Peripheral Arterial

Disease:

Simulation Training
Curriculum

1
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
Indications
Treatment Options
Prognosis

2
Peripheral Arterial Disease: Etiology

• Atherosclerosis
• Degenerative diseases: Marfan and Ehlers-
Danlos syndrome, neurofibromatosis,
arteriomegaly
• Dysplastic disorders: Fibromuscular dysplasia
• Vascular inflamation : Takayasu’s disease
• In situ thrombosis
• Thromboembolism

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 3
 Atherosclerosis:
A Progressive and Systemic Process
Plaque
Occlusive Rupture/
Fatty Fibrous Atherosclerotic Fissure & Unstable
Normal Streak Plaque Plaque Thrombosis Angina

MI

Coronary
Death

Stroke
Effort Angina
Clinically Silent Claudication Critical
Renovascular Dz Leg
Increasing Age Ischemia

4
 Peripheral Arterial Disease:
Overlap of Atherosclerotic Disease
Peripheral Arterial
Disease

38% overlap
> 2 Vascular beds

Coronary artery Cerebrovascular

disease disease

Patients with one manifestation often have

coexisted disease in other vascular beds

Ness et al Am J Geriatr Soc 1999; 47:1255-6 5

 SF-36 Physical Function Scores

Intermittent
Claudication
Average
Average
Well
CLI CHF COPD Adult
Adult

No. of
People

30 34 36 38 50 55
Physical Component Score

Adapted from Ware JE. Ann Rev Pub Health. 1995;16:327-354. 6

Atherosclerosis Disease in the U.S.

Prevalence
(millions)
Coronary heart disease 13.2

Cerebrovascular disease 4.8

Peripheral arterial disease 8.0 – 12.0

Ness J et al J Am Geriat Soc 1999; 47: 1255-1256

7
Risk of Ischemic Events in Atherosclerotic
Clinical Syndromes

*Sudden death defined as death documented within 1 hour and attributed to Coronary Heart Disease (CHD)
† Includes only fatal MI and other CHD; does not include nonfatal MI
1. Adult treatment Panel II Circulation 1994; 89: 1333 – 1435
2. Kannel et al J Cardiovasc Risk 1994;1:333-339
3. Witerdink et al Arch Neurol 1992; 49: 857 – 863
8
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
Indications
Treatment Options
Prognosis

9
 Prevalence of PAD in 1990s

Projected
US
Age Abnormal ABI Prevalence

40-59 3% 2.1 million

60-69 8% 1.6 million
>70 19% 4.7 million
Total 8.4 million

Criqui et al N Engl J Med 1992;326:381-86

Hiatt et al Circulation 1995;91:1472-79 10
 Peripheral Arterial Disease
Prevalence by age
25

20
PAD Prevalence

15
Men
Women
10

0
<60 60-64 65-69 70-74 >75
Age Groups

Criqui et al Circulation 1985; 71: 510-5 (77)

11
 Risk Factors for PAD
Reduced Increased

Smoking
Diabetes
Hypertension
Hypercholesterolemia
Hyperhomocysteinemia
Fibrinogen
C-Reactive Protein
Alcohol

Relative Risk .5 1 2 3 4 5 6

Newman et al Circulation 1993;88:837-845.

Hiatt WR et al Circulation 1995;92:614-621.
Graham et al JAMA 1997;277:1775-1781.
TASC Working Group J Vasc Surg 2000;31(1, pt 2):S1-S288.
Ridker PM et al Circulation 1998;97:425-428. 12
Nobel Risk Factors as Predictors of PDA

Adjusted for age, smokin, DM, family history, HTN, exercise level, and BMI

Ridker et al JAMA 2001; 285:2481-5

Pradhan et al Circulation 2002; 106: 820-5 13
 Lower Extremity PAD: Prevalence

• Affects a large proportion of most adult

populations worldwide
• Increases with age and with exposure to
atherosclerotic risk factors.
• Defined by
– Claudication as a symptomatic marker
– Abnormal ankle-to brachial systolic blood pressure
– Underlying atherosclerosis risk factor profile
– Presence of other concomitant manifestations of
atherosclerosis

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 14
Risk of developing lower extremity PAD

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 15
Prevalence of intermittent claudication in
various studies

Dormandy JA, Rutherford RB J VAsc Surg 2000;31: S1-S296 16

 Mean Prevalence of intermittent
claudication in large population studies

0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74

Age group

Dormandy JA, Rutherfors RB J Vasc Surg 2000; 31: S1-S296 17

Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
Indications
Treatment Options
Prognosis

18
CVD

CAD

RVD

PAD

19
 Peripheral Arterial Disease:
Clinical Diagnosis
• Must have a high index of suspicion
• Must perform a thorough physicial examination
• Determine the global atherosclerotic burden
• Utilize the vascular diagnostic laboratory
• Magnetic resonance angiography is rapidly
replacing invasive testing
• Reserve arteriography for cases requiring
intervention

TCT 2005 20
 Vascular Review of Systems
• Any exertional limitation of the lower extremity
muscles or any history of walking impairment
(fatigue, numbness, aching, or pain
• Any poorly healing or non healing of the legs or feet
• Any pain at rest localized at the lower leg or foot
and its association with the upright or recumbent
positions
• Postprandial abdominal pain that reproducibly is
provoked by eating and is associated with weight
loss
• Family history of a first-degree relative with
Abdominal Aortic Aneurysm

ACC/AHA Guidelines 21
 Vascular Physical Examination
• Measurement of blood pressure in both arm and notation of
any interarm assymetry
• Palpation of the carotid pulses and notation of the carotid
upstroke and amplitude and presence of bruits
• Auscultation of the abdomen and flank for bruits
• Palpation of the pulses at the brachial, radial ulnar, femoral,
popliteal, dorsalis pedis, and posterior tibial sites.
Performance of Allen’s test when knowledge of hand
perfusion is needed
• Auscultation of both femoral ateries for the presence of bruits
• Pulse intensity should be recorded numerically: 0, absent; 1,
diminished; 2, normal; 3, bounding
• Additional findings: distal hair loss, trophic sin changes
hypertrophic nails

ACC/AHA Guidelines 22
 Physical Examination
Dorsalis Pedis Popliteal Artery

Posterior Tibial Femoral Pulse

Beard JD. BMJ. 2000;320:854. 23

 Signs of PAD

• Decreased or absent pulses

• Bruits
• Muscle atrophy
• Pallor of feet with elevation
• Dependent rubor
• Signs of chronic ischemia:
Hair loss, thickened nails, smooth & shiny
skin, coolness, pallor or cyanosis

24
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
 Clinical Manifestations
Diagnosis
Indications
Treatment Options
Prognosis

25
Clinical Presentation of PAD Patients

Chronic limb ischemia

Asymptomatic Acute Limb Ischemia

PAD

Stable
Claudication

Hirsch AT. Fam Pract Recertification. 2000;15(suppl):6-12. 26

 Lower Extremity Arterial Disease in the
Population > 55 y
Population >55 y

Asymptomatic Intermittent Chronic critical

ABI <0.9 claudication leg ischemia
10% 5% 1%

Peripheral vascular Other cardiovascular

outcomes morbidity / total mortality

Worsening Lowe extremity Major Nonfatal 5-y

claudication bypass surgery Amputation Cardiovascular event Mortality
16% 7% 4% 20% 30%

Repeat Major Cardiovascular Non-cardiovascular

Revascularization Amputation Cause cause
26% 20% 75% 25%

Weitz et al Circulation 1996; 94(11):3026-3049 27

 Individuals at Risk for Lower-extremity
Peripheral Arterial Disease
• Age less than 50 years, with diabetes and one other
atherosclerosis risk factor (smoking, dyslipidemia,
hypertension, or hyperhomocysteinemia)
• Age 50 to 69 years and history of smoking or diabetes
• Age 70 years and older
• Leg symptoms with exertion (suggestive of claudication)
or ischemic rest pain
• Abnormal lower extremity pulse examination
• Known atherosclerotic coronary, carotid, or renal artery
disease

ACC/AHA Guidelines 28
 Common Sites of Claudication

25-30%

80-90%

40-50% Tibial and Foot

peroneal
arteries

Adapted from TCT 2005 29

Classification of Peripheral Arterial Disease

FONTAINE RUTHERFORD
Stage Clinical Grade Category Clinical

I Asymptomatic 0 0 Asymptomatic

IIa Mild claudication I 1 Mild claudication

IIb Moderate–severe claudication I 2 Moderate claudication

I 3 Severe claudication

III Ischemic rest pain II 4 Ischemic rest pain

IV Ulceration or gangrene III 5 Minor tissue loss

IV 6 Ulceration or gangrene

Dormandy JA, Rutherfors RB J Vasc Surg 2000; 31(1): S1-S296 30

Pathophysiology of Intermittent Claudication
Intermittent claudication is associated with:
• Metabolic abnormalities stemming from
reduced blood flow and O2 delivery1
• Significant reduction (50%) in muscle fibers
compared with controls2
• Smaller type I and II muscle fibers with
greater arterial ischemia2
• Hyperplastic mitochondria and
demyelination of nerve fibers3

1 Lundgren et al Am J Physiol. 1988;255:H1156-64.

2 Hedberg et al. Eur Vasc Surg. 1989;3:315-22.
3 Farinon et al. Clin Neuropathol 1984;3:240-52.
32
 PAD Symptom Severity

• Maximal walking speed

– Normal = 3-4 mph
– PAD = 1-2 mph
• Maximal walking distance
– Normal = unlimited
– PAD, 31% difficulty walking in home
– PAD, 66% difficulty walking 1/2 block
• Peak VO2
– PAD reduced 50% (NYHA class III CHF)

Otsuka data set, J Appl Physiol 1992;73:346 33

Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
 Diagnosis
Indications
Treatment Options
Prognosis

34
 Diagnostic Methods
• Ankle-and Toes – Brachial Indices, segmental
pressure examination
• Pulse volume recording
• Continuous wave doppler ultrasound
• Treadmill exercise testing with and without ABI
assessments and 6 minute walk test
• Duplex ultrasound
• Computed tomographic angiography
• Magnetic resonance angiography
• Contrast angiography
Hirsh et al Circulation 2006; 113(11): e463-654
ACC/AHA Guidelines 35
Typical Noninvasive Vascular Laboratory Tests for Lower
Extremity PAD Patients by Clinical Presentation
Clinical presentation Noninvasive vascular test
Asymptomatic lower extremity PAD ABI

Claudication ABI, PVR, or segmental pressures

Duplex ultrasound
Exercise test with ABI or assess
functional status
Possible pseudoclaudication Exercise test with ABI

Postoperative vein graft follow-up Duplex ultrasound

Femoral pseudoaneurysm; iliac or Duplex ultrasound

popliteal aneurysm
Suspected aortic aneurysm; serial AAA Abdominal ultrasound, CTA, or MRA
follow-up
Candidate for revascularization Duplex ultrasound, MRA, or CTA

ACC/AHA Guidelines
Adapted from primary cardiology, 2nd ed., Braunwald E, Goldman L,
eds. “Recognition and management of peripheral arterial disease”. 36
 Diagnostic Algorithm for PDA
History, Physical examination
Suggestive of PDA? NO Search for alternate diagnosis

Yes

Ankle-Brachial Index

<0.9 >0.9 >1.30

Vascular Lab Referral
•Segmental pressures, PVR
Still suspicious? •Graded treadmill test

Anatomic Assessment: DUS, MRA, CTA

PAD

TCT 2005
37
Diagnosis of asymptomatic PAD and
Atypical Leg Pain
Individual at risk of PAD

Perform a resting ankle-brachial index measurement

ABI > 1.30 ABI 0.91 to 1.30 ABI < 0.90

(abnormal) (borderline & normal) (abnormal)

Pulse volume recording

Toe-brachial index Measure ankle-brachial index after exercise test
(Duplex ultrasound)

Normal results: Normal:

Abnormal results Decreased
No PAD No PAD

Evaluate other causes

of leg symptoms

Confirmation of
PAD diagnosis
ACC/AHA Guidelines 38
 Diagnosis of Claudication
Classic claudication symptoms:
Muscle fatigue, cramping, or pain that reproducibly begins
during exercise and that promptly resolves with rest

Chart document the history of walking impairment

and specific lifestyle limitations

Document pulse examination

Exercise ABI
ABI ABI >0.90 (TBI, segmental pressure, or
duplex ultrasound examination)
ABI less than or equal to 0.90 Abnormal results Normal results

Confirmed PAD diagnosis No PAD or consider arterial

entrapment syndromes

ACC/AHA Guidelines 39
 Diagnosis of Acute Limb Ischemia
Rapid or sudden decrease in limb perfusion threatens tissue viability

History and physical examination; determine time of onset of symptoms

Emergent assessment of severity of ischemia:

Loss of pulses
Loss of motor and sensory function
Vascular laboratory assessment

ABI, TBI, or duplex ultrasound

Nor or minimal PAD Severe PAD documented:

• ABI less than 0.4
Consider and evaluate source of: • Flat PVR waveform
atheroembolism, thromboembolism • Absent pedal flow
or phlegmasia cerulea dolens

ACC/AHA Guidelines 40
 Diagnosis of Critical Limb Ischemia
Chronic Symptoms: Ischemic rest pain, gangrene, nonhealing wound
Ischemic etiology must be established promptly:
By examination and objective vascular studies
Implication: Impending limb loss

History and physical examination:

• Document lower extremity pulses
• Document presence of ulcers or infection

Assess factor that may contribute to limb risk: diabetes, neuropathy, chronic renal
failure, infection

ABI, TBI, or duplex ultrasound

Severe lower extremity PAD No or minimal atherosclerotic

ABI less than 0.4; flat PVR waveform; arterial occlusive disease
absent pedal flow

ACC/AHA Guidelines 41
 The Ankle-Brachial Index
• The resting ABI should be used to stablish the
lower extremity PAD diagnosis in patients with
suspected lower extremity PAD
– Exertional leg symptoms
– Non healing wounds
– 70 years and older or 50 years and older with
history of smoking or diabetes
• ABI should be measured in both legs in all new
patients with PAD of any severity to confirm the
diagnosis and establish a baseline

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 42
 The Ankle-Brachial Index

• The toe-brachial index should be used to

establish the lower extremity PAD diagnosis in
patients in whom lower extremity PAD is clinically
suspected but in whom the ABI test is not reliable
due to noncompressible vessels (advance age or
diabetes)
• Leg segmental pressure measurements are useful
to establish the lower extremity PAD diagnosis
when anatomic localization of lower extremity
PAD is required to create a therapeutic plan

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 43
Effectiveness of the ABI vs Other Common
Screening Test
Diagnostic Test Sensitivity, % Specificity, %
Pap smear 1 30 - 87 86 – 100

Fecal occult blood test 2 37 - 78 87 – 98

Mammography 3 75 - 90 90 – 95

ABI 4,5,6 95 100

Belch JJ et al, Arch Intern Med, 2003;163:884

1. Nanda et al Ann Intern Med 2000;132:810-9
2. Allison et al New Eng J Med 1996;334:155-9
3. Ferrini et al Ame J Prev Med 1996;12:340-1
4. Dormandy et al Semin Vasc Surg 1999;12:96 -108
5. Fowkes et al Inter J Epid 1991; 20:384-392
6. Newman et al Arterioscler Thromb Vasc Biol. 1999;19:538–545
44
TCT 2005
45
 The Ankle-Brachial Index

Ankle systolic pressure

ABI = Brachial systolic pressure
• Ankle and brachial systolic pressures taken using a hand-
held Doppler instrument
• Supine, after ~10 minutes rest
Normal ABI 0.90-1.30
PAD ABI <0.90
Rest pain/ulceration ABI <0.40
Non-compressible ABI >1.30

46
Segmental Pressures/ Pulse Volume
Recordings

TCT 2005
47
64 yo Male with Right Hip Discomfort with
Walking
Treadmill stress test

TCT 2005
48
 Peripheral Arterial disease:
Duplex Ultrasound
Benefits
• Can establish the lower
extremity PAD diagnosis,
establish localization, and
define severity of local lower
extremity arterial stenoses
• Can be useful to select
candidates for endovascular or
surgical revascularization
Limitations
• Accuracy is diminished in
proximal aortoiliac arterial
segments in some individuals
• Dense arterial calcification can
limit diagnostic accuracy
• Sensitivity is diminished for
detection of stenoses
downstream from a proximal
stenosis
• Diminished predictive value in
surveillance or prosthetic
bypass grafts

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 49
 Peripheral Arterial Disease:
Magnetic Resonance
Benefits
• Useful to asses PAD anatomy
and presence of significant
stenoses
• Useful to select patients who
are candidates for
endovascular or surgical
revascularization
Limitations
• Tends to overestimate the
degree of stenosis
• May be inaccurate in arteries
treated with metal stents
• Can not be used in patients
with contraindications to the
magnetic resonance technique

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 50
 Peripheral Arterial Disease: MR
Arterial segment n=226 Moderate stenosis > 50% lumen reduction
Sensitivity (%) Specificity (%) Agreement (k ±SE)
Iliac arteries 100 85.7 087± 0.12
Femoropopliteal arteries 95.6 90.3 086 ± 0.06
Calf arteries 96.8 96.1 0.90 ± 0.04
Overall 96.5 94.3 0.90 ± 0.03

Arterial segment n=226 Severe stenosis > 75% lumen reduction

Sensitivity (%) Specificity (%) Agreement (k ±SE)
Iliac arteries 100 100 100± 0.00
Femoropopliteal arteries 97.0 90.7 087 ± 0.06
Calf arteries 96.4 96.2 0.89 ± 0.05
Overall 97.0 95.0 0.90 ± 0.03
The following grading scale was used: grade 1, 0–9% (normal, irregularity of vessel wall);
grade 2, 10–49% (mild stenosis); grade 3, 50–74% (moderate stenosis); grade 4, 75–99%
(severe stenosis); grade 5, 100% (occlusion

Deutschmann et al Cardiovasc Interv Rad 2006; Apr 19 51

3D moving-table MR
angiogram of a 58-year-old
man .The image shows a long
stenosis of the left superficial
femoral artery (long arrows)
and occlusion of the
reconstituted popliteal artery
(short arrows). Furthermore,
occlusion of the right
superficial femoral artery
(arrowheads) with
reconstitution in the middle
third can be seen (arrowheads)

Deutschmann et al Cardiovasc Interv Rad 2006; Apr 19 52

 Peripheral Arterial Disease:
Computed Tomographic Angiography
Benefits
• Useful to asses PAD anatomy and
presence of significant stenoses
• Useful to select patients who are
candidates for endovascular or
surgical revascularization
• Helpful to provide associated soft
tissue diagnostic information that may
be associated with PAD presentation
• Metal clips, stents, and metallic
prostheses do not cause significant
CTA artifacts
• Scan times are significantly faster
than for MRA
Hirsh et al Circulation 2006; 113(11): e463-654
ACC/AHA Guidelines
Limitations
• Single-detector computed
tomography lacks accuracy for
detection of stenosis
• Spatial resolution lower than digital
subtraction angiography
• Accuracy and effectiveness not as
well determined as MRA
• Asymmetrical opacification in legs
may obscure arterial phase in some
vessels
• Requires iodinated contrast and
ionizing radiation
• Venous opacification can obscure
arterial filling
53
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
 Indications
Treatment Options
Prognosis

54
Automatic Indications for Revascularization

• Gangrene
• Non-healing ulcers
• Ischemic rest pain
• Claudication causing lifestyle deterioration
refractory to pharmacologic intervention and
behavioral modification

55
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
Indications
 Treatment Options
Prognosis

56
 Peripheral Arterial Disease:
Goals of Therapy

• Improvement in quality of life and functional

status
• Identification and treatment of established
systemic atherosclerosis
 Prolong survival
• Prevention of progression of atherosclerosis
 Aggressive risk factor intervention
• Limb salvage

57
 What are you trying to achieve?

Symptom relief?
Healing?
Survival benefit?

End organ function preservation?

58
 Treatment of Asymptomatic PAD and
Atypical Leg Pain
Confirmation of PAD diagnosis

Risk factor normalization:

•Immediate smoking cessation
•Treat hypertension
•Treat lipids
•Treat Diabetes mellitus: hbA1c less than 0.7% †

Pharmacological Risk Reduction:

Antiplatelet therapy
(ACE inhibition) ‡
† It is not yet proven that treatment of diabetes mellitus will significantly reduce PAD – specific (limb
ischemic) end points. Treatment of diabetes mellitus should be continued according to established
guidelines
‡The benefit of ACE inhibition in individuals without claudication has not been specifically
documented in prospective clinical trials, but has been extrapolated from other “at risk populations.

ACC/AHA Guidelines 59
Treatment of Symptomatic Lower Extremity
Atherosclerotic Occlusive Disease:

Nonoperative Endovascular Surgery

• Risk factor • Transluminal • Endarterectomy
modification angioplasty • Bypass grafting
• Exercise • Endovascular stents • Autogenous
• Drugs (including • Intra-arterial prosthetic
thrombolytic agents thrombolytic therapy • Amputation

Weitz et al Circulation 1996; 94; 3026-49 60

 Treatment of Claudication
Confirmed PAD diagnosis

No significant Lifestyle-limiting symptoms Lifestyle-limiting symptoms with

Functional disability Evidence of inflow disease

• No claudication treatment Supervised Pharmacological Further anatomic definition

• Follow –up visit annually to exercise program therapy: by more extensive
monitor for development of Cilostazol noninvasive or angiographic
ischemic symptoms (Pentoxifyline) diagnostic techniques
Three-month trial

Three-month trial
Pre/post program
exercise testing for Endovascular therapy
efficacy Or surgical bypass per
anatomy

Clinical Improvement: Significant disability despite

Follow-up visits at least annually medical therapy and/or
endovascular therapy

Evaluation for additional endovascular

or surgical revascularization
ACC/AHA Guidelines 61
 Claudication Exercise Programs

• Supervised 3 times/week, 2 times unsupervised

• Duration: 3 to 6 months
• Effective at improving exercise performance, walking
ability and physical functioning
• Safe
• Cost-effective
• Availability of supervised programs is limited
• Require discipline and motivation
• Benefits dissipate unless exercise regimen is
maintained

62
 Effect of Exercise Conditioning
on Treadmill Exercise Time

Control

15 Exercise training
Exercise Time
(minutes)

10

0
Baseline 6 weeks 12 weeks

Duration of Treatment

Hiatt et al. Circulation. 1990 63

 Meta-Analysis of Exercise Training
in Claudication
Exercise Training
180
Control
Change in Treadmill Walking

160
140
Distance (%)

120
100
80
60
40
20
0
ICD ACD

Gardner et al., JAMA, 1995 64

Mechanisms of Action of Exercise Therapy
in Peripheral Arterial Disease

• Enlarging the radius of the supply vessel

• Enhance collateral growth (unlikely)
• Increase pressure gradient across stenosis
• Increase oxidative capacity of muscle cells
• Increase in Type I muscle fibers
• Higher ‘fluidity’ of arterial blood flow
• Enhanced oxygen affinity of hemoglobin
• Improved endothelial function

66
Cornerstones of Medical Therapies in PAD

Antiplatelet Exercise
Statins

Smoking cessation Cilostazol

Ace Inhibitors

67
Efficacy of ACE-I, Stantins and Antiplatelet
therapy in PAD

*PAD Subgroup only

APTC Antiplatelet Trialists’ Collaboration BMJ 1994; 308:81-106
CAPRIE Steering Committee Lancet 1996; 348: 1329-1339
HOPE Study Investigators N Engl J Med 2000; 342:145-153
HPS Collaborative group Lancet; 2002; 360:7-22 68
 CAPRIE Study
Efficacy of Clopidogrel in Primary Analysis of MI,
Ischemic Stroke, or Vascular Death

ITT Analysis

CAPRIE Steering Committee Lancet 1996; 348: 1329-1339 69

 CAPRIE Study
Outcome by Subgroup

CAPRIE Steering Committee Lancet 1996; 348: 1329-1339 70

 Heart Protection Study:
STATIN worse
Vascular Event by Prior Disease
Baseline STATIN PLACEBO Risk ratio and 95% CI
Feature (10269) (10267) STATIN STATIN
Better Worse

Previous MI 1007 1255

Other CHD (not MI) 452 597
Prior MI or Other CHD 568 681
(19.9%) (25.4%)
No prior CHD
CVD 182 215
PAD n = 3748 332 427 24% SE 2.6
reduction
Diabetes 279 369 (2P<.001)
ALL PATIENTS 2042 2606
(19.9%) (25.4%)

0.4 0.6 0.8 1.0 1.2 1.4

Heart Protection Study Collaborative Group. Lancet.
2002;360:7-22. 71
The HOPE Study: PAD Subgroup Analysis

No. of Incidence of
Patients Composite Outcome
in Placebo Group

PAD 4046 22.0

No PAD 5251 14.3

0.6 0.8 1.0 1.2

Relative Risk in Ramipril Group

The Heart Outcomes Prevention and Evaluation Study

Investigators N. Engl. J. Med. 2000; 342: 145-153 73
Antithrombotic Trialists’ Collaboration: PAD

• 42 clinical trials
• 9,214 patients with PAD
• 23% reduction in serious adverse vascular events
(P=.004)
• Benefits similar among PAD subtypes (intermittent
claudication, peripheral grafting, and peripheral
angioplasty)

Antithrombotic Trialist’s Collaboration. BMJ. 2002;324:71-86.

74
Pharmacotherapy for PAD
FDA Approved Drugs

• Pentoxifylline
• Cilostazol

Drugs Under Investigation

• Atorvastatin
• Rosiglitazone
• Propionyl- L-Carnitine
• L-Arginine
• Prostaglandins
• Angiogenic Factors: VEGF,bFGF

75
Pharmacologic Effects of Cilostazol
Antiplatelet
activity In vitro
inhibition
Antithrombotic
of vascular
activity
smooth muscle
cells

Decreases
Vasodilatation
triglycerides

Mildly increases Increases

Heart rate HDL -C

Increases
Blood flow

Adapted from TCT 2005 76

Effect of Cilostazol on walking distance in
patients with intermittent Claudication

Hiatt WR N Engl J Med 2001; 344: 1608 - 1621 77

Effect of Cilostazol vs. Pentoxifylline on Walking
Distance in Patients with Claudication
Cilostazol 100 mg bid po
Pentoxifylline 400 mg tid
50
Placebo
Baseline MWD (mean)
Percent Change from

40 *
30

20

10 * Ppoints
<0.05 at all time

0
0 4 8 12 16 20 24
Weeks of Treatment

Dawson, et al. Am. J. Med., 2000. 78

Effect of Simvastatin on Intermittent
Claudication in 4S

4.0 Placebo
Simvastatin
RR = .62
3.0
p< 0.008
% 2.0

1.0
0
0 1 2 3 4 5
Years

Pederson et al. Am. J. Cardiol., 1998 79

Effect of Atorvastatin on Pain Free Walking
Time in Patients with Intermittent
Claudication

*p = 0.025 for 80 mg. dose at 12 months

Mohler EM, et al., Circulation, 2003;108:1481-1486 80

Therapeutic Angiogenesis for PAD

82
 Treatment of Acute Limb Ischemia
Severe PAD documented

Immediate anticoagulation:
Unfractionated heparin or low molecular heparin

Obtain prompt vascular specialist consultation

Diagnostic testing strategy / therapeutic plan

Assess etiology:
-Embolic -Leg bypass graft thrombosis -Poplietal cyst or entrapment
-Progressive PAD and -Arterial trauma -Phlegmasia cerulea dolens
in situ thrombosis -Ergotism -Hypercoagulable state

Viable limb salvageable limb salvageable limb Nonviable limb

Threatened marginally Threatened immediately

Amputation
Revascularization: thrombolysis, endovascular, surgical

ACC/AHA Guidelines 83
 Treatment of Critical Limb ischemia
Severe lower extremity PAD documented

Systemic antibiotics if skin ulceration and limb infection are present

Patient is not a Obtain prompt vascular specialist consultation

candidate for Diagnostic testing strategy / therapeutic plan
revascularization
Patient is a candidate for revascularization

Define limb arterial anatomy and assess clinical severity of ischemia

Medical Imaging of relevant arterial circulation (non invasive and angiographic)

therapy or
amputation Revascularization possible Revascularization not possible:
Medical therapy or amputation

Ongoing vascular surveillance-risk factor normalization

Written instruction for self-surveillance

ACC/AHA Guidelines 84
 Endovascular Treatment of Critical
Limb Ischemia
1. For individuals with combined inflow and
I IIa IIb III
outflow disease with CLI, inflow lesions should
be addressed first
2. If it is unclear whether hemodynamically
significant inflow disease exists, intra-arterial
pressure measurements across suprainguinal
lesions should be measured before and after
the administration of a vasodilator

I IIa IIb III 1. For individuals with combined inflow and outflow
disease, in whom symptoms of CLI or infection
persist after inflow revascularization, an outflow
revascularization procedure should be performed

ACC/AHA Guidelines 85
 Lower Limb Bypass Surgery
• Risk of MI ranges from 1.9 to 3.4%
• Death 1.3 to 6%
• Wound infection 10-30%
• Scar-related neuropathic pain in 23%
• 30% of grafts will require revision during their lifetime

Why?
High risk population
Widespread atherosclerotic
disease
High incidence of diabetics thus the
infection risk

86
 Peripheral Arterial Disease:
Surgical Treatment of Claudication
I IIa IIb III
1. Individuals with claudication symptoms who have
significant functional disability that is vocational or
lifestyle limiting, who are unresponsive to exercise
or pharmacotherapy, and who have a reasonable
likelihood of symptomatic improvement
2. A preoperative cardiovascular risk evaluation should
be taken
in those patients with lower extremity PAD in whom
a major vascular surgical intervention is planned

ACC/AHA Guidelines 87
 Peripheral Arterial Disease:
Surgical Treatment of Claudication

I IIa IIb III 1. Because the presence of more aggressive

atherosclerotic occlusive disease is associated with
less durable results in patients < 50 years of age, the
effectiveness of surgical intervention in this population
for intermittent claudication is unclear

I IIa IIb III 1. Surgical intervention is not indicated to prevent

progression to limb-threatening ischemia in patients
with intermittent claudication

ACC/AHA Guidelines 88
 Peripheral Arterial Disease:
Surgical Treatment of Critical Limb ischemia

I IIa IIb III 1. For individuals with combined inflow and outflow
disease with CLI, inflow lesions should be addressed
first
2. For individuals with combined inflow and outflow
disease in whom symptoms of CLI or infection persist
after inflow revascularization, and outflow
revascularization procedure should be performed

ACC/AHA Guidelines 89
 Peripheral Arterial Disease:
Surgical Treatment of Critical Limb ischemia
1. Patients who have significant necrosis of the weight –
bearing portions (in ambulatory patients), an
I IIa IIb III
uncorrectable flexion contracture, paresis of the
extremity, refractory ischemic rest pain, sepsis, or a
limited life time expectancy due to comorbid
conditions should be evaluated for primary amputation
of the leg

I IIa IIb III

1. Surgical and endovascular intervention is not
indicated in patients with severe decrements in
limb perfusion in the absence of clinical
symptoms of CLI

ACC/AHA Guidelines 90
Peripheral Arterial Disease

Etiology
Epidemiology
Physical examination
Clinical Manifestations
Diagnosis
Indications
Treatment Options
 Prognosis

91
 Endovascular Treatment:
Interpreting Outcomes
• Changing technology: PTA vs stent
• Evolving medical therapy
• Case series
• Heterogenous lesions: stenosis vs occlusion
• Heterogenous population: symptom status
• Outcome measures:
• Hemodynamic vs clinical patency
• CFA flow pattern • absence of sxs
• ABI • improvement of sxs
• Thigh/brachial index

92
 Peripheral Arterial Disease: Prognosis

• The prognosis of patients with PAD is determined

by an increased risk for cardiovascular ischemic
event due to concomitant coronary artery disease
and cerebrovascular artery disease
• The prognosis of the limb is determined by:
– The extend of the arterial disease
– The acuity of limb ischemia
– The feasibility and rapidity of restoring arterial
circulation to the foot

Hirsh et al Circulation 2006; 113(11): e463-654

ACC/AHA Guidelines 93
Peripheral Arterial Disease: Prognosis

Patients with chronic Patients with acute

arterial occlusive disease occlusive events
and continued
progression of the
symptoms to CLI

Prognosis is related to
the rapidity and
completeness of
revascularization before
Prognosis is very poor the onset of irreversible
unless revascularization ischemic tissue or nerve
can be established damage

94
 PAD and Relative Risk of Death
6.6
7 5.9 2.9 –14.9
3.0 – 11.4
Relative Risk (95% Cl)

4 3.1
1.9 – 4.9
3

0
All Causes Cardiovascular Coronary Heart
Disease Disease

Cause of Death

Adapted from Criqui et al N Engl J Med 1992; 326: 381-386 96

 Relative 5-Year Mortality Rates

100
86

80
Patients (%)

60
39
40 32
23
18
20 8

0
Prostate Hodgkin's Breast PAD Colorectal Lung Cancer*
Cancer* Disease Cancer* Cancer*

* American Cancer Society. Cancer Facts and Figures, 2000.

† Criqui MH, et al. N Engl J Med. 1992;326:381-386. 97
Peripheral Arterial Disease: Survival Curve

Criqui et al N Engl J Med 1992; 326: 381-386 99

 5 Year Risk of Developing Ischemic
Ulceration
Follow up of 1244 Claudicants over 15 years
50
Risk of Ischemic

40 DM Present DM Absent
Ulceration (%)

30

20

10

0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
ABI

Aquino, R. J Vasc Surg 2001; 34(6): 962

100
 ABI: Predictor of Survival

100

90

80 ABI >0.85
Survival (%)

70

60 ABI 0.4-0.85

50

40 ABI <0.4

30

20
0 2 4 6 8 10
Year

McKenna et al Atherosclerosis 1991;87:119-128. 101

Relative Risk of CV Mortality by ABI and
CVD Status
Cardiovascular Health Study
15 Relative 6-Year CV Mortality
Relative Risk (95% CI)

N=5714

10

0
ABI >0.9 ABI <0.9 ABI >0.9 ABI <0.9
No CVD† CVD Present†
†P<0.01 within groupings, Cox proportional hazards model.
CV Death includes death from CHD, MI, sudden death, or stroke.

Adapted from Newman et al. Arterioscler Thromb Vasc. Biol.

1999;19:538-545 102
Age-Adjusted Mortality rates and number of deaths in men
with possible, probable and No Intermittent claudication

Rates are for 1,000 person-years

All causes mortality include 13 deaths in the gropus without intermitent claudication in which
the specific cause of death was unknow
Percent, percentage of deaths attributed to each cause or group of causes
Tests for differences between possible or probable intermittent claudication and non
intermittent claudication groups: *p < 0.001; †p <0.05; ‡p <0.01

Smith et al Circulation 1990;82(6): 1925 - 1931 103