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

The Role of the Cardiologist in Peripheral Vascular Disease Evolving Role of Exercise, ACE-inhibitors, Intervention and Surgical Options

Olin JW et al. Role of the cardiologist in peripheral vascular

disease. J Am Coll Cardiol 1992;19:235-236.

Robert L. Frye should be congratulated for his excellent piece (on the President’s page) on the roll of the cardiologist in peripheral vascular disease (JACC 1991;18:641-2). The time is long overdue to recognize the fact that vascular medicine is more than just interventional therapy, imaging or the medical care of the vascular surgical patient. Without a thorough understanding of the etiology, pathophysiology, and natural history of the disease, as well as a knowledge of medical, surgical and interventional therapies, care for the patient will be less than optimal. The notion that a cardiologist who is trained in interventional therapy can apply these same procedures to the peripheral vasculature, is a misconception….

Peripheral Artery Disease with Claudication

or Critical Limb Ischemiaof CLI

• Tobacco

• Chronic Kidney Disease

– Most Common Cause of Chronic Kidney Disease

–Diabetes

• Diabetes

– Most Common Cause of Diabetes

–Obesity

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

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 Arterial Disease Prescription

• Decrease cardiovascular events and death

– Stop smoking

– Walking program

– Control blood pressure to goal

–ACE inhibitor

– LDL cholesterol <70 mg/dL or high dose statin therapy

– Antiplatelet therapy

• Improve symptoms and Quality of Life

– Walking program

– Cilostazol

– ? Ramipril

– Foot Care

– Revascularization (primarily endovascular in 2014)

• 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

Use of cardioprotective medications in the

first 18 months after incident diagnosis.

Subherwal S et al. Circulation 2012;126:1345-1354

Antiplatelet

Statin

ACE Inhibitor

Levels of Disease

• Aorto-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

–ACE Inhibitors?

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

feasible, stent placement

– If short segment SFA disease is identified, can proceed

directly with stenting

Circulation. 2012;125:130-139

Hypothesis and Treatment Groups

• Iliac stent revascularization will result in at least a 30%

more improvement in treadmill walking performance than

supervised exercise

• 3 Treatment Groups

– Optimal medical care (OMC)

–Cilostazol 100 mg BID and written and oral advise about exercise and

monthly contact

– Stent revascularization and OMC

–OMC plus aortoiliac stenting

– Supervised exercise and OMC

–OMC plus 78 weeks of supervised exercise, 3 x week, 1 hour sessions

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

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

1. Health Care Purchasers (Commissioners) Don’t Like Supervised Exercise

2. Patient’s Don’t Like Supervised Exercise-looking for a quick fix (pills or intervention)

3. Clinicians Don’t Like Supervised Exercise- As they say “Asking Vascular Surgeons and Interventional Radiologists (and Interventional Cardiologists) to embrace societal guidelines on intermittent claudication may be akin to asking “Turkeys to vote for Christmas”

Popplewell MA, Bradbury AW. Eur J Vasc Endovasc Surg 2014;48:608-610.

ACC/AHA/ESVS/ESC all give supervised exercise a Class I Level of Evidence A recommendation. Multiple randomized prospective trials demonstrating efficacy.

6 Month Change in Study Outcome

Every Subgroup Benefited

Frequency: 3–5 days per week

Modality Treadmill (can be adapted for walking outside)

Method 1.Begin at 2 mph and a gradient of 0 (flat)

2.Stop exercise when pain is 3–4 on claudication pain scale*

3.When the pain has ceased, resume exercise at the same intensity

4.Repeat rest and exercise cycles

5.Progress to a higher work load when the patient can walk for 8 minutes without having

to stop for leg symptoms:

a) Increase speed by 0.2 mph each time the patient can walk for 8 min

b) Once patients can walk at 3.4 mph, or reach a speed at which they can no

longer keep up, begin increasing the grade by 1%–2%

Duration The total exercise period, including rest periods, should equal 50 minutes per day

*Claudication pain scale: 1=no pain; 2=onset of claudication; 3=mild pain or

discomfort; 4=moderate pain or discomfort; 5=severe pain or discomfort

Home Exercise Program

Weinberg MD, Lau JF, Olin JW. Nat Rev Cardiol. 2011;8:429-441.

Antiplatelet activity

Antithrombotic activity

Produces vasodilation

Mildly increases heart rate

Increases blood flow

Increases HDL-C

Decreases triglycerides

In vitro inhibition of vascular smooth

muscle cells Cilostazol

Pharmacologic Effects of Cilostazol

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

A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication

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

A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication

Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral

Artery Disease and Intermittent Claudication: A Randomized Controlled Trial

JAMA. 2013;309:453-60.

75 Seconds

255 Seconds

ABI Increased!

• Relative to placebo: – increases in VEGF-A by 38%

– Increases in FGF-2 by 64%

– Decreases in • D-dimer by 24%

• hsCRP by 13%

• sVCAM-1 by 14%

• ICAM-1 by 15%

Clinical outcome (n=737) was evaluated in a composite variable:

• patient reported leg function

– Improved

– Unchanged

– Deteriorated

• amputation

• death

• Patent reconstruction at 1 year was also counted as improvement.

Eur J Vasc Endovasc Surg 2014;47:615-620.

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.

Interventional Procedure Performed

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

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

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.

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.

Vorapaxar in PAD

Indications for Intervention in Patients With PAD

• Life-style disabling claudication

• Rest pain

• Ischemic ulcers

interfering

Guiding Principles for Revascularization

in Patients With PAD

1. Always assess inflow (aortoiliac) and outflow (run off to the feet)

2. Only revascularize for claudication if the patient has no other

condition that will limit their walking (i.e. spinal stenosis, severe

heart failure or COPD)

3. In treating CLI with ischemic ulcers, always try to provide straight

line flow into the foot

4. All patients undergoing revascularization should be receiving

maximal medical therapy to reduce the risk of MI, stroke and CV

death

5. Patients undergoing revascularization should be put on a walking

program after the revascularization

6. 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

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

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

Aortic Occlusion (cont)

Pre Post 10 x 94 Wallstents

Recommendations Class Level

When revascularization is indicated, an endovascular-

first strategy is recommended in all femoropopliteal

TASC A-C lesions

I C

Primary stent implantation should be considered in

femoropopliteal TASC B lesions

IIa A

A primary endovascular approach may also be

considered in TASC D lesions in patients with severe

comorbidities and if an experienced interventionist is

available

IIb C

ESC Guidelines—Diagnosis and Treatment of PAD

Recommendations for Revascularization

in Patients With Femoropopliteal Lesions

Tendera M. Eur Heart J. 2011: first published online August 26, 2011

Recommendations Class Level

When revascularization in the infrapopliteal segment is

indicated, the endovascular-first strategy should be

considered

IIa C

For infrapopliteal lesions, angioplasty is the preferred

technique, and stent implantation should be considered only

if PTA is insufficient

IIa C

Recommendations for Revascularization

in Patients With Infrapopliteal Lesions

ESC Guidelines—Diagnosis and Treatment of PAD (cont)

Tendera M. Eur Heart J. 2011: first published online August 26, 2011

JAMA Surgery Oct 2014

The PAD Prescription

• Decrease cardiovascular events and death

– Stop smoking

– Walking program

– Control blood pressure to goal

–ACE inhibitor

– LDL cholesterol <70 mg/dL or high dose statin

– Antiplatelet therapy

• Improve symptoms and Quality of Life

– Walking program

– Cilostazol

– ? Ramipril

– Foot Care

– Revascularization (under most circumstances,

endovascular first