peripheral_arterial_disease

8/14/2019 peripheral_arterial_disease

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Epidemiology


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Definition of Peripheral Arterial Disease (PAD)

The presence of a stenosis or

occlusion in the aorta or

arteries of the limbs

Usually caused byatherosclerosis

Associated with an increasedrisk of cardiovascular andcerebrovascular events,including death, MI, andstroke


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Clinical Manifestations of Atherosclerotic

Disease

Renovascular disease

Coronary artery disease

Carotid artery disease

Peripheral arterial disease

Transient ischemic attackStroke

Stable angina pectorisAcute coronary syndromes

Intermittent claudicationCritical limb ischemia

Hypertension

Renal insufficiency


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0% 5% 10% 15% 20% 25% 30% 35%

29%PARTNERS5

Age >70, or between 50-69 with diabetes or smoking

11.7%San Diego2

Mean Age=66

19.8%Diehm4

Age 65

19.1%Rotterdam3Age >55

14.5%NHANES1

Age 70

4.3%

Documented Presence of PAD

When common risk

factors were included,

the prevalence of PAD

was ~1/3 of patients

1. Selvin E, Erlinger TP. NHANES. Circulation.2004;110:738-743.

2. Criqui MH, et al. Circulation.1985;71:510-515.

3. Diehm C, et al.Atherosclerosis. 2004;172:95105.4. Meijer WT, et al.Arterioscler Thromb Vasc Biol. 1998;18:185-192.

5. Hirsch AT, et al. JAMA.2001;286:1317-1324.

NHANES1

Age >40


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Prevalence of PAD Increases With Age

Adapted from Golomb BA, et al. In: Creager MA, ed. Management of Peripheral Arterial Disease: Medical,

Surgical and Interventional Aspects; 2000:1-18.

Meijer WT, et al.Arterioscler Thromb Vasc Biol. 1998;18:185-192.

Criqui MH, et al. Circulation. 1985;71:510-515.

0

10

20

30

40

50

60

PatientsWithPAD(%)

55-59 60-64 65-69 70-74 75-79 80-84 85-89

Age Group (years)

Rotterdam Study (ABI


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The Aging Population

0

5

10

15

20

25

10 20 30 40 50 60 70 80 90

Age (years)

Population(millions)

1980199020002010

17% of the population 55-70 years of age has PAD

Fowkes FG, et al. Int J Epidemiol.1991;20:384-392.

PAD = peripheral arterial disease

N=1592


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Risk Factors


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Independent Risk Factors for PAD*

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

* PAD diagnosis based on ABI


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Diabetes Increases Risk of PAD

IGT = oral glucose tolerance test value 140 mg/dL but


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The Metabolic Syndrome

People with the metabolic syndrome are at increased riskof coronary heart disease, stroke, diabetes, and PAD

Characterized by a group of metabolic risk factors:

Abdominal obesity (waist circumference) >40 inches men and >35 inches in women

Serum triglycerides 150 mg/dL

Serum high-density lipoprotein cholesterol (HDL-C)


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PAD Risk Factors are Synergistic

Systolic Blood Pressure 105 150 195Total cholesterol 185 260 335Impaired glucose

Adapted from TASC Working Group. J Vasc Surg.2000;31:S13.

RiskofIntermittentClaudication

(8-yearrate

per1000)

N=2950.8

2.5

14.6

2.6

8.0

36.6

0

10

20

30

40Nonsmoker

Smoker


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Screening Techniques and

Diagnostic Criteria


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Clinical Manifestations of PAD

Asymptomatic

Intermittent claudication

Discomfort, ache, cramping in leg withexerciseresolves with rest

Functional impairment Slow walking speed, gait disorder

Rest pain

Pain or paresthesias in foot or toes, worsened by leg

elevation and improved by dependency Ischemic ulceration and gangrene


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Clinical Presentation of PAD

Initial PAD Presentation

Symptomatic PAD

Atypical Leg Pain

40-50%

IntermittentClaudication

10-35%

Critical LimbIschemia

1-2%

Asymptomatic PAD20-50%

Hirsch AT, Haskal ZJ, Hertzer NR, et al. Available at http://www.acc.org/clinical/guidelines/pad/summary.pdf.

Accessed December 13, 2005.


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Symptoms of Intermittent Claudication

Aching, pain, tiredness, tightness, cramping in the

buttocks, thigh, calf, or foot brought on by exercise

and relieved by rest

Reproducible with a consistent level ofexercise from day to day

Completely resolve within 5 minutes after

exercise stops Occur again at the same distance once

walking resumes


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Causes of Pseudoclaudication

Spinal canal stenosis

Peripheral neuropathy

Peripheral nerve pain

Herniated disc impinging on sciatic nerve

Osteoarthritis of the hip or knee

Venous claudication

Chronic compartment syndrome Muscle spasms/cramps/restless leg syndrome

Cold feet


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Does the Patient Have Intermittent

Claudication?

Claudication Pseudoclaudication

Characteristic of

discomfort

Cramping, tightness,

aching, fatigue

Same, tingling,

burning, numbness

Location of

discomfort

Buttock, hip, thigh,

calf, foot Same

Exercise-induced Yes Variable

Distance Consistent Variable

Occurs with standing No Yes

Action for relief Stand Sit, change position

Time to reliefLess than 5 minutes Up to 30 minutes


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Clinical History

Past medical history Does the patient have a history of atherosclerosis

elsewhere?

Does the patient have significant comorbidities?

Does the patient have risk factors for atherosclerosis? Family history

Does the patient have a family history ofatherosclerosis or abdominal aortic aneurysm?

Review of symptoms

Does the patient have symptoms in other vascularbeds?


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Comprehensive Vascular Examination

Pulse Examination

Carotid

Radial/ulnar

Femoral

Popliteal Dorsalis pedis

Posterior tibial

Scale

0 = absent

1 = diminished

2 = normal

Physical Examination Bilateral arm blood

pressure

Cardiac exam

Palpation of abdomenfor potential aneurysmal

disease

Auscultation for bruits

Examination of legs and

feet


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Screening Techniques

Role of Ankle-Brachial Index


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Indications for an ABI

History of classic or suspected claudication History of CLI (rest pain, gangrene, nonhealing wound)

Any diabetic patient >50 years old

Any diabetic patient 70 years old

All patients >50 years old who smoke or have diabetes

Tradition

al

AHA-A

CC

ADA

Hirsch AT, et al. JAMA. 2001;286:1317-1324.

American Diabetes Association. Diabetes Care. 2003;26:3333-3341.

ADA = American Diabetes Association; AHA = American Heart Association; ACC = American College of Cardiology


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ABI Testing:

Highly Sensitive and Specific

Effectiveness of ABI vs Other Common Screening Tests

Dormandy JA, et al. Semin Vasc Surg. 1999;12:96-108.

Nanda K, et al.Ann Intern Med. 2000;132:810-819.

Allison JE, et al. N Engl J Med. 1996;334:155-159.

Ferrini R, et al.Am J Prev Med. 1996;12:340-341.

Diagnostic Test Sensitivity (%) Specificity (%)

ABI

95 99

Pap smear 30-87 86-100

Fecal occult-blood test 37-69 87-98

Mammography 75-90 90-95


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ABI =

The Ankle-Brachial Index (ABI)

Ankle systolic pressureBrachial systolic pressure


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Using the ABI

PT = posterior tibial; DP = dorsalis pedis; SBP = systolic blood pressure.

Right ABI80/160 = 0.50

Brachial SBP160 mmHg

PT SBP 120 mmHg

DP SBP 80 mmHg

Brachial SBP150 mmHg

PT SBP 40 mmHg

DP SBP 80 mmHg

Left ABI120/160 = 0.75

HighestBrachial SBP

Highest of PTor DP SBP

ABI(normal >0.90)


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Automated Blood Pressure Determination

Accurately Measures ABI

1.41.21.00.80.60.4

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

D

opplerLeftABI

Oscillometric Left ABI

201 consecutive subjects underwent standard Doppler and oscillometricmeasurement of the ABI

Sensitivity 88%

Specificity 85%Positive PV 65%

Negative PV 96%

Beckman JA, et al.Hypertension. 2006;47:35-38.

r2= 0.62


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ABI Limitations

Incompressible arteries (elderly patients, patients withdiabetes, renal failure, etc)

Resting ABI may be insensitive for detecting mildaortoiliac occlusive disease

Not designed to define degree of functional limitation

Normal resting values in symptomatic patients maybecome abnormal after exercise

Does not distinguish between stenosis and occlusion


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Diagnostic Tests


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Diagnostic Tests

Segmental blood pressure recording

Segmental pulse volume recording

Exercise stress testing

Continuous wave Doppler and duplex

ultrasonography

Magnetic resonance angiography (MRA) Computed tomographic angiography (CTA)

Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Guidelines for the Management of Patients With

Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic).


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Segmental Limb Pressure

150

110

108

62

0.54

150

146

100

84

0.44ABI

150 150Brachial


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Pulse Volume Recordings


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Color Duplex Ultrasonography


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Color Duplex Ultrasonography


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Magnetic Resonance Angiography (MRA)

MRA has virtually replaced contrastarteriography for PAD diagnosis

Excellent arterial picture

No ionizing radiation

Noniodine-based intravenous contrastmedium rarely causes renalinsufficiency or allergic reaction

~10% of patients cannot have MRAbecause of

Claustrophobia

Pacemaker/implantable cardioverter-defibrillator

Obesity


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Computed Tomographic Angiography (CTA)

Requires iodinated contrast

Requires ionizing radiation

Produces an excellentarterial picture


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Differential Diagnosis


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PAD: A Full Differential Diagnosis

Atherosclerosis

Vasculitis

Fibromuscular dysplasia

Atheroembolic disease

Thrombotic disorders

Trauma

Radiation

Popliteal aneurysm Thromboangiitis

obliterans (Buergers

disease)

Popliteal entrapment

Cystic adventitial disease

Coarctation of aorta

Vascular tumor

Iliac syndrome of the

cyclist

Pseudoxanthoma

elasticum

Persistent sciatic artery

(thrombosed)


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PAD: A Full Differential Diagnosis

Popliteal EntrapmentSyndrome

Popliteal Adventitial Cyst

Popliteal Aneurysm

Thromboangiitis Obliterans(Buergers disease)

Arteritis

Fibromuscular Dysplasia

Atherosclerosis85%

5%

10%


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Pathophysiology of

Atherothrombosis


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The Normal Artery


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Pathophysiology of Atherothrombosis

Adapted from Libby P. Nature. 2002;420:868-874


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Platelet Cascade in Thrombus Formation

Handin RI. Harrisons Principles of Internal Medicine.

vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339-345.

Schafer AI.Am J Med. 1996;101:199-209.

GP Ib = glycoprotein Ib; ADP = adenosinediphosphate; 5 HT = serotonin; TXA2=thromboxane A2; GP IIb/IIIa = glycoprotein IIb/IIIa.

Adhesion1

Lipid corePlatelets

Collagen

GP la/lla bind

von Willebrand

Factor/GP lb bind


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Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339-345.



Activation2

Thrombin

ADP5 HTTXA2


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Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339-345.



Aggregation3

Fibrinogen

ActivatedGP llb/llla

Ath th b i P th h i l


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Atherothrombosis Pathophysiology:Endothelial Dysfunction

Viles-Gonzalez JF, et al. Eur Heart J. 2004;25:1197-1207.

NO = nitric oxide; PGI2= prostacyclin; SMC = smooth muscle cell;TxA2= thromboxane A2; ET-1 =endothelin 1; TF = tissue factor; MMPs = matrix metalloproteinases; solid line = induces; broken line =inhibits.


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Ath th b i P th h i l


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Atherothrombosis Pathophysiology:Endothelial Dysfunction

Viles-Gonzalez JF, et al. Eur Heart J. 2004;25:1197-1207.

FDP = fibrin degradation product; PAI-1 = plasminogen activator inhibitor-1; tPA = tissue plasminogen activator;NO = nitric oxide; PGI2= prostacyclin; SMC = smooth muscle cell;TxA2= thromboxane A2; ET-1 = endothelin 1;TF = tissue factor; VIIa = factor VIIa; Xa = factor Xa; MMPs = matrix metalloproteinases; solid line = induces;broken line = inhibits; downward-pointing open arrow = decreases; upward-pointing open arrow = increases.


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Atherosclerosis: Intravascular Ultrasound of

a Ruptured Plaque

From Ziada K and Bhatt DL. In Bhatt DL: Essential Concepts in Cardiovascular Intervention, ReMEDICA 2004.


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Physiology of Acute Thrombosis

A. Injury


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B. Initiation


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C. Extension (recruitment)


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D. Perpetuation (stabilization)


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The Activated Platelet

Platelet Activators Blood

Thrombin Thromboxane A2 Adenosine diphosphate

Vessel wall Collagen von Willebrand factor

Platelet Inhibitors Nitric oxide Prostacyclin

Ruggeri ZM. Nature Medicine. 2002;8:1227-1234.

A t i l St i C L f P


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Arterial Stenosis Causes Loss of Pressure

and Flow

An 80% stenosis causes a

pressure drop at rest

Turbulent flow downstreamof stenosis cases a loss ofkinetic energy

Normal Laminar Flow

Turbulent Flow Behind Stenosis


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0

5

10

15

20

25

30

35

Rest Low Medium High

Control

PAD

Supply-Demand in PAD

Flow(mL/1

00mL/min)

Bauer T, Hiatt WR, In Press.

Exertion Level


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Natural History of PAD


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The Natural History of PAD

Increased risk for cardiovascular ischemic eventsdue to concomitant coronary artery disease andcerebrovascular disease

Cardiovascular events are more frequent thanischemic limb events in any lower extremity PADcohort, regardless of presentation




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Overlap Between PAD, CAD, and CVD

Bhatt DL, et al. REACH Investigation. Presented at: American College of Cardiology Annual Scientific

Session; March 8, 2005; Orlando, FL.Abstract 1127-96.

Patients with one manifestationoften have coexistent disease in other vascular beds.

PAD

36.9%

9.5%

39.4%

14.2%

CVD

CAD


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Natural History of PAD: 5-year Outcomes

StableClaudication

70-80%

WorseningClaudication

10-20%

Critical LimbIschemia

1-2 %

Non-CV Causes25%

CV Causes75%

Mortality15-30%

Nonfatal CV Events15-30%

Limb MorbidityLimb MorbidityCardiovascular Morbidity

and Mortality


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PAD and Relative Risk of Death

Criqui MH, et al. N Engl J Med.1992;326:381-386.

RelativeRisk

(95%CI)

Cause of Death

All Causes Cardiovascular

Disease

Coronary Heart

Disease

3.1

(1.9- 4.9)

5.9

(3.0-6.6)

6.6

(2.9- 14.9)

0

2

4

6

8

10

3.1

(1.9-4.9)

5.9

(3.0-6.6)

6.6

(2.9-14.9)

0

2

4

6

8

10


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PAD Survival Curve

Criqui MH, et al. N Engl J Med.1992;326:381386.

Normal Subjects

Asymptomatic PAD

Symptomatic PAD

Severe Symptomatic PAD

100

75

50

25

0 2 4 6 8 10 12

Survival(%)

Year


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Cause of Death in IC Patients

Dormandy JA, et al. J Vasc Surg. 2000;31:S1-S296.

Cerebral11%

Cardiac55%

Nonvascular25%

Other

vascular9%

CHD Risk Increases With Decreases in


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CHD Risk Increases With Decreases in

Ankle Brachial Index (ABI)

Five-YearIncidenceof

CVDeaths,%*

*Including aneurysm, thromboembolism, stroke, and myocardial infarction.

Leng GC, et al. BMJ.1996;313:1440-1444.

0

10

20

30

>1.1 1.1-1.01 1.0-0.91 0.9-0.71


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Association Between ABI and All-Cause

Mortality

Baseline ABI

010203040506070

Mortality(%)

Adapted from Resnick HE. Circulation. 2004;109:733-739.

N=4393


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0

20

40

60

80

>3.0 1.0-3.0 0.90

0.7-0.9


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Disease in Patients with Symptomatic

PAD (OHSU Study)

Nicoloff AD, et al. J Vasc Surg. 2002; 35:38-47.

0 6 12 18 24 30 36 42 48 54 60

0%

25%

50%

75%

100%ABI progression

Carotid stenosis progression

ABI or carotid progression

Subjects(%)

Months

OHSU = Oregon Health and Science University

N=397


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Critical Limb Ischemia (CLI)

Peripheral Arterial Disease Complication:


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Peripheral Arterial Disease Complication:

Ischemic Ulcer

Amputation


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Amputation

C iti l Li b I h i (CLI)


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Critical Limb Ischemia (CLI)

Fate of Patients With CLI After Initial Treatment


Summary of 19 studies

on 6-month outcomesDead20%

Alive Without

Amputation45%

Alive WithAmputation

35%

Early and 2-year Fate of the Below-


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Early and 2 year Fate of the Below

Knee Amputee


Early After 2 Years

2 Healing15%

Above-kneeAmputation

15%

1 Healing60%

Contra-lateral

Amputation15%

Above-knee

Amputation15%

Death30%FullMobility

40%

Peri-operative

Death10%


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Treatment of Peripheral

Arterial Disease


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Two Goals in Treating Patients With PAD

Improve ability to walk Important increase in

peak walking distance

Improvement in quality

of life indicators

Prevent progression tocritical limb ischemia and

amputation

Decrease mortality from MI,stroke, and cardiovascular

death

Decrease nonfatal MI

and stroke

Limb Outcomes

Outcomes in

Cardiovascular

Morbidity and Mortality


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Peripheral Arterial Disease

Management of Cardiovascular

Risks


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Antiplatelet Therapy

Antiplatelet therapy reduces the risk of MI, stroke, and vasculardeath in patients with established PAD

Aspirin is a well-recognized antiplatelet drug that has been shown tobenefit patients with CVD and PAD

Clopidogrel is the only antiplatelet agent approved by the FDA toreduce the risk of MI, stroke, or vascular death in patients withestablished PAD

Other antiplatelet drugs used to treat PAD include

Dipyridamole

Ticlopidine

Picotamide

Suloctidil

Indobufen

Sulphinpyrazone

Mechanisms of Action of Oral


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COX = cyclooxygenase; PDE = phosphdiesterase.Schafer AI. Am J Med.1996;101:199-209.

Antiplatelet Therapies

Risk of Occlusive Vascular Events in High-Risk


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g

Patients: Antithrombotic Trialists Collaboration

Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86.

APT=antiplatelet therapy with aspirin, clopidogrel,

dipyridamide, or a glycoprotein IIb/IIIa antagonist

N=9706

Intermittent

claudication (N=26)

Reduced Increased

Risk versus Control

1.0 1.5 2.00.50.0

6.4 7.9

Peripheral

grafting (N=12)5.4 6.5

Peripheral

angioplasty (N=4)2.5 3.6

All PAD trials (N=42) 5.8 7.1

Risk Category(number of trials) APT Control

Patients with Event (%)

Intermittent

claudication (N=26)

Reduced IncreasedReduced Increased

6.4 7.9

Peripheral

grafting (N=12)5.4 6.5

Peripheral

angioplasty (N=4)2.5 3.6

All PAD trials (N=42) 5.8 7.1

Risk Category(number of trials)

Efficacy of Clopidogrel vs Aspirin in MI,


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Ischemic Stroke, or Vascular Death

Months of Follow-Up

Cumulative

EventRate(%)

0

4

8

12

16

Clopidogrel

Aspirin

OverallRelative Risk

Reduction

8.7%*

0 3 6 9 12 15 18 21 24 27 30 33 36

Aspirin

5.83%

5.32%Clopidogrel

*ITT analysis.CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

Mean Follow-up = 1.91 years

N=19,185

Risk Reduction of Clopidogrel vs Aspirin in


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Risk Reduction of Clopidogrel vs Aspirin in

Patients With Atherosclerotic Vascular Disease

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

N=19,185

Stroke

-10 0 10-20-30

Myocardial Infarction

PAD

All Patients

Aspirin Favored

-40 20 30

Clopidogrel Favored


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Peripheral Arterial Disease

Risk Factor Modification

Lifestyle Interventions for PAD


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Lifestyle Interventions for PAD

Cognitive-behavioral therapy

Identify smokingas major risk

factor

Smoking

Weight lossExercise

Actively monitordiabetes

Type 2 diabetes

DASH diet

Exercise

Measure blood

pressureHypertension

Weight loss to

reach ideal bodyweight

Measure weight,

body-mass indexObesity

TherapyActionTarget

DASH = Dietary Approaches to Stop Hypertension

Intensive BP Therapy in Patients With


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Diabetes: Benefits in the PAD Group

Moderate treatment (137/81), n=227Mean BP 137 mmHg

OddsofM

I,Stroke,

orVascularDeath

Baseline ABI

Intensive treatment* (128/75), n=220

Mean BP 128 mmHg

ABCD = Appropriate Blood Pressure Control in Diabetes StudyReprinted with permission from Mehler PS, et al. Circulation. 2003;107:753-756.

50

0

10

20

30

40

1.31.21.10.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

*enalapril or nisoldipine

PAD was defined as an ABI


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Vascular Event by Prior Disease

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

MI - myocardial infarction; CHD - coronary heart disease;CVD - cerebrovascular disease; PAD - peripheral arterialdisease; CI - confidence interval; SE - standard error

Previous MI 23.5 29.4

Other CHD 18.9 24.2

No prior CHD or CVD 18.7 23.6

Peripheral arterial disease 24.7 30.5

Diabetes 13.8 18.6All patients 19.8 25.2

1.0 1.2 1.40.80.60.4

24% Reduction

(p


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Updated LDL-C Goals, Treatment Cutpoints

Grundy SM, et al. Circulation. 2004;110:227-239.

Risk Category

Low-density

LDL-C Goal

Initiate

Therapeutic

Lifestyle Change

Consider

Drug Therapy

High risk:

CHD or CHD risk

equivalents*

(10-year risk >20%)


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PAD Lipid Recommendations

Reduce CV mortality risk Statin to achieve NCEP guidelines of LDL-C


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Guidelines for CVD Prevention: Lifestyle

Modification

Lifestyle Changes

30 minutes moderate-intensity physical activity

daily

Smoking cessation Weight maintenance/reduction

Heart-healthy low cholesterol diet

Expert Panel/Writing Group. Circulation. 2004;109:672-693.

American Heart Association Evidence-Based


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Guidelines for CVD Prevention: Treatment Targets

Blood Pressure

Baseline BP


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NCEP Expert Panel.ATP III Guidelines. 2001. NIH publication 01-3670.

NCEP ATP-III LDL-C Goals

LDL-C goal 20% risk for

development of CHD

HOPE: Primary Endpoints


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HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

HOPE: Primary Endpoints

~42% of Placebo and Ramipril-Treated Patients had PAD

500 1000 1500

0.00

0.05

0.10

0.15

0.20

0

Days of Follow-up

Pro

portionReachingEnd-Point

Placebo

Ramipril

P


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History of CAD 7477

No history of CAD 1820

Prior MI 4892

No prior MI 4405

Cerebrovascular disease 1013

No cerebrovascular disease 8284

Peripheral vascular disease 4051

No peripheral vascular disease 5246

Microalbuminuria 1956

No microalbuminuria 7341

No. of

Patients Reduced Increased

Relative Risk in Ramipril Group

0.6 0.8 1.0 1.2

HOPE: Benefits in CV Risk Subgroups

HOPE: PAD Outcomes


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

HOPE: PAD Outcomes

Peripheral arterial

disease (n=4046)

Reduced Increased

Relative Risk in Ramipril Group

0.5

No peripheral arterial

disease (n=5251)0.3

Incidence of

Composite Outcome

in Control Group (%)

1.0 1.20.80.6

Efficacy of ACE-I, Statins, and Antiplatelet


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y

Therapy in PAD

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.

Heart Protection Study Collaborative Group. Lancet.2002;360:7-22.

placebo 6.0%

CAPRIE*clopidogrel

4.9%

3.7%

0 1 2 3 4 5 6 7

HOPE* ramipril

4.4%

3.4%

placebo

HPS*placebo

simvastatin6.1%

4.9%

aspirin

Event Rate (% per year)

APTC*

No. of Patients

in Subgroup

(>9000)

(>6000)

(4051)

(2701)P< 0.001

P< 0.001

*PAD subgroups only.

PAD Risk Reduction Therapies


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PAD Risk-Reduction Therapies

Life Style Modifications 30 minutes moderate-intensity physical activity daily

Weight maintenance/reduction

Low cholesterol diet

Smoking

Complete cessation Diabetes mellitus

HbA1c


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Medical Therapy of Claudication

Nonpharmacologic Options

Intermittent Claudication:


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Exercise Therapy

Frequency: 3-5 supervised sessions/week Duration: 35 to 50 minutes of exercise/session

Type of exercise: treadmill or track walking to

near-maximal claudication pain Length: 6 months or more

Results: 100%-150% improvement in maximal

walking distance

Improvement in quality of life

Stewart KJ, et al. N Eng J Med. 2002;347:1941-1951.

Efficacy of Exercise Training as a


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Therapeutic Intervention for Claudication

0

50

100

150

200

250

300

%Improv

ement

Pain-Free Peak

Treadmill Walking Time

Controlled trialsUncontrolled trials

96 %

134 %

Gardner AW, Poehlman ET. JAMA. 1995;274:975-980.

Effects of Exercise Training on Claudication


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Gardner AW, Poehlman ET. JAMA. 1995;274:975-980.

Exercise Training

Control

200

0

20

40

60

80

100

120

140

160

180

Onset ofClaudication Pain

MaximalClaudication Pain

ChangeinTreadmill

WalkingDis

tance(%)

Meta-analysis of 21 Studies


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Medical Therapy of

ClaudicationPharmacologic Options

Cilostazol vs. Pentoxifylline: Increased


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Walking Distance in Claudication

Cilostazol 100 mg 2x/day (n=227)Pentoxifylline 400 mg 3x/day (n=232)

Placebo (n=239)

P


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Distance in Patients with IC

Girolami B, et al.Arch Intern Med.1999;159:337-345.

Di Perri and Guerrini, 1983 24 24

Donaldson et al, 1984 40 40

Gillings et al, 1987 67 61

StudyTreatment Control

(n) (n)

Lindgarde et al, 1989 76 74

Rudofsky et al, 1992 75 79

0 100 200-100-200-300

Ernst et al, 1992 20 20

Meta-analysis 302 298

300Pain-Free Walking Distance (m)

Effect of Cilostazol on Walking Distance

i P ti t With Cl di ti


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in Patients With Claudication

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

Meta-analysis of 4 randomized, placebo-controlled trials

Pentoxifylline, 1200 mg/day698

Cilostazol, 200 mg/day

Cilostazol, 200 mg/day516

Compound, dose N

Cilostazol, 100 mg/day

Cilostazol, 200 mg/day 239

1.0 1.4 1.60.80.6

Cilostazol, 200 mg/day 81

1.8

Placebo

1.2Relative Increase in Maximum Walking Distance (ratio of

change in exercise performance versus placebo)

Treatment Favored

Contraindications to Cilostazol Use


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CHF of any severity

Any known or suspected hypersensitivityto any of its components

Cilostazol and several of its metabolites are inhibitors of

phosphodiesterase III. Several drugs with this

pharmacologic effect have caused decreased survival

compared to placebo in patients with class III-IV congestive

heart failure. PLETAL is contraindicated in patients with

congestive heart failure of any severity.

PLETALPackage Insert, 1999.


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Revascularization

Surgical and Endovascular Options

Indications for Intervention


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Indications for Intervention

Persistent, lifestyle limiting claudication despitemaximal medical therapy

Rest pain

Nonhealing ulcer Gangrene

Options in Revascularization


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Options in Revascularization

Endovascular Reconstruction Options Percutaneous transluminal angioplasty (PTA)

Stents

Surgical Reconstruction OptionsAortoiliac/aortofemoral reconstruction

Femoropopliteal bypass (above-knee and

below-knee)

Femorotibial bypass

Aortoiliac Occlusive Disease


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Aortoiliac Occlusive DiseaseAngioplasty + Stenting


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Angioplasty + Stenting

High procedural success rates (90%)

Excellent long-term patency (up to 70%

at 5 years)

No clear benefit of primary stenting vs

angioplasty and selective stent

placement

Factors associated with a poor outcome

Long segment occlusion

Multifocal stenoses Eccentric calcification

Poor runoff

Aortoiliac Occlusive Disease (contd)Aortobiiliac/Aortobifemoral Bypass


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Aortobiiliac/Aortobifemoral Bypass

Excellent long-term patencyrate

85%-90% at 5 years

Requires generalanesthesia

Can be done via laparotomy

or retroperitoneal exposure

Aortoiliac Occlusive Disease (contd)Axillobifemoral bypass


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Axillobifemoral bypass

Patency rate lower than that ofaortobifemoral bypass

30%-70% at 5 years

Avoids laparotomy

Useful in patients who have History of aortoiliac surgery

Severe aortic calcification

Hostile abdomen

Can be done in the debilitatedpatient after induction of localanesthesia

Femoropopliteal Occlusive Disease


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Femoropopliteal DiseaseEndovascular Options


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Endovascular Options

Excellent procedural success Low complication rates (3%-6%)

Reported patency varies widely

30%-80% at one year

Nitinol stents may have betterpatency than stainless steel

No clear benefit of primary stenting vs

angioplasty alone

Femoropopliteal DiseaseEndovascular Options


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Endovascular Options

Limited by recurrent stenosis Numerous adjuncts to minimize

effect of restenosis

Drug-eluting stents

Atherectomy catheter Cryoplasty balloon

Laser atherectomy

Brachytherapy

Infrainguinal Bypass for Limb Salvage:

Ideal Res lts


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Ideal Results

Uncomplicated operation Prompt wound healing

Rapid return to premorbid functional status

Long-term symptom relief Cure of ischemia

No recurrence of ischemic ulcer

No need for repeated surgery

Femoropopliteal Occlusive Disease:

Surgical Bypass


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Surgical Bypass

Bypass of choice for superiorfemoral artery or above-kneepopliteal occlusion

Choice of conduitvein vs

poly-tetrafluoroethylene Have similar above-knee

patency rate

Vein has better below-knee

patency rate Limb salvage rates are 70% at5 yrs

Tibial Occlusive Disease


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Tibial Occlusive DiseaseAngioplasty + Stenting


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Angioplasty + Stenting

Small case series

Feasible, safe

Little long-term data

Provides anothertherapeutic alternative in

this complex patient

population

Dorsalis Pedis (DP) Bypass


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1032 DP bypasses in 865patients between January 1990

and January 2000

DP bypasses were 28% of all

infrainguinal procedures done

5-year patency:

Primary = 57%

Secondary = 63% Limb salvage at 5 years = 78%

Pomposelli FB, et al. J Vasc Surg 2003;37:307-315.

Durability of Endovascular Procedures


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Primary Patency (%, 95% CI)

Mean

1-year data

2-year data

3-year data

4-year data

5-year data

Femoropopliteal Stent

0 20 40 60 80 100

Infrapopliteal PTA

Femoropopliteal PTA

Iliac PTA

Iliac Stent



Durability of Surgical Interventions for

Inflow Improvement


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Inflow Improvement

Inflow ProcedureOperative

Mortality

(%)Expected Patency

Rate at Follow-up

(%) Follow-upAortobifemoral bypass 3.3 87.5 5 yearsAortoiliac or aortofemoral

bypass 1-2 85-90 5 yearsIliac endarterectomy 0 79-90 5 yearsFemorofemoral bypass 6 71 5 yearsAxillofemoral bypass 6 49-80 3 yearsAxillofemoral-femoral bypass 4.9 63-67.7 5 years



Durability of Surgical Interventions for

Outflow Improvement


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Outflow Improvement

Outflow Procedure

Operative

Mortality (%)

Expected Patency Rate

At Follow-up (%) Follow-up

Femoral-popliteal

Vein, above the knee 1.3-6.3 66 5years

Prosthetic, above then knee 1.3-6.3 47 5years

Vein, below the knee 1.3-6.3 66 5yearsProsthetic, below the knee 1.3-6.3 33 5years

Femoral-tibial

Vein 1.3-6.3 74-80 5years

Prosthetic 1.3-6.3 25 3 years

Blind segment bypass 2.7-3.2 64-67 2 years

Composite sequential bypass 0-4 28-40 5 years

Profundaplasty 0-3 49-50 3 years



Limb Salvage and Overall Survival


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Feinglass J, et al. J Vasc Surg.2001;34:283-290.

Major amputation afterfemoropopliteal bypass

20 40 60 80 100

Follow-up in Months

Major amputation aftertibial bypass

Survival0.4

0.5

0.6

0.7

0.8

0.9

1.0

Kaplan-Meier

(Probability)

N=4288

VA National Surgical Quality Improvement Program

Outcomes in Patients Following Limb

Salvage Procedure


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Salvage Procedure

Conte MS, et al. Presented at: Society for Vascular Surgery; June 16, 2005; Chicago, IL.

Mortality Primary

Patency

Limb

Salvage

Patients(%)

0

20

40

60

80

100

PREVENT III Trial: QoL


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2.81.1

4.71.4*5.11.4*

*P


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Morbidity

6565 vascular operations in 5126 patientsbetween January 1990 and May 2000

4052 lower extremity revascularization

1679 carotid

834 aortic Outcomes

Mortality: 1.14%

MI: 1.59%

CHF: 1.13%

Hamdan AD, et al.Arch Surg. 2002;137:417-421.

CARP Trial: Effect of Prior Coronary

Revascularization on Mortality after Vascular


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Surgery

McFalls EO, et al. N Engl J Med. 2004;351:2795-2804.

N=510

0

20

40

60

80

100

2.7-YearMo

rtality(%)

No

Revascularization

After

Revascularization

22% 23%

Management of Leg Symptoms in Patients

With PAD


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With PAD

Claudication: Assess severity

Treadmill ACD/ICD

Questionnaires SF-36/WIQ

PAD

Critical LegIschemia

Symptoms improve Symptoms deteriorate

ContinueLocalize the lesion:

Hemodynamic localizationDuplex ultrasound imaging

Magnetic resonance angiography

Conventional angiography

Revascularization:Angioplasty

Bypass surgery

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

Claudication therapy:

Supervised exerciseCilostazol


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Future Therapies

Medical Therapies Under Investigation

for PAD


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for PAD

Cilostazol analogs Nitric acidderivative of aspirin

Immune modulation therapy

Liposome-encapsulated form of prostaglandin E-1

Angiogenic growth factors Hypoxia inducible factor1

Hepatocyte growth factor

Vascular endothelial growth factor-2

Endothelial progenitor cells

Investigational Devices for PAD


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Cryo-balloon Enhanced external counterpulsation (EECP)

Paclitaxel-eluting stent

SilverHawk plaque excision system


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2005 ACC/AHA Guidelines for

the Management of Peripheral

Arterial DiseaseIntroduction to the Guidelines

Why a PAD Guideline?


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Aid in the recognition, diagnosis, and treatmentof PAD of the aorta and lower extremities

Address the prevalence, impact on quality of life,

cardiovascular ischemic risk, and risk of critical

limb ischemia



Classification of Recommendations


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Class I: Evidence and/or general agreementthatprocedure or treatment is beneficial, useful, and effective

Class II: Conflicting evidenceand/or divergence of opinion

about usefulness or efficacy of a procedure or treatment

Class IIa: Weight ofevidence or opinion favors usefulnessor efficacy

Class IIb: Usefulness or efficacy is less well establishedby

evidence or opinion

Class III: Evidence and/or general agreementthatprocedure is not useful or effectiveand in some cases may

be harmfulHirsch AT, Haskal ZJ, Hertzer NR, et al. Available at http://www.acc.org/clinical/guidelines/pad/summary.pdf.


Levels of Evidence


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Level of Evidence A: Data derived from multiplerandomized clinical trials or meta-analyses

Level of Evidence B: Data derived from a single

randomized trial or nonrandomized studies

Level of Evidence C: Only consensus opinionof

experts, case studies, or standard of care

Supporting Vascular Societies


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Collaborative reported from

American Association for Vascular Surgery/Society for Vascular Surgery Society for Cardiovascular Angiography and Interventions

Society of Interventional Radiology

Society for Vascular Medicine and Biology

ACC/AHA Task Force on Practice Guidelines (Writing Committee toDevelop Guidelines for the Management of Patients With Peripheral

Arterial Disease

Endorsed by

American Association of Cardiovascular and Pulmonary Rehabilitation

National Heart, Lung, and Blood Institute

Society for Vascular Nursing

TransAtlantic Inter-Society Consensus Vascular Disease Foundation



Definition of PAD


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Vascular diseases caused primarily by athero-sclerosis and thromboembolic pathophysiological

processes

Encompasses stenotic, occlusive, and

aneurysmal disease

Affects the normal structure and function of the

aorta, its visceral arterial branches, and the

arteries of the lower extremities Exclusive of the coronary arteries

The Natural History of PAD


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Increased risk for cardiovascular ischemic eventsdue to concomitant coronary artery disease and

cerebrovascular disease

Cardiovascular events are more frequent than

ischemic limb events in any lower extremity PADcohort, regardless of presentation


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Arterial DiseaseDiagnosis

Diagnosis of PAD: The Ankle-Brachial Index


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Use resting ABI to establish lower extremity PADdiagnosis

Use ABI to establish baseline in all new patients

with PAD, regardless of severity

Use toe-brachial index in patients with non-

compressible vessels




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Arterial DiseaseRisk Factor Management

Risk Factor Management:

Lipid-lowering Drugs


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p g g

All patients with PAD: Statin treatment to achieveLDL level


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yp g

Target blood pressure


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p

Encourage proper foot careAppropriate footwear, chiropody/podiatric

medicine, daily foot inspection, skin cleansing,

and topical moisturizing creams

Urgently address skin lesions and ulcerations

Target HbA1C


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Risk Factor Management:

Homocysteine-lowering Drugs


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y g g

Value of folic acid and B12 vitamin supplementsfor homocysteine levels >14 M is not well

established



Risk Factor Management: Antiplatelet and

Antithrombotic Treatments


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Antiplatelet therapy can reduce the risk of MI,stroke, or vascular death

Aspirin 75-325 mg per day is safe and effective

Clopidogrel 75 mg per day is an effectivealternative to aspirin

Warfarin is not indicated




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Arterial DiseaseTreatment for Claudication

Claudication Treatment: Exercise


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Supervised exercise training should be the initialtreatment

30-45 minute sessions

3 or more times per week

At least 12 weeks

Value of unsupervised exercise programs is not

well established



Claudication Treatment:

Cilostazol and Pentoxifylline


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Cilostazol 100 mg PO BID Can improve symptoms

Can increase walking distance

Indicated for all patients with lifestyle-limiting

claudication Contraindicated in patients with heart failure

Pentoxifylline 400 mg TID

Consider as an alternative to cilostazol

Effectiveness of pentoxifylline is marginal and not wellestablished




Other Medical Therapies


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Value of L-arginine, propionyl-L-carnitine, andginkgo biloba unknown

Oral prostaglandins do not improve walking

distance

Vitamin E is not recommended

Chelation therapies are not indicated and may

have harmful effects




Endovascular Therapies


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Only indicated for patients with

Vocational or lifestyle-limiting disability;

Reasonable likelihood of symptomatic improvement;

Prior failure of exercise therapy or pharmacological

therapy; and, Favorable risk-benefit ratio

Not indicated as a prophylactic treatment forasymptomatic patients

Preferred method for revascularization of TransatlanticInter-society Consensus type A iliac and femoropoplitealarterial lesions



Claudication Treatment: Stenting


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Evaluate iliac artery stenoses with translesional pressure

gradients Endovascular intervention not indicated in the absence of

significant pressure gradient across a stenosis despite

flow augmentation with vasodilators

Provisional stent placement is indicated as a salvagetherapy for iliac arteries after suboptimal or failed balloon

dilation

Stenting is effective for

Common iliac artery stenoses External iliac artery stenoses



Claudication Treatment: Stenting and

Adjunctive Techniques


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Primary stent placement is not recommended in the femoral,popliteal, or tibial arteries

Stents and other adjunctive techniques can be useful

In femoral, popliteal, and tibial arteries

As salvage therapies for suboptimal or failed balloon dilation

Value of stents, atherectomy, cutting balloons, thermal devices, andlasers for femoral-popliteal arterial lesions is not well establishedexcept as salvage therapies after balloon dilation

Value of uncoated/uncovered stents, atherectomy, cutting balloons,

thermal devices, and lasers for infrapopliteal lesions is not wellestablished except as a salvage therapy after balloon dilation




Surgical Revascularization


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Indicated for patients With significant functional disability from symptoms

Who are unresponsive to exercise or pharmacotherapy

Who have a reasonable likelihood of symptomatic

improvement

Value of surgical intervention in patients


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Medical Treatment of Critical Limb Ischemia


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Parenteral pentoxifylline is not useful Parenteral prostaglandin E-1 or iloprost for 7-28days May reduce ischemic pain

May facilitate ulcer healing Is effective in only a small fraction of patients

Oral iloprost does not reduce the risk ofamputation or death

Value of angiogenic growth factors not wellestablished



Endovascular Treatment of Critical

Limb Ischemia


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For combined inflow and outflow disease Inflow lesions should be addressed first

Perform outflow revascularization if symptoms

or infection persist after inflowrevascularization

Assess inflow disease with intra-arterial pressure

measures across suprainguinal lesions before

and after administration of a vasodilator



Thrombolytic Treatment of Critical

Limb Ischemia


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Catheter-based thrombolysis is effective andbeneficial for patients with Rutherford category I-IIa acute limb ischemia of less than 14 daysduration

Mechanical thrombectomy can be used as anadjunctive therapy for acute limb ischemia

Catheter-based thrombolysis or thrombectomymay be considered for Rutherford category IIb

acute limb ischemia of more than 14 daysduration



Surgical Treatment of Critical Limb Ischemia


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For combined inflow and outflow disease

Address inflow lesions first Perform outflow revascularization if symptoms or infection persists

after inflow revascularization

Consider primary amputation for patients with

Significant necrosis of weight-bearing portions of the foot

An uncorrectable flexion contracture Paresis

Refractory ischemic rest pain

Sepsis

Very limited life expectancy due to comorbid conditions

Surgical or endovascular intervention is not indicated

For patients with severe decrements in limb perfusion (eg, ABI

peripheral_arterial_disease

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