cilostazol treatment intermittent claudication
TRANSCRIPT
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
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0
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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.
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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
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.
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)
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.
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)
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.
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.
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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.
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0 4 8 12 16 20 24
Mete
rs (
mean
)
Weeks of Treatment
*
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* P < 0.05 vs. placebo
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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
Cilostazol, 200 mg/day
Cilostazol, 100 mg/day
Cilostazol, 200 mg/day
Cilostazol, 200 mg/day
Four Randomized, Placebo Controlled Trials
Relative Improvement Over Placebo
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10
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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.
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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
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*
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.
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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).
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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.
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Pharmacotherapy of Claudication