Peripheral Vascular Disease:
What the Internist Needs to
Know?
Yerem Yeghiazarians, MD
UCSF Medical Center
May 18, 2009
Some slides courtesy of Dr. Heather Gornik and Dr. Joseph Garasic
Objectives
„ The
scope of the problem and the link between
peripheral arterial disease and cardiovascular
risk
„ Identification
and diagnosis of patients with
peripheral arterial disease
„ Management
of patients with PAD
Atherosclerosis is a Pan Vascular Process
„ Coronary
Artery Disease (CAD)
„ Peripheral
Arterial Disease (PAD)
„ Cerebrovascular
„ Renovascular
„ Mesenteric
„ Aortic
Disease (CVD)
Hypertension
Ischemia
aneurysm
„ Vasculogenic
Erectile Dysfunction
PAD Remains a Clinical Challenge
10 Million
U.S. PAD
Patients
Just 4% of all PAD
patients are treated
interventionally
2.5 Million Patients
Diagnosed
Your Patient Has Never Heard of PAD?
(S)He is not alone!
N=2501 people surveyed
PAD Aware
(26%)
Not Aware
of PAD
(74%)
PAD Aware
Not Aware
“PAD Aware” defined by “somewhat” or “very familiar” responses
Gaps in Public Knowledge of Peripheral Arterial Disease: The First National PAD Public
Awareness Survey. Circulation 2007;116(18):2086-94
How do we diagnosis PAD?
History
Physical Exam
Diagnostic Testing
Peripheral Artery Disease
Varied spectrum of clinical presentation
– Asymptomatic PAD - abnormal ABI test
– Symptomatic PAD - leg pain
– Critical Limb Ischemia
– Acute Limb Ischemia
Leg Symptoms Among Patients with
PAD in Ambulatory Care Setting
11%
N=1857 Patients with ABI < 0.9
34%
No Pain
Atypical Leg Pain
Classic
Claudication
55%
Hirsch, et al. PARTNERS Study. JAMA 1999; 286:1317
Critical Limb Ischemia =
Vascular Urgency
„ Non-healing
ulcer
„ Gangrene
„ Ischemic
Æ
Rest pain
Urgent consideration
of revascularization
Acute Limb Ischemia=
Vascular Emergency
ƒ The
6 Ps:
ƒ Pain
ƒ Pallor
ƒ Paresthesias
ƒ Pulselessness
Evaluate for
emergent
revascularization
ƒ Paralysis
ƒ Poikilothermia or Polar (cold leg)
The Comprehensive Vascular Examination
Carotid Bruits
Subclavian Bruits
Bilateral Blood Pressures
Brachial Pulses
Abdominal Aorta
Radial Pulses
Allen Test
Femoral Pulses and Bruits
Popliteal Pulses
Posterior Tibial Pulses
Inspect feet for ulcers
Dorsalis Pedis Pulses
The Ankle-Brachial Index
ABI =
Ankle systolic pressure
Brachial systolic pressure
• Cornerstone of PAD Diagnosis
• Ankle and brachial systolic pressures taken using a
hand-held Doppler device
• Supine position
• After 5+ minutes of rest
Normal
PAD
Severe PAD
Non-compressible
ABI
ABI
ABI
ABI
0.90-1.30
<0.91
<0.40
>1.30
Performance of the ABI Test
TEST
SENSITIVITY
SPECIFICITY
ABI
95-97%
99-100%
PULSE EXAM 50%
(DP)
PULSE EXAM 71%
(PT)
73%
91%
Ouriel K, et al. Surgery. 1982 Jun;91(6):686-93.
Criqui Circ 1985;71:516
Pulse Volume Recordings
Upper thigh
Upper thigh
Pulse Volume Recordings
Iliac/common
femoral
Lower thigh
Lower thigh
Calf
Calf
Ankle
Ankle
SFA/popliteal
Below knee
Limitations of the ABI
„ Appropriately
trained staff to perform it
„ ABI correlates poorly with symptoms and functional
limitations
„ Decreased sensitivity for mild disease or inflow
disease
– Exercise ABI critical for patients with
suspected PAD and normal resting ABI
„ Falsely
elevated ABI for patients with “medial
calcinosis” or calcified vessels
– Diabetes mellitus
– Renal failure
– Hyperparathyroidism
Do Non-Compressible Vessels Have any
Meaning for a Diabetic? Yes!
ƒ
ƒ
ƒ
Non-compressible vessels (high ABI)
independent predictor of adverse
outcome
Significant PAD is generally present
though ABI number is not interpretable
Do not consider an ABI > 1.3 “normal”
Toe-Brachial Index
„ Ratio
of toe pressure to
brachial pressure
„ Room must be warm to avoid
vasoconstriction
„ Great toe pressure measured
using small digit cuff and a
flow sensor
– Doppler
– Strain gauge
– Photoplethysmography
„ Digital vessels almost always
compressible
„ Normal TBI > 0.7
Bonham PA. Nursing. 2003;33:54.
Anatomic Imaging Options for PAD
„ Duplex
–
–
–
–
u/s
Least expensive
Labor intensive
Not a road map
Generally reserved for f/u
„ MRA
–
–
–
Angiographic projections
Tends to overestimate dz
Pacemaker
contraindication
– Stent drop-out
– Careful in setting of renal
insufficiency
„ CT
angiography
– Requires IV contrast
– Radiation exposure
„ Digital
Subtraction
Arteriography
– Invasive
– Requires IV contrast
– Radiation exposure
– Typically reserved for
intervention
Prevalence ofIntermittent
Intermittent
Claudication in
Claudication
Men
12
10
8
Percent 6
Atypical or No Symptoms
4
2
0
<50
50-59
60-69
Age (years)
>70
The Edinburgh Artery Study, The Scottish Heart Health Study and the Limburgh Study, reviewed in:
FGR Fowkes ed. Epidemiology of Peripheral Vascular Disease. Springer -Verlag, 1991
What is the Prevalence of PAD
in the Clinic?
„ PARTNERS
study (2001)
„ 6,979
ambulatory care patients in 350
primary care practices
„ ABIs
measured for all enrolled patients
– Aged 70+
– Aged 50-69+ with diabetes mellitus or
tobacco history
„ PAD
„ Only
prevalence 29% overall
11% of patients with abnormal ABI had
Hirsch AT, et al. JAMA. 2001;286;1317.
classic symptoms
Risk Factors for PAD
Smoking
Diabetes
Hypertension
Hypercholesterolemia
Hyperhomocysteinemia
Fibrinogen
C-Reactive Protein
Alcohol
.5
TASC Working Group.
Management of PAD.
www.tasc-PAD.
1
2
3
Relative Risk
4
5
PAD is a Marker of Atherosclerosis and CV Risk
„ 60-80%
of patients with PAD have CAD in at least one
coronary vessel1,2
„ Up
to 15-25% of patients with PAD have a significant
carotid stenoses of >70%3,4
„
PAD a true coronary “risk equivalent”
„ 21%
of patients with P.A.D. will have MI, stroke,
cardiovascular death or hospitalization within 1 year5
– Compared to 15% of patients with established coronary artery
disease or prior heart attack!
1.
2.
3.
4.
5.
Valentine RJ, et al. J Vasc Surg. 1994 Apr;19(4):668-74.
McFalls EO, et al. CARP Trial. N Engl J Med. 2004 Dec 30;351(27):2795-804.
Klop RB, et al. Eur J Vasc Surg. 1991 Feb;5(1):41-5.
Cheng Sw, et al. Cardiovasc Surg. 1999 Apr;7(3):303-9.
Steg, et al. REACH Registry. JAMA 2007
Natural History of PAD
Population
> 55 years of age
Intermittent claudication
5%
Other
cardiovascular
morbidity/total mortality
Peripheral vascular
outcomes
Stable
claudication
73%
Worsening
claudication
16%
Lower
extremity
bypass surgery
7%
Major
amputation
4%
Nonfatal
cardiovascular
event (MI/stroke)
20%
Adapted
Adapted from
from Weitz
Weitz Jl
Jl et
et al.
al. Circulation.
Circulation. 1996;94:3026-3049.
1996;94:3026-3049.
5-year
mortality
30%
Cardiovascular
cause
75%
Low ABI: Independent Predictor of
Survival
100
N=744 vascular lab patients
Survival (%)
90
ABI >0.85
80
70
60
ABI 0.4-0.85
50
40
ABI <0.4
30
20
0
2
4
6
8
Year
McKenna M, Wolfson S, Kuller L. Atherosclerosis. 1991;87:119-128.
10
All Cause Mortality
ABI and CV Risk
N=4393 American Indians
Strong Heart Study
Optimal ABI?
ABI
Resnick, et al. Circulation. 2004; 109(6) 733.
ABI Increases CV Risk Prediction
Beyond the Framingham Score
„ ABI
Collaboration. JAMA (2008)
„ Meta-analysis of 16 cohort studies involving 480,325
person-years of data
– e.g., ARIC, Edinburgh, Framingham offspring,
Strong Heart, San Diego, Rotterdam
„ Lowest risk of death in ABI 1.11 – 1.4 range
„ For each Framingham risk category, low ABI (<.91)
doubles CV event and death rate
„ ABI adds additive information to Framingham risk
score
– Risk reclassification or modification of treatment
„ 19% of men
ABI Collaboration. JAMA. 2008;300:197.
„ 36% of women
ACC/AHA Consensus Guidelines: Who
should have an ABI test?
Class I recommendation:
The resting ABI should be used to establish the lower extremity
PAD diagnosis in patients with:
– Exertional leg symptoms
– Non-healing wounds
– Asymptomatic patients at high risk
Adults > 70 years of age
„ Adults > 50 years of age with diabetes or tobacco use
„
Hirsch, AT, et al. ACC/AHA Guidelines for the Management of Patients with PAD. 2005.
U.S. Preventive Services Task Force:
Who Should Have an ABI Test?
„ The
USPSTF recommends against routine screening for
!
peripheral arterial disease (PAD)
No one without symptoms
„ On
what basis? Screening for PAD among asymptomatic
adults in the general population would have few or no benefits
because:
9 the prevalence of PAD in this group is low (!!)
9 there is little evidence that treatment of PAD at this
asymptomatic stage of disease improves health outcomes.
9 screening asymptomatic adults with the ABI could lead to
some small degree of harm, including false-positive results
and unnecessary work-ups
U.S. Preventive Services Task Force. Screening for Peripheral Arterial Disease:
Recommendation Statement. AHRQ Publication No. 05-0583-A-EF, August 2005.
http://www.ahrq.gov/clinic/uspstf05/pad/padrs.htm.
Management of PAD:
A Three-Pronged Approach
Prevent MI,
Prevent
MI,
stroke, and
Stroke,
death and
Death
All patients with PAD
Symptomatic patients
Protect the
Feet: Prevent
Amputation
Management
of the Patient
with PAD
Treat Intermittent
Claudication:
Improve QOL
Foot Care and Ulcer Prevention
„ Meticulous
„ Daily
foot and nail care
foot self-inspection
„ Appropriate
footwear
„ PAD
patients with diabetes
at highest risk for amputation
„ Collaborate
with podiatry
colleagues when appropriate
„ Review
warning signs of critical limb ischemia (CLI)
– Advise patients when to call in to report an ulcer
„ Reinforce
importance of foot care at each office visit
Preventing Cardiovascular
Events in Patients with PAD
„ Smoking
cessation
„ Antiplatelet therapy
„ Lipid lowering therapy
– Statins
– Other agents
„ Antihypertensive therapy
– Ace-inhibitors or ARBs
– Other agents
„ Glycemic control for the diabetic patient
Beneficial Effects of Smoking Cessation
in Patients with PAD
„ Decreases
likelihood of:
– Amputation1
– Need for revascularization2
– Failure of arterial bypass grafts3
„ Improves
pain free and maximal walking times
compared to patients who continue to smoke4,5
„ Improves survival6
1Lasila
R, Lepantalo M. Acta Chir Scand. 1988;154:635.
T, Bergstrom R. Acta Med Scand. 1987;221:253.
3Willigendael, et al. J Vasc Surg. 2005;42:67.
4Gardner AW. Vasc Med. 1996;1:181.
5Quick CR, Cotton LT. Br J Surg. 1982;69:S24.
6Faulkner KW. Med J Aust. 1983;1:217.
2Jonason
Anti-Platelet Therapy: Antithrombotic
Trialists’ Collaboration Meta-analysis
„ Meta-analysis
of anti-platelet therapy for
cardiovascular disease
„ 42
clinical trials enrolled patients
with PAD
„ 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 Trialists’ Collaboration. BMJ. 2002;324:71.
CAPRIE: Efficacy of Clopidogrel vs. Aspirin in
MI, Ischemic Stroke, or Vascular Death
N= 19,185
Aspirin
Cumulative Event Rate (%)
16
Aspirin
5.83%
12
8
Clopidogrel
5.32%
Clopidogrel
4
p = 0.043
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Months of Follow-Up
CAPRIE Steering Committee. Lancet. 1996;348:1329.
8.7%*
Overall
Relative Risk
Reduction
Aspirin 325 mg/d vs.
Clopidogrel 75 mg/day
ACC/AHA PAD Guidelines: Antiplatelet Therapy
I IIa IIb III
Antiplatelet therapy is indicated to reduce the risk of
myocardial infarction, stroke, or vascular death in
individuals with atherosclerotic lower extremity PAD.
I IIa IIb III
Aspirin, in daily doses of 75 to 325 mg, is recommended
as safe and effective antiplatelet therapy to reduce the
risk of myocardial infarction, stroke, or vascular death in
individuals with atherosclerotic lower extremity PAD.
I IIa IIb III
Clopidogrel (75 mg per day) is recommended as an
effective alternative antiplatelet therapy to aspirin to
reduce the risk of myocardial infarction, stroke, or
vascular death in individuals with atherosclerotic lower
extremity PAD.
Hirsch AT, et al. ACC/AHA Guidelines for the Management of Patients with PAD 2005.
Primary Endpoint rate (%)
CHARISMA: Effect of Combination
Anti-Platelet Therapy on Major CV Events
Placebo + ASA*
7.3%
8
Clopidogrel + ASA*
6.8%
N=15,603
6
4
RRR: 7.1% [95% CI: -4.5%, 17.5%]
p=0.22
2
0
0
6
12
18
24
Months since randomization
*All patients received ASA 75-162 mg/day
Bhatt DL, Fox KA, Hacke W, et al. NEJM. 2006;354:1706.
30
CHARISMA Study: Subset Analysis by
Category of Inclusion Criteria
N=9,478 subset with prior MI, ischemic stroke (IS), or symptomatic PAD
Prior MI
But 60% Increase in
Placebo Clopidogrel
HR (95% & CI)
Moderate Bleeding
with0.774
Dual
8.3%
6.6%
(0.613, 0.978)
Anti-Platelet Therapy
Prior IS
Prior PAD
10.7%
0.780 (0.624, 0.976)
Dual anti-platelet therapy
8.7%
7.6%
0.869 (0.671, 1.125)
not for everyone
Entire Cohort
0.5
8.4%
8.8%
1.0
Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982.
7.3%
2.0
0.829 (0.719, 0.956)
P-value
0.031
0.029
0.085
0.010
Multiple Benefits of Statins in PAD
Prevent MI, stroke, and CV death
„ Other benefits
– Shown to improve claudication in single-center studies1
– May slow rate of functional decline among patients with
PAD2
– Use associated with improved patency of infrainguinal
bypass grafts3
– Use associated with decreased perioperative
complication rate among patients undergoing major
vascular surgery4,5,6
„
1Mohler
E, et al. Circulation. 2003;108:1481.
J, et al. J Am Coll Cardiol. 2006;47:998.
3Abbruzzese TA, et al. J Vasc Surg. 2004;39:1178.
4Poldermans, et al. Circulation. 2003;107:1848.
5Durazzo AE, et al. J Vasc Surg. 2004;36:967.
6Feringa HH, et al. J Amer Coll Cardiol. 2007;50:1649.
2Giri
ACC/AHA Guidelines for the
Management of Patients with PAD
Class I
Statins are indication for all patient with PAD to achieve
an LDL<100mg/dl
Class IIa
Treatment with a statin to achieve a target LDL of <70 mg/
dl is reasonable for patients with LE PAD at very high risk
for ischemic events.
Hirsch et al. JACC 2006.
The HOPE Study: Effect of Ramipril on
MI, Stroke or Cardiovascular Death
Proportion of
Patients with major CV Event
n = 9,297
0.20
RR=0.78
p < 0.001
Placebo
0.15
0.10
Ramipril
0.05
0.00
0
500
1000
1500
Days of Follow-up
The Heart Outcomes Prevention and Evaluation Study Investigators. N Engl J Med. 2000;342:145.
The HOPE Study:
PAD Subgroup Analysis
No. of
Patients
Incidence of
Composite Outcome
in Placebo Group
PAD
4051
22.0
No PAD
5246
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.
ONTARGET: ARBs as Alternatives
to ACE-Inhibitors
Cumulative Hazard Ratio
0.20
0.15
N=25,620
2,468 with PAD
Telmisartan
Ramipril
Telmisartan plus ramipril
0.10
0.10
0.00
0
No. at Risk
Telmisartan 8542
8576
Ramipril
Telmisartan 8502
plus ramipril
N Engl J Med 2008;358:1547.
1
2
3
4
Years of Follow-up
8177
8214
8133
7778
7832
7738
7420
7472
7375
7051
7093
7022
5
1687
1703
1718
Therapies for Intermittent
Claudication
„ Supervised
exercise rehabilitation
„ Medical therapy
– Pentoxifylline
– Cilostazol
„ Revascularization
– Percutaneous
– Surgical
Efficacy of Supervised Exercise Training for
Claudication: Findings of Meta-analyses
„ Up
to 180% improvement in pain free walking
distance1
„ 120 – 150% improvement in maximal walking
distance1,2
„ Predictors of greatest clinical response1:
– Enrollment in walking only focused program
– Sessions > 30 minutes each
– At least 3 sessions per week
– Training with walking to near-maximal pain
– > 6 month program
1Gardner
2Leng
AW, Poehlman ET. JAMA.1995;274:975.
GC, et al. Cochrane Review 2000. CD000990.
Pharmacotherapy for PAD
FDA Approved
Drugs
„ Pentoxifylline
„ Cilostazol
„ Naftidrofuryl
(Europe)
1Creager
MA, et al. Vasc Med 2008;13:5.
Trial. AHA 2007.
2PROVIDENCE
3Wilson
Am, et al. Circulation. 2007;116:188.
Investigational
„ Niacin
„ Propionyl-L-carnitine
„ New PDE inhibitors
„ Serotonin antagonists
„ Angiogenic Factors
ƒ HiF 1α
ƒ VEGF
ƒ bFGF
„ Stem cell therapy
Symptomatic Therapies
Therapy
Mechanism
Pentoxifylline
(Trental®)
• ↓ Blood viscosity
Cilostazol (Pletal®)
• ↓ Platelet aggregation
• Trigger vasodilation
• Improve lipid profile
Fernandez BB Jr. Am J Med Sci. 2002;323:244-251.
251
ACC/AHA PAD Guidelines: Pharmacotherapy for
Claudication
I IIa IIb III
I IIa IIb III
I IIa IIb III
Cilostazol (100 mg orally 2 times per day) is indicated
as an effective therapy to improve symptoms and
increase walking distance in patients with lower
extremity PAD and IC.
A therapeutic trial of cilostazol should be considered in
all patients with lifestyle-limiting claudication (in the
absence of heart failure).
Pentoxifylline (400 mg 3 times per day) may be
considered as second-line alternative therapy to
cilostazol to improve walking distance in patients with
IC. The clinical effectiveness of pentoxifylline as
therapy for IC is marginal and not well established (C).
Hirsch AT, et al. ACC/AHA Guidelines for the Management of Patients with PAD 2005.
Cilostazol Caveats and Cautions
BLACK BOX WARNING: Cilostazol is contraindicated in
patients with congestive heart failure of any severity
„ Extensive CYP 3A4 (and CYP2C19) Metabolism
– Consider 50 mg BID starting dose
„ With CYP 3A4 inhibitors (e.g., ketoconazole,
erythromycin, diltiazem, fluoxetine, others)
„ With CYP2C19 inhibitors (e.g., omeprazole)
„ Cilostazol blood levels may be increased
„ Cilostazol does not increase blood levels of statins
„ Side effects of cilostazol are common1
– Abnormal stools or diarrhea (~15-20%)
– Palpitations or tachycardia (~15%)
– Headaches (25-35%)
„
1Source:
cilostazol package insert
Indications for Revascularization
Absolute Indications
„
„
Acute limb ischemia
Critical limb ischemia
– Rest pain
– Tissue loss
„ Non-healing ulceration
„ Tissue necrosis –
gangrene
Relative Indications
„
„
Lifestyle-limiting
claudication with poor
response to
pharmacotherapy +/exercise training
Lifestyle-limiting
claudication with impaired
QOL (primary therapy)
Which Intervention is
Best for Lower Extremity
PAD?
Percutaneous
Surgical
Balloon it
Stent it
Subintimally
dissect it
Options
Excise it
Lace it
Freeze it
Remove it
The SFA is Unique
Knee Extension
Knee Flexion
Forces Exerted on Stents in SFA
1.
Extension / Contraction
2.
Flexion
3.
Torsion
Compression
4.
Type
I
Type
II
Type
III
Type
IV
The Changing Landscape of
Peripheral Revascularization
979% Increase
Anderson PL, et al. J Vasc Surg. 2004;39:1200.
Durability of Surgical vs. Endovascular Outcomes for
Claudication1
„
Aortoiliac Revascularization
ƒ Aorto-bifem BPG
ƒ Iliac PTA
„
5-year
10-year
85-91%
79-86%
5-year
71%
Femoropopliteal Revascularization
ƒ Fem-pop BPG vein
5-year
ƒ Fem-pop BPG PTFE
5-year
ƒ Fem-pop PTA
ƒ Fem-pop PTA + stent
1Norgren
3-year
3-year
L et al. TASC II. J Vasc Surg. 2007;45:S5.
80%
65-75%
48-61%
64-66%
Summary
•
•
•
•
•
Vascular disease is a multi-system disease
Classic coronary risk factors are also predictive of
PAD occurrence
Conservative management involves a combination
of risk factor modification, pharmacologic, and
non-pharmacologic therapies
The best therapy for patients with PAD is the best
therapy for patients with CAD!
The utility and durability of lower extremity
revascularization varies with anatomic level of
disease
PAD Patient Education
Resources
Stay in Circulation Campaign
www.aboutpad.org
• NHLBI Health Information Center
www.nhlbi.nih.gov/health/infoctr
„ P.A.D. Coalition
www.PADCoalition.org
•
For referrals:
Yerem Yeghiazarians, MD
[email protected]
415-353-3817
THANK YOU