peripheral arterial disease: missed opportunity for cardiovascular intervention

Peripheral Arterial Disease: missed opportunity for

cardiovascular intervention

Subhash Banerjee, MDChief, Division of Cardiology

VA North Texas Healthcare SystemAssociate Prof. in MedicineUT Southwestern Med. Ctr.

Oct. 2013

NIC Kolkata 2013

Worldwide PAD Trends (2013)

54·8 million in southeast Asia

Fowkes et al. Lancet 2013

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

29%

11.7%

19.8%19.1%

14.5%

4.3%

Prevalence of PAD

PARTNERS5Aged >70 years, or 50–69 years with a history diabetes or smoking

San Diego2Mean age 66 years

Diehm4Aged 65 years

Rotterdam3Aged >55 years

NHANES1

Aged 70 years

NHANES1

Aged >40 years

NHANES=National Health and Nutrition Examination Study; PARTNERS=PAD Awareness, Risk, and Treatment: New Resources for Survival [program].1. Selvin E, Erlinger TP. Circulation. 2004;110:738-743.2. Criqui MH, et al. Circulation. 1985;71:510-515.3. Diehm C, et al. Atherosclerosis. 2004;172:95-105. 4. Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192. 5. Hirsch AT, et al. JAMA. 2001;286:1317-1324.

In a primary care population defined

by age and common risk factors, the

prevalence of PAD was approximately

one in three patients

Gender Differences in the Prevalence of PAD

Adapted from Diehm C. Atherosclerosis. 2004;172:95-105 with permission from Elsevier.

Pre

vale

nce

(%)

WomenMen

6880 Consecutive Patients (61% Female) in 344 Primary Care Offices

<7002468

10121416

70–74 75–79 80–84 >85Age (years)

18

PAD: More Prevalent Than Many Leading Diseases

Source: American Cancer Society, American Heart Association, Alzheimers Disease Education/Referral Center, American Diabetes Association, SAGE Group

Diabetes CAD PAD Cancer CHF Stroke Alzheimers0

2

4

6

8

10

12

14

16

18

Disease Prevalence (Millions)

17

12.612

8.9

4.8 54

Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

Relative Risk

SmokingDiabetesHypertensionHypercholesterolemiaHyperhomocysteinemiaRenal insufficiencyAge (per 10 years)

Reduced Increased

Risk Factors for PAD

1 2 3 4 5 60

Diabetes Increases the Risk of PAD

22.4*19.9*

12.5

0

5

10

15

20

25

Normal GlucoseTolerance

Impaired Glucose Tolerance

Diabetes

Pre

vale

nce

of P

AD

(%)

Impaired glucose tolerance was defined as oral glucose tolerance test value ≥140 mg/dL but <200 mg/dL.*P.05 vs. normal glucose tolerance. Lee AJ, et al. Br J Haematol. 1999;105:648-654.

Age <50 years with diabetes, and one additional risk factor (e.g., smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)

Age 50 to 69 years and history of smoking or diabetes

Age ≥70 years Leg symptoms with exertion (suggestive of

claudication) or ischemic rest pain Abnormal lower extremity pulse examination Known atherosclerotic coronary, carotid, or renal

artery disease

Based on the epidemiologic evidence, an “at risk” population for PAD can be defined as:

Individuals “At Risk” for Lower Extremity PAD

ACC/AHA PAD Guidelines 2011

Using the Ankle-Brachial Index (ABI)

ABI=ankle-brachial index; DP=dorsalis pedis; PT=posterior tibial; SBP=systolic blood pressure.

Right ABI80/160=0.50

Brachial SBP160 mm Hg

PT SBP 120 mm HgDP SBP 80 mm Hg

Brachial SBP150 mm Hg

PT SBP 40 mm HgDP SBP 80 mm Hg

Left ABI120/160=0.75

Highest brachial SBP

Highest of PT or DP SBP

ABI(Normal >0.90)

Interpreting the Ankle-Brachial Index

ABI Interpretation

1.00–1.39

Normal

0.91–0.99

Borderline

0.41–0.90

Mild-to-moderate disease

≤0.40 Severe disease≥1.40 Non-compressible

(DM & CKD) ACC/AHA PAD Guidelines 2011

Ankle Brachial Index (ABI)

Diagnostic test Sensitivity Specificity

ABI < 0.90 95% 100%

Pap smear 30-87% 86-100%

Fecal occult blood 37-78% 87-98%

Mammography 75-90% 90-95%

Arch Intern Med. 2003;163:884-892

29% of Patients in a Target Population Were Diagnosed With PAD Using An Office-Based ABI

Patients diagnosed with PADPAD onlyPAD and CVD

PARTNERS: Prevalence of PAD and Other CVD in Primary Care Practices

29%44%

56%

ABI=ankle-brachial index; CVD=cardiovascular disease. Hirsch, AT et al. JAMA. 2001;286:1317-24.

Association Between ABI and All‑Cause Mortality*

01020304050607080

<0.61(n=156)

0.61-0.70(n=141)

0.71-0.80(n=186)

0.81-0.90(n=310)

0.91-1.00(n=709)

1.01-1.10(n=1750)

1.11-1.20(n=1578)

1.21-1.30(n=696)

1.31-1.40(n=156)

>1.40(n=66)

Baseline ABI

Tota

l Mor

talit

y (%

)

Age range=mid- to late-50s; ABI=ankle-brachial index; *Median duration of follow-up was 11.1 (0.1–12) years.O’Hare AM et al. Circulation. 2006;113:388-393.

N=5748

Risk increases at ABI values below 1.0 and above 1.4

Clinical Presentation of PAD

~15%Classic (Typical)

Claudication

~33%Atypical Leg Pain

(functionally limited)

50%Asymptomatic

1%-2%Critical

Limb Ischemia (CLI)

Claudication: impairs patient quality of life by causing painful cramps and dysfunction while walking

CLI: rest pain, non-healing or poorly healing ulcers, or gangrene

Do you have leg pain?

Long-Term Survival in Patients With PAD

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

Normal subjects

Asymptomatic PAD

Symptomatic PAD

Severe symptomatic PAD

100

75

50

25

0 2 4 6 8 10 12

Surv

ival

(%

)

Year

624 men and women who were residents of a predominantly white, upper-middle-class community in southern CA

Natural History of Atherosclerotic Lower Extremity PAD

PAD Population (50 years and older)

Initial clinical presentation

Asymptomatic PAD20%-50%

Atypical leg pain40%-50%

Claudication10%-35%

Critical limb ischemia1%-2%

Progressive functional

impairment

1-year outcomes

Alive w/ 2 limbs50%

Amputation

25%

CV mortality

25%5-year outcomes

(to next slide)

Hirsch AT, et al. Circulation. 2006;113:e463-654.

Claudication10%-35%

5-year outcomes

Limb morbidity

Stable claudication

70%-80%

Worsening claudicatio

n10%-20%

Critical limb ischemia1%-2%

Amputation(see CLI data)

CV morbidity & mortality

Nonfatal CV event(MI or stroke) 20%

Mortality15%-30%

CV causes 75%

Non-CV causes

25%

Hirsch AT, et al. Circulation. 2006;113:e463-654.

Asymptomatic PAD20%-50%

Atypical leg pain40%-50%

For each of these PAD clinical syndromes

Natural History of Atherosclerotic Lower Extremity PAD

CLI=critical limb ischemia; CV=cardiovascular; MI=myocardial infarction

PAD: More Prevalent and MoreDeadly Than Many Leading Diseases

Disease Prevalence (Millions)

0%

10%

20%

30%

40%

50%

ColorectalCancer

39%

30%28%

21%

14%

PAD Stroke CAD BreastCancer

Source: American Cancer Society, American Heart Association, Alzheimers Disease Education/Referral Center, American Diabetes Association, SAGE Group

Five-Year Mortality Rate

Diabetes CAD PAD Cancer CHF Stroke Alzheimers0

2

4

6

8

10

12

14

16

18 17

12.612

8.9

4.8 54

Prevalence of Abnormal ABI in Patients with Established CAD

ABI<0.9(58.4%)

ABI=0.9-1.4(38.7%)

ABI>1.4(2.9%)

Banerjee et al. ACC 2013

Cardiovascular Events Based on ABI Values and Presence of Diabetes Mellitus

no DM, normal ABI DM, normal ABI no DM, abnormal ABI DM, abnormal ABI0

5

10

15

20

25

1.16

4.483.91

5.524.65

5.977.03

14.29

2.33 2.24

0

4.223.45

4.23

6.15

13.46

7.95

12.4111.45

20.63

1-Ye

ar E

vent

Rat

e (%

)

p=0.006p=0.40

p=0.29

Death Non-fatal myocardial infarction Stroke Repeat coronary revascularization MACE


Freedom From MACE


Hazard ratio (HR) and 95% confidence interval (CI) for MACE in patients with: DM and normal ABI (HR=1.7, 95% CI: 0.71-4.06, P=0.24)no DM and abnormal ABI (HR=2.03, 95% CI: 0.83-4.98, P=0.12) and DM with abnormal ABI (HR=4.85, 95% CI: 2.22-10.61, p=0.0001) compared to the reference or control group (no DM and normal ABI)

DM: diabetes mellitusABI: ankle-brachial index

Cardiovascular Events in Patients with PAD

Ann Surg 1984;199:223-33

Potential reasons for excess CV events:

Increased vasospasm Increased burden of ‘vulnerable’ atheroma Systemic vascular inflammation Reduced fibrinolytic activity Hypercoagulability Reduced positive vascular remodeling

Lumen Lumen

Atheroma

Vessel wall

Progression of Coronary Atherosclerosis in PAD

CAD: coronary artery diseasePAD: peripheral arterial disease

Hussein et al. J Am Coll Cardiol, 2011; 57:1220-1225

3,479 patients with CAD from 3 statin RCT216 with PAD & 3,263 without concomitant PAD

No PAD PAD0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Serial Intravascular ultrasound assessments

Change in % atheroma volume

+ remodelling - remodelling

p = 0.009

+0.58 ± 0.38

+0.23 ± 0.3

Benefit from LDL Reduction Retained in PAD

CAD: coronary artery diseasePAD: peripheral arterial diseaseLDL: low density lipoprotein

Hussein et al. J Am Coll Cardiol, 2011; 57:1220-1225

3,479 patients with CAD from 3 statin RCT216 with PAD & 3,263 without concomitant PAD

Serial Intravascular ultrasound Assessments:

More extensive atherosclerosis Greater calcifications More constrictive remodeling Greater disease progression of

atherosclerosis PAD patients retain the ability to

derive a benefit from intensive risk modification strategies

Change in Total atheroma volume (mm3)

-3.5

-2.5

-1.5

-0.5

0.5

1.5

LDL<70No PAD

LDL<70PAD

LDL>70No PAD

LDL>70PAD

–3.0 ± 1.9

1.0 ± 1.4

–3.3 ± 1.1

–1.6 ± 1.0

p = 0.04 p < 0.001

CAPRIE – study design• 19 185 patients with recent IS, recent MI or

established PAD

• Clopidogrel 75 mg od versus aspirin 325 mg od

• Follow-up of 1–3 years (mean 1.91 years)

• Combined primary endpoint of IS, MI or vascular death

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

1CAPRIE Steering Committee. Lancet 1996;348:1329–1339.2Antiplatelet Trialists' Collaboration. BMJ 1994;308:81–106.3Fisher LD. J Am Coll Cardiol 1998;31(Suppl A):49A.

CAPRIE – efficacy profile of clopidogrel

Time from Randomization (Months)

Even

t rat

e/10

00 p

atie

nts/

year

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

Event rate per year

Placebo3 *

Aspirin1

Clopidogrel1

7.7%5.8%5.3%

* extrapolated curve 3

Based on the APTC findings,2 in a population similar to CAPRIE, for each 1000 patients treated per year, aspirin can be expected to prevent 19 events and clopidogrel, 24.1

0

40

80

120

160 8.7% relative risk reduction,

p = 0.043

5877

532419

Antiplatelet Therapy in PAD

Aspirin + Clopidogrel (75 mg per day) to reduce the risk CV events, not at an increased risk of bleeding.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Antiplatelet therapy is indicated to reduce the risk of CV events. Clopidogrel only as an alternative to Aspirin.


Antiplatelet therapy is indicated to reduce the risk of CV events in asymptomatic individuals with ABI 0.91-0.99 (C); ABI<0.91 (A)


ACC/AHA PAD Guidelines 2011

Effect of Smoking Cessation on Survival

0

20

40

60

80

100

0 1 2 3 4 5

Australian censusTobacco abstinenceContinued tobacco use

Years Postoperative

Faulkner KW, et al. Med J Aust. 1983;1:217-219.

133 Patients observed after bypass graft or lumbar sympathectomy

Cum

ulat

ive

Surv

ival

(%

)

Atorvastatin in Patients With Claudication and PAD

PFWT=pain-free walking time.*P=.03. No change in ABI over 12 months.

Mohler ER et al. Circulation. 2003;108:1481-1486.

*

Baseline Month 3 Month 6 Month 12

Mea

n ch

ange

from

bas

elin

e in

PFW

T (s

ec)

0

25

50

75

100

125

10 mg

Placebo80 mg

n=354ABI<0.9 or 20% decrease in exercise ABILDL<160 mg/dl

Intensive Antihypertensive Therapy in PAD: The ABCD Trial

0

10

20

30

40

Moderate treatment n = 227

Odds

of M

I, St

roke

or

Vas

cula

r Dea

th

Baseline ABI0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

Intensive treatment n = 227 *enalapril or nisoldipine

Mehler, et al. Circulation. 2003;107;753-756.ABCD: Appropriate Blood Pressure Control in Diabetes

Odds are calculated using moderate treatment and a baseline ABI of 1.0 as a reference

50

Difficulties for treatment specific to the femoro-popliteal segment

Extension / Contraction

Torsion

Compression

Flexion

Hostile environment for stent implantation

Endovascular Interventional Toolbox

Laser

Cryoplasty

Silverhawk

Nitinol self-expanding Stents

Primary Patency (%, 95% CI)

Durability of Endovascular Procedures

Mean1-year data2-year data3-year data4-year data5-year data

Femoropopliteal Stent

0 20 40 60 80 100

Infrapopliteal PTA

Femoropopliteal PTA

Iliac PTA

Iliac Stent

Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.CI=confidence interval; PTA=percutaneous transluminal angiography

Claudication Treatment Comparative Effectiveness (CLEVER Study 6m)

Hirsch et al. AHA 2011 “Late-breaking Trial

Peak Walking Time (min)Change from baseline at 6m

Pair-wise comparisonsDifference (min) p

Exercise vs. Medical 4.6 (95% CI, 2.7-6.5) <0.001

Stenting vs. Medical 2.5 (95% CI, 0.6-4.4) 0.02

Exercise vs. Stenting 2.1 (95% CI, 0.0-4.2) 0.04

Claudication Onset Time (min)Change from baseline at 6m

Pair-wise comparisonsDifference (min) p

Exercise vs. Medical 2.2 <0.003

Stenting vs. Medical 2.9 0.0006

Exercise vs. Stenting 0.7 0.43

Medical Exercise Stenting0

0.5

1

1.5

2

2.5

3

3.5

4

0.7

3.0

3.6

Medical Exercise Stenting0

1

2

3

4

5

6

7

1.2

3.7

5.8

Stenting QOL > ExerciseQOL or Medical RxQOL

Endovascular intervention is not indicated as prophylactic therapy in an asymptomatic patient with lower extremity PAD.


There is no evidence that any symptomatic clinical outcome can be improved, or adverse limb event averted (including amputation) by any prophylactic revascularization method, including angioplasty or

vascular surgical bypass.

Revascularization for Claudication

Surgery Cardiology

Interdisciplinary Approach to PAD

Antiplatelet

Smoking cessation Exercise

Cilostazol

Endovascular

SurgicalStatin

ACEPTA-Surgical Bridge

Take Home Message PAD is a common, yet serious, disease that raises the risk of

heart attack and stroke

PAD is not always symptomatic and may be silent in a vast majority of patients

Evaluation of PAD should be part of routine physical examination

Appropriate and timely interventions (medical & revascularization) can significantly improve cardiovascular outcomes

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peripheral arterial disease: missed opportunity for cardiovascular intervention

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