Advances in the Medical Management of Peripheral Arterial Disease

1
Advances in theMedical Management of Peripheral
Arterial Disease

• Randall M. Zusman, MD
• Associate Professor of Medicine
• Harvard Medical School
• Director
• Division of Hypertension and Vascular Medicine
• Massachusetts General Hospital
• Boston, Massachusetts

2
Key Question

• How many of your patients with CV risk do
• you test for peripheral arterial disease?
• 0-24
• 25-50
• 51-75
• 76-100
• Use your keypad to vote now!

3
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.

4
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.
5
Key Question

• How common is PAD?
• 1-4 million Americans
• 4-8 million Americans
• 8-12 million Americans
• 12-16 million Americans
• Use your keypad to vote now!

6
PAD Scope of the Problem

• PAD is caused by atherosclerotic occlusion of
  the arteries to the legs
• Common, but often overlooked
• Exact prevalence is unknown
• PAD 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
Statistics2005 Update. 2005 Hiatt WR. N Engl J
Med. 20013441608-1621.
7
PAD Scope of the Problem
16
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
14
13
12
8-12
10
Prevalence (millions)
8
6
4
5.4
2
0
Stroke
PAD
CHD
Includes MI and angina pectoris. CHD coronary
heart disease. American Heart Association. Heart
Disease and Stroke Statistics2005 Update. 2005.
8
PAD Prevalence Increases With Age
Rotterdam Study (ABI lt.9) San Diego
Study (PAD by noninvasive tests)
60
50
40
Patients With PAD ()
30
20
10
0
55-59
60-64
65-69
70-74
75-79
80-84
85-89
Age Group (y)
ABI ankle-brachial index. Creager M, ed.
Management of Peripheral Arterial Disease.
Medical, Surgical and Interventional Aspects.
2000.
9
REACHScope of the ProblemCerebro- and
Cardiovascular Disease
63 of PAD patients had polyvascular disease N
7013
Cerebro-vascular
Coronary artery
14.2
9.5
39.4
Peripheral artery
Polyvascular 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.
10
Key Question

• PAD increases the risk of CHD death
• by approximately
• 1-2
• 3-4
• 5-6
• 6-7
• 7-8
• Use your keypad to vote now!

11
PAD Increased Risk of Mortality
Patients with large-vessel PAD are at 6 the
risk of dying from CHD compared with patients
without PAD
10.0
8.0
6.6 (2.9-14.9)
6.0
Relative Risk of Death (95 CI)
4.0
3.1 (1.9-4.9)
2.0
0.0
Death From Coronary Heart Disease
All-Cause Mortality
Cause of Death
ABI 0.8. Adapted from Criqui MH et al. N Engl J
Med. 1992326381-386.
12
HOPEPAD Increased Risk of Mortality
PAD doubled mortality rate (17.5 vs 8.5) after
mean follow-up of 4.5 years
Clinical PAD SubPAD ABI lt0.6 SubPAD ABI 0.6- ?
0.9 No-PAD ABI gt0.9
0.25
0.20
0.15
Kaplan-Meier Rates
0.10
0.05
P lt.0001
0
0
500
1000
1500
2000
Days of Follow-up
HOPE Heart Outcomes Prevention
Evaluation. Ostergren J et al. Eur Heart J.
20042517-24.
13
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. 20012861317-1324.
14
PAD Prevalence in the
Primary Care Office Setting
NHANES1 Age gt40
4.3
The prevalence of PAD in primarycare clinics
was almostin high-risk patients
San Diego2 Mean age 66
11.7
30
NHANES1 Age 70
14.5
Rotterdam4 Age gt55
19.1
Diehm3 Age 65
19.8
PARTNERS5 Age gt70, or between 50-69 with history
of diabetes or smoking
29
0
5
10
15
20
25
30
35
NHANES National Health and Nutrition
Examination Survey. PARTNERS PAD Awareness,
Risk, and Treatment New Resources for Survival
program. 1. Selvin E, Erlinger TP. NHANES.
Circulation. 2004110738-743 2. Criqui MH et
al. Circulation. 198571510-515 3. Meijer WT et
al. Arterioscler Thromb Vasc Biol.
199818185-192 4. Diehm C et al.
Atherosclerosis. 200417295-105 5. Hirsch AT et
al. JAMA. 20012861317-1324.
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PARTNERSDetecting PAD With Symptoms
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
In patients with ABI 0.9. Hirsch AT et al.
JAMA. 20012861317-1324
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PAD Symptoms
Patients With PAD
Asymptomatic PAD 40
Symptomatic PAD
American Heart Association. Heart Disease and
Stroke Statistics2005 Update. 2005 Criqui MH et
al. Vasc Med. 1996165-71.
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PAD Diagnostic Critical Pathway
Clinical Evaluation History and Physical

• Referral to Vascular Lab
• Assessment of location/ severity is desired
• Patients with poorly compressible vessels
• Normal ABI where PAD suspicion is high

• Vascular Lab Evaluation
• Segmental pressures
• Pulse volume recordings
• Treadmill

PAD Diagnosis
PAD Diagnosis
Adapted from American Diabetes Association.
Diabetes Care. 2003263333-3341.
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Key Question

• The most common risk factor for PAD is
• Diabetes
• Smoking
• Hypertension
• Total cholesterol level
• Use your keypad to vote now!

19
PAD Common Risk Factors
?Lesser risk
Greater risk ?
Diabetes
4.05
Smoking
2.55
Patients with diabetes are at a 4x higher risk
of developing symptomatic PAD versus the general
population
Hypertension
1.51
Total cholesterol (10 mg/dL)
1.10
0 1 2 3 4 5 6
Age gt40 years
PAD diagnosis based on ABI lt0.90. Newman AB et
al. Circulation. 199388837-845.
20
PAD Physical Examination
Perform With Patients Pants/Shoes Off Examine Limb And Compare With the Opposite Limb Perform With Patients Pants/Shoes Off Examine Limb And Compare With the Opposite Limb
Absent/diminished femoral or pedal pulsesespecially 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 gt40 seconds indicates severe ischemia) Ischemic tissue ulceration (punched-out, painful, little bleeding), gangrene
Additional examination by palpation and
auscultation to detect abnormal aortic aneurysm
or bruit
Gey DC et al. Am Fam Physician. 200469525-532.
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Concept of ABI
Systolic BP in the leg should be approximately
the same as that in the arm
Leg Pressure
Therefore, the ratio of systolic BP in the leg
versus the arm should be approximately 1 or
slightly higher
1
Arm Pressure
ABI is 95 sensitive and 99 specific for
angiographically diagnosed PAD
Adapted from Weitz JI et al. Circulation.
1996943026-3049.
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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. 2003263333-3341 Dormandy JA et al. J
Vasc Surg. 200031S1-S296.
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Calculating ABI
Right Leg ABI
Left Leg ABI
Higher right ankle pressure (DP or PT
pulse) Higher arm pressure (either arm)
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. 20013441608-1621.
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ABI Workshops

• Demonstrations available throughout the day

25
PARTNERS Incorporating ABI Into Primary Care
After Clinicians Participated in PARTNERS
88
Clinicians thought it feasible to incorporate ABI
into daily practice
Mohler, ER et al. Vasc Med. 20049253-260.
26
PAD Diagnostic Critical Pathway
Clinical Evaluation History and Physical

• Referral to Vascular Lab
• Assessment of location/ severity is desired
• Patients with poorly compressible vessels
• Normal ABI where PAD suspicion is high

• Vascular Lab Evaluation
• Segmental pressures
• Pulse volume recordings
• Treadmill

PAD Diagnosis
PAD Diagnosis
Adapted from American Diabetes Association.
Diabetes Care. 2003263333-3341.
27
Vascular Laboratory Results Segmental Pressures

• Segmental pressures can help localize lesion
• Considered abnormal when there is a
• gt20 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
Holland T. Ostomy Wound Manage. 20024838-49.
28
Vascular Laboratory Test Pulse Volume Recordings
Provides Segmental Waveform Analysis,
A Qualitative
Assessment of Blood Flow
UpperThigh
LowerThigh
Calf
Ankle
Normal
Normal tracingincludes initial systolic peak
with a dicrotic wave on the down slope
PAD
Abnormal tracing characterized by a rounded
systolic peak that is lower, as well as the lack
of a dicrotic wave on the downslope
Data provided by Mark Creager, MD. Holland T.
Ostomy Wound Manage. 20024838-49.
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Treadmill Test Function Testing to Aid Diagnosis
Clinical Evaluation History and Physical
Suspect PAD
Atypical Symptoms for PAD
ABI
Normal ABI with typical symptoms of claudication

• 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

PAD Diagnosis
Adapted from American Diabetes Association.
Diabetes Care. 2003263333-3341.
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Key Question

• The goals of therapy for PAD are
• Relieve exertional symptoms
• Improve walking capability
• Improve quality of life
• Relieve ischemic pain at rest
• Heal ischemic ulceration
• Prevent limb loss
• All of the above
• Use your keypad to vote now!

31
PAD Treatment Goals

• For patients with claudication
• Relieve exertional symptoms
• Improve walking capability
• Improve quality of life
• For patients with critical leg ischemia
• Same as above, and
• Relieve ischemic pain at rest
• Heal ischemic ulceration
• Prevent limb loss

Hiatt WR. N Engl J Med. 20013441608-1621.
32
PAD Aggressive Risk Factor Modification
Essential1
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. 200469525-532 Hiatt WR. N
Engl J Med. 20013441608-1621 Stewart KJ et al.
N Engl J Med. 20023471941-1951.
33
PAD Aggressive Risk Factor Modification
EssentialSmoking Cessation
40
35
PlaceboNicotine replacement Buproprion Bupropion
andnicotine replacement
30
25
Percentage of Patients Abstaining
20
15
10
5
0
6 months
12 months
Jorenby DE et al. N Engl J Med. 1999340685-691.
34
Meta-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 gt30 min
• 3 sessions/wk
• Walk to near-maximal pain
• gt6-month program

CPT current procedural terminology. 1. Gardner
AW et al. JAMA. 1995274975-980 2. Kanjwal MK
et al. JKPractitioner. 200411225-232.
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PAD Aggressive Risk Factor Modification
Essential2
Treat Hyperlipidemia Goal LDL lt100 mg/dL ? Serum cholesterol ? Endothelial function ? Disease progression Modifies other atherosclerotic risks Statins Niacins
Treat Hypertension Goal lt140/90 mm Hg lt130/80 mm Hg (diabetes or renal insufficiency) Data support aggressive treatment impact on PAD outcomes unclear ACE inhibitors Beta-blockers can be used
Control Diabetes Goal A1C lt7 or as close to normal (lt6) 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. 200469525-532 Hiatt WR. N Engl
J Med. 20013441608-1621 Norgren L et al. J
Vasc Surg. 200745S5A-S67.
36
HPS PAD Aggressive Risk Factor Modification
EssentialLipids
Type of major vascular event Simvastatin-Allocated(10269) Placebo-Allocated(10267) Event Rate Ratio (95 CI) Event Rate Ratio (95 CI)
Coronary events 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Nonfatal MI 357 (3.5) 574 (5.6) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Coronary death 587 (5.7) 707 (6.9) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Subtotal major coronary events 898 (8.7) 1212 (11.8) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Strokes 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Nonfatal strokes 366 (3.6) 499 (4.9) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Fatal strokes 96 (0.9) 119 (1.2) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Subtotal any strokes 444 (4.3) 585 (5.7) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Revascularization 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Coronary 513 (5.0) 725 (7.1) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Noncoronary 450 (4.4) 532 (5.2) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Subtotal any revascularization 939 (9.1) 1205 (11.7) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
Any Major Vascular Event 2033 (19.8) 2585 (25.2) 0.73 (0.67-0.79)P lt.0001 0.75 (0.66-0.86)P lt.0001 0.76 (0.70-0.83)P lt.0001 0.76 (0.72-0.81)P lt.0001
0.4
0.6
0.8
1.0
1.2
1.4
Simvastatin Better
Placebo Better
HPS Heart Protection Study. HPS Collaborative
Group. MRC/BHF. Lancet. 20023607-22.
37
HOPE PAD Aggressive Risk Factor Modification
EssentialAntihypertensive Therapy
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
0.8
1.0
1.2
Relative Risk in Ramipril Group
HOPE Study Investigators. N Engl J Med.
2000342145-153.
38
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. 200469525-532.
39
CAPRIEClopidogrel Versus ASA MI, Ischemic
Stroke, or Vascular Death
16
8.7 Overall RRR (P .045)
Clopidogrel ASA
5.83
12
5.32
(N 19,185)
8
Cumulative Event Rate ()
Subjects had a recent MI, recent ischemic stroke,
or symptomatic PAD
4
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Months of Follow-up
Median follow-up 1.91 years
ITT analysis RRR relative risk
reduction. CAPRIE Steering Committee. Lancet.
19963481329-1339.
40
CAPRIESafety Profile
Patients 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
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 with a history of ASA intolerance were
  excluded from CAPRIE. PLAVIX Prescribing
  Information. Data on file, Sanofi-Synthelabo
  Inc.

41
Tolerability Profile
CAPRIE
Patients 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
ASA-intolerant patients excluded. PLAVIX
Prescribing Information. Data on file,
Sanofi-Synthelabo Inc.
42
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)

43
Case Study
44
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

45
Patient Case Study

• Physical examination
• Height 5'9?
• Weight 190 lb
• BMI 28.1 kg/m2
• Waist circumference 40?
• BP 168/110 mm Hg
• Pulse 72 bpm

BMI body mass index.
46
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

47
Laboratory Results

• Lipid panel
• Total cholesterol 346 mg/dL
• LDL 170 mg/dL
• HDL 29 mg/dL
• Triglyceride 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.
48
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
  pulsesnormal 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

49
Decision Point

• What is this patients risk category?
• High
• Moderately high
• Moderate
• Either moderate or moderately high
• Low
• Use your keypad to vote now!

50
Therapeutic Considerations

• Diagnostic intervention
• Evaluate vascular status ABI results
• Right 1.00
• Left 0.56
• Appropriate management includes
• Control BP
• Manage dyslipidemia and diabetes
• Initiate antiplatelet therapy
• Smoking cessation
• Exercise program
• Follow-up in 1 month

51
Q A
52
PCE Takeaways
53
PCE PAD Takeaways

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

54
Key Question

• Will you use ABI testing to diagnose patients at
• risk for PAD?
• Not likely
• Somewhat likely
• Very likely
• Extremely likely
• Use your keypad to vote now!