Peripheral Arterial Peripheral Arterial DiseaseDisease

Mehul Bhatt, MDMehul Bhatt, MD

Interventional Cardiology / Vascular Interventional Cardiology / Vascular MedicineMedicine

Athens Heart CenterAthens Heart Center

Two Major Goals in Treating Patients With Two Major Goals in Treating Patients With PADPAD

Improved ability to walkImproved ability to walk

Increase in peak walking Increase in peak walking distancedistance

Improvement in quality-Improvement in quality-of-life (QoL)of-life (QoL)

Prevention of progression to Prevention of progression to critical limb ischemia and critical limb ischemia and amputationamputation

Treatment of critical limb Treatment of critical limb ischemia and amputationischemia and amputation

• Decrease in morbidity Decrease in morbidity from non-fatal MI and from non-fatal MI and strokestroke

• Decrease in Decrease in cardiovascular mortality cardiovascular mortality from fatal MI and strokefrom fatal MI and stroke

Limb outcomes

Cardiovascular morbidity and mortality

outcomes

Medical TreatmentMedical Treatment Smoking cessationSmoking cessation Statin therapyStatin therapy Blood pressure controlBlood pressure control Oral antiplatelet therapyOral antiplatelet therapy Exercise therapyExercise therapy Pentoxifylline / CilostazolPentoxifylline / Cilostazol

Effect of Smoking Cessation on Effect of Smoking Cessation on SurvivalSurvival

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

ula

tive S

urv

ival (%

)

Heart Protection Study:Heart Protection Study:Vascular Event by Prior DiseaseVascular Event by Prior Disease

CBD=cerebrovascular disease; CHD=congestive heart disease. Reprinted with permission from Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22 from Elsevier.

Previous MI23.5

29.4

Other CHD 18.9

24.2No prior CHD or CBV

disease18.7

23.6

Diabetes13.8

18.6

All patients19.8

25.2

1.0 1.2 1.40.80.60.4

24% Reduction (P<.0001)

Existing diseaseStatin Control

Incidence of events

(n=10,269)

(n=10,267) Statin

favoredPlacebo

Risk vs Control

PAD24.7

30.5

Considerations for the Treatment of Considerations for the Treatment of Hypertension in PADHypertension in PAD

Blood pressure lowering is indicated to Blood pressure lowering is indicated to reduce the risk of stroke, MI, CHF, CRF, reduce the risk of stroke, MI, CHF, CRF, and death.and death.

Only major reductions in perfusion Only major reductions in perfusion pressure may worsen claudication (21 pressure may worsen claudication (21 mm Hg decrease in SBP resulted in a 9% mm Hg decrease in SBP resulted in a 9% decrease in absolute claudication decrease in absolute claudication distance).distance).

Individuals with PAD should receive Individuals with PAD should receive hypertension treatment according to hypertension treatment according to current national guidelines (e.g., JNC-7).current national guidelines (e.g., JNC-7).

CRF=chronic renal failure; CHF=congestive heart failure.

- Blockers Are Not - Blockers Are Not Contraindicated in PADContraindicated in PAD

In a meta analysis of 11 randomized In a meta analysis of 11 randomized controlled trials beta-blocker therapy controlled trials beta-blocker therapy did not worsen claudication in did not worsen claudication in patients with PAD.patients with PAD.

Beta blockers had no significant Beta blockers had no significant effect on pain-free walking distance effect on pain-free walking distance compared with placebo in pooled compared with placebo in pooled analysis.analysis.

Radack K. Arch Intern Med. 1991;151:1769.

N=9214.Data from 197 randomized trials comparing an antiplatelet agent (APT; aspirin, clopidogrel,

dipyridamole, or a glycoprotein IIb/IIIa antagonist) vs control or another antiplatelet agent.APT=antiplatelet; CRTL=control.

Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.

CategoryCategory APTAPT CTRLCTRL Reduction Reduction (%)(%)

Intermittent 6.4% 7.9%Intermittent 6.4% 7.9% 23±9 23±9claudicationclaudication

Peripheral artery 5.4% 6.5% Peripheral artery 5.4% 6.5% 22±16 22±16bypass graftbypass graft

PeripheralPeripheral 2.5% 2.5% 3.6% 3.6%29±3529±35

angioplastyangioplasty

All high-risk patientsAll high-risk patients 22±2 22±2

((PP<.001)<.001)1.00.50.0 1.5 2.0

Antithrombotic Trialists’ Collaboration (ATC):Antithrombotic Trialists’ Collaboration (ATC):

Meta-Analysis of Vascular Events in Antiplatelet Trials in Patients With PADMeta-Analysis of Vascular Events in Antiplatelet Trials in Patients With PAD

Risk Reduction of Clopidogrel vs. Aspirin in Risk Reduction of Clopidogrel vs. Aspirin in Patients With Atherosclerotic Vascular DiseasePatients With Atherosclerotic Vascular Disease

Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

Stroke

0 10 20-10-20

MI

PAD

All patients

Aspirin favored

-30 30 40

Clopidogrel favored

N=19,185

Intermittent Claudication:Intermittent Claudication:Exercise Therapy (Supervised)Exercise Therapy (Supervised)

FrequencyFrequency:: 3–5 supervised sessions/week 3–5 supervised sessions/week DurationDuration:: 35–50 minutes of 35–50 minutes of

exercise/sessionexercise/session Type of exerciseType of exercise:: treadmill or track walking treadmill or track walking

to near-maximal claudication painto near-maximal claudication pain LengthLength:: 6 months 6 months ResultsResults:: 100%–150% improvement in 100%–150% improvement in

maximal walking distance and associated maximal walking distance and associated improvement in quality-of-lifeimprovement in quality-of-life

Stewart KJ et al. N Eng J Med. 2002;347:1941-1951.

Effects of Exercise Training Effects of Exercise Training on Claudicationon Claudication

Gardner AW, Poehlman ET. JAMA. 1995;274:975-980.

Exercise Training

Control

200

0

20

40

60

80

100

120

140

160

180

Onset of Claudication Pain

Maximal Claudication Pain

Change in T

readm

ill W

alk

ing

Dis

tance

(%

)

Meta-analysis of 21 Studies

*

*

* P < 0.05

Pharmacotherapy for Pharmacotherapy for ClaudicationClaudication

FDA Approved DrugsFDA Approved Drugs: : Pentoxifylline (Trental)Pentoxifylline (Trental)

Cilostazol (Pletal)Cilostazol (Pletal)

Anecdotal Treatments:Anecdotal Treatments: Ranolaxine (Ranexa)Ranolaxine (Ranexa)

Enhanced external counter-pulsation (EECP)Enhanced external counter-pulsation (EECP)

0

10

20

30

40

50

0 4 8 12 16 20 24Treatment (weeks)

Perc

en

tag

e C

han

ge F

rom

B

ase

line M

WD

(m

ean

)

Cilostazol vs. Pentoxifylline: Cilostazol vs. Pentoxifylline: Relative Efficacy to Improve Walking Distance in ClaudicationRelative Efficacy to Improve Walking Distance in Claudication

Cilostazol 100 mg 2 times/day (n=227)Pentoxifylline 400 mg 3 times/day (n=232)Placebo (n=239)

MWD=maximal walking distance. *P<0.001 vs pentoxifylline.

Reprinted from Dawson DL, et al. Am J Med. 2000;109:523-530 with permission from Elsevier.

**

Contraindications to Cilostazol UseContraindications to Cilostazol Use

ProvisosProvisos:: ““CHF of any severity” (systolic dysfunction)CHF of any severity” (systolic dysfunction) Any known or suspected hypersensitivity to any Any known or suspected hypersensitivity to any

of its componentsof its components

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared with placebo in patients with Class III-IV CHF. PLETAL® is contraindicated in patients with CHF of any severity.

CHF=congestive heart failure.

Pletal® (cilostazol) Package Insert. Rockville, Md: Otsuka America Pharmaceutical, Inc; 1999.