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M. Costantino et al.
Fig. 3.12 Duplex imaging in the cuneiform window visualizing the Lateral Plantar Artery using the Lateral Plantar
Vein as a landmark
Fig. 3.13 Various pedal ow directions based on proximal disease patterns (MM: medial malleolus)
3 Determining theAppropriate Workup
45
Fig. 3.14 Class 4 PAT illustrating the severity of peripheral arterial disease
of a procedural endpoint. The endpoint is a PAT
of less than 180ms [30]. Additional benets of
intraoperative ultrasound include guidance
through chronic total occlusions (CTO), challenging stenoses, and conrmation of intraluminal position.
Real-time intraoperative ultrasound allows the
operator to know which disease burden needs to
be addressed before there is successful reperfusion of the foot utilizing PAT. With a highly
skilled ultrasound technologist performing intermittent pedal ultrasound throughout the case, the
operator will know if single or multiple lesions
Fig. 3.15 Wire tip engaging a chronic total occlusion in
the Supercial Femoral Artery
need to be treated to relieve rest pain or heal
ulcers. This has signicant benets in reducing
the number of staged procedures and more
3.4.4 Advanced Intraoperative
Duplex Ultrasound
importantly, eliminating a subjective opinion
about improved perfusion based on angiography.
PAT is an objective number that is quantiable
Intraoperative ultrasound is underutilized in the
endovascular suite. The benet of intraoperative
ultrasound includes real-time objective evidence
and reproducible. For example, in a patient with
diffuse Supercial Femoral Artery, Popliteal, and
signicant Tibial disease, a real- time objective
46
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M. Costantino et al.
endpoint allows the operator to know whether a
femoropopliteal intervention is adequate (based
on the PAT number), or whether further intervention into the tibial territory must be performed in
the same setting.
Guidance through chronic total occlusions
(CTO) is extremely helpful in selective patients.
The operator can be more aggressive with wires
and catheters, knowing that the intraluminal position is maintained (Fig.3.15). Ultrasound is also
used to detail the location of the calcications
with softer channels to help guide the direction of
catheters and wires toward the small channels,
which can improve successful crossing. If the
artery is densely calcied, then intraoperative
ultrasound may not be benecial. Conrmation
of intraluminal position can be used many times
throughout the case. This saves signicant time
when ultrasound can be placed on the limb while
the operator is working, to conrm intraluminal
position of a catheter or wire, rather than having
to exchange the wire for a catheter and then perform angiography. Ideally, the ultrasound technologist would have already mapped the entire
limb from groin to pedal level, becoming intimately familiar with each patient’s anatomy and
pathology. This allows the operator to move
quickly along with the ultrasound technologist,
who has an advanced understanding of the
patient’s arterial anatomy, including patent or
occluded vessels, and will know the best window
for ultrasound imaging.
In conclusion, intraoperative ultrasound is an
inexpensive advanced tool, with no radiation or
additional disposable equipment costs.
Ultrasound gives the operator valuable information that uoroscopy may lack. Intraoperative
and pedal duplex ultrasound should be a fundamental technique for advanced CLTI interventions to aid in operative success.
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Beginning andManaging
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Underlying Comorbidities
ZaeemBillah, ZacharyChadnick, KartikKansagra,
AliKimyaghalam, SreekumarMadassery,
AustinShinagawa, KuldeepSingh,
andGeogyVatakencherry
4
4.1 Peripheral Arterial Disease
Medications
AustinShinagawa, ZaeemBillah,
KartikKansagra and GeogyVatakencherry
4.1.1 Introduction
Peripheral artery disease (PAD) often occurs concurrently with other manifestations of global atherosclerosis, predominantly coronary artery, and
cerebrovascular disease. Patients with PAD are at
a very high risk of morbidity and mortality due to
cardiovascular (CV) events such as myocardial
infarction (MI), stroke, or sudden cardiac death.
Z. Billah · K. Kansagra · A. Shinagawa
G. Vatakencherry
Department of Interventional Radiology, Kaiser
Permanente Los Angeles Medical Center,
Los Angeles, CA, USA
Z. Chadnick · A. Kimyaghalam
Department of Surgery, Staten Island University
Hospital– Northwell Health, New York, NY, USA
e-mail: Alik@auamed.net
S. Madassery (*)
Department of Vascular and Interventional Radiology,
Rush University Medical Center, Chicago, IL, USA
K. Singh
Department of Surgery, Division of Vascular Surgery,
Staten Island University Hospital– Northwell Health,
New York, NY, USA
e-mail: Ksingh7@northwell.edu
Several studies have highlighted the burden of
atherosclerotic disease in the PAD population,
including the PARTNER trial, REACH registry,
and EUCLID trial [1–3].
• According to the REACH registry, 3.7% of
patients with a single bed of arterial disease
had a 1-year composite outcome of MI, stroke,
or CV death, with an even higher incidence of
6% in patients with polyvascular disease.
• Thus, it is imperative that modern vascular
specialists treating PAD understand and opti-
mize the medical management of atheroscle-
rotic disease in their patients.
Medical management in the PAD population
is aimed at reducing the risk of both major
adverse cardiovascular events (MACE) and
major adverse limb events (MALE) [4].
• MACE are typically dened as MI, stroke, and
CV death, whereas MALE encompass signi-
cant interval events in PAD course progres-
sion, such as the need for peripheral
revascularization or amputation/limb loss.
• Modication of cardiovascular risk factors
(i.e., smoking, hypertension, dyslipidemia,
and diabetes) through lifestyle and pharma-
ceutical intervention is the foundation of PAD
medical management.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
S. Madassery, A. Patel (eds.), Limb Preservation for the Vascular Specialist,
https://doi.org/10.1007/978-3-031-36480-8_4
49
50
Z. Billah et al.
4.1.1.1 Lifestyle Modication andRisk
Reduction
The vascular specialist must assume the role of a
“lifestyle coach” for their patient. Lifestyle
modications such as tobacco cessation, diet
optimization, and exercise modication are
crucial elements of PAD management, as these
interventions alone have the potential to
signicantly alter a patient’s disease course and
functional status.
Tobacco Cessation
Smoking is an important modiable risk factor
for the development and progression of PAD.
• Epidemiological data based on the ARIC
(Atherosclerosis Risk in Communities) study
showed that patients who smoked for ≥25
pack years (versus non-smokers) were 4 times
more likely to develop PAD and 1.5–2 times
more likely of having CAD or stroke [5].
• Additional data found that even exposure to
secondhand smoke correlates directly with the
development of atherosclerotic disease [6].
• Smoking cessation is demonstrated to lower
the risk of critical limb ischemia (CLI),
amputation, and death, as well as slow the
decline in ankle-brachial index over time.
an adjunct to the above evidence-based
therapies.
Diet Modication
Epidemiological studies have demonstrated that
a healthy diet is associated with a lower incidence
of PAD [8].
• Vascular specialists should encourage patients
to consume a healthy diet rich in vegetables,
fruits, nuts, whole grains, lean protein, and
ber, while limiting sugar and sweeteners,
trans- or saturated fats, rened grains, and red
meat.
• Dietary modication is especially important
to address in patients with diabetes. Even so, it
is crucial to consider how a patient’s diet is
affected by their socioeconomic status and
availability of healthy food options, referring
them to the appropriate resources if needed.
Parodi etal. prospectively studied the effect of
aggressive hydration on 132 patients with severe
claudication or rest pain whose symptoms did not
improve despite maximal medical therapy
comprised of risk factor reduction, supervised
exercise protocols, and treatment with Cilostazol
[9].
Multiple modalities have been shown to be
efcacious for achieving smoking cessation in
individuals with tobacco use disorders. The
EAGLES study was a randomized controlled trial
(RCT) assessing the use of Varenicline,
Bupropion, and Nicotine Patch in smokers with
and without psychiatric disorders [7].
• It showed that Varenicline was more effective
than placebo, nicotine patch, and Bupropion
in helping patients who were smoking achieve
abstinence. In addition, both a nicotine patch
and Bupropion were more effective than a
placebo alone.
• Based on this data, Varenicline should be
considered as the rst-line option for
smoking cessation. This can be supple-
mented with more rapid-onset nicotine gum
or lozenge. Smoking cessation counseling is
• This study showed that hydration with over 2
liters of uid intake daily and protein
supplementation (0.6 g/kg of protein daily
with goal albumin above 4 g/dL) was
associated with an increase in distance to
claudication and even improvement in anklebrachial index.
• However, aggressive hydration, such as in this
protocol, should be avoided in patients with
heart failure, dialysis dependence, and/or endstage liver disease.
Exercise Therapy
Exercise therapy is well-studied in PAD, particularly in patients who suffer from claudication.
Although the exact mechanism of improved
function following exercise therapy is uncertain,
there is a clear benet of exercise therapy as evidenced by multiple trials.
4 Beginning andManaging Underlying Comorbidities
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51
The CLEVER study was a multicenter RCT
that randomized 111 patients with aortoiliac PAD
to optimal medical care alone, optimal medical
care plus supervised exercise, or optimal medical
care plus stent revascularization [10].
• This study found that there was a statistically
signicant increase in peak walking time for
both the supervised exercise and stent
revascularization groups over optimal medical
therapy alone.
However, supervised exercise therapy may not
be accessible or feasible for much of the PAD
population. One alternative that addresses some
of the barriers of supervised exercise therapy is
home-based exercise therapy (HBET).
• Multiple studies, including the GOALS and
MOSAIC trials, have found signicant clinical
value in HBET [11, 12].
• One such regimen that vascular specialists can
prescribe to their patients is that of high-
intensity exercise, as supported by the nd-
ings of the LITE trial [13]. This RCT compared
the outcomes of low- versus high-intensity
walking exercise in 305 patients, who were
instructed to either walk at a comfortable pace
or a pace inducing moderate-to-severe isch-
emic leg symptoms, respectively.
– The trial showed that high-intensity HBET
was signicantly more effective for
increasing 6-minute walk distance than
low-intensity HBET; furthermore, the lowintensity HBET group failed to demonstrate a benet over the nonexercise control
group.
One prescription the authors recommend is
exercising for 30min at least three times a week
by walking to near-maximal claudication
discomfort (7/10 pain intensity), then resting
(until pain subsides to a 3/10), and then resuming
walking.
• Patients should be encouraged to maintain a
log of their daily steps, time spent walking,
and total distance walked.
• The vascular specialist can then reference this
log at follow-up visits and encourage or coach
the patient on their exercise habits accordingly.
4.1.1.2 Medical Optimization
Involvement in pharmacotherapy for PAD
patients gives vascular specialists tremendous
opportunity to dramatically alter the natural
history of their patient’s lives and limbs. While
often managed by the patient’s primary care
physician, each vascular specialist should provide
their expertise and guidance on optimizing the
management of these conditions in the setting of
PAD.Unfortunately, there is still a great deal of
underutilization of life and limb-saving medical
treatments in the PAD population. This section
will review which therapeutic options have the
strongest proven benet in PAD, specically
lipid-lowering therapies, antihypertensives,
glycemic control, and antithrombotics.
Lipid-Lowering Therapies
Lipid-lowering therapies (LLT) can reduce the
deleterious effects of dyslipidemia on cardiovascular disease by rectifying imbalances in cholesterol levels, stabilizing atherosclerotic plaques,
and even decreasing systemic inammation.
• Several studies have found that a reduction in
low-density lipoprotein cholesterol (LDL-c) is
associated with reduced MACE and MALE
[14].
• This led society guidelines to strongly recommend LLT for all patients with PAD [15, 16].
Despite this, dyslipidemia in PAD is often
inadequately treated, and so vascular specialists should ensure that all patients with PAD
are prescribed the appropriate LLT when
possible.
• The LLT with the strongest demonstrated benet in PAD patients are statins, ezetimibe, and
proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors.
Also, statins have also been found to improve
pain-free walking distance [17]. These benets
are enhanced in patients who are suffering from
CLI [18].
52
Z. Billah et al.
Table 4.1 Statin intensities as classied by the 2018
American College of Cardiology/American Heart
Association Task Force cholesterol guidelines
Statin intensity High Moderate Low
Average LDL-c
Reduction
Rosuvastatin 20–40mg 5–10mg
Atorvastatin 40–80mg 10–20mg
Simvastatin 20–40mg 10mg
Pravastatin 40–80mg 10–20mg
Lovastatin 40–80mg 20mg
Fluvastatin XL 80mg
Fluvastatin 40mg BID 20–40mg
Pitavastatin 1–4mg
LDL-c: Low-density lipoprotein cholesterol; XL:
Extended-release; BID: Twice a day
≥50%
30–49% <30%
• Higher-intensity statins (Table 4.1) confer a
stronger benet than lower-intensity statins,
although statin strength is sometimes limited
by patient age and patient tolerance mainly
due to statin-associated myopathy [19].
Overall, since it is possible that 40% of the
PAD population are not receiving any form of
LLT, our primary recommendation is to ensure
that all patients with PAD are on a maximally
tolerated dose of statin to reduce the risk of
MACE and MALE.
• If the goal LDL-c reduction of ≥50% or LDLc<55/70 mg/dL is not achieved with statin
therapy alone, adjunctive therapy with
Ezetimibe and/or PCSK9 inhibitors (Repatha,
injectable drug given every 2 weeks) should
be considered on an individual basis.
Antihypertensives
Hypertension is highly prevalent in the PAD population (over 80% in one registry); however, it is
unfortunately less often treated in patients with
PAD than those with other manifestations of cardiovascular disease [20, 21]. Inadequately treated
hypertension should be identied and managed
by the vascular specialist, as undertreated elevations in blood pressure are strongly associated
with an increased risk of MACE [22].
Antihypertensive regimens are highly variable
and are generally selected to address specic
comorbidities.
• While no single antihypertensive strategy is
proven to be superior, angiotensin-converting
enzyme inhibitors (ACEi) have the strongest
evidence for reducing MACE in the PAD
population, as demonstrated in the HOPE
trial [23–25].
• ARBs are also demonstrated to be effective
for MACE reduction and are a reasonable
alternative to ACEi [26, 27].
• It should also be mentioned that, although a
point of historic controversy, there is a lack of
evidence that β-blockers increase the risk of
MALE or adversely affect walking capacity in
PAD [28]. Therefore, the use of β-blockers for
other indications, such as prior myocardial
infarction or heart failure should not be
restricted in the PAD population.
The landmark RCT SPRINT was performed
to compare the outcomes of “intensive”
(<120mmHg) versus “standard” (<140mmHg)
blood pressure control in patients with increased
cardiovascular risk and without diabetes [29].
• This study found a lower rate of MACE in the
patients with the more aggressive systolic
blood pressure goal of <120mmHg, although
the proportion of study participants with PAD
was relatively low.
• As there is a lack of high-quality evidence
dening the most appropriate blood pressure
goals for the PAD population, the most recent
2017 ACC/AHA Task Force hypertension
guidelines advise that patients with PAD be
treated similarly to patients without PAD.
Specically, these guidelines recommend a
target blood pressure goal of <130/85mmHg
in the presence of atherosclerotic cardiovascular disease [22].
Glucose-Lowering Therapies
Diabetes is a well-established risk factor for the
development of PAD [30]. Patients with diabetes
have a propensity for peripheral neuropathy with
loss of protective sensation and thus developing
non-healing wounds vulnerable to infection.
Diabetes is known to elevate the risk of microvascular complications including retinopathy, neuropathy, and nephropathy; fortunately, the
4 Beginning andManaging Underlying Comorbidities
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53
incidence of these complications can be reduced
with proper glycemic control.
• The target glycated hemoglobin level for
patients with PAD is <7.0%. More aggressive
glucose lowering to aglycated hemoglobin
<6.0/6.5% increases the risk of hypoglycemic
episodes [31, 32].
Patients with Type 2 diabetes and obesity
should be encouraged to lose weight by achieving
a caloric decit through dietary modication,
exercise, and behavioral interventions [33].
• Weight loss of ≥10% of initial body weight is
associated with a lower incidence of MACE,
although an initial goal of ≥2–5% weight loss
may be a more feasible goal for many patients
[34].
• First-line therapy for diabetes generally also
includes metformin, a safe and inexpensive
medication that may be associated with a
reduction in MACE [35, 36]. Renal function
should always be considered in a patient prior
to initiation/continuing metformin.
Two newer classes of glucose-lowering thera-
pies, sodium-glucose transporter 2 (SGLT2)
inhibitors and glucagon-like protein (GLP)-1
receptor agonists, have strong evidence for
MACE reduction in patients with concomitant
PAD and diabetes.
• Similar cardioprotective effects were seen with
multiple GLP-1 receptor agonists, specically
liraglutide, semaglutide, and dulaglutide, as
demonstrated by the LEADER, SUSTAIN-6,
and REWIND trials, respectively [43–45].
• In summary, SGLT2 inhibitors and GLP-1
receptor agonists are demonstrated to have
substantial benets in the diabetic population. The American Diabetes Association
guidelines recommend using these medications for all patients with concomitant PAD
and diabetes, independent of glycated hemoglobin level or metformin use [46]. However,
the current cost and coverage of these medications present signicant challenges for this proposed universal application.
Close coordination with primary care physi-
cians and endocrinologists is essential to achieve
optimal outcomes in these patients.
4.1.1.3 Antithrombotic Therapy
Thrombosis is suspected to signicantly contribute to the progression of PAD and occurrence of
MALE.There is pathologic evidence that thrombi,
particularly in the infrapopliteal arteries, are a
major component of luminal stenosis and occlusion [4]. Recent literature is further dening the
role of antithrombotic therapy in the PAD population for MACE and MALE reduction (Table4.2).
Antiplatelets are mainly recommended for the
prevention of MACE in patients with PAD [15, 16].
• Numerous RCTs have demonstrated this
reduction in MACE with the use of SGLT2
inhibitors, specically empagliozin, canagliozin, and dapagliozin [37–40].
• SGLT2 inhibitors are also consistently associated with a reduction in heart failure hospitalizations as well as slowing the progression of
renal disease [41, 42].
• Importantly, while earlier studies such as
CANVAS showed canagliozin to be associated with a signicant increase in minor
amputations, the later CREDENCE trial found
no increased risk of MALE with canagliozin
use [38, 39]. Given the results from CANVAS,
patients with active wounds should be closely
observed if on canagliozin.
• The main antiplatelet therapies used for this
purpose are Aspirin and P2Y12 inhibitors
(i.e., clopidogrel and ticagrelor).
• Aspirin is primarily used in patients with symptomatic PAD as its efcacy in patients with
asymptomatic, marginally low ankle- brachial
index (ABI) is unclear [47–49]. However, even
the effectiveness of aspirin for MACE reduction
in symptomatic PAD is controversial [50, 51].
• In addition, the CAPRIE trial, comparing
clopidogrel and aspirin monotherapy, found
clopidogrel to be associated with fewer occurrences of MACE than aspirin [52].
• The EUCLID trial found that ticagrelor confers no additional benet in MACE reduction
as compared to clopidogrel [1].
54
Table 4.2 Contraindications and Side Effects for Commonly Used Medications in PAD.Common side effects are classied as >1% occurrence, uncommon classied as <1% occurrence rate
Drug Contraindications Side effects
ACE
inhibitors
Angiotensin
Receptor
Blockers
Statins Absolute: Active severe hepatic disease,
GLP-1
agonists
SGLT2
inhibitors
Aspirin Absolute: Active peptic ulcer, hypersensitivity,
P2Y12
inhibitors
Anti-Xa
inhibitors
Cilostazol Absolute: Heart failure, ischemic heart disease,
Absolute: Pregnancy, breastfeeding, previous
angioedema from ACEi, bilateral renal artery
stenosis, hypersensitivity
Relative: Impaired renal function, aortic valve
stenosis, hypovolemia/dehydration, hemodialysis
Absolute: Pregnancy, breastfeeding, bilateral
renal artery stenosis, hypersensitivity, use with
aliskiren
Relative: Hypersensitivity, severe liver disease,
hypovolemia
pregnancy, breastfeeding, use with Gembrozil
Relative: Use with other drugs which cause
myopathy, CYP3A4 inhibitors
Absolute: Pregnancy, hypersensitivity, GFR <30,
gastroparesis, inammatory bowel disease,
MEN2A/2B, personal or family hx of medullary
thyroid cancer
Relative: GFR 30–50, pancreatitis
Absolute: GFR <30, second or third trimester of
pregnancy, ESRD/Dialysis, hypersensitivity, type
1 diabetes, or history of DKA
Relative: Hypovolemia, osteopenia
bleeding disorder, recent GI or intracranial bleed,
severe liver disease, thrombocytopenia
Relative: Age <21, concurrent use of
anticoagulant, NSAID use
Absolute: Hypersensitivity, active bleeding
Relative: High bleeding risk, thrombocytopenia,
neuraxial anesthesia
Absolute: Active bleeding, hypersensitivity,
valvular heart disease,
Relative: High bleeding risk, neuraxial
anesthesia, Pregnancy, severe hepatic impairment
active bleeding, hypersensitivity
Relative: Severe hepatic impairment
Common: Dry cough, fatigue, dizziness,
headache, fatigue, weakness, hypotension,
hyperkalemia
Uncommon: Decreased taste, upset stomach,
rash, angioedema, jaundice
Common: URI, back pain, sinusitis, diarrhea,
cough, headache, dizziness, edema
Uncommon: Hyperkalemia, liver failure, kidney
failure, angioedema
Common: Myopathy, transaminase elevation,
Uncommon: New-onset diabetes,
rhabdomyolysis, hepatotoxicity
Common: Nausea, vomiting, diarrhea,
dizziness, tachycardia, headaches, dyspepsia,
minor hypoglycemia, injection site reaction
Uncommon: Pancreatitis, hypersensitivity, acute
renal failure, thrombocytopenia
Common: UTI, mycotic GU infections, URI,
dyslipidemia, nausea, constipation, dysuria
Uncommon: Hypotension, Ketoacidosis, acute
kidney injury, bone fractures
Common: Upset stomach, nausea, heartburn,
drowsiness, mild headache
Uncommon: Hypersensitivity, Reye syndrome,
intracerebral hemorrhage, GI bleed,
thrombocytopenia
Common: Bleeding, bruising, fever, muscle
pain rash/pruritus
Uncommon: Thrombotic thrombocytopenic
purpura, life-threatening bleeding
Common: Bleeding, Abdominal pain, fatigue,
dizziness, mild rash
Uncommon: Life-threatening bleeding,
anaphylaxis, hepatic dysfunction
Common: Headache, diarrhea, palpitations
Uncommon: Bleeding
Z. Billah et al.
• Therefore, clopidogrel monotherapy is the
antiplatelet regimen with the strongest
evidence for MACE reduction.
Dual antiplatelet therapy (DAPT) with both
aspirin and a P2Y12 inhibitor is another proposed
antithrombotic regimen.
• The CHARISMA trial failed to show a MACE
reduction with clopidogrel-based DAPT but
did nd increased bleeding risk [53].
• Subsequent trials suggested a possible reduction in MACE and MALE with ticagrelor-
based DAPT, but consistently at the cost of
increased major bleeding risk [54, 55].
• The more novel thrombin-receptor antagonist
vorapaxar was found to reduce MACE and
potentially MALE in the PAD population but
increased the risk of bleeding in patients with
prior cerebrovascular events [56, 57].
• Presently, there is no clear benet of DAPT or
vorapaxar for prevention of MACE and both
are associated with increased bleeding risk.
Anticoagulation is another potential strategy
for primary prevention in patients with
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