Curr Cardiol Rep (2015) 17:57
DOI 10.1007/s11886-015-0611-y
INTERVENTIONAL CARDIOLOGY (S RAO, SECTION EDITOR)
Limb Ischemia: Cardiovascular Diagnosis and Management
from Head to Toe
Sreekanth Vemulapalli 1 & Manesh R. Patel 1 & W. Schuyler Jones 1
# Springer Science+Business Media New York 2015
Abstract Peripheral arterial disease (PAD) affects an estimat-
ed 27 million people in Europe and North America. Limb
ischemia, defined as ischemic rest pain, ischemic ulcerations,
or ischemic gangrene, represents the most severe manifesta-
tion of PAD and is associated with significant cardiovascular
and limb morbidity and mortality. Critical limb ischemia
(CLI), defined as limb ischemia symptoms for greater than
2 weeks, is characterized by a cascade of hemodynamically
significant macrovascular atherosclerotic obstruction and mi-
crovascular changes culminating in decreased muscle perfu-
sion, disrupted muscle energy metabolism, and inflammation.
In contrast, acute limb ischemia (ALI) is defined as limb is-
chemia symptoms characterized by sudden onset of less than
2 weeks duration resulting in hemodynamically compromised
limb perfusion. Diagnosis of both ALI and CLI is dependent
on history, physical examination, and a combination of ana-
tomic and hemodynamic assessment of the limb. Given that
the risk factors for ALI and CLI overlap with risk factors for
atherosclerotic coronary and neurovascular disease, the man-
agement of limb ischemia is focused on both endovascular or
surgical limb salvage and cardiovascular risk factor control.
Despite advancements in endovascular and surgical revascu-
larization techniques, limb morbidity remains high; clinical
trials of angiogenic and cell-based therapies are ongoing. Car-
diovascular risk reduction in patients with limb ischemia also
remains suboptimal and future studies will focus on novel
antiplatelet agents.
This article is part of the Topical Collection on Interventional Cardiology
* Sreekanth Vemulapalli
sreekanth.vemulapalli@duke.edu
1
Duke Clinical Research Institute and Division of Cardiology, Duke
University Medical Center, Box 3026, Durham, NC 27710, USA
Keywords Critical limb ischemia . Acute limb ischemia .
Peripheral artery disease . Revascularization . Wound care .
Cardiovascular risk reduction
Introduction
Peripheral artery disease (PAD) affects an estimated 27 mil-
lion people in North America and Europe, and the prevalence
of PAD is thought to be about 12 % with men being affected
more commonly than women [1]. Despite the high prevalence
of PAD, it is often under-diagnosed, as it often presents with
atypical symptoms, especially in women [2]. PAD is a marker
of systemic atherosclerosis, especially cerebrovascular and
coronary disease [3], and its most severe form, limb ischemia,
is associated with significant cardiovascular and limb morbid-
ity and mortality. Since physicians often fail to recognize signs
and symptoms of lower extremity vascular disease [4], the aim
of this review is to examine the guidelines and evidence for
the diagnosis and management of critical and acute limb
ischemia.
Critical Limb Ischemia
Definition and Epidemiology
Critical limb ischemia (CLI) is defined as a manifestation of
peripheral artery disease characterized by either chronic ische-
mic rest pain, ischemic ulcerations, or ischemic gangrene [5,
6]. Based on billing claims data, the national prevalence of
CLI was estimated to be 168,549 cases in 2004 with an inci-
dence of a further 262,121 cases from 2004 to 2008 [7]. Al-
though CLI represents a minority of all presentations of PAD,
epidemiologic data from the 1980s and 1990s suggest that it is
characterized by 25 % 1-year cardiovascular mortality and
57 Page 2 of 12
25 % 1-year amputation rate [6]. Consequently, patients with
CLI are difficult to study longitudinally, and little data exists
regarding contemporary outcomes. As a proxy for CLI, mul-
tiple recent studies have examined patients with known PAD
who undergo lower extremity amputation. A recent medicare
analysis of these patients demonstrated mortality of 13.5 % at
30 days, 48.3 % at 1 year, and 70.9 % at 3 years [8].
Pathophysiology and Etiologies of CLI
CLI is characterized by derangements in multiple aspects of
lower limb function, including hemodynamic compromise,
alterations in oxidative stress, skeletal muscle metabolism,
and inflammation (Fig. 1). Hemodynamically, CLI is often
associated with multi-segment disease. Particularly prevalent
is involvement of the small caliber below-the-knee vessels.
Macrovascular changes in CLI are accompanied by microvas-
cular changes, including loss of capillary density and endothe-
lial dysfunction thought to be mediated by ischemia and in-
flammation [9]. Importantly, chronic ischemia in the lower
extremity musculature has also been shown to result in
Fig. 1 Pathophysiology of critical limb ischemia
Curr Cardiol Rep (2015) 17:57
increased free radical production and subsequent mitochondri-
al damage in PAD patients [10]. Consequently, multiple
in vivo imaging studies have demonstrated abnormal phos-
phocreatine metabolism in patients with pad [11, 12].
Presentation and Evaluation of CLI
Although intermittent claudication may progress to CLI,
many CLI patients are either initially minimally symptomatic
or do not seek care prior to presenting with symptoms of CLI.
Typically, presentation includes limb pain at rest with or with-
out accompanying tissue loss. Resting limb pain also typically
improves with the limb in a dependent position. Ascertain-
ment of factors predisposing patients to CLI, including diabe-
tes and chronic kidney disease, is also helpful. Determination
of the duration of symptoms is important in differentiating
CLI, which implies chronic symptoms, from ALI. By conven-
tion, CLI refers to chronic ischemia and symptoms of greater
than 14-day duration.
In the cases of tissue loss, differentiating between arterial,
venous, and neuropathic ulcerations is important, especially in
Curr Cardiol Rep (2015) 17:57
the patient without a history of PAD or in the patient with
multiple potential causes of tissue loss, such as diabetic neu-
ropathy or venous insufficiency. Arterial ulcers are classically
described as occurring on the toes and foot and being associ-
ated with severe pain, whereas neuropathic ulcers typically
occur on the sole of the foot and venous ulcers on the lateral
aspect of the leg/malleolus. Together, the history and physical
exam can aid the clinician in classifying the patient with CLI
by available clinical classification systems (Table 1).
Previous studies have highlighted the difficulty of relying
on patient history and physical examination alone for the di-
agnosis of PAD with or without symptoms [13]. This is espe-
cially true given the rising incidence of diabetes, wherein
many foot lesions are of mixed neuroischemic etiology. As a
result, current guidelines suggest that patients Bat risk^ of CLI
should be screened with arterial testing to verify the contribu-
tion of arterial disease to symptoms. The ankle-brachial
(ABI), toe brachial indices (TBI), and transcutaneous oxygen
measurement are easily obtained in the vascular lab and are
first-line studies for the detection of PAD in the patient with
suspected CLI. Furthermore, absolute systolic blood pressures
of ≤50 mm Hg at the ankle or ≤30 mm Hg at the toe, or TcPO2
<30 mm Hg are indicative of likely amputation in the absence
of revascularization [5]. For patients in whom measurement of
the ABI, TBI, and TcPO2 is not possible due to noncompress-
ible vessels, poor waveform, or overlying ulceration, lower
extremity arterial ultrasound may also be used to document
the presence of PAD. Together, these noninvasive tests form
the basis of a hemodynamic definition of CLI (Table 2) [14].
Using the newly validated wound, ischemia, and foot infec-
tion (WIfI) system [15••], these simple vascular lab tests can
help the clinician more accurately classify the patient with CLI
according to risk for amputation and benefit of
revascularization.
Treatment of Critical Limb Ischemia
The goals of treatment in CLI are twofold: (1) limb salvage
and (2) cardiovascular risk reduction (Fig. 2).
Table 1 Classification systems of critical limb ischemia
Fontaine Rutherford
Stage Description Grade Category
I Asymptomatic 0 0
IIa Mild claudication I 1
IIb Moderate to severe claudication I 2
I 3
III Ischemic rest pain II 4 patients with CLI and infrainguinal disease to four arms: (1)
IV Ulceration or gangrene III 5 infrainguinal PAD without significant infrapopliteal disease,
III 6 (2) infrainguinal PAD with significant infrapopliteal disease,
Page 3 of 12 57
Table 2 Hemodynamic definitions of critical limb ischemia
Patients with tissue loss Patients with ischemic rest pain
Ankle pressure<70 mm Hg Ankle pressure<50 mm Hg
Toe pressure<50 mm Hg Toe pressure<30 mm Hg
Transcutaneous PO2 <40 mm Hg Transcutaneous PO2 <20 mm Hg
Skin perfusion pressure< Skin perfusion pressure<30 mm Hg
40 mm Hg
Limb Salvage
Although current guidelines [5, 6] suggest that revasculariza-
tion should not be attempted in nonsalvageable limbs, existing
data suggest that assessments of limb viability vary widely
among vascular specialists [16]. Though the WIfI classifica-
tion system attempts to address the difficulties in predicting
which patients will benefit from attempted revascularization,
it does not take into account patient outcomes such as quality
of life. In light of the significant morbidity [17] and mortality
[8] associated with lower extremity amputation, physicians
should err toward attempted revascularization when technical-
ly feasible.
Surgical Versus Endovascular Revascularization
Improvement in endovascular revascularization techniques
over the past 20 years has led to a significant increase of their
use in limb salvage, with reports of excellent results [18, 19].
However, there are few randomized data directly comparing a
strategy of surgical versus endovascular revascularization in
CLI. The bypass versus angioplasty in severe ischemia of the
leg (BASIL) trial was conducted in the 1990s in the UK to
compare a surgical bypass first treatment strategy versus a
balloon angioplasty first strategy. Among 452 patients with
5.5 years of follow-up, surgical bypass was associated with a
significantly lower immediate failure rate, higher 30-day mor-
bidity, and lower 12-month reintervention. There was no sig-
nificant difference in 30-day mortality or in the primary end-
point of amputation-free survival by intention-to-treat analysis
[20]. A secondary analysis revealed that bypass was associat-
ed with improved survival and a trend toward improved
amputation-free survival [21, 22]. The generalizability of the
BASIL trial in contemporary practice is limited since
endovascular therapies have progressed beyond balloon an-
gioplasty and randomization was not stratified by anatomy,
specifically infrapopliteal disease. Given the changes in both
endovascular and surgical technique since the trial enrollment
period, the NIH-sponsored BEST-CLI trial will randomize
(3) ischemic rest pain, and (4) tissue loss with or without rest
57 Page 4 of 12
Fig. 2 Diagnosis and
management of critical limb
ischemia. ABI ankle brachial
index, CLI critical limb ischemia,
CTA computed tomographic
angiography, MRA magnetic
resonance angiography, TcPO2
transcutaneous oxygen pressure,
TBI toe brachial index, US
ultrasound
pain. At the present time, apart from clear-cut situations such
as CLI in a nonoperative candidate, little consensus and sig-
nificant variability exist regarding the choice of endovascular
versus surgical revascularization [23, 24].
Though a thorough review of newer endovascular and sur-
gical revascularization techniques is beyond the scope of this
review, the angiosome concept of revascularization merits
mention. Classically, revascularization strategy in CLI
attempted to restore straight-line pulsatile flow in the inflow
vessels and at least one of the three infrapopliteal vessels
down to the foot. In this model, improvement of blood flow
to the affected area of the foot may be dependent on collateral
flow. Although not yet widely validated, the angiosome con-
cept suggests that restoration of flow in the artery supplying
the region of interest in the effected leg or foot may be more
effective [25, 26].
Wound Care
While revascularization is a mainstay of lower extremity care
in CLI, wound care is an important adjunct and may be the
primary treatment in patients who are not revascularization
candidates [5, 6]. The basic tenets of wound care include (1)
removal of necrotic/fibrotic tissue from the ulcer, (2) keeping
a moist wound environment, (3) prevention/treatment of in-
fection, and (4) pressure relief. Little in the way of systematic
evaluation of wound care strategies exists; however, in a series
of 142 patients with CLI treated at a comprehensive wound
Curr Cardiol Rep (2015) 17:57
center without revascularization, 77 % remained amputation
free at 12 months. Additionally, 52 % of patients successfully
healed their wounds [27]. Multiple nonsurgical techniques,
including hyperbaric therapy, negative pressure (wound vac)
therapy, bioengineered tissues, topical growth factors, and en-
zymatic or ultrasonographic debridement, can all be used. Due
to the lack of RCT and comparative effectiveness studies in
CLI wound care, current practice guidelines do not make any
recommendations regarding wound care modalities.
Cardiovascular Risk Reduction
Among patients with CLI, 25 % will experience cardiovascu-
lar mortality within 1 year [6]. Consequently, current guide-
lines emphasize antiplatelet therapy and risk factor control in
patients with CLI [5, 6].
Smoking Cessation
Mortality, graft occlusion, risk of amputation, and cardiovas-
cular event rates are all related to smoking in a dose-dependent
fashion [28, 29]. Data regarding the effect of smoking cessa-
tion on cardiovascular and limb outcomes in patients with CLI
is sparse; however, an analysis from the international Reduc-
tion of Atherothrombosis for Continued Health (REACH)
Registry demonstrated an association between improved car-
diovascular outcomes and risk factor control, including
smoking cessation, among patients with PAD [30]. A
Curr Cardiol Rep (2015) 17:57
subsequent single-center analysis of patients with PAD indi-
cated that adherence to guideline recommended therapies, in-
cluding smoking cessation, was associated with a reduction in
cardiovascular and limb outcomes [31•].
Antihypertensive Therapy
Although antihypertensive therapy is well accepted to lower
cardiovascular event rates in patients with uncontrolled blood
pressure, evidence for the effect of antihypertensive therapy
on cardiovascular outcomes in patients with PAD or CLI is
lacking. A Cochrane analysis of antihypertensive therapy in
PAD concluded that the quality of evidence was too poor to
assess whether antihypertensive therapy was beneficial or
risky [32]. Nevertheless, the Inter-Society Consensus for the
Management of PAD TASC II, European Society of Cardiol-
ogy, and American Heart Association guidelines all suggest a
target blood pressure below 140/90 mm Hg for patients with
PAD and CLI and below 130/80 mm Hg for those who also
have diabetes or chronic kidney disease [5, 6, 33]. Data re-
garding the choice of antihypertensive in patients with PAD or
CLI is also limited. Retrospective analysis of the Anti-Lipid
Lowering Heart Attack Trial (ALLHAT) revealed no differ-
ence in the development of PAD or cardiovascular endpoints
in patients randomized to chlorthalidone, amlodipine, or
lisinopril [34].
Antiplatelet Therapy
Antiplatelet agents are a cornerstone of cardiovascular risk
reduction in patients with established atherosclerotic disease.
Though multiple publications from the antithrombotic trialists
collaboration have established the efficacy of antiplatelets in
subgroups of patients with PAD (23 % risk reduction in vas-
cular events including MI, stroke, and vascular death), the
benefit appeared to derive from nonaspirin antiplatelet drugs
including ticlopidine, clopidogrel, picotamide, and
dipyridamole [35]. A subsequent meta-analysis of 18 prospec-
tive, randomly controlled trials of aspirin alone or in combi-
nation with other drugs for the prevention of cardiovascular
events in patients with PAD showed no significant aspirin
benefit in the combined primary endpoint of nonfatal MI,
nonfatal stroke, and cardiovascular death. Despite these find-
ings, current guidelines continue to recommend aspirin from
75 to 325 mg daily to reduce the risk of MI, stroke, and
vascular death in symptomatic patients with PAD (including
CLI). Alternatively, on the basis of an 8.7 % relative risk
reduction in MI, ischemic stroke, or vascular death in the
Clopidogrel versus Aspirin in Patients at Risk of Ischemic
Events (CAPRIE) trial, clopidogrel has earned a class I rec-
ommendation as an alternative to aspirin in PAD [36].
Page 5 of 12 57
Novel Antiplatelet Agents
Ticagrelor, a reversible nonthienopyridine inhibitor of the
platelet P2Y12 receptor, was shown to lower mortality in
acute coronary syndromes as compared to clopidogrel in the
PLATO trial. A secondary analysis of patients with PAD in the
PLATO trial revealed a nonsignificant decrease in CV death,
MI, or stroke with ticagrelor versus clopidogrel [37]. On the
strength of these findings, the ongoing EUCLID trial has ran-
domized more than 13,500 patients to clopidogrel versus
ticagrelor for the prevention of cardiovascular outcomes in
patients with PAD.
Vorapaxar is a novel antiplatelet agent that works by antag-
onism of protease-activated receptor-1, the primary receptor
for thrombin on human platelets. Two recent secondary anal-
yses of vorapaxar in patients with PAD have failed to demon-
strate significant reductions in cardiovascular endpoints; how-
ever, vorapaxar has been associated with decreased incidence
of acute limb ischemia and peripheral revascularization [38,
39]. As a result, future investigations of vorapaxar may focus
on acute limb ischemia and lower extremity revascularization.
Hyperlipidemia
In symptomatic patients with PAD, statins should be used to
reduce the risk of cardiovascular events. A secondary analysis
of 6748 patients in the Heart Protection Study indicated signif-
icant reductions in total mortality, vascular mortality, coronary
heart disease events, strokes, and noncoronary revasculariza-
tion in those treated with simvastatin [40]. Importantly, there
was no threshold cholesterol level for this effect. As a result,
statin therapy with a goal LDL<100 mg/dl is given a class I
recommendation in the guidelines for patients with PAD, while
goal of <70 mg/dl is given a class IIa recommendation [6].
Investigational Therapies
Currently, investigational therapies in PAD are primarily fo-
cused in two specific areas: (1) angiogenic growth factors and
(2) stem cell therapies for angiogenesis. Multiple small trials
in gene transfer of angiogenic growth factors have included
intramuscular injection of either fibroblast growth factor
(FGF) [41], hepatocyte growth factor (HGF) [42], or vascular
endothelial growth factor (VEGF) [43]. The majority of these
studies have shown these treatments to be safe though results
with regard to efficacy endpoints, such as wound healing, pain
relief, and improvements in ABI or TBI, are mixed [44–46].
Along with gene transfer, stem cell therapy has shown
promise in CLI. The majority of stem cell therapies for CLI
use granulocyte colony-stimulating factor to trigger produc-
tion of autologous peripheral blood mononuclear cells, endo-
thelial progenitor cells, and/or CD 34+ cells which are then
harvested and injected intramuscularly. Single arm pilot
57 Page 6 of 12
studies in CLI have demonstrated improved perfusion, low
amputation rates plus improvements in walking distances
and ABIs [47, 48]. A meta-analysis of trials of stem cell ther-
apy for PAD concluded that autologous stem cell therapy was
effective in improving pain-free walking distance, ABI, TcO2,
pain, ulcer healing, and amputation rate [49]. Although both
angiogenic growth factor therapy and stem cell therapy appear
promising for patients with incomplete revascularization, fur-
ther randomized control trial evidence will be necessary to
demonstrate efficacy and safety.
Acute Limb Ischemia
Definition and Epidemiology
Acute limb ischemia (ALI) is defined as a sudden decrease in
limb perfusion that causes a potential threat to limb viability
[5, 6]. More than 200,000 patients in the USA were affected
by acute limb ischemia in 2000; greater than one in eight
underwent in-hospital amputation, and in-hospital mortality
approached 10 % [50, 51]. Existing estimates of the cost of
ALI admissions rival costs associated with ST-elevation myo-
cardial infarction care, ranging from $6000 to $45,000.
Despite the clinical burden of acute limb ischemia, its ep-
idemiologic characterization remains limited. A number of
administrative claims based studies have attempted to further
characterize trends in the incidence of acute limb ischemia
[51, 52•]. Most recently, Korbathina et al. used the national
inpatient sample database to demonstrate a decrease in the rate
of admissions for ALI and CLI from 42.4 per 100,000 people
between 1988 and 1997 to 23.3 per 100,000 people between
1998 and 2007. During the same periods, in-hospital mortality
decreased from 8.28 to 6.34 %, while amputation rates de-
creased from 9.0 % between 1988 and 1997 versus to 7.3 %
between 1998 and 2007 [52•]. Despite the falling incidence of
ALI and improving in-hospital mortality, 1-year mortality has
been unchanged from 1988 to 2009 and remains at 42.5 %
[53].
Pathophysiology and Etiologies of ALI
The pathophysiology of ALI differs from that of CLI
and informs diagnostic and treatment algorithms. A
1998 survey study by Campbell et al. conducted in
Great Britain indicated that 41 % of admissions for
ALI were due to native thrombosis, while 38 % were
due to embolism, 15 % due to occlusion of a bypass
graft or angioplasty site, 3 % due to thrombosis of a
popliteal aneurysm, and 2 % due to trauma and iatro-
genesis each. Few other epidemiologic data exist regard-
ing the etiologies of acute limb ischemia; however,
analysis of the handful of clinical trials in ALI reveals
significant variation in the etiology of ALI, in part
Curr Cardiol Rep (2015) 17:57
related to the variations within the enrolled patient
populations [54–56].
Native thrombosis is most likely to occur at a site of ath-
erosclerotic plaque or at sites of prior revascularization. In
patients with lower extremity atherosclerotic disease, the path-
ophysiologic principles leading to lower extremity in situ
thrombosis are thought to be similar to those governing coro-
nary disease and may occur by two mechanisms. Progressive
arterial luminal narrowing may result in stasis and eventually
thrombosis or plaque rupture leading to platelet and coagula-
tion factor activation. Recent, carefully adjudicated clinical
events data from The Trial to Assess the Effects of SCH
530348 in Preventing Heart Attack and Stroke in Patients
With Atherosclerosis (TRA2P-TIMI 50) indicates that, among
patients with peripheral arterial disease, there is a nearly 4 %
rate of hospitalization for acute limb ischemia [38].
Patients with previous lower extremity revascularization
are at particular risk for acute in situ thrombosis. Autogenous
bypass grafts are most likely to thrombose at the anastomotic
sites, retained valves, or sites of technical difficulties. Alter-
natively, thrombosis may occur at any point along synthetic
grafts, even in the absence of conduit abnormalities. In
endovascularly revascularized lower extremity vessels,
thrombin-antithrombin complexes (TAT), D-dimer, and fibri-
nopeptide A levels become elevated in the plasma for approx-
imately 4 weeks after ballooning and stenting, resulting in
hypercoagulability [57, 58]. Thus, thrombosis is most likely
in the first 4 weeks after intervention. Unlike the phenomenon
of coronary stent thrombosis, aggregate data on acute throm-
bosis of endovascularly revascularized lower extremity arter-
ies are sparse. Acute thrombosis of endovascularly
revascularized lower extremities is dependent on revasculari-
zation strategy (balloon angioplasty, bare metal stenting, drug
eluting stent, and drug-coated balloon) as well as the size of
the target vessel, and patient comorbidities. Early occlusion of
PTA in the iliac artery appears to be low, whereas it climbs to
5–25 % in the femoropopliteal arteries [59]. In contrast, a
recent report of PTA versus DES in the superficial femoral
artery indicated 30-day patency of ∼50 % for PTA and
∼99 % for DES [60].
In addition to sites of atherosclerosis and previous revas-
cularization, native thrombosis can occur at arterial aneu-
rysms. Among lower extremity arterial aneurysms, popliteal
aneurysms are the most common, with an incidence of 0.1–
2.8 % [6, 61, 62], and often occur in patients without overt
lower extremity atherosclerotic disease. Nevertheless, risk fac-
tors for popliteal aneurysms mimic risk factors for other large
artery aneurysms and include smoking, hypertension, and age.
The mechanism of popliteal aneurysm-induced acute limb
ischemia is usually aneurysm thrombosis versus embolism
of thrombi to downstream infrapopliteal arteries.
Finally, inflammatory arterial diseases and hypercoagula-
ble states represent important, though infrequent causes of in
Curr Cardiol Rep (2015) 17:57
situ thrombosis and ALI. HIV, malignancy, antiphospholipid
syndrome, hyperhomocysteinemia, and medium to large ves-
sel arteridities such as Buerger’s disease, Takayasu’s arteritis,
giant cell arteritis, Behcet’s disease, and polyarteritis nodosa
have all been associated with ALI. Little data exists regarding
epidemiology and outcomes of ALI in these diseases.
Apart from in situ thrombosis, cardiovascular embolism
represents the next most common cause of acute limb ische-
mia. Typical sources of embolism include aortic aneurysms,
popliteal aneurysms, and cardiac sources of emboli, such as
atrial fibrillation and left ventricular thrombi. Although no
systematic assessment of the frequency of ALI among patients
with atrial fibrillation exists, the rate of systemic embolism in
two recent trials of novel anticoagulants was 0.18–0.26 % [63,
64].
Presentation and Evaluation of ALI
Current guidelines suggest rapid evaluation and assessment of
patients with limb threatening ischemia so as to facilitate ap-
propriate referral for revascularization, where possible [5, 6,
15••]. Goals of history taking are characterization of the time
of onset and severity of limb ischemia, identification of the
ischemic etiology where possible, and identification of key
cardiopulmonary comorbidities that may affect suitability for
revascularization. The clinical presentation is marked by the
B6 Ps^: ischemic rest pain, pulselessness, pallor, parasthesias,
paralysis, and poikilothermia. By convention, the diagnosis of
acute limb ischemia generally presumes a presentation within
2 weeks of the onset of symptoms, though this timepoint is
derived from the relationship between symptom duration and
intra-arterial thrombolytic therapy efficacy, and is not validat-
ed based on biologic or epidemiologic data. A recent single-
center registry of 74 patients with ALI reported a median time
to presentation of 0.75 days with an interquartile range of 0.27
to 3.29 days [65•]. Though differences in time to presentation
are a function of access to care and symptom recognition, the
range of times to presentation may be due in part due to the
varying etiologies of ALI. In patients with preexisting athero-
sclerotic disease, ALI events can be thought of as acute on
chronic ischemic disease, often in the presence of coexisting
collaterals. As a result of collateral circulation, symptoms may
be less intense and more insidious, corresponding with a lon-
ger time to presentation.
Patients presenting with suspected ALI should undergo a
complete vascular and cardiopulmonary examination de-
signed to assess limb perfusion and cardiopulmonary comor-
bidities. Given that the quality of lower extremity pulse exams
is variable, a complete vascular examination should include
hand-held Doppler assessment of the dorsalis pedis and pos-
terior tibial pulses. If pulses are present, limb perfusion pres-
sures of <50 mm Hg, as measured using an inflatable cuff at
the ankle, are indicative of ischemia. In order to standardize
Page 7 of 12 57
the clinical description of ALI severity and aid in therapeutic
decision-making, the Society for Vascular Surgery has
adopted a grading system similar in concept to the Rutherford
system in CLI (Table 3) [66].
Treatment of ALI
Initial treatment of suspected ALI should consist of heparin
bolus plus infusion and should be based on bedside examina-
tion [5, 67]. Further decision-making regarding revasculariza-
tion is dependent on limb viability, anatomy, and patient co-
morbidities. In general, rapid imaging to define the level and
severity of arterial obstruction is encouraged to (1) help define
in situ thrombosis versus embolism and (2) surgical versus
endovascular approach to revascularization. There have been
no systematic evaluations of the test characteristics of Doppler
ultrasonography, computed tomographic angiography, or
magnetic resonance angiography for the diagnosis of ALI,
so choice of imaging technique should be based on rapidity
of access and local expertise. Although current guidelines [5,
6] suggest that imaging should not be pursued in stage III ALI,
existing data in CLI suggest that assessments of limb viability
vary widely among vascular specialists [16]. In light of the
significant morbidity [17] and mortality [8] associated with
lower extremity amputation, physicians should err toward
attempted revascularization when technically feasible (Fig. 3).
Revascularization: Catheter Directed Thrombolysis Versus
Surgical Revascularization
Though revascularization for ALI has traditionally been sur-
gical, improvements in endovascular devices over the past 2
decades have spawned a number of endovascular techniques
that are potentially suitable for revascularization in ALI. Cur-
rently, high-quality comparative effectiveness data exist only
for catheter-directed thrombolysis versus surgical revascular-
ization. Three main trials comparing catheter-directed throm-
bolysis with surgical revascularization exist, with differing
results, in part due to differing inclusion criteria [54, 56, 68].
A meta-analysis of these studies and several others showed
similar rates of limb salvage and mortality at 30 days,
6 months, and 1 year; however, stroke (1.3 vs. 0 %; OR=
6.41; 95 % CI 1.57 – 26.22), major hemorrhage (8.8 vs.
3.3 %; OR=2.80; 95 % CI 1.70 – 4.60) and distal emboliza-
tion (12.4 vs. 0 %; OR=8.35; 95 % CI 4.47–15.58) were more
likely at 30 days with catheter thrombolysis [69].
In general, patients in whom an additional 12–24 h of is-
chemia cannot be tolerated, who have a nonviable limb, or
who have contraindications to thrombolysis (active bleeding,
recent major surgery, recent intracranial hemorrhage, or vas-
cular brain neoplasm) should not undergo catheter thrombol-
ysis. Furthermore, data from STILE suggests that thrombi less
than 14 days old are most likely to respond to catheter
57 Page 8 of 12 Curr Cardiol Rep (2015) 17:57

Table 3 Stages of acute limb ischemia

Stage Description and prognosis Findings Doppler signal

Sensory loss Muscle weakness Arterial Venous

I Limb not immediately threatened None None Audible Audible

II Limb threatened
IIa Marginally threatened, salvageable if promptly treated Minimal (toes) or none None Inaudible Audible
IIb Immediately threatened, salvageable with immediate More than toes, associated Mild, moderate Inaudible Audible
revascularization with rest pain
III Irreversibly damaged with major tissue loss or permanent Profound, anesthetic Profound, paralysis Inaudible Inaudible
nerve damage inevitable

thrombolysis (Fig. 4). Conversely, patients with high surgical
risk due to cardiopulmonary comorbidities may be more ap-
propriate for endovascular revascularization. The TASC II
guidelines suggest that surgical revascularization is generally
the preferred method for revascularization in supra-inguinal
occlusions and bypass graft occlusions [5]. However, these
recommendations remain controversial in light of rapidly ad-
vancing surgical and endovascular techniques.
Newer Endovascular Revascularization Techniques
With the rapid improvement of endovascular revasculariza-
tion techniques, there has been an increase in the use of
thromboembolectomy, catheter thrombolysis, and percutane-
ous angioplasty for ALI [52•]. Although devices for thrombus
a s p i r a t i o n , r h e o l y t i c th r o m b e c t o m y, m e c h a n i c a l
thrombectomy, and ultrasound-assisted thrombolysis exist,
none of these devices have been prospectively compared
against catheter thrombolysis [70–72].
Post-Revascularization and Long-Term Management
Short-term post-revascularization management is directed to-
ward ensuring continued limb perfusion through arterial pa-
tency and detection of reperfusion injury. Given that
prolonged leg muscle ischemia is associated with increases
in creatine phosphokinase, inflammatory lymphokines, and
free radicals [73, 74], reperfusion can result in limb injury.
Reperfusion injury is characterized by limb swelling and ele-
vated compartmental pressures, tissue compression, and final-
ly clinical compartment syndromes. The clinical compartment
syndrome is marked by pain, hypoesthesia, and weakness of

Fig. 3 Diagnosis and

management of acute limb
ischemia. ALI acute limb
ischemia
Curr Cardiol Rep (2015) 17:57
Fig. 4 Case example of acute limb ischemia. An 85-year-old Caucasian
woman presented to primary care clinic with persistent left calf and foot
pain × 2 days. On exam, she was found to have an irregular heart rate, and
her left foot was cold and without a pulse. On ECG, she was diagnosed
with atrial fibrillation. She underwent lower extremity duplex
ultrasonography (a) that demonstrated no flow in the left popliteal
the limb in association with elevated creatine kinase levels and
myoglobinuria. In the lower extremity, anterior compartment
syndrome is the most common and is marked by loss of
dorsiflexion of the foot and diminished sensation on the dor-
sum of the foot and in the first web space. Treatment of com-
partment syndrome usually requires surgical fasciotomy.
Long-term management of patients presenting with ALI
should focus on aggressive risk factor modification for those
with in situ thrombosis and underlying lower extremity ath-
erosclerotic disease as an etiology. One-year mortality remains
elevated, likely because of cardiovascular mortality in these
patients. Ideally, this would include adequate blood pressure
control, smoking cessation, and lipid management, preferably
with statin therapy. Long-term antiplatelet therapy is also in-
dicated in these patients. However, despite guideline recom-
mendations for the use of aspirin, the oral antiplatelet of
choice is unknown. Among patients presenting with embolic
ALI, a search for an embolic source should include evaluation
for atrial fibrillation, popliteal and aortic aneurysms, and par-
adoxical emboli with consideration for prolonged oral
anticoagulation.
Page 9 of 12 57
artery. The following day, she underwent invasive angiography (b), and
popliteal artery occlusion was confirmed on digital subtraction
angiography (arrow). A thrombolysis catheter was placed and flow was
restored, as confirmed by repeat digital subtraction angiography on the
next day (c). She was treated with long-term vitamin K antagonism
(warfarin)
Quality Improvement and Processes of Care in Limb Ischemia
Little is known about the Breal-world^ treatment of limb ische-
mia, and few studies evaluating the impact of guideline-based
care on limb and cardiovascular outcomes exist [75]. A recent
single-center prospective registry of all patients presenting with
ALI has provided the first validation that limb ischemia time
before revascularization is a key predictor of amputation free
survival and mortality [65•]. Despite the creation of evidence-
based guidelines focused on both limb and cardiovascular out-
comes in patients with limb ischemia, mortality remains high
[8], though amputation rates appear to be falling concurrently
with increasing rates of endovascular intervention [76]. Addi-
tionally, although limb ischemia specific data are not available,
there remains significant variation in the application of
guideline-recommended medical therapy [77] and revasculari-
zation strategies in PAD [24]. Up to one third of patients un-
dergo no vascular testing in the year prior to lower extremity
amputation, suggesting that lower extremity vascular disease is
under-recognized by internists and cardiologists, who evaluate
these patients for cardiovascular risk factors [78•]. Such data
57 Page 10 of 12
suggests that adoption of standardized evaluation and manage-
ment pathways for limb ischemia, as has been done for ST-
elevation myocardial infarction [79], may improve patient care.
Improved outcomes for limb salvage and cardiovascular risk
reduction in patients with limb ischemia will require dedicated
randomized trials of new therapies and treatment strategies, as
well as better national quality assessment registries to increase
adherence to currently available therapies.
Conclusion
CLI and ALI represent medical urgencies and emergencies re-
quiring rapid evaluation and management by vascular specialists
focused on limb salvage and optimal cardiovascular risk reduc-
tion. Though limb loss is associated with significant morbidity
and mortality, patients presenting with ALI or CLI are more
likely to suffer cardiac-related morbidity and mortality. Limited
health services data suggest significant variations in care for CLI
and ALI in concert with suboptimal adherence to guideline-
recommended diagnostic testing and medical therapies. Though
studies showing improved outcomes for patients treated with
guideline-based diagnostic and treatment strategies are lacking,
under-treatment of PAD risk factors and under-recognition of
signs and symptoms of limb ischemia may provide targets for
improved patient management. Finally, for those patients failing
currently available treatment, clinical trials of angiogenic and
cell-based therapies for wound healing and novel antiplatelet
agents for cardiovascular risk reduction are ongoing.
Compliance with Ethics Guidelines
Conflict of Interest Sreekanth Vemulapalli reports grants from Boston
Scientific and personal fees from Medtronic and Abbott Vascular.
Manesh R. Patel reports grant support from Astra Zeneca and personal
fees from Medtronic.
W. Schuyler Jones reports grants from American Heart Association,
AstraZeneca, Daiichi Sankyo, and Boston Scientific Corporation.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N,
et al. Heart disease and stroke statistics–2008 update: a report from
Curr Cardiol Rep (2015) 17:57
the American Heart Association Statistics Committee and Stroke
Statistics Subcommittee. Circulation. 2008;117:e25–e146.
2. Hirsch AT, Allison MA, Gomes AS, Corriere MA, Duval S, Ershow
AG, et al. A call to action: women and peripheral artery disease: a
scientific statement from the American Heart Association.
Circulation. 2012;125:1449–72.
3. Steg PG, Bhatt DL, Wilson PW, D’Agostino Sr R, Ohman EM,
Rother J, et al. One-year cardiovascular event rates in outpatients
with atherothrombosis. Jama. 2007;297:1197–206.
4. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager
MA, Olin JW, et al. Peripheral arterial disease detection, awareness,
and treatment in primary care. Jama. 2001;286:1317–24.
5. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA,
Fowkes FG, et al. Inter-society consensus for the management of
peripheral arterial disease (tasc ii). J Vasc Surg. 2007;45(Suppl S):
S5–S67.
6. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA,
Halperin JL, et al. Acc/aha 2005 practice guidelines for the man-
agement of patients with peripheral arterial disease (lower extrem-
ity, renal, mesenteric, and abdominal aortic): a collaborative report
from the American Association for Vascular Surgery/Society for
Vascular Surgery, Society for Cardiovascular Angiography and
Interventions, Society for Vascular Medicine and Biology, Society
of Interventional Radiology, and the ACC/AHA Task Force on
practice guidelines (writing committee to develop guidelines for
the management of patients with peripheral arterial disease): en-
dorsed by the American Association of Cardiovascular and
Pulmonary Rehabilitation; National Heart, Lung, and Blood
Institute; Society for Vascular Nursing; Transatlantic Inter-society
Consensus; and Vascular Disease Foundation. Circulation.
2006;113:e463–654.
7. Nehler MR, Duval S, Diao L, Annex BH, Hiatt WR, Rogers K, et al.
Epidemiology of peripheral arterial disease and critical limb ische-
mia in an insured national population. J Vasc Surg. 2014;60:686–95.
8. Jones WS, Patel MR, Dai D, Vemulapalli S, Subherwal S, Stafford
J, et al. High mortality risks after major lower extremity amputation
in medicare patients with peripheral artery disease. Am Heart J.
2013;165:809–15. 815 e801.
9. Coats P, Wadsworth R. Marriage of resistance and conduit arteries
breeds critical limb ischemia. Am J Physiol Heart Circ Physiol.
2005;288:H1044–50.
10. Bhat HK, Hiatt WR, Hoppel CL, Brass EP. Skeletal muscle mito-
chondrial DNA injury in patients with unilateral peripheral arterial
disease. Circulation. 1999;99:807–12.
11. Isbell DC, Berr SS, Toledano AY, Epstein FH, Meyer CH, Rogers
WJ, et al. Delayed calf muscle phosphocreatine recovery after ex-
ercise identifies peripheral arterial disease. J Am Coll Cardiol.
2006;47:2289–95.
12. Anderson JD, Epstein FH, Meyer CH, Hagspiel KD, Wang H, Berr
SS, et al. Multifactorial determinants of functional capacity in pe-
ripheral arterial disease: uncoupling of calf muscle perfusion and
metabolism. J Am Coll Cardiol. 2009;54:628–35.
13. Khan NA, Rahim SA, Anand SS, Simel DL, Panju A. Does the
clinical examination predict lower extremity peripheral arterial dis-
ease? Jama. 2006;295:536–46.
14. Patel MR, Conte MS, Cutlip DE, Dib N, Geraghty P, Gray W et al.
Consensus definitions for evaluation of patients with lower extrem-
ity peripheral artery disease: the peripheral academic research c-
onsortium (parc). J Am Coll Cardiol. in press
15.•• Mills JL Sr., Conte MS, Armstrong DG, Pomposelli FB, Schanzer
A, Sidawy AN et al. The society for vascular surgery lower extrem-
ity threatened limb classification system: risk stratification based on
wound, ischemia, and foot infection (wifi). J Vasc Surg. 2014;59:
220–234 e221-222. This manuscript describes the WIFI risk
classification system for limb ischemia, as well as its predictive
ability for major adverse limb events.
Curr Cardiol Rep (2015) 17:57
16. Connelly J, Airey M, Chell S. Variation in clinical decision making
is a partial explanation for geographical variation in lower extremity
amputation rates. Br J Surg. 2001;88:529–35.
17. Thompson MM, Sayers RD, Reid A, Underwood MJ, Bell PR.
Quality of life following infragenicular bypass and lower limb am-
putation. Eur J Vasc Endovasc Surg Off J Eur Soc Vasc Surg.
1995;9:310–3.
18. Bosiers M, Scheinert D, Peeters P, Torsello G, Zeller T, Deloose K,
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;55:390–8.
19. Rocha-Singh KJ, Jaff M, Joye J, Laird J, Ansel G, Schneider P, et al.
Major adverse limb events and wound healing following
infrapopliteal artery stent implantation in patients with critical limb
ischemia: the xcell trial. Catheter Cardiovasc Interv Off J Soc Card
Angiograph Interv. 2012;80:1042–51.
20. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF,
et al. Bypass versus angioplasty in severe ischaemia of the leg
(basil): multicentre, randomised controlled trial. Lancet. 2005;366:
1925–34.
21. Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I,
et al. Bypass versus angioplasty in severe ischaemia of the leg
(basil) trial: analysis of amputation free and overall survival by
treatment received. J Vasc Surg. 2010;51:18S–31S.
22. Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FG, Gillespie I,
et al. Bypass versus angioplasty in severe ischaemia of the leg
(basil) trial: an intention-to-treat analysis of amputation-free and
overall survival in patients randomized to a bypass surgery-first or
a balloon angioplasty-first revascularization strategy. J Vasc Surg.
2010;51:5S–17S.
23. Bradbury A, Wilmink T, Lee AJ, Bell J, Prescott R, Gillespie I, et al.
Bypass versus angioplasty to treat severe limb ischemia: factors that
affect treatment preferences of UK surgeons and interventional ra-
diologists. J Vasc Surg. 2004;39:1026–32.
24. Goodney PP, Travis LL, Nallamothu BK, Holman K, Suckow B,
Henke PK, et al. Variation in the use of lower extremity vascular
procedures for critical limb ischemia. Circ Cardiovasc Qual
Outcomes. 2012;5:94–102.
25. Neville RF, Attinger CE, Bulan EJ, Ducic I, Thomassen M, Sidawy
AN. Revascularization of a specific angiosome for limb salvage:
does the target artery matter? Ann Vasc Surg. 2009;23:367–73.
26. Iida O, Nanto S, Uematsu M, Ikeoka K, Okamoto S, Dohi T, et al.
Importance of the angiosome concept for endovascular therapy in
patients with critical limb ischemia. Catheter Cardiovasc Interv Off
J Soc Cardiac Angiograph Interv. 2010;75:830–6.
27. Marston WA, Davies SW, Armstrong B, Farber MA, Mendes RC,
Fulton JJ, et al. Natural history of limbs with arterial insufficiency
and chronic ulceration treated without revascularization. J Vasc
Surg. 2006;44:108–14.
28. Critchley JA, Capewell S. Mortality risk reduction associated with
smoking cessation in patients with coronary heart disease: a sys-
tematic review. Jama. 2003;290:86–97.
29. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking
cessation and the risk of stroke in middle-aged men. Jama.
1995;274:155–60.
30. Cacoub PP, Abola MT, Baumgartner I, Bhatt DL, Creager MA,
Liau CS, et al. Cardiovascular risk factor control and outcomes in
peripheral artery disease patients in the reduction of atherothrom-
bosis for continued health (reach) registry. Atherosclerosis.
2009;204:e86–92.
31.• Armstrong EJ, Chen DC, Westin GG, Singh S, McCoach CE, Bang
H, et al. Adherence to guideline-recommended therapy is associated
with decreased major adverse cardiovascular events and major ad-
verse limb events among patients with peripheral arterial disease. J
Am Heart Assoc. 2014;3:e000697. This study describes the
Page 11 of 12 57
efficacy of medical therapy for cardiovascular event prevention
in patients with PAD.
32. Lane DA, Lip GY. Treatment of hypertension in peripheral arterial
disease. Cochrane Database Syst Rev. 2013;12, CD003075.
33. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm
M, et al. 2013 ESH/ESC guidelines for the management of arterial
hypertension: the task force for the management of arterial hyper-
tension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). Eur Heart J. 2013;34:
2159–219.
34. Piller LB, Simpson LM, Baraniuk S, Habib GB, Rahman M, Basile
JN, et al. Characteristics and long-term follow-up of participants
with peripheral arterial disease during ALLHAT. J Gen Intern
Med. 2014;29:1475–83.
35. Antithrombotic Trialists C. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention of death,
myocardial infarction, and stroke in high risk patients. BMJ.
2002;324:71–86.
36. Committee CS. A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (caprie). Caprie
steering committee. Lancet. 1996;348:1329–39.
37. Patel MR, Becker RC, Wojdyla DM, Emanuelsson H, Hiatt WR,
Horrow J et al. Cardiovascular events in acute coronary syndrome
patients with peripheral arterial disease treated with ticagrelor com-
pared with clopidogrel: data from the plato trial. Eur J Prevent
Cardiol. 2014
38. Bonaca MP, Scirica BM, Creager MA, Olin J, Bounameaux H,
Dellborg M, et al. Vorapaxar in patients with peripheral artery dis-
ease: results from tra2{degrees}p-timi 50. Circulation. 2013;127:
1522–9.
39. Jones WS, Tricoci P, Huang Z, Moliterno DJ, Harrington RA,
Sinnaeve PR, et al. Vorapaxar in patients with peripheral artery
disease and acute coronary syndrome: insights from thrombin re-
ceptor antagonist for clinical event reduction in acute coronary syn-
drome (tracer). Am Heart J. 2014;168:588–96.
40. Heart Protection Study Collaborative G. Mrc/bhf heart protection
study of cholesterol lowering with simvastatin in 20,536 high-risk
individuals: a randomised placebo-controlled trial. Lancet.
2002;360:7–22.
41. Niebuhr A, Henry T, Goldman J, Baumgartner I, van Belle E, Gerss
J, et al. Long-term safety of intramuscular gene transfer of non-viral
fgf1 for peripheral artery disease. Gene Ther. 2012;19:264–70.
42. Morishita R, Makino H, Aoki M, Hashiya N, Yamasaki K, Azuma
J, et al. Phase i/iia clinical trial of therapeutic angiogenesis using
hepatocyte growth factor gene transfer to treat critical limb ische-
mia. Arterioscler Thromb Vasc Biol. 2011;31:713–20.
43. Muona K, Makinen K, Hedman M, Manninen H, Yla-Herttuala S.
10-year safety follow-up in patients with local VEGF gene transfer
to ischemic lower limb. Gene Ther. 2012;19:392–5.
44. Powell RJ, Goodney P, Mendelsohn FO, Moen EK, Annex BH,
Investigators HGFT. Safety and efficacy of patient specific intra-
muscular injection of HGF plasmid gene therapy on limb perfusion
and wound healing in patients with ischemic lower extremity ulcer-
ation: results of the hgf-0205 trial. J Vasc Surg. 2010;52:1525–30.
45. Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga
M, et al. Results of a double-blind, placebo-controlled study to
assess the safety of intramuscular injection of hepatocyte growth
factor plasmid to improve limb perfusion in patients with critical
limb ischemia. Circulation. 2008;118:58–65.
46. Shigematsu H, Yasuda K, Iwai T, Sasajima T, Ishimaru S, Ohashi Y,
et al. Randomized, double-blind, placebo-controlled clinical trial of
hepatocyte growth factor plasmid for critical limb ischemia. Gene
Ther. 2010;17:1152–61.
47. Gabr H, Hedayet A, Imam U, Nasser M. Limb salvage using intra-
muscular injection of unfractionated autologous bone marrow
mononuclear cells in critical limb ischemia: a prospective pilot
57 Page 12 of 12
clinical trial. Exp Clin Transplant Off J Middle East Soc Org
Transplant. 2011;9:197–202.
48. Lara-Hernandez R, Lozano-Vilardell P, Blanes P, Torreguitart-
Mirada N, Galmes A, Besalduch J. Safety and efficacy of therapeu-
tic angiogenesis as a novel treatment in patients with critical limb
ischemia. Ann Vasc Surg. 2010;24:287–94.
49. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy
for peripheral arterial disease meta-analysis and systematic review
of the literature. Atherosclerosis. 2010;209:10–7.
50. Earnshaw JJ, Whitman B, Foy C. National audit of thrombolysis for
acute leg ischemia (natali): clinical factors associated with early
outcome. J Vasc Surg. 2004;39:1018–25.
51. Eliason JL, Wainess RM, Proctor MC, Dimick JB, Cowan Jr JA,
Upchurch Jr GR, et al. A national and single institutional experience
in the contemporary treatment of acute lower extremity ischemia.
Ann Surg. 2003;238:382–9. discussion 389–390.
52.• Korabathina R, Weintraub AR, Price LL, Kapur NK, Kimmelstiel
CD, Iafrati MD, et al. Twenty-year analysis of trends in the inci-
dence and in-hospital mortality for lower-extremity arterial throm-
boembolism. Circulation. 2013;128:115–21. This study describes
the changing epidemiology of acute limb ischemia in the United
States.
53. Baril DT, Ghosh K, Rosen AB. Trends in the incidence, treatment,
and outcomes of acute lower extremity ischemia in the united states
medicare population. J Vasc Surg. 2014;60:669–77.
54. Results of a prospective randomized trial evaluating surgery versus
thrombolysis for ischemia of the lower extremity. The stile trial.
Ann Surg. 1994;220:251–266; discussion 266–258
55. Nilsson L, Albrechtsson U, Jonung T, Ribbe E, Thorvinger B,
Thorne J, et al. Surgical treatment versus thrombolysis in acute
arterial occlusion: a randomised controlled study. Eur J Vasc Surg.
1992;6:189–93.
56. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant
urokinase with vascular surgery as initial treatment for acute arterial
occlusion of the legs. Thrombolysis or peripheral arterial surgery
(topas) investigators. N Engl J Med. 1998;338:1105–11.
57. Tsakiris DA, Tschopl M, Jager K, Haefeli WE, Wolf F, Marbet GA.
Circulating cell adhesion molecules and endothelial markers before
and after transluminal angioplasty in peripheral arterial occlusive
disease. Atherosclerosis. 1999;142:193–200.
58. Tschopl M, Tsakiris DA, Marbet GA, Labs KH, Jager K. Role of
hemostatic risk factors for restenosis in peripheral arterial occlusive
disease after transluminal angioplasty. Arterioscler Thromb Vasc
Biol. 1997;17:3208–14.
59. Schillinger M, Mlekusch W, Haumer M, Sabeti S, Ahmadi R,
Minar E. Angioplasty and elective stenting of de novo versus re-
current femoropopliteal lesions: 1-year follow-up. J Endovasc Ther
Off J Int Soc Endovasc Specialists. 2003;10:288–97.
60. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB,
et al. Sustained safety and effectiveness of paclitaxel-eluting stents
for femoropopliteal lesions: 2-year follow-up from the zilver ptx
randomized and single-arm clinical studies. J Am Coll Cardiol.
2013;61:2417–27.
61. Pulli R, Dorigo W, Troisi N, Innocenti AA, Pratesi G, Azas L, et al.
Surgical management of popliteal artery aneurysms: which factors
affect outcomes? J Vasc Surg. 2006;43:481–7.
62. Duffy ST, Colgan MP, Sultan S, Moore DJ, Shanik GD. Popliteal
aneurysms: a 10-year experience. Eur J Vasc Endovasc Surg Off J
Eur Soc Vasc Surg. 1998;16:218–22.
63. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J,
Parekh A, et al. Dabigatran versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2009;361:1139–51.
Curr Cardiol Rep (2015) 17:57
64. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM,
Hanna M, et al. Apixaban versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2011;365:981–92.
65.• Duval S, Keo HH, Oldenburg NC, Baumgartner I, Jaff MR,
Peacock JM, et al. The impact of prolonged lower limb ischemia
on amputation, mortality, and functional status: the friends registry.
Am Heart J. 2014;168:577–87. This manuscript describes a sin-
gle center description of the epidemiology of limb ischemia as
well as the importance of time to treatment for outcomes in
acute limb ischemia.
66. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn
S, et al. Recommended standards for reports dealing with lower
extremity ischemia: revised version. J Vasc Surg. 1997;26:517–38.
67. Alonso-Coello P, Bellmunt S, McGorrian C, Anand SS, Guzman R,
Criqui MH, et al. Antithrombotic therapy in peripheral artery dis-
ease: antithrombotic therapy and prevention of thrombosis, 9th ed:
American College of chest physicians evidence-based clinical prac-
tice guidelines. Chest. 2012;141:e669S–90S.
68. Ouriel K, Shortell CK, DeWeese JA, Green RM, Francis CW,
Azodo MV, et al. A comparison of thrombolytic therapy with op-
erative revascularization in the initial treatment of acute peripheral
arterial ischemia. J Vasc Surg. 1994;19:1021–30.
69. Berridge DC, Kessel DO, Robertson I. Surgery versus thrombolysis
for initial management of acute limb ischaemia. Cochrane Database
Syst Rev. 2013;6, CD002784.
70. Raabe RD. Ultrasound-accelerated thrombolysis in arterial and ve-
nous peripheral occlusions: fibrinogen level effects. J Vasc Interv
Radiol: JVIR. 2010;21:1165–72.
71. Rogers JH, Laird JR. Overview of new technologies for lower ex-
tremity revascularization. Circulation. 2007;116:2072–85.
72. Sarac TP, Hilleman D, Arko FR, Zarins CK, Ouriel K. Clinical and
economic evaluation of the trellis thrombectomy device for arterial
occlusions: preliminary analysis. J Vasc Surg. 2004;39:556–9.
73. Eliason JL, Wakefield TW. Metabolic consequences of acute limb
ischemia and their clinical implications. Semin Vasc Surg. 2009;22:
29–33.
74. Currie IS, Wakelin SJ, Lee AJ, Chalmers RT. Plasma creatine ki-
nase indicates major amputation or limb preservation in acute lower
limb ischemia. J Vasc Surg. 2007;45:733–9.
75. Vemulapalli S, Curtis LH. Putting the vascular back into cardiovas-
cular research: ST-segment-elevation myocardial infarction as a
blueprint for improving care in patients with acute limb ischemia.
Circulation. 2013;128:89–91.
76. Goodney PP, Tarulli M, Faerber AE, Schanzer A, Zwolak RM.
Fifteen-year trends in lower limb amputation, revascularization,
and preventive measures among medicare patients. JAMA Surg.
2014
77. Subherwal S, Patel MR, Tang F, Smolderen KG, Jones WS, Tsai
TT, et al. Socioeconomic disparities in the use of cardioprotective
medications among patients with peripheral artery disease: an anal-
ysis of the American College of Cardiology’s Ncdr Pinnacle
Registry. J Am Coll Cardiol. 2013;62:51–7.
78.• Vemulapalli S, Greiner MA, Jones WS, Patel MR, Hernandez AF,
Curtis LH. Peripheral arterial testing before lower extremity ampu-
tation among medicare beneficiaries, 2000 to 2010. Circ Cardiovasc
Qual Outcomes. 2014;7:142–50. This manuscript describes in-
complete use of guideline directed vascular testing prior to low-
er extremity amputation.
79. Jollis JG, Roettig ML, Aluko AO, Anstrom KJ, Applegate RJ, Babb
JD, et al. Reperfusion of Acute Myocardial Infarction in North
Carolina Emergency Departments I. Implementation of a statewide
system for coronary reperfusion for ST-segment elevation myocar-
dial infarction. Jama. 2007;298:2371–80.