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CHAPTER 6 Peripheral Artery Disease
Goal Benefi ts Strategies
(3) Reduce future
atherothrombotic
events
• Same strategies as in (2)
• Consider ACE inhibitor
blocker as agents of choice
for hypertensive patients
unless renal artery stenosis
is present.
• Consider low-dose ACE
inhibitor for normotensive
patients with PAD.
• Can use beta-blockers if
indicated despite PAD
(careful when CLI is
present)
• Consider screening for
subclinical disease in other
territories if indicated
(carotid and renal artery
stenosis, CAD).
• Review strategies,
especially smoking
cessation, exercise, and
medication compliance,
with patient each visit.
(4) Avoid limb
amputation
• Preserve mobility,
independence
and overall quality of
life and survival
• All the above
• Early identifi cation and
prompt treatment of ALI
and CLI
• Monitor the patency of
prior endovascular and
surgical revascularization
procedures and consider
assisted patency when
indicated.
• Proper foot care for all
and regular podiatry care
for diabetics
• Early referral to specialized
wound centers and
vascular specialist when
spontaneous or traumatic
ulcerations develop
Table 6.3 Continued
cardiovascular and cerebrovascular events in this high-risk population is the
cornerstone of management for both symptomatic and asymptomatic individu-
als. Proper foot care and footwear and daily foot inspection with skin cleansing
along with topical moisturizing creams and lotions to prevent dry skin combined
with prompt treatment of skin lesions or ulcerations are recommended.
27
Complete smoking cessation is a critical step toward improving systemic
and limb outcomes. Jonason and Bergstrom followed 343 patients with IC for
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CHAPTER 6 Peripheral Artery Disease
7 years and reported progression to rest pain in 16 percent of smokers com-
pared to 0 percent of those who quit smoking within 1 year after the initial
evaluation.
28
We adopt the recommendation of the American College of Cardiology/
American Heart Association Clinical Guidelines (2011 focused update) on
peripheral artery disease and ask about smoking status at every visit. We
also offer current smokers referral to formal smoking cessation program
as well as pharmacotherapy to assist with quitting and maintenance of
tobacco-free status. When indicated, we recruit the primary care physicians
in this process.
1
A supervised treadmill exercise program (STEP) is recommended as fi rst-
line therapy for treatment of claudication.
6,27–29
To obtain and maintain benefi t,
several principles need to be followed in a formal STEP. It should be adminis-
tered three to fi ve times per week for 30 minutes each session. The patient is
instructed to maintain walking speed at claudication intensity for 3 to 5 minutes
and stop when pain is moderate. Walking is then resumed until moderate dis-
comfort returns, and the cycle is repeated. During each subsequent session, an
attempt should be made to incorporate 5-minute increments per session to
reach a goal of 50- to 60-minute sessions. The program should be carried out
for a minimum of 6 months and followed by a maintenance phase to maintain
the gains in leg function and walking distance.
28
The benefi ts of STEP on walking distance were demonstrated in two large
meta-analyses of published trials.
30,31
Both pain-free walking distance (by
180 percent or 100 meters) and walking time (up to 5 minutes) improved.
Likewise, the CLEVER study (Claudication: Exercise Vs. Endoluminal
Revascularization Study) documented a remarkable 5.8-minute improvement
in walking time with supervised exercise combined with cilostazol compared to
3.7 minutes in patients with claudication who received contemporary endovas-
cular therapy for aortoiliac obstructive disease combined with cilostazol. Self-
administered, unsupervised home exercise was associated with very modest
(1.2 minute) improvement in this study.
32
An important recent study confi rmed that the benefi ts of STEP appear to
extend to asymptomatic PAD patients and those presenting with atypical symp-
toms. The signifi cance of this study stems from the fact that these groups make
up the vast majority of the PAD population encountered in real-life practice. A
notable improvement in 6-minute walk distance (+20.9 m) was evident in the
exercise group at the 6-month follow-up visit. In contrast, the control group
suffered a decline in walking distance by a mean of –15 m, for a mean increase
of 35.9 m between groups (95 percent CI, 15.32–56.54 m; p < 0.001).
29
Pharmacotherapy is adopted in all PAD patients to improve risk factor pro-
fi le, decrease adverse cardiovascular events, and improve leg symptoms.
Antiplatelet therapy with either aspirin 75 to 325 mg daily (class Ia) or clopi-
dogrel 75 mg daily (class Ib) is recommended for all symptomatic patients.
Their use in asymptomatic patients has not been proven effective. A semi-
nal study by Belch et al. prospectively studied 1,276 adults aged 40 or more
with DM and an ABI of 0.99 or less but no symptomatic CVD. After a median
follow-up of 6.7 years, aspirin was not effective in the primary prevention of
cardiovascular events. The 2011 ACCF/AHA focused update on the 2005 PAD
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CHAPTER 6 Peripheral Artery Disease
guidelines gives a class IIa recommendation to using aspirin for asymptomatic
PAD patients. Dual antiplatelet therapy may be reasonable for select symptom-
atic PAD patients who are not at increased risk of bleeding and who are at high
perceived cardiovascular risk (class IIb).
1,33,34
Treatment with statins has proven benefi ts in this population. The Heart
Protection Study randomized 20,536 patients with diabetes or symptomatic CAD,
PAD, or cerebrovascular disease to treatment with simvastatin (40 mg daily) or
placebo for 5 years. Incident vascular events were reduced signifi cantly in the
study population (24 percent), and PAD patients had comparable benefi ts to
those received by patients with symptomatic CAD.
35
Statin therapy may also have
benefi cial effects on decreasing incident IC in patients with CAD,
36
increase pain-
free walking time,
37
and improve overall lower extremity functional capacity.
38
Statins received class Ia recommendations, mainly for their systemic benefi ts.
27
Absent renal artery stenosis, angiotensin-converting enzyme (ACE) inhibi-
tors are the agent of choice to treat hypertension in individuals with PAD.
The Heart Outcomes Prevention Evaluation (HOPE) study enrolled 9,297 high-
risk patients (more than 55 years of age) with evidence of vascular disease or
diabetes plus one other cardiovascular risk factor.
39
They were randomized
to receive ramipril (10 mg daily) or placebo for a mean of 5 years. A total
of 4,051 participants were enrolled on the basis of symptomatic PAD. The
treatment group achieved a 22 percent relative risk reduction in the primary
end point of stroke, MI, or cardiovascular death compared with those who
received placebo. Importantly, the average baseline BP in the study participants
was 139/79 mmHg, and thus the benefi ts of ACE inhibitors in this population
appear to extend to normotensive patients.
40
It is important to emphasize that
the priority is to achieve goal blood pressure regardless of the agent used.
Cilostazol is a phosphodiesterase type 3 inhibitor with vasodilator and mild
antiplatelet properties; it is also an inhibitor of vascular smooth muscle pro-
liferation. Based on the results of several randomized trials, the U.S. Food &
Drug Administration (FDA) approved cilostazol in 1999 for treatment of IC.
Compared to placebo, cilostazol therapy (100 mg twice a day for 3 to 6 months)
increased pain-free and maximal walking distance by up to 50 percent.
40–44
It
should be given 30 to 60 minutes before or 2 hours after meals. Most common
side effects include headache, palpitations, diarrhea, and dizziness. We treat
elderly patients and those who develop side effects with 50 mg twice a day and
discontinue the medication after 3 months if no benefi t is observed. Cilostazol
is contraindicated in patients with history of heart failure of any severity.
Revascularization therapy is indicated for acute limb ischemia, critical limb
ischemia, and lifestyle- or economically-limiting claudication. The choice of
endovascular therapy (EVT) versus surgical bypass is dependent on several fac-
tors. Lesion characteristics that favor EVT include short-segment stenosis or
occlusion, while long, diffuse, and anatomically complex lesions may be bet-
ter treated surgically. Patients’ preference and the presence of comorbidities
that place them at high risk for perioperative complications or impede their
postoperative recovery and rehabilitation are also taken into account. Recent
advances in EVT techniques, improved operator skill set, and the evolution of
new endovascular tools have made most lesions amenable to an endovascular-
fi rst strategy. Referral to the vascular medicine clinic is generally recommended
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CHAPTER 6 Peripheral Artery Disease
to optimize medical therapy prior to proceeding with revascularization
procedures.
Summary
PAD is a common clinical problem in daily practice that has remarkable implica-
tions on systemic and functional outcomes. Both symptomatic and asymptom-
atic PAD patients are at particularly high risk for atherothrombotic events, and
intensive global cardiovascular risk reduction strategies are strongly recom-
mended. Most PAD patients are either asymptomatic or have atypical exertional
leg discomfort. The ABI has a central role in the diagnosis and cardiovascular
risk stratifi cation and should be incorporated in the routine evaluation of at-
risk patients. Medical therapy, an exercise program, and smoking cessation are
the pillars of management in most cases, and revascularization procedures are
advocated for acute limb ischemia, critical limb ischemia, and lifestyle-limiting
claudication refractory to conservative measures. Endovascular therapy fi rst is
rapidly emerging as the preferred revascularization strategy in most cases.
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40. Dawson DL, Cutler BS, Meissner MH, et al . Cilostazol has benefi cial effects in
treatment of intermittent claudication: results from a multicenter, randomized,
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41. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances
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42. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for
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CHAPTER 6 Peripheral Artery Disease
44. Strandness DE Jr, Dalman RL, Panian S, et al. Effect of cilostazol in patients with
intermittent claudication: a randomized, double-blind, placebo-controlled study.
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45. Zheng ZJ, Sharrett AR, Chambless LE, et al . Associations of ankle-brachial index
with clinical coronary heart disease, stroke and preclinical carotid and popliteal
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46. Fabsitz RR, Sidawy AN, Go O, et al. Prevalence of peripheral arterial disease
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9595
Chapter 7
Lipid-Modifying Therapy
Chintan Patel , Roger S. Blumenthal , and Seth S. Martin
Introduction
In 1913, Dr. Nikolai N. Anichkov’s laboratory implicated cholesterol in the
formation of atherosclerosis, the substrate for atherothrombosis.
1
Since then,
a wealth of research has established the clinical importance of this link and
delivered effective interventions. This chapter provides an overview of the pri-
mary and secondary prevention of coronary heart disease (CHD), stroke, and
other forms of atherosclerotic cardiovascular disease (ASCVD) through lipid-
modifying therapies.
Epidemiology of lipid disorders
Low-density lipoprotein cholesterol (LDL-C)
Consistent with the fundamental role of LDL particles in carrying cholesterol
into the arterial wall and stimulating infl ammatory cascades, numerous epide-
miologic studies have shown an association of higher LDL-C concentrations with
higher risk for ASCVD.
2
The correlation between LDL-C and ASCVD has been
strengthened by investigations of young adults with inherited dyslipidemia, dem-
onstrating early subclinical atherosclerosis. Moreover, Mendelian randomization
studies are compatible with a causal role of LDL-C in ASCVD.
3
Polymorphisms
in genes yielding early and long-term exposure to lower LDL-C levels confer
strong protection against CHD.
3
For the same amount of LDL-C lowering, the
magnitude of risk reduction associated with maintaining low LDL-C levels from
an early age, as in Mendelian randomization studies, is considerably greater than
the risk reduction seen with lowering LDL-C later in life in statin trials (Fig. 7.1),
supporting the emerging dogma “the earlier the better.”
Another major dogma is “the lower the better.” Consistent with the strong
evidence base, LDL-C lowering is a central target of lipid-modifying therapy
in worldwide clinical practice guidelines.
4–8
A large body of data from epide-
miologic studies and clinical trials is consistent with a log-linear relationship
between LDL-C levels and relative risk for CHD (Fig. 7.2). Pooled data of statin
trials
9–11
indicate that we have not yet identifi ed an LDL-C level below which
patients do not benefi t from LDL-C lowering and that an ideal LDL-C is at least
below 70 mg/dL. At such low LDL-C levels, multiple studies have shown that
patients often see a reduction in atherosclerosis progression or even plaque
regression.
12–14
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CHAPTER 7 Lipid-Modifying Therapy
Lower LDL-C
Genetic Studies
Statin Trials
Genetic Studies
Statin Trials
Genetic Studies
Statin Trials
Genetic Studies
Statin Trials
312,321
169,138
312,321
169,138
312,321
169,138
312,321
169,138
0.40 0.50 0.60 0.70 0.80 0.90 1.0
8.4×10
–19
8.4×10
–19
8.4×10
–19
8.4×10
–19
0.46 (0.41–0.51)
0.76 (0.74–0.78)
0.67 (0.64–0.72)
0.87 (0.86–0.88)
0.82 (0.80–0.85)
0.93 (0.93–0.94)
0.91 (0.89–0.92)
0.96 (0.96–0.97)
1.0 mmol/L
(38.7 mg/dl)
0.5 mmol/L
(19.3 mg/dl)
0.25 mmol/L
(9.7 mg/dl)
0.125 mmol/L
(4.8 mg/dl)
Meta-Analysis
Sample
Size (N) OR (95% CI) p (difference)
Figure 7.1 Comparative CHD Risk Reduction of Earlier and Later LDL-C Lowering. Boxes represent the summary point estimate of the OR for the association between
each unit lower LDL-C and the risk of CHD, for both meta-analyses combining data from Mendelian randomization studies adjusted per unit lower LDL-C and meta-analyses
of statin trials adjusted per unit lower LDL-C. Bars represent 95% CI. Darker boxes are genetic studies and lighter boxes are statin trials. (Source: From Ference BA et al.
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: A Mendelian randomization analysis. J
Am Coll Cardiol 2012;60:2636, with permission.)
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CHAPTER 7 Lipid-Modifying Therapy
Concerns have been raised about severe reductions in LDL-C causing
adverse effects. Well-conducted studies have been mostly reassuring in this
regard. Neonates, adult primates, and hunter-gatherer populations have LDL-C
levels ranging from 30 to 80 mg/dL.
12,15–17
Remarkably, people with heterozy-
gous hypobetalipoproteinemia have LDL-C levels on the order of 30 mg/dL
without adverse effects, and in fact they benefi t from longer life expectancy,
perhaps from less atherogenicity.
12,18
Consistent with these data, in statin trials,
there was no evidence of heterogeneity across baseline LDL-C levels (Fig. 7.3).
Even those patients starting with the lowest LDL-C levels (<80 mg/dL) derived
benefi tted from further LDL-C lowering.
High-density lipoprotein cholesterol (HDL-C)
HDL particles are heterogeneous and comprise a mixture of apoproteins (45
to 55 percent), phospholipids (26 to 32 percent), esterifi ed cholesterol (15 to
20 percent), free cholesterol (3 to 5 percent), and triglycerides (5 percent). The
inverse association of HDL-C with ASCVD may be explained by its role as a
reverse cholesterol transporter, antioxidant, anti-infl ammatory, and antifi brin-
olytic molecule.
19
In the Framingham Heart Study and the Atherosclerosis Risk in
Communities (ARIC) study, individuals with HDL-C levels below 35 mg/dL had
an eightfold higher incidence of ASCVD compared to individuals with HDL-C
levels above 65 mg/dL.
20–22
Overall, observational studies have recorded a 2 to
3 percent increase in ASCVD risk for every 1-mg/dL decrease in HDL-C.
23,24
While HDL-C is associated with protection from ASCVD, causality remains
uncertain. Targeting drug therapies at HDL-C raising remains an unproven
strategy. Some notable recent failures include niacin on a background of statin
therapy in patients with well-controlled LDL-C as well as cholesterol ester
transfer protein inhibitors. It also bears mentioning that in a recent Mendelian
randomization study, a genetic variant that specifi cally increases plasma HDL-C
did not reduce the risk of myocardial infarction.
25
It is challenging to reconcile
3.7
2.9
2.2
Relative Risk for
Coronary Heart Disease
(Log Scale)
LDL-Cholesterol (mg/dL)
1.7
1.3
1.0
40 70 100 130 160 190
Figure 7.2 Log-Linear Relationship between LDL-C Levels and Relative Risk for CHD.
This relationship is consistent with a large body of epidemiological data and with data
available from clinical trials of LDL-lowering therapy. These data suggest that for every
30-mg/dL change in LDL-C, the relative risk for CHD is changed in proportion by about
30%. The relative risk is set at 1.0 for LDL-C = 40 mg/dL. (Source: From Grundy SM et al.
Implications of recent clinical trials for the National Cholesterol Education Program
Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:724, with permission.)
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