105 CHAPTER
Lower Extremity Arterial Disease:
Medical Management and
Decision Making
JESSICA P. SIMONS, WILLIAM P. ROBINSON, and ANDRES SCHANZER
MEDICAL MANAGEMENT 1378
Risk Factor Modification 1378
Exercise Therapy for Claudication 1379
Pharmacologic Treatment of Claudication 1380
Cilostazol 1380
DECISION MAKING FOR
REVASCULARIZATION 1380
Defining Treatment Success 1382
Limb- and Patient-Centered Outcomes 1382
Claudication 1382
Chronic Limb-Threatening Ischemia 1383
Treatment Guidelines According to Anatomic Disease
Classification 1383
Trans-Atlantic Inter-Society Consensus
Classification 1383
Runoff Score 1383
TREATMENT GUIDELINES ACCORDING TO
PRESENTATION 1384
Claudication 1384
Medical Therapy Versus Revascularization 1385
Endovascular Treatment Versus Open Surgery 1386
The management of lower extremity peripheral artery disease
(PAD) represents one of the most challenging problems for the
vascular specialist. Although its worldwide prevalence is
unknown, it is estimated that 8 to 12 million Americans are
affected by lower extremity PAD.1,2 In an analysis of 2381
patients participating in the United States National Health and
Nutrition Examination Survey, the prevalence of PAD was found
to be 4.3% overall, progressively increasing with each decade
of aging: 0.9% (40 to 49 years of age); 2.5% (ages of 50 to
59); 4.7% (ages of 60 to 69); and 14.5% (age >69).3 The
Chronic Limb-Threatening Ischemia 1386
Medical Therapy Versus Revascularization 1387
Limb Amputation Versus Revascularization 1387
Endovascular Treatment Versus Open Surgery 1387
Situational Perfusion Enhancement 1388
BASIL Trial 1388
Threatened Limbs, With or Without Peripheral Arterial
Disease 1389
Impact of Conduit Availability, Preoperative Functional
Status, and Comorbid Disease 1389
Conduit Availability 1389
Influence of Comorbid Conditions and Preoperative
Functional Status 1389
RISK PREDICTION MODELS 1390
ANGIOGENESIS FOR PERIPHERAL ARTERIAL
DISEASE 1390
Future Developments 1392
Future Trends 1393
Decision Analysis 1393
Cost Considerations 1394
Unmet Needs 1394
prevalence of PAD is expected to increase in the United States
and worldwide as the population ages, cigarette smoking persists,
and the epidemics of diabetes mellitus, hypertension, and obesity
continue to grow.2
In accordance with the increasing prevalence of PAD, the
number of lower extremity revascularization procedures has
been increasing; among US Medicare beneficiaries, the number
of revascularizations has increased from 357 to 581 per 100,000
between 1996 and 2006.4 Decisions regarding the management
of lower extremity PAD pose a unique challenge owing to the
1377
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making 1377.e1

Abstract Keywords
Decision making in lower extremity peripheral artery disease peripheral artery disease
represents one of the most challenging and nuanced algorithms exercise therapy
in vascular surgery. Optimal management is highly individualized, lower extremity bypass
tailored to patient-specific goals, factoring in clinical presentation, peripheral intervention
anatomic pattern of disease, conduit availability, functional amputation-free survival
status, perioperative risk, and long-term survival. Medical TASC II
management, principles of decision-making, and future directions
for treatment of peripheral artery disease are discussed herein.
1378 SECTION 15 Lower Extremity Chronic Arterial Disease
complex interplay of factors that must be considered, including
the underlying pathology and its natural history, anatomic defect,
degree of ischemia, availability of conduit, comorbid conditions,
functional status, ambulation potential, and suitability of
anatomy for successful revascularization. Appropriate manage-
ment of lower extremity PAD requires a firm understanding
of these factors for good decision making.
Patients with lower extremity ischemia are typically divided
into two groups—those with intermittent claudication and those
with chronic limb-threatening ischemia (CLTI)—depending
on symptoms at presentation. The term “chronic limb-threatening
ischemia” is now preferred to describe the condition previously
referred to as critical limb ischemia. Claudication and CLTI
are managed differently because of major differences in their
natural histories and expected clinical outcomes after treatment.
In general, there is more consensus among clinicians regarding
decision making for CLTI because the natural history of
untreated CLTI more frequently leads to limb loss than does
claudication. Appropriate decision making requires an under-
standing of the systemic nature of the disease. Patients with
CLTI often have severe associated cardiovascular comorbidities
and are generally older and in poorer health than those with
claudication. Treatment must therefore be structured accordingly.
In contrast, patients with claudication typically seek treatment
for the relief of lifestyle-limiting pain with ambulation. These
patients exhibit a more benign natural history with respect to
limb loss, with amputation rates of 1% to 7% at 5 years and
clinical deterioration of the limb in only 25%.5-7 As with CLTI,
claudication is a marker of significant systemic atherosclerosis,
with associated cardiovascular mortality rates at 1, 5, and 10
years as high as 12%, 42%, and 65%, respectively.5-7 All patients
with PAD require medical management of their cardiovascular
disease, and many also benefit from either endovascular or open
revascularization, as discussed later.
MEDICAL MANAGEMENT
Because atherosclerosis is a systemic disease, the initial treatment
of lower extremity PAD must include risk factor modification.
PAD patients are at significantly increased risk for premature
cardiovascular events, including myocardial infarction (MI),
stroke, and death.8,9 PAD is an important indirect marker for
systemic atherosclerosis.10 Any patient older than 40 years who
is found to have an ankle-brachial index (ABI) of less than 0.90
has significant PAD, even in the absence of symptoms.11 Interest-
ingly, more than 50% of patients with an abnormal ABI fail
to show typical symptoms of claudication or CLTI, owing to
the coexistence of other major comorbidities, a condition
sometimes referred to as “chronic subclinical lower extremity
ischemia.”12 There is wide agreement that risk factor modification
is indicated for any patient with lower extremity PAD, regardless
of symptom presence or severity. Several guidelines have been
published13-17 regarding the use of screening for PAD, including
a clinical practice guideline from the Society for Vascular Surgery
(SVS) Lower Extremity Guidelines Writing Group.18 The authors
recommend accepted preventive strategies for systemic athero-
sclerosis and comprehensive tobacco cessation interventions,
as well as education on signs and symptoms of progression of
PAD to the symptomatic state. As a corollary, a systematic
review of screening for PAD concluded that there was no evidence
for revascularization in patients with asymptomatic PAD,
although screening may help to identify a population in whom
aggressive medical therapy may be warranted to prevent car-
diovascular and cerebrovascular events.19 The natural history
of asymptomatic PAD is also not well studied. Unfortunately,
there are currently no data available to accurately predict which
patients will go on to develop symptoms in the future.
Risk Factor Modification
The risk factors associated with PAD are similar to those clas-
sically linked with coronary artery disease (CAD). Investigators
from the Framingham Heart Study analyzing “factors of risk”
for CAD were first to identify demographic and comorbid
factors independently associated with systemic atherosclerosis.20
Numerous reports since have confirmed that advanced age,
tobacco use, diabetes, dyslipidemia, and hypertension are the
primary risk factors associated with PAD (Fig. 105.1). More
recent studies have identified non-Hispanic black race,3,21 chronic
renal insufficiency,3,22 and elevated homocysteine levels23,24 as
additional factors. All patients with the diagnosis of PAD require
appropriate risk factor modification, regardless of whether more
aggressive therapy is also being contemplated. Risk factor
modification is discussed in detail in Section 2: Atherosclerotic
Risk Factors.
Odds ratio
1 2 3 4
Smoking
Diabetes
Hypertension
Dyslipidemia
Hyperhomocysteinemia
Male sex
Age, per 10 years
Renal insufficiency
Figure 105.1 Odds ratios for risk factors for symptomatic peripheral artery
disease. (Adapted from Norgren L, Hiatt WR, Dormandy JA, et al. TASC II
Working Group. Inter-Society Consensus for the Management of Peripheral Arterial
Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5-S61.)
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
Exercise Therapy for Claudication
Multiple reports have clearly demonstrated improvements in
pain-free ambulation and overall walking performance with
structured exercise training.7,25-27 Data from more than 20
randomized trials have confirmed that exercise therapy is the
best initial treatment of intermittent claudication.27 The benefits
of exercise extend beyond improvement in the symptoms of
claudication. Regular aerobic exercise reduces cardiovascular
risk by lowering cholesterol and blood pressure and by improving
glycemic control. In most patients, claudication initiates a
downward spiral of cardiovascular deconditioning that can result
in an annual mortality rate as high as 12%.27 Ambulation distance
can decline at a rate of 8.4 m/year beginning with symptom
onset.28 This cycle can be halted and even reversed with exercise
training. In a recent report from Japan, Sakamoto and colleagues
showed that the implementation of structured exercise resulted
in a 5-year cardiovascular event–free survival rate of 80.5% in
patients with PAD, compared with 56.7% in untreated matched
controls.29
The current American College of Cardiology/American Heart
Association (ACC/AHA) guidelines support supervised exercise
for the treatment of intermittent claudication as a level IA
BOX 105.1 Key Components of a Structured Exercise Program for Claudication
Role of the Primary Clinician
• Establish the diagnosis of PAD using the ABI or other objective
vascular laboratory evaluations.
• Determine that claudication is the major symptom limiting
exercise.
• Discuss the risks and benefits of therapeutic alternatives, including
pharmacologic, percutaneous, and surgical interventions.
• Initiate systemic atherosclerosis risk modification.
• Perform treadmill stress testing.
• Provide formal referral to a claudication exercise rehabilitation
program.
a
Exercise Guidelines for Claudication
• Include warm-up and cool-down periods of 5-10 min each.
Types of Exercise
• Treadmill or track walking is the most effective exercise for
claudication.
• Resistance training may be beneficial for individuals with other
forms of cardiovascular disease, and its use (as tolerated) for
general fitness is complementary to but not a substitute for
walking.
Intensity
• Initially, set the treadmill to a speed and grade that elicits
claudication symptoms within 3-5 min.
ABI, Ankle-brachial index; PAD, peripheral artery disease.
a
These general guidelines should be individualized and based on the results of treadmill stress testing and the patient’s clinical status. A full discussion of the exercise precautions
for persons with concomitant diseases can be found elsewhere for patients with diabetes (Ruderman N, Devlin JT, Schneider S, Kriska A. Handbook of Exercise in Diabetes.
Alexandria, VA: American Diabetes Association; 2002), hypertension (ACSM’s Guidelines for Exercise Testing and Prescription. In: Franklin BA, ed. Baltimore, MD: Lippincott,
Williams & Wilkins; 2000), and coronary artery disease (Guidelines for Cardiac Rehabilitation and Secondary Prevention/American Association of Cardiovascular and Pulmonary
Rehabilitation. Champaign, IL: Human Kinetics; 1999).
From Stewart KJ, Hiatt WR, Regensteiner JG, et al. Exercise training for claudication. N Engl J Med. 2002;347:1941-1951.
1379
recommendation.15 The guidelines suggest that exercise training,
in the form of walking, should be performed for a minimum
of 30 to 45 minutes per session, 3 to 4 times per week, for a
period not less than 12 weeks. During each session, the patient
should be encouraged to walk until the limit of lower extremity
pain tolerance is reached, followed by a short period of rest
until pain relief is obtained, then a return to exercise. This cycle
should be followed for the duration of the session. As the
pain-free interval of ambulation increases, the level of exercise
should be increased (Box 105.1).25
Although exercise therapy would appear easy to implement,
effectiveness is often limited by poor patient compliance. Studies
have shown the superiority of clinic-based exercise programs
over home-based programs.7 However, effective exercise training
is not possible in up to 34% of patients because of comorbid
medical conditions, and an additional 30% of patients simply
refuse to participate in exercise training.30 In addition, supervised
exercise training programs are usually not covered by third-party
insurance plans, although it may be in the near future by
Medicare. Therefore, even though exercise therapy in motivated
patients offers proven benefits, its effectiveness is applicable
to only approximately one-third of patients presenting with
intermittent claudication.
• Patients walk at this workload until they experience claudication of
moderate severity, at which point they take a brief rest period,
either standing or sitting, to permit symptoms to resolve.
Duration
• The exercise-rest-exercise pattern should be repeated throughout
the exercise session.
• The initial duration usually consists of 35 min of intermittent
walking. This should be increased by 5 min each session until
50 min of intermittent walking can be accomplished.
Frequency
• Perform treadmill or track walking 3-5 times per week.
Role of Direct Supervision
• As walking ability improves, the exercise workload should be
increased by modifying the treadmill grade or speed (or both) to
ensure the stimulus of claudication pain during the workout.
• As walking ability improves, it is possible that cardiac signs and
symptoms (e.g., dysrhythmia, angina, ST-segment depression) may
appear. These events should prompt physician reevaluation.
1380 SECTION 15 Lower Extremity Chronic Arterial Disease
Pharmacologic Treatment of Claudication
Pharmacologic therapy for intermittent claudication has been
the subject of intense research for more than 30 years. To date,
only two drugs (pentoxifylline and cilostazol) have achieved
FDA approval for the treatment of intermittent claudication
in the United States. However, a number of other medications
have been investigated, with varying degrees of evidence sup-
porting their efficacy (Table 105.1). These include a number
of drugs and supplements with various reported mechanisms
of action such as changes in tissue metabolism (naftidrofuryl,
levocarnitine), enhanced nitric oxide production (L-arginine),
and vasodilatory effects (statins, buflomedil, prostaglandins,
angiotensin-converting enzyme inhibitors, K-134).
Cilostazol
Cilostazol (Pletal) gained FDA approval in 1999 for the treatment
of intermittent claudication. Oral administration of this phos-
phodiesterase III inhibitor increases cyclic adenosine mono-
phosphate (cAMP) and results in a variety of physiologic effects,
including the inhibition of smooth muscle cell contraction and
platelet aggregation. Cilostazol is also thought to decrease smooth
muscle cell proliferation, a process that has been implicated in
coronary artery restenosis following percutaneous transluminal
angioplasty.31 Finally, cilostazol has a beneficial effect on plasma
lipid concentrations, resulting in a decrease in serum triglycerides
and an increase in HDL. Although the precise mechanism by
which cilostazol improves the symptoms of intermittent claudica-
tion is unknown, it is likely a combination of these effects.
Several controlled clinical trials, including a meta-analysis,
have confirmed the efficacy of cilostazol.32,33,34 Results have
shown increased maximal walking distances up to 50%, as well
as significant improvements in health-related quality of life
(QoL) measures.33 There is also increasing evidence that cilostazol
may modulate the synthesis of vascular endothelial growth factor
(VEGF), potentially stimulating angiogenesis in patients with
chronic lower extremity ischemia.35
The benefits of cilostazol in the treatment of intermittent
claudication were compared with those of pentoxifylline in a
randomized controlled trial performed by Dawson and associ-
ates.32 They found that cilostazol therapy significantly increased
maximal walking distance by 107 m (54% increase), compared
with a 64-m improvement in the pentoxifylline group (30%
increase). There was no difference in maximal walking distance
improvement between the pentoxifylline and placebo groups.
Regarding the durability of the effect, a recent pooled analysis
of nine randomized controlled trials demonstrated a significant
benefit in maximal walking distance compared with placebo at
6 months.36
Cilostazol has a moderate but notable adverse effect profile
that includes headache, diarrhea, and gastrointestinal discomfort.
Its use is contraindicated in patients with congestive heart failure,
and high plasma drug levels may result when taken in combina-
tion with other medications metabolized by the liver via the
cytochrome P-450 pathway.
The adverse effects of cilostazol can be minimized by initiating
a progressive treatment regimen, starting at 50 mg/day for 1
week, increasing to 50 mg twice a day the following week, and
finally achieving the standard dose of 100 mg twice a day in
week 3. Of the pharmacologic agents used to treat claudication,
cilostazol has the most data supporting its clinical use.
DECISION MAKING FOR
REVASCULARIZATION
Patients with lower extremity PAD present with a wide spectrum
of symptoms, ranging from asymptomatic, to only minor
exertional leg pain, significant walking impairment, or even
ulceration or gangrene. Therefore the first critical step in decision
making for the treatment of PAD is to confirm that PAD is
responsible for the patient’s symptoms (see Chapter 18). In
brief, noninvasive vascular laboratory testing is indicated for
patients with a history consistent with vasculogenic claudication,
rest pain/metatarsalgia, or tissue loss. Measurement of ABI is
the most common PAD screening and diagnostic tool used.
An ABI of ≤0.90 is highly sensitive and specific for the identifica-
tion of PAD when compared with the “gold standard” of invasive
arteriography (evidence of a hemodynamically significant
peripheral arterial stenosis).16 Complete physical examination
will often disclose pulse deficits, but intact pulses at rest do not
exclude hemodynamically significant PAD. After the symptom
complex (either claudication or CLTI) is determined to be
secondary to PAD, decision making depends on symptom
severity and whether the symptoms are acute or chronic. The
following discussion relates to chronic lower extremity ischemia;
acute ischemia is discussed in Chapter 100.
Decision making regarding revascularization is based first
on symptom status and a sophisticated understanding of the
natural history of the patient’s condition. Treatment strategies
may thus be very different for patients with disabling claudication
compared with those with CLTI because the risk of limb loss
is dramatically different for the two conditions. Anatomic
classification systems, such as the Trans-Atlantic Inter-Society
Consensus (TASC) classification system, may assist in gauging
the extent of angiographic disease. Although the TASC II
classification system can be helpful in the revascularization
decision-making process (i.e., endovascular or open), athero-
sclerotic burden as measured by arteriography is not the sole
factor upon which treatment decisions should be made. Notably
absent from the TASC classification system are any features
relating to degree of ischemia, wounds, infection, functional
status, and conduit availability, all of which are extremely
important determinants of revascularization success. Clearly,
angiographic anatomy alone cannot guide therapy.
Another critical element of decision making focuses on
determining whether a patient will achieve meaningful benefit
from a technically successful procedure. Technical success does
not always equate directly with clinical success. As a result, it
is important to assess baseline functional status, as well as the
burden of comorbid conditions. Patients who are either bed-
bound at baseline or who have prohibitive medical risk may
incur significantly more benefit from a treatment that differs
from the TASC II recommendations (based on lesion type alone),
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
TABLE 105.1 Pharmacologic Treatment of Claudication
Drug Mechanism of Action
Pentoxifylline Methylxanthine derivative;
improves oxygen delivery
by enhancing red blood cell
deformability; may inhibit
platelet aggregation34
Cilostazol Phosphodiesterase III
inhibitor; inhibits smooth
muscle cell contraction and
platelet aggregation
Naftidrofuryl Serotonin antagonist thought
to improve aerobic
metabolism
Levocarnitine Carrier molecule involved in
the transport of long-chain
fatty acids; increases the
availability of energy
substrate for skeletal
muscle metabolism
HMG-CoA reductase Unknown; may alter
inhibitors vasomotor tone or
stimulate angiogenesis143
Buflomedil145,146 α1 and α2 antagonist, causing
vasodilation; also inhibits
platelet aggregation and
enhances red blood cell
deformability
L-Arginine149,150 Amino acid precursor of
endothelial-derived nitric
oxide; indirectly modulates
vasodilation of vascular
smooth muscle
Prostaglandins: Vasodilatory effects; inhibit
Prostaglandin E1,120 platelet aggregation
prostaglandin I2,152-154
Angiotensin- Vasodilation through
converting enzyme reduction in angiotensin II,
inhibitors sympathetic inhibition, and
improvement in endothelial
function through
preservation of bradykinin52
K-134155 Novel phosphodiesterase III
inhibitor; inhibits smooth
muscle cell contraction and
platelet aggregation
FDA, Food and Drug Administration; GI, gastrointestinal; HMG-CoA, hydroxy-3-methylglutaryl-coenzyme A; MWD, maximal walking distance; PFWD, pain-free
walking distance.
Clinical Benefit
Improved PFWD and MWD
over placebo65,135,136
Improved MWD compared
with pentoxifylline and
placebo135,137,138
Improved PFWD; no
improvement in MWD139,140
Improved PFWD and MWD
compared with placebo141;
no benefit was seen over
exercise alone142
Improved pain-free walking
time; no improvement in
maximal walking time
compared with placebo144
Improved PFWD and MWD
compared with placebo147
Improved MWD (with IV
administration) compared
with placebo150; no
improvement over placebo
when studied with oral
formulation over 6 months118
Prostaglandin E1 improved
MWD compared with
placebo120; beraprost
(prostaglandin I2) has
demonstrated conflicting
results152-154
Ramipril improved pain-free
walking time and maximal
walking time over placebo52
Primary analysis showed no
benefit; mixed effects model
showed both K-134 and
cilostazol to improve peak
walking time
Adverse Effects
May interfere with blood
clotting, particularly
when taken in
combination with
warfarin
Headaches, diarrhea, GI
discomfort;
contraindicated in
patients with history of
congestive heart failure
Minor GI, flatulence,
abdominal discomfort
Flu-like symptoms
Headache, abdominal pain,
constipation; rarely,
increased liver enzymes,
cholestatic hepatitis,
rhabdomyolysis
Lethal and nonlethal
neurologic and
cardiovascular adverse
events have been
reported148
GI distress151
Headache, flushing, GI
distress119,120
Hypotension, headache,
cough; rarely,
hepatotoxicity,
Stevens-Johnson
syndrome, angioedema
Headache, nausea,
diarrhea, tachycardia
1381
Current Clinical Role
FDA approved for use
FDA approved for use
Widely available in
Europe; not FDA
approved
Available over the
counter as a dietary
supplement, not
subject to FDA
approval
FDA approved for
cardiovascular
protection, not
specifically for
treatment of
claudication
Not FDA approved;
studied in phase 2
trials
Not FDA approved;
studied in phase 2
trials
Not FDA approved;
studied in phase 2
trials
FDA approved for
cardiovascular
protection, not
specifically for
treatment of
claudication
Not FDA approved;
studied in phase 2
trials
1382 SECTION 15 Lower Extremity Chronic Arterial Disease

to more appropriately balance the chances for functional limb
salvage with the risks of periprocedural morbidity. Included in
this evaluation is an assessment of the available conduit, should
bypass be required. The challenge of decision making in PAD
is accurately assessing each of these factors and synthesizing a
plan that optimizes the likelihood of a favorable outcome for
each individual patient.
Defining Treatment Success
Optimal treatment must ultimately be tailored to each patient.
Although the general goal of any revascularization, whether for
claudication or CLTI, is to increase the perfusion to the extremity
as measured by physiologic testing, there are several other aspects
that define treatment “success.” These will not be the same for
every patient with lower extremity PAD.
Limb- and Patient-Centered Outcomes
Traditional definitions of treatment success included technical
outcomes such as graft/stent patency. However, graft patency
may not correlate well with limb preservation; Simons et al.
found that 10% of patients who underwent lower extremity
bypass for CLTI failed to achieve clinical improvement despite
having a patent graft at 1 year postoperatively.37 Other outcome
measures such as survival or amputation-free survival (AFS)
have also been widely used. Some have questioned the appro-
priateness of these endpoints. In a critique of the Bypass Versus
Angioplasty in Severe Ischemia of the Leg (BASIL) trial,38 Conte
noted that lower extremity bypass is generally not offered as a
life-saving therapy, and therefore survival is not an appropriate
measure for comparisons between revascularization strategies.39
In addition, Conte stressed the importance of limb- and patient-
centered outcomes, such as freedom from re-intervention. This
shift toward more patient-centered outcomes is reflected in
the SVS objective performance goals (OPGs) (https://www
.vascularweb.org/research/clinicalresearch/Pages/cli-objective
-performance-goals.aspx). These guidelines were developed
specifically for comparative evaluations of different treatments
for CLTI,40,41 but the endpoints chosen are key components of
treatment success for PAD, namely major adverse limb events,
which included both freedom from major amputation as well
as from re-intervention. This novel approach shifts the focus
of outcome measures from technical success rates such as primary
and secondary patency to one that acknowledges a burden
incurred by the patient with each intervention that is required
to maintain that limb and function (Table 105.2).
Claudication
For patients with claudication, surgeon-defined, procedural
endpoints may not accurately capture all relevant outcomes.
Some have challenged the traditional approach to patients with
claudication.42,43 Given the more benign natural history with
respect to limb loss, nonoperative therapy is traditionally recom-
mended as the first line of treatment; limb loss is therefore not
a logical measure of treatment success. Kalbaugh and colleagues,
using the Short Form (36) Health Survey (SF-36), found that

TABLE 105.2 Chronic Limb-Threatening Ischemia Endpoint Definitions and Event Rates Reported by the Society for
Vascular Surgery Working Group for the Development of Objective Performance Goals for Evaluating
Catheter-Based Treatmenta
Endpoint Definition Event Rate (%) (95% CI)
Safety Outcomes (30 Day)
Major adverse cardiovascular Myocardial infarction, stroke, or death (any cause). 6.2 (4.7-8.1)
event (MACE)
Major adverse limb event Above-ankle amputation of the index limb or major re-intervention (new bypass 6.1 (4.6-7.9)
(MALE) graft, jump/interposition graft revision, or thrombectomy/thrombolysis).
Amputation Above-ankle amputation of the index limb. 1.9 (1.1-3.1)
Efficacy Outcomes (1 Year; All Rates Are Freedom From Event)
Perioperative death or MALE Perioperative death (30 days), or any MALE 76.9 (74.0-79.9)
Amputation-free survival (AFS) Above-ankle amputation of the index limb or death (any cause). 76.5 (73.7-79.5)
Re-intervention or amputation Any re-intervention, above ankle amputation of the index limb, or stenosis 46.5 (42.3-51.2)
or stenosis (RAS)
Re-intervention or amputation Any re-intervention or above ankle amputation of the index limb. 61.3 (58.0-64.9)
(RAO)
Limb salvage Freedom from above-ankle amputation 88.9 (86.7-91.1)
Survival Freedom from death (any cause) 85.7 (83.3-88.1)
a
As reported by the Society for Vascular Surgery Working Group for the development of objective performance goals for evaluating catheter-based treatment.
CI, Confidence interval.
Data are pooled from prospective trials of vein bypass surgery in CLTI.
From Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of
critical limb ischemia. J Vasc Surg. 2009;50:1462-1473.
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
reassurances about the benign natural history of their condition
did little to alleviate patients’ symptoms. Conversely, intervention
for claudication improved QoL scores considerably. Improve-
ments were similar to those found after coronary artery bypass
surgery for angina and were half as beneficial as hip replacement
surgery. In a more recent series, Taylor and coworkers reported
significant symptomatic improvement after intervention for
claudication in nearly 80% of treated patients.44 Revascularization
in this series was exceedingly safe, with no early amputations
and a 99% limb salvage rate at 5 years.
Although it is accepted that revascularization is not appropri-
ate in every case, there is clear evidence that QoL is improved
by revascularization in many instances.45-48 Indeed, the recent
focus on patient-oriented endpoints has stimulated new research
in the objective measurement of QoL for patients undergoing
lower extremity revascularization. Various questionnaires have
emerged as tools to measure QoL. Unfortunately, there is no
consensus on the ideal questionnaire to use for the evaluation
of patients with PAD. The two most commonly used surveys
are the SF-36 and the Nottingham Health Profile.49,50
Chronic Limb-Threatening Ischemia
Taylor and colleagues recently studied 331 consecutive patients
treated for Rutherford class 5 and 6 ischemia (tissue loss).51 A
bypass was deemed clinically successful if all four outcome criteria
were met: (1) bypass patency until wound healing occurred, (2)
limb salvage for at least 1 year, (3) maintenance of ambulatory
status for at least 1 year, and (4) survival for at least 6 months.
The authors found acceptable results when examining these
components separately, including a graft patency rate of 72%
and a limb salvage rate of 73% at 36 months. However, the
clinical success rate, defined as the achievement of all four
criteria, was only 44%. Furthermore, patients who presented
with impaired ambulatory status, end-stage renal disease, gan-
grene, and infrainguinal disease (each independent statistical
predictors) were especially prone to failure (Table 105.3).51
Prospects for a successful outcome became progressively dismal
as the number of independent negative predictors increased.
Patients harboring two of these independent predictors of
failure experienced approximately a 33% probability of success;
those with three predictors, a 10% probability of success; and
those with all four independent predictors of failure, less than
a 5% probability of success. Similar studies using consensus
definitions of success are needed to help guide decision-
making regarding who should receive intervention and who
should not.
Treatment Guidelines According to Anatomic
Disease Classification
Several classification systems have been developed that character-
ize PAD on the basis of anatomic descriptions of lesion type
and location. The major goals have included standardization
of reporting disease burden, development of methods to
correlate disease burden with clinical severity, and development
of recommendations for method of intervention. Although
these classification schemes provide some value, they notably
1383
TABLE 105.3 Probability of Failure After Bypassa
When the Clinical Condition Is Present
at Presentation
Probability of Odds Ratio
Predictor Variable Failure (%) (95% CI)
Impaired ambulation 58 6.4 (2.9-14.4)
Infrainguinal disease 46 3.9 (1.6-9.8)
ESRD 35 2.5 (1.2-5.4)
Gangrene 34 2.4 (1.5-4.0)
Hyperlipidemia 11 0.6 (0.34-0.93)
a
Defined as patent bypass until healed, limb salvage for 1 year, maintenance
of ambulation for 1 year, and survival for 6 months.
CI, Confidence interval; ESRD, end-stage renal disease.
From Taylor SM, Cull, DL, Kalbaugh CA, et al. Critical analysis of clinical
success after surgical bypass for lower extremity ischemic tissue loss using a
standardized definition combining multiple parameters: a new paradigm of
outcome assessment. J Am Coll Surg. 2007;204:831-839.
fail to capture major factors that determine the success of
intervention.
Trans-Atlantic Inter-Society
Consensus Classification
In January 2000 the TASC for the Management of Peripheral
Arterial Disease published a document authored by a working
group of representatives from 14 surgical vascular, cardiovascular,
and radiologic societies.52 An updated document (TASC II)
was published in January 2007. These important works not
only classified the lesions but also provided treatment recom-
mendations according to lesion type. The TASC working group
has classified anatomic patterns of disease involvement (types
A through D) for both the aortoiliac (Fig. 105.2) and femo-
ropopliteal (Fig. 105.3) segments, based on recommended
treatment (endovascular versus open surgery). The TASC working
group advocated endovascular treatment for TASC type A lesions
and open surgical treatment for TASC type D lesions. For
TASC type B and C lesions, the authors concluded that there
was insufficient evidence to definitively recommend one modality
over the other.53
Runoff Score
In 1986 the SVS and the International Society for Cardiovascular
Surgery published reporting standards for lower extremity
ischemia, which included the description of a runoff score to
characterize the status of the outflow vessels distal to the distal
anastomosis of a lower extremity revascularization procedure54;
this was revised to the current version in 199755 to better
incorporate the contribution of pedal vessels. The score values
range from 0 to 10 (with 0 being completely patent, disease-free
outflow) that is calculated based on the degree of occlusion
and the relative contribution to outflow of each vessel. This
formula translates into a description of the resistance in the
outflow bed and therefore was designed to facilitate comparisons
of expected bypass patencies. A simplified four-level version
1384 SECTION 15 Lower Extremity Chronic Arterial Disease

TYPE A LESIONS

(≤

TYPE B LESIONS

(≤

TYPE D LESIONS

Figure 105.2 Trans-Atlantic Inter-Society Consensus classification of aortoiliac lesions. AAA, Abdominal aortic
aneurysm; CFA, common femoral artery; CIA, common iliac artery; EIA, external iliac artery. (Redrawn from Norgren
L, Hiatt WR, Dormandy JA, et al. TASC II Working Group. Inter-Society Consensus for the Management of
Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5-S61.)

(scores 0 to 3) is also described that applies the weighting units
to the outflow in an all-or-none fashion based on the presence
of any hemodynamically significant stenosis. The authors note
explicitly that neither of these systems should be used to the
exclusion of other systems, and do not offer these as a scheme
for making treatment decisions.
TREATMENT GUIDELINES
ACCORDING TO PRESENTATION
Claudication
Traditional treatment recommendations for intermittent claudica-
tion have balanced the risk of intervention against the natural
history of the disease. It has long been appreciated that claudica-
tion is a marker for more serious potential manifestations of
systemic atherosclerosis. With the goal of preserving life and
limb, many experts agree that the best strategy is to initiate
systemic medical therapy aimed at reducing cardiac morbidity.
This strategy is based on the low relative risk of limb loss in
patients with claudication compared with the significant relative
risk of stroke, MI, and death. The ACC/AHA guidelines suggest
that the risk of major limb amputation for a patient with
intermittent claudication is approximately 1% per year, whereas
the risk of cardiac death is approximately 3% to 5% per
year.15,56-58 Treatment strategies have therefore stressed cardio-
vascular risk factor modification and medical therapy as the
best initial treatment for patients with PAD symptoms limited
to intermittent claudication. Medical treatment for intermittent
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making 1385

TYPE A LESIONS

≤
≤

TYPE B LESIONS

≤5 cm
≤

TYPE C LESIONS

TYPE D LESIONS

FA FA >

Figure 105.3 Trans-Atlantic Inter-Society Consensus classification of femoropopliteal lesions. CFA, Common
femoral artery; SFA, superficial femoral artery. (Redrawn from Norgren L, Hiatt WR, Dormandy JA, et al. TASC II
Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg.
2007;45(Suppl S):S5–S61.)

claudication consists of smoking cessation, exercise training,
and pharmacologic therapy, as already described. Revasculariza-
tion is recommended only in cases of severe claudication and
only after medical therapy has failed.
Medical Therapy Versus Revascularization
The role of smoking cessation in treating the symptoms of
claudication is unclear. Although studies have shown that
smoking cessation can improve walking distance in some cases,
these findings are not universal.59 However, the association
between tobacco cessation and the reduction of subsequent
cardiovascular events is undisputed. The rationale for smoking
cessation is therefore based on reducing patient mortality and
slowing the overall atherosclerotic disease process.
Currently available pharmacologic agents for claudication
have already been discussed (see section “Pharmacologic Treat-
ment of Claudication”). The ACC/AHA guidelines recommend,
in addition to routine antiplatelet therapy, a therapeutic trial
of cilostazol (100 mg 2 times a day) as an effective method for
increasing overall ambulation (class I recommendation). This
agent is limited to patients with PAD and intermittent claudica-
tion and no history of congestive heart failure, because cilostazol
1386 SECTION 15 Lower Extremity Chronic Arterial Disease
is a phosphodiesterase-3 inhibitor capable of exacerbating
ventricular dysfunction.15 Unfortunately, adverse effects prevent
the routine use of cilostazol in up to 15% of patients.32,33
When comparing medical to endovascular therapy, there are
abundant data supporting the efficacy of medical therapy. For
instance, the Edinburgh walking study consisted of a randomized
trial to determine outcome differences in patients with intermit-
tent claudication treated with angioplasty and stent versus
medical management (daily low-dose aspirin, lifestyle modifica-
tion) after 2 years. These investigators found no difference in
maximal walking distance, treadmill distance until onset of
claudication, and QoL measures between the two groups.60
Supervised exercise therapy has also been compared with primary
stenting for disabling claudication due to aortoiliac occlusive
disease in the Claudication: Exercise Versus Endoluminal
Revascularization (CLEVER) trial.61 At 6-month follow-up,
they reported that change in peak walking time was greatest
for supervised exercise, intermediate for stenting, and least with
pharmacologic therapy (mean change versus baseline, 5.8 ±
4.6, 3.7 ± 4.9, and 1.2 ± 2.6 minutes, respectively; P < .04 for
the comparison of supervised exercise versus stenting). QoL
evaluation revealed significant improvements in both the
supervised exercise and the stenting groups compared with
pharmacologic therapy, but the benefit was greater in the stenting
group than in the exercise group.
In summary, when weighing medical therapy versus revas-
cularization for the treatment of intermittent claudication, the
risk-to-benefit ratio favors initial medical therapy in most cases.
However, medical therapy may be effective in as few as 30%
of patients because of noncompliance and drug intolerance.
When revascularization is chosen, modern approaches have
become predominantly endovascular owing to its reduced
procedural risks compared with open surgery. However, an
analysis of practice patterns in New England between 2003
and 2009 demonstrated that an increasing proportion of lower
extremity bypass procedures were performed for claudication
in recent years (from 19% to 31%, P < .0001). In addition,
the percent of patients with a history of previous endovascular
intervention has steadily increased (from 13% to 23%, P =
.02).62 The authors suggest that the high rates of prior endo-
vascular intervention seen may reflect a “treatment trap”; after
the decision has been made to intervene procedurally for
claudication, surgeons may feel obliged to perform an open
revascularization if a prior endovascular approach has failed to
resolve symptoms. Of note, the 1-year incidence of major
amputation after intervention on claudicants was 1.6% in this
study; although this is low, it is a devastating outcome after a
procedure for claudication. Clinical decision making ultimately
must incorporate not only the risks and benefits of various
treatment strategies but also a discussion of realistic expectations
as to the extent to which treatment will improve symptoms
and improve QoL.
Endovascular Treatment Versus Open Surgery
(see Chapters 106 through 110)
Ultimately, the selection of the best method of revascularization
for an individual with claudication is based on a balance between
the risks of the specific intervention and the degree and durability
of improvement that can be expected from the intervention.53
Because the natural history of vasculogenic claudication is rela-
tively benign, that balance usually does not favor open surgery.
In contrast, its relatively low morbidity and mortality make
endovascular therapy particularly attractive,53 and when it is
anatomically feasible, endovascular therapy is often preferred
to open surgery for most cases of claudication.60 However, it
is important to note that a growing body of evidence suggests
that the concept that an endovascular option “does not burn
any bridges” is false.63,64
Anatomy is one of several important considerations when
selecting the best interventional modality for patients with
claudication as well as those with CLTI. Prospective studies
dating to the 1980s have characterized the arterial lesions and
anatomy most conducive to long-term patency after angioplasty.
Johnston and colleagues demonstrated in a prospective analysis
that the arterial anatomy and clinical presentation most amenable
to long-term patency and success using angioplasty were focal
arterial lesions in large-diameter vessels with adequate outflow.65
Outcomes were more favorable in nondiabetic patients presenting
with claudication than in those with CLTI. The arterial segment
best managed with percutaneous transluminal angioplasty is
thus the common iliac artery, a vessel with all the favorable
anatomic characteristics identified by Johnston’s study. Athero-
sclerotic lesions in this segment are usually focal and possess
good outflow. Angioplasty patency rates at 5 years generally
exceed 70%.44 Conversely, long-segment arterial disease, such
as a long superficial femoral artery occlusion, is probably best
treated with open bypass from the standpoint of durability of
the revascularization. Diffuse multisegmental disease, more
common with CLTI, can present a therapeutic dilemma.
Chronic Limb-Threatening Ischemia
CLTI is defined as chronic lower extremity PAD with either
ischemic rest pain or the tissue loss (nonhealing ulcers or
gangrene) (see Chapter 104). Typically, symptoms have to be
present for more than 2 weeks and associated with an ankle
pressure less than 50 mm Hg or a toe pressure less than 30 mm
Hg.60 Although far fewer patients present with CLTI than with
intermittent claudication, CLTI patients consume the vast
majority of treatment resources. A surprisingly small fraction
of patients (<5%) with intermittent claudication progresses to
CLTI. Patients with “chronic subclinical ischemia”—those with
low perfusion and ankle pressures but who are asymptomatic
for a variety of reasons—are also at risk for the development
of limb ischemia.60
Prognosis for CLTI is considerably worse than for intermittent
claudication; as many as 25% of CLTI patients progress to
major limb amputation within 1 year, and 25% die of cardio-
vascular complications within 1 year.66 However, CLTI popula-
tions are quite heterogeneous and it is therefore difficult to
precisely define its natural history. For example, CLTI patients
in the placebo arm of the Circulase trial experienced an 87%
limb salvage rate at 6 months,67 a limb salvage rate not dissimilar
from the treatment arms in the BASIL trial (Bradbury AW) or
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
the PREVENT III trial.68 Decision making for CLTI commonly
poses three dilemmas: whether to treat medically or with
intervention; if treating with intervention, whether to amputate
or revascularize; and if revascularizing, whether to use endo-
vascular intervention or open surgery.
Medical Therapy Versus Revascularization
The natural history of untreated CLTI is poorly understood
because most functional patients receive some type of revascu-
larization. Limb loss and cardiac death are common; 1-year
mortality ranges from 20% to 30%, with cardiac deaths out-
numbering noncardiac deaths four to one.69 The best information
regarding the natural history of nonrevascularized limbs in
patients with CLTI comes from the placebo arms of pharma-
cotherapy trials of patients with unreconstructable vascular
disease. Results suggest that this subgroup has a dismal prognosis,
with nearly 40% of limbs progressing to amputation at 6
months.70 Therefore, in functional patients, some type of
revascularization is almost always preferable to medical therapy.
However, medical therapy for CLTI is not without some
noteworthy successes. Indeed, wound care centers have become
common adjuncts to many vascular surgical practices (see
Chapter 115). Ischemic ulcer healing rates of 55% have been
reported from dedicated centers using modern wound care
methods such as negative-pressure wound therapy, intense
débridement, and antibiotic therapy.71 However, wound healing
in such situations is often slow, laborious, and unpredictable.
To date, pharmacotherapy for CLTI has failed to yield any
major breakthroughs. The routine use of prostanoids, vasodila-
tors, antiplatelet agents, and even hyperbaric oxygen for the
treatment of ischemic ulcers remains of unproven benefit.71
In summary, revascularization is an essential component in
the relief of CLTI. Although medical adjuncts geared at risk
factor modification may be important to slow the progression
of systemic atherosclerotic disease, they play a secondary role
in the treatment of the severely ischemic limb. In those rare
cases in which vascular disease is truly unreconstructable, a
trial of intensive wound care, preferably at a dedicated wound
care center, may yield satisfactory healing rates for motivated
patients with superficial ulcerations, or it may avoid major
limb amputation in high-risk patients who are approaching the
end of life.
Limb Amputation Versus Revascularization
For the overwhelming majority of patients with CLTI, revas-
cularization is the interventional treatment of choice. However,
primary limb amputation continues to be required in 10% to
40% of CLTI patients, owing to overwhelming infection or
unreconstructable vascular disease.72 Unreconstructable vascular
disease accounts for nearly 60% of patients requiring secondary
amputation.71 In many of these cases, revascularization has failed
due to disease progression, recurrent ischemia, or persistent
infection or necrosis despite a patent revascularization.
Although counterintuitive, limb amputation and prosthetic
rehabilitation can be an excellent option, offering an expedient
return to a reasonable QoL in selected cases. Maintenance of
ambulation can exceed 70%, and maintenance of independence
1387
can exceed 90% in young, good-risk patients after below-knee
amputation.73 Clearly, amputation should be considered a tool
capable of extending functionality and not a failure of treatment
in these cases. If there is the potential for some degree of
rehabilitation, the limb amputation should be performed at
the lowest possible level at which healing can be expected,
because the work of walking increases dramatically as the level
of amputation becomes more proximal. Typically, patients with
well-controlled medical comorbidities, a palpable femoral pulse,
a warm calf, and no signs of infection are likely to heal after a
below-knee amputation (see Chapters 111 and 112).
The use of an immediate postoperative prosthesis (IPOP)
may also aid in expediting a patient’s recovery following
below-knee amputation. This technique, first described in the
1960s, gained favor following a publication, the Prosthetic
Research Study, by Burgess and colleagues.74 They reported
that the use of a rigid cast placed intraoperatively facilitated
faster healing and return to ambulation. Folsom and colleagues
studied this technique in a population where the indication
for amputation was not trauma, but rather severe infection
or unreconstructable PAD.75 Of 65 patients, 86% returned to
independent ambulation, with an average time to ambulation
of 15.2 days following below-knee ambulation. A more recent
comparative analysis of IPOP compared with traditional soft
dressings demonstrated no difference in complication rates, and a
lower incidence of revision (soft dressings 27.6% vs. IPOP 5.4%,
P = .021).76
Patients with major tissue loss who are too sick or infirm to
realize the benefit of limb revascularization should undergo
palliative primary above-knee amputation. However, judging
patients “too sick or infirm” can be difficult. Obviously, a
nonambulatory, elderly, nursing-home patient with knee
contractures and neuropathic heel ulcers would qualify for a
palliative above-knee amputation. For patients who are minimally
ambulatory, with multiple comorbidities, the decision is less
clear-cut. An individualized judgment is required to determine
whether these patients will be better served by primary amputa-
tion or limb revascularization. In a single-institution study of
1000 consecutive revascularizations for CLTI, preoperative
functional performance status was the most important predictor
of postoperative functional outcome—even more important
than limb salvage itself.77 This finding strongly suggests that
there is a definite subset of patients who are too sick or debilitated
to realize the functional benefits of revascularization. Although
more work is needed to better define such patients, this cohort
is likely best suited for primary amputation.
Endovascular Treatment Versus Open Surgery
(see Chapters 106 to 110)
For many years, the classic treatment approach for CLTI has
been open surgery. CLTI is usually associated with multilevel
arterial disease that is not ideally suited to percutaneous interven-
tion. Diffuse, extensive PAD causing CLTI in both aortoiliac
and femoropopliteal locations (see Figs. 105.2 and 105.3) is
best treated by surgical bypass according to TASC.78 However,
the primacy of surgical bypass for CLTI management has been
challenged in recent years and has become the subject of intense
1388 SECTION 15 Lower Extremity Chronic Arterial Disease
debate. Those who favor open surgery for the treatment of
CLTI often cite superior reconstruction patency and increased
durability.79-81 However, open surgery is usually associated with
higher perioperative morbidity and longer hospitalization.82 In
addition, long-term postoperative graft surveillance is necessary
to maintain a patent infrainguinal bypass, as has been shown
in well-performed studies from both Europe and North America
suggesting that such surveillance is economically justified by
preventing vein graft occlusion and late amputation.83,84 A
re-intervention rate of 20% to 30% to treat failing grafts due
to intrinsic vein graft stenoses is usually necessary to maintain
the increased durability attributed to open surgery.83,85 Last,
successful surgery depends on the presence of a suitable venous
conduit for bypass.86,87 Those who favor interventional treatment
cite the low morbidity and mortality associated with a procedure
that is usually performed on an outpatient basis.88 Although
proponents acknowledge the limited reconstruction patency
rates associated with endovascular treatment, especially for the
high-risk lesions often encountered in CLTI, they argue that
restenosis rarely jeopardizes subsequent surgery.88-90 In contrast,
others have found that prior ipsilateral intervention has a negative
influence on subsequent bypass. An analysis of the BASIL data
by treatment received found 1-year AFS was 40% for bypass
that followed a failed endovascular intervention, compared with
70% for the bypass-only group.64 The authors therefore do not
endorse the concept of a “free shot” with an endovascular first
approach. Nolan et al. also found a correlation of graft failure
and prior endovascular intervention; in a study of CLTI patients
who underwent lower extremity bypass in New England, those
with a prior failed endovascular intervention had a higher
incidence of major amputation (31% vs. 20%; P = .046) and
graft occlusion (28% vs. 18%; P = .009) at 1 year.91 Although
a causative relationship has not been established, the concept
of “burning bridges” with an aggressive endovascular-first
approach clearly deserves further study.
Situational Perfusion Enhancement
Proponents of endovascular intervention frequently cite the
phenomenon of situational perfusion enhancement and its
role in the treatment of CLTI. They argue that there is a
population of asymptomatic patients with subclinical lower
extremity ischemia and very low perfusion pressures. These
patients become symptomatic only when they develop incidental
foot ulceration and do not have the circulatory reserve to heal.
A boost in arterial perfusion, even transiently, usually allows
healing of the ulcer. After the ulcer is healed, maintenance of
enhanced perfusion is not critical, and recurrent ischemia is
usually well tolerated as the patient resumes the subclinical
ischemic state. Endovascular intervention proponents therefore
argue that inferior reconstruction patency rates after such
interventions are inconsequential. Although the phenomenon
of situational perfusion enhancement has been observed and
reported anecdotally, it should be accepted with caution. If
the ulceration is a sporadic event (e.g., the result of minor
incidental trauma), a situational boost to perfusion could be
sufficient to accomplish healing. However, if the ulcer is the
result of neuropathic changes in the foot, in which case ulcer
recurrence is the rule rather than the exception, a more durable
reconstruction is probably indicated. The role of situational perfu-
sion enhancement in patients who develop ischemic rest pain is
likewise unclear.
BASIL Trial
There is a striking paucity of level I data to guide decision
making for endovascular treatment versus open surgery. In
the United Kingdom the BASIL study represents the only
randomized controlled multicenter trial comparing angioplasty
to open surgery for severe limb ischemia.92 In this study of
nearly 450 patients randomized to bypass or balloon angioplasty
for the initial treatment of infrainguinal disease, the findings
support much of what is known about the two modalities
and underscore several important caveats. Using AFS as the
primary endpoint, the authors found that patients treated with
bypass first had comparable outcomes to patients treated with
balloon angioplasty first at 6 months (amputation or death =
21% with bypass first vs. 26% with balloon angioplasty first;
P = not significant). Although the early mortality was similar
in both treatment groups, surgery was associated with higher
morbidity. Crossover treatment after initial therapy (surgery
to angioplasty or angioplasty to surgery) was common in both
treatment groups, with more than half the angioplasty arm and
approximately one-third of the surgical arm requiring further
intervention. At the end of 5 years, 55% of patients were alive
without amputation, 8% were alive with amputation, 8% were
dead after amputation, and 29% were dead without amputation.
After 2 years, both AFS (hazard ratio, 0.37; P = .008) and
overall survival (hazard ratio, 0.34; P = .004) were better in the
surgical arm.
The BASIL trial reinforces several principles. It clearly supports
the phenomenon of situational perfusion enhancement. Patients
who have lower extremity ulceration that would be expected
to heal with conventional wound therapy and enhanced perfusion
within 6 months are good angioplasty candidates. The TASC
document currently recommends angioplasty over open surgery
when the desired outcomes of the two modalities are compa-
rable.78 However, angioplasty is probably not appropriate when
recurrent ulceration and persistent ischemic symptoms are
expected to exceed 6 months. The advantage of having surgery
first becomes apparent at 2 years. If it appears that the patient’s
life expectancy or the course of the disease will exceed 2 years,
surgery is probably the more appropriate first intervention.
Finally, the degree of treatment crossover in the BASIL trial
was arguably its most remarkable finding. It stresses that
angioplasty and open surgery are not “either-or” therapies but
are complementary. It underscores the importance of training
surgeons who manage lower extremity ischemia so that they
possess both open and endovascular skill sets.93
Ongoing Trials
The lack of high-quality evidence to guide therapy in patients
with CLTI has prompted the initiation of two more large-scale
trials that deserve mention. The BASIL-2 trial (http://www
.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/
portfolio-v/Basil-2/index.aspx, accessed 27 March 2016) is a
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
multicenter, randomized clinical trial of “vein-bypass first” or
“best endovascular therapy first” approach in patients with severe
limb ischemia; it began recruitment across England, Scotland,
and Northern Wales in June 2014.94 The investigators seek to
recruit 600 patients over a 3-year period. The primary outcome
is AFS. A number of secondary outcomes will also be analyzed,
including major adverse limb events, health-related QoL, crossover
and re-intervention rates, and cost-effectiveness measures.
In the United States a similar effort is underway to further
define the best treatment strategy for patients with CLTI, the
Best Endovascular versus Best Surgical Therapy in Patients with
CLI Trial (BEST-CLI) (ClinicalTrials.gov: NCT02060630;
www.BESTCLI.com, accessed March 27, 2016).95 This multi-
center clinical trial seeks to randomize 2100 patients with CLTI,
across the United States and Canada, to either best open or
best endovascular therapy; the first patient was enrolled in
September 2014. The primary endpoint is major adverse limb
events. Planned secondary endpoints include freedom from
clinical failure and from hemodynamic failure, health-related
QoL, and cost-utility analysis.
Hopefully, these two landmark studies, if completed suc-
cessfully, will better inform the complex decision-making process
necessary to choose between endovascular treatment and open
surgery for patients with CLTI.
Threatened Limbs, With or Without Peripheral
Arterial Disease
In recognition of the fact that PAD patients are a subset of
patients at risk for limb loss due to a variety of potential etiologies
(diabetes mellitus, most commonly), the SVS commissioned
the Lower Extremity Guidelines Working Group to create a
more comprehensive classification system to serve as a more
robust decision-making aid for this broader category of patients.
This new classification framework, entitled the SVS Threatened
Limb Classification System [Mills JL, Conte MS, Armstrong
DG, et al. The Society for Vascular Surgery Lower Extremity
Threatened Limb Classification System: risk stratification
based on wound, ischemia, and foot infection. J Vasc Surg.
2014;59:220–234.] incorporates three major factors that impact
amputation risk and clinical management: Wound, Ischemia,
and foot Infection (WIfI). The intent of this new SVS WIfI
classification system is to stage patients across a broad spectrum
of lower extremity arterial occlusive disease of varying severity
and distribution. In the SVS WIfI system, wounds are classified
from grade 0 through grade 3, based on size, depth, severity,
and anticipated difficulty achieving wound healing. Ischemia
is classified from grade 0 through grade 4 according to ABI,
ankle systolic pressure, toe systolic pressure, or transcutaneous
oximetry. Infection is classified from grade 0 through grade 3
based on simple objective clinical observations. The combination
of grades is used to categorize the limb into one of four clinical
stages that correlate with major amputation risk at 1 year. Multiple
studies have validated the SVS WIfI system as an accurate way
in which to predict amputation risk and stratify patients to
permit more meaningful analyses of outcomes for various forms
of therapy in this challenging heterogeneous population.96-101
1389
Impact of Conduit Availability, Preoperative
Functional Status, and Comorbid Disease
Decision making in the treatment of lower extremity PAD has
focused on how to treat patients. In the future, as the financial
condition of the healthcare system continues to deteriorate,
decision making will focus on who to treat. It is naïve to believe,
for instance, that all patients who present with CLTI will benefit
from aggressive intervention. Indeed, in the BASIL study cited
earlier, an independent data-monitoring committee overseeing
patient enrollment in this trial found that half the patients with
severe limb ischemia were regarded as unsuitable or unfit for
any form of revascularization. The authors concluded that
patients eligible for revascularization represent the tip of an
iceberg, the true dimensions of which remain incompletely
defined.92 Interventional treatment cannot and should not be
offered to everyone. The true task, then, is to refine definitions
of success and construct tools using evidence-based data to help
distinguish patients who will benefit from therapy from those
who will not. This necessitates study of not just those who
undergo revascularization, but also those patients for whom
either palliation or primary amputation is offered in order to
truly capture the denominator of this problem.
Conduit Availability
The availability of adequate conduit for open bypass plays a
critical role in the decision of how best to treat a patient with
lower extremity PAD, particularly CLTI. Great saphenous vein
of adequate caliber, even if it must be harvested from the
contralateral leg, remains the conduit of choice for open bypass.102
It has been shown to have superior durability compared with
all other conduit choices: prosthetic grafts, short saphenous
vein, spliced arm vein, and vein cuffs.103 In the absence of
good-caliber great saphenous vein for bypass, an endovascular
revascularization becomes a more attractive option. Having said
that, multiple authors have demonstrated excellent outcomes
in large surgical bypass series using alternative autogenous vein
options (cephalic vein, basilic vein, short saphenous vein).104-106
Performance of vein mapping prior to arteriography is essential
because of the strong influence it can have on the decision of
how aggressively to pursue an endovascular revascularization
strategy.
Influence of Comorbid Conditions and
Preoperative Functional Status
The patient’s ability to tolerate an open revascularization must
be assessed as part of the decision-making process. Several studies
have sought to identify factors associated with perioperative
morbidity and mortality. Using data on 9556 patients identified
from the National Surgical Quality Improvement Program
between 2007 and 2009, the 30-day mortality associated with
lower extremity bypass was 1.8%.107 The incidence of nonfatal
cardiac complications is higher. In a cohort of 2907 patients
who underwent lower extremity bypass in New England between
2003 and 2007, cardiac complications occurred in 7.2%.62
1390 SECTION 15 Lower Extremity Chronic Arterial Disease
TABLE 105.4 Morbidity After Infrainguinal Bypass
for Claudication and Chronic
Limb-Threatening Ischemia
First Year 3-5 Years
Time for healing 15-20 weeks —
Wound complications (%) 15-25 — scores provide evidence-based risk stratification, individualized
Persistent lymphedema (%) 10-20 Unknown
Graft stenosis (%) 20 20-30
Graft occlusion (%) 10-20 20-40
Major amputation (%) 5-10 10-20
Graft infection (%) 1-3 —
Perioperative death (%) 1-2 — and some important differences described in more detail in
All death (%) 10 30-50
Adapted from Norgren L, Hiatt WR, Dormandy JA, et al. TASC II Working
Group. Inter-Society Consensus for the Management of Peripheral Arterial
Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5–S61.
Several other complications, both local and systemic, have been
well described (Table 105.4). These are discussed, as well as
recommendations for preoperative risk assessment, in Chapter
32 and Section 7.
Beyond the risk of perioperative complications, the likelihood
a patient will derive mid- to long-term benefit from an open
revascularization must be included in the decision-making
process. Several studies have sought to characterize risk factors
for poor outcomes after open bypass. Among those with CLTI,
several predictors of reduced AFS are well established (Table
105.5). Although many of these are comorbid conditions such
as advanced age and chronic kidney disease, others are elements
of functional status, such as preoperative ambulation or inde-
pendent living. In addition, prior contralateral major amputation
has been shown to predict worse outcomes after open bypass.108
Although none of these studies identifies a single risk factor
that is prohibitive for open bypass, for patients who present
with a constellation of risk factors, including impaired functional
status, the likelihood of long-term benefit from revascularization
is reduced.
RISK PREDICTION MODELS
Decision making in lower extremity PAD requires a highly
individualized approach based on a number of preoperative
factors. Several risk prediction models have been developed to
aid in patient-specific risk stratification. These tools use statistical
modeling based on patient data to identify predictors of a specific
outcome, then apply a weighting system to them, such that a
score may be given that corresponds to a likelihood of that
outcome. For an individual patient, the score is based on the
presence or absence of these factors. The sum then corresponds
to a risk category, derived from the statistical modeling. The
performance of the risk score can be assessed by tests of dis-
crimination and calibration and should ideally be validated
using data from another cohort of patient data. An ideal risk
score uses easily obtainable and clearly defined factors that are
available preoperatively. This allows the surgeon to calculate
the score and offer a bedside risk prediction. However, it is
important to note that these risk scores are derived using a
specific endpoint, at a specific point in time, and therefore
should similarly be narrowly applied. When used properly, risk
to each patient. Several scores have been described; they differ
slightly in the outcome they predict, and the time point at
which the outcome is predicted.109-112 In addition, some have
been externally validated in additional patient cohorts and have
been tested using new endpoints. There is some commonality
among the most widely recognized grading systems (Table 105.6),
later sections. However, it is important to note that prediction
models complement clinical judgment rather than replace it,
and more research is needed to optimize these models. In
particular, some have suggested that future study should
incorporate clinical inputs beyond those used in the models
described later, such as the degree of ischemia, extent of tissue
loss, and presence of infection.113
ANGIOGENESIS FOR PERIPHERAL
ARTERIAL DISEASE
For patients with CLTI who lack a revascularization option,
novel alternative therapies may offer benefit. Angiogenesis is a
naturally occurring phenomenon in response to tissue ischemia
and is promoted by proangiogenic factors, including VEGF,
fibroblast growth factor, hypoxia-inducible factor-1α, and
hepatocyte growth factor114,115 Following the first case report
using VEGF in a human subject by Isner and colleagues in
1996,116 the modulation of growth factors to stimulate angio-
genesis has become an area of interest in the treatment of lower
extremity PAD, particularly in patients who are not candidates
for surgical or interventional techniques. The concept of thera-
peutic angiogenesis entails efforts to increase the concentration
of proangiogenic factors, thereby stimulating growth of new
blood vessels from preexisting blood vessels to treat ischemic
disease; this may be accomplished by administration of recom-
binant proteins or gene therapy that induces overexpression of
these factors.114,117 Therapeutic angiogenesis may also be induced
by implantation of stem cells and endothelial progenitor cells.
Both bone marrow–derived and peripheral blood–derived stem
cells have been studied for their utility in stimulating vasculo-
genesis; both intraarterial and intramuscular techniques have
been studied. The putative concept by which angiogenesis
improves limb perfusion is through the enlargement of collateral
blood vessels and possible direct stimulation of wound healing
by growth factors. Preclinical animal models, such as the rabbit
hind limb ischemia model, have clearly shown that angiogenic
gene therapy can improve limb perfusion compared with
placebo-treated animals. Growth factors act as mitogens that
stimulate endothelial cell proliferation in response to local
tissue ischemia, but the mechanism has not been completely
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making 1391

TABLE 105.5 Recent Studies Identifying Independent Predictors for Select Outcomes in Patients With Chronic
Limb-Threatening Ischemia
Inclusion Primary Outcome
Author Year Journal n, Study Type Criteria Measure Significant Predictors
Robinson 2009 JVS 1646, single Bypass surgery Patency High-risk conduit, CLI, smoking,
et al.117a center series for CLI or age ≥65 years, African
claudication American, female
Schanzer 2007 JVS 1404, multicenter Bypass surgery Patency Graft diameter, graft length,
et al.117b RCT for CLI nonsingle segment GSV,
popliteal artery origin
Bradbury 2010 JVS 452, multicenter Bypass surgery Death Age, MI, stroke, tissue loss, ankle
et al.117c RCT and angioplasty pressure, number of detectable
for SLI ankle pressures, creatinine,
smoking, BMI, Bollinger score,
diabetes
Goodney 2010 JVS 2306, multicenter Bypass surgery Death CHF, diabetes, CLI, absence of
et al.117d registry for CLI or single segment GSV, age >80
claudication years, dialysis, emergent
procedure
Schanzer 2008 JVS 1404, multicenter Bypass surgery Death Statin therapy, age ≥75 years,
et al.117e RCT for CLI CAD, CKD stage 4/5, tissue loss
Owens 2007 JVS 456, single center Bypass surgery Death Age, CKD Stage 4/5
et al.117f series for CLI or
claudication
Schanzer 2009 JVS 1166, multicenter Bypass surgery Amputation-free Age ≥75 years, dialysis, tissue
et al.117g registry for CLI survival loss, anemia, advanced CAD
Schanzer 2008 JVS 1404, multicenter Bypass surgery Amputation-free Age ≥75 years, dialysis, tissue
et al.117h RCT for CLI survival loss, anemia, advanced CAD
Biancari 2007 World Journal 3925, multicenter Bypass surgery Amputation-free Diabetes, CAD, foot gangrene,
et al.117i of Surgery registry for CLI survival urgent operation
Goodney 2009 Ann Vasc 2306, multicenter Bypass surgery Amputation or loss Age 40-49 years, nonambulatory
et al.117j Surg registry for CLI or of secondary preoperatively, dialysis,
claudication patency diabetes, CLI, composite vein
grafts, tarsal bypass target,
nursing home preoperatively
Rossi et al.117k 2003 Ann Vasc 468, single center Bypass surgery Amputation Gender, nonautologous conduit,
Surg series for CLI or re-do bypass
claudication or
aneurysm
Toursarkissian 2002 JVS 124, single center Bypass surgery Amputation Angiographic score, foot score,
et al.117l series for CLI or diabetes
claudication
Alback 1998 Eur J Vasc 132, single center Bypass surgery Amputation “Ad-Hoc” grading system of
et al.117m Surg series for CLI or outflow arteries
claudication
Simons 2010 JVS 1457, multicenter Bypass surgery Clinical failure Dialysis, preoperative ambulation
et al.117n registry for CLI (persistent with assistance, history CABG
symptoms and/or or PCI
amputation) despite
bypass patency
Goodney 2009 JVS 1400, multicenter Bypass surgery Ambulatory failure Nonambulatory preoperatively,
et al.117o registry for CLI or CLI, age ≥70 years,
claudication postoperative MI,
postoperative amputation
Taylor 2006 JVS 1000, single Bypass surgery Ambulatory Female, diabetes, renal
et al.117p center series for CLI deterioration/ insufficiency, dementia,
failure homebound preoperatively,
postoperative amputation
Continued
1392 SECTION 15 Lower Extremity Chronic Arterial Disease

TABLE 105.5 Recent Studies Identifying Independent Predictors for Select Outcomes in Patients With Chronic
Limb-Threatening Ischemia—cont’d
Inclusion Primary Outcome
Author Year Journal n, Study Type Criteria Measure Significant Predictors
Nguyen 2006 JVS 1404, multicenter Bypass surgery Decreased Diabetes, postoperative graft
et al.47 RCT for CLI improvement in related event
quality of life
Taylor 2006 JVS 1000, single Bypass surgery Nonindependent Age ≥70 years, ulceration,
et al.117p center series for CLI living previous stroke, dementia,
nonambulatory, postoperative
amputation
BMI, Body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; CLI, critical
limb ischemia; GSV, great saphenous vein; JVS, Journal of Vascular Surgery; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized
controlled trial.
From Robinson WP 3rd, Owens CD, Nguyen LL, Chong TT, Conte MS, Belkin M. Inferior outcomes of autogenous infrainguinal bypass in Hispanics: an analysis of
ethnicity, graft function, and limb salvage. J Vasc Surg. 2009;49(6):1416–1425. doi:10.1016/j.jvs.2009.02.010. PMID: 19497500.

TABLE 105.6 Comparison of the Finland National Vascular (Finnvasc), Project of Ex-Vivo Graft Engineering by
Transfection III (PREVENT III), Bypass Versus Angioplasty in Severe Limb Ischemia (BASIL) Grading
Systems, and the Vascular Quality Initiative (VQI)-Derived Risk Adjustment Model
Finnvasc PREVENT III BASIL VQI-Derived
Score Application
Critical limb ischemia Critical limb ischemia Severe limb ischemia Critical limb ischemia
Factor
Advanced age ++ + +
Coronary artery disease + + ++
Diabetes mellitus + +
Obesity ++ +
Chronic kidney disease/dialysis + ++++ ++ +++
Tissue loss + +++ +++ +
Smoking +++
Anatomic factors + +
Functional status ++
Outcome Predicted
Mortality and limb loss Amputation-free survival Survival (2 years) Amputation-free survival
(30 days) (1 year) (1 year)

delineated.118 Several studies of therapeutic angiogenesis have
now been conducted, including phase III clinical trials.119-124
Overall, the data have failed to demonstrate a consistently
significant clinical benefit for any of these therapies. Results of
several phase II and III clinical trials are summarized in Table
105.7.117b-117c
Future Developments
Alternative strategies for the pharmacologic treatment of vascular
disease are under investigation, including those aimed at the
neovascularization of ischemic tissue and the prevention of
intimal hyperplasia. Similar to other fields, such as oncology,
the mapping of the human genome promises to advance
therapeutic approaches to the treatment of lower extremity
PAD. Several target genes and small molecules that are regulated
by oxygen tension have been implicated in stimulating angio-
genesis via the hypoxia-inducible factor pathway; research is
ongoing to define the therapeutic potential of prolyl-4-hydroxylase
inhibitors, mediators of the thioredoxin systems, the peroxisome
proliferator-activated receptor gamma coactivator 1-α protein,
microRNAs, and oligonucleotides.125 Therapeutic ultrasound
has also been investigated in mouse models of hind limb ischemia
for the potential to stimulate neovascularization via multiple
angiogenic pathways.126 Investigations of immune modulation
therapy, targeting the inflammatory component of vascular
disease in an effort to decrease the development and progression
of atherosclerosis and possibly angioplasty-associated intimal
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making 1393

TABLE 105.7 Summary of Phase II and III Trials of Molecular and Cellular Proangiogenic Agents in Patients With
Peripheral Artery Disease
Trial Therapy Population Result
Growth Factors
Rajagopalan et al. (RAVE) 2003126a VEGF 105 patients with disabling No difference in walking distance or quality of life
claudication
Kusumanto et al. 2006126b VEGF 54 patients with diabetes No difference in amputation rate at 100 days
and critical limb ischemia
Nikol et al. (TALISMAN) 2008126c FGF 125 patients with critical No difference in ulcer healing at 25 weeks
limb ischemia
Powell et al. (HGF-STAT) 2008126d HGF 104 patients with critical No difference in adverse event rates; no difference in
limb ischemia major amputation or death at 6 months
Shigematsu et al. HGF 40 patients with critical Significant improvement in rest pain or ulcer size at 12
(TREAT-HGF) 2010126e limb ischemia weeks (70.4% HGF versus 30.8% placebo, P = .014)
Belch et al. (TAMARIS) 2011126f FGF 525 patients with critical No difference in major amputation or death at 1 year
limb ischemia
Stem Cells
Walter et al. (PROVASA) 2011 BMMNC 40 patients with critical No difference in ABI or major amputation at 3 months
limb ischemia
Powell et al. (RESTORE-CLI) 2012 BMMNC 77 patients with critical No difference in amputation-free survival at 12 months
(Ixmyelocel-T) limb ischemia
Teraa et al. (JUVENTAS) 2015 BMMNC 160 patients with severe No difference in major amputation at 6 months
limb ischemia
BMMNC, Bone marrow mononuclear cells; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; PBMNC, peripheral blood mononuclear cells;
VEGF, vascular endothelial growth factor.

hyperplasia, are encouraging. Other areas of research aimed at
advancing our understanding of vascular disease include viral-
directed gene transfer, targeted antibiotic therapy, and alternative
circulating cell–free oxygen delivery vectors.
Future Trends
Decision Analysis
Decision analysis is a field of study that applies statistical methods
and probabilities from existing literature to model various
hypothetical outcomes for a given set of competing options.127
Decision analysis begins with identifying a problem for which
there is more than one potential solution. A decision tree is
then constructed that incorporates a valuation of any number
of factors that would influence the decision, along with the
likelihood of each branch along the decision tree occurring,
such that the outcome associated with several different choices
can be simulated. Rather than just imagining the outcome
associated with different choices, decision analysis allows for
predictions of outcomes, based on input data from the existing
literature. Decision analysis is often applied to clinical scenarios
where randomized controlled trials of competing therapies cannot
be carried out. It often incorporates factors such as cost and
QoL associated with various treatment options. One of the
most important roles of model-based decision analysis is to
identify which data parameters or assumptions can change policy
decisions. This is done through sensitivity analysis, in which
each parameter is varied through a wide range of possible values.
If this variation does not lead to a change in policy conclusions,
one can feel confident that the results of the analysis are likely
to hold true in most clinical scenarios. Conversely, if an uncertain
parameter is found to be influential, this may identify an
important area for future research. Decision analysis can play
an important role in clinical decision making in the treatment
of PAD.
Brothers and colleagues used decision analysis to assess three
different strategies for the management of CLTI: primary
amputation, revascularization, or expectant management (Fig.
105.4).128 They found that revascularization was associated with
a gain of 1.1 quality-adjusted life years (QALYs) compared with
primary amputation and 1.2 QALYs compared with expectant
management. In terms of cost associated with the three treatment
strategies, sensitivity analysis predicted revascularization to be
the least costly treatment per QALY, as long as 1-month patency
exceeds 11%. The authors conclude that revascularization offers
the greatest benefit in terms of QALY and cost in the manage-
ment of CLTI.
Nolan and colleagues applied decision analysis to treatment
of claudicants with TASC B and C lesions of the superficial
femoral artery.129 Using a hypothetical cohort of claudicants
with either TASC B or C lesions, they modeled treatment with
either angioplasty and stenting or great saphenous vein bypass
for the outcome measure of QALYs. They found that TASC B
lesions were best treated with angioplasty and stenting. However,
1394 SECTION 15 Lower Extremity Chronic Arterial Disease

Ambulatory
U[amb-reamp]
No heal Amputate Die
U[die]
Nonambulatory
U[non-reamp]
Primary Die
U[die]
Amputation Ambulatory
U[amb-amp]
Heal Nonambulatory
U[non-amp]

Remain the same

Expectant U[same]
Require amputation (above)
Management

Ambulatory
U[amb-byp-amp]
Thrombose Amputate (above) Die
U[die]
Nonambulatory
U[non-byp-amp]
Thombose Die
U[die]
Patent (below)
U[mult]
Bypass Die
U[die]
Operation No heal Amputate (above)
Patent Heal Patent
U[byp]
Thrombose (above)

Figure 105.4 Decision tree of principal management options for patients with critical limb ischemia. Square nodes
represent a decision point and round nodes represent a probability of an event occurring based on existing literature.
The outcomes, which in this study are utility values (translated into quality-adjusted life years [QALYs]), are designated
with the following abbreviations: byp, success after revascularization; mult, success after multiple revascularizations;
amb-amp, ambulatory after amputation; non-amp, nonambulatory after amputation; amb-reamp, ambulatory after
reamputation; non-reamp, nonambulatory after reamputation; amb-by, ambulatory after amputation following failed
revascularization; non-byp-amp, nonambulatory after failed revascularization and amputation; same, condition remains
the same; die, death occurs. (From Brothers TE, et al. Justification of intervention for limb-threatening ischemia: a
surgical decision analysis. Cardiovasc Surg. 1999;7:62–69.)

for patients with TASC C lesions, angioplasty and stenting was
preferred only in certain conditions. Using sensitivity analyses,
they showed that stenting surpasses efficacy of open bypass for
TASC C lesions if the primary patency of stenting is greater
than 32% at 5 years, if patient age is greater than 80 years, or
if operative mortality for open bypass exceeds 6%.
Cost-effectiveness analyses are another type of decision analysis
with several applications in healthcare research, and clinical
decision making in PAD. Barshes and colleagues recently
published a review of the methods of cost-effectiveness analysis,
anticipating their increased utility as a healthcare financial crisis
looms in the United States (Fig. 105.5).130 We believe that
decision analysis and cost-effectiveness analyses will play a
growing role in informing decision making in PAD in the
coming years.
Cost Considerations
As healthcare costs continue to rise, decision making will
increasingly be influenced by governmental and third-party
payers. There is conflicting evidence regarding the most cost-
effective methods of treating lower extremity PAD. Although
there is evidence that revascularization is cost-effective compared
with primary amputation,86,131-134 the cost differential between
strategies varies depending on the expense of rehabilitation after
primary amputation in most series.132 Indeed, primary amputa-
tion for patients forgoing rehabilitation (as might occur in a
nursing-home patient) is cheaper than revascularization. Therefore
economic decision-making depends on the patient’s postoperative
rehabilitation potential, which is often determined by preopera-
tive functional status.77 Despite the debate concerning the
economic merits of one treatment over another, most would
agree that the current financial system can ill afford to pay for
multiple revascularizations of a single ischemic limb. The scenario
becomes even more cost-prohibitive if, after multiple revascu-
larizations, major limb amputation results anyway. Future
economic decision making will therefore require the identification
of the most cost-effective single treatment for patients who
present with PAD and, more specifically, CLTI.
Unmet Needs
Definitive high-level evidence on which to base treatment
decisions, with an emphasis on clinical and cost effectiveness,
continues to be lacking. Treatment decisions in PAD are
individualized, based on life expectancy, functional status,
anatomy of the arterial occlusive disease, and surgical risk. For
patients with aortoiliac disease, endovascular therapy has become
first line therapy for all but the most severe patterns of occlusion,
and aortofemoral bypass surgery is a highly effective and durable
 CHAPTER 105 Lower Extremity Arterial Disease: Medical Management and Decision Making
More costly
More costly
Less effective More costly
(new strategy is More effective
dominated)
Fewer QALYs More QALYs
Less costly
Less costly More effective
Less effective (new strategy
dominates)
Less costly
Figure 105.5 Two-dimensional plane demonstrating the relationship of incremental
costs (vertical axis) and incremental effectiveness (horizontal axis) for two possible
interventions. If a new intervention is both more costly and less effective than a
current intervention (upper left quadrant), it is not economically preferred. If a
new intervention is less costly and more effective (lower right quadrant), it is economi-
cally preferred. Formal cost-effectiveness analysis is useful for situations described
by the upper right and lower left quadrants. Most frequently, a cost-effectiveness
analysis focuses on the upper right quadrant to address the question of whether
the more effective treatment is “worth” its greater cost. QALYs, Quality-adjusted
life years. (From Barshes NR. A primer on cost-effectiveness analyses for vascular
surgeons. J Vasc Surg. 2012;55(6);1794–800.)
treatment for the latter group. For infrainguinal disease, available
data suggest that surgical bypass with vein is the preferred therapy
for patients likely to survive 2 years or more, and for those
with long segment occlusions or severe infrapopliteal disease
who are acceptable surgical risk. Endovascular therapy may be
preferred in patients with reduced life expectancy, those who
lack usable vein for bypass or who are at elevated risk for
operation, and those with less severe arterial occlusions. Patients
with nonreconstructable disease, extensive necrosis involving
weight bearing areas, nonambulatory status, or other severe
comorbidities may be considered for primary amputation or
palliative measures. Given the myriad of contributing factors,
each with its own extensive list of possible values, the possible
combinations of disease states and patient situations are perhaps
too numerous to ever study individually. A “clean” study,
comparing two treatments in a population that is balanced on
all factors may not be achievable, even in the best of randomized
controlled trials. Despite herculean efforts on the part of the
BASIL-2 and BEST-CLI investigators, it stands to be determined
whether either of these studies will ultimately provide conclusive
enough evidence that providers feel these questions of optimal
treatment have been answered once and for all.
Third-party payers in our current healthcare system will
increasingly insist on the delivery of evidence-based care. Quality
1395
will be defined, increasingly monitored, and financially linked
to compliance with Medicare All-Care measures. Care for lower
extremity PAD will increasingly become protocol driven, placing
a premium on value and durability. For all of the important
reasons previously mentioned, future studies should continue
to analyze the impact of comorbidities in patients with PAD.
These studies need to be conducted in patients undergoing
surgical bypass, endovascular repair, primary amputation, and
conservative treatment because the effect of comorbidities can
be very different based on the treatment type. A diverse set of
standardized endpoints that attempt to capture the diverse
experience relevant to patients with PAD needs to be defined.
The time points at which these endpoints are studied also should
be standardized. In this way, valid risk estimates can continue
to inform the way we take care of patients and, in doing so,
improve evidence-based patient care. Finally, the definitive
treatment of lower extremity PAD has traditionally relied on
procedural therapy, either open or endovascular revascularization.
We are now at an exciting time point where mapping of the
human genome, improved understanding of angiogenesis, and
the growing ability to manipulate stem cell differentiation all
hold great promise in providing meaningful medical solutions
that may render many interventions unnecessary or render them
more effective.
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Bradbury AW. BASIL Trial Participants. Bypass versus angioplasty
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controlled trial. Lancet. 2005;366:1925–1934.
This rare randomized controlled multicenter trial concluded that surgery
and angioplasty have similar amputation-free survival at 6 months
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complementary nature of the two treatment approaches.
Conte MS, Bandyk DF, Clowes AW, et al. Results of PREVENT III:
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This large, multicenter trial evaluated the efficacy of edifoligide for the
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Conte MS, Pomposelli FB, Clair DG, et al. on behalf of the Society
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reviewed the current evidence supporting clinical care in the management
of asymptomatic peripheral artery disease and intermittent claudication.
Although first acknowledging the paucity of level 1 evidence, the group
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1396 SECTION 15 Lower Extremity Chronic Arterial Disease
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everyday vascular surgery practice using a large, regional database.
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previously established systems. This WIfI score was intended “to permit
more meaningful analysis of outcomes for various forms of therapy
in this challenging, but heterogeneous population.” WIfI assigns a
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foot infection. The resultant score corresponds to four threatened limb
clinical stages that estimate risk of amputation and potential benefit
of revascularization.
Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus
for the Management of Peripheral Arterial Disease (TASC II). J
Vasc Surg. 2007;45(supplS):S5–S67.
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functional outcome after revascularization for critical limb ischemia:
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Although retrospective, this large series demonstrated that functional
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profoundly impacted by the patient’s preoperative medical condition
and functional status.
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