79
CHAPTER
Chronic Lower Limb Ischemia:
Management Strategies
Amit Kumar, Atul Mathur
INTRODUCTION
Peripheral arterial disease (PAD) is a term implying obstruction
of blood flow to lower or upper extremities, most commonly
caused by atherosclerosis but can be secondary to embolism,
thrombosis, vasculitis, fibromuscular dysplasia and few other
uncommon conditions.
EPIDEMIOLOGY OF PAD
Peripheral arterial disease affects both men and women and all
ethnic groups. The prevalence increases with age, affecting up to
14–29% of elderly population.1 Risk factors are similar to those of
coronary artery disease (CAD) (Table 1).
NATURAL HISTORY OF PAD
Presence of PAD is a marker of extensive atherosclerosis. Sixty to
eighty percent of patients have CAD in at least 1-vessel.2 Up to
25% of patients have a carotid stenosis of more than 70%.3 Myocardial infarction (MI), stroke and death are common in patients
TABLE 1: Odds ratio of PAD according to risk factors1
Risk factors
Odds ratio (95% CI)
Cigarette smoking
Diabetes mellitus
Hypertension
Hypercholestrolemia
Hyperhomocysteinemia
Chronic kidney disease
Insulin resistance
C-reactive protein
4.46 (2.25–8.84)
2.71(1.03–7.12)
1.75 (0.97–3.13)
1.68 (1.09–2.57)
1.92 (0.95–3.88)
2.00 (1.08–3.70)
2.06 (1.10–4.00)
2.20 (1.30–3.60)
with PAD with a 5-year mortality of 30%4 and a 20% risk of non
fatal MI or stroke over 5 years.4 Figure 1 shows survival trend in
patients with PAD.5
CLINICAL PRESENTATION
Symptoms
Intermittent claudication is the most typical presentation in
patients with PAD. Severe PAD, including those of embolic or
thrombotic origin can present with rest pain. Location of pain
correlates to the site of obstruction, e.g. hip or thigh pain points
to aortoiliac disease. Fontaine has devised classification of PAD
based on the severity of symptoms (Table 2).
Physical Findings
Absent or diminished pulses, discrepant blood pressure between
arms or legs or vascular bruit are important signs. Presence of
pallor or cyanosis, dependent rubor, ulceration or gangrene
suggests PAD and are more often seen in patients with severe
form of the disease. Pallor can be elicited by repeated dorsiflexion
and plantarflexion of foot after raising it above the heart level.
The legs are then placed in dependent position and time of return
of hyperemia noted. Non-healing ulcers, gangrene and ischemic
rest pain are features of critical limb ischemia (CLI) and warrant
urgent referral to interventionist or vascular surgeon.
Longstanding ischemia may manifest as muscle atrophy,
hair loss, thick and brittle toenails, loss of subcutaneous fat
and smooth shiny skin. The six Ps of pain, pallor, pulselessness,
paresthesia, paralysis and poikilothermia (cold limb) are seen
in patients with acute limb ischemia (ALI) and is a vascular
emergency requiring immediate hospitalization and vascular
intervention.
524
SECTION 7: Peripheral Vascular Intervention
Fig. 1: Kaplan-Meier survival curves based on mortality from all causes among normal subjects and subjects with symptomatic or
asymptomatic large-vessel peripheral arterial disease (LV-PAD)
Ankle-Brachial Index—The Key to
Diagnosis of PAD
Normal resting ABI does not always rule out PAD. If the ABI is
borderline or normal and the clinical suspicion of PAD is high,
ABI should be repeated after exercise. Treadmill protocol or
standing calf raises can be undertaken. ABI may fall by 20% or
more in patients with significant PAD, especially in patients
with aortoiliac disease. An ABI greater than 1.3 is not normal
and is consistent with the presence of non-compressible vessels
(medial calcinosis) (Table 3). This is more commonly seen
in patients with diabetes mellitus, chronic kidney disease or
obesity. Confirmation of PAD in these patients requires imaging
modalities.
IMAGING STUDIES
Commonly used imaging modalities are duplex ultrasound, MR
angiography, CT angiography and conventional angiography.
Color-coded duplex ultrasound is an effective noninvasive
TABLE 2: Fontaine classification
Stage
Symptoms
I
II
IIa
IIb
III
IV
Asymptomatic
Intermittent claudication
Claudication on walking >200 m
Claudication on walking <200 m
Rest and nocturnal pain
Necrosis, gangrene
TABLE 3: Ankle–brachial index
ABI = Ankle Systolic Pressure/Brachial Systolic Pressure
Normal
Borderline
PAD
Severe PAD
Non-compressible
ABI
ABI
ABI
ABI
ABI
1.00–1.30
0.91–0.99
≤0.90
≤0.40
>1.30
Abbreviations: PAD, peripheral arterial disease; ABI, ankle–brachial index
means for diagnosing and assessing the severity of peripheral
arterial stenosis. A twofold increase in systolic velocity at the site
of stenosis is suggestive of 50% or greater stenosis. A threefold
increase would suggest 75% or greater stenosis. With critical
stenosis, the peak systolic velocity falls and the flow distal to
stenosis becomes monophasic. The sensitivity and specificity
of duplex ultrasound is more than 90% when compared with
angiography. CT angiography permits excellent spatial resolution,
can measure the length of total occlusion and can visualize
collaterals. The images can be displayed in three dimensions and
can be rotated for better assessment. It is now an important tool in
planning vascular intervention. MR Angiography has sensitivity
and specificity similar to that of CT angiography in the diagnosis
of PAD and is used in place of CT angiography in patients with
renal, allergic or other complications. Conventional angiography
is most important as it gives on-site information during vascular
intervention.
MANAGEMENT OF LOWER
EXTREMITY PAD
There are two main goals of management:
1. Prevention of myocardial infarction, stroke, and deaths.
2. Treat leg symptoms and prevent amputation.
Smoking cessation, antiplatelets, lipid lowering therapy
(Heart Protection Study included 3,748 patients with
symptomatic PAD and no known CAD), good blood pressure
control and intensive glycemic control are important aspects in
the prevention of CAD and slowing down of further deterioration
of PAD. CAPRIE (clopidogrel versus aspirin in patients at risk of
ischemic events) study6 demonstrated incremental benefit of
clopidogrel over aspirin. Unfortunately antiplatelets still remains
underprescribed in patients with PAD as compared to patients
with CAD.
Statins have been shown to slow the rate of functional decline
among patients with PAD. Statins are associated with improved
patency of infrainguinal bypass grafts. Heart Protection Study7
which included 3,748 patients with symptomatic PAD and no
known CAD showed significant benefit of simvastatin over
CHAPTER 79: Chronic Lower Limb Ischemia: Management Strategies
placebo in preventing all cause mortality, cardiovascular (CV)
mortality and first major vascular event.
Intensive blood pressure in ABCD (Appropriate Blood
Pressure Control in Diabetes) Trial8 with nisoldipine or
enalapril eliminated inverse relationship of ABI and outcome
as compared to standard therapy. In HOPE (Heart Outcomes
Prevention Evaluation) study9 which included 4,046 patients with
symptomatic PAD, ramipril led to 22% reduction in major CV
events in patients with atherosclerotic vascular disease or diabetes
along with other risk factors. Any class of antihypertensive agents
can be prescribed in patients with PAD. Beta-blockers can be
safely prescribed and are especially important in patients with
underlying CAD or left ventricular (LV) dysfunction.
Pharmacotherapy for PAD
Only two drugs, pentoxyfylline and cilostazol have been
approved for the treatment of claudication in patients with
PAD. Pentoxyfylline, xanthine derivative acts by improving
hemorheologic properties, including its ability to decrease blood
viscosity and improve erythrocyte flexibility. Pentoxyfylline has
only marginal efficacy, increasing walking distance by only 14%
as compared to placebo. Cilostazol is a phosphodiesterase III
inhibitor thereby increasing cAMP concentration and inhibiting
platelet aggregation. Cilostazol has been shown in trials to
improve claudication distance10 (Fig. 2). Cilostazol should not be
used in patients with congestive heart failure of any severity. Few
drugs are under investigation like niacin, l-arginine, serotonin
antagonists, angiogenic factors, stem cell therapy amongst
others.
Critical Limb Ischemia: Endovascular and
Open Surgical Treatment for Limb Salvage
The determination of the best method of revascularization for
treatment of symptomatic PAD depends on the risk of a specific
intervention and the degree and durability of the improvement
that can be expected from the intervention. In general, the
outcomes of revascularization depend upon the extent of the
disease in the subjacent arterial tree (inflow, outflow, the size and
length of the diseased segment), the degree of systemic disease
(comorbid conditions) and the type of procedure performed.
Clinical variables impacting the outcome also include diabetes,
renal failure, smoking and the severity of ischemia.
In infrainguinal arterial obstructive disease, choice of
therapy is guided by the anatomy and extent of disease. Bypass is
preferred in extensive disease with long lesions and percutaneous
transluminal angioplasty (PTA) offered for less extensive disease.
Whatever studies are available do not show superiority of one
over the other.11 Patency following PTA is highest for lesions in
the common iliac artery and progressively decreases for lesions
in more distal vessels. Endovascular treatment of infrainguinal
disease in patients with intermittent claudication is an established
treatment modality. The technical and clinical success rate of
PTA of femoropopliteal artery stenoses in all series exceeds 95%12
in properly chosen cases (Figs 3 and 4).
Endovascular procedures below the popliteal artery are
usually indicated for limb salvage; however, there are no data
comparing endovascular procedures to bypass surgery for
intermittent claudication in this region. Choice of therapy again
is guided by the anatomy and extent of disease.
Endovascular techniques to treat peripheral arterial occlusive
disease include PTA with balloon dilation, stents, atherectomy,
laser, cutting balloons, thermal angioplasty, and fibrinolysis.
Drug-eluting balloon (DEB) is a relatively recent addition
in the armamentarium. Paclitaxel is the primary drug for DEB
because of its rapid uptake and prolonged retention. Though
limited in design the SIROCCO I and II Trials, THUNDER trial
and FemPac trial demonstrated a signal of biological efficacy.
Surgical techniques include aortobifemoral bypass which is
recommended for patients with symptomatic, hemodynamically
significant, aorto-bi-iliac disease requiring intervention. Iliac
endarterectomy, aortoiliac or iliofemoral bypass in the setting
of acceptable aortic inflow should be used for the treatment of
unilateral disease or in conjunction with femoral-femoral bypass
for the treatment of a patient with bilateral iliac artery occlusive
disease if the patient is not a suitable candidate for aortobifemoral
bypass grafting. Axillofemoral bypass is indicated for the
treatment of patients with CLI who have extensive aortoiliac
disease and are not candidates for other types of intervention.
Nearly all studies that have compared vein with prosthetic
conduit for arterial reconstruction of the lower extremity have
demonstrated the superior patency of vein. In its absence,
polytetrafluoroethylene (PTFE) or polyester filament may be
used with an expected lower but acceptable patency rate. The
need for retreatment or revision is greater with synthetic material
over time.
Femoral–tibial bypass grafting with autogenous vein should
rarely be necessary for the treatment of intermittent claudication
because of the increased risk of amputation associated with
failure of such grafts. Bypasses to the tibial arteries with prosthetic
material should be avoided at all costs for the treatment of
the claudicant because of very high risks of graft failure and
amputation.
ACUTE LIMB ISCHEMIA
Fig. 2: Results of four randomized placebo controlled trials of
cilostazol for the treatment of claudication
Acute limb ischemia is any sudden decrease in limb perfusion
causing a potential threat to limb viability. Presentation is
normally up to 2 weeks following the acute event. The history
should focus on the severity of ALI. Is the limb viable (if there is
no further progression in the severity of ischemia), is its viability
immediately threatened (if perfusion is not restored quickly), or
are there already irreversible changes that preclude foot salvage?13
525
526
SECTION 7: Peripheral Vascular Intervention
A
Type A lesions: (a) Unilateral or bilateral stenosis of CIA; (b) Unilateral or bilateral single, short (<3 cm)
stenosis of EIA
Management: Endovascular therapy is the treatment of choice
B
Type B lesions: (a) Short stenosis of infrarenal aorta; (b) Unilateral CIA
occlusion; (c) Single or multiple stenosis totaling 3–10 cm involving
EIA not extending into CFA; (d) Unilateral occlusion of EIA not involving
the origin of internal iliac or CFA
Management – Endovascular therapy is the preffered treatment
Management: Endovascular treatment is the preferred treatment for
type B lesions and surgery is the preferred treatment for good-risk
patients with type C lesions
C
Type C lesions: (a) Bilateral CIA occlusion; (b) Bilateral EIA stenosis 3–10 cm long not extending into CFA; (c) Unilateral EIA stenosis extending
into CFA; (d) Unilateral EIA occlusion involving the origin of internal iliac artery and/or CFA; (e) Heavily calcified unilateral EIA occlusion with or
without involvement of origin of internal iliac and/or CIA.
Management: Surgery is preferred in good-risk patients
D
Type D lesions: (a) Infrarenal aortoiliac occlusions; (b) Diffuse disease involving the aorta and both iliac arteries; (c) Diffuse multiple stenosis
involving the unilateral CIA, EIA and CFA; (d) Unilateral occlusion of both CIA and EIA; (e) Bilateral occlusion of EIA; (f) Iliac stenosis in patients
requiring open abdominal aortic or iliac surgery like AAA
Management: Surgery is the treatment of choice
Fig. 3: TransAtlantic Inter-Society Consensus (TASC) classification of aortoiliac lesions and the preferred treatment option
Abbreviations: CIA, common iliac artery; EIA, external iliac artery; CFA, common femoral artery; AAA, abdominal aortic aneurysm
CHAPTER 79: Chronic Lower Limb Ischemia: Management Strategies
Type A lesions: (a) Single stenosis ≤10 cm in length; (b) Single occlusion ≤5 cm in
length
Management: Endovascular therapy is the treatment of choice
Type B lesions: (a) Multiple lesions (stenosis or occlusion), each ≤5 cm; (b) Single stenosis or
occlusion ≤15 cm not involving the infrageniculate popliteal artery; (c) Single or multiple lesion
in absence of continuous tibial vessels to improve inflow for a distal bypass; (d) Heavily calcified
occlusion ≤5 cm; (d) Single popliteal stenosis
Management: Endovascular treatment is the preferred strategy
TASC B and C lesions: Endovascular
treatment is the preferred treatment
for type B lesions and surgery is the
preferred treatment for good-risk
patients with type C lesions
Type C lesions: (a) Multiple stenosis or occlusion totaling ≥15 cm; (b) Recurrent stenosis or occlusion that needs
treatment after two endovascular intervention
Management: Surgery is preferred in good-risk patients
Type D lesions: (a) CTO of CFA or SFA (>20 cm) involving the popliteal
artery; (b) CTO of popliteal artery and proximal trifurcation vessel
Management: Surgery is the treatment of choice for type D lesions
Fig. 4: TransAtlantic Inter-Society Consensus (TASC) classification of femoral popliteal lesions CFA, common femoral artery; SFA, superficial
femoral artery; CTO, chronic total occlusion and the preferred treatment approach
527
528
SECTION 7: Peripheral Vascular Intervention
Arteriography or CT angiography is the preferred imaging modality in this situation. Time is critical in the management of ALI.
Immediate anticoagulation with heparin is indicated. Based on the
results of randomized trials, there is no clear superiority for thrombolysis versus surgery on 30 day limb salvage or mortality. Catheter
directed thrombolysis has a proven role in the management. Advantages of thrombolytic therapy over balloon embolectomy include
the reduced risk of endothelial trauma and clot lysis in branch vessels too small for embolectomy balloons. Percutaneous aspiration
thrombectomy (PAT) and percutaneous mechanical thrombectomy
(PMT) provide alternative nonsurgical modalities for the treatment
of ALI without the use of pharmacologic thrombolytic agents. Combination of these techniques with pharmacologic thrombolysis may
substantially speed up clot lysis, which is important in more advanced ALI where time to revascularization is critical. In practice,
the combination is almost always used.
In cases of suprainguinal occlusion (no femoral pulse) open
surgery may be the preferred choice of treatment. For instance, a
large embolus in the common proximal iliac artery or distal aorta
may most effectively be treated with catheter embolectomy.
Infrainguinal causes of ALI, such as embolism or thrombosis, are
often treated with endovascular methods.
REFERENCES
1.
Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial
disease in the United States: results from the National Health and Nutrition
Examination Survey, 1999-2000. Circulation. 2004;110(6):738-43.
2. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization
before elective major vascular surgery. N Engl J Med. 2004;351(27):
2795-804.
3. RB Klop, Eikelboom BC, Taks AC. Screening of the internal carotid arteries
in patients with peripheral vascular disease by color-flow duplex
scanning. Eur J Vasc Surg. 1991;5(1):41-5.
4. Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic
arterial insufficiency of the lower extremities: a critical review.
Circulation. 1996;94(11):3026-49.
5. Criqui MH ,Langer RD, Fronek A, et al. Mortality over a period of
10 years in patients with peripheral arterial disease. N Engl J Med.
1992;326(6):381-6.
6. Gent M, Beaumont D, Blanchard J, et al. A randomised, blinded, trial
of clopidogrel versus aspirin in patients at risk of ischaemic events
(CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.
7. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol-lowering with simvastatin in 20,536
8.
9.
10.
11.
12.
13.
high-risk individuals: a randomised placebo-controlled trial. Lancet.
2002;360(9326):7-22.
Mehler PS, Coll JR, Estacio R, et al. Intensive blood pressure control
reduces the risk of cardiovascular events in patients with peripheral
arterial disease and type 2 diabetes. Circulation. 2003;107(5);753-6.
Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting–
enzyme inhibitor, ramipril on cardiovascular events in high-risk patients.
The Heart Outcomes Prevention Evaluation Study Investigators. N Engl
J Med. 2000;342(3):145-53.
Hiatt WR. Medical treatment of peripheral arterial disease and
claudication. N Engl J Med. 2001;344(21):1608-21.
Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angioplasty in
severe ischaemia of the leg (BASIL): multicentre, randomised controlled
trial. Lancet. 2005;366(9501):1925-34.
Muradin GS, Bosch JL, Stijnen T, et al. Balloon dilation and stent
implantation for treatment of femoropopliteal arterial disease: metaanalysis. Radiology. 2001;221(1):137-45.
Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for
reports dealing with lower extremity ischemia: revised version. J Vasc
Surg. 1997;26(3):517-38.