Jeffrey W. Olin, D.O., F.A.C.C., F.A.H.A.

Professor of Medicine (Cardiology)

Director of Vascular Medicine &

the Vascular Diagnostic Laboratory

Icahn School of Medicine at Mount Sinai

Peripheral Artery Disease Role of Exercise, Endovascular and Surgical Options

Peripheral Artery Disease (PAD)

• The presence of a stenosis or occlusion in the aorta or arteries of the limbs

• Usually caused by atherosclerosis

• Associated with an increased risk of death, myocardial infarction, and stroke

• May impair walking or cause critical limb ischemia

• The global burden of PAD is estimated to be 202 million persons

10%

40%50%

Classic Claudication Atypical Leg Pain Asymptomatic

Some Not So Well Known Facts

• Only 8%–10% of patients with

peripheral arterial disease (PAD)

have “classic” claudication

• ~40% of patients with PAD have

“atypical” leg symptoms

• ~50% of patients with PAD are

asymptomatic with regard to the

leg

ABI and Mortality

Ankle Brachial Index Collaboration. JAMA 2008.

Association of ABI with all-cause mortality in a meta-analysis of 16 cohort studies including 48,294 subjects and 480,325 person-years of follow-up.

Diehm, C. et al. Circulation 2009;120:2053-2061

The German Epidemiological Trial on ABI Study: Event-free Survival by PAD status

Reinecke et al. Eur Heart J 2015;36:932-938

Death (n= 10,880) Amputation (n= 7,825)

Contemporary PAD Outcomes in Germany

n = 41,882 PAD patients hospitalized during 2009 – 2011

Followed until 2013, (mean 1144 days)

Cardiovascular Risk Increases

With Decreases in ABI

>1.1 1.1–1.01 1.0–0.91 0.9–0.71 <0.7

ABI

CH

D E

ven

t O

utc

om

es*

per Y

ear (

%)

0

1

2

3

4

5-year risk:

10%

5-year risk:

19%

Framingham “High Risk” = 20% at 10 years Every patient with PAD is at “very high risk”

PAD *Fatal or nonfatal MI

2%

3.8%

1.4%

Leng GC et al. Brit Med J. 1996;313:1440-1444.

0

1

2

0

1

3

0

1

0

2

1

0

3

2

1

0

4

3

2

1

0

3.8%

2%

3.8%

The Peripheral Artery Disease Prescription

Olin JW et al. J Am Coll Cardiol 2016, In Press.

• 7458 eligible participants aged >40 years

• Prevalence of PAD is 5.9%, or 7.1 million US adults

with PAD – Statin use 30.5%

– ACE/ARB use 24.9%

– Aspirin use 35.8%

• Among patients with PAD (and no other clinical

cardiovascular disease), use of multiple preventive

therapy was associated with a 65% lower all-cause

mortality (HR 0.35, P=0.02)

Pande RL et al. Circulation. 2011;124:17-23.

National Health and Nutrition Examination

Study, 1999–2004

Armstrong E et al. J Am Heart Assoc 2014;3:e000697.

Adherence to Guideline-Recommended Medical Therapies

and Outcomes in Peripheral Artery Disease.

Major Adverse CV Events Major Adverse Limb Events

A total of 237 (32%) patients met all four guideline-recommended therapies

(antiplatelet, statin, ACE, smoking cessation)

The Efficacy of Statin Therapy The Heart Protection Study

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

Previous MI 23.5 29.4

Other CHD 18.9 24.2

No prior CHD or CBV disease 18.7 23.6

Diabetes 13.8 18.6

All patients 19.8 25.2

1.2 1.4 0.6 0.4

24% Reduction

(P<.0001)

Existing disease

Statin Control

Incidence of events

(n=10,269) (n=10,267) Statin favored Placebo

Risk vs Control

PAD 24.7 30.5

0.8 1.0

ACE Inhibitors in PAD

The HOPE Trial

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

History of CAD 7477

No history of CAD 1820

Prior MI 4892

No prior MI 4405

CBV disease 1013

No CBV 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

Collagen

Thrombin

TXA2

ADP

TXA2

ADP Phosphodiesterase

ADP

(fibrinogen

receptor)

GP IIb/IIIa Activation

COX

Clopidogrel bisulfate

Ticlopidine HCl

ASA

Dipyridamole

cAMP

Mechanisms of Action of Oral Antiplatelet Therapies

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

Ticagrelor- reversible P2Y12 inhibitor

Vorapaxar

-40 -30 -20 -10 0 10 20 30 40

Aspirin better Clopidogrel better

CAPRIE

Stroke

MI

PAD

All patients

• 3867 (20.2%) had diabetes

• ~ 1/3 PAD patients had diabetes

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

Population RRR (95% CI) P

Qualifying CAD, CVD, or PAD 0.88 (0.77, 0.998) .046

(n=12,153)

Multiple risk factors 1.20 (0.91, 1.59) .20

(n=3,284)

Overall population* 0.93 (0.83, 1.05) .22

(N=15,603)

CHARISMA: Clopidogrel plus Aspirin vs. Aspirin Alone on MI, Stroke, or CV Death

0.6 0.8 1.4 1.2

Clopidogrel better Placebo better

1.6 0.4

Bhatt DL, Fox KA, Hacke W, et al. New England Journal of Medicine, 2006

CHARISMA: Outcomes in the PAD Cohort

P Cacoub et al., Euopean Heart Jounal, 2009

EUCLID Study Design

Primary Endpoint: cardiovascular death, myocardial infarction, or ischemic stroke

Inclusion Criteria: Symptomatic PAD AND

one of the following:

A.ABI ≤0.80 at Visit 1

≤0.85 at Visit 2

OR

B.Prior lower extremity

revascularization > 30

days

Key Exclusion Criteria: Poor

metabolizer for CYP2C19

Patients requiring dual anti-platelet therapy

Patients with Symptomatic PAD

Ticagrelor 90 mg bid

Clopidogrel 75 mg od

N=11,500

Follow-Up Visits 2, 6, 12 Months; Every 6 months after 1st year

Telephone visits @ a 3 month interval between regular visits

Duration: approximately 18 month recruitment and 18 month follow up

1:1

Double-blind

Double-dummy

Vorapaxar- TRA2P Timi 50

Morrow D et al. N Engl J Med 2012.

0%

2%

4%

6%

8%

10%

12%

14%

0 180 360 540 720 900 1080

Effect of Vorapaxar on Cardiovascular

Events in PAD Cohort

CV Death, MI, or Stroke

11.3%

11.9%

Hazard Ratio 0.94;

95% CI (0.78 - 1.14)

p = 0.53

Placebo

Vorapaxar

N = 3767

Days from randomization

P-interaction:

PAD vs. MI/CVA = 0.35

PAD vs. MI cohort = 0.16

12

10

8

6

4

2

14

Even

t R

ate

(%

)

Vorapaxar in PAD

Circulation. 2012;125:130-139

Murphy T P et al. Circulation 2012;125:130-139

CLEVER Primary Endpoint:

Peak Walking Time Secondary Endpoints:

QOL,

Supervised Exercise

Better than Stenting,

P<0.001)

Stenting Better than

Supervised Exercise

The ERASE Trial Endovascular Revascularization and Supervised Exercise

vs. Supervised Exercise for Intermittent Claudication

Fahkry et al., JAMA. 2015;314(18):1936-1944

The ERASE Trial Endovascular Revascularization and Supervised Exercise

vs. Supervised Exercise for Intermittent Claudication

Fahkry et al., JAMA. 2015;314(18):1936-1944

Claudication Treatment—Exercise

• Supervised exercise training should be the

initial treatment

–30–45 minute sessions

–3 or more times per week

–At least 12 weeks

• Value of unsupervised exercise programs

is not well established

Rooke T et al. J Am Coll Cardiol. 2013;61:1555-70

Pande R et al. Vascular Medicine 2010;15:181-188.

Double-Blind, Randomized Controlled Trials of

Cilostazol In Patients with Intermittent Claudication

Medical Therapy (all patients)

• Detailed written and verbal (28 page booklet):

– Risk factors

– Management

– Structured training advice

• Perform submaximal walk exercise sessions for at least 30 min/day

at least 3 times/week. Nordic pole use was encouraged.

– This program was evaluated and reinforced at 3 and 6 months.

• Aspirin or clopidogrel, statin therapy and cilostazol 100mg twice daily

in all patients

• Additional risk factors (hypertension, diabetes, smoking) managed

according to national guidelines by primary doctor.

Medical Outcomes Study Short Form 36 version 1 (SF-36) and Vascular Quality of Life

Questionnaire (VascuQoL) subscale effect sizes calculated between baseline and 12 months

for patients with invasive treatment (INV) and noninvasive treatment (NON).

Nordanstig J et al. Circulation. 2014;130:939-947

• Significantly larger improvement

was found in the invasive versus

noninvasive group regarding the

SF-36 Physical Component

Summary (P<0.001) and 2 SF-36

physical subscales (physical

functioning and bodily pain)

between baseline and 12

months.

• The change in VascuQoL total

score and 3 of 5 domain scores

(activities, symptoms, and

emotional) were significantly

larger in the invasive versus the

noninvasive group

Change in treadmill walking distances at 12-month follow-up.

Nordanstig J et al. Circulation. 2014;130:939-947

Guiding Principles for Revascularization

in Patients With PAD

Patients with PAD should have their feet inspected during every office

visit. This is the single most important thing you can do to prevent

amputations.

Olin JW, Sealove B. Mayo Clin Proc. 2010;85(7):678-692

Indications for Revascularization

• Iliac disease

– Hip, thigh, or buttock claudication

– Reduced or absent femoral pulses

– Imaging to identify iliac disease and stenting

• Infrainguinal disease

– Trial of medical therapy for 4–6 months:

–Structured exercise program

–Cilostazol

– If failure, additional imaging to define anatomy and, if

feasible, stent placement

– If short segment SFA disease is identified, can proceed

directly with stenting

Indications for Intervention in Patients With PAD

• Life-style disabling claudication

• Rest pain

• Ischemic ulcers

interfering

Case—A 62-Year-Old Diabetic Man

• ½ block calf claudication, Lt > Rt

• Heavy smoker

• ABI 0.41 on the right and 0.43 on the left

• Femoral pulse 1+ bilaterally

• Popliteal, DP, and PT=0

RESILIENT TRIAL

Nitinol Stent Implantation vs. Balloon

Angioplasty for Superficial Femoral Artery Disease

Schillinger M et al. N Engl J Med 2006;354:1879-88. d

6 month 10 Endpoint (Angio) 12 month 20 Endpoint (Duplex)

Treatment of superficial-femoral-artery disease by primary implantation of a self-

expanding nitinol stent yielded results that were superior to those with the currently

recommended approach of balloon angioplasty with optional secondary stenting.

Rosenfield K et al. N Engl J Med 2015;373:145-153

LEVANT 2 Trial Efficacy of Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease

476 patients with

symptomatic femoral-

popliteal disease were

randomized in a 2:1

manner to angioplasty

with a paclitaxel-coated

balloon or to standard

angioplasty.

The primary efficacy end

point was primary

patency of the target

lesion at 12 months

(defined as freedom from

binary restenosis or from

the need for target-lesion

revascularization).

JAMA Surgery Oct 2014

• NHLBI-sponsored prospective, randomized, multicenter,

open label superiority trial

• 2,100 patients at 120 clinical sites in United States and Canada

• 4-year trial extending from 2014-2017, with each patient having

minimum of 2 year follow-up

The Peripheral Artery Disease Prescription

Olin JW et al. J Am Coll Cardiol 2016, In Press.