Critical Limb Ischemia

Sarah Elsayed, MDa, Leonardo C. Clavijo, MD, PhDb,*

KEYWORDS
 Critical limb ischemia  Diagnosis  Management  Endovascular  Guidelines  Review

KEY POINTS
 Certain patient populations should be screened for peripheral artery disease.
 Critical limb ischemia is becoming increasingly prevalent. A high index of suspicion is warranted
and early referral is recommended.
 Meticulous history and physical examination are necessary.
 Arterial profile is performed for patients suspected with peripheral artery disease or critical limb
ischemia.
 Once critical limb ischemia is confirmed, lesion location and severity should be promptly
diagnosed.
 In addition to guideline-directed medical therapy, different revascularization options are weighed.
 Coronary artery disease is the major cause of death in the critical limb ischemia population.

Critical limb ischemia (CLI), the most advanced

form of peripheral artery disease (PAD), carries
grave implications with regard to morbidity and
mortality. This article is a comprehensive review
of CLI, including different treatment options and
current review of the literature. PAD has been estimated to reduce quality of life in about 2 million
symptomatic Americans, and millions more Americans without claudication are likely to suffer
PAD-associated impairment.
This impairment leads to significant morbidity
and health care expenditures. Perhaps, more
importantly, PAD is a powerful independent predictor of coronary artery disease (CAD) and cerebrovascular disease events and mortality (Fig. 1).1
The incidence of CLI in the United States is estimated at 1% of the population aged 50 years
and at approximately double that rate in those
older than 70 years. Within 1 year of CLI diagnosis,
40% to 50% of diabetics will experience an amputation, and 20% to 25% will die. The estimated

cost for treating CLI in the United States alone is

$10 to $20 billion per year, but just a 25% reduction in amputations could save $2.9 to $3.0 billion
annually.2
CLI is defined as limb pain that occurs at rest or
impending limb loss that is caused by severe
compromise of blood flow to the affected extremity. The term CLI should be used for patients with
chronic ischemic rest pain, ulcers, or gangrene
attributable to objectively proven arterial occlusive disease. The term CLI implies chronicity
and is to be distinguished from acute limb
ischemia. CLI is defined by most vascular clinicians as those patients in whom the untreated
natural history would lead to major limb amputation within 6 months.3

CAUSES OF CRITICAL LIMB ISCHEMIA

CLI is usually caused by atherosclerosis; however,
it can also be caused by atheroembolic or thromboembolic disease, vasculitis, in situ thrombosis
related to hypercoagulable states, thromboangiitis
obliterans, cystic adventitial disease, or trauma.

a
Vascular Medicine Graduated Fellow, Division of Cardiovascular Medicine, University of Southern California,
1510 San Pablo Street, Suite 322, Los Angeles, CA 90033, USA; b Interventional Cardiology Fellowship Program,
Vascular Medicine and Peripheral Interventions, Division of Cardiovascular Medicine, University of Southern
California, 1510 San Pablo Street, Suite 322, Los Angeles, CA 90033, USA
* Corresponding author.
E-mail address: lclavijo@usc.edu

Cardiol Clin 33 (2015) 3747

http://dx.doi.org/10.1016/j.ccl.2014.09.008
0733-8651/15/$ see front matter 2015 Elsevier Inc. All rights reserved.

cardiology.theclinics.com

DEFINITION AND PREVALENCE OF CRITICAL

LIMB ISCHEMIA

Elsayed & Clavijo

38

mortality in patients with CLI compared to those

without, this should prompt clinicians to recognize
the ideal care strategies to optimize risk factors
and be aware of the possibility of CAD, cerebrovascular disease, and aortic aneurysmal disease.

NEW CLASSIFICATION OF CRITICAL LIMB

ISCHEMIA
CLI was first defined in 1982. The purpose of these
2 prior classification systems was to classify risk of
amputation and benefit of revascularization. Over
the last 40 years, diabetes has become increasingly prevalent, and there has been significant
advent of revascularization strategies, especially
endovascular therapy. The Society of Vascular
Surgery Lower Extremity Guidelines Committee
created a comprehensive new classification
termed the Society of Vascular Surgery (SVS)
Lower Extremity Threatened Limb Classification
System (Table 2). This classification system includes 3 factors: wound, ischemia, and foot infection (SVS WIfI).4
The SVS grade from each table is then categorized into 5 clinical stages in ascending order:
very low, low, moderate, high, and unsalvageable
foot. These categories provide risk stratification
of amputation risk at 1 year and estimated likelihood of benefit of revascularization (assuming
infection can be controlled first).

Fig. 1. Prevalence overlap of different vascular territories in peripheral arterial disease (PAD). (From
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(Suppl S):S12A;
with permission.)

Factors that increase the risk of limb loss in patients with CLI include:
 Factors that reduce blood supply
 Diabetes mellitus
 Severe renal failure
 Severe heart failure, shock
 Vasospastic diseases
 Smoking
 Factors that increase demand for blood flow
to the microvascular bed
 Infection (cellulitis, osteomyelitis)
 Skin breakdown
 Trauma

EVALUATION OF CRITICAL LIMB ISCHEMIA

PATIENTS
History

CLASSIFICATION OF PERIPHERAL ARTERY

DISEASE AND CRITICAL LIMB ISCHEMIA

 Patients with CLI present with ischemic rest

pain with or without skin changes, which is
worse when supine and tends to lessen
when the extremity is in the dependent
position.

Fontaines Stages and Rutherfords Categories

are used to classify the degree of ischemia and
salvageability of the limb (Table 1). CLI is a
component of the more advanced stages. Given
the 3- to 5-fold increase in cardiovascular (CV)

Table 1
Classification of peripheral arterial disease and critical limb ischemia
Fontaine

Rutherford

Stage

Clinical

Grade

Category

Clinical

I
IIa
IIb

Asymptomatic
Mild claudication
Moderate-severe claudication

III
IV

Rest pain
Ulcers or gangrene

0
I
I
I
II
III
IV

0
1
2
3
4
5
6

Asymptomatic
Mild claudication
Moderate claudication
Severe claudication
Rest pain
Minor tissue loss
Ulcers or gangrene

From 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(Suppl S):S29A; with permission.

Critical Limb Ischemia

Table 2
Society of Vascular Surgery lower extremity threatened limb classification system
Wound (W)
Grade

Ulcer

Gangrene

0
1
2
3

No ulcer
Small shallow ulcer
Deeper ulcer with exposed bone, tendon
Extensive deep ulcer full thickness

No gangrene
No gangrene
Gangrene limited to digits
Extensive gangrene forefoot/midfoot

Ischemia (I)
Grade

ABI

Ankle Systolic Pressure

TP, TcPO2

0
1
2
3

0.80
0.60.79
0.40.59
0.39

>100 mm Hg
70100 mm Hg
5070 mm Hg
<50 mm Hg

60 mm Hg
4059 mm Hg
3039 mm Hg
<30 mm Hg

Foot Infection (fI)

Clinical Manifestation of Infection

SVS

Infection Severity

No symptoms or signs of infection

Infection present (at least 2 signs: local swelling, erythema,
tenderness, warmth, purulent discharge)
Local skin and subcutaneous tissue (no deep tissue involvement, no
systemic signs)
Local Infection involving deeper tissues (no systemic signs)
Local infection with systemic signs

0
1

Uninfected
Mild

2
3

Moderate
Severe

Abbreviations: TcPO2, transcutaneous oximetry; TP, toe pressure.

Adapted from Mills J, Conte M, Armstrong D, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg 2014;59:22034.

 Rest pain may be so severe that it has been

described as worse than terminal cancer.
This leads to severe decline in functional
status.
 Individuals with diabetes may have concomitant neuropathy and may present with painless CLI and tissue loss, which is challenging
to diagnose early.
 CLI may develop as progression of PAD or it
may be the initial presentation, which may
raise the suspicion for thromboembolic
disease.
History is essential with regard to time course of
CLI. Acute versus chronic presentation must be
differentiated given different treatment and management approaches. Although patients with CLI
(chronic) do not require immediate intervention,
they will definitely need a thorough evaluation
and likely early revascularization. A meticulous
vascular history is warranted, which includes
symptom assessment of coronary and cerebral circulations, and global atherosclerosis risk assessment that encompasses smoking, diabetes,

hypertension, hypercholesterolemia, and elevated

levels of C-reactive protein. Moreover, in individuals with elevated C-reactive protein, levels of soluble intercellular adhesion molecule-1, a leukocyte
adhesion molecule that is upregulated by inflammatory cytokines, were independently associated
with the future development of lower-extremity
PAD. Precipitating factors such as trauma, removal
of toenail, or infection should also be identified.

Physical Examination
 Physical examination should be thorough and
aimed at palpating pulses at different levels to
anticipate the level of obstruction.
 Physical examination should have a systematic approach and signs of chronic ischemia
should be evaluated:
 Rubor of the dependent extremity (Fig. 2)
 Early pallor upon elevation of the extremity
 Reduced capillary refill
 Loss of hair and brittle nails of the extremity
 Manifestations of atheroembolic disease as
livedo reticularis

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Elsayed & Clavijo

Fig. 2. Physical examination findings. (A) Rutherford grade 4, dependent rubor. (B) Rutherford grade 5. (C) Rutherford class 6.

 Motor and sensory assessment is always

necessary.
 Source of infection should be detected.
 Distinction should be made between ulcers
ischemic in origin (toes, foot) versus venous
(often malleolar) versus neuropathic (foot, sole).
 Patients with a history of critical limb ischemia
should be assessed at least biannually for
recurrence by thorough physical examination
and inspection of the feet.

DIAGNOSIS
Baseline investigations should be done, including
hematologic and biochemical tests, such as complete blood count, fasting blood glucose level, hemoglobin A1c level, serum creatinine level, fasting
lipid profile, and urinalysis (for glycosuria and proteinuria). Resting electrocardiogram is important
for perioperative evaluation. Also, transthoracic
echocardiography and nuclear stress test are

often done to provide risk stratification before

high-risk peripheral vascular surgery.
A single academic center performed a retrospective review of CLI patients undergoing bypass
surgery using a contemporary preoperative evaluation. There was a low incidence of perioperative
mortality and morbidity.5
Objectives for diagnostic evaluation of patients
with CLI should be directed at:
 Confirmation of the diagnosis.
 Localization of the responsible lesion(s) with
range of severity (usually multilevel disease).
 Assessment of the hemodynamic requirements for successful revascularization.
 Assessment of individual patients endovascular or operative risk.
Arterial profile provides useful information, such
as baseline ankle-brachial index (ABI), ankle or toe
pressure measurement, toe-brachial index, waveform analysis, and localization of lesion (Fig. 3).

Critical Limb Ischemia

Fig. 3. Ankle-brachial index (A)
and toe-brachial index (B), both
with normal triphasic waveforms.

 ABI less than 1.0 is abnormal and greater than

1.4 is considered noncompressible (Table 3).3
 Generally, measurement of an absolute systolic blood pressure 50 mm Hg at the ankle
and 30 mm Hg at the toe will often imply
that spontaneous healing will not occur in
the absence of successful revascularization.
If there is major tissue loss, a toe pressure of
30 to 40 mm Hg may still not be sufficient to
promote healing.
 ABI less than 0.90 is up to 95% sensitive and
specific for detecting angiographic arterial
disease, which was identified by the Trans
Atlantic Inter-Society Consensus (TASC)
working group in 2000.
The predictors of nonhealing were found to be
insulin-dependent diabetes mellitus, end-stage
renal disease dependent on hemodialysis, and
major tissue loss after endovascular therapy.6
Similar factors were found relevant after bypass
surgery.7 Some believe that angiosome-directed
endovascular revascularization is more beneficial
to promote wound healing.8

Table 3
Ankle-brachial index interpretation
Ankle-Brachial Index

Interpretation

1.01.4
0.900.99
0.7.089
0.400.69
0.40

Normal
Borderline
Mild
Moderate
Severe

From Rooke T, Hirsch A, Misra S, et al. 2011 ACCF/AHA

focused update of the guideline for the management
of patients with peripheral artery disease (updating
the 2005 guideline). Circulation 2011;124:2025; with
permission.

The next step is localization of the lesion(s) and

identification of severity, which can be done invasively or noninvasively before endovascular or surgical intervention. Imaging of the lower limb
arteries can be done using duplex ultrasound
scan, digital subtraction angiography (DSA), magnetic resonance angiography, or computed tomographic angiography (Table 4).9 DSA provides
diagnostic and interventional opportunities and is
the commonly performed method to identify lower
extremity arterial anatomy.
On the other hand, individuals who present with
clinical features to suggest atheroembolization,
such as onset of signs and symptoms of CLI after
recent catheter manipulation with associated systemic fatigue or muscle discomfort, symmetric
bilateral limb symptoms, or increasing creatinine
level, should be evaluated for more proximal aneurysmal disease such as aortoiliac, common
femoral, or popliteal aneurysms.

MANAGEMENT
Management is optimally directed at:
 Increasing blood flow to the affected extremity to relieve rest pain.
 Healing ischemic ulcerations and wound care.
 Avoiding limb loss.
This management is achieved by guidelinedirected medical therapy and risk factor modification. The mainstay of therapy remains to be
revascularization by endovascular or surgical
means for potential candidates.

Medical Therapy
Medical therapy strategies include the use of
antiplatelet agents, anticoagulant medications,
intravenous prostanoids, rheologic agents, and
optimization of risk factors for all CLI patients,

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Elsayed & Clavijo

Table 4
Characteristics of imaging methods used to diagnose peripheral arterial disease

Characteristic

Duplex Ultrasound

Digital-Subtraction
Angiography

Advantages

 Noninvasive
 Can visualize &
quantitate
severity.
 Operator
dependent
 Limited by dense
calcification

 Gold Standard
 High resolution
 Can guide
intervention
 Invasive
 Radiation
 Contrast
 2 dimensional

Disadvantages

Magnetic
Resonance
Angiography (MRA)

Computed
Tomographic
Angiography (CTA)







 Noninvasive
 Higher resolution
than MRA
 3D
 Radiation (25% of
dose with DSA)
 Contrast
 Limited by
calcification

Noninvasive
No radiation
No contrast
3D
Lower resolution
than CTA
 Claustrophobia
 Image artifact if
stent present

Adapted from White C. Intermittent claudication. N Engl J Med 2007;356:1246.

especially for those who are poor revascularization

candidates because of multiple comorbidities.
However, few of these clinical interventions
have been evaluated adequately or have been
proven to offer predictable improvements in limb
outcomes in prospective clinical trials. The
201110 and 201311 American College of Cardiology Foundation/American Heart Association
(AHA) Guidelines for the Management of PAD
address all therapies and emphasize the importance of screening for PAD. Currently, asymptomatic patients 65 years old should receive a
resting ABI, as should patients 50 years old
with a history of smoking or diabetes mellitus.
This new recommendation stems from the
German Epidemiologic Trial on ABI study group
that included 6880 patients 65 years of age. In
total, 21% of this cohort had asymptomatic or
symptomatic PAD.
 Antiplatelet therapy with aspirin is currently
recommended for symptomatic PAD patients
(class 1).
 The Critical Limb Ischemia Prevention Study
(CLIPS) showed direct evidence, for the first
time, that PAD patients treated with lowdose aspirin had a decrease in major vascular
events (P 5 .022) and CLI (P 5 .014).10
 The combination of aspirin and clopidogrel
may be considered to reduce CV events in patients with symptomatic lower extremity PAD,
low risk of bleeding events, and high CV risk
(class IIb).
 In the Clopidogrel for High Atherothrombotic
Risk and Ischemic Stabilization, Management, and Avoidance (CHARSIMA) trial, stable, high-CV-risk patients were randomly
assigned to receive aspirin plus clopidogrel
versus aspirin only and were followed up for







a mean of 2.3 years. The authors concluded

that dual antiplatelet therapy did not confer a
difference in primary outcome of CV death,
myocardial infarction, or stroke compared
with aspirin monotherapy. Interestingly, the
symptomatic PAD cohort showed a benefit
with clopidogrel (6.9% vs 7.9%; relative risk,
0.88; P 5 .046).
b-blockers are recommended to treat hypertension in patients with PAD (class I).
Angiotensin-converting enzyme inhibitors are
recommended in patients with PAD to
reduced adverse CV events (class IIa).
Goal low-density lipoprotein is less than
100 mg/dL with use of statin (class I).
Smoking cessation is also recommended
(class I).
Warfarin in addition to antiplatelet therapy is
contraindicated in the absence of any other
proven indication for warfarin in patients with
PAD (class III).

The Project or Ex-Vivo Vein Graft Engineering

via Transfection (PREVENT) III trial, a prospective,
randomized controlled trial using molecular therapy to prevent vein graft failure in CLI patients
undergoing infrainguinal bypass surgery, did a
post-hoc analysis showing mortality benefit with
statin in the CLI population.12 Treatment of infection may decrease the metabolic demands that
impede wound healing. Investigation of angiogenic therapies, via administration of gene or protein, to enhance collateral blood flow, has offered
promise as a potential strategy to treat CLI, but
further investigations are needed to prove their
significant utility and cost effectiveness.
Parenteral administration of pentoxifylline is not
useful in the treatment of CLI. Parenteral administration of prostaglandin E-1or iloprost for 7 to

Critical Limb Ischemia

28 days may be considered to reduce ischemic
pain and facilitate ulcer healing in patients with
CLI, but its efficacy is likely to be limited to a small
percentage of patients as specifically mentioned in
the 2006 American College of Cardiology (ACC)/
AHA management of PAD guidelines. Oral iloprost
is not an effective therapy to reduce the risk of
amputation or death in patients with CLI. Cilostazol remains first-line medical treatment when
applicable for patients with claudication to increase walking distance.
Mohler and Giri13 reviewed the significant differences between the ACC/AHA management of
PAD guidelines and the TASC II guidelines for
treatment and diagnosis of PAD, which are
mentioned briefly. In addition to slightly different
evidence grading systems, HbA1c is recommended to be less than 7% by both guidelines but
closer to 6% per TASC II. The TASC II guidelines
recommend that the initial strategy for reducing
lipid levels should focus on the use of dietary modifications, whereas the ACC/AHA guidelines
recommend the use of statins as first-line therapy
for lipid level reduction (Table 5).
The most recent 2013 ACC/AHA guidelines on
the treatment of blood cholesterol to reduce
atherosclerotic CV risk in adults advocate the
use of high-intensity statin therapy in patients
with PAD who are less than 75 years of age (class
I recommendation). No specific low-density lipoprotein goal was recommended in this particular
document.14
It is worth emphasizing that primary care physicians should refer patients with CLI in a timely
fashion to vascular specialists to expedite treatment, prevent further deterioration, and reverse
the ischemic process if feasible. In the PAD Awareness, Risk, and Treatment: New Resources for
Survival (PARTNERS) Study, 6979 patients were
enrolled in a multicenter cross-sectional study.

 The study investigators found that 83% of patients were aware of their PAD diagnosis but
only 49% of physicians were aware.
 Hypertension and hyperlipidemia were
treated less often in the PAD cohort (88%
and 56%, respectively, P<.001) compared
with the CAD group (95% and 73%, respectively, P<.001).
 Antiplatelet agents were prescribed in 54% of
PAD patients compared with 71% of patients
with CAD (P<.001). The authors concluded
that PAD is underdiagnosed and subsequently undertreated in the primary care
setting.15
Currently, the concept of aspirin plus clopidogrel
high on treatment platelet reactivity resistance is
evolving. This has been studied in the CAD population but was only recently shown in a CLI subgroup. Clopidogrel resistance was found in 75%
of CLI patients and aspirin resistance in 28.5% in
a small cohort of CLI patients.16 In the Platelet
Responsiveness to Clopidogrel Treatment after
Peripheral Endovascular Procedures (PRECLOP)
study, 100 patients were enrolled into a prospective study, and all received clopidogrel daily,
before and after infrainguinal angioplasty or stenting. VerifyNow P2Y12 was used. Cox multivariate
regression analysis identified high platelet reactivity (platelet reactivity units 234) as the only independent predictor of an increased number of
adverse events (hazard ratio, 16.9; 95% confidence interval [CI], 555; P<.0001).17 This may be
the direction of tailoring treatment in CLI but it is
not currently guideline driven.
The use of pneumatic compression devices is
now emerging especially in patients with CLI and
nonreconstructible anatomy. In a study of 171 patients, this device was found to be cost effective
and clinically effective. The toe pressure increased

Table 5
Comparison between ACC/AHA and TASC II guidelines for management of peripheral arterial disease
patients

Evidence grading system

HbA1C Goal
Second-Line med to cilostazol
in claudication
Initial med for HTN
Initial strategy for hyperlipidemia

ACC/AHA

TASC II

ABC and Roman

numeral classifications
<7%
Pentoxifylline

ABC system
Closer to 6%
Naftidrofuryl

Not specified
Statins

Thiazide or ACEi
Dietary modification

Abbreviation: ACEi, angiotensin-converting enzyme inhibitor; HTN, hypertension.

Data from Mohler E, Giri J. Management of peripheral arterial disease patients: comparing the ACC/AHA and TASC-II
guidelines. Curr Med Res Opin 2008;24:251113.

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Elsayed & Clavijo

Fig. 4. Angiograms of patient
with critical limb ischemia before
(A) and after (B) revascularization.

from 39.9 to 54.2 mm Hg (P 5 .0001). Median

amputation-free survival (AFS) was 18 months
and limb salvage at 3.5 years was 94%.18

Endovascular and Surgical Treatment

The goal of revascularization in patients with CLI is
to establish inline flow to the foot. Examples are
shown in Figs. 4 and 5. If it is unclear whether hemodynamically significant inflow disease exists,
intra-arterial pressure measurements across
suprainguinal lesions should be measured with or
without the administration of a vasodilator (given
possible false low trans-stenotic pressure gradient
in the setting of severe outflow disease). Catheterbased thrombolysis is generally reserved for patients with acute limb ischemia.
The Bypass versus Angioplasty in Severe
Ischemia of the Leg (BASIL) trial evaluated patients
with severe lower limb ischemia caused by infrainguinal disease who had a life expectancy of 2 years
after an intervention and were randomly assigned

to receive bypass surgery first versus balloon angioplasty (PTA) first as revascularization strategies.19 Of note, this trial was performed in the
predrug-eluting stent (DES) era.
 Bradbury and colleagues19 determined that
the primary endpoint of AFS, as well as the
secondary endpoint of overall survival (OS),
was not different between the 2 strategies at
1 and 3 years.
 Considering the follow-up period as a whole,
AFS and OS did not differ between treatments; however, for patients surviving
beyond 2 years from randomization, bypass
was associated with reduced hazard ratio
(HR) for OS (HR, 0.61; 95% CI 0.500.75;
P 5 .009) but not for AFS (HR, 0.85; 95% CI,
0.501.07; P 5 .108) during the subsequent
follow-up period.
 Vein bypasses and angioplasties performed
better than prosthetic bypasses.

Fig. 5. Critical limb ischemia patient with patent stent in the anterior tibial artery on gray-scale duplex ultrasound scan (left) and with color Doppler (right). (Not the same patient shown in Fig. 4.)

Critical Limb Ischemia

Table 6
Comparison of outcomes between major trials
TASC II24

PaRADISE25

BASIL26

Major amputation

30% at 1 y

6% at 3 y

Symptom relief FAILURE

Patient population

20%
Benchmark

1%
 All CLI
 Older
 Renal failure

11% at 1 y
18% at 3 y

 <25% CLI
 Younger
 Low risk

 These findings suggest that in patients with

SLI caused by infrainguinal disease, the decision whether to perform bypass surgery or
balloon angioplasty first appears to depend
on anticipated life expectancy.
 Patients expected to live less than 2 years
should usually be offered balloon angioplasty
first, as it is associated with less morbidity and
lower costs.
 Patients with longer expected longevity
should be offered bypass surgery initially,
but this depends on the individual comorbidities, since it is worth noting that the patients
in the BASIL trial did not have significant
comorbidities.
Thus, multiple survival prediction models were
proposed to aid in clinical decision making according to multiple factors, including below-knee
Bollinger angiogram score, body mass index,
age, diabetes, serum creatinine level, and smoking
status in the COX model. The Weibull model

includes the same parameters in addition to presence of tissue loss, number of ankle pressure measurements detectable, maximum ankle pressure
measured, a history of myocardial infarction or
angina, and history of stroke or transient ischemic
attack (but not diabetes). Furthermore, the Weibull
model can be used to help predict outcomes for
individuals and subsequent optimal decision making for choice of procedure.20
The Preventing Leg Amputations in Critical Limb
Ischemia with Below-the-Knee Drug Eluting Stents
(PARADISE) trial was a prospective, nonrandomized trial that investigated the efficacy and safety
of DES in below-the-knee CLI.21 CLI patients
treated with DES had a 3-year limb salvage rate
of 94%, which exceeded historic controls of
balloon angioplasty and bypass surgery (Table 6).
The randomized, controlled trials for DES in CLI
are summarized in Table 7.
Egorova and colleagues22 analyzed data from
inpatient hospitalizations and outpatient surgeries
discharge databases from 1998 to 2007 and found

Table 7
Summary of prospective randomized controlled trials in CLI: balloon expandable DES versus PTA versus
bare metal stents (BMS) and the PREVENT III trial (surgical bypass)
Trial
a

Achilles DES
Achilles PTAa
Destiny DESb
Destiny BMSb
Yukon DESc
Yukon BMSc
Prevent IIId

Intervention

Death (%)

Patency (%)

TLR (%)

Amputation (%)

Cypher
Balloon
Xcience
Vision
Sirolimus
BMS
Bypass

200

140

161

1400

10
12
16
16
17.1
14
16

77.6
58.1
85
54
80.6
55.6
61

10
16.5
9
34
9.7
17.5
22.9

13.8
20
2.4
2.4
3.4
4.3
12

Abbreviation: TLR, target lesion revascularization.

a
Scheinert D, Katsanos K, Zeller T, et al. A prospective randomized multicenter comparison of balloon angioplasty and
infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results
from the achilles trial. J Am Coll Cardiol 2012;60(22):22905.
b
Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg 2012;55(2):3908.
c
Rastan A, Tepe G, Krankenberg H, et al. Sirolimus-eluting stents versus bare-metal stents for treatment of focal lesions
in infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial. Eur Heart J 2011;32(18):227481.
d
Conte MS, Bandyk DF, Clowes AW, et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the
prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg 2006;43(4):74251.

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Elsayed & Clavijo

that the volume of major amputations decreased
by 38% as a result of endovascular lower extremity revascularization (LER) techniques, as its use
doubled during this time. The volume of open
LER decreased by 67% from 1998 to 2007. It is
worth noting that interventions declined by 20%
for CLI but increased by nearly 50% for claudication. Although patients today have more comorbidities, regardless of whether treated for
claudication or CLI, the rates of amputation, the
procedural morbidity and mortality, and the length
of hospital stay have all significantly decreased. Infrainguinal surgical bypass with at least 3 mm vein
conduit at 1 year has a primary, assisted primary,
and secondary patency of 68.4%, 93.3%, and
95.2%, respectively.23
4.

Primary Amputation
Patients who have significant necrosis of the
weight-bearing portions of the foot (in ambulatory
patients), an uncorrectable flexion contracture,
paresis of the extremity, refractory ischemic rest
pain, sepsis, or a limited life expectancy because
of comorbid conditions should be evaluated for
primary amputation of the leg. Surgical or endovascular intervention is not indicated in patients
with severe decrements in limb perfusion (ie,
ABI <0.4) in the absence of clinical symptoms of
CLI. It is worth noting that active progressive
infection may lead to wet gangrene and guillotine
amputation.

SUMMARY
The long-term prognosis of patients with PAD is
worse than in patients with CAD. Vascular patients
receive fewer medications than do CAD patients.
Cardiovascular and cerebrovascular complications are the major causes of death. We need to
close the survival gap in PAD patients, which can
be facilitated by a multidisciplinary team including
vascular medicine, vascular surgery, interventional
cardiology, and primary care.

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