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1) Epidemiology

a) Basics
i) The management of the patient with PAD has to be planned in context of the epidemiology of the disease, its
natural history and, in particular, the modifiable ris factors for the systemic disease as well as those that
predict deterioration of the circulation to the limb
b) !ntermittent claudication
i) "sually diagnosed by history of muscular leg pain on exercise that is relie#ed on short rest$ %e#eral
&uestionnaires ha#e been de#eloped for epidemiological use$ !n looing at methods for identifying !' in the
population, it must be remembered that while it is the main symptom of PAD, the measurement of this
symptom does not always predict the presence of absence of PAD$
ii) A patient with &uite se#ere PAD may not ha#e the symptom of !' because some other condition limits exercise
or they are sedentary$ !n contrast, some patients with what seems to be !' may not ha#e PAD (for example,
spinal stenosis can produce symptoms lie !' in the absence of #ascular disease)$)iewise, patients with #ery
mild PAD may de#elop symptoms of !' only when they become #ery physically acti#e
*) +is ,actors
a) Basics
i) Although the #arious factors described are usually referred to as ris factors, in most cases the e#idence is only
an association$ The criteria used to support a ris factor re&uire a prospecti#e, controlled study that altering
the factor alters the de#elopment or course of PAD, such as has been shown for smoing cessation or
treatment of dyslipidemia$ +is may be conferred by other metabolic or circulatory abnormalities associated
with diabetes
b) +ace
i) The -ational .ealth and -utrition Examination in the "nited %tates found that an AB! / 0$10 was more common
in non2.ispanic Blacs (3$45) than in 6hites (7$75)$ %uch difference in the pre#alence of PAD was
confirmed by the recent 8E-9A (8enetic Epidemiology -etwor of Arteriopathy) study, which also showed
that the difference was not explained by a difference in classical ris for atherosclerosis$
c) 8ender
i) The pre#alence of PAD, symptomatic or asymptomatic, is slightly greater in men than women, primarily in the
younger age groups$ !n patients with !', the ratio of men to women is between 1:1 and *:1$ This ratio
increases in some studies to at least ;:1 !n more se#ere stages of the disease, such as chronic ')!$ 9ther
studies ha#e, howe#er, shown a more e&ual distribution of PAD between genders and e#en a predominance
of women with ')!$
d) Age
i) The striing increase in both the incidence and pre#alence of PAD with increasing age is apparent from the
earlier discussion of epidemiology$
ii)
e) %moing
i) The relationship between smoing and PAD has been recogni<ed since 1111, when Erb reported that !' was
three2times more common among smoers than among non2smoers$ !nter#entions to decrease or eliminate
cigarette smoing ha#e, therefore, long been ad#ocated for patients with !'$ !t has been suggested that the
association between smoing and PAD may be e#en stronger than that between smoing and coronary artery
disease ('AD)$
ii) ,urthermore, a diagnosis of PAD is made approximately a decade earlier in smoers than in non2smoers$ The
se#erity of PAD tends to increase with the number of ciagerettes smoed$ .ea#y smoers ha#e a four2fold
higher ris of de#eloping !' compared with non2smoers$ %moing cessation is associated with a decline in
the incidence of !'$ +esults from the Edinburgh Artery %tudy found that the relati#e ris of !' was ;$3 in
smoers compared with ;$0 in ex2smoers (who had discontinued smoing for less than = years$)
f) Diabetes mellitus
i) >any studies ha#e shown an association between diabetes mellitus and the de#elopment of PAD$ 9#erall, !' is
about twice as common among diabetic patients than among non2diabetic patients$ !n patients with diabetes,
for e#ery 15 increase in hemoglobin A1c there is a corresponding *?5 increased ris of PAD$
ii) 9#er the last decade, mounting e#idence has suggested that insulin resistance plays a ey role in a clustering
of cardiometabolic ris factors which include hyperglycemia, dyslipidemia, hypertension, and obesity$ !nsulin
resistance is a ris factor for PAD e#en in sub@ects without diabetes, raising the ris approximately 705 to
=05$
iii) PAD in patients with diabetes is more aggressi#e compared to non2diabetics, with early large #essel
in#ol#ement coupled with distal symmetrical neuropathy$ The need for a ma@or amputation is fi#e2 to ten2times
higher in diabetics than non2diabetics$ This is contributed to by sensory neuropathy and decreased resistance
to infection$ Based on these obser#ations, a consensus statement from the American Diabetes Association
recommends PAD screening with an AB! e#ery = years in patients with diabetes$
g) .ypertension
i) .ypertension is associated with all forms of cardio#ascular disease, including PAD$ .owe#er, the relati#e ris for
de#eloping PAD is less for hypertension than diabetes or smoing$
h) Dyslipidemia
i) !n the ,ramingham study, a fasting cholesterol le#el greater than 3 mmolA) (*30 mgAd)) was associated with a
doubling of the incidence of !' but the ratio of total to high2density lipoprotein (.D)) cholesterol was the best
predictor of occurrence of PAD$ !n another study, patients with PAD had significantly higher le#els of serum
triglycerides, #ery low2density lipoprotein (B)D)) cholesterol, B)D) triglycerides, B)D) proteins, intermediate
density lipoprotein (!D)) cholesterol, and !D) triglycerides and lower le#els of .D) than controls$
ii) Although some studies ha#e also shown that total cholesterol is a powerful independent ris factor for PAD,
others ha#e failed to confirm this association$ !t has been suggested that cigarette smoing may enhance the
effect of hypercholesterolemia$ There is e#idence that treatment of hyperlipidemia reduces both the
progression of PAD and the incidence of !'$ An association between PAD and hypertriglyceridemia has also
been reported and has been shown to be associated with the progression and systemic complications of PAD$
)ipoprotein(a) is a significant independent ris factor for PAD$
i) !nflammatory marers
i) %ome recent studies ha#e shown that '2reacti#e protein ('+P) was raised in asymptomatic sub@ects who in the
subse&uent fi#e years de#eloped PAD compared to an age2matched control group who remained
asymptomatic$ The ris of de#eloping PAD in the highest &uartile of baseline '+P was more than twice that in
the lowest &uartile
@) .yper#iscosity and hypercoagulable states
i) +aised hematocrit le#els and hyper#iscosity ha#e been reported in patients with PAD, possibly as a
conse&uence of smoing$ !ncreased plasma le#els of fibrinogen, which is also a ris factor for thrombosis,
ha#e been associated with PAD in se#eral studies$ Both hyper#iscosity and hypercoagulability ha#e also been
shown to be marers or ris factors for a poor prognosis$
) .yperhomocysteinemia
i) The pre#alence of hyperhomocysteinemia is as high in the #ascular disease population, compared with 15 in
the general population$ !t is reported that hyperhomocystenemia is detected in about ;05 of young patients
with PAD$ The suggestion that hyperhomocysteinemia may be an independent ris factor for atherosclerosis
has now been substantiated by se#eral studies$ !T may be a stronger ris factor for PAD than for 'AD$
l) 'hronic renal insufficiency
i) There is an association of renal insufficiency with PAD, with some recent e#idence suggesting it may be causal$
!n the .E+% study (.eart and EstrogenAProgestin +eplacement %tudy), renal insufficiency was independently
associated with future PAD e#ents in postmenopausal women
m) %ummary
i) ,igure A* summari<es graphically the approximate influence or association between some of the abo#e factors
and PAD, taing a global #iew of the existing e#idence
ii)
;) ,ate of the )eg
a) Asymptomatic
i) E#idence suggests that the progression of the underlying PAD is identical whether or not the sub@ect has
symptoms in the leg$ There is nothing to suggest that the ris of local deterioration, with progression to critical
limb ischemia (')!), is dependent on the presence or absence of symptoms of intermittent claudication$
6hether symptoms de#elop or not depends largely on the le#el of acti#ity of the sub@ect$ This is one of the
reasons why some patientsC initial presentation is with ')!, in the absence of any earlier !'$
ii) ,or example, a patient who has a reduction in their AB! @ust abo#e the ischemic rest pain le#el but who is too
sendentary to claudicate, may de#elop ')! because of wounds resulting from relati#ely minor (often self
inflicted) trauma that cannot heal at this le#el of perfusion$ !t is important to detect this subgroup of patients at
a time when protecti#e foot care and ris factor control ha#e their greatest potential to ameliorate outcomes$
,unctional decline o#er two years is relati#e to baseline AB! and the nature of the presenting limb symptoms$
A lower AB! was associated with a more rapid decline in, for example, ?2minute wal distance$
b) !ntermittent 'laudication
i) Although PAD is progressi#e in the pathological sense, its clinical course as far as the leg is concerned is
surprisingly stable in most cases$ .owe#er, the symptomatic PAD patient continues to ha#e significant
functional disability$ )arge population studies pro#ide the most reliable figures$ All of the e#idence o#er the
last 70 years since the classic study by Bloor has not materially altered the impression that only about a
&uarter of patients with !' will e#er significantly deteriorate$
ii) This symptomatic stabili<ation may be due to the de#elopment of collaterals, metabolic adaptation of ischemic
muscle, or the patient altering his or her gait to fa#or non2ischemic muscle groups$ The remaining *=5 of
patients with !' deteriorate in terms of clinical stageD this is most fre&uent during the first year after diagnosis
(35 2 15) compared with *5 to ;5 per year thereafter$ This clinical stability is rele#ant to the patientCs
perception of their se#erity of claudication$ 6hen these patients ha#e a comprehensi#e assessment of their
actual functional status, measured waling distance does progressi#ely deteriorate o#er time$
iii) >ore recent re#iews also highlight that ma@or amputation is a relati#ely rare outcome of claudication, with only
15 to ;$;5 of patients with !' needing ma@or amputation o#er a =2year period$ The Basle and ,ramingham
studies, which are the two large2scale studies that ha#e looed at unselected patients, found that less than
*5 of PAD patients re&uired ma@or amputation$ Although amputation is the ma@or fear of patients told they
ha#e circulatory disease of the legs, they can be assured that this is an unliely outcome, except in diabetes
patients$
i#) !t is difficult to predict the ris of deterioration in a recent claudicant$ The #arious ris factors mentioned in
section A* probably all contribute to the progression of PAD$ A changing AB! is possibly the best indi#idual
predictor, because if a patientCs AB! rapidly deteriorates it is most liely to continue to do so in the absence of
successful treatment$ !t has been shown that in patients with !', the best predictor of deterioration of PAD
(e$g$ need for arterial surgery or ma@or amputation), is an AB! of E0$=0 with a ha<ard ratio of more than *
compared to patients with an AB! F 0$=0$ %tudies ha#e also indicated that in those patients with !' in the
lowest strata of anle pressure (i$e$ 70 G ?0 mm.g), the ris of progression to se#ere ischemia or actual limb
loss is 4$=5 per year$
c) Acute )eg !schemia
i) Acute limb ischemia denotes a &uicly de#eloping or sudden decrease in limb perfusion, usually producing new
or worsening symptoms and signs, and often threatening limb #iability$ Progression of PAD from claudication
to rest pain to ischemic ulcers or gangrene may be gradual or progress rapidly reflecting sudden worsening of
limb perfusion$ Acute limb ischemia may also occur as the result of an embolic e#ent or a local thrombosis in
a pre#iously asymptomatic patient$
d) 'o2existing #ascular disease
i) Because PAD, 'AD, anad cerebral artery disease are all manifestations of atherosclerosis, it is not surprising
that the three conditions commonly occur together$
7) ,ate of the Patient
a) Asymptomatic and claudicating peripheral arterial disease patients
i) The increased ris of cardio#ascular e#ents in patients with PAD is related to the se#erity of the disease in the
legs as defined by an AB! measurement$ The annual o#erall ma@or cardio#ascular e#ent rate (myocardial
infarction, ischemic stroe and #ascular death) is approximately =5 2 35$
=) >anagement of 'ardio#ascular +is ,actors and 'o2existing disease
a) +is ,actors
i) The initial clinical assessment for PAD is a history and physical examination$ A history of intermittent
claudication is useful in raising in raising the suspicion of PAD, but significantly underestimates the true
pre#alence of PAD$ !n contrast, palpable pedal pulses on examination ha#e a negati#e predicti#e #alue of
o#er 105 that may rule out the diagnosis in many cases$ !n contrast, a pulse abnormality (Absent or
diminished) significantly o#erestimates the true pre#alence of PAD$ Thus, ob@ecti#e testing is warranted in all
patients suspected of ha#ing PAD$
ii) The primary non2in#asi#e screening test for PAD is the AB!$ !n the contest of identifying a high2ris population,
persons who should be considered for AB! screening in the primary care or community setting include:
(1) %ub@ects with exertional leg symptoms
(*) %ub@ects aged =0 G ?1 years who also ha#e cardio#ascular fis factosr and all patients o#er the age of 30
(;) %ub@ects with a 102year ris of cardio#ascular e#ent between 105 and *05 in whom further ris
stratification is warranted$
iii) Patients with PAD, defined as an AB! / 0$10, are nown to be at high ris for cardio#ascular e#ents$ >ortality
rates in patients with PAD a#erage *5 per year and the rates of non2fatal myocardial infarction, stroe and
#ascular death are =5 to 35 per year$ !n addition, the lower the AB!, the higher the ris of cardio#ascular
e#ents$ A similar increased mortality ris has also been obser#ed in patients with an increased AB!$ Therefore,
an abnormal AB! identifies a high2ris population that needs aggressi#e ris factor modification and anti2
platelet therapy$
b) >odification of atherosclerotic ris factors
i) !ntro
(1) Patients with PAD typically ha#e multiple cardio#ascular ris factors, which puts them at maredly
increased ris for cardio#ascular e#ents$ This section will discuss an approach to each of the ma@or ris
factors of this disorder
ii) %moing cessation
(1) %moing is associated with a mared increased ris for peripheral atherosclerosis$ The number of pac
years is associated with disease se#erity, an increased ris of amputation, peripheral graft occlusion and
mortality$ 8i#en these associations, smoing cessation has been a cornerstone of management of PAD
as is the case for 'AD$ 9ther drugs for smoing cessation are becoming a#ailable$
(*) !n middle2aged smoers with reduced pulmonary function, physician ad#ice to stop smoing, coupled with
a formal cessation program and nicotine replacement is associated with a **5 cessation rate at = years
compared with only a =5 cessation rate in the usual care group$ By 17 years, the inter#ention group had
a significant sur#i#al ad#antage$
(;) The role of smoing cessation in treating the symptoms of claudication is not as clearD studies ha#e shown
that smoing cessation is associated impro#ed waling distance is some, but not all patients$ Therefore,
patients should be encouraged to stop smoing primarily to reduce their ris of cardio#ascular e#ents, as
well as their ris of progression to amputation and progression of disease, but should not be promised
impro#ed symptoms immediately upon cessation$ +ecent studies ha#e shown a three2fold increased ris
of graft failure after bypass surgery with continued smoing with a reduction in that ris to that of non2
smoers with smoing cessation$
(7) Recommendation 1$ %moing cessation in peripheral arterial disease
All patients who smoe should be strongly and repeatedly ad#ised to stop smoing$
All patients who smoe should recei#e a program of physician ad#ice, group counseling sessions,
and nicotine replacement$
'essation rates can be enhanced by the addition of antidepressant drug therapy (bupropion) and
nicotine replacement
iii) 6eight reduction
(1) Patients who are o#erweight (body mass index HB>!I *= G ;0) or who are obese (B>! F ;0) should recei#e
counseling for weight reduction by inducing negati#e caloric balance with reduction of calorie intae,
carbohydrate restriction and increased exercise$
i#) .yperlipidemia
(1) !ndependent ris factors for PAD include ele#ated le#els of total cholesterol, low2density lipoprotein ()D))
cholesterol, triglycerides, and lipoprotein(a)$ ,actors that are protecti#e for the de#elopment of PAD are
ele#ated high2density lipoprotein (.D)) cholesterol and apolipoportein (a21) le#els$
(2) Recommendation 2
All symptomatic PAD patients should ha#e their low2density lipoprotein ()D)) cholesterol lowered to
E*$=1 mmolA) (E100 mgAd))
!n patients with PAD and a history of #ascular disease in other beds (e$g$ coronary artery disease) it is
reasonable to lower )D) cholesterol le#els to E1$41 mmolA) (E30 mgAd))
All asymptomatic patients with PAD and no other clinical e#idence of cardio#ascular disease should
also ha#e their )D) cholesterol le#el lowered to E*$=1 mmolA) (E100 mgAd))
!n patients with ele#ated triglyceride le#els where the )D) cannot be accurately calculated, the )D)
le#el should be directly measured and treated to #alues listed abo#e$ Alternati#ely, the non2.D)
cholesterol le#el can be calculated with a goal of E;$;? mmolA) (E1;0 mgAd)), and in high2ris
patients the le#el should be E*$=1 mmolA) (E100 mgAd))
Dietary modifications should be the initial inter#ention to control abnormal lipid le#els
!n symptomatic PAD patients, statins should be the primary agents to lower )D) cholesterol le#els to
reduce the ris of cardio#ascular e#ents
,ibrates andAor niacin to raise .D)2cholesterol le#els and lower triglyceride le#els should be
considered in patients with PAD who ha#e abnormalities of these lipid fractions$
#) .ypertension
(1) .ypertension is associated with a two2 to three2fold increased ris for PAD$ .ypertension guidelines
support the aggressi#e treatment of blood pressure in patients with atherosclerosis, indicating PAD$ !n this
high2ris group the current recommendation is a goal of E170A10 mm.g, and E1;0A40 mm.g if the patient
also has diabetes or renal insufficiency$
(*) +egarding drug choice, all drugs that lower blood pressure are effecti#e at reducing the ris of
cardio#ascular e#ents$ Thia<ide diuretics are first2line agents, angiotensin con#erting en<yme (A'E)
inhibitors or angiotensin receptor blocers should be used in patients with diabetic renal disease or in
congesti#e heart failure, and calcium channel blocers for difficult to control hypertension >ost patients
will re&uire multiple agents to achie#e desired blood pressure goals$ The A'E inhibitor drugs ha#e also
shown benefit in PAD, possibly beyond blood2pressure lowering in high2ris groups$
(;) Recommendation 3$ 'ontrol of hypertension in PAD patients
All patients with hypertension should ha#e blood pressure controlled to E170A10 mm.g or E1;0A40
mm.g if they also ha#e diabetes or renal insufficiency
J-' B!! and European guidelines for the management of hypertension in PAD should be followed
Thia<ides and A'E inhibitors should be considered as initial blood2pressure lowering drugs in PAD to
reduce the ris cardio#ascular e#ents$
Beta2adrenergic blocing drugs are not contraindicated in PAD$
#i) Diabetes
(1) Diabetes increases the ris of PAD approximately three2 to four2fold, and the ris of claudication two2fold$
>ost patients with diabetes ha#e other cardio#ascular ris factors (smoing, hypertension and
dyslipidemia) that contribute to the de#elopment of PAD$ Diabetes is also associated with peripheral
neuropathy and decreased resistance to infection, which leads to an increased ris of foot ulcers and foot
infections$
(*) Recommendation 4: 'ontrol of diabetes in PAD
Patients with diabetes and Pad should ha#e aggressi#e control of blood glucose le#els with a
hemoglobin A1c goal of E3$05 or as close to ?5 as possible$
#ii) .omocysteine
(1) An ele#ated plasma homocysteine le#el is an independent ris factor for PAD$ 6hile supplement with B2
#itamins andAor folate can lower homocysteine le#els, high2le#el e#idence for the benefits in terms of
pre#enting cardio#ascular e#ents is lacing$ Two studies of supplemental B #itamins and folic acid in
patients with 'AD demonstrated no benefit and e#en a suggestion of harm, so their therapy cannot be
recommendend$
(*) Recommendation 5: "se of folate supplementation in PAD
Patients with PAD and other e#idence of cardio#ascular disease should not be gi#en folate
supplements to reduce their ris of cardio#ascular e#ents$
#iii) Antiplatelet drugs
(1) Recommendation 6: Antiplatelet therapy in PAD
All symptomatic patients with or without a history of other cardio#ascular disease should be
prescribed an antiplatelet drug long term to reduce the ris of cardio#ascular morbility and mortality$
AspirinAA%A is effecti#e in patients with PAD who also ha#e clinical e#idence of other forms of
cardio#ascular disease (coronary or carotid)
The use of aspirinAA%A in patients with PAD who do not ha#e clinical e#idence of other forms of
cardio#ascular disease can be considered$
'lipidogrel is effecti#e in reducing cardio#ascular e#ents in a subgroup of patients with symptomatic
PAD, with or without other clinical e#idence of cardio#ascular disease$
ix) 'AD
(1) Recommendation 7: >anagement of coronary Artery disease in PAD patients
Patients with clinical e#idence of 'AD (angina, ischemic congesti#e heart failure) should be e#aluated
and managed according to current guidelines$
Patients with PAD considered for #ascular surgery may undergo further ris stratification and those
found to be at #ery high ris managed according to current guidelines for coronary re#asculari<ation
+outine coronary re#asculari<ation in pereparation for #ascular surgery is not recommended$
(*) Recommendation 8: "se of beta2blocing agents before #ascular surgery
6hen there are no contraindications, beta2adrenergic blocers should be gi#en perioperati#ely to
patients with peripheral arterial disease undergoing #ascular surgery in order to decrease cardiac
morbidity and mortality$
x) 'o2existing diseases
(1) Recommendation 9: >anagement of carotid artery disease in PAD
The management of symptomatic carotid artery disease in patients with PAD should be based on
current guidelines$
(*) Recommendation 10: >anagement of renal artery disease in PAD
6hen renal artery disease is suspected in PAD patients, as e#idenced by poorly controlled
hypertension or renal insufficiency, patients should be treated according to current guidelines and
consider referral to a cardio#ascular physician$
?) !ntermittent 'laudication
a) 'haracteri<ation of patients
i) Definition of intermittent claudication and limb symptoms in PAD
(1) The ma@ority of patients with PAD ha#e limited exercise performance and waling ability$ As a
conse&uence, PAD is associated with reduced physical functioning and &uality of life$ !- patients with
PAD, the classical symptom is intermittent claudication (which means to limb), which is muscle discomfort
in the lower limb reproducibly produced by exercise and relie#ed by rest within 10 minutes$ Patients may
describe muscle fatigue, aching or cramping of exertion that is relie#ed by rest$
(*) The symptoms are most commonly locali<ed to the calf, but may also affect the thigh or buttocs$ Typical
claudication occurs in up to 1A; of all patients with PAD$ !mportantly, patients without classical claudication
also ha#e waling limitations that may be associated with atypical or limb symptoms$ Typical claudication
may not occur in patients who ha#e co2morbidities that pre#ent sufficient acti#ity to produce limb
symptoms (i$e$ congesti#e heart failure, se#ere pulmonary disease, musculoseletal disease) or in
patients who are so deconditioned that exercise is not performed$ Therefore, patients suspected of ha#ing
PAD should be &uestioned about any limitations they experience during exercise of the lower extremities
that limits their waling ability$
(;) PAD is caused by atherosclerosis that leads to arterial stenosis and occlusions in the ma@or #esels
supplying the lower extremities$ Patients with intermittent claudication ha#e normal blood flow at rest
(and, therefore, ha#e no limb symptoms at rest)$ 6ith exercise, occlusi#e lesions in the arterial supply of
the leg muscles limits the increase in blood flow, resulting in a mismatch between oxygen supply and
muscle metabolic demand that is associated with the symptom of claudication$ Ac&uired metabolic
abnormalities in the muscle of the lower extremity also contribute to the reduced exercise performance
ii) Differential Diagnosis
Condition Location Prevalence Characteritic !""ect o"
e#ercie
!""ect o"
ret
!""ect o"
$oition
%ther
characreritic
'alf !' 'alf muscles ; G =5 of
adult
population
'ramping,
aching
discomfort
+eproducible
onset
Kuicly
relie#ed
-one >ay ha#e atypical
limb symptoms on
exercise
Thigh and
buttoc !'
Buttocs,
hip, thigh
+are 'ramping,
aching
discomfort
+eproducible
onset
Kuicly
relie#ed
-one !mpotence
>ay ha#e normal
pedal pulse with
isolated iliac artery
disease
,oot !' ,oot arch +are %e#ere pain on
exercise
+eproducible
onset
Kuicly
relie#ed
-one Also may present
as numbness
'hronic
'ompartment
%yndrome
'alf muscles +are Tight, bursting
pain
After much
exercise
(@ogging)
%ubsides
#ery slowly
+elief with
ele#ation
Typically hea#y
muscled athletes
Benous
claudication
Entire leg,
worse in calf
+are Tight, bursting
pain
After waling %ubsides
slowly
+elief
speeded by
ele#ation
.istory of
iliofemoral deep
#ein thrombosis,
signs of #enous
congestion,
edema
-er#e +oot
'ompression
+adiates
down leg
'ommon %harp
lancinating pain
!nduced by
sitting,
standing or
waling
9ften
present at
rest
!mpro#ed
by change
in position
.istory of bac
problems
6orst with sitting
+elief when
supine or sitting
%ymptomatic
baers 'yst
Behind
nee, down
calf
+are %welling,
tenderness
6ith exercise Present at
rest
-one -ot intermittent
.ip arthritis )ateral hip,
thigh
'ommon Aching
discomfort
After #ariable
degree or
exercise
-ot &uicly
relie#ed
!mpro#ed
when not
weight
bearing
%ymptoms
#ariable
.istory of
degenerati#e
arthritis
%pinal
stenosis
9ften
bilateral
buttocs,
posterior leg
'ommon Pain and
weaness
>ay mimic !' Bariable
relief but
can tae a
long time
to reco#er
+elief by
lumber
spine
flexion
6orse with
standing and
extending spine
,ootAanle
arthritis
Anle, foot,
arch
'ommon Aching pain After #ariable
degree of
exercise
-ot &uicly
relie#ed
>ay be
relie#ed by
not bearing
weight
Bariable, may
related to acti#ity
le#el and present
at rest
iii) 'auses of occlusi#e arterial lesions in lower extremity arteries potentially causing claudication
Atherosclerosis
Arteritis
'ongenital and ac&uired aortic coarctation
Endofibrosos if external iliac artery (iliac artery syndrome in cyclists)
,ibromuscular dysplasia
Peripheral emboli
Popliteal aneurysm (with secondary thromboembolism)
Ad#entitial cyst of the popliteal artery
Popliteal entrapment
Primary #ascular tumors
Pseudoxanthoma elasticum
+emote trauma or irradiation in@ury
Taayasu Arteritis
T.romboangiitis obliterans (BuergerCs disease)
Thrombosis of a persistent sciatic artery
b) Physical Exmamination
i) The physical examination should assess the circulatory system as a whole$ Ley components of the general
examination include measurement of blood pressure in both arms, assessment of cardiac murmurs, gallops
or arrhythmias, and palpation for an abdominal aortic aneurysm (does not include the presence of an
aneurysm$) )ess specific aspects of the physical examination for PAD include changes in color and
temperature of the sin of the feet, muscle atrophy from inability to exercise, decreased hair growth and
hypertrophied, slow2growing nails$ The presence of a bruit in the region of the carotid, aorta or femoral
arteries may arise from turbulence and suggest significant arterial disease$ .owe#er, the absence of a bruit
does not exclude arterial disease$
ii) The specific peripheral #ascular examination re&uires palpation of the radial, ulnar, brachial, carotid, femoral,
popliteal, dorsalis pedis, and posterior tibial artery pulses$ The posterior tibial artery is palpated at the medial
malleolus$ !n a small number of healthy adults, the dorsalis pedis pulse on the dorsum of the foot may be
absent, due to branching of the anterior tibial artery at the le#el of the anle$ !n this situation, the distal aspect
of the anterior tibial artery may be detected and assessed at the anle$ Also, a terminal branch of the
peritoneal artery may be palpated at the lateral mallolus$
iii) ,or simplicity, pulses may be graded from 0 (absent), 1 (diminished) and * (normal)$ An especially prominent
pulse at the femoral andAor popliteal location should raise the suspicion of an aneurysm$ A diminished or
absent femoral pulse suggests aorto2iliac artery occlusi#e disease, which reduces inflow to the limb$ !n
contrast, a normal femoral, but absent pedal pulse suggests significant arterial disease in the leg with
preser#ed inflow$ Pulses should be assessed in both legs and pulse abnormalities correlated with leg
symptoms to determine the laterali<ation of the disease
i#) Patients with an isolated occlusion of an internal iliac (hypogastric) artery may ha#e normal femoral and pedal
pulses at rest and after exercise, but buttocs claudication (and impotence in males)$ %imilar symptoms may
occur in patients with stenosis of the common or external iliac artery$ These patients may ha#e normal pulses
at rest, but loss of the pedal pulses after exercise$ The loss of the pedal pulse is coincident with a drop in
anle pressure due to the inability of the large #essels (in the presence of occlusi#e disease) to pro#ide
sufficient flow to maintain distal pressure with muscle #asodilation during exercise$
#) Despite the utility of the pulse examination, the finding of absent pedal pulses tends to o#er2diagnose PAD,
whereas if the symptom of the classic claudication is used to identify PAD, it will lead to a significant under2
diagnosis of PAD$ Thus, PAD must be confirmed in suspected patients with non2in#asi#e testing using the
anle2brachial index, or other hemodynamic or imaging studies described below$
#i) Recommendation 11: .istory and physical examination in suspected PAD
!ndi#iduals with ris factors for PAD, limb symptoms on exertion or reduced limb function should
undergo a #ascular history to e#aluate for symptoms of claudication or other limb symptoms that limit
waling ability$
Patients at ris for PAD or patients with reduced limb function should also ha#e a #ascular
examination e#aluating peripheral pulses
Patients with a history or examination suggesti#e of PAD should proceed to ob@ecti#e testing including
an anle2brachial index$
c) Diagnostic E#aluation of Patients with PAD
i) Anle Pressure measurements (Anle2brachial index HAB!I)
(1) >easuring the pressure in the anle arteries has become a standard part of the initial e#aluation of
patients with suspected PAD$ A common method of measurement uses a 10 G 1* cm
sphygmomanometer cuff placed @ust abo#e the anle and a Doppler instrument used to measure the
systolic pressure of the posterior tibial and dorsalis pedis arteries of each leg$ These preasures are then
normali<ed to the higher brachial pressure of either arm to form the anle2brachial index (AB!)$ The index
leg is often defined as the leg with the lower AB!$
(*) The AB! pro#ides considerable information$ A reduced AB! in symptomatic patients confirmed the
existence of hemodynamically significant occlusi#e disease between the heart and the anle, with a lower
AB! indicating a greater hemodynamic se#erity of occlusi#e disease$ The AB! can ser#e as an aid in
differential diagnosis, in that patients with exercise2related leg pain of non2#ascular causes will ha#e a
normal anle pressure at rest and after exercise$ !n patients with PAD who do not ha#e classic
claudication (Are either asymptomatic or ha#e atypical symptoms) a reduced AB! is highly associated with
reduced limb function$ This is defined as reduced waling speed andAor a shortened waling distance
during a timed ?2minute wal$
(;) ,rom a systemic persepecti#e, a reduce AB! is a potent predictor of the ris of future cardio#ascular
e#ents$ This ris is related to the degree of reduction of the AB! (lower AB! predicts higher ris) and is
independent of other standard ris factors$ The AB! thus has the potential to pro#ide additional ris
stratification in patients with ,ramingham ris between 105 and *05 in 10 years, in that an abnormal AB!
in this intermediate ris group would mo#e the patient to high ris in need of secondary pre#ention
whereas a normal AB! would lower the estimate of ris indicating the need for primary pre#ention
strategies$
(7) The #alue of a reduced AB! is summari<ed as follows:
Defects in significant PAD in (sedentary) asymptomatic patients
"sed in the differential diagnosis of leg symptoms to identify a #ascular etiology
!dentifies patients with reduced limb function (inability to wal defined distances or at usual
waling speed)
Pro#ides ey information on long2term prognosis, with an AB! / 0$10 associated with a ; G ? fold
increased ris of cardio#ascular mortality
Pro#ides further ris stratification, with a lower AB! indicating worse prognosis
.ighly associated with coronary and cerebral artery disease
'an be used for further ris stratification in patients with a ,ramingham ris score between 105 2
*05
(=) !n some patients with diabetes, renal insufficiency, or other diseases that cause #ascular calcification, the
tibial #essels at the anle become non2compressible$ This lead to a false ele#ation of the anle pressure$
These patients typically ha#e an AB! F 1$70, and in some of these patients, the Doppler signal at the
anle cannot be obliterated e#en at cuff pressures of ;00 mm.g$ !n these patients additional non2in#asi#e
diagnostic testing should be performed to e#aluate the patient for PAD$ Alternati#e tests include toe
systolic pressure, pulse #olume recordings, transcutaneous oxygen measurements or #ascular imaging
(most commonly with duplex ultrasound)$ 6hen any of these tests is abnormal, a diagnosis of PAD can e
reliably made$
(?) Recommendation 12& +ecommendations for AB! screening to detect PAD in the indi#idual patient
An AB! should be measured in
All patients who ha#e exertional leg symptoms
All patients between the age of =0 G ?1 and who ha#e a cardio#ascular ris factor (particularly
diabetes or smoing)
All patients age M 30 years regardless of ris2factor status
All patients with a ,raminghan ris score 105 2 *05
d) 9utcome Assessment of !ntermittent 'laudication in 'linical Practice
i) !ntrmittent claudication is a symptom of PAD that profoundly limits the patientCs ability to wal and as a result is
associated with a reduced exercise performance$ This reduction in exercise performance can be easily
&uantified with a graded treadmill test where the time of onset of claudication pain (claudication onset time)
and pea waling time can be determined at baseline$ The treadmill test will also allow the clinician to
determine if the patient experiences typical claudication pain with exercise, or other symptoms that limit
exercise$ This assessment will help guide therapy because if claudication is not the ma@or symptom limiting
exercise then specific claudication therapies may not be indicated$
ii) 9nce claudication is established as the ma@or symptom limiting exercise, then the primary goal of claudication
therapy is to relie#e the symptoms during waling and impro#e exercise performance and community
acti#ities$ Appropriate treatment of the claudicant must address both the specific lower2extremity disability and
the systemic impact of the disease$ !deally, treatment will result in an impro#ement in both the #ascular status
of the lower extremity and reduce the patientCs subse&uent ris of fatal and non2fatal cardio#ascular e#ents$ !-
clinical trials of claudication therapy, the primary endpoint is usually a treadmill test of the pea waling time
or distance as well as the time or distance for the onset of claudication$ The same parameters can be
assessed to determine the clinical benefit of any claudication therapy in an indi#idual patient$
iii) Recommendation 13: Determining success of treatment for !'
(1) Patient based outcome assessment (including a focused history of change in symptoms) is the most
important measure$ .owe#er, if &uantitati#e measurements are re&uired the following may be used:
(a) 9b@ecti#e measures include an increase in pea exercise performance on a treadmill
(b) Patient2based measures would include an impro#ement on a #alidated, disease2specific health status
&uestionnaireD or the physical functioning domain on a #alidated generic health status &uestionnaire$
e) Treatment
i) 9#erall strategy and basic treatment
(1) 9#erall %trategy
(i) Patients with claudication experience re#ersible muscle ischemia during waling that is
characteri<ed by cramping and aching in the affected muscle$ These symptoms result in a se#ere
limitation in exercise performance and waling ability$ The exercise limitation is associated with
mared impairments in waling distance, waling speed, and o#erall function$ Patients with
claudication are physically impaired and, therefore, the treatment goals are to relie#e symptoms,
impro#e exercise performance and daily functional abilities$
(ii) The initial approach to the treatment of limb symptoms should focus on structure exercise and, in
selected patients, pharmacotherapy to treat the exercise limitation of claudication (ris factor
modification and antiplatelet therapies are indicated to decrease the ris of cardio#ascular e#ents
and impro#e sur#i#al$)
(iii) ,ailure to respond to exercise andAor drug therapy would lead to the next le#el of decision maing,
which is to consider limb re#asculari<ation$ .owe#er, in patients in whom a proximal lesion is
suspected (findings of buttocs claudication, reduced or absent femoral pulse) the patient could
be considered for re#asculari<ation without initially undergoing extensi#e medical therapy$
(*) Exercise rehabilitation
(a) !n patients with claudication, there is a considerable body of e#idence to support the clinical benefits of
a super#ised exercise program in impro#ed exercise performance and community2based waling
ability$ This inter#ention has been thoroughly re#iewed, both in terms of mechanism of the training
effect, as well as practical guidelines for the exercise program$
(b) %e#eral studies ha#e suggested that some le#el of super#ision of necessary to achie#e optimal results
(general, unstructured recommendations to exercise by the physician do not result in any clinical
benefit$) !n prospecti#e studies of super#ised exercise conducted for ; months or longer, there are
clear increases in treadmill exercise performance and a lessening of claudication pain se#erity during
exercise$
(c) The predictors of response to the training program to the training program include achie#ing a high
le#el of claudication pain during the training sessions and ? months or longer of formal training and
waling exercise (Bersus other training modalities$) Training on a treadmill has been shown to be
more effecti#e than strength training or combinations of training modalities$
(d) .owe#er, different modes of exercise training ha#e been applied including upper extremity cycle
ergometer exercise that is associated with a training response$ The mechanisms of response to
exercise training ha#e been re#iewed pre#iously and include impro#ements in waling efficiency,
endothelial function and metabolic adaptations in seletal muscle$
(e) The exercise prescription should be based on exercise session that are held three times a wee,
beginning with ;0 minutes of training but then increasing to approximately 1 hour per session$ During
the exercise session, treadmill exercise is performed at a speed and grade that will induce
claudication within ; G = minutes$ The patient should stop waling when claudication pain is
considered moderate (a less optimal training response will occur when the patient stops at the onset
of claudication$) The patient will then rest until claudication has abated, after which the patient should
resume waling until moderate claudication discomfort recurs$
(f) This cycle of exercise and rest should be at least ;= minutes at the start of the program and increase
to =0 minutes as the patient becomes comfortable with the exercise sessions (but always a#oiding
excessi#e fatigue or leg discomfort$) !n subse&uent #isits, the speed or grade of the treadmill is
increased if the patient is able to wal for 10 minutes or longer at the lower worload without reaching
moderate claudication pain$ Either speed or grade can be increased, but an increased grade is
recommended if the patient can already wal at * mph (;$* mAh)$ An additional goal of the program
is to increase patient waling speed up to the normal ;$0 mph (7$4 mAh) from the a#erage PAD
patient waling speed of 1$= G *$0 mph (approximately *$7 G ;$* mAh)$
(g) >any patients may ha#e contraindications for exercise (e$g$ se#ere 'AD, musculoseletal limitations
or neurological impairments)$ 9ther patients may be unwilling to participate in super#ised sessions if
they ha#e long distances to tra#el to the exercise facility, if an appropriate rehabilitation program is not
a#ailable in their area, or if the expenses incurred are too great$ The pre#alence of contraindications
to an exercise program ranges from 15 2 ;75 depending on the population studied$
(h) The ma@or limitations of exercise rehabilitation is the lac of a#ailability of a super#ised setting to refer
patients$ Though exercise therapy is of pro#en effecti#eness, some patients are simply not willing to
persist with an exercise program in order to maintain the benefit$ !n addition, a claudication exercise
program in a patient with diabetes who has se#ere distal neuropathy may precipitate foot lesions in
the absence of proper footwear$
(i) Recommendation 14: Exercise therapy in !'
%uper#ised exercise should be made a#ailable as part of the initial treatment for all patients
with PAD
The most effecti#e programs employ treadmill or trac waling that is of sufficient intensity to
bring on claudication, followed by rest, o#er the course of a ;0 G ?0 minute session$ Exercise
sessions are typically conducted three times a wee for ; months$
(;) Pharmacotherapy
(a) !ntro
(i) Patients with !' should all recei#e drug and lifestyle treatment for their cardio#ascular ris factors
and coexisting diseases to pre#ent cardio#ascular e#ents (myocardial infarction, stroe and
death) associated with atherosclerosis$ .owe#er, this approach will typically not pro#ide a
significant reduction or elimination of symptoms of claudication$ Thus, claudication drug therapy
for relief of symptoms typically in#ol#es different drugs than those that would be used for ris
reduction (an exception may be lipid2lowering therapy)$ .owe#er, a number of types of drugs
ha#e been promoted for symptom relief, with #arying le#els of e#idence to support their use$
,inally, current drug therapy options do not pro#ide the same degree of benefit as does a
super#ised exercise program or successful re#asculari<ation$
(b) Drugs with e#idence of clinical utility in claudication
(i) Cilostazol
1$ 'ilosta<ol is a phosphodiesterase !!! inhibitor with #asodilator, metabolic and antiplatelet
acti#ity$ The benefits of this drug ha#e been described in a meta2analysis of six randomi<ed,
controlled trials in#ol#ing 13=1 patients, including 370 on placebo, *41 on cilosta<ol =0 mg
twice daily (B!D), 3;0 on cilosta<ol 100 mg B!D$ The 3; on cilosta<ol 1=0 mg B!D and *;* on
pentoxyifylline 700 mg thrice2daily (T!D) were excluded from the analysis$ This analysis
demonstrated that the net benefit of cilosta<ol o#er placebo in the primary endpoint of pea
treadmill performance ranged from =0 G 30 meters depending on the type of treadmill test
performed$
*$ 'ilosta<ol treatment also resulted in a significant o#erall impro#ement in the &uality of life
measures from the 6!K and %,2;?$ !n a study comparing cilosta<ol to pentoxyifylline,
cilosta<ol was more effecti#e$ %ide effects included headache, diarrhea, and palpitations$ An
o#erall safety analysis of *30* patients re#ealed that the rates of serious cardio#ascular
e#ents, and all2cause and cardio#ascular mortality was similar between drug and placebo
groups$
;$ .owe#er, since the drug is in the phosphodiesterase !!! inhibitor class of drugs, it should not be
gi#en to patients with any e#idence of congesti#e heart failure because of a theoretical
concern for increased ris of mortality$ This drug has the best o#erall e#idence for treatment
benefit in patients with claudication$
(c) Drugs with insufficient e#idence of clinical utility in claudication
(i) Pentoxyifylline
1$ Pentoxyifylline lowers fibrinogen le#els, impro#es red cell and white cell deformability and thus
lowers blood #iscosity$ 6hile early trials were positi#e on the endpoint of impro#ement in
treadmill exercise performance, later studies demonstrated that pentoxifylline was no more
effecti#e than placebo on impro#ing treadmill waling distance or functional status assessed
by &uestionnaires$ %e#eral meta2analyses ha#e concluded that the drug is associated with
modest increases in treadmill waling distance o#er placebo, but the o#erall clinical benefits
were &uestionable$ The clinical benefits of pentoxifylline in impro#ing patient2assessed &uality
of life ha#e not been extensi#ely e#aluated$ 6hile tolerability of the drug is acceptable,
pentoxifylline does not ha#e an extensi#e safety database$
(ii) Antithrombotic agents
1$ AspirinAA%A and other antiplatelet agents (clopidogrel) are important in the long2term treatment
of patients with PAD to reduce their ris of cardio#ascular e#ents with well established
efficacy$ .owe#er, no studies ha#e shown a benefit of antiplatelet or anticoagulant drugs in
the treatment of claudication$
(iii) Vasodilators
1$ Arteriolar #asodilators were the first class of agents used to treat claudication$ Examples
include drugs that inhibit the sympathetic ner#ous system (alpha blocers), direct2acting
#asodilators (papa#erine), beta*2adrenergic agonists (nylidrin), calcium channel blocers
(nifedipine) and angiotensin2con#erting en<yme inhibitors$ These drugs ha#e not been shown
to ha#e clinical efficacy in randomin<ed, controlled trials$
*$ There are se#eral theoretical reasons why #asodilators may not be effecti#e, including the
possibility that #asodilator drugs may create a steal phenomenon by dilating #essels in
normally perfused tissues thus shifting the distribution of blood flow away from muscles
supplied by obstructed arteries$
(d) Recommendation 15: Pharmacotherapy for symptoms of !'
A ;2 to ?2 month course of cilosta<ol should be first2line pharmacotherapy for the relief of
claudication symptoms, as e#idence shows both an impro#ement in treadmill exercise
performance and in &uality of life
3) 'hronic 'ritical )imb !schemia
a) -omenclature and Definitions
i) 'ritical limb ischemia (')!) is a manifestation of PAD that describes patients with typical chronic ischemic rest
pain or patients with ischemic sin lesions, either ulcers or gangrene$ The term ')! should only be used in
relation to patients with chronic ischemic disease, defined as the presence of symptoms for more than *
wees$ !t is important to note in this section that there are limited data a#ailability compared with the other
sections$ ')! populations are difficult to study, with large numbers of patients lost to follow2up or dying in
longitudinal studies, leading to incomplete data sets$
ii) 'lassification of Peripheral Arterial Disease: ,ontaineCs and +utherford 'ategories
'ontaine R(ther"ord
)ta*e Clinical +rade Cate*or, Clinical
! Asymptomatic 0 0 Asymptomatic
!!a >ild claudication ! 1 >ild claudication
!!b >oderate to se#ere claudication ! * >oderate claudication
! ; %e#ere claudication
!!! !schemic rest pain !! 7 !schemic rest pain
!B "lceration or gangrene !!! = >inor tissue loss
!!! ? >a@or tissue loss
iii) The diagnosis of ')! should be confirmed by the AB!, toe systolic pressure or transcutaneous oxygen tension$
!schemic rest pain most commonly occurs below an anle pressure of =0 mm.g or a toe pressure less than
;0 mm.g$ 9ther causes of pain at rest should, therefore, be considered in a patient with an anle pressure
abo#e =0 mm.g, although ')! could be the cause$
i#) %ome ulcers are entirely ischemic in etiologyD others initially ha#e other causes (e$g$ traumatic, #enous, or
neuropathic) but will not heal because of the se#erity of the underlying PAD$ .ealing re&uires an inflammatory
response and additional perfusion abo#e that re&uired for supporting intact sin and underlying tissues$ The
anle and toe pressure le#els needed for healing are, therefore, higher than the pressures found in ischemic
rest pain$ ,or patients with ulcers or gangrene, the presence of ')! is suggested by anle pressures less than
30 mm.g or a toe systolic pressure less than =0 mm.g$ (!t is important to understand that there is not
complete consensus regarding the #ascular hemodynamic parameters re&uired to mae the diagnosis of
')!$)
#) Recommendation 16: 'linical definition of ')!
The term critical limb ischemia should be used for all patients with chronic ischemic rest pain, ulcers
or gangrene attributable to ob@ecti#ely pro#en arterial occlusi#e disease$ The term ')! implies
chronicity and is to be distinguished from acute limb ischemia$
#i) Patients presumed at ris for critical limb ischemia
(1) -atural history studies of claudication document that few patients progress to ')!$ >any patients who
present with ')! are asymptomatic prior to its de#elopment$ .owe#er, research in this area is lacing,
understandably, for patients who are asymptomatic and can only be detected by more routine AB! testing$
b) Prognosis
i) !t is important to diagnosis ')! because it confers a prognosis of high ris for limb loss and for fatal and non2
fatal #ascular e#ents, myocardial infarction and stroe$ !n general, the prognosis is much worse than that of
patients with intermittent claudication$ 9bser#ational studies of patients with ')! who are not candidates for
re#asculari<ation suggest that a year after the onset of ')!, only about half the patients will be ali#e without a
ma@or amputation, although some of these may still ha#e rest pain, gangrene, or ulcers$ Approximately *=5
will ha#e died and *=5 will ha#e re&uired a ma@or amputation$ Their prognosis is in many ways similar to that
of some malignancies$
ii) The diagnosis of ')! thus predicts a poor prognosis for life and limb$ Patients should ha#e aggressi#e
modification of their cardio#ascular ris factors and should be prescribed anti2platelet drugs$ "ltimately, much
of the care of ')! patients is palliati#e in nature, an issue that is #ery important when considering
re#asculari<ation or amputation$
iii) Recommendation 17: 'ardio#ascular ris modification in critical limb ischemia
')! patients should ha#e aggressi#e modification of their cardio#ascular ris factors$
c) 'linical Presentation and E#aluation
i) Pain
(1) ')! is dominated by pedal pain (except in diabetic patients, where superficial pain sensation may be
altered and they may experience only deep ischemic pain, such as calf claudication and ischemic rest
pain)$ !n most cases, the pedal pain is intolerably se#ereD it may respond to foot dependency, but
otherwise responds only to opiates$ The pain is caused by ischemia, areas of tissue loss, ischemic
neuropathy or a combination of theseD it occurs or worsens with reduction of perfusion pressure$ !n most
cases, waling capacity is #ery se#erely impaired, with waling often becoming almost impossible$
(*) !schemic rest pain most typically occurs at night (when the limb is no longer in a dependent position) but in
se#ere cases can be continuous$ The pain is locali<ed in the distal part of the foot or in the #icinity of an
ischemic ulcer or gangrenous toe$ The pain often waes the patients at night and forces them to rub the
foot, get up, or tae a short wal around the room$ Partial relief may be obtained by the dependent
position, whereas ele#ation and cold increase the se#erity of the pain$ 9ften patients sleep with their
ischemic leg dangling o#er the side of the bed, or sitting in an armchairD as a conse&uence anle and foot
edema de#elop$ !n se#ere cases, sleep becomes impossible because pain sets in after only a short
period of supine rest, causing in many patients a progressi#e further decline of their general physical and
psychological condition$
(;) !schemic rest pain is often accompanied by pain caused by peripheral ischemic neuropathy, the
mechanism of which is not well established$ This results in se#ere, sharp, shooting pain that does not
necessarily follow the anatomic distribution of the ner#es but usually is most pronounced at the distal part
of the extremity$ The pain often occurs at night, with episodes lasting minutes to hours but with constant
diffuse pain remaining in between$ !schemic rest pain should not be confused with neuropathic pain$
ii) "lcer and gangrene
(1) Patients with ')! may also present with ischemic ulcers or gangrene$ !t is important to note that some
patients may progress through rest pain into tissue loss$ .owe#er, in many patients, notably those with
diabetic neuropathy, the initial presentation is with a neuroischemic ulcer or gangrene$ There are
significant differences between patients with and without diabetes at this stage of ')!$
(*) 8angrene usually affects the digits in a bedridden patient, the heel (as this is a pressure point)$ !n se#ere
cases, gangrene may in#ol#e the distal parts of the forefoot$ !t is usually initiated by a minor local trauma$
)ocal pressure (ill fitting shoes) or the use of local heat (increasing metabolic demands) can also lead to
ulcer and gangrene formation on other locations on the foot or leg$ 8angrenous tissue, if not infected, can
form an eschar, shrin and e#entually mummify and, if the underlying circulation is ade&uate enough (or
has been made ade&uate enough by treatment) to support the process, spontaneous amputation may
follow$
(;) !n contrast to the focal and proximal atherosclerotic lesions of PAD found typically in other high2ris
patients, in patients with ')! and diabetes the occlusi#e lesions are more liely to be more diffuse and
distally located, particularly in infrageniculate arteries$ !mportantly, PAD in patients with diabetes is usually
accompanied by peripheral neuropathy with impaired sensory feedbac, enabling the silent progression of
the ischemic process$ Thus, a patient with diabetes and se#ere, asymptomatic PAD could also ha#e a
Npi#otal e#entC that leads acutely to an ischemic ulcer and a limb2threatening situation$ A common example
is the use of new, tight or ill fitting shoes in a patient with neuropathy$ Thus, an asymptomatic, usually
undiagnosed patients can lapse, apparently abruptly, into ')!$ By identifying a patient with sub2clinical
disease and instituting pre#enti#e measures, it may be possible to a#oid ')! or at least prompt early
referral if the patient de#elops ')!$
iii) Differential diagnosis of ulcers
(1) The ma@ority of lower2leg ulcers abo#e the anle ha#e a #enous origin whereas ulcers in the foot are most
liely due to arterial insufficiency$
(*) 'haracteristics of common foot and leg ulcers$
%ri*in Ca(e Location Pain -$$earance Role o"
revac(lari.ation
Arterial %e#ere PAD,
BuergerCs
Toes, foot, anle %e#ere Barious shape,
pale base, dry
!mportant
Benous Benous
insufficiency
>alleolar,
especially medial
>ild !rregular, pin
base, moist
-one
>ixed
#enousAarterial
Benous
insufficiency O
PAD
"sually malleolar >ild !rregular, pin
base
!f non2healing
%in infarct %ystemic
disease,
embolism
)ower third of
leg, malleolar
%e#ere %mall, often
multiple
-one
-europathic -europathy
from diabetes,
#itamin
deficiency
,ootAplantar
surface (6eight2
bearing),
associated
deformity
-one %urrounding
callus, often
deep, infected
-one
-euroischemic Diabetic
neuropathy O
ischemia
)ocations
common to both
ischemic and
neuroischemic
as arterial
+educed
due to
neuropathy
As arterial As arterial
(;) Recommendation 18: E#aluation of PAD in patients with diabetes
All diabetic patients with an ulceration should be e#aluated for PAD using ob@ecti#e testing
d) Differential diagnosis of ischemic rest pain
i) Diabetic neuropathy
(1) Diabetic neuropathy usually results in a decrease in sensation$ !n some patients, neuropathy can result in
se#ere, seriously disabling pain in the foot$ This is often described as a burning or shooting sensation that
is fre&uently worse at night, when there is less distraction, maing it more difficult to distinguish from
atypical ischemic rest pain$ (!t should be noted that this type of pain is seen in the relati#ely early NneuriticC
phase of diabetic neuropathy, often before diabetic neuropathy has become clinically recogni<ed)
(*) Diagnostic features that may be helpful in distinguishing diabetic neuropathy from ischemic rest pain are a
symmetrical distribution in both legs, association with cutaneous hypersensiti#ity and failure to relie#e it
by dependency of the foot$ The patient may ha#e other signs of a diabetic neuropathy, such as decreased
#ibratory sensation and decreased reflexes$
ii) -er#e root compression
(1) A number of spinal conditions may result in ner#e root compression, gi#ing rise to continuous pain$ !t is
typically associated with bacache and the pain distribution following one of the lumbosacral dermatomes$
e) !n#estigation of critical limb ischemia
i) Physical examination
(1) As a ma@ority of patients with ')! ha#e not suffered earlier symptoms of PAD (intermittent claudication) it is
important to ha#e the diagnosis of ')! in mind when examining any patient with leg pain or ulcer
de#elopment
(*) The first step is to document the location and &uality of the pulses$ 9ther less specific findings may include
hair loss, muscle atrophy, atrophy of subcutaneous tissues and sin and appendages, dry fissured sin,
discoloration and dependent hyperemia$
(;) !n patients with ulcers there may be other etiologies besides arterial disease$ %welling is usually only a
feature when there is acti#e infection or rest pain that pre#ents patients from ele#ating their foot at night$
ii) Recommendation 19: Diagnosis of ')!
')! is a clinical diagnosis but should be supported by ob@ecti#e tests
iii) Recommendation 20: !ndications for e#aluation for ')!
All patients with ischemic rest pain symptoms or pedal ulcers should be e#aluated for ')!
f) Pre#ention of ')!
i) Basics
(1) As with all forms of systemic atherosclerosis, early detection of PAD and aggressi#e management of
cardio#ascular ris factors should reduce the incidence and se#erity of ')!$ ,or example, smoing
cessation is associated with a decreased ris of progression from earlier stages of PAD to ')!$
ii) +is factors associated with the foot
(1) Early identification of the patient who is at ris for ')! is essential in order to recogni<e potential problems
and de#elop pre#entati#e inter#ention strategies to a#oid complications$ Patients with a therosclerosic
PAD, BuergerCs disease, diabetes and any other condition that can cause a loss of protecti#e sensation to
the foot or interferes with wound healing are at ris of de#eloping ulcerations and a future amputation$
Persons with diabetes are at a higher ris for de#eloping lower extremity complications$ A thorough foot
examination will assist in identifying those patients who are at ris$ 9nce an indi#idual is classified as high
ris, a #isual foot inspection should be performed at e#ery #isit and referral to a foot care speciali<e for
further assessment is recommended$
iii) Recommendation 21: !mportance of early idenfication of PAD
Early identification of patients with PAD at ris of de#eloping foot problems is essential for limb
preser#ation$ This can be achie#ed by daily #isual examination by the patient or their family and, at
e#ery #isit referral to foot specialist$
g) Treatment
i) 9#erall strategy
(1) The primary goals of the treatment of ')! are to relie#e ischemic pain, heal (neuro)ischemic ulcers,
pre#ent limb loss, impro#e patient function and &uality of life and prolong sur#i#al$ A primary outcome
would be amputation2free sur#i#al$ !n order to achie#e these outcomes, most patients will ultimately need
a re#asculari<ation procedure re&uiring referral to a #ascular specialist$
(*) 9ther components of treatment of patients with ')! are medical inter#entions to control pain and infection
in the ischemic leg, pre#ention of progression of the systemic atherosclerosis, and optimi<ation of cardiac
and respiratory function$ ,or some ')! patients with se#ere co2morbidities or a #ery limited chance of
successful re#asculari<ation, a primary amputation may be the most appropriate treatment$
'ardio#ascular ris factor control is mandatory in ')! patients as well as in all PAD patients$
ii) Basic treatment: pain control
(1) Pain management is essential in impro#ing function and &uality of life$ The hallmar of ')! is ischemic
rest pain and painful ulcerations$ Pain is usually located to sin and possibly bone structures$ Pain control
is a critical aspect of the management of these patients$ !deally, relief of pain is achie#ed by reperfusion of
the extremity$ .owe#er, while planning the re#asculari<ation, ade&uate pain control must be a goal of
management in all patients$ ,urthermore, in patients for whom re#ascuarli<ation is not an option, narcotic
pain relief is commonly used$
(*) Physicians should assess pain se#erity and ade&uacy of pain relief in all patients at regular #isits$ !nitial
attempts at pain relief should include the use of acetaminophenAparacetamol or non2steroidal anti2
inflammatory medications, although the latter are rarely effecti#e and narcotic medications are fre&uently
re&uired$ 'aution should be used in the latter in patients with hypertension, or renal insufficiency$ 'ontrol
of pain is usually more effecti#e if analgesia is gi#en regularly rather than on demand$ Placing the affected
limb in the dependent position pro#ides partial relief of ischemic pain in some patients$ Therefore, tilting
the bed downward may be a helpful measure in addition to analgesia$ Patients with ')! Are often
depressed and pain control can be impro#ed by use of antidepressant medications$
(;) Recommendation 22: Early referral in ')!
Patients with ')! should be referred to a #ascular specialist early in the course of their disease to
plan for re#asculari<ation options
(7) Recommendation 23: >ultidisciplinary approach to treatment of ')!
A multidisciplinary approach is optimal to control pain, cardio#ascular ris factors and other co2morbid
disease
iii) +e#asculari<ation
(1) The natural history of ')! is such that inter#ention is indicated to sal#age a useful and pain2free extremity$
The treatment chosen depends upon the pre2morbid condition of patient and the extremity as well as
estimating the ris of inter#ention based on co2morbid conditions and the expected patency and durability
of the reconstruction$ !n ')!, multi2le#el disease is fre&uently encountered$ Ade&uate inflow must be
established prior to impro#ements in the outflow$
(*) After re#asculari<ation, ulcer healing may re&uire ad@uncti#e treatments that may be best achie#ed in
collaboration between the #ascular specialist and specialists in foot care$
(;) Recommendation 24: 9ptimal treatment for patients with ')!
+e#asculari<ation is the optimal treatment for patients with ')!
(7) Recommendation 25: Treatment for infections in ')!
%ystemic antibiotic therapy is re&uired in ')! patients who de#elop cellulitis or spreading infection
(=) Recommendation 26: >ultidisciplinary care in ')!
Patients with ')! who de#elop foot ulceration re&uire multidisciplinary care to a#oid limb loss$
i#) Amputation
(1) >a@or amputation (abo#e the anle) in ')! is necessary and indicated when there is o#erwhelming
infection that threatens the patientCs life, when rest pain cannot be controlled, or when extensi#e necrosis
has destroyed the foot$ "sing these criteria, the number of ma@or limb amputations should be limited$
(*) !t is the implicit goal of amputation to obtain primary healing of the lower extremity at the most distal le#el
possible$ The energy expenditure of ambulation increases as the le#el of amputation rises from calf to
thigh$ Preser#ation of the nee @oint and a significantly length of the tibia permits the use of lightweight
prostheses, minimi<es the energy of ambulation, and enables older or more frail patients to wal
independently$ Therefore, the lowest le#el of amputation that will heal is the ideal site for limb transaction$
(;) Recommendation 27: Amputation decisions in ')!
The decision to amputate and the choice of the le#el should tae into consideration the potential for
healing, rehabilitation and return of &uality of life$
#) Pharomacotherapy for ')!
(1) Antiplatelet drugs
(a) Although long2term treatment with aspirinAA%A and ticlopidine may reduce progression of femoral
atherosclerosis and exert a beneficial effect on the patency of peripheral by2passes$ There is no
e#idence that these drugs would impro#e outcomes in ')!$ .owe#er, as in all patients with PAD,
antiplatelet drugs do reduce the ris of systemic #ascular e#ents
#i) ,uture Aspects of Treatment of ')!
(1) The most striing feature of ')! is the dismal prognosis for both life and limb outcomes no matter what
treatment is employed$ This is because most patients ha#e generali<ed atherosclerosis$ 9ne may,
therefore, consider what magnitude of treatment options is realistic for the single patient$ A successful
re#asculari<ation may reduce pain and impro#e &uality of life for a limited period of time, but fre&uently
this goal is not achie#ed$ Amputation may be a good alternati#e to reduce pain, though amputees may
ha#e an e#en more reduced life expectancy$ >edical treatment that fa#orably modifies cardio#ascular ris
is recommended for all patients, while symptomatic treatment of the limb has to be indi#iduali<ed$
4) Acute )imb !schemia (A)!)
a) Definition and -omenclature
i) DefinitionAetiology of Acute )imb !schemia
(1) Acute limb ischemia (A)!) is any sudden decrease in limb perfusion causing a potential threat to limb
#iability$ Presentation is normally up to * wees following the acute e#ent$
b) E#aluation
i) 'linical e#aluation of Acute )imb !schemia
(1) .istory
(a) Basics
(i) The history should ha#e two primary aims: &uerying leg symptoms relati#e to the presence and
se#erity of limb ischemia (present illness) and obtaining bacground information (e$g$ history of
claudication, recent inter#ention on the proximal arteries or diagnostic cardiac catheteri<ation),
pertaining to etiology, differential diagnosis and the presence of significant concurrent disease$
(b) Present Illness
(i) )eg symptoms in A)! relate primarily to pain or function$ The abruptness and time of onset of the
pain, its location and intensity, as well as change in se#erity o#er time, should all be explored$ The
duration and intensity of the pain and presence of motor or sensory changes are #ery important in
clinical decision2maing and urgency of re#asculari<ation$ ,or example, thrombolysis may be less
effecti#e for thrombosis of F* wees duration compared with more acute thrombosis$
(c) Past history
(i) !t is important to as whether the patient has had leg pain before (e$g$ a history of claudication),
whether there ha#e been inter#entions for Npoor circulationC in the past, and whether the patient
has been diagnosed as ha#ing heart disease (e$g$ atrial fibrillation) or aneurysms (i$e$ possible
embolic sources)$ The patient should also be ased about serious concurrent disease or
atherosclerotic ris factors (hypertension, diabetes, tobacco abuse, hyperlipidemia, family history
of cardio#ascular disease, stroes, blood clots or amputations$)
(*) Physical examination
(a) The findings of A)! may include = Ps
Pain: Time of onset, location and intensity, change o#er time
P(lelene: the accuracy of pedal pulse palpation is highly #ariable and, therefore, absent pulse
findings are suggesti#e but not diagnostic of A)! and palpable pulses alone do not rule it out$ Bedside
measurement of anle blood pressure should be performed immediately$ "sually, #ery low pressure is
obtained or the Doppler signal may be absent$ !f performed correctly, the finding of absent flow
signals in the foot arteries is highly consistent with a diagnosis of A)!
Pallor: 'hange in color and temperature is a common finding in A)! (although temperature may be
sub@ect to en#ironmental conditions)D the finding is most important when different from the
contralateral limb$ Benous filling may be slow or absent
Paretheia: -umbness occurs in more than half the patient
Paral,i: Poor prognostic sign
(;) Recommendation 29: Assessment of A)!
Due to inaccuracy of pulse palpation and the physical examination, all patients with suspected
A)! should ha#e Doppler assessment of peripheral pulses immediately at presentation to
determine if a flow signal is present$
ii) 'linical 'lassification of A)!
(1) Basics
(a) The main &uestion to be answered by the history and physical examination is the se#erity of the A)!,
which is the ma@or consideration in early management decisions$ !% the limb #iable (if there is no
further progression in the se#erity of ischemia), is its #iability immediately threatened (if perfusion is
not restored &uicly), or are there already irre#ersible changes that preclude foot sal#ageP
(b) Three findings that help separate NthreatenedC from N#iableC extremities
Presence of rest pain
%ensory loss
>uscle weaness
(c) >uscle rigor, tenderness, or findings of pain with passi#e mo#ement are later signs of ad#anced
ischemia and probable tissue loss$
(*) Recommendation 30: 'ases of suspected A)!
All patients with suspected A)! should be e#aluated immediately by a #ascular specialist who
should direct immediate decision maing and perform re#asculari<ation because irre#ersible
ner#e and muscle damage may occur within hours$
iii) Differential Diagnosis
(1) Arterial trauma or dissection
(a) 9#ert arterial trauma is not difficult to diagnose, but iatrogenic trauma, especially as a result of recent
arterial catheteri<ation, is often o#erlooed$ !t should be considered in all hospitali<ed patients
undergoing in#asi#e diagnosis and treatment who present with femoral artery occlusion$
(*) Thromboembolism
(a) Arterial embolism is suspected in patients with atrial arrhythmia (flutterAfibrillation), congesti#e heart
failure, or #al#ular heart disease$ A rare cause can be paradoxical emboli<ation in a patient with
#enous thromboembolism and a cardiac septal defect$ The contralateral limb is often normal$ Patients
usually do not ha#e any antecedent claudication symptoms$
(b) Arteriographic findings include multiple areas with arterial filling defects (particularly at bifurcations),
morphology (meniscus sign) consistent with embolus, lac of collaterals and absence of
atherosclerotic disease in unaffected segments$ Echocardiography (often transesophageal) is useful
to locate the source of thromboemboli$
i#) >anagement
(1) Recommendation 31: Anticoagulant therapy in A)!
!mmediate parenteral anticoagulant therapy is indicated in all patients with A)!$ !n patients
expected to undergo imminent imaging therapy on arri#al, heparin should be gi#en$
c) Treatment of A)!
i) Basics
(1) The initial goal of treatment for A)! is to pre#ent thrombus propagation and worsening ischemia$
Therefore, immediate anticoagulation with heparin is indicated$ The standard therapy (except in cases of
heparin antibodies) is unfractionated heparin intra#ensouly$ Based on the results of randomi<ed trials,
there is no clear superiority for thrombolysis #ersus surgery on ;0 day limb sal#age or mortality$ Access to
each is a ma@or tissue, as time is often critical$ -ational registry data from Europe and the "nited %tates
indicate that surgery is used three2 to fi#e2fold more fre&uently than thrombolysis$
ii) %urgery
(1) !ndications
(a) !mmediate re#asculari<ation is indicated for the profoundly ischemic limb (class !!b)$ !t may also be
considered in those with profound sensory and motor deficits of #ery short duration, as
re#ascuarli<ation completed within a few hours of onset of se#ere symptoms may produce
remarable reco#ery$ Beyond this short window, ma@or neuromuscular damage is ine#itable$ The
method of re#asculari<ation (open surgical or endo#ascular) may differ depending on anatomic
location of occlusion, etiology of A)!, contraindications to open or endo#ascular treatment and local
practice patterns$
(b) Pre#iously, urgency of treatment made surgery the treatment of choice in many cases$ .owe#er,
recent methodological ad#ances within endo#ascular management, and recognition that impro#ed
circulation significantly precedes patency with his approach, ha#e made the time factor less important
if endo#ascular ser#ice is readily a#ailable$
1) +e#asculari<ation
a) )ocali<ation of disease
i) The determination of the best method of re#asculari<ation for treatment of symptomatic PAD is based upon the
balance between the ris of a specific inter#ention and the degree and durability of the impro#ements that can
be expected from this inter#ention$ Ade&uate inflow and appropriate outflow are re&uired to eep the
re#asculari<ed segment functioning$ The location and morphology of the disease must be characteri<ed prior
to carrying out any re#asculari<ation to determine the most appropriate inter#ention$ A #ariety of methods
yielding both anatomic and physiologic information are a#ailable to assess the arterial circulation$
10) -on2in#asi#e Bascular )aboratory and !maging
a) -on2in#asi#e Bascular )aboratory
i) Basics
(1) The routine e#aluation of patients with PAD can include a referral to the #ascular laboratory$ -on2in#asi#e
hemodynamic measurements can pro#ide an initial assessment of the location and se#erity of the arterial
disease$ These tests can be repeated o#er time to follow disease progression$
ii) %egmental limb systolic pressure measurement (%)P)
(1) %egmental limb pressure measurements are widely used to detect and segmentally locali<e
hemodynamically significant large2#essel occlusi#e lesions in the ma@or arteries of the lower extremities$
%egmental pressure measurements are obtained in the thigh and calf in the same fashion as the anle
pressure$ A sphygmomanometer cuff is placed at a gi#en le#el with a Doppler probe o#er one of the pedal
arteries, and the systolic pressure in the ma@or arteries under the cuff is measured$ The location of
occlusi#e lesions is apparent from the pressure gradients between the different cuffs$
(*) )imitations of the method include:
(a) >issing isolated moderate stenosis (usually iliac) that produce little or no pressure gradient at rest
(b) ,alsely ele#ated pressures in patients with diabetes calcified, incompressible arteries
(c) The inability to differentiate between arterial stenosis or occlusion
iii) %egmental plethysmography or pulse #olume recordings (PB+)
(1) A plethysmograph is an instrument that detects and graphically records changes in limb #olume$ )imb
cuffs are placed around the leg at selected locations and connected to a plethysmograph, which produces
a pulse #olume recording (PB+)$ -ormally, a single large thigh cuff is used along with a regular2si<ed calf
and anle cuffs, plus a brachial cuff that reflects the undampened cardiac contribution to arterial pulsatility$
The latter is useful in standardi<ing the lower2limb PB+ and in detecting poor cardiac function as a cause
of low2amplitude tracings$ To obtain accurate PB+ wa#eforms the cuff inflated to Q?0 G ?= mm.g, which
is sufficient to detect #olume changes without resulting in arterial occlusion$
(*) %)P and PB+ measurements alone are 4=5 accurate compared with angiography in detecting and
locali<ing significant occlusi#e lesions$ ,urthermore, when used together, the accuracy approached 1=5$
,or this reason, these two diagnostic methods are commonly used together when e#aluating PAD$ "sing
%)P and PB+ in combination ensures that patients with diabetes who ha#e calcified arteries sufficient to
produce falsely ele#ated %)P will be readily recogni<ed and correctly assessed by PB+$
b) !maging Techni&ues
i) Angiography
(1) Angiography, considered the Rgold standardS imaging test, carries certain riss: approximately 0$15 ris of
se#ere reaction to contrast medium, 0$35 complications ris se#ere enough to alter patient management,
and 0$1?5 mortality ris and significant expense$ 9ther complications include arterial dissection,
atheroemboli, contrast2induced renal failure and access site complications (i$e$ pseudoanerysm,
arterio#enous fistula and hematoma)$
(*) These problems ha#e been greatly mitigated by technological impro#ements in the procedure, including
the use of nonionic contrast agents, digital subtraction aigography, intra2aterial pressure measurements
across a stenosis with and without #asodilator (significant pea systolic difference = G 10 mm.g pre2
#asodilation and 10 G 1= mm.g post2#asodilation), and more sophisticated image pro@ection and retention
(;) Alternati#ely, carbon dioxide and magnetic resonance contrast agents (i$e$ gadolinium) can be used
instead of con#entional contrast media$ !n high2ris (e$g$ renal impairment) patients, restriction to a partial
study with selected #iews rather than #isuali<ing the entire infrarenal arterial tree has decreased the
contrast load, length of study and associated riss$ Despite this, full angiography, with #isuali<ation from
the le#el of the renal arteries to the pedal arteries using digital substraction angiography (D%A)
techni&ues, remain the choice in most cases$
ii) Recommendation 43: !ndications and methods to locali<e arterial lesions
Patients with intermittent claudication who continue to experience limitations to their &uality of life
after appropriate medical therapy (Exercise rehabilitation andAor pharmacotherapy) or patients with
critical limb ischemia, may be considered for re#asculari<ation if they meet the following additional
criteria
o A suitable lesion for re#ascluarli<ation is identified
o The patient does not ha#e any systemic contraindications for the procedure
o The patient desire additional therapy
!nitial disease locali<ation can be obtained with hemodynamic measures including segmental limb
pressures or pulse #olume recording
6hen anatomic locali<ation of arterial occlusi#e lesions is necessary for decision maing, the
following imaging techni&ues are recommended: duplex ultrasonography, magnetic resonance
angiography and computed tomographic angiography (depending on local a#ailability, experience,
and cost$)