Cilostazol treatment intermittent claudication

Benefit on PAD Cohort

Intervention Treadmill/QoL Limitations Indicated

Exercise 100% / Improved Availability 50%-85%

Motivation

Cilostazol 50% / Improved CHF 50%-85%

Medication AEs

Angioplasty Improvement Proximal 10%-15%

arteries best

Surgery 150% / Improved Graft failure < 5%

Morbidity, mortality

Frequency: 3–5 supervised sessions/week Duration: 35–50 minutes of exercise/session Type of exercise: treadmill or track walking

to near-maximal claudication pain Length: 6 months Results: 100%–150% improvement in

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

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

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

Supervised Exercise Rehabilitation

A program of supervised exercise training is recommended as an initial treatment modality for patients with intermittent claudication.

Supervised exercise training should be performed for a minimum of 30 to 45 minutes, in sessions performed at least three times per week for a minimum of 12 weeks.

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


Warm-up: Approximately 5 minutes Repeated exercise periods: End at

moderate claudication level Rest Periods: Until claudication abates

Warm-up

This exercise interventional program has not been shown to be efficacious in a “home” setting. It requires a specific

procedure and environment, much like invasive interventional procedures.

Exercise Rest Exercise Exercise Cool

Down

Rest

Primary clinician role: Establish the PAD diagnosis using the ABI

measurement or other objective vascular laboratory evaluations

Determine that claudication is the major symptom limiting exercise

Discuss risk/benefit of claudication therapeutic alternatives, including pharmacological, percutaneous, and surgical interventions

Initiate systemic atherosclerosis risk modification Perform treadmill stress testing Provide formal referral to a claudication exercise

rehabilitation program

Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

Exercise Guidelines for Claudication: Warm-up and cool-down period: 5 to 10 minutes each Types of exercise:

Treadmill and track walking are the most effective exercise for claudication

Resistance training has conferred benefit to individuals with other forms of cardiovascular disease, and its use, as tolerated, for general fitness is complementary to but not a substitute for walking

Intensity: The initial workload of the treadmill is set to a speed and grade that

elicit claudication symptoms within 3 to 5 minutes Patients walk at this workload until they achieve claudication of

moderate severity, which is then followed by a brief period of standing or sitting rest to permit symptoms to resolve


Exercise Guidelines for Claudication: Duration:

The exercise-rest-exercise pattern should be repeated throughout the exercise session

The initial duration will usually include 35 minutes of intermittent walking and should be increased by 5 minutes each session until 50 minutes of intermittent walking can be accomplished

Frequency Treadmill or track walking 3 to 5 times per week

Key Elements of an Effective PAD Therapeutic Claudication Exercise Program (2)


Role of Direct Supervision: As patients improve their walking ability, the exercise

workload should be increased by modifying the treadmill grade or speed (or both) to ensure that there is always the stimulus of claudication pain during the workout

As patients increase their walking ability, there is the possibility that cardiac signs and symptoms may appear (e.g., dysrhythmia, angina, or ST-segment depression). These events should prompt physician re-evaluation

These general guidelines should be individualized and based on the results of treadmill stress testing and the clinical status of the patient. A full discussion of the exercise precautions for persons with concomitant diseases can be found elsewhere for diabetes *

*(Ruderman N, Devlin JT, Schneider S, Kriska A. Handbook of Exercise in Diabetes. Alexandria, Va: American Diabetes Association; 2002), (ACSM's Guidelines for Exercise Testing and Prescription. In: Franklin BA, ed. Baltimore, Md: Lippincott Williams & Wilkins; 2000), (Guidelines for Cardiac Rehabilitation and Secondary Prevention/American Association of Cardiovascular and Pulmonary Rehabilitation. Champaign, Ill: Human Kinetics; 1999).

Key Elements of an Effective PAD Therapeutic Claudication Exercise Program (3)


The usefulness of unsupervised exerciseprograms is not well established as aneffective initial treatment modality forpatients with intermittent claudication.

Hirsch AT, et al. J Am Col Cardiol. 2006;47:1239-1312.

The lack of proven efficacy for home-based, unsupervised exercise may be due to:

• A lack of compliance with the minimum “exercise dose”;• A lack of progression of the workload in the absence of

professional supervision;• A lack of confidence by the patient that it is safe to advance

into moderate claudication discomfort severity.


FDA Approved Drugs: Pentoxifylline

Cilostazol

There is inadequate evidence of clinical efficacy or a therapeutic role for:

L-arginine, propionyl-L-carnitine, gingko biloba, oral prostaglandins,

vitamin E, or chelation therapy.

Drug Class: Methylxanthine

Approved: August 1984

Dosing: 400 mg tid

Pharmacologic Hemorheologic agentProperties: Some vasodilation

Weak antiplatelet activity

In Favor of Placebo In Favor of Pentoxifylline

ICD Week 24

ACD Week 24

Minimum ICD Week 16-24

Minimum ACD Week 16-24

100 80 60 40 20 0 20 40 60 80 100

Lindgarde, et al. Vascular Medicine. 1996;1:145-154.Porter, et al. Am Heart J. 1982;104:66-72.Lindgarde, et al. Circulation. 1989;80:1459-1456.

US Study: n = 128Scandinavian Study: n = 150

Effect of Pentoxifylline on Claudication Distance: Pooled Analysis of US and Scandinavian Studies

ICD=intermittent claudication distanceACD=absolute claudication distance

Drug Class: Phosphodiesterase III

inhibitor derivative

Approved: January 1999

Dosing: 100 mg bid

Pharmacologic Platelet aggregation inhibitorProperties: Vasodilation

HDL-cholesterol (10%) Triglycerides (15%)Inhibits smooth muscle

cell proliferation in vitro

Effect of Cilostazol on Walking Distance in Patients With Claudication

Beebe, et al. Arch Internal Medicine. 1999;159:2041-50.

60

80

100

120

140

160

180

200

220

240

260

0 4 8 12 16 20 24

Mete

rs (

mean

)

Weeks of Treatment

*

*

*

*

** *

*

* P < 0.05 vs. placebo

*

*

**

**

*

*

**

**

MaximalWalking Distance

Pain-FreeWalking Distance

Cilostazol 100 mg bid(n=140)Cilostazol 50 mg bid(n=139)Placebo (n=140)

Hiatt WR. N Engl J Med. 2001;344;1608-21. Copyright © 2001 Massachusetts Medical Society. All rights reserved.

0.60.6 0.80.8 1.01.0 1.21.2 1.41.4 1.61.6 1.81.8

No. of Patients

698698

516516

239239

8181

Cilostazol, 200 mg/day

Pentoxifylline, 1200 mg/day





Four Randomized, Placebo Controlled Trials

Relative Improvement Over Placebo

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 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.

**

0

5

10

15

20

25

30

Wk 4 Wk 8 Wk 16 Wk 20 Wk 24

Physi

cal Sum

mary

Sco

re

Placebo Cilostazol 100 mg bid

Medical Outcome Scale SF-36

**

**

*

Base ASA Clop Cilo ASA +Cilo

ASA +Clop

ASA +Clop +Cilo

Clop +Cilo

Error bars demonstrate SE.*P0.05 versus baseline.

**P0.05 versus all single agents and versus ASA + Cilo and Clop + Cilo.ASA=aspirin 325 mg qd; Base=baseline bleeding time; Cilo=cilostazol 100 mg bid; Clop=clopidogrel 75 mg qd.

Wilhite DB, et al. J Vasc Surg. 2003;38:710-713.

*

**

*

** **20181614121086420B

leedin

g T

ime (

min

ute

s)

Medications for Patients With PAD

Therapeutic Goal

Drug

To Reduce Ischemic Events

To Improve Claudication Symptoms

Clopidogrel Yes No(Plavix®)

Cilostazol No Yes(Pletal®)

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

of 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.

Pharmacotherapy of Claudication

Cilostazol (100 mg orally two times per day) is indicated as an effective therapy to improve symptoms and increase walking distance in patients with lower extremity PAD and intermittent claudication (in the absence of heart failure).


Pentoxifylline (400 mg 3 times per day) may be considered as second-line alternative therapy to cilostazol to improve walking distance in patients with intermittent claudication.

The clinical effectiveness of pentoxifylline as therapy for claudication is marginal and not well established.



Pharmacotherapy of Claudication

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Cilostazol treatment intermittent claudication