Advances in theMedical Management of

Peripheral Arterial DiseaseRandall M. Zusman, MD

Associate Professor of MedicineHarvard Medical School

DirectorDivision of Hypertension and Vascular Medicine

Massachusetts General HospitalBoston, Massachusetts

Key Question

How many of your patients with CV risk do

you test for peripheral arterial disease?

1. 0%-24%

2. 25%-50%

3. 51%-75%

4. 76%-100%

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Faculty Disclosure

Dr Zusman: advisory board member, research support, speakers bureau: AstraZeneca, Bristol-Myers Squibb Company, Forest Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc, sanofi-aventis Group, Sankyo Co., Ltd.

Learning Objectives

Describe the prevalence and disease burden of PAD

State medical treatments for improving leg symptoms of the patient with PAD

Discuss interventions used to prevent systemic complications in the patient with PAD

PAD = peripheral arterial disease.

Key Question

How common is PAD?

1. 1-4 million Americans

2. 4-8 million Americans

3. 8-12 million Americans

4. 12-16 million Americans

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PAD: Scope of the Problem

PAD is caused by atherosclerotic occlusion of the arteries to the legs

Common, but often overlookedExact prevalence is unknownPAD may be asymptomatic or present with

atypical symptoms Approximately 8-12 million Americans have PAD Associated with significant morbidity and mortality

resulting from MI, stroke, death

MI = myocardial infarction.American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005; Hiatt WR. N Engl J Med. 2001;344:1608-1621.

PAD: Scope of the Problem

Stroke PAD CHD*0

2

4

6

8

10

12

14

Pre

vale

nce

(m

illi

on

s)

16

5.4

138-12

PAD affects 8-12 million Americans,

second only to CHD*

Proportionately, for every 4 patients seen with CHD*, clinicians might expect to see

approximately 3 patients with PAD

*Includes MI and angina pectoris.CHD = coronary heart disease. American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005.

PAD: Prevalence Increases With Age

ABI = ankle-brachial index.Creager M, ed. Management of Peripheral Arterial Disease. Medical, Surgical and Interventional Aspects. 2000.

Rotterdam Study (ABI <.9) San Diego Study (PAD by noninvasive tests)

Age Group (y)

Pat

ien

ts W

ith

PA

D (

%)

0

10

20

30

40

50

60

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

REACH—Scope of the Problem:Cerebro- and Cardiovascular Disease

*PAD patients with polyvascular disease had concomitant symptomatic cerebrovascular disease and/or CVD. REACH = REduction of Atherothrombosis for Continued Health.

Bhatt DL et al. American College of Cardiology Scientific Session. March 8, 2005.

Coronary artery

Peripheral artery

39.4%

14.2%

9.5%

Polyvascular disease

63% of PAD patients had polyvascular* disease

N = 7013

Cerebro-vascular

Key Question

PAD increases the risk of CHD death by approximately:

1. 1×-2×

2. 3×-4×

3. 5×-6×

4. 6×-7×

5. 7×-8×

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Cause of Death

PAD: Increased Risk of Mortality

0.0

2.0

4.0

6.0

8.0

10.0

All-Cause Mortality

Death From Coronary Heart Disease

Rel

ativ

e R

isk

of

Dea

th

(95%

CI)

3.1(1.9-4.9)

6.6(2.9-14.9)

Patients with large-vessel PAD*

are at ~6× the risk of dying from

CHD comparedwith patients without PAD

*ABI ≤0.8.Adapted from Criqui MH et al. N Engl J Med. 1992;326:381-386.

HOPEPAD: Increased Risk of Mortality

HOPE = Heart Outcomes Prevention Evaluation.Ostergren J et al. Eur Heart J. 2004;25:17-24.

PAD doubled mortality rate (17.5% vs 8.5%) after mean follow-up of 4.5 years

0.25

0.20

0.15

0.10

0.05

0

0 500 1000 1500 2000

P <.0001Kap

lan

-Mei

er R

ates

Days of Follow-up

Clinical PADSubPAD ABI <0.6SubPAD ABI 0.6- 0.9No-PAD & ABI >0.9

PAD in Primary Care: Underdiagnosed

Prevalence is high, yet clinician awareness of PAD diagnosis is relatively low

Simple ABI measurement identifies many patients with previously unrecognized PAD

Atherosclerosis risk factors are prevalent in patients with PAD Received less intensive treatment for lipid disorders

and hypertension Prescribed antiplatelet therapy less frequently

than patients with CVD

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

NHANES = National Health and Nutrition Examination Survey. PARTNERS = PAD Awareness, Risk, and TreatmentNew Resources for Survival program. 1. Selvin E, Erlinger TP. NHANES. Circulation. 2004;110:738-743; 2. Criqui MH et al. Circulation. 1985;71:510-515;3. Meijer WT et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192; 4. Diehm C et al. Atherosclerosis. 2004;172:95-105; 5. Hirsch AT et al. JAMA. 2001;286:1317-1324.

PAD: Prevalence in the Primary Care Office Setting

29%

19.8%

19.1%

14.5%

11.7%

4.3%

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

The prevalence of PAD in primary

care clinics was almost

in high-risk patients

PARTNERS5

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

San Diego2 Mean age = 66

Diehm3 Age ≥65

Rotterdam4 Age >55

NHANES1 Age ≥70

NHANES1

Age >40

30%

The authors concluded that up to 90%*

of patients with PAD would be missed if healthcare

providers relied solely on the classic symptoms of intermittent claudication

Healthcare providers should also routinely inquire about

atypical symptoms

90% did not have

classic intermittent claudication symptoms

PARTNERS

Detecting PAD With Symptoms

*In patients with ABI ≤0.9.Hirsch AT et al. JAMA. 2001;286:1317-1324

PAD: Symptoms

American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005;Criqui MH et al. Vasc Med. 1996;1:65-71.

Typical Symptoms(Intermittent Claudication)

~10%Exercise calf painNot present at restRelieved within 10

minutes by rest

Atypical Symptoms~50%

Occlusion may develop slowly, allowing collateral

circulation to develop

Asymptomatic PAD~40%

Patients With PAD

Symptomatic PAD

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

PAD: Diagnostic Critical Pathway

PAD Diagnosis

Vascular Lab Evaluation Segmental pressures Pulse volume recordings Treadmill

ABI Not AvailableABI Available

PAD Diagnosis

Referral to Vascular Lab Assessment of location/

severity is desired Patients with poorly

compressible vessels Normal ABI where PAD

suspicion is high

Clinical Evaluation:History and Physical

Key Question

The most common risk factor for PAD is:

1. Diabetes

2. Smoking

3. Hypertension

4. Total cholesterol level

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PAD: Common Risk Factors*

*PAD diagnosis based on ABI <0.90.Newman AB et al. Circulation. 1993;88:837-845.

◄Lesser risk

0 1 2 3 4 5 6

1.10

1.51

2.55

Total cholesterol (10 mg/dL)

Hypertension

Diabetes

Smoking

Greater risk ►

Patients with diabetes are at a 4x higher risk of developing

symptomatic PAD versus the general

population

4.05

Age >40 years

PAD: Physical Examination

Perform With Patient’s Pants/Shoes Off

Examine Limb And Compare With the Opposite Limb

Absent/diminished femoral or pedal pulses—especially after exercising the limb

Arterial bruits

Hair loss

Poor nail growth (brittle nails)

Dry, scaly, atrophic skin

Dependent rubor

Pallor with leg elevation after 1 minute at 60º (normal color should return in 10-15 seconds; >40 seconds indicates severe ischemia)

Ischemic tissue ulceration (punched-out, painful, little bleeding), gangrene

Gey DC et al. Am Fam Physician. 2004;69:525-532.

Additional examination by palpation and auscultation to detect abnormal aortic aneurysm or bruit

Concept of ABI

Adapted from Weitz JI et al. Circulation. 1996;94:3026-3049.

÷ ≈ 1

ABI is 95% sensitive and 99% specific for angiographically diagnosed PAD

Systolic BP in the leg should be approximately the same as that in the arm

Therefore, the ratio of systolic BP in the leg versus the arm should be approximately 1 or slightly higher

Arm Pressure

Leg Pressure

Measuring ABI

Gather equipment needed Position patient Measure the brachial BP Position the cuff above the ankle Measure pressure in the DP artery Measure pressure in the PT artery Repeat the process in opposite leg

DP = dorsalis pedis; PT = posterior tibial.American Diabetes Association. Diabetes Care. 2003;26:3333-3341; Dormandy JA et al. J Vasc Surg. 2000;31:S1-S296.

Calculating ABI

Higher right ankle pressure

(DP or PT pulse)

Higher arm pressure (either arm)

=

Right Leg ABI Left Leg ABI

Higher left ankle pressure

(DP or PT pulse)

Higher arm pressure (either arm)

=

ABI Interpretation≤0.90 is diagnostic of PAD

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

ABI Workshops

Demonstrations available throughout the day

PARTNERS Incorporating ABI Into Primary Care

Weekly Increase in ABI Use in Office

358%

Monthly Increase inABI Use in Office

300%

88%

Mohler, ER et al. Vasc Med. 2004;9:253-260.

Clinicians thought it feasible to

incorporate ABI into daily practice

Clinicians thought it feasible to

incorporate ABI into daily practice

After Clinicians Participated in PARTNERS:

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

PAD: Diagnostic Critical Pathway

PAD Diagnosis

Vascular Lab Evaluation Segmental pressures Pulse volume recordings Treadmill

ABI Not AvailableABI Available

PAD Diagnosis

Referral to Vascular Lab Assessment of location/

severity is desired Patients with poorly

compressible vessels Normal ABI where PAD

suspicion is high

Clinical Evaluation:History and Physical

Holland T. Ostomy Wound Manage. 2002;48:38-49.

Vascular Laboratory Results: Segmental Pressures

• Segmental pressures can help localize lesion

• Considered abnormal when there is a

>20 mm Hg difference between adjacent segments within the same leg and between the original segment and the corresponding segment on the contralateral leg

Brachial Brachial artery

Upper thigh Proximal femoral artery

Lower thigh Distal femoral artery

Calf DP, PT, and proximal arteries

Ankle PT or DP artery

Provides Segmental Waveform Analysis, A Qualitative Assessment of Blood Flow

Data provided by Mark Creager, MD.Holland T. Ostomy Wound Manage. 2002;48:38-49.

Normal

PAD

Normal tracingincludes initial systolic peak with a dicrotic wave on the down slope

Vascular Laboratory Test: Pulse Volume Recordings

UpperThigh

LowerThigh Calf Ankle

Abnormal tracing characterized by a rounded systolic peak that is lower, as well as the lack of a dicrotic wave on the downslope

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

Atypical Symptoms

for PAD

PAD Diagnosis

Treadmill Test: Function Testing to Aid Diagnosis

Treadmill Function Testing• Patients with claudication will normally display a drop in ankle pressure after

exercise• May also be used to assess treatment efficacy and evaluate overall physical

function

Normal ABI with typical symptoms of claudication

ABI

Suspect PAD

Clinical Evaluation: History and Physical

Key Question

The goals of therapy for PAD are:1. Relieve exertional symptoms2. Improve walking capability3. Improve quality of life4. Relieve ischemic pain at rest5. Heal ischemic ulceration6. Prevent limb loss7. All of the above

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PAD: Treatment Goals

For patients with claudicationRelieve exertional symptoms Improve walking capability Improve quality of life

For patients with critical leg ischemiaSame as above, and

Relieve ischemic pain at restHeal ischemic ulcerationPrevent limb loss

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

PAD: Aggressive Risk Factor Modification Essential—1

Smoking Cessation

Goal: Abstinence

↓ Severity of claudication (probably)

Slows progression to critical leg ischemia

↓ MI risk, vascular deaths

Pharmacotherapy (NRT, nortriptyline, clonidine, bupropion) + counseling

Exercise

Goal: As frequently and as long as possible

↑ Peak walking time↑ Peak oxygen consumption↑ Pain-free walking time↑ Quality of life ↑ Routine daily activities

Therapeutic exercise training

NRT = nicotine replacement therapy.Gey DC et al. Am Fam Physician. 2004;69:525-532; Hiatt WR. N Engl J Med. 2001;344:1608-1621; Stewart KJ et al. N Engl J Med. 2002;347:1941-1951.

PAD: Aggressive Risk Factor Modification Essential—Smoking Cessation

Jorenby DE et al. N Engl J Med. 1999;340:685-691.

PlaceboNicotine replacementBuproprionBupropion andnicotine replacement

40

35

30

25

20

15

10

5

0Per

cen

tag

e o

f P

atie

nts

A

bst

ain

ing

6 months 12 months

CPT = current procedural terminology.1. Gardner AW et al. JAMA. 1995;274:975-980; 2. Kanjwal MK et al. JK–Practitioner. 2004;11:225-232.

Distance to Maximal Claudication Pain

Distance to Onset of Claudication Pain

At 6 months

122% 179%

Per

cen

tag

e In

crea

seMeta-Analysis Supervised Exercise Essential to Improve Intermittent Claudication Symptoms

AMA has published a CPT code for supervised PAD rehabilitation (93668)2

Greatest improvement: • Sessions lasted >30 min• 3 sessions/wk• Walk to near-maximal pain• >6-month program

PAD: Aggressive Risk Factor Modification Essential—2

Treat Hyperlipidemia

Goal:

LDL <100 mg/dL

↓ Serum cholesterol↑ Endothelial function↓ Disease progressionModifies other atherosclerotic risks

StatinsNiacins

Treat Hypertension

Goal:

<140/90 mm Hg

<130/80 mm Hg (diabetes or renal insufficiency)

Data support aggressive treatment; impact on PAD outcomes unclear

ACE inhibitorsBeta-blockerscan be used

Control Diabetes

Goal:

A1C <7% or as close to normal (<6%) as possible

↓ CVD and MI rates; trend for PAD outcomes ↓ Limb infection, amputation↓ Microvascular complication risk

Diet, exercise, pharmacotherapy

A1C = glycosylated hemoglobin.Gey DC et al. Am Fam Physician. 2004;69:525-532; Hiatt WR. N Engl J Med. 2001;344:1608-1621; Norgren L et al. J Vasc Surg. 2007;45:S5A-S67.

HPS PAD: Aggressive Risk Factor Modification Essential—Lipids

HPS = Heart Protection Study.HPS Collaborative Group. MRC/BHF. Lancet. 2002;360:7-22.

Type of major vascular event

Simvastatin-Allocated(10269)

Placebo-Allocated(10267)

Event Rate Ratio (95% CI)

Coronary events

0.73 (0.67-0.79)P <.0001

0.75 (0.66-0.86)P <.0001

0.76 (0.70-0.83)P <.00010.76 (0.72-0.81)P <.0001

Nonfatal MI 357 (3.5%) 574 (5.6%)

Coronary death 587 (5.7%) 707 (6.9%)Subtotal: major coronary events 898 (8.7%) 1212 (11.8%)

Strokes

Nonfatal strokes 366 (3.6%) 499 (4.9%)

Fatal strokes 96 (0.9%) 119 (1.2%)

Subtotal: any strokes 444 (4.3%) 585 (5.7%)

Revascularization

Coronary 513 (5.0%) 725 (7.1%)

Noncoronary 450 (4.4%) 532 (5.2%)

Subtotal: any revascularization 939 (9.1%) 1205 (11.7%)

Any Major Vascular Event 2033 (19.8%) 2585 (25.2%)

0.4 0.6 0.8 1.0 1.2 1.4Simvastatin Better Placebo Better

HOPE PAD: Aggressive Risk Factor Modification Essential—Antihypertensive Therapy

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

No. of Patients

Incidence of Composite Outcome in

Placebo Group

Overall 9297 17.8

PAD 4046 22.0

No PAD 5251 14.3

0.6

Relative Risk in Ramipril Group

0.8 1.0 1.2

PAD: Antiplatelet and Vasodilator Therapy

ASA 81-325 mg/d PO Recommended by ACCP; not FDA-approved

Clopidogrel 75 mg/d PO

Fewer side effects than ASA in CAPRIE trial; significantly less TTP risk than ticlopidine

Pentoxifylline 1.2 g/d PO

Some effect on walking ability; insufficient data to support widespread use

Cilostazol 100 mg BID PO

Correct dosage critical; avoid in patients with CHF; reduce dose in patients taking CCBs; GI side effects

ACCP = American College of Chest Physicians; ASA = aspirin; CAPRIE = Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CCB = calcium channel blocker; CHF = chronic heart failure; GI = gastrointestinal; TTP = thrombotic thrombocytopenic purpura. Adapted from Gey DC et al. Am Fam Physician. 2004;69:525-532.

8.7%Overall RRR

(P = .045)*

Months of Follow-up

Cu

mu

lati

ve E

ven

t R

ate

(%)

0

4

8

12

16

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

Clopidogrel ASA

Median follow-up = 1.91 years

5.32%

5.83%

Subjects had a recent MI, recent ischemic stroke, or symptomatic PAD

(N = 19,185)

*ITT analysis: RRR = relative risk reduction.CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

CAPRIEClopidogrel Versus ASA: MI, Ischemic Stroke, or Vascular Death

CAPRIE

Safety Profile

•Patients with a history of ASA intolerance were excluded from CAPRIE. PLAVIX Prescribing Information. Data on file, Sanofi-Synthelabo Inc.

Although the risk of myelotoxicity with clopidogrel appears to be low, this possibility should be considered when a patient receiving clopidogrel has fever or another sign of infection.

% Patients

Clopidogrel

(n = 9599)

ASA* (n =

9586)

GI hemorrhage 2.0 2.7

Hospitalization due to GI hemorrhage

0.7 1.1

GI ulcers 0.7 1.2

Intracranial hemorrhage 0.4 0.5

Severe neutropenia 0.04 0.02

Tolerability Profile*

*ASA-intolerant patients excluded.PLAVIX Prescribing Information. Data on file, Sanofi-Synthelabo Inc.

CAPRIE

% Patients

Clopidogrel (75 mg/d)

ASA*

(325 mg/d)

Abdominal pain 5.6 7.1

Purpura (bruising) 5.3 3.7

Dyspepsia 5.2 6.1

Diarrhea 4.5 3.4

Rash 4.2 3.5

Pruritus 3.3 1.6

Discontinuation due to adverse GI events 3.2 4.0

Gastritis 0.8 1.3

PAD: When to Refer

Primary care team is not confident making the diagnosis or lacks resources required to make such a diagnosis

Patient has continued symptoms despite a reasonable trial and adherence to best medical therapy

Patient has critical limb ischemia (rest pain, gangrene, or ulceration)

Case Study

Patient Case Study

58-year-old Latino male History of diabetes and hypertension

Treated episodically at local clinic No current medications

Has taken antihypertensive and oral hypoglycemic agents in the past

Patient Case Study

Physical examinationHeight: 5'9″Weight: 190 lbBMI: 28.1 kg/m2

Waist circumference: 40″BP: 168/110 mm HgPulse: 72 bpm

BMI = body mass index.

Presenting Symptoms

Presents to the clinic after referral from emergency department where he was evaluated and discharged after an episode of chest pain Coronary event ruled out by labs and diagnostic studies

Admits that he has never been on medication for more than 3 months at a time Has no health benefits and works as a construction worker

Does not drink alcohol but smokes 1 pack/day x 30 years Complains of fatigue and inability to maintain his current

productivity at the work site

Laboratory Results

Lipid panelTotal cholesterol: 346 mg/dLLDL: 170 mg/dLHDL: 29 mg/dLTriglyceride: 280 mg/dL

A1C: 9.2% BUN and creatinine: 19/1.4 mg/dL

BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

Physical Examination

CV: RRR S1 and S2 with no murmurs or gallops Chest: clear to A/P Abdomen: rotund, but no pulsatile masses or distention Vascular: no bruits; upper extremity pulses—normal limits

Lower extremity pulses reveal normal femoral bilaterally Right popliteal, DP, and PT palpable Left shows decreased popliteal, DP, and PT

Musculoskeletal: no evidence of foot ulceration or dependent rubor

Neurologic: sensory function intact in upper and lower extremities

Decision Point

What is this patient’s risk category?

1. High

2. Moderately high

3. Moderate

4. Either moderate or moderately high

5. Low

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Therapeutic Considerations

Diagnostic intervention Evaluate vascular status ABI results

Right = 1.00Left = 0.56

Appropriate management includes: Control BP Manage dyslipidemia and diabetes Initiate antiplatelet therapy Smoking cessation Exercise program Follow-up in 1 month

Q & A

PCE Takeaways

PCE: PAD Takeaways

PAD is underrecognized and undertreated ABI can identify PAD Aggressive lifestyle changes and drug therapy

can save lives

Key Question

Will you use ABI testing to diagnose patients at

risk for PAD?

1. Not likely

2. Somewhat likely

3. Very likely

4. Extremely likely

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