms may occur in patients with stenosis of the com- reduced ABI in symptomatic patients confirms the
mon or external iliac artery. These patients may also existence of hemodynamically significant occlusive
have normal pulses at rest, but loss of the pedal pulses disease between the heart and the ankle, with a lower
after exercise. The loss of the pedal pulse is coincident ABI indicating a greater hemodynamic severity of oc-
with a drop in ankle pressure due to the inability of the clusive disease. The ABI can serve as an aid in differen-
large vessels (in the presence of occlusive disease) to tial diagnosis, in that patients with exercise-related leg
provide sufficient flow to maintain distal pressure pain of non-vascular causes will have a normal ankle
with muscle vasodilation during exercise. pressure at rest and after exercise. In patients with
Despite the utility of the pulse examination, the PAD who do not have classic claudication (are either
finding of absent pedal pulses tends to over-diagnose asymptomatic or have atypical symptoms) a reduced
PAD, whereas if the symptom of classic claudication ABI is highly associated with reduced limb function.
is used to identify PAD, it will lead to a significant This is defined as reduced walking speed and/or
under-diagnosis of PAD.86 Thus, PAD must be con- a shortened walking distance during a timed 6-minute
firmed in suspected patients with non-invasive testing walk. From a systemic perspective, a reduced ABI is
using the ankle-brachial index, or other hemodynamic a potent predictor of the risk of future cardiovascular
or imaging studies described below. events, as discussed in section B1.1. This risk is re-
lated to the degree of reduction of the ABI (lower
ABI predicts higher risk) and is independent of
other standard risk factors. The ABI thus has the

Recommendation 11. History and physical

examination in suspected peripheral arterial Table C2. Causes of occlusive arterial lesions in lower extremity
disease (PAD) arteries potentially causing claudication

Atherosclerosis (PAD)
 Individuals with risk factors for PAD, limb Arteritis
Congenital and acquired coarctation of aorta
symptoms on exertion or reduced limb func- Endofibrosis of the external iliac artery (iliac artery syndrome in
tion should undergo a vascular history to eval- cyclists)
uate for symptoms of claudication or other Fibromuscular dysplasia
Peripheral emboli
limb symptoms that limit walking ability [B]. Popliteal aneurysm (with secondary thromboembolism)
 Patients at risk for PAD or patients with re- Adventitial cyst of the popliteal artery
duced limb function should also have a vascular Popliteal entrapment
Primary vascular tumors
examination evaluating peripheral pulses [B]. Pseudoxanthoma elasticum
 Patients with a history or examination sugges- Remote trauma or irradiation injury
tive of PAD should proceed to objective testing Takayasu’s disease
Thromboangiitis obliterans (Buerger’s disease)
including an ankle-brachial index [B]. Thrombosis of a persistent sciatic artery

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S22 L. Norgren and W. R. Hyatt et al.

Fig. C1. Measurement of the ABI. ABI e ankle-brachial index.

potential to provide additional risk stratification in  Identifies patients with reduced limb function (in-
patients with Framingham risk between 10% and ability to walk defined distances or at usual walking
20% in 10 years, in that an abnormal ABI in this in- speed)
termediate-risk group would move the patient to  Provides key information on long-term prognosis,
high risk in need of secondary prevention whereas with an ABI 0.90 associated with a 3e6-fold in-
a normal ABI would lower the estimate of risk indi- creased risk of cardiovascular mortality
cating the need for primary prevention strategies  Provides further risk stratification, with a lower ABI
(see Fig. B1). indicating worse prognosis
The ABI should become a routine measurement in  Highly associated with coronary and cerebral artery
the primary care practice of medicine. When used in disease
this context, screening of patients aged 50e69 years  Can be used for further risk stratification in patients
who also had diabetes or a smoking history, or screen- with a Framingham risk score between 10%e20%
ing all persons over the age of 70 resulted in a preva-
lence of PAD of 29%.11 The reproducibility of the ABI In some patients with diabetes, renal insufficiency, or
varies in the literature, but it is significant enough that other diseases that cause vascular calcification, the tib-
reporting standards require a change of 0.15 in an iso- ial vessels at the ankle become non-compressible. This
lated measurement for it to be considered clinically leads to a false elevation of the ankle pressure. These
relevant, or >0.10 if associated with a change in clin- patients typically have an ABI >1.40 and, in some of
ical status. The typical cut-off point for diagnosing these patients, the Doppler signal at the ankle cannot
PAD is 0.90 at rest. be obliterated even at cuff pressures of 300 mmHg. In
The value of a reduced ABI is summarized as these patients additional non-invasive diagnostic test-
follows: ing should be performed to evaluate the patient for
PAD (discussed in section G1.3). Alternative tests in-
 Confirms the diagnosis of PAD clude toe systolic pressures, pulse volume recordings,
 Detects significant PAD in (sedentary) asymptom- transcutaneous oxygen measurements or vascular im-
atic patients aging (most commonly with duplex ultrasound).
 Used in the differential diagnosis of leg symptoms When any of these tests is abnormal, a diagnosis of
to identify a vascular etiology PAD can be reliably made.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S23

testing. A second alternative is to inflate a thigh cuff

Recommendation 12. Recommendations for well above systolic pressure for 3 to 5 minutes, pro-
ankle-brachial index (ABI) screening to detect ducing a similar degree of ‘‘reactive’’ hyperemia.
peripheral arterial disease in the individual The decrease in ankle pressure 30 seconds after cuff
patient. deflation is roughly equivalent to that observed
1 minute after walking to the point of claudication
An ABI should be measured in: on a treadmill. Unfortunately, many patients do not
tolerate the discomfort associated with this degree
 All patients who have exertional leg symptoms and duration of cuff inflation and, in modern vascular
[B]. laboratories, this is rarely performed.
 All patients between the age of 50e69 and who Discussion of additional diagnostic tests to estab-
have a cardiovascular risk factor (particularly lish the diagnosis of PAD can be found in section G.
diabetes or smoking) [B]. Fig. C2 shows an algorithm for the diagnosis of PAD.
 All patients age 70 years regardless of risk-
factor status [B].
 All patients with a Framingham risk score
10%e20% [C]. C3 Outcome Assessment of Intermittent
Claudication in Clinical Practice
C2.2 Exercise testing to establish the diagnosis
of peripheral arterial disease Intermittent claudication is a symptom of peripheral
arterial disease that profoundly limits the patient’s
As discussed above, patients with claudication who ability to walk and as a result is associated with a re-
have an isolated iliac stenosis may have no pressure duced exercise performance. This reduction in exercise
decrease across the stenosis at rest and, therefore, performance can be easily quantified with a graded
a normal ABI at rest. However, with exercise the treadmill test where the time of onset of claudication
increase inflow velocity will make such lesions hemo- pain (claudication onset time) and peak walking time
dynamically significant. Under these conditions, exer- can be determined at baseline. The treadmill test will
cise will induce a decrease in the ABI that can be also allow the clinician to determine if the patient ex-
detected in the immediate recovery period and thus periences typical claudication pain with exercise, or
establish the diagnosis of PAD. The procedure requires other symptoms that limit exercise. This assessment
an initial measurement of the ABI at rest. The patient is will help guide therapy because if claudication is not
then asked to walk (typically on a treadmill at 3.2 km/ the major symptom limiting exercise then specific
h (2 mph), 10%e12% grade) until claudication pain claudication therapies may not be indicated.
occurs (or a maximum of 5 minutes), following which Once claudication is established as the major symp-
the ankle pressure is again measured. A decrease in tom limiting exercise, then the primary goal of claudi-
ABI of 15%e20% would be diagnostic of PAD. If cation therapy is to relieve the symptoms during
a treadmill is not available then walking exercise walking and improve exercise performance and com-
may be performed by climbing stairs or in the hallway. munity activities. Appropriate treatment of the claudi-
cant must address both the specific lower-extremity
disability and the systemic impact of the disease. Ide-
C2.3 Alternative stress tests for patients who cannot ally, treatment will result in an improvement in both
perform treadmill exercise the vascular status of the lower extremity and reduce
the patient’s subsequent risk of fatal and non-fatal car-
Certain patient populations should not be asked to un- diovascular events. In clinical trials of claudication
dergo treadmill testing as previously described, therapy, the primary endpoint is usually a treadmill
including those who have severe aortic stenosis, uncon- test of the peak walking time or distance as well as
trolled hypertension or patients with other exercise- the time or distance for the onset of claudication.88
limiting co-morbidities, including advanced congestive The same parameters can be assessed to determine
heart failure or chronic obstructive pulmonary disease.87 the clinical benefit of any claudication therapy in an in-
Patients who cannot perform treadmill exercise can dividual patient. In addition, changes in the physical
be tested with active pedal plantar flexion. Active domains of the Medical Outcomes Short Form 36 (SF-
pedal plantar flexion has demonstrated excellent 36) or the Walking Impairment Questionnaire (WIQ)
correlation with treadmill testing, and should be serve as patient-based measures of treatment effect.
considered an appropriate alternative to treadmill The complete assessment of the outcomes of treatment

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S24 L. Norgren and W. R. Hyatt et al.

Fig. C2. Algorithm for diagnosis of peripheral arterial disease. TBI e toe brachial index; VWF e velocity wave form; PVR e
pulse volume recording. Reproduced with permission from Hiatt WR. N Engl J Med 2001;344:1608e1621.

of the claudicant, therefore, requires the use of both cramping and aching in the affected muscle. These
clinical and patient-based parameters. symptoms result in a severe limitation in exercise per-
formance and walking ability. The exercise limitation is
associated with marked impairments in walking dis-
Recommendation 13. Determining success of tance, walking speed and overall function. Patients
treatment for intermittent claudication. with claudication are physically impaired and, there-
fore, the treatment goals are to relieve symptoms,
Patient-based outcome assessment (including improve exercise performance and daily functional
a focused history of change in symptoms) is the abilities. The initial approach to the treatment of limb
most important measure; however, if quantitative symptoms should focus on structured exercise and,
measurements are required the following may be in selected patients, pharmacotherapy to treat the exer-
used: cise limitation of claudication (risk factor modification
and antiplatelet therapies are indicated to decrease the
1. Objective measures include an increase in peak risk of cardiovascular events and improve survival).
exercise performance on a treadmill [B]. Failure to respond to exercise and/or drug therapy
2. Patient-based measures would include an im- would lead to the next level of decision making, which
provement on a validated, disease-specific is to consider limb revascularization. However, in pa-
health status questionnaire; or the physical tients in whom a proximal lesion is suspected (findings
functioning domain on a validated generic of buttocks claudication, reduced or absent femoral
health status questionnaire [B]. pulse) the patient could be considered for revasculari-
zation without initially undergoing extensive medical
therapy. The overall strategy is summarized in Fig. C3.
C4 Treatment of Intermittent Claudication
C4.1.2 Exercise rehabilitation
C4.1 Overall strategy and basic treatment In patients with claudication, there is a considerable
for intermittent claudication body of evidence to support the clinical benefits of
a supervised exercise program in improving exercise
C4.1.1 Overall strategy performance and community-based walking ability.
Patients with claudication experience reversible muscle This intervention has been thoroughly reviewed,
ischemia during walking that is characterized by both in terms of mechanism of the training effect,

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S25

Fig. C3. Overall treatment strategy for peripheral arterial disease. BP e blood pressure; HbA1c e hemoglobin A1c; LDL e
low density lipoprotein; MRA e magnetic resonance angiography; CTA e computed tomographic angiography.
Reproduced with permission from Hiatt WR. N Engl J Med 2001:344:1608e1621.

as well as practical guidelines for the exercise during the training sessions and 6 months or longer of
program.89,90 Several studies have suggested that formal training and walking exercise (versus other train-
some level of supervision is necessary to achieve opti- ing modalities). Training on a treadmill has been shown
mal results (general, unstructured recommendations to be more effective than strength training or combina-
to exercise by the physician do not result in any clinical tions of training modalities. However, different modes
benefit). In prospective studies of supervised exercise of exercise training have been applied including upper
conducted for 3 months or longer, there are clear in- extremity cycle ergometer exercise that is associated
creases in treadmill exercise performance and a lessen- with a training response. The mechanisms of response
ing of claudication pain severity during exercise.91 to exercise training have been reviewed previously and
The predictors of response to the training program include improvements in walking efficiency, endothelial
include achieving a high level of claudication pain function and metabolic adaptations in skeletal muscle.90

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S26 L. Norgren and W. R. Hyatt et al.

The exercise prescription should be based on exer-

cise sessions that are held three times a week, begin- Recommendation 14. Exercise therapy in inter-
ning with 30 minutes of training but then increasing mittent claudication
to approximately 1 hour per session. During the exer-
cise session, treadmill exercise is performed at a speed  Supervised exercise should be made available
and grade that will induce claudication within as part of the initial treatment for all patients
3e5 minutes. The patient should stop walking when with peripheral arterial disease [A].
claudication pain is considered moderate (a less  The most effective programs employ treadmill
optimal training response will occur when the patient or track walking that is of sufficient intensity
stops at the onset of claudication). The patient will then to bring on claudication, followed by rest,
rest until claudication has abated, after which the over the course of a 30e60 minute session. Ex-
patient should resume walking until moderate claudi- ercise sessions are typically conducted three
cation discomfort recurs. This cycle of exercise and times a week for 3 months [A].
rest should be at least 35 minutes at the start of the
program and increase to 50 minutes as the patient
becomes comfortable with the exercise sessions with atherosclerosis. However, this approach will typ-
(but always avoiding excessive fatigue or leg discom- ically not provide a significant reduction or elimination
fort). In subsequent visits, the speed or grade of the of symptoms of claudication. Thus, claudication drug
treadmill is increased if the patient is able to walk for therapy for relief of symptoms typically involves differ-
10 minutes or longer at the lower workload without ent drugs than those that would be used for risk reduc-
reaching moderate claudication pain. Either speed tion (an exception may be lipid-lowering therapy).
or grade can be increased, but an increased grade is However, a number of types of drugs have been
recommended if the patient can already walk promoted for symptom relief, with varying levels of
at 2 mph (3.2 km/h). An additional goal of the evidence to support their use. Not all the drugs
program is to increase patient walking speed up to presented in this section are universally available, so
the normal 3.0 mph (4.8 km/h) from the average access to certain agents may be limited in certain coun-
PAD patient walking speed of 1.5e2.0 mph (approx- tries. Finally, current drug therapy options do not
imately 2.4e3.2 km/h). provide the same degree of benefit as does a supervised
Many patients may have contraindications for exer- exercise program or successful revascularization.
cise (e.g. severe CAD, musculoskeletal limitations or
neurological impairments). Other patients may be un-
willing to participate in supervised sessions if they C4.2.1 Drugs with evidence of clinical utility in
have long distances to travel to the exercise facility, if claudication
an appropriate rehabilitation program is not available Note that not all these drugs are available in every country.
in their area, or if the expenses incurred are too great. Cilostazol
The prevalence of contraindications to an exercise pro- Cilostazol is a phosphodiesterase III inhibitor with
gram ranges from 9%e34% depending on the popula- vasodilator, metabolic and antiplatelet activity. The
tion studied. The major limitation of exercise benefits of this drug have been described in a meta-
rehabilitation is the lack of availability of a supervised analysis of six randomized, controlled trials involving
setting to refer patients. Though exercise therapy is of 1751 patients, including 740 on placebo, 281 on cilos-
proven effectiveness, some patients are simply not tazol 50 mg twice-daily (BID), 730 on cilostazol
willing to persist with an exercise program in order to 100 mg BID. The 73 on cilostazol 150 mg BID and
maintain the benefit. In addition, a claudication 232 on pentoxifylline 400 mg thrice-daily (TID) were
exercise program in a patient with diabetes who has excluded from the analysis.92 This analysis demon-
severe distal neuropathy may precipitate foot lesions strated that the net benefit of cilostazol over placebo
in the absence of proper footwear. in the primary endpoint of peak treadmill performance
ranged from 50e70 meters depending on the type of
treadmill test performed. Cilostazol treatment also re-
C4.2 Pharmacotherapy for intermittent claudication sulted in a significant overall improvement in the qual-
ity of life measures from the WIQ and SF-36. In a study
Patients with IC should all receive drug and lifestyle comparing cilostazol to pentoxifylline, cilostazol was
treatment for their cardiovascular risk factors and coex- more effective.93 Side effects included headache,
isting diseases to prevent cardiovascular events diarrhea, and palpitations. An overall safety analysis
(myocardial infarction, stroke and death) associated of 2702 patients revealed that the rates of serious

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S27

cardiovascular events, and all-cause and cardiovascu- are several promising studies evaluating the effects
lar mortality was similar between drug and placebo of statin drugs on exercise performance. While the re-
groups.94 However, since the drug is in the phosphodi- sults are preliminary, several positive trials suggest
esterase III inhibitor class of drugs, it should not be that further study is warranted.101,102 Further studies
given to patients with any evidence of congestive heart are ongoing to determine the clinical benefits of
failure because of a theoretical concern for increased these observations, including prevention of disease
risk of mortality. This drug has the best overall evidence progression in addition to symptom relief.
for treatment benefit in patients with claudication.
Naftidrofuryl
Naftidrofuryl has been available for treating inter- C4.2.3 Drugs with insufficient evidence of clinical
mittent claudication for over 20 years in several Euro- utility in claudication
pean countries. It is a 5-hydroxytryptamine type 2 Pentoxifylline
antagonist and may improve muscle metabolism, Pentoxifylline lowers fibrinogen levels, improves red
and reduce erythrocyte and platelet aggregation. In cell and white cell deformability and thus lowers blood
a meta-analysis of five studies involving a total of viscosity. While early trials were positive on the end-
888 patients with intermittent claudication, naftidro- point of improvement in treadmill exercise perfor-
furyl increased pain-free walking distance by 26% mance, later studies demonstrated that pentoxifylline
compared with placebo ( p ¼ 0.003).95 Similar results was no more effective than placebo on improving tread-
showing benefits on treadmill performance and quality mill walking distance or functional status assessed
of life were confirmed in three recent studies of over by questionnaires. Several meta-analyses have con-
1100 patients followed for 6e12 months.96e98 In all cluded that the drug is associated with modest increases
three studies the same dose of 600 mg/day was in treadmill walking distance over placebo, but the
administered. Side effects were minor and not overall clinical benefits were questionable.103e105
different to placebo; most frequently occurring com- The clinical benefits of pentoxifylline in improving
plaints in the different studies were mild gastro- patient-assessed quality of life have not been exten-
intestinal disorders. sively evaluated. While tolerability of the drug is
acceptable, pentoxifylline does not have an extensive
safety database.
C4.2.2 Drugs with supporting evidence of clinical Isovolemic hemodilution
utility in claudication Isovolemic hemodilution has been advocated for
Carnitine and Propionyl-L-Carnitine the treatment of claudication, presumably by lower-
Patients with peripheral arterial disease develop ing viscosity of whole blood, but it is still uncertain
metabolic abnormalities in the skeletal muscles of whether the increase in blood flow compensates for
the lower extremity. Thus, claudication is not simply the decrease in oxygen-carrying capacity of the blood.
the result of reduced blood flow, and alterations in There are insufficient trials to support this therapy
skeletal muscle metabolism are part of the pathophys- and it is only of historical interest.
iology of the disease. L-carnitine and propionyl- Antithrombotic agents
L-carnitine interact with skeletal muscle oxidative Aspirin/ASA and other antiplatelet agents (clopi-
metabolism, and these drugs are associated with im- dogrel) are important in the long-term treatment of
proved treadmill performance. Propionyl-L-carnitine patients with PAD to reduce their risk of cardiovascu-
(an acyl form of carnitine) was more effective than lar events with well established efficacy. However, no
L-carnitine in improving treadmill walking distance. studies have shown a benefit of antiplatelet or antic-
In two multicenter trials of a total of 730 patients, oagulant drugs in the treatment of claudication.106
initial and maximal treadmill walking distance Vasodilators
improved more with propionyl-L-carnitine than Arteriolar vasodilators were the first class of
placebo.99,100 The drug also improved quality of life agents used to treat claudication. Examples include
and had minimal side effects as compared with pla- drugs that inhibit the sympathetic nervous system
cebo. Additional trials in the broad population of pa- (alpha blockers), direct-acting vasodilators (papaver-
tients with claudication will be necessary to establish ine), beta2-adrenergic agonists (nylidrin), calcium
the overall efficacy and clinical benefit of these drugs. channel blockers (nifedipine) and angiotensin-
Lipid lowering drugs converting enzyme inhibitors. These drugs have not
Patients with PAD have endothelial and metabolic been shown to have clinical efficacy in randomized,
abnormalities secondary to their atherosclerosis, controlled trials.107 There are several theoretical
which may be improved with statin therapy. There reasons why vasodilators may not be effective,

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S28 L. Norgren and W. R. Hyatt et al.

including the possibility that vasodilator drugs may Buflomedil

create a steal phenomenon by dilating vessels in Buflomedil has an alpha-1 and -2 adrenolytic effects
normally perfused tissues thus shifting the distribu- that result in vasodilatation. This drug has antiplatelet
tion of blood flow away from muscles supplied by effects, results in improvements in red cell deformabil-
obstructed arteries. ity and weakly antagonizes calcium channels. Two rel-
L-Arginine atively small studies have shown marginally positive
L-arginine has the ability to enhance endothelium- effects on treadmill performance.117,118 However, con-
derived nitric oxide and, thus, improve endothelial cerns have been raised about publication bias of only
function. One study of nutritional supplementation positive trials. Therefore, evidence is insufficient to
with L-arginine improved pain-free but not peak support the use of this agent at this time.
walking time.108 However, a recent study of L-arginine Defibrotide
treatment in acute myocardial infarction showed no Defibrotide is a polydeoxyribonucleotide drug
clinical benefit and excess mortality.108 Further studies with antithrombotic and hemorheological properties.
would be needed to determine if this treatment would Several small studies suggest a clinical benefit, but
have benefit and no unacceptable risk. larger trials would be necessary to better understand
Acyl coenzyme A-cholesterol acyltransferase inhibitors the clinical benefits and any risks of therapy.119e121
Drugs in this class may reduce cholesterol accumu- Other agents
lation in arterial plaque, thus affecting the natural Several studies have evaluated the role of Vitamin E,
history of atherosclerosis. A study with avasimibe chelation therapy, omega-3 fatty acids, ginko-biloba
in claudication demonstrated no clear evidence of and lowering of homocysteine levels in the treat-
efficacy and possible adverse effects on low-density ment of claudication. None of these therapies have
lipoprotein cholesterol levels.109 proven effective.
5-Hydroxytryptamine antagonists
Ketanserin is a selective serotonin (S2) antagonist
that lowers blood viscosity and also has vasodilator
and antiplatelet properties. Controlled trials of this
drug have shown it not to be effective in treating Recommendation 15. Pharmacotherapy for
claudication.110 Importantly, the drug has been associ- symptoms of intermittent claudication
ated with increased risk of mortality in a subgroup of
patients treated with potassium-wasting diuretics,  A 3- to 6-month course to determine efficacy of
precluding its role for any indication.111 cilostazol should be first-line pharmacotherapy
AT-1015 is a selective 5-hydroxytryptamine antago- for the relief of claudication symptoms, as evi-
nist that was studied in multiple doses in claudication. dence shows both an improvement in treadmill
The drug was ineffective, and there were toxicity con- exercise performance and in quality of life [A].
cerns at the highest dose.112 Therefore, this drug cannot  Naftidrofuryl can also be considered for treat-
be recommended at this time. ment of claudication symptoms [A].
Sarpogrelate showed promising results in 364 pa-
tients followed for 32 weeks, without safety concerns.113
Additional trials will be necessary to determine the
overall benefits and safety of drugs in this class. C5 Future Treatments for Claudication
Prostaglandins
Prostaglandins have been used in several studies Angiogenic growth factors
in patients with critical leg ischemia with some suc- Vascular endothelial growth factor (VEGF) and
cess in wound healing and limb preservation. In pa- basic fibroblast growth factor (bFGF) are mitogenic
tients with claudication, prostaglandin E1 (PGE1) agents that stimulate the development of new vessels.
has been best studied. Intravenous administration of When bFGF protein was given intra-arterially,
a prodrug of PGE1 showed positive effects on tread- patients with claudication had an improvement in ex-
mill performance.114 Several studies have been per- ercise performance.122 Newer applications deliver the
formed with oral beraprost. While there was agent as gene therapy in a viral vector given intra-
a positive trial in Europe, there have been negative muscularly. Unfortunately, initial studies have not
trials in the USA.115,116 While intravenous administra- been positive with VEGF.123 Therefore, more studies
tion of PGE1 may have modest benefits, the overall will be needed to address the overall efficacy and
evidence does not support the use of this drug class modes and frequency of administration of angiogenic
for claudication. factors in the treatment of claudication.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S29

SECTION D e CHRONIC CRITICAL the vascular hemodynamic parameters required to

LIMB ISCHEMIA make the diagnosis of CLI.)

D1 Nomenclature and Definitions Recommendation 16. Clinical definition of criti-

cal limb ischemia (CLI)
Critical limb ischemia (CLI) is a manifestation of pe-
ripheral arterial disease (PAD) that describes patients  The term critical limb ischemia should be used
with typical chronic ischemic rest pain (see Table D1, for all patients with chronic ischemic rest pain,
Fontaine and Rutherford classifications, respectively) ulcers or gangrene attributable to objectively
or patients with ischemic skin lesions, either ulcers proven arterial occlusive disease. The term
or gangrene. The term CLI should only be used in CLI implies chronicity and is to be distin-
relation to patients with chronic ischemic disease, guished from acute limb ischemia [C].
defined as the presence of symptoms for more than
2 weeks. It is important to note in this section that
there are limited data available compared with the D1.1 Patients presumed at risk for critical limb ischemia
other sections. CLI populations are difficult to study,
with large numbers of patients lost to follow-up or A subgroup of PAD patients fall outside the definition
dying in longitudinal studies, leading to incomplete of either claudication or CLI. These patients have
data sets. severe PAD with low perfusion pressures and low
The diagnosis of CLI should be confirmed by the ankle systolic pressures, but are asymptomatic. They
ankle-brachial index (ABI), toe systolic pressure or are usually sedentary and, therefore, do not claudicate,
transcutaneous oxygen tension. Ischemic rest pain or they may have diabetes with neuropathy and
most commonly occurs below an ankle pressure of reduced pain perception. These patients are presumed
50 mmHg or a toe pressure less than 30 mmHg. Other vulnerable to develop clinical CLI. The natural
causes of pain at rest should, therefore, be considered history of this subgroup of severe PAD is not well-
in a patient with an ankle pressure above 50 mmHg, characterized, but outcomes of excess mortality and
although CLI could be the cause. amputation would be expected. The term ‘chronic sub-
Some ulcers are entirely ischemic in etiology; others clinical ischemia’ has been ascribed to this subgroup.
initially have other causes (e.g. traumatic, venous, or Natural history studies of claudication document
neuropathic) but will not heal because of the severity that few patients progress to CLI. Many patients who
of the underlying PAD. Healing requires an inflam- present with CLI are asymptomatic prior to its devel-
matory response and additional perfusion above opment.54 However, research in this area is lacking,
that required for supporting intact skin and underly- understandably, for patients who are asymptomatic
ing tissues. The ankle and toe pressure levels needed and can only be detected by more routine ABI testing.
for healing are, therefore, higher than the pressures
found in ischemic rest pain. For patients with ulcers D1.2 Prognosis
or gangrene, the presence of CLI is suggested by an
ankle pressure less than 70 mmHg or a toe systolic It is important to diagnose CLI because it confers
pressure less than 50 mmHg. (It is important to under- a prognosis of high risk for limb loss and for fatal
stand that there is not complete consensus regarding and non-fatal vascular events, myocardial infarction
Table D1. Classification of peripheral arterial disease: Fontaine’s and stroke. In general, the prognosis is much worse
stages and Rutherford’s categories than that of patients with intermittent claudication.
Observational studies of patients with CLI who are
Fontaine Rutherford
not candidates for revascularization suggest that
Stage Clinical Grade Category Clinical
a year after the onset of CLI, only about half the
I Asymptomatic 0 0 Asymptomatic patients will be alive without a major amputation,
IIa Mild claudication I 1 Mild claudication
IIb Moderate to I 2 Moderate although some of these may still have rest pain,
severe claudication gangrene or ulcers (see section A). Approximately
claudication
25% will have died and 25% will have required
I 3 Severe
claudication a major amputation. Their prognosis is in many
III Ischemic rest pain II 4 Ischemic rest pain ways similar to that of some malignancies. The
IV Ulceration or III 5 Minor tissue loss diagnosis of CLI thus predicts a poor prognosis for
gangrene III 6 Major tissue loss
life and limb. Patients should have aggressive

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S30 L. Norgren and W. R. Hyatt et al.

modification of their cardiovascular risk factors and maining in between. Ischemic rest pain should not be
should be prescribed antiplatelet drugs. Ultimately, confused with neuropathic pain (see section D4.1).
much of the care of CLI patients is palliative in nature,
an issue that is very important when considering D2.2 Ulcer and gangrene
revascularization or amputation.
Patients with CLI may also present with ischemic ul-
Recommendation 17. Cardiovascular risk modifi- cers or gangrene. It is important to note that some pa-
cation in critical limb ischemia (CLI) tients may progress through rest pain into tissue loss.
However, in many patients, notably those with dia-
betic neuropathy, the initial presentation is with a neu-
 CLI patients should have aggressive modifica-
roischemic ulcer or gangrene. There are significant
tion of their cardiovascular risk factors [A].
differences between patients with and without diabe-
tes at this stage of CLI; these are delineated in section
D2 Clinical Presentation and Evaluation D2.4 which specifically addressed diabetic foot ulcers.
Gangrene usually affects the digits or, in a bedridden
D2.1 Pain patient, the heel (as this is a pressure point). In severe
cases, gangrene may involve the distal parts of the fore-
CLI is dominated by pedal pain (except in diabetic pa- foot. It is usually initiated by a minor local trauma.
tients, where superficial pain sensation may be altered Local pressure (ill fitting shoes) or the use of local
and they may experience only deep ischemic pain, heat (increasing metabolic demands) can also lead to
such as calf claudication and ischemic rest pain). In ulcer and gangrene formation on other locations on
most cases, the pedal pain is intolerably severe; it the foot or leg. Gangrenous tissue, if not infected, can
may respond to foot dependency, but otherwise re- form an eschar, shrink and eventually mummify and,
sponds only to opiates. The pain is caused by ische- if the underlying circulation is adequate enough (or
mia, areas of tissue loss, ischemic neuropathy or has been made adequate enough by treatment) to sup-
a combination of these; it occurs or worsens with re- port the process, spontaneous amputation may follow.
duction of perfusion pressure. In most cases, walking In contrast to the focal and proximal atherosclerotic
capacity is very severely impaired, with walking often lesions of PAD found typically in other high-risk
becoming almost impossible. patients, in patients with CLI and diabetes the occlu-
Ischemic rest pain most typically occurs at night sive lesions are more likely to be more diffuse and dis-
(when the limb is no longer in a dependent position) tally located, particularly in infrageniculate arteries.
but in severe cases can be continuous. The pain is local- Importantly, PAD in patients with diabetes is usually
ized in the distal part of the foot or in the vicinity of an accompanied by peripheral neuropathy with impaired
ischemic ulcer or gangrenous toe. The pain often wakes sensory feedback, enabling the silent progression of
the patients at night and forces them to rub the foot, get the ischemic process. Thus, a patient with diabetes
up, or take a short walk around the room. Partial relief and severe, asymptomatic PAD could also have a ‘piv-
may be obtained by the dependent position, whereas otal event’ that leads acutely to an ischemic ulcer and
elevation and cold increase the severity of the pain. Of- a limb-threatening situation. A common example is
ten, patients sleep with their ischemic leg dangling the use of new, tight or ill fitting shoes in a patient
over the side of the bed, or sitting in an armchair; as with neuropathy. Thus, an asymptomatic, usually
a consequence ankle and foot edema develop. In severe undiagnosed patient can lapse, apparently abruptly,
cases, sleep becomes impossible because pain sets in into CLI. By identifying a patient with sub-clinical dis-
after only a short period of supine rest, causing in ease and instituting preventive measures, it may be
many patients a progressive further decline of their possible to avoid CLI or at least prompt early referral
general physical and psychological condition. if the patient develops CLI.
Ischemic rest pain is often accompanied by pain
caused by peripheral ischemic neuropathy, the mecha- D2.3 Differential diagnosis of ulcers
nism of which is not well established. This results in
severe, sharp, shooting pain that does not necessarily The majority of lower-leg ulcers above the ankle have
follow the anatomic distribution of the nerves but usu- a venous origin whereas ulcers in the foot are most
ally is most pronounced at the distal part of the extrem- likely due to arterial insufficiency (see Fig. D1).
ity. The pain often occurs at night, with episodes lasting Table D2 depicts the common characteristics of foot
minutes to hours but with constant diffuse pain re- and leg ulcers.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S31

that approximately 30% of people with diabetes

have mild-to-severe forms of diabetic nerve damage.
Many diabetic foot ulcers and lower extremity ampu-
tations can be prevented through early identification
of the patient at risk and preventive foot care, by
both the health care provider and the patient, as
described in the section D6 on the prevention of CLI.

D2.4.1 Pathways to ulceration

The most common pathway associated with the
development of diabetic ulcers include: neuropathy
(loss of protective sensation), coupled with pressure
points (foot deformity) and repetitive activity.126
Motor nerve defects and limited joint mobility
can cause foot deformities, with pressure points
further predisposing the patient to foot lesions.
Consequences of autonomic neuropathy include loss
of sweating, dry fissured skin and increased arteriove-
nous shunting. Healing requires a greater increase in
perfusion than needed to maintain intact skin.

D2.4.2 Types of ulcers and presentation

Diabetic foot ulcerations can be divided into three
broad categories: ischemic, neuro-ischemic and neuro-
pathic ulcers. The presentation of the classical neuro-
pathic and ischemic ulcers is depicted in Table D3.
Although the majority of diabetic ulcers are neuro-
pathic (Fig. D3), ischemia has to be excluded in all ul-
cers given its major impact on outcome. All patients
with a foot ulcer should have an objective assessment
Fig. D1. Approximate frequencies of various ulcer of their vascular status at first presentation and on a reg-
etiologies.
ular basis; the assessment should include history (clau-
dication), pulses and ABI. Pulse examination alone is
an inadequate vascular examination in these patients.
D2.4 Diabetic foot ulcers Any diabetic patient with a foot ulcer should be further
evaluated in the vascular laboratory (see section G).
While CLI is a significant risk factor for non-healing of Increased arteriovenous shunt blood flow, due to
diabetic foot ulcers, it is not the sole major factor asso- autonomic neuropathy, can result in a relatively
ciated with the development of diabetic foot lesions. warm foot, falsely reassuring the clinician. The clini-
Diabetic foot ulcers are, therefore, discussed sepa- cian should be aware of the relative incompressibility
rately in this section. Fig. D2 demonstrates of calcified distal arteries in a diabetic, such that the
the distribution of diabetic foot ulcers. Diabetic foot ABI may be within normal limits. Due to the possibil-
complications are the most common cause of non- ity of a falsely elevated ABI, the importance of toe
traumatic lower extremity amputations in the world. pressures and tcPO2 measurements cannot be under-
It is estimated that 15% of people with diabetes estimated (see Section D5). Some patients have clear
will develop a foot ulcer during their lifetime and signs of critical limb ischemia e for example a toe or
approximately 14%e24% of people with a foot ulcer tcPO2 pressure <30 mmHg e while in others the
will require an amputation. Up to 85% of amputations blood flow is impaired to a lesser degree e for exam-
may be prevented by early detection and appropriate ple toe pressures between 30e70 mmHg e but they
treatment.124 Risk factors for ulcer formation include are still unable to heal foot lesions.
peripheral neuropathy, which leads to an insensate Symptoms and signs of neuropathic versus ischemic
foot and structural foot deformity. It is estimated ulcers appear in Table D3.

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S32 L. Norgren and W. R. Hyatt et al.

Table D2. Characteristics of common foot and leg ulcers

Origin Cause Location Pain Appearance Role of

revascularization
Arterial Severe PAD, Buerger’s Toes, foot, ankle Severe Various shape, Important
disease, pale base, dry
Venous Venous insufficiency Malleolar, esp. medial Mild Irregular, pink None
base, moist
Mixed venous/arterial Venous Usually malleolar Mild Irregular, pink base If non-healing
insufficiency þ PAD
Skin infarct Systemic disease, Lower third of leg, malleolar Severe Small, often multiple None
embolism
Neuropathic Neuropathy from Foot/plantar surface None Surrounding callus, None
diabetes, vitamin (weight-bearing), often deep, infected
deficiency, etc associated deformity
Neuroischemic Diabetic Locations common to both Reduced As arterial As arterial
neuropathy þ ischemia ischemic and neuroischemic due to
As arterial neuropathy

and the dorsalis pedis artery are open beyond these

Recommendation 18. Evaluation of peripheral occlusions and serve as potential distal targets for
arterial disease (PAD) in patients with diabetes a bypass.

 All diabetic patients with an ulceration should

be evaluated for PAD using objective test- D3.1 Skin microcirculation
ing [C].
The skin microcirculation is unusual in many ways,
most notably that nutritional capillary blood flow
only represents approximately 15% of the normal total
D3 Macrocirculatory Pathophysiology in Critical blood flow in the foot, the remainder having a non-
Limb Ischemia nutritive thermoregulatory function only. Patients
with CLI develop microcirculatory defects including
CLI occurs when arterial lesions impair blood flow to endothelial dysfunction, altered hemorheology and
such an extent that the nutritive requirements of the white blood cell activation and inflammation. The nor-
tissues cannot be met. This is usually caused by mul- mal function of the skin microcirculation can be consid-
tilevel arterial occlusive disease.128 In some cases, the ered in regard to two aspects: a complex microvascular
hemodynamic consequences of arterial lesions may be flow regulatory system and a series of defense mecha-
compounded by a decreased cardiac output. nisms. The microvascular flow-regulating system
CLI is considered to be the result of multisegment includes extrinsic neurogenic mechanisms, intrinsic
arterial occlusive disease in most cases. Realizing local mediators and modulation by circulating humoral
this is most important in managing patients with pre- and blood-borne factors. The endothelium also partici-
sumed rest pain, as the influence of circulation on the pates in the regulation of flow by the release of vasodi-
pain syndrome can be difficult to determine, partic- latory mediators such as prostacyclin and nitric oxide
ularly in a patient with neuropathy. and several endothelium-derived contractile factors
(e.g. endothelin). In addition to the microvascular
 Patients with diffuse multisegment disease, both su- flow-regulating system, there are several microvascu-
pra and infrainguinal are significant management lar defense mechanisms. In CLI, there is a maldistribu-
problems, as proximal revascularizations may not re- tion of the skin microcirculation in addition to
main patent due to lack of arterial outflow without a reduction in total blood flow. The importance of the
additional infrainguinal procedures. Should a major local microcirculatory response in individual patients
amputation be required, the risk of non-healing is with CLI is suggested by the wide overlap in ankle or
considerable due to proximal occlusive disease toe blood pressure, which assess the macrocirculation,
 In patients with diabetes, arteries proximal to the in patients with and without CLI.
knee joint are often spared or moderately diseased, Capillary microscopy studies have confirmed an het-
and the majority of occlusions occur at the tibial pe- erogeneous distribution of skin microcirculatory flow.
roneal trunk and distally. Often, the peroneal artery This is also accompanied by a reduction in tcPO2.129

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S33

Fig. D2. Distribution of diabetic foot ulcers.125 Copyright Ó 1999 American Diabetes Association from Diabetes Care, Vol. 22,
1999; 157e162. Modified with permission from The American Diabetes Association.

In summary, although PAD is the underlying and severe, seriously disabling pain in the foot. This is of-
principal defect in patients with CLI, the low tissue ten described as a burning or shooting sensation that
perfusion pressure sets up a number of complex local is frequently worse at night, when there is less distrac-
microcirculatory responses, which may contribute to tion, making it more difficult to distinguish from atyp-
rest pain and trophic changes. Many of these pro- ical ischemic rest pain. (It should be noted that this
cesses can be viewed as an inappropriate response type of pain is seen in the relatively early ‘neuritic’
of the microcirculatory flow regulatory mechanism phase of diabetic neuropathy, often before diabetic
and its normal defense mechanisms. Therefore, al- neuropathy has been clinically recognized.) Diagnos-
though the primary aim of treatment must be the cor- tic features that may be helpful in distinguishing
rection of the PAD, attempts to manipulate and diabetic neuropathy from ischemic rest pain are a
normalize the microcirculatory changes pharmacolog- symmetrical distribution in both legs, association
ically may enhance the results of revascularization with cutaneous hypersensitivity and failure to relieve
and may be one option in patients in whom revasc- it by dependency of the foot. The patient may have
ularization is impossible or has failed. other signs of a diabetic neuropathy, such as
decreased vibratory sensation and decreased reflexes.

D4 Differential Diagnosis of Ischemic Rest Pain

D4.2 Complex regional pain syndrome
The various causes of foot pain that may be mistaken
for ischemic rest pain are considered in their appro-
Patients with complex regional pain syndrome (for-
ximate order of frequency.
merly named causalgia or reflex sympathetic dystro-
phy) are often referred to vascular specialists for
D4.1 Diabetic neuropathy evaluation of their limb circulation. In general, the cir-
culation is adequate (ABI, toe-brachial index [TBI]
Diabetic neuropathy usually results in a decrease in normal). One form of complex regional pain
sensation. In some patients neuropathy can result in syndrome is caused by inadvertent ischemic damage

Fig. D3. Relative prevalence of different diabetic ulcer etiologies.127

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S34 L. Norgren and W. R. Hyatt et al.

Table D3. Symptoms and signs of neuropathic versus ischemic D4.6 Buerger’s disease (thrombangitis obliterans)
ulcers

Neuropathic ulcer Ischemic ulcer Buerger’s disease also may present with rest pain in
Painless Painful the toes or feet, usually in younger smokers, and is
Normal pulses Absent pulses no longer exclusively seen in male patients. The path-
Regular margins, typically Irregular margins ophysiology is distal limb ischemia, due to an occlu-
punched-out appearance
Often located on plantar Commonly located on toes, sive, inflammatory vascular process involving both
surface of foot glabrous margins arteries and veins.
Presence of calluses Calluses absent
or infrequent
Loss of sensation, reflexes Variable sensory findings D4.7 Miscellaneous
and vibration
Increase in blood flow Decrease in blood flow
(AV shunting) A number of other miscellaneous conditions can
Dilated veins Collapsed veins give rise to pain in the foot, including local inflamma-
Dry, warm foot Cold foot
Bony deformities No bony deformities tory diseases such as gout, rheumatoid arthritis,
Red appearance Pale, cyanotic digital neuroma, tarsal tunnel nerve compression or
plantar fasciitis.

to peripheral nerves that may be associated with de-

layed revascularization and, therefore, may be classi- D5 Investigations of Critical Limb Ischemia
fied as a postoperative complication. This is one of
the rare conditions in which lumbar sympathectomy D5.1 Physical examination
may be indicated.
As a majority of patients with CLI have not suffered
earlier symptoms of PAD (intermittent claudication)
D4.3 Nerve root compression it is important to have the diagnosis of CLI in
mind when examining any patient with leg pain or
A number of spinal conditions may result in nerve root ulcer development.
compression, giving rise to continuous pain. It is typi- A first step is to document the location and quality
cally associated with backache and the pain distribu- of the pulses. Other less specific findings may include
tion following one of the lumbosacral dermatomes. hair loss, muscle atrophy, atrophy of subcutaneous
tissues and skin and appendages, dry fissured skin,
discoloration and dependant hyperemia.
D4.4 Peripheral sensory neuropathy other than
In patients with ulcers there may be other etiologies
diabetic neuropathy
besides arterial disease (see Fig. D1 and Table D2).
Swelling is usually only a feature when there is active
Any condition giving rise to isolated sensory neurop-
infection or rest pain that prevents patients from
athy can produce pain in the foot, which can be
elevating their foot in bed at night.
confused with ischemic rest pain. Peripheral neurop-
athy other than that caused by diabetic neuropathy D5.2 Investigations
may be caused by vitamin B12 deficiency, or syringo-
myelia. Leprosy also may rarely result in a neuro-  General investigations of atherosclerotic disease
pathic ulcer. Alcohol excess, toxins, and some (see section B)
commonly used drugs, such as some cancer chemo-  Physiologic e Confirmation of the diagnosis and
therapy agents, may on rare occasion produce a quantification of the arterial flow
peripheral neuropathy. B Ankle pressure e In patients with ischemic ulcers

are typically 50e70 mmHg and in patients with

D4.5 Night cramps ischemic rest pain typically 30e50 mmHg
B Toe pressures e should include toe pressures in

Night cramps, as opposed to restless legs, are very diabetic patients (critical level <50 mmHg)
common and occasionally difficult to diagnose. They B tcPO2 (critical level <30 mmHg)

are usually associated with muscle spasm and usually B Investigation of microcirculation (usually used as

involve the calf, very rarely the foot alone. They may a research tool) e CLI is associated with redu-
be associated with chronic venous insufficiency, but ced total flow as well as maldistribution of flow
their precise cause is unknown. and activation of an inflammatory process. A

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S35

combination of tests to assess healing and quantify D6.2 The role of peripheral neuropathy
flow may be indicated due to the rather poor sen-
sitivity and specificity of the single test. Tests Loss of protective sensation or peripheral neuropathy
include: places the patient at a higher risk for developing foot
 Capillaroscopy related complications. Foot deformities may be the re-
 Fluorescence videomicroscopy sult of motor neuropathy. Therefore, recognition of
 Laser Doppler fluxometry structural deformities such as hammer toes and bun-
 Anatomic (Imaging) e Refer to section G ions, or altered biomechanics such as callus formation
due to prominent bony deformity, as well as limited
joint mobility identify the patient as high risk. Foot-
wear should be inspected to determine if it provides
Recommendation 19. Diagnosis of critical limb
adequate support and protection for the foot. Properly
ischemia (CLI)
fitting shoes must accommodate any foot deformities.
Improper or poorly fitting shoes are a major contributor
 CLI is a clinical diagnosis but should be to foot ulcerations, especially for people with diabetes.
supported by objective tests [C]. Preventive foot care strategies for patients at risk of
developing foot complications is essential for limb
preservation. These strategies include patient edu-
cation and appropriate management of high-risk
Recommendation 20. Indications for evaluation patients. Patients should be educated on the impor-
for critical limb ischemia tance of self-care of the feet, including proper foot
care and footwear assessment. Early detection of foot
 All patients with ischemic rest pain symptoms problems and early intervention may decrease the fre-
or pedal ulcers should be evaluated for CLI [B]. quency and severity of lower extremity complications.
Soft, conforming rather than correctional orthotics are
valuable. Therefore, patients (or their family if their
vision is impaired) should be performing daily foot
inspections at home.
D6 Prevention of Critical Limb Ischemia

As with all forms of systemic atherosclerosis, early Recommendation 21. Importance of early identi-
detection of PAD and aggressive management of car- fication of peripheral arterial disease (PAD)
diovascular risk factors should reduce the incidence
and severity of CLI. For example, smoking cessation  Early identification of patients with PAD at risk
is associated with a decreased risk of progression of developing foot problems is essential for
from earlier stages of PAD to CLI130 (see section B). limb preservation [C]. This can be achieved
by daily visual examination by the patient or
D6.1 Risk factors associated with the foot their family and, at every visit, referral to the
foot specialist.
Early identification of the patient who is at risk for
CLI is essential in order to recognize potential prob-
lems and develop preventive intervention strategies D7 Treatment of Critical Limb Ischemia
to avoid complications. Patients with atherosclerotic
PAD, Buerger’s disease, diabetes and any other condi- D7.1 Overall strategy (Fig. D4)
tion that can cause a loss of protective sensation to
the foot or interferes with wound healing are at risk The primary goals of the treatment of CLI are to relieve
of developing ulcerations and a future amputation. ischemic pain, heal (neuro)ischemic ulcers, prevent
Persons with diabetes are at a higher risk for develop- limb loss, improve patient function and quality of
ing lower extremity complications. A thorough foot life and prolong survival. A primary outcome would
examination will assist in identifying those patients be amputation-free survival. In order to achieve these
who are at risk. Once an individual is classified outcomes, most patients will ultimately need a revas-
as high risk, a visual foot inspection should be cularization procedure requiring referral to a vascular
performed at every visit and referral to a foot care specialist. Other components of treatment of patients
specialist for further assessment is recommended. with CLI are medical interventions to control pain

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S36 L. Norgren and W. R. Hyatt et al.

Fig. D4. Algorithm for treatment of the patient with critical limb ischemia. Contraindications are: patients not fit for
revascularization; revascularization not technically possible; benefit cannot be expected (i.e. widespread ulceration-
gangrene e see also section D7.5). CLI e critical limb ischemia; MRA e magnetic resonance angiography; CTA e computed
tomographic angiography.

and infection in the ischemic leg, prevention of partial relief of ischemic pain in some patients. There-
progression of the systemic atherosclerosis, and fore, tilting the bed downward may be a helpful mea-
optimization of cardiac and respiratory function. For sure in addition to analgesia. Patients with CLI are
some CLI patients with severe co-morbidities or often depressed and pain control can be improved
a very limited chance of successful revascularization, by use of antidepressant medications.
a primary amputation may be the most appropriate
treatment. Cardiovascular risk factor control is man-
datory in CLI patients as well as in all PAD patients
Recommendation 22. Early referral in critical
(see section B).
limb ischemia (CLI)
D7.2 Basic treatment: pain control
 Patients with CLI should be referred to a vascu-
Pain management is essential in improving function lar specialist early in the course of their disease
and quality of life. The hallmark of CLI is ischemic to plan for revascularization options [C].
rest pain and painful ulceration. Pain is usually lo-
cated to skin and possibly bone structures. Pain con-
trol is a critical aspect of the management of these
Recommendation 23. Multidisciplinary approach
patients. Ideally, relief of pain is achieved by reperfu-
to treatment of critical limb ischemia
sion of the extremity. However, while planning the re-
vascularization, adequate pain control must be a goal
of management in all patients. Furthermore, in pa-  A multidisciplinary approach is optimal to con-
tients for whom revascularization is not an option, trol pain, cardiovascular risk factors and other
narcotic pain relief is commonly needed. co-morbid disease [C].
Physicians should assess pain severity and ade-
quacy of pain relief in all patients at regular visits.
Initial attempts at pain relief should include the use D7.3 Revascularization
of acetaminophen/paracetamol or nonsteroidal anti-
inflammatory medications, although the latter are The natural history of CLI is such that intervention is in-
rarely effective and narcotic medications are fre- dicated to salvage a useful and pain-free extremity. The
quently required. Caution should be used in the latter treatment chosen depends upon the pre-morbid
in patients with hypertension, or renal insufficiency. condition of the patient and the extremity as well as
Control of pain is usually more effective if analgesia estimating the risk of intervention based on co-morbid
is given regularly rather than on demand. Placing conditions and the expected patency and durability
the affected limb in the dependent position provides of the reconstruction. In CLI, multi-level disease is

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S37

frequently encountered. Adequate inflow must be and aggressively treated. Severe foot infections in di-
established prior to improvement in the outflow. abetic patients are usually polymicrobial with gram
After revascularization, ulcer healing may require positive cocci, gram negative rods and anaerobic or-
adjunctive treatments that may be best achieved in ganisms.133 Once the clinical diagnosis of an infection
collaboration between the vascular specialist and is made and cultures of the wound obtained, empiric
specialists in foot care. antibiotic treatment should be initiated immediately.
(See also section F.) Broad spectrum antibiotic therapy can be adjusted
once the causative micro-organisms are determined
D7.4 Management of ulcers and results of the culture sensitivity have been
obtained. A growing concern is the rise in the inci-
The management of the patient with CLI and foot dence of multidrug-resistant Staphylococcus aureus,
ulcers illustrates the need for a multidisciplinary which is up to 30% in some studies.134 Management
approach to the treatment of CLI patients. These of a deep infection usually also includes drainage
patients should be treated according to the follow- and debridement of necrotic tissue. Antibiotic therapy
ing principles. is believed to be important in the prevention of fur-
Restoration of perfusion ther spreading of infection in patients with CLI.
The successful treatment of a foot ulcer rests with Once the acute infection is under control, a revascular-
the possibility of increasing the perfusion to the foot. ization procedure can be performed in a second stage.
The determination of whether or not a revasculariza-
tion procedure is possible will set the tone for the en-
suing treatment. A revascularization procedure
should be considered if clear signs of CLI are present Recommendation 24. Optimal treatment for
or if healing does not occur in a neuro-ischemic ulcer patients with critical limb ischemia (CLI)
despite optimal off-loading, treatment of infection, if
present, and intensive wound care. After revasculari-  Revascularization is the optimal treatment for
zation, local wound care and possibly foot salvage patients with CLI [B].
procedures must be considered.
Local ulcer care and pressure relief
Prior to a revascularization procedure the ulcer can
be treated with a non-adherent gauze and should be
off-loaded if there is an increase in pressure or shear Recommendation 25. Treatment for infections in
stress. Off-loading can be achieved by several methods critical limb ischemia (CLI)
including shoe modifications, orthotics and casting
techniques,16,131,132 depending on the localization of  Systemic antibiotic therapy is required in CLI
the ulcer and the severity of the ischemia. Once perfu- patients who develop cellulitis or spreading
sion is improved, adequate off-loading becomes more infection [B].
important as the increase in blood flow may not com-
pensate for the repetitive tissue trauma due to poorly
fitted shoes. The local treatment of a revascularized
foot ulcer can be carried out in many fashions and Salvage procedures
a multitude of products exist. An in-depth discussion Limb salvage after revascularization is defined as
of each ulcer care product is beyond the scope of this preservation of some or all of the foot. An attempt at
work but the basic principles of wound care should a foot salvage procedure should take place after a
be adhered to. These principles include: removing revascularization procedure has been performed if
necrotic/fibrotic tissue from the ulcer, keeping a moist possible. A waiting period of at least 3 days has been
wound environment and eliminating infection, as suggested, this allows for sufficient time for the resto-
discussed below. ration of perfusion and for demarcation to occur.
Treatment of infection The level of adequate circulation, extent of infec-
Local infection is a severe complication of a neuro- tion, if any and remaining function of the foot are fac-
ischemic ulcer, as it tends to run a more severe course tors considered when choosing the level of a foot
and should be treated urgently. Signs of systemic tox- salvage procedure. Foot salvage procedures can be di-
icity, such as fever or elevated C-reactive protein, are vided into two categories. The first category involves
uncommon. The infection should be identified as amputation of some part of the foot. Table D4 shows
early as possible and its level of involvement assessed the different levels of local foot amputations.

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S38 L. Norgren and W. R. Hyatt et al.

Table D4. Different levels of local foot amputations

Recommendation 26. Multidisciplinary care in
Digit (partial or total)
Ray (digit and metatarsal)
critical limb ischemia (CLI)
Midfoot (transmetatarsal; tarso-metatarsal; transverse tarsal)
Symes (ankle)  Patients with CLI who develop foot ulceration
require multidisciplinary care to avoid limb
loss [C].

The natural history of a minor foot amputation

should be considered when choosing the appropriate
level of amputation in order to account for the sub- D7.5 Amputation
sequent changes in mechanical force and pressure
on the foot. For example, a hallux or partial first Major amputation (above the ankle) in CLI is neces-
ray amputation increases the resultant vector of sary and indicated when there is overwhelming infec-
force on the second ray (through metatarsal shaft). tion that threatens the patient’s life, when rest pain
This increase in force traversing through the second cannot be controlled, or when extensive necrosis has
ray can cause a contracture of the second toe, lead- destroyed the foot. Using these criteria, the number
ing to an increased pressure at both the sub metatar- of major limb amputations should be limited.
sal head area and the distal pulp of the toe. These Primary amputation is defined as amputation of
changes in pressure require appropriate shoe and the ischemic lower extremity without an antecedent
insole modifications to avoid foot complications. attempt at revascularization. Amputation is consid-
A high percentage of patients with a great toe ered as primary therapy for lower limb ischemia
and/or first ray amputation go on to have a second only in selected cases. Unreconstructable arterial dis-
amputation either on the same foot or the contra- ease is generally due to the progressive nature of the
lateral foot. underlying atherosclerotic occlusive disease.
Amputation of the lateral toes and rays (fourth and Revascularization of the lower extremity remains the
fifth digits) does not cause the same increase in me- treatment of choice for most patients with significant
chanical force and pressure on the adjacent digits as arterial occlusive disease.
described above. Hence, the considerations of shoe Unreconstructable vascular disease has become the
wear and inner sole modifications are different with most common indication for secondary amputation,
this scenario. accounting for nearly 60% of patients. Secondary am-
When multiple medial rays are involved or the is- putation is indicated when vascular intervention is no
chemia is proximal to the metatarsal heads, but distal longer possible or when the limb continues to deteri-
to the tarso-metatarsal joint, a mid foot amputation orate despite the presence of a patent reconstruction.
should be considered. A transmetatarsal amputation Persistent infection despite aggressive vascular
provides a stump adequate for walking with minimal reconstruction is the second most common diagnosis.
shoe and innersole modifications. Many amputations can be prevented and limbs pre-
The second category of foot salvage involves the served through a multi-armed, limb-salvage treatment
debridement of the wounds, including excision of of ischemic necrosis with antibiotics, revascularization
bone. These procedures permit the foot to keep its and staged wound closure that may necessitate the use
general outward appearance intact, while disturbing of microvascular muscle flaps to cover major tissue
the internal architecture that is causing the increased defects. On the other hand, and very importantly,
pressure. Foot salvage procedures, short of amputa- amputation may offer an expedient return to a useful
tion, that can be used in the revascularized foot quality of life, especially if a prolonged course of treat-
include exostectomy, arthroplasty, metatarsal head ment is anticipated with little likelihood of healing.
excision and calcanectomy. Non-ambulatory elderly patients with CLI represent
Diabetes control and treatment of co-morbidity a particularly challenging group. These patients fre-
As in all patients with diabetes, those with concom- quently have flexion contractures that form from the
itant CLI should have optimization of glycemic con- prolonged withdrawal response to the pain. Aggres-
trol. Diabetic patients with a neuro-ischemic foot sive vascular reconstruction does not provide these
ulcer frequently have a poor health status. Factors patients with a stable and useful limb, and primary
that can negatively affect wound healing such as amputation is a reasonable option.135 Therefore, the
cardiac failure or poor nutritional status should be important issue is to identify a subgroup of CLI patients
evaluated and treated appropriately. better served by an amputation than attempts of

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S39

revascularization. Technical aspects, foot wound

healing issues and co-morbidities of the patients Recommendation 27. Amputation decisions in
should be considered. critical limb ischemia (CLI)
It is the implicit goal of amputation to obtain pri-
mary healing of the lower extremity at the most  The decision to amputate and the choice of the
distal level possible. The energy expenditure of am- level should take into consideration the poten-
bulation increases as the level of amputation rises tial for healing, rehabilitation and return of
from calf to thigh. Preservation of the knee joint quality of life [C].
and a significant length of the tibia permits the use
of lightweight prostheses, minimizes the energy of
ambulation, and enables older or more frail patients
to walk independently.136 Therefore, the lowest D7.6 Pharmacotherapy for critical limb ischemia
level of amputation that will heal is the ideal site
for limb transection. When open or endovascular intervention is not tech-
Clinical determination of the amputation level re- nically possible or has failed, the question arises as
sults in uninterrupted primary healing of the below- to whether pharmacological treatment is an option.
knee stump in around 80% and the above-knee stump The consequences of the severely reduced perfusion
in around 90% of cases.137 Measurement of tcPO2 pressure on the distal microcirculation have to be
combined with clinical determination may be of value overcome. Pharmacotherapy, or any other treatment
to predict healing at various levels of amputation.138 that produces modest improvements in circulation,
Figures from specialized centers are better than the is more likely to be successful in patients who were
global figures shown in Fig. A6. Amputations have asymptomatic before developing their foot lesion
variable outcome and more risk with higher proximal and in those with shallow foot lesions where the level
amputations. Ambulatory status of patients after of ischemia is close to the margin (i.e. those with
amputation is shown in Table D5. borderline perfusion pressures).
A major amputation that is above the foot will re-
quire a prosthesis. Meticulous technique is essential D7.6.1 Prostanoids
to ensure a well-formed and well-perfused stump Prostanoids prevent platelet and leukocyte activation
with soft tissue covering the transected end of the and protect the vascular endothelium, which could
bone. Major amputations are usually performed at play a role in the management of CLI. These drugs
the below-knee (preferred) or above-knee level de- are administered parenterally over several weeks.
pending on the level of arterial occlusion and tissue Side effects include flushing, headache, and hypoten-
ischemia. A return to independent ambulation is the sion of a transient nature. Nine double-blind random-
ultimate challenge for patients undergoing major ized trials on prostanoid treatment have been
amputation of the lower extremity. Patients with published.146e154 Three PGE1 studies showed a benefit
a well-healed below-knee amputation stump on reducing ulcer size, but these studies did not show
have a greater likelihood of independent ambulation favorable outcomes on other critical clinical end-
with a prosthesis than those with an above-knee points. Six studies of the stable PGI2 analog, iloprost,
amputation, who have a less than 50% chance of were performed, not all of which were positive. A
independent ambulation. meta-analysis of the data demonstrated that patients

Table D5. Ambulatory status 6e12 months following amputation

Author (year) N Percentage fitted Percentage* Comments

with a prosthesis Ambulatory
Ruckley (1991)139 191 80% 74% Randomized trial
Siriwardena (1991)140 267 e 63% US VAMC Data
Hagberg (1992)141 24 100% 96%
Houghton (1992)142 193 e 16% 20% LFU
Stirnemann (1992)143 126 70% 70% Primary versus Failed bypass
McWhinnie (1994)144 61 66% 52%
Nehler (2003)145 94 e 39% 11% LFU
*
Time intervals are 6e12 months postoperatively from below-knee amputation (BKA). Modest ambulatory results are due to 1) mortality
prior to rehabilitation; 2) failure to heal BKA; 3) failure to complete rehabilitation program.
LFU e lost to follow up; VAMC e Veterans Affairs Medical Center.

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S40 L. Norgren and W. R. Hyatt et al.

on active treatment had a greater chance (55% vs. D7.7 Other treatments
35%) to survive and keep both legs during the
follow-up period. In clinical practice, iloprost seems D7.7.1 Hyperbaric oxygen
to be of benefit to about 40% of patients in whom A Cochrane review160 concluded that hyperbaric ther-
revascularization is not possible. In a recent trial of apy significantly reduced the risk of major amputation
lipo-ecraprost versus placebo, this prostanoid failed in patients with diabetic ulcers. However, the results
to reduce death and amputation during 6 months fol- should be interpreted with caution because of method-
low-up.155 Prediction of response is, however, difficult ological shortcomings. Other pathologies related to
and prostanoids are rarely used due to these facts. PAD and diabetes were not evaluated using this kind
of treatment. Therefore, given the absence of proven
D7.6.2 Vasodilators benefit and high cost, this therapy is not generally rec-
Direct-acting vasodilators are of no value, as they will ommended. Nonetheless, hyperbaric oxygen may be
primarily increase blood flow to non-ischemic areas. considered in selected patients with ischemic ulcers
who have not responded to, or are not candidates
D7.6.3 Antiplatelet drugs for, revascularization.
Although long-term treatment with aspirin/ASA and
ticlopidine may reduce progression of femoral athero-
D7.7.2 Spinal cord stimulation
sclerosis and exert a beneficial effect on the patency of-
A Cochrane review161 of six studies including patients
peripheral by-passes (Cochrane review156) there is no
with CLI concluded that spinal cord stimulation was
evidence that these drugs would improve outcomes
significantly better than conservative treatment in im-
in CLI. However, as in all patients with PAD, antiplate-
proving limb salvage in patients without any option
let drugs do reduce the risk of systemic vascular events.
to vascular reconstruction.
D7.6.4 Anticoagulants
Unfractionated heparin is frequently used as prophy- D8 Health Economics
laxis and as adjuvant treatment to vascular surgical
procedures, but has not been tried for symptoms of Studies published on the cost of treating CLI present
CLI. Two studies have looked at low molecular weight data on surgical revascularization, percutaneous
heparin (LMWH) in CLI patients with ulcers. These transluminal angioplasty and stenting and primary
were negative trials. Vitamin K antagonists have not amputation.162e166
been tried for the treatment of symptoms of CLI. Whatever the treatment considered, the costs are
Defibrinating agents have not been shown to im- multiplied by a factor 2 to 4 when the procedure ini-
prove healing of ischemic ulcers or to reduce the number tially planned has failed for, example angioplasty
of amputations. requiring immediate or delayed crossover grafting,
bypass requiring revision after thrombosis or second-
D7.6.5 Vasoactive drugs
ary amputation, and when renal and pulmonary co-
A Cochrane review157 evaluated eight trials on intra-
morbidities or complications are present. Results are
venous naftidrofuryl for CLI. The drug was not effec-
consistent across countries, although individual costs
tive in reducing the symptoms of CLI. Pentoxifylline
of procedures vary. The order of magnitude for the
was evaluated in two placebo controlled studies in
cost of PTA is $10,000 ($20,000 if the procedure fails
patients with CLI, with inconclusive results.158,159
initially or later), the cost for bypass grafting is
$20,000 ($40,000 if revision is required), the cost for
Recommendation 28. Use of prostanoids in criti- amputation is $40,000. Adding rehabilitation will
cal limb ischemia (CLI) usually double the costs.

 Previous studies with prostanoids in CLI sug-

gested improved healing of ischemic ulcers D9 Future Aspects of Treatment of Critical
and reduction in amputations [A]. Limb Ischemia
 However, recent trials do not support the ben-
efit of prostanoids in promoting amputation- The most striking feature of CLI is the dismal progno-
free survival [A]. sis for both life and limb outcomes no matter what
 There are no other pharmacotherapies that can treatment is employed. This is because most patients
be recommended for the treatment of CLI [B]. have generalized atherosclerosis. One may, therefore,
consider what magnitude of treatment options is

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S41

realistic for the single patient. A successful revascular- E2 Evaluation

ization may reduce pain and improve quality of life
for a limited period of time, but frequently this goal E2.1 Clinical evaluation of acute limb ischemia
is not achieved. Amputation may be a good alterna-
tive to reduce pain, though amputees may have an E2.1.1 History
even more reduced life expectancy. Medical The history should have two primary aims: querying
treatment that favorably modifies cardiovascular risk leg symptoms relative to the presence and severity of
is recommended for all patients, while symptomatic limb ischemia (present illness) and obtaining back-
treatment of the limb has to be individualized. ground information (e.g. history of claudication, recent
Preliminary trials of intramuscular gene transfer intervention on the proximal arteries or diagnostic
utilizing naked plasmid DNA encoding phVEGF165 cardiac catheterization), pertaining to etiology, differ-
have given promising results on symptoms of CLI167 ential diagnosis and the presence of significant con-
while others have been negative. Several trials are us- current disease.
ing viral vectors to increase gene transfer efficiency. Present illness
Besides vascular endothelial growth factor (VEGF), Leg symptoms in ALI relate primarily to pain or
fibroblast growth factor, angiopoietin and other growth function. The abruptness and time of onset of the
factors are under investigation.168 Preliminary trials of pain, its location and intensity, as well as change in
intramuscular injection of autologous bone-marrow severity over time, should all be explored. The
mononuclear cells to stimulate vascular growth169 duration and intensity of the pain and presence of
have been promising. Most trials are in Phase I or II motor or sensory changes are very important in clini-
and the appropriate use of gene therapy in vascular cal decision-making and urgency of revascularization.
practice remains to be proven. For example, thrombolysis may be less effective for
In conclusion, there is low-level evidence for spinal thrombosis of >2 weeks duration compared with
cord stimulation to improve outcome of patients with more acute thrombosis (post hoc analysis of the
CLI, should revascularization not be possible. Prosta- STILE data174).
noid treatment may also be of value; however, only Past history
a limited proportion of patients will respond to this It is important to ask whether the patient has had
treatment, as mentioned. Results of other pharmaco- leg pain before (e.g. a history of claudication),
therapies are far from good.170,171 Gene therapy has whether there have been interventions for ‘poor circu-
shown promising early efficacy but further trials lation’ in the past, and whether the patient has been
are warranted. diagnosed as having heart disease (e.g. atrial fibrilla-
tion) or aneurysms (i.e. possible embolic sources). The
patient should also be asked about serious concurrent
SECTION E e ACUTE LIMB ISCHEMIA
disease or atherosclerotic risk factors (hypertension,
diabetes, tobacco abuse, hyperlipidemia, family
E1 Definition and Nomenclature for Acute history of cardiovascular disease, strokes, blood clots
Limb Ischemia or amputations). A more complete discussion of risk
factors can be found in section A.
E1.1 Definition/etiology of acute limb ischemia
E2.1.2 Physical examination
Acute limb ischemia (ALI) is any sudden decrease in The findings of ALI may include ‘‘5 P’s’’:
limb perfusion causing a potential threat to limb via-
bility. Presentation is normally up to 2 weeks follow-  Pain: time of onset, location and intensity, change
ing the acute event. Fig. E1 shows the frequency of over time
different etiologies for ALI.  Pulselessness: the accuracy of pedal pulse palpation
Timing of presentation is related to severity of is highly variable and, therefore, absent pulse find-
ischemia and access to healthcare. Patients with em- ings are suggestive but not diagnostic of ALI and pal-
bolism, trauma, peripheral aneurysms with emboli pable pulses alone do not rule it out. Bedside
and reconstruction occlusions tend to present early measurement of ankle blood pressure should be per-
(hours) due to lack of collaterals, extension of throm- formed immediately (technique see section C). Usu-
bus to arterial outflow, or a combination of both. On ally, very low pressure is obtained or the Doppler
the other hand, later presentations e within days e signal may be absent. If performed correctly, the find-
tend to be restricted to those with a native thrombosis ing of absent flow signals in the foot arteries is highly
or reconstruction occlusions (Fig. E2). consistent with a diagnosis of ALI

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S42 L. Norgren and W. R. Hyatt et al.

Fig. E1. Etiology of acute limb ischemia. (Summarizes Berridge et al. 2002 and Campbell et al. 1998172,173).

 Pallor: change in color and temperature is a com- The three findings that help separate ‘threatened’
mon finding in ALI (although temperature may be from ‘viable’ extremities (Table E1) are:
subject to environmental conditions); the finding is
most important when different from the contralat-  Presence of rest pain,
eral limb. Venous filling may be slow or absent  Sensory loss, or
 Paresthesia: numbness occurs in more than half of  Muscle weakness
patients
 Paralysis: is a poor prognostic sign Muscle rigor, tenderness, or findings of pain with
passive movement are late signs of advanced ischemia
and probable tissue loss.
Recommendation 29. Assessment of acute limb
ischemia (ALI)
Recommendation 30. Cases of suspected acute
 Due to inaccuracy of pulse palpation and the limb ischemia (ALI)
physical examination, all patients with sus-
pected ALI should have Doppler assessment  All patients with suspected ALI should be eval-
of peripheral pulses immediately at presenta- uated immediately by a vascular specialist who
tion to determine if a flow signal is present [C]. should direct immediate decision making and
perform revascularization because irreversible
nerve and muscle damage may occur within
E2.1.3 Clinical classification of acute limb ischemia hours [C].
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 deci-
sions. Is the limb viable (if there is no further progres- Data presented summarize both registry and clini-
sion in the severity of ischemia), is its viability cal trial data and show the frequency of different cat-
immediately threatened (if perfusion is not restored egories of acute limb ischemia on presentation
quickly), or are there already irreversible changes (Fig. E3).
that preclude foot salvage?

Fig. E2. Time to presentation in relation to etiology.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S43

Table E1. Separation of threatened from viable extremities175

Category Description/prognosis Findings Doppler signalsy

Sensory loss Muscle weakness Arterial Venous
I. Viable Not immediately threatened None None Audible Audible
II. Threatened
a. Marginal Salvageable if promptly Minimal (toes) or none None (Often) inaudible Audible
treated
b. Immediate Salvageable with immediate More than toes, associated Mild, moderate (Usually) inaudible Audible
revascularization with rest pain
III. Irreversible Major tissue loss or Profound, anesthetic Profound, Inaudible Inaudible
permanent nerve damage paralysis (rigor)
inevitable
y
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):517e538.

 Category III: all patients from registries who un- invasive diagnosis and treatment who present with
dergo primary amputation femoral artery occlusion.
 Category II: all patients from randomized trials who Thoracic aortic dissections may progress distally to
present with sensory loss involve the abdominal aorta and also an iliac artery.
 Category I: all patients from randomized trials who Tearing interscapular or back pain associated with hy-
present without sensory loss pertension would obviously point to such a thoracic
aortic dissection, but these may be obscured by other
E2.1.4 Differential diagnosis of acute limb ischemia events and the patient’s inability to give a good his-
There are three levels of differential diagnosis in ALI: tory. It should be considered when faced with acute
unilateral or bilateral iliac occlusion.
Ergotism
1. Is there a condition mimicking arterial occlusion?
Ergotism is rare. It may affect almost any artery
2. Are there other non-atherosclerotic causes of arte-
and may progress to thrombosis but rarely presents
rial occlusion present and, if not,
as an immediately threatened limb.
3. Is the ischemia caused by an arterial thrombosis or
HIV arteriopathy
embolus?
HIV patients with severe immune compromise and
CD4 counts less than 250/cm3 can develop acute
The conditions that can cause or mimic acute ischemia of upper or lower extremities. This entity
arterial occlusion are listed in Table E2. involves the distal arteries with an acute and chronic
Arterial trauma or dissection cellular infiltrate in the vasa vasorum and viral protein
Overt arterial trauma is not difficult to diagnose, in the lymphocytes. Occasionally, a hypercoaguable
but iatrogenic trauma, especially as a result of recent focus is found, but primarily the occlusion appears
arterial catheterization, is often overlooked. It should due to the underlying vasculopathy. Standard therapies
be considered in all hospitalized patients undergoing including thrombectomy, bypass and thrombolysis

Fig. E3. Categories of acute limb ischemia on presentation. *Some of these patients are moribund. In some series this group
is up to 15%.

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S44 L. Norgren and W. R. Hyatt et al.

Table E2. Differential diagnosis of acute limb ischemia leg may help to identify the cause. These patients also
*Conditions mimicking acute limb ischemia tend to have dilated femoral arteries and may have
- Systemic shock (especially if associated with chronic abdominal aortic aneurysms. Once suspected, duplex
occlusive disease) ultrasound is the quickest way to confirm the diagnosis.
- Phlegmasia cerulea dolens
- Acute compressive neuropathy
Thromboembolism
Arterial embolism is suspected in patients with
Differential diagnosis for acute limb ischemia (other than atrial arrhythmia (flutter/fibrillation), congestive
acute PAD)
- Arterial trauma
heart failure, or valvular heart disease. A rare cause
- Aortic/arterial dissection can be paradoxical embolization in a patient with ve-
- Arteritis with thrombosis (e.g. giant cell arteritis,
nous thromboembolism and a cardiac septal defect.
thromboangiitis obliterans)
- HIV arteriopathy
The contralateral limb is often normal. Patients usu-
- Spontaneous thrombosis associated with a hypercoagulable ally do not have any antecedent claudication symp-
state toms. Arteriographic findings include multiple areas
- Popliteal adventitial cyst with thrombosis
- Popliteal entrapment with thrombosis
with arterial filling defects (particularly at bifurca-
- Vasospasm with thrombosis (e.g. ergotism) tions), morphology (meniscus sign) consistent with
- Compartment syndrome
embolus, lack of collaterals and absence of atheroscle-
Acute PAD rotic disease in unaffected segments. Echocardiogra-
- Thrombosis of an atherosclerotic stenosed artery phy (often transesophageal) is useful to locate the
- Thrombosis of an arterial bypass graft
source of thromboemboli.
- Embolism from heart, aneurysm, plaque or critical stenosis
upstream (including cholesterol or atherothrombotic emboli Atheroembolism
secondary to endovascular procedures) Embolism of cholesterol crystals and other debris
- Thrombosed aneurysm with or without embolization
from friable atherosclerotic plaques in proximal ar-
*
Two of the three conditions (deep vein thrombosis, neuropathy) teries may lodge in the distal circulation and infarct
that may mimic arterial occlusion should be expected to have arte- tissue. Although also called ‘‘blue toe syndrome’’ for
rial pulses, except if occult chronic peripheral arterial disease
existed prior to the acute event. Low cardiac output makes the
the appearance of painful cyanotic lesions on the
chronic arterial ischemia more manifest in terms of symptoms toes of affected patients, more proximal organs such
and physical findings. as the kidneys, bowel and pancreas may also be
affected by atheroemboli.
have been used, with relatively high reocclusion and Thrombosed arterial segment
amputation rates. Patients with thrombosed arterial segments often
Popliteal adventitial cysts and popliteal entrapment have atherosclerotic disease at the site of thrombosis.
Popliteal adventitial cysts and popliteal entrap- They may have an antecedent history of claudication
ment may be discovered before they induce throm- and the contralateral limb often has abnormal circula-
bosis if they cause claudication, but they sometimes tion. Some hypercoagulable states, such as antiphos-
first present with thrombosis. Like a thrombosed pholipid antibody syndrome or heparin-induced
popliteal aneurysm, the degree of ischemia is often thrombocytopenia can also cause thrombosis in situ,
severe. Popliteal entrapment affects younger pa- and these should be considered in patients without
tients, but popliteal adventitial cysts can present at other overt risk factors for arterial disease.
an older age and may be indistinguishable from Thrombosed arterial bypass graft
peripheral arterial disease (PAD). The absence of ath- Patients with thrombosed arterial bypass grafts
erosclerotic risk factors and the location of the have a prior history of vascular disease, limb incisions
obstruction, best ascertained by duplex scan, should from previous surgery and a thrombosed graft that
suggest the etiology. can be visualized on duplex imaging.
Thrombosed popliteal artery aneurysm Compartment syndrome
Thrombosed popliteal artery aneurysms are com- See section E3.7.1.
monly mistaken for acute arterial embolism. The popli-
teal artery is the sole axial artery traversing the knee.
Severe ischemia results either because thrombosis E2.2 Investigations for acute limb ischemia
occurs in the absence of previous arterial narrowing
and the lack of collateral vessels or because prior Patients with ALI should be evaluated in the same
asymptomatic or symptomatic embolization has oc- fashion as those with chronic symptoms (see section
cluded the majority of the tibial outflow. As popliteal G) but the severity and duration of ischemia at the
aneurysms are bilateral in approximately 50% of cases, time of presentation rarely allow this to be done at
detecting a prominent popliteal pulse in the opposite the outset. Ideally, all patients with acute ischemia

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S45

should be investigated with imaging, however, the E3 Treatment of Acute Limb Ischemia
clinical condition and access to appropriate medical
resources may preclude such investigations. The initial goal of treatment for ALI is to prevent throm-
bus propagation and worsening ischemia. Therefore,
immediate anticoagulation with heparin is indicated.
E2.2.1 Other routine laboratory studies The standard therapy (except in cases of heparin anti-
The following laboratory studies should be obtained bodies) is unfractionated heparin intravenously
in patients with ALI: electrocardiogram, standard (Fig. E4). Based on the results of randomized trials,172
chemistry, complete blood count, prothrombin time, there is no clear superiority for thrombolysis versus
partial thromboplastin time and creatinine phosphoki- surgery on 30 day limb salvage or mortality. Access to
nase level. Patients with a suspected hypercoagulable each is a major issue, as time is often critical. National
state will need additional studies seeking anticardioli- registry data from Europe176 and the United States177
pin antibodies, elevated homocysteine concentration indicate that surgery is used three- to five-fold more
and antibody to platelet factor IV. frequently than thrombolysis.

E3.1 Endovascular procedures for acute limb ischemia

E2.2.2 Imaging e arteriography
Arteriography is of major value in localizing an ob-
E3.1.1 Pharmacologic thrombolysis
struction and visualizing the distal arterial tree. It
Three randomized studies have confirmed the im-
also assists in distinguishing patients who will bene-
portant role of catheter-directed thrombolytic
fit more from percutaneous treatment than from
therapy in the treatment of ALI.174,178,179 The less in-
embolectomy or open revascularization procedures.
vasive nature of a catheter-based approach to this
In limb-threatening ischemia, an important consider-
patient population can result in reduced mortality
ation is whether the delay in performing formal angio-
and morbidity compared with open surgery. Throm-
graphy in an angiographic suite can be tolerated.
bolytic therapy is, therefore, the initial treatment of
Angiography makes the most sense when catheter-based
choice in patients in whom the degree of severity
treatment is an option.
allows time (i.e. severity levels I and IIa). More re-
cent advances in endovascular devices and tech-
E2.2.3 Other imaging techniques niques, however, allow for more rapid clot removal
Computed tomographic angiography/Magnetic resonance and may permit treatment of patients with more ad-
angiography vanced degree of ischemia. Advantages of thrombo-
Computed tomographic angiography (CTA) and lytic therapy over balloon embolectomy include the
magnetic resonance (MR) angiography may also be reduced risk of endothelial trauma and clot lysis in
used in the setting of ALI to diagnose and delineate branch vessels too small for embolectomy balloons.
the extent of disease. MR imaging of the vasculature Gradual low-pressure reperfusion, may be advanta-
can be cumbersome and time-consuming which may geous to the sudden, high-pressure reperfusion
delay treatment. The advantages of CTA include its associated with balloon embolectomy. Systemic throm-
speed, convenience and ability for cross-sectional bolysis has no role in the treatment of patients with ALI.
imaging of the vessel. The main disadvantage of The choice of lytic therapy depends on many factors
CTA is its dependence on iodinated contrast media. such as location and anatomy of lesions, duration of
In patients with ALI who may also require catheter the occlusion, patient risk factors (co-morbidities)
angiography and intervention, this added load of and risks of procedure. Because emboli newly arrived
contrast might increase the risk of renal injury to in the leg may have previously resided for some time
the patient. at their site of origin, these ‘old’ emboli may be more
resistant to pharmacological thrombolysis than ‘re-
cent’ in-situ thrombus. Contraindications to pharma-
Recommendation 31. Anticoagulant therapy in cologic thrombolysis must be taken into consideration.
acute limb ischemia (ALI)
E3.1.2 Contraindications to thrombolysis
 Immediate parenteral anticoagulant therapy is See Table E3
indicated in all patients with ALI. In patients
expected to undergo imminent imaging/ E3.1.3 Other endovascular techniques
therapy on arrival, heparin should be given [C]. When thrombolysis reveals underlying localized
arterial disease, catheter-based revascularization

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S46 L. Norgren and W. R. Hyatt et al.

Fig. E4. Algorithm for management of acute limb ischemia. Category I e Viable Category IIA e Marginally Threatened
Category IIB e Immediately Threatened; a Confirming either absent or severely diminished ankle pressure/signals; *In
some centers imaging would be performed.

becomes an attractive option. Stenoses and occlusions speed up clot lysis, which is important in
are rarely the sole cause of ALI or even severe chronic more advanced ALI where time to revascularization
symptoms but these commonly lead to superimposed is critical. In practice, the combination is almost
thrombosis and, therefore, should be treated to avoid always used.
recurrent thrombosis. Percutaneous aspiration thrombectomy (PAT)
Percutaneous aspiration thrombectomy (PAT) and PAT is a technique that uses thin-wall, large-lumen
percutaneous mechanical thrombectomy (PMT) pro- catheters and suction with a 50-mL syringe to remove
vide alternative non-surgical modalities for the treat- embolus or thrombus from native arteries, bypass
ment of ALI without the use of pharmacologic grafts and run-off vessels. It has been used together
thrombolytic agents. Combination of these techniques with fibrinolysis to reduce time and dose of the
with pharmacologic thrombolysis may substantially fibrinolytic agent or as a stand-alone procedure.
Percutaneous mechanical thrombectomy (PMT)
Table E3. Contraindications to thrombolysis Most PMT devices operate on the basis of hydrody-
namic recirculation. According to this concept, disso-
Absolute contraindications lution of the thrombus occurs within an area of
1. Established cerebrovascular event (excluding TIA within previous
2 months) continuous mixing referred to as the ‘‘hydrodynamic
2. Active bleeding diathesis vortex.’’ This selectively traps, dissolves, and evacu-
3. Recent gastrointestinal bleeding (within previous 10 days) ates the thrombus. Non-recirculation devices, which
4. Neurosurgery (intracranial, spinal) within previous 3 months
5. Intracranial trauma within previous 3 months function primarily by direct mechanical thrombus
Relative contraindications
fragmentation, have been used less frequently for pe-
1. Cardiopulmonary resuscitation within previous 10 days ripheral arterial disease because of the higher risk of
2. Major nonvascular surgery or trauma within previous 10 days peripheral embolization and higher potential for vas-
3. Uncontrolled hypertension (systolic >180 mmHg or diastolic
>110 mmHg)
cular injury. The efficiency of PMT depends mainly on
4. Puncture of noncompressible vessel the age of the thrombus; fresh thrombus responds bet-
5. Intracranial tumor ter than older organized clot. Small clinical series have
6. Recent eye surgery
demonstrated short-term (30 day) limb salvage of
Minor contraindications 80%e90%.
1. Hepatic failure, particularly those with coagulopathy
2. Bacterial endocarditis
3. Pregnancy
4. Active diabetic proliferative retinopathy E3.2 Surgery
These contraindications were established for systemic thrombolysis.
The markedly improved safety profile of regional thrombolysis is E3.2.1 Indications
well recognized, and the risk benefit of regional thrombolysis in Immediate revascularization is indicated for the pro-
various above conditions is highly dependent on individual physi-
cian practice/experience. The only contraindication in the TOPAS foundly ischemic limb (class IIb) (Table E1). It may
trial was pregnancy. also be considered in those with profound sensory

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S47

and motor deficits of very short duration, as revascu- E3.2.2 Surgical technique
larization completed within a few hours of onset of Emboli are preferentially removed surgically if they
severe symptoms may produce remarkable recovery. are lodged proximally in the limb or above the ingui-
Beyond this short window, major neuromuscular nal ligament. Surgery may also be considered if the
damage is inevitable. The method of revascularization involved limb has no underlying atherosclerosis.
(open surgical or endovascular) may differ depending When no further clot can be retrieved, some form of
on anatomic location of occlusion, etiology of intraoperative assessment of the adequacy of clot re-
ALI, contraindications to open or endovascular treat- moval is required. The most common of these is
ment and local practice patterns. Previously, urgency ‘completion’ angiography; alternatively, ultrasound-
of treatment made surgery the treatment of choice based methods may be used.
in many cases. However, recent methodological Distal clot may be treated by intraoperative throm-
advances within endovascular management, and rec- bolysis with instillation of high doses of thrombolytic
ognition that improved circulation significantly pre- agents for a brief period followed by irrigation or addi-
cedes patency with this approach, have made the tional passages of the balloon catheter. Repeat angio-
time factor less important if endovascular service is graphy followed by clinical and Doppler examination
readily available. of the patient should be performed on the operating
In considering operative versus percutaneous re- table. However, as described in section E3.2.1,
vascularization, it must be recognized that the time catheter-directed thrombolysis may have advantages
from the decision to operate until reperfusion may if conditions allow its use.
be substantially longer than anticipated because of In patients with arterial thrombosis, an underlying
factors outside of the surgeons’ control (e.g. operating local lesion and residual thrombus must be sought af-
theater availability, anesthesia preparation, technical ter clot extraction. Often this may be suspected from
details of the operation). the tactile sensations and need for deflation at points
Anatomic location of the acute occlusion during the withdrawal of the inflated balloon catheter.
In cases of suprainguinal occlusion (no femoral Here completion angiography will help decide be-
pulse) open surgery may be the preferred choice of tween proceeding with a bypass or PTA. Fortunately,
treatment. For instance, a large embolus in the com- arterial thrombosis superimposed on an already nar-
mon proximal iliac artery or distal aorta may most rowed artery will ordinarily cause a less severe degree
effectively be treated with catheter embolectomy. of ischemia because of predeveloped collaterals. Un-
Also, suprainguinal graft occlusion may best be der these circumstances, patients may not be operated
treated with surgery in most cases. Endovascular on initially but rather undergo catheter-directed
management with femoral access of a proximal lesion lytic therapy.
(often involving thrombosis) may not be possible/ In patients with suprainguinal occlusion extra-
appropriate or available (see below). anatomic bypass surgery may be required.
Infrainguinal causes of ALI, such as embolism or
thrombosis, are often treated with endovascular
methods. Initial therapy with catheter-based thrombol-
ysis should be considered in cases of acute thrombosis Recommendation 32. Completion arteriography
due to vulnerable atherosclerotic lesions or late bypass
graft failures. In this manner, the underlying occlusive  Unless there is good evidence that adequate
disease is revealed and appropriate adjunctive circulation has been restored, intraoperative
management may be chosen. angiography should be performed to identify
In cases of trauma, for many reasons, surgery will any residual occlusion or critical arterial lesions
be the treatment of choice in the majority of cases. requiring further treatment [C].
Infrainguinal grafts often occlude due to obstructive
lesions proximal to, within and distal to the graft,
thus, simple thrombectomy will not solve the under-
lying lesion. Catheter-based thrombolysis, on the E3.3 Results of surgical and endovascular procedures
other hand, will dissolve clot and identify the for acute limb ischemia
responsible underlying lesion. Endovascular treatment
of these lesions may then be employed. If the lesion is Catheter-directed thrombolysis (CDT) has become
discrete this may suffice, and even if the underlying a commonly employed technique in the treatment of
disease is diffuse and extensive, it may serve as a ALI. Between 1994 and 1996, three large, prospective,
temporizing measure, a bridge to a later bypass. randomized trials174,178,179 were reported that focused

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S48 L. Norgren and W. R. Hyatt et al.

on the comparison of CDT and surgical revasculariza- E3.4 Management of graft thrombosis
tion for treatment of ALI. Limb salvage and mortality
rates are recognized as the most important outcome, In general, at least one attempt to salvage a graft
and the 1-year data are summarized in Table E4.172 should be done, although individual considerations
Comparison of these studies is limited by certain may apply. When treating late graft thrombosis, the
differences in protocol and case mix (e.g. acute vs. main goals are to remove the clot and correct the un-
subacute or chronic limb ischemia; thrombotic vs. derlying lesion that caused the thrombosis. Alteration
embolic occlusion; native vs. bypass graft occlusion; in the inflow and outflow arteries is usually caused
proximal vs. distal occlusions). End points in each by the progression of atherosclerosis and should be
of the studies also vary: the Rochester study used treated with either PTA/stent or bypass grafting, as
‘‘event free survival’’; the STILE trial used ‘‘compos- detailed elsewhere. Lesions intrinsic to the graft are
ite clinical outcome’’; and the TOPAS study used dependent on the type of conduit. Venous bypass
‘‘arterial recanalization and extent of lysis.’’ Only grafts may develop stenoses, typically at the site of
the Rochester trial showed any advantage for CDT a valve. After thrombolysis and identification of the
by primary end points. However, the late end point lesion, it may be treated with either PTA/stent or sur-
of limb salvage, required in these trials, may have gical revision, the latter usually being favored for its
favored surgery, as CDT was naturally linked with superior long-term results. Prosthetic grafts develop
endovascular treatment of the underlying lesions intimal hyperplasia, typically at the distal anastomo-
(the patient being in a radiology suite at the time). sis. These rubbery lesions respond differently to PTA
Except for discrete lesions, PTA is not as durable than do the typical eccentric atherosclerotic plaque
as bypass, the inevitable result of being randomized and do not yield as durable results. Many surgeons
to surgery. Such linkage may be inevitable in have suggested that treatment should be exposure of
randomized trials, but in practice the underlying le- the involved anastomosis, with graft thrombectomy
sion(s) should be treated by the method giving the and patch angioplasty of the narrowed graft/artery
most durable results. anastomosis or replacement of the graft. However, in
The data from the randomized, prospective studies case of the latter, the expected patency using another
in ALI, suggest that CDT may offer advantages when type of graft should be considered (i.e. replacing a
compared with surgical revascularization. These ad- failing vein graft).
vantages include reduced mortality rates and a less
complex surgical procedure in exchange for a higher E3.5 Management of a thrombosed popliteal aneurysm
rate of failure to avoid persistent or recurrent ische-
mia, major complications and ultimate risk of ampu- Patients with thrombosed popliteal artery aneurysms
tation. In addition, it appears that reperfusion initially undergo arteriography. If a distal tibial target
with CDT is achieved at a lower pressure and may is present, then they are treated as a critical limb is-
reduce the risk of reperfusion injury compared to chemia case with tibial bypass. If no tibial targets
open surgery. Thus, if the limb is not immediately or are identified on arteriography, regional thrombolysis
irreversibly threatened, CDT offers a lower-risk is the treatment of choice providing the limb is viable.
opportunity for arterial revascularization. Using this Small series demonstrate successful identification of
approach, the underlying lesions can be further tibial targets in over 90% and successful surgical
defined by angiography, and the appropriate percuta- revascularization.
neous or surgical revascularization procedure can be
performed. Therefore, it seems reasonable to recom- E3.6 Amputation
mend CDT as initial therapy in these particular
settings, to be potentially followed by surgical Amputation in ALI may be complicated by bleeding
revascularization as needed. due to an increased prevalence of concomitant

Table E4. Comparison of catheter-directed thrombolysis and surgical revascularization in treatment of limb ischemia

Results at Catheter-Directed Thrombolysis (CDT) Surgical Revascularization

Patients Limb salvage Mortality Patients Limb salvage Mortality
Rochester178 12 months 57 82% 16% 57 82% 42%
STILE174 6 months 246 88.2% 6.5% 141 89.4% 8.5%
TOPAS179 12 months 144 82.7% 13.3% 54 81.1% 15.7%

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S49

anticoagulation. In addition, the site of amputation is alkalinizing the urine and eliminating the source of
more often proximal, as the calf muscle is usually myoglobin. Mannitol and plasmapheresis have not
compromised. The ratio of above-knee to below- been found to be beneficial.
knee amputation is 4:1 compared to the usual 1:1 for
critical limb ischemia. The incidence of major amputa-
tion is up to 25%. When further evaluated, 10%e15% E4 Clinical Outcomes
of patients thought to be salvageable undergo therapy
and ultimately require major amputation, and 10% of E4.1 Systemic/limb
patients with ALI present unsalvageable.
Mortality rates for ALI range from 15%e20%. The
cause of death is not provided in most series and ran-
E3.7 Immediate post-procedural issues domized trials. Major morbidities include major
bleeding requiring transfusion/and or operative in-
E3.7.1 Reperfusion injury tervention in 10%e15%, major amputation in up to
Compartment syndrome 25%, fasciotomy in 5%e25% and renal insufficiency
Fasciotomy following successful revascularization in up to 20%. Functional outcomes have at present
for ALI was required in 5.3% of cases in the United not been studied.
States from 1992e2000. Fasciotomy for presumably Improvement in arterial circulation is relatively sim-
more severe cases in tertiary referral hospitals is ple to assess in that the vast majority of patients with
25%.177 With extremity reperfusion, there is increased ALI have no pedal Doppler signals at presentation
capillary permeability, resulting in local edema and or they have an ankle-brachial index (ABI) 0.20.
compartment hypertension. This leads to regional ve- Therefore, any improvement in these parameters
nule obstruction, nerve dysfunction and, eventually, postoperatively is considered successful.
capillary and arteriolar obstruction and muscle and
nerve infarction. Clinical presentation includes pain E4.2 Follow-up care
out of proportion to physical signs, paresthesia and
edema. Compartment pressures can be measured, All patients should be treated with heparin in the im-
and pressures of 20 mmHg are a clear indication mediate postoperative period. This should be fol-
for fasciotomy. The anterior compartment is most lowed by warfarin often for 3e6 months or longer.
commonly involved, but the deep posterior compart- Patients with thromboembolism will need long-term
ment (in which the tibial nerve is located) is the most anticoagulation, from years or life long. However,
functionally devastating if affected. there are no clear guidelines regarding duration of
therapy. The risk of recurrent limb ischemia in the
Recommendation 33. Treatment of choice for randomized trials was high during the follow-up
compartment syndrome interval.174,178,179 Therefore, prolonged warfarin
therapy is an appropriate strategy, despite the cumu-
 In case of clinical suspicion of compartment lative bleeding risk. It is important to seek the source
syndrome, the treatment of choice is a four- of embolism after revascularization, whether cardiac
compartment fasciotomy [C]. or arterial; however, in many cases no source
is identified.
Certainly, if long-term anticoagulation is contrain-
Rhabdomyolysis dicated, due to bleeding risk factors, platelet inhibi-
Laboratory evidence for myoglobinuria is observed tion therapy should be considered. Appropriate
in up to 20%. Half of patients with creatine kinase systemic therapies as outlined above (see section B)
levels >5000 units/L will develop acute renal failure. should be provided.
Urine myoglobin >1142 nmol/L (>20 mg/dL) is also
predictive of acute renal failure. The pathophysiology E5 Economic Aspects of Acute Limb Ischemia
involves tubular necrosis by myoglobin precipitates
(favored in a acidic urine), tubular necrosis due to The recent literature has added very little to the find-
lipid peroxidation and renal vasoconstriction (exacer- ings presented in the first TASC document. When
bated by fluid shifts into the damage muscle compart- thrombolysis is used in association with angioplasty,
ment). Clinical features include tea colored urine, the costs are identical to those of surgical revasculari-
elevated serum creatine kinase and positive urine zation at roughly $20,000. The relative benefits of
myoglobin assay. Therapy is primarily hydration, surgery have been discussed above. The choice of

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S50 L. Norgren and W. R. Hyatt et al.

strategy is based on availability and outcome rather of the diseased segment), the degree of systemic
than on cost considerations.180 disease (co-morbid conditions that may affect life ex-
pectancy and influence graft patency) and the type
E6 Future Management of procedure performed. Results of large-scale clinical
trials must be considered within the context of the
The increased use of percutaneous therapies with or individual patient’s situation, considering all co-
without surgical revascularization is the trend for fu- morbidities when deciding upon a recommended
ture therapy in ALI. The use of protection devices to treatment course for that individual.
prevent embolization, as in the carotid circulation, The endovascular techniques for the treatment of pa-
will also become part of therapy. Alternative oral tients with lower extremity ischemia include balloon
therapies for anticoagulation may hold promise. angioplasty, stents, stent-grafts and plaque debulking
procedures. Thrombolysis and percutaneous throm-
bectomy have been described in the section on
SECTION F e REVASCULARIZATION acute limb ischemia. Surgical options include autoge-
nous or synthetic bypass, endarterectomy or an intra-
F1 Localization of Disease operative hybrid procedure.
Outcomes of revascularization procedures depend
The determination of the best method of revasculari- on anatomic as well as clinical factors. Patency following
zation for treatment of symptomatic peripheral arte- percutaneous transluminal angioplasty (PTA) is highest
rial disease (PAD) is based upon the balance between for lesions in the common iliac artery and progressively
risk of a specific intervention and the degree and dura- decreases for lesions in more distal vessels. Anatomic
bility of the improvement that can be expected from this factors that affect the patency include severity of disease
intervention. Adequate inflow and appropriate out- in run off arteries, length of the stenosis/occlusion and
flow are required to keep the revascularized segment the number of lesions treated. Clinical variables impact-
functioning. The location and morphology of the ing the outcome also include diabetes, renal failure,
disease must be characterized prior to carrying out smoking and the severity of ischemia.
any revascularization to determine the most appropri-
ate intervention. A variety of methods yielding both
anatomic and physiologic information are available to
assess the arterial circulation. (Refer to section G for Recommendation 35. Choosing between tech-
preferred imaging techniques.) niques with equivalent short- and long-term clin-
In a situation where a proximal stenosis is of ques- ical outcomes
tionable hemodynamic significance, pressure measure-
ments across it to determine its significance (criteria:  In a situation where endovascular revasculari-
threshold peak systolic difference 5e10 mmHg pre- zation and open repair/bypass of a specific le-
vasodilatation and 10e15 mmHg post-vasodilatation) sion causing symptoms of peripheral arterial
may be made. A recent development, that is yet to be disease give equivalent short-term and long-
validated, is direct flow measurements using a thermo- term symptomatic improvement, endovascular
dilution catheter rather than pressure gradients. techniques should be used first [B].
Hyperemic duplex scanning has also been suggested.

F1.1 Classification of lesions

Recommendation 34. Intra-arterial pressure mea-
surements for assessment of stenosis While the specific lesions stratified in the following
TASC classification schemes have been modified
 If there is doubt about the hemodynamic signif- from the original TASC guidelines to reflect inevitable
icance of partially occlusive aortoiliac disease, technological advances, the principles behind the clas-
it should be assessed by intra-arterial pressure sification remain unchanged. Thus ‘A’ lesions repre-
measurements across the stenosis at rest and sent those which yield excellent results from, and
with induced hyperemia [C]. should be treated by, endovascular means; ‘B’ lesions
offer sufficiently good results with endovascular
In general, the outcomes of revascularization de- methods that this approach is still preferred first,
pend upon the extent of the disease in the subjacent unless an open revascularization is required for
arterial tree (inflow, outflow and the size and length other associated lesions in the same anatomic area;

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S51

‘C’ lesions produce superior enough long-term results F2 Aortoiliac (Supra Inguinal) Revascularization
with open revascularization that endovascular
methods should be used only in patients at high risk F2.1 Endovascular treatment of aorto-iliac
for open repair; and ‘D’ lesions do not yield good occlusive disease
enough results with endovascular methods to justify
them as primary treatment. Finally it must be under- Although aortobifemoral bypass appears to have bet-
stood that most PAD requiring intervention is charac- ter long-term patency than the currently available en-
terized by more than one lesion, at more than one dovascular strategies for diffuse aortoiliac occlusive
level, so these schemes are limited by the necessity disease, the risks of surgery are significantly greater
to focus on individual lesions. than the risks of an endovascular approach, in terms
of not only mortality but also major morbidity and
F1.2 Classification of inflow (aorto-iliac) disease delay in return to normal activities. Therefore, the
(Fig. F1, Table F1) assessment of the patient’s general condition and
anatomy of the diseased segment(s) become central
in deciding which approach is warranted.
Recommendation 36. Treatment of aortoiliac
The technical and initial clinical success of PTA of
lesions
iliac stenoses exceeds 90% in all reports in the litera-
ture. This figure approaches 100% for focal iliac
 TASC A and D lesions: Endovascular therapy is lesions. The technical success rate of recanalization
the treatment of choice for type A lesions and of long segment iliac occlusions is 80%e85% with or
surgery is the treatment of choice for type D without additional fibrinolysis. Recent device devel-
lesions [C]. opments geared towards treatment of total occlusions,
 TASC B and C lesions: Endovascular treat- however, have substantially improved the technical
ment is the preferred treatment for type B success rate of recanalization.181
lesions and surgery is the preferred treatment Becker et al. found 5-year patency rate of 72% in an
for good-risk patients with type C lesions. analysis of 2697 cases from the literature, noting a bet-
The patient’s co-morbidities, fully informed ter patency of 79% in claudicants.182 Rutherford and
patient preference and the local operator’s Durham found a similar 5-year patency of 70%.183 A
long-term success rates must be considered recent study reported a primary patency of 74% (pri-
when making treatment recommendations mary assisted patency of 81%) 8 years after stent
for type B and type C lesions [C]. placement suggesting durability of patency of iliac
artery stenting.184 Factors negatively affecting the
patency of such interventions include quality of run
F1.3 Classification of femoral popliteal disease off vessels, severity of ischemia and length of diseased
(Fig. F2, Table F2) segments. Female gender has also been suggested
to decrease patency of external iliac artery stents.185
Table F3 presents the estimated success rate of iliac
Recommendation 37. Treatment of femoral popli- artery angioplasty from weighted averages (range)
teal lesions from reports of 2222 limbs.
Choice of stent versus PTA with provisional stent-
 TASC A and D lesions: Endovascular therapy is ing was addressed in a prospective randomized,
the treatment of choice for type A lesions and multicenter study.186 Results showed that PTA with
surgery is the treatment of choice for type D provisional stenting had a similar outcome to primary
lesions [C]. stenting with 2-year reintervention rates of 7% and
 TASC B and C lesions: Endovascular treat- 4%, respectively, for PTA and primary stenting (not
ment is the preferred treatment for type B le- significant). The 5-year outcomes of the groups were
sions and surgery is the preferred treatment also similar with 82% and 80% of the treated iliac
for good-risk patients with type C lesions. artery segments remaining free of revascularization
The patient’s co-morbidities, fully informed procedures after a mean follow-up of 5.6 years
patient preference and the local operator’s 1.3.187 A meta-analysis by Bosch and Hunink com-
long-term success rates must be considered pared the results of aortoiliac PTA versus aortoiliac
when making treatment recommendations stenting using a Medline search of the post-1989 liter-
for type B and type C lesions [C]. ature and yielded only six articles (including 2116
patients) with sufficient detail to allow stratification

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S52 L. Norgren and W. R. Hyatt et al.

Fig. F1. TASC classification of aorto-iliac lesions. CIA e common iliac artery; EIA e external iliac artery; CFA e common
femoral artery; AAA e abdominal aortic aneurysm.

over subgroups with various risk levels for long-term occlusion. The relative risk of long-term failure was
patency.188 Technical success was higher for stenting, reduced by 39% after stent placement compared
whereas complication rates and 30-day mortality rates with PTA. This robust report uses data from older
did not differ significantly. In patients with intermit- studies and it is reasonable to expect that the newer
tent claudication the severity-adjusted 4-year primary techniques and equipment available today would
patency rates (95% confidence intervals) after lead to even better results.
excluding technical failures, for PTA and stenting, The outcome of two different self-expanding stents
were: 68% (65%e71%) and 77% (72%e81%), respec- for the treatment of iliac artery lesions was compared
tively. Including technical failures, the 4-year primary in a multicenter prospective randomized trial.189 The
patency rates are 65% (PTA) versus 77% (stent) for 1-year primary patencies were 94.7% and 91.1% (not
stenosis and 54% (PTA) versus 61% (stent) for significant), respectively, with similar complication

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S53

Table F1. TASC classification of aorto-iliac lesions Reported 5-year primary patency rates range from
60% to 94%, reflecting a degree of variability depending
Type A lesions
- Unilateral or bilateral stenoses of CIA upon the operator.
- Unilateral or bilateral single short (3 cm) In some situations, when an abdominal approach is
stenosis of EIA to be avoided due to anatomic considerations (‘hostile
Type B lesions
- Short (3 cm) stenosis of infrarenal aorta abdomen’) or cardiac and/or pulmonary risks, a
- Unilateral CIA occlusion modified retroperitoneal approach or a unilateral by-
- Single or multiple stenosis totaling 3e pass with a femoro-femoral crossover may be used.
10 cm involving the EIA not extending
into the CFA Consideration should be given to using an axillo (bi)
- Unilateral EIA occlusion not involving the femoral (Fig. F4) or cross-over femoral (Fig. F5)
origins of internal iliac or CFA bypass in patients with increased co-morbidities,
Type C lesions
- Bilateral CIA occlusions making a transabdominal approach less desirable.
- Bilateral EIA stenoses 3e10 cm long not Patency rates depend upon the indication for the
extending into the CFA reconstruction and the justification for the unilateral
- Unilateral EIA stenosis extending into the
CFA bypass (normal inflow artery versus high surgical
- Unilateral EIA occlusion that involves the risk). In some cases, patency of unilateral bypass can
origins of internal iliac and/or CFA be supplemented by endovascular means. The
- Heavily calcified unilateral EIA occlusion
with or without involvement of origins of thoracic aorta has also been used as an inflow artery.
internal iliac and/or CFA Extra-anatomic bypass rarely performs as well as
Type D lesions aortobifemoral bypass in diffuse disease and, there-
- Infra-renal aortoiliac occlusion
- Diffuse disease involving the aorta and fore, is seldom recommended for claudication. Evi-
both iliac arteries requiring treatment dence is lacking in recommending the preferred
- Diffuse multiple stenoses involving the material for anatomic or extra-anatomic prosthetic
unilateral CIA, EIA and CFA
- Unilateral occlusions of both CIA and EIA bypass procedures. Table F4 summarizes the patency
- Bilateral occlusions of EIA at 5 and 10 years after aortobifemoral bypass and
- Iliac stenoses in patients with AAA re- Table F5 the patency rates at 5 years after extra-
quiring treatment and not amenable to
endograft placement or other lesions re- anatomic bypass.
quiring open aortic or iliac surgery

CIA e common iliac artery; EIA e external iliac artery; CFA e

common femoral artery; AAA e abdominal aortic aneurysm.
F3 Infrainguinal Revascularization

and symptomatic improvement rates regardless of the F3.1 Endovascular treatment of infrainguinal arterial
type of stent. occlusive disease

Endovascular treatment of infrainguinal disease in

F2.2 Surgical treatment of aorto-iliac occlusive disease patients with intermittent claudication is an estab-
lished treatment modality. The low morbidity and
Bilateral surgical bypass from the infra-renal abdomi- mortality of endovascular techniques such as PTA
nal aorta to both femoral arteries is usually recom- makes it to the preferred choice of treatment in lim-
mended for diffuse disease throughout the aortoiliac ited disease such as stenoses/occlusions up to 10 cm
segment (Fig. F3). The aorta may be approached via in length.
a transperitoneal or retroperitoneal approach. Interest The technical and clinical success rate of PTA of
is increasing in laparoscopic approach. The configura- femoropopliteal artery stenoses in all series exceeds
tion of the proximal anastomosis (end-to-end versus 95% (range 98%e100%, standard error 1.0%).192 De-
end-to-side) has not been reliably shown to influence vice developments such as hydrophilic guide wires
patency. The use of PTFE versus Dacron as a conduit and technical developments, such as subintimal re-
in this position is based on the preference of the sur- canalization, provide high recanalization rates in total
geon. Younger patients (<50 years of age) with lower occlusions of more than 85% (range 81%e94%, stan-
primary and secondary patency have a greater need dard error 2.9%).193 The technique of subintimal an-
for secondary bypass.190 gioplasty is not as dependent on length, but rather
Recent interest in endarterectomy has been revived on the presence of normal vessel above and below
although it is not as widely practiced as bypass the occlusion to allow access.194 Table F6 summarizes
grafting and may be more technically challenging. pooled results of femoral popliteal dilatations.

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S54 L. Norgren and W. R. Hyatt et al.

Fig. F2. TASC classification of femoral popliteal lesions. CFA e common femoral artery; SFA e superficial femoral artery.

The mid- and long-term patency rates were lesion and outflow disease were most commonly
summarized in a meta-analysis by Muradin192 and found as independent risk factors for restenoses.
in three randomized studies assessing the efficacy Recently, a study by Schillinger of 172 patients suc-
of stents.195e197 cessfully undergoing PTA of the superficial femoral
Risk factors for recurrence were analyzed by multi- and popliteal arteries observed that 6-month patency
variate stepwise backward regression analyses in var- rates were related to hs-CRP levels at baseline and
ious studies. Clinical stage of disease (intermittent at 48 hours after intervention.198 SSA and fibrinogen
claudication versus critical limb ischemia), length of level were not significantly predictive.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S55

Table F2. TASC 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 Fig. F3. Bilateral bypass from infra renal abdominal aorta to
treatment after two endovascular both femoral arteries.
interventions
Type D lesions
- Chronic total occlusions of CFA or SFA bypass surgery was 82%, demonstrating that for
(>20 cm, involving the popliteal artery) long superficial femoral artery (SFA) stenoses or oc-
- Chronic total occlusion of popliteal artery clusions, surgery is better than PTA. This contrasts
and proximal trifurcation vessels
a recent randomized study of 452 patients which dem-
CFA e common femoral artery; SFA e superficial femoral artery. onstrated no difference in amputation-free survival
at 6 months; however, surgery was somewhat
There is general agreement that for acute failure of more expensive.201
PTA of an SFA lesion, stent placement is indicated. A Medical treatment after PTA and stent placement is
recent randomized trial has demonstrated signifi- recommended to prevent early failure because of
cantly higher primary patency rates of stenting vs. thrombosis at the site of intervention. Standard therapy
PTA of femoropopliteal artery lesions TASC A and B is heparinization during the intervention to increase ac-
at 1-year follow up.199 tivated clotting time to 200e250 seconds. After PTA
Randomized trials comparing PTA versus bypass and stenting of femoropopliteal arteries, a life-long
surgery (BP) in infrainguinal arterial obstructive dis- antiplatelet medication is recommended to promote
ease are almost nonexistent. This can be explained patency (acetylsalicylic acid or clopidogrel). Life-long
partially by the following facts: BP is more commonly antiplatelet therapy is also recommended to prevent
performed in extensive disease with long lesions and cardiovascular events as recommended in section B.
CLI. PTA is more commonly performed in limited dis-
ease with IC and short obstructions (following the
original TASC recommendations 34 and 35). However,
Wolf et al. published a multicenter, prospective ran-
domized trial comparing PTA with BP in 263 men
who had iliac, femoral or popliteal artery obstruc-
tion.200 This study of patients randomly assigned to
BP or PTA showed no significant difference in out-
comes during a median follow-up of 4 years (survival,
patency and limb salvage). In 56 patients, cumulative
1-year primary patency after PTA was 43% and after

Table F3. Estimated success rate of iliac artery angioplasty from

weighted averages (range) from reports of 2222 limbs

% Claudication Technical Primary patency

success
1 yr 3 yr 5 yr
76% (81e94) 96% (90e99) 86% 82% 71%
(81e94) (72e90) (64e75)
Fig. F4. Axillo (bi) femoral bypass.

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S56 L. Norgren and W. R. Hyatt et al.

Table F5. Patency rates at 5 years after extra-anatomic bypass

Procedure 5-year % patency (range)

Axillo uni femoral bypass 51 (44e79)
Axillo bi femoral bypass 71 (50e76)
Femoral femoral bypass 75 (55e92)

treated. The complication rate (2.4%e17% depending

upon the definition) can usually be treated by endo-
vascular or surgical techniques and a failed angio-
plasty does not preclude subsequent bypass.
It remains controversial whether infrapopliteal PTA
and stenting should be performed in patients with IC
for improvement of outflow and for an increased
patency of proximal PTA, stenting and bypass surgery.
There is insufficient evidence to recommend infra-
Fig. F5. Cross-over femoral bypass. popliteal PTA and stenting in patients with inter-
mittent claudication.
Much of the supporting evidence for peri-procedural
antiplatelet and adjuvant therapy is extrapolated
F3.3 Surgical treatment of infrainguinal occlusive disease
from that related to the coronary circulation.
In the case of multilevel disease, the adequacy of inflow
F3.2 Endovascular treatment of infrapopliteal must be assessed anatomically or with pressure
occlusive disease measurements and occlusive disease treated prior to
proceeding with an outflow procedure. In some situa-
Endovascular procedures below the popliteal artery tions, a combined approach with dilatation of proximal
are usually indicated for limb salvage and there are lesions and bypassing of distal lesions should
no data comparing endovascular procedures to be performed.
bypass surgery for intermittent claudication in A recent study has shown a trend towards increas-
this region. ingly complex bypass grafts (composite and spliced
Angioplasty of a short anterior or posterior tibial vein) to more distal arteries in patients with greater
artery stenosis may be performed in conjunction co-morbidities, such as diabetes, renal failure and cor-
with popliteal or femoral angioplasty. Use of this onary artery disease; however, mortality rates have re-
technique is usually not indicated in patients with mained constant.202 A recent large study showed that
intermittent claudication. gender did not adversely affect the morbidity or
There is increasing evidence to support a recom- mortality of lower extremity revascularization.
mendation for angioplasty in patients with CLI and
infrapopliteal artery occlusion where in-line flow to F3.3.1 Bypass
the foot can be re-established and where there is Infrainguinal bypass procedures need to arise from a pat-
medical co-morbidity. In the case of infrapopliteal ent and uncompromised inflow artery although the
angioplasty, technical success may approach 90% actual level (common femoral artery versus superficial
with resultant clinical success of approximately 70% femoral or popliteal artery) does not correlate with
in some series of patients with CLI. Salvage rates are patency. If the infrainguinal bypass is constructed
reported as being slightly higher.
Predictors of successful outcome include a shorter Table F6. Pooled results of femoral popliteal dilatations
length of occlusion and a lesser number of vessels 1-year % 3-year % 5-year %
191 patency patency patency
Table F4. Patency at 5 and 10 years after aortobifemoral bypass (range) (range) (range)
Indication 5-year % patency 10-year % patency PTA: stenosis 77 (78e80) 61 (55e68) 55 (52e62)
(range) (range) PTA: occlusion 65 (55e71) 48 (40e55) 42 (33e51)
PTA þ stent: 75 (73e79) 66 (64e70)
Claudication CLI Claudication CLI stenosis
Limb based 91 (90e94) 87 (80e88) 86 (85e92) 81 (78e83) PTA þ stent: 73 (69e75) 64 (59e67)
Patient based 85 (85e89) 80 (72e82) 79 (70e85) 72 (61e76) occlusion

CLI e critical limb ischemia. PTA e Percutaneous Transluminal Angioplasty.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S57

following an inflow procedure, patency is improved by Table F7b. Randomized trials of types of conduits206e209
making the proximal anastomosis to a native artery Above-knee femoral popliteal bypass 5-year patency
rather than the inflow graft (usually limb of aortobife-
Vein 74e76%
moral bypass).203 The quality of the outflow artery is PTFE 39e52%
a more important determinant of patency than the actual
PTFE e polytetrafluoroethylene graft.
level where the distal anastomosis is performed. A distal
vessel of the best quality should be used for the distal secondary 39.7%).204 The consequences of a prosthetic
anastomosis. There is no objective evidence to preferen- graft occlusion may be more severe than a vein graft
tially select either tibial or peroneal artery, since they occlusion.205 A recent study questioned the wisdom
are typically of equal caliber. The results of femoral crural of using a prosthetic graft when acceptable vein was
bypass have not been subjected to meta-analysis. available in order to ‘save the vein’. Using this strat-
Five-year assisted patency rates in grafts constructed egy, up to 33% of subsequent secondary bypass grafts
with vein approach 60% and those constructed with did not have adequate vein available at that time. The
prosthetic material are usually less than 35%. Reports long saphenous vein (also known as the greater sa-
have documented the suitability of constructing bypass phenous vein), either in a reversed or in situ configu-
grafts to plantar arteries with reasonable success rates ration offers the best match of size and quality. In its
(5-year salvage 63%, 5-year primary patency 41%). absence, other venous tissue including contralateral
long saphenous vein, short (lesser) saphenous vein,
femoral vein and arm vein have been used (Fig. F7).
Recommendation 38. Inflow artery for femoro- There is no difference in patency rates between in
distal bypass situ and reversed vein grafts. Differences in outcome
will depend upon indications for surgery, the quality
 Any artery, regardless of level (i.e. not only the of the vessels, and co-morbidities. Venous grafts all
common femoral artery), may serve as an in- have better results than prosthetic materials.
flow artery for a distal bypass provided flow
to that artery and the origin of the graft is not
compromised [C]. Recommendation 40. Femoral below-knee popli-
teal and distal bypass

Recommendation 39. Femoral distal bypass out-  An adequate long (greater) saphenous vein is
flow vessel the optimal conduit in femoral below-knee
popliteal and distal bypass [C]. In its absence,
 In a femoral tibial bypass, the least diseased another good-quality vein should be used [C].
distal artery with the best continuous run-off
to the ankle/foot should be used for outflow re-
gardless of location, provided there is adequate F3.3.3 Adjunct procedures
length of suitable vein [C]. When a prosthetic bypass graft is placed into the be-
low-knee popliteal or distal artery adjunct proce-
dures, such as arteriovenous fistula at or distal to
F3.3.2 Conduit the bypass and the use of a vein interposition/cuff,
Vein has better long-term patency than prosthetic in have been suggested. However, randomized trials210
the infra inguinal region (Table F7). Over the short have shown that the addition of a distal arteriovenous
term, PTFE has delivered near equivalent results in fistula adds no benefit with respect to patency and,
the above-knee position (Fig. F6). A meta-analysis therefore, cannot be recommended. The use of a ve-
suggests much less satisfactory results of polytetra- nous cuff or patch has been promising in the below-
fluoroethylene-coated grafts (PTFE) to the infra- knee popliteal or distal anastomosis in some series,
popliteal arteries (5-year patency: primary 30.5%, although no comparison trials indicate the best type
Table F7a. 5-year patency following femoral popliteal bypass191 of patch technique.211
Claudication CLI F3.3.4 Profundoplasty
Vein 80 66 Stenosis at the origin of the profunda femoris
Above-knee PTFE 75 47 artery may lead to decreased flow through collateral
Below-knee PTFE 65 65
vessels in the presence of a SFA occlusion and may
CLI e critical limb ischemia; PTFE e polytetrafluoroethylene graft. compromise the patency of an aortic/extra anatomic

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S58 L. Norgren and W. R. Hyatt et al.

Fig. F6. Above-knee femoral popliteal bypass. Fig. F7. Femoral tibial bypass.

inflow operation. In the presence of SFA occlusion it is

of duplex scanning with set parameters for interven-
recommended that a stenosis of the profunda femoris
tion including angioplasty (open or transluminal) or
artery be corrected during inflow procedures. Isolated
short segment interposition. This recommendation
profundoplasty as an inflow procedure (sparing a
has recently been questioned by a randomized, con-
femoral distal bypass) may be considered in the
trolled trial showing no cost benefit of such an
presence of: 1) excellent inflow; 2) >50% stenosis of
approach.212 In the presence of an occluded but
the proximal 1/3 profunda; and 3) excellent collateral
established graft, thrombolysis may be indicated in
flow to the tibial vessels.
the very early stages to remove clot and reveal the
cause of the thrombosis. When limb salvage is as-
F3.3.5 Secondary revascularization procedures sessed following failure of an infrainguinal bypass
Secondary patency results from the salvage of an oc- the original indication for surgery is an important fac-
cluded bypass and assisted patency results from tor. The 2-year limb salvage rates for occluded grafts
pre-occlusion intervention. The non-tolerance of vein done for claudication is 100%, for rest pain is 55%
grafts to thrombosis and the success of assisted pa- and when done for tissue loss is 34%. The early occlu-
tency support the previous recommendations that all sion of a graft (<30 days occlusion) led to a very poor
venous bypass grafts be followed by a regular regime 2-year limb salvage rate of 25%.213

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S59

F4 Antiplatelet and Anticoagulant Therapies clinical benefit or quality of life improvement at 18

months. The previous recommendation of routine
Adjuvant therapy has been recommended to improve duplex scanning following autogenous lower extremity
the patency rate following lower extremity bypass bypass has proven to be not cost-effective according to
grafts. Antiplatelet agents have a beneficial effect this study.212 In practice, many surgeons continue a
that is greater in prosthetic than in autogenous program of vein graft surveillance awaiting further
conduits.156 A meta-analysis published in 1999 dem- confirmation of the findings of this trial.
onstrated that the relative risk of infra inguinal graft
occlusion in patients on aspirin/ASA was 0.78.214
The recommendation for aspirin/ASA therapy is sim- Recommendation 42. Clinical surveillance pro-
ilar for patients undergoing lower extremity balloon gram for bypass grafts
angioplasty.59 The addition of dipyridamole or ticlopi-
dine has been supported by some studies but larger  Patients undergoing bypass graft placement in
randomized trials will be necessary to make a firm the lower extremity for the treatment of claudi-
recommendation.215 Autogenous grafts may be cation or limb-threatening ischemia should be
treated with warfarin216 but this is accompanied by entered into a clinical surveillance program.
a risk of hemorrhage and this decision must be This program should consist of:
made on an individual patient basis.59 All patients B Interval history (new symptoms)

should receive antiplatelet therapy following a revas- B Vascular examination of the leg with palpa-

cularization. For those receiving anticoagulation, and tion of proximal, graft and outflow vessel
in those few treated with both antiplatelet agents pulses
and anticoagulants, extra vigilance is required due B Periodic measurement of resting and, if possi-

to the increased risk of bleeding. Recent articles have ble, post-exercise ankle-brachial indices
been published expressing concern that patients  Clinical surveillance programs should be per-
undergoing intervention for PAD are not receiving formed in the immediate postoperative period
the optimal care for their atherosclerotic process. As and at regular intervals (usually every 6
previously stated, all patients should undergo assess- months) for at least 2 years [C].
ment and treatment for their underlying atherosclero-
sis regardless of the need for intervention for
limb salvage. F6 New and Advancing Therapies

Newer surgical techniques have tended to involve

Recommendation 41. Antiplatelet drugs as adju- minimally invasive arterial reconstructions including
vant pharmacotherapy after revascularization laparoscopic aortic reconstructions. The use of com-
bined therapies (transluminal and operative) may
 Antiplatelet therapy should be started preoper- lead to ‘minimally’ invasive surgery. In infrainguinal
atively and continued as adjuvant pharmaco- reconstruction the use of semi-closed endarterectomy
therapy after an endovascular or surgical is gaining some interest. Additionally, in the attempt
procedure [A]. Unless subsequently contraindi- to reduce the morbidity of wound complications
cated, this should be continued indefinitely [A]. and the negative effects of this on patency, the use
of endoscopic vein preparation and/or harvest is
being investigated.
F5 Surveillance Programs Following Recently drug-eluting stents were tested in a ran-
Revascularization domized study against bare stents in femoropopliteal
artery obstructive disease in claudicants.218 This study
Following construction of an infrainguinal autoge- evaluated the effectiveness of nitinol self-expanding
nous bypass graft, it has been recommended in the stents coated with a polymer impregnated with siroli-
past that a program of regular graft review with du- mus (rapamycin) versus uncoated nitinol stents in
plex scanning be undertaken.217 The purpose of this patients with IC and SFA obstructions. The in-stent
is to identify lesions that predispose to graft thrombo- mean lumen diameter was significantly larger in the
sis and allow their repair prior to graft occlusion. A sirolimus-eluting stent group (4.95 mm versus
recent multicentered, randomized, controlled trial 4.31 mm in the uncoated stent group; p ¼ 0.047). The
has shown that duplex surveillance after venous results of this trial require further confirmation and
femoral distal bypass grafts leads to no significant longer-term follow up. Results of a recent small

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S60 L. Norgren and W. R. Hyatt et al.

Table F8. Cumulative observed morbidity outcomes for bypass in compared with the PTA. Cumulative patency was
critical limb ischemia
also significantly higher at 12 months (63.6% versus
Parameter Short term Long term 35.5%). Advice for general use will require more
(first year) (3e5 years) extensive and longer-term study.
Mean time to pedal wound healing 15e20 weeks e The focus of newer adjuvant therapies is to increase
Incisional wound complications* 15%e25% e the robustness of percutaneous interventions making
Persistent severe ipsilateral 10%e20% Unknown
lymphedemax them more applicable and durable to a broader range
Graft stenosis** 20% 20%e30% of lesions. These local therapies must be combined with
Graft occlusion 10%e20% 20%e40% systemic management of the atherosclerotic process.
Graft surveillance studies 100% 100%
Major amputation 5%e10% 10%e20% Table F8 summarizes the cumulative observed
Ischemic neuropathy Unknown Unknown morbidity outcomes for bypass in critical limb ische-
Graft infectiony 1%e3% e mia, and Fig. F8 summarizes the average results for
Perioperative death (primarily 1%e2% e
cardiovascular) surgical treatment.
All death (primarily cardiovascular) 10% 30%e50%
*
Not all requiring reoperation. SECTION G e NON-INVASIVE VASCULAR
x
Not well-studied.
**
Greater in series of composite and alternate vein conduit. LABORATORY AND IMAGING
y
Greatest in prosthetic grafts.

G1 Non-invasive Vascular Laboratory

randomized trial suggest early results of primary niti-
nol stenting of SFA dilatations had a superior result to The routine evaluation of patients with peripheral
dilatation alone.199 arterial disease (PAD) can include a referral to the
The impact of ePTFE coated stents (stentgrafts) was vascular laboratory. Non-invasive hemodynamic mea-
tested in a randomized trial by Saxon et al.219 At surements can provide an initial assessment of the loca-
2 years follow-up, primary patency remained 87% tion and severity of the arterial disease. These tests can
(13 of 15 patients) in the stentgraft group versus only be repeated over time to follow disease progression.
25% (three of 12 patients) in the PTA group ( p ¼ 0.002).
Endovascular brachytherapy (BT) with g-emitting
G1.1 Segmental limb systolic pressure measurement
sources such as 192Ir was investigated with respect
to the rate of intimal hyperplasia and restenoses.220
Segmental limb pressure (SLP) measurements are
Minar et al. tested endovascular BT in femoropopliteal
widely used to detect and segmentally localize hemo-
obstructions and IC in a randomized trial. The overall
dynamically significant large-vessel occlusive lesions
recurrence rate after 6 months was significantly
in the major arteries of the lower extremities. Segmen-
lower (28.3% versus 53.7%) for the PTA þ BT group
tal pressure measurements are obtained in the thigh
and calf in the same fashion as the ankle pressure. A
sphygmomanometer cuff is placed at a given level
with a Doppler probe over one of the pedal arteries,
and the systolic pressure in the major arteries under
the cuff is measured. The location of occlusive lesions
is apparent from the pressure gradients between the
different cuffs. Limitations of the method include:
(1) missing isolated moderate stenoses (usually iliac)
that produce little or no pressure gradient at rest; (2)
falsely elevated pressures in patients with diabetes
calcified, incompressible arteries; and (3) the inability
to differentiate between arterial stenosis or occlusion.

G1.2 Segmental plethysmography or pulse

volume recordings
Fig. F8. Results summary: Average results for surgical treat-
ment. FP e femoropopliteal; BK e below knee; PTA e A plethysmograph is an instrument that detects and
Percutaneous Transluminal Angioplasty; AxiuniFem e
Axillounifemoral bypass; AxbiFem e Axillobifemoral graphically records changes in limb volume. Limb
bypass; ABF e Aortobifemoral bypass. cuffs are placed around the leg at selected locations

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S61

and connected to a plethysmograph, which produces triphasic pattern to a biphasic and, ultimately, monopha-
a pulse volume recording (PVR). Normally, a single sic appearance in those patients with significant
large thigh cuff is used along with regular-sized calf peripheral arterial disease (PAD). When assessed over
and ankle cuffs, plus a brachial cuff that reflects the the posterior tibial artery, a reduced or absent forward
undampened cardiac contribution to arterial pulsatil- flow velocity was highly accurate for detecting PAD
ity. The latter is useful in standardizing the lower-limb (and also isolated tibial artery occlusive disease that
PVR and in detecting poor cardiac function as a cause may occur in patients with diabetes).12 While the test is
of low-amplitude tracings. To obtain accurate PVR operator-dependent, it provides another means to detect
waveforms the cuff is inflated to w60e65 mmHg, PAD in patients with calcified tibial arteries.
which is sufficient to detect volume changes without
resulting in arterial occlusion.
SLP and PVR measurements alone are 85% accu- G2 Imaging Techniques
rate compared with angiography in detecting and lo-
calizing significant occlusive lesions. Furthermore, G2.1 Indications for and types of imaging in patients with
when used together, the accuracy approached intermittent claudication or critical limb ischemia
95%.221 For this reason, these two diagnostic methods
are commonly used together when evaluating PAD. Imaging is indicated if some form of revascularization
Using SLP and PVR in combination ensures that pa- (endovascular or open surgical) would be advised if
tients with diabetes who have calcified arteries suffi- a suitable lesion is demonstrated. The patient’s dis-
cient to produce falsely elevated SLP will be readily ability and functional limitations due to impaired
recognized and correctly assessed by PVR. walking ability should be the major determinant in
deciding on revascularization. This is considered in
terms of claudication distance and the effect of this
G1.3 Toe pressures and the toe-brachial index limitation on the patient’s lifestyle, as well as their
independence and capacity for self care. In cases of
Patients with long-standing diabetes, renal failure and critical limb ischemia (CLI), imaging and revasculari-
other disorders resulting in vascular calcification can zation are mandatory, provided contraindications do
develop incompressible tibial arteries, which cause not prohibit surgical or endovascular intervention.
falsely high systolic pressures. Non-compressible The expense and morbidity rate for duplex scanning
measurements are defined as a very elevated ankle and other non-invasive methods are far less than for in-
pressure (e.g. 250 mmHg) or ankle-brachial index vasive angiography. With the introduction of magnetic
(ABI) >1.40. In this situation, measurement of toe resonance angiography (MRA) and computed tomo-
pressures provides an accurate measurement of distal graphic angiography (CTA), it is now possible to use
limb systolic pressures in vessels that do not typically non-invasive imaging in many situations to assess the
become non-compressible. A special small occlusion suitability of the underlying lesions for the proposed in-
cuff is used proximally on the first or second toe tervention before committing to invasive angiography.
with a flow sensor, such as that used for digital pleth-
ysmography. The toe pressure is normally approxi-
G2.2 Choice of imaging methods
mately 30 mmHg less than the ankle pressure and
an abnormal toe-brachial index (TBI) is <0.70. The
The main reason for imaging is to identify an arterial
measurement of toe pressures requires a non-invasive
lesion that is suitable for revascularization with either
vascular laboratory with standard environmental con-
an endovascular or open surgical technique. The
ditions, expertise and equipment necessary to make
current options for imaging are angiography, duplex
the measurement. False positive results with the TBI
ultrasound, MRA and CTA. Potential side effects
are unusual. The main limitation in patients with dia-
and contraindications should be considered in choos-
betes is that it may be impossible to measure toe pres-
ing the imaging modality. Intra-arterial angiography
sure in the first and second toes due to inflammatory
requires contrast medium that is potentially nephro-
lesions, ulceration, or loss of tissue.
toxic. Multidetector computed tomographic angiogra-
phy (MDCTA) requires a contrast medium load of
G1.4 Doppler Velocity Wave Form analysis >100 mL. Several methods exist to reduce renal injury,
including hydration and protective drugs such as
Arterial flow velocity can be assessed using a continuous- N-acetylcysteine. The usage of alternate contrast
wave Doppler at multiple sites in the peripheral agents (see G2.2.1) may also be considered. Where
circulation. Doppler waveforms evolve from a normal the use of iodinated contrast medium is to be

Eur J Vasc Endovasc Surg Vol 33, Supplement 1, 2007

S62 L. Norgren and W. R. Hyatt et al.

restricted or avoided, MRA and also duplex ultraso- with selected views rather than visualizing the entire
nography may allow planning for surgery. infrarenal arterial tree has decreased the contrast
load, length of study and associated risks. Despite
G2.2.1 Angiography this, full angiography, with visualization from the level
Angiography, considered the ‘‘gold standard’’ imaging of the renal arteries to the pedal arteries using digital
test, carries certain risks: approximately 0.1% risk of se- subtraction angiography (DSA) techniques, remains
vere reaction to contrast medium, 0.7% complications the choice in most cases.
risk severe enough to alter patient management, and
0.16% mortality risk and significant expense. Other G2.2.2 Color-assisted duplex ultrasonography
complications include arterial dissection, atheroem- Color-assisted duplex imaging has been proposed as
boli, contrast-induced renal failure and access site an attractive alternative to angiography. In addition
complications (i.e. pseudoaneurysm, arteriovenous to being completely safe and much less expensive, du-
fistula and hematoma). These problems have been plex scanning, in expert hands, can provide most of the
greatly mitigated by technological improvements in essential anatomic information plus some functional
the procedure, including the use of nonionic contrast information (for instance, velocity gradients across ste-
agents, digital subtraction angiography, intra-arterial noses). The lower extremity arterial tree can be visual-
pressure measurements across a stenosis with ized, with the extent and degree of lesions accurately
and without vasodilator (significance peak systolic assessed and arterial velocities measured. Disadvan-
difference 5e10 mmHg pre-vasodilatation and tages include the length of the examinations and vari-
10e15 mmHg post-vasodilatation), and more sophisti- ability of skill of the technologist. In addition, crural
cated image projection and retention. Alternatively, arteries are challenging to image in their entirety.
carbon dioxide and magnetic resonance contrast
agents (i.e. gadolinium) can be used instead of con- G2.2.3 Magnetic resonance angiography
ventional contrast media. In high-risk (e.g. renal In many centers, MRA has become the preferred
impairment) patients, restriction to a partial study imaging technique for the diagnosis and treatment

Table G1. Comparison of different imaging methods

Modality Availability Relative risk and Strengths Weaknesses Contraindications

complications
X-Ray Widespread High ‘‘Established modality’’ 2D images Renal insufficiency
contrast Access site Limited planes Contrast allergy
angiography complications Imaging pedal vessels
Contrast nephropathy and collaterals in the
Radiation exposure setting of occlusion
requires prolonged
imaging and
substantial radiation
MDCTA Moderate Moderate Rapid imaging Calcium causes Renal insufficiency
Contrast nephropathy Sub-millimeter ‘‘blooming artifact’’ Contrast allergy
Radiation exposure voxel resolution Stented segments
3D volumetric difficult to visualize
information from
axial slices
Plaque morphology
MRA Moderate None True 3D imaging Stents cause artifact but Intracranial
modality; Infinite alloys such as nitinol devices, spinal
planes and orientations produce minimal stimulators,
can be constructed artifact pace-makers,
Plaque morphology cochlear implants
from proximal and intracranial
segments with clips and shunts are
additional sequences absolute
Calcium does not cause contraindications
artifact
Duplex Widespread None Hemodynamic Operator dependent None
information and time consuming to
image both lower
extremities
Calcified segments
are difficult to assess

MDCTA e Multidetector computed tomography angiography; MRA e magnetic resonance angiography.

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 TASC II Inter-Society Consensus on Peripheral Arterial Disease S63

planning of patients with PAD. The advantages of G2.2.4 Multidetector computed tomography angiography
MRA include its safety and ability to provide rapid Multidetector computed tomography angiography
high-resolution three-dimensional (3D) imaging of (MDCTA) is being widely adopted for the initial diag-
the entire abdomen, pelvis and lower extremities in nostic evaluation and treatment planning of PAD. The
one setting. The 3D nature of magnetic resonance im- rapid evolution of technology and the deployment of
aging implies that image volumes can be rotated and fast MDCTA multislice systems in the community and
assessed in an infinite number of planes. MRA is use- the familiarity with CT technology and ease of use
ful for treatment planning prior to intervention and in are some factors driving its popularity. Multislice
assessing suitability of lesions for endovascular ap- MDCTA enables fast imaging of the entire lower
proaches. Pre-procedure MRA may minimize use of extremity and abdomen in one breath-hold at sub-
iodinated contrast material and exposure to radiation. millimeter isotropic voxel resolution. Although
The high magnetic field strength in MRA excludes prospectively designed studies with MDCTA are
patients with defibrillators, spinal cord stimulators, currently lacking, there are emerging data that the
intracerebral shunts, cochlear implants etc., and the sensitivity, specificity and accuracy of this technique
technique also excludes the <5% patients affected by may rival invasive angiography.226,227
claustrophobia that is not amenable to sedation. Stents The major limitations of MDCTA include the usage
within segments of peripheral vessels may produce of iodinated contrast (z120 mL/exam), radiation ex-
a susceptibility artifact that can render evaluation of posure and the presence of calcium.226 The latter can
these segments difficult. However, the signal loss cause a ‘blooming artifact’ and can preclude assess-
with stents is extremely dependent on the metallic al- ment of segments with substantive calcium. Stented
loy, with nitinol stents producing minimal artifact. In segments can also cause significant artifact and may
contrast to CTA (see section G2.2.4), the presence of preclude adequate evaluation. However, the ability
calcium in vessels does not cause artifacts on MRA to evaluate vessel wall lumen in stented and calcified
and this may represent a potential advantage in exam- segments is dependent on the technique (window/
ining diffusely calcified vessels in patients with diabe- level, reconstruction kernel, and type of image
tes and patients with chronic renal failure. [maximum intensity projection versus multiplanar
MRA techniques can be gadolinium contrast-based reformation etc]).
(contrast-enhanced MRA or CE-MRA) or non-con-
trast-based (time-of-flight techniques). In general, CE-
MRA techniques utilize a moving table (floating table) Recommendation 43. Indications and methods to
approach and sequentially following a bolus of con- localize arterial lesions
trast through multiple (usually 3e4) stations extending
from the abdomen to the feet. CE-MRA has replaced  Patients with intermittent claudication who
non-contrast MRA for the assessment of peripheral continue to experience limitations to their qual-
vessels, as this technique provides rapid imaging ity of life after appropriate medical therapy (ex-
with substantively better artifact-free images.222 ercise rehabilitation and/or pharmacotherapy)
Time-resolved CE-MRA is usually performed in con- or patients with critical limb ischemia, may be
junction with moving table CE-MRA, providing an considered candidates for revascularization if
additional examination of infra-inguinal vessels and they meet the following additional criteria: (a)
dynamic images free of venous contamination. a suitable lesion for revascularization is identi-
CE-MRA has a sensitivity and specificity of >93% fied; (b) the patient does not have any systemic
for the diagnosis of PAD compared with invasive angi- contraindications for the procedure; and (c) the
ography.222 A number of studies have demonstrated patient desires additional therapy [B].
that CE-MRA has better discriminatory power than  Initial disease localization can be obtained with
color-guided duplex ultrasound for the diagnosis of hemodynamic measures including segmental
PAD. Recent advancements in CE-MRA methodolo- limb pressures or pulse volume recording [B].
gies that include refinements such as usage of a venous  When anatomic localization of arterial occlu-
occlusion cuff around the thigh to modulate contrast sive lesions is necessary for decision making,
delivery to the foot, and parallel imaging methods the following imaging techniques are recom-
have greatly improved the ability to image distal mended: duplex ultrasonography, magnetic
vessels in a high resolution manner (<1  1 mm in resonance angiography and computed tomo-
plane).223,224 MRA may consistently pick up more graphic angiography (depending on local
patent vessels than DSA below the knee and could availability, experience, and cost) [B].
potentially obviate the need for invasive angiography.225

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S64 L. Norgren and W. R. Hyatt et al.

To summarize, if a patient qualifies for invasive 12 CRIQUI MH, VARGAS V, DENENBERG JO, HO E, ALLISON M,
LANGER RD et al. Ethnicity and peripheral arterial disease: the
therapy, angiography will, ultimately, be required in San Diego Population Study. Circulation 2005;112(17):2703e2707.
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the NHLBI Genetic Epidemiology Network of Arteriopathy
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mainly to characterize specific lesions in regard to 14 SELVIN E, MARINOPOULOS S, BERKENBLIT G, RAMI T, BRANCATI FL,
their suitability for endovascular treatment. However, POWE NR et al. Meta-analysis: glycosylated hemoglobin and car-
diovascular disease in diabetes mellitus. Ann Intern Med 2004;
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arterial disease. Diabetes Care 2005;28(8):1981e1987.
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2002;106(12):1505e1509. Accepted 15 September 2006

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