ACC NY Cardiovascular Symposium

Peripheral Vascular Disease:

Watch the Heart and the Brain

Evolving Role of Exercise, ACE-Inhibitors, Interventional and

Surgical Options

Mark A. Creager, M.D

President, American Heart Association

Dartmouth-Hitchcock Heart and Vascular Center

Geisel School of Medicine at Dartmouth

Lebanon, NH

Conflicts of Interest

• None

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

Age,

years

Women, % Men, %

HIC LMIC HIC LMIC

25–29 2.70 3.96 2.76 1.21

30–34 3.20 4.46 3.27 1.50

35–39 3.78 5.01 3.88 1.87

40–44 4.47 5.62 4.58 2.33

45–49 5.28 6.31 5.41 2.89

50–54 6.23 7.08 6.38 3.58

55–59 7.33 7.92 7.51 4.43

60–64 8.60 8.87 8.82 5.47

65–69 10.08 9.91 10.33 6.74

70–74 11.77 11.05 12.07 8.28

75–79 13.71 12.32 14.05 10.13

80–84 15.91 13.70 16.30 12.33

85–89 18.38 15.22 18.83 14.94

90–94 21.14 16.87 21.65 17.99

95–99 24.20 18.65 24.77 21.50

Global Prevalence of PAD

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

– The prevalence increases with age

– In HIC, the prevalence of PAD is similar between women and men

– In LMIC, the prevalence of PAD was higher in women than men at most ages

Estimated Age-Specific PAD

Prevalence for Women and Men in HIC

and LMIC

Fowkes FG, et al. Lancet. 2013;382(9901):1329-1340.

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

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

REACH Registry One Year Event Rates for the

Composite of CV Death, MI and Stroke

Steg PG et al,. JAMA 2007;297(11): 1197-1206.

4.5

6.5

5.4

2.2

0

1

2

3

4

5

6

7CADPADCVDRisk Factors

Perc

ent

CAD CVD PAD Risk Factors

The REACH Registry recruited >68,000 outpatients aged ≥45 years

with established CV disease or ≥3 risk factors from 44 countries.

Approximately 25% of the

patients with PAD had a

history of MI, 30% had

angina, 16% had a previous

stroke, and 15% had a

previous TIA

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

Death Amputation

Contemporary PAD Outcomes in Germany

n = 41,882 PAD patients hospitalized during 2009 – 2011Followed until 2013, (mean 1144 days)

7,825 patients were amputated and 10,880 died.

Physican Use of Secondary Prevention Therapies in PAD

18.7%

0 20% 40% 60% 80%

Statin use

20.8%ACE/ARB use

27.4%Anti-platelettherapy use

34.3%

65.8%

57.5% PAD with CVD

PAD without CVD

p<0.0001*

* Statistical comparison by Chi-square testPande et al., Circulation, 2011

The Efficacy of Statin TherapyThe 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 1.40.6 0.4

24% Reduction24% Reduction24% Reduction24% Reduction

((((PPPP<.0001)<.0001)<.0001)<.0001)

Existing diseaseStatin 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

REACH Registry: Statin Therapy and AdverseLimb Outcomes in Patients with PAD

Multivariate modeling

Statin use (Y/N)

(N = 5,861)

Multivariate modeling

Time-varying statin use (N =

5,006)

Multivariate modeling

Propensity analysis

(N = 5,642)

All-cause mortality 0.82 (0.72 – 0.95) P=0.009 0.79 (0.65 – 0.94) P=0.0098 0.96 (0.84 – 1.09) P=0.51

CV mortality 0.83 (0.69 – 0.99) P=0.04 0.78 (0.61 – 0.98) P=0.034 0.90 (0.77 – 1.06) P=0.21

Non-fatal MI 0.89 (0.66 – 1.20) P=0.44 0.80 (0.58 – 1.11) P=0.18 0.69 (0.53 – 0.89) P=0.004

Non-fatal stroke 0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006

Worsening claudication or

new CLI

0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005

New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003

New amputation 0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001

Non-fatal stroke 0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006

Worsening claudication or

new CLI

0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005

New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003

New amputation 0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001

Kumbhani D J et al. Eur Heart J 2014Days from Randomization

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

Mean change from baseline

in PFWT (sec)

0

25

50

75

100

125

10 mg

Placebo80 mg

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 1820Prior MI 4892

No prior MI 4405CBV disease 1013

No CBV disease 8284Peripheral vascular disease 4051

No peripheral vascular disease 5246Microalbuminuria 1956

No microalbuminuria 7341

No. ofPatients

ReducedReducedReducedReduced IncreasedIncreasedIncreasedIncreasedRelative risk in ramipril group

0.6 0.8 1.0 1.2

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: Affect of Clopidogrel plus Aspirin vs. Aspirin Alone

on MI, Stroke, or CV Death

0.6 0.8 1.41.2Clopidogrel better Placebo better

1.60.4

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

TIMI TRA2oP: Effect of Vorapaxar on CV Events in PAD

0%

2%

4%

6%

8%

10%

12%

14%

0 180 360 540 720 900 1080

CV Death, MI, or Stroke

Placebo

Vorapaxar

N = 376711.3%

11.9%

Hazard Ratio 0.94;95% CI (0.78 - 1.14)

p = 0.53

Morrow DA, Braunwald E, Bonaca MP. N Engl J Med. 2012; 366: 1404-1413Days from Randomization

Eve

nt

Ra

te

0%

1%

2%

3%

4%

5%

0 180 360 540 720 900 1080

Effect of Vorapaxar on Limb Vascular Events in PAD

Hospitalization for Acute Limb Ischemia

Pre-specified, adjudicated

2.3%

3.9%

Hazard Ratio 0.5895% CI 0.39 to 0.86

p = 0.006

PlaceboVorapaxar

N = 3767

Days from randomization

4

3

2

1

5

Event

Rate

(%

)

Bonaca et al Circulation. 2013;127:1522-1529

00 180 360 540 720 900 1080

0%

5%

10%

15%

20%

25%

0 180 360 540 720 900 1080

Effect of Vorapaxar on Limb Vascular Events

Peripheral Revascularization

Prespecified

18.4%

22.2%

Hazard Ratio 0.84;

95% CI 0.73 to 0.97

p = 0.017

PlaceboVorapaxar

N = 3767

Days from randomization

20

15

10

5

25

Eve

nt

Ra

te

(%)

Bonaca et al Circulation. 2013;127:1522-1529

0

0 180 360 540 720 900 1080

Treatment of Symptomatic PAD

• Medical Therapy

• Exercise Training

• Revascularization

– Endovascular Intervention vs. Open

– Surgical Revscularizartion

Effect of Cilostazol on Maximal Walking Distance:

A Meta-analysis

0

20

40

60

Pe

rce

nt

Me

an

Ch

an

ge

fro

m B

ase

lin

e

in M

axi

ma

l W

alk

ing

Dis

tan

ce

**

Cilostazol 100 mg

Cilostazol 50 mg

Placebo

Pentoxifylline

Pande et al., Vasc Med 2010 15: 181

Nine randomized, placebo controlled trials

Claudication: Exercise vs. Endoluminal Revascularization

The CLEVER Study

Pair-Wise Comparisons

Difference (minutes) P Value

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

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

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

Peak Walking TimeChange from Baseline to Six (6) Months

Min

ute

s

TP Murphy et al., Circulation, Published online 11.16.11

min

ute

s

n = 22 n = 43 n = 46

The ERASE TrialEndovascular Revascularization and Supervised Exercise

vs. Supervised Exercise for Intermittent Claudication

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

The IRONIC Trial:Improved Walking Distance with an Invasive vs.

Noninvasive Strategy

n =158

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

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

The IRONIC Trial:Improved Quality of Life with an Invasive Strategy

The BASIL StudyAngioplasty vs Bypass Surgery

on Amputation Free Survival in Patients with CLI

BASIL Trial Participants, Lancet, 366:1925, 2005

• 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

Thank you!