Transcript Pharmacotherapy of Claudication

Medical Therapy for
Intermittent Claudication
Treatment of Claudication:
Therapeutic Choice & Evidence
Intervention
Exercise
Benefit on
Treadmill/QoL
100% / Improved
Limitations
Availability
PAD Cohort
Indicated
50%-85%
Motivation
Cilostazol
50% / Improved
CHF
50%-85%
Medication AEs
Angioplasty
Improvement
Proximal
10%-15%
arteries best
Surgery
150% / Improved
Graft failure
Morbidity, mortality
< 5%
Intermittent Claudication:
Exercise Therapy (Supervised)
• 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.
Effects of Exercise Training
on Claudication
Change in Treadmill Walking
Distance (%)
200
180
Meta-analysis of 21 Studies
Exercise Training
*
160
Control
140
*
120
100
80
60
40
20
0
* P < 0.05
Onset of
Claudication Pain
Maximal
Claudication Pain
Gardner AW, Poehlman ET. JAMA. 1995;274:975-980.
Supervised Exercise Rehabilitation
I IIa IIb III
A program of supervised exercise training is
recommended as an initial treatment modality for
patients with intermittent claudication.
I IIa IIb III
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.
The PAD Exercise Training Prescription
Warm-up
Exercise
Rest
Exercise
Rest
Exercise
Cool
Down
•
•
•
Warm-up: Approximately 5 minutes
Repeated exercise periods: End at moderate
claudication level
Rest Periods: Until claudication abates
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.
Key Elements of an Effective PAD Therapeutic
Claudication Exercise Program
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.
Key Elements of an Effective PAD Therapeutic
Claudication Exercise Program (1)
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.
Key Elements of an Effective PAD Therapeutic
Claudication Exercise Program (2)
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
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.
Key Elements of an Effective PAD Therapeutic
Claudication Exercise Program (3)
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 STsegment 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).
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.
PAD Guideline-Based Care:
Claudication Treatment via Home Exercise
I IIa IIb III
The usefulness of unsupervised exercise
programs is not well established as an
effective initial treatment modality for
patients with intermittent claudication.
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.
Hirsch AT, et al. J Am Col Cardiol. 2006;47:1239-1312.
Pharmacotherapy for Claudication
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.
Pentoxifylline
Drug Class:
Methylxanthine
Approved:
August 1984
Dosing:
400 mg tid
Pharmacologic
Properties:
Hemorheologic agent
Some vasodilation
Weak antiplatelet activity
Effect of Pentoxifylline on Claudication Distance:
Pooled Analysis of US and Scandinavian Studies
US Study: n = 128
Scandinavian Study: n = 150
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
ICD=intermittent claudication distance
ACD=absolute claudication distance
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.
Cilostazol
Drug Class:
Phosphodiesterase III
inhibitor derivative
Approved:
January 1999
Dosing:
100 mg bid
Pharmacologic
Properties:
Platelet aggregation inhibitor
Vasodilation
 HDL-cholesterol (10%)
 Triglycerides (15%)
Inhibits smooth muscle cell
proliferation in vitro
Effect of Cilostazol on Walking Distance
in Patients With Claudication
*
260
*
240
*
Meters (mean)
220
*
200
*
*
180
160
*
*
*
*
140
*
120
*
100
*
80
*
*
*
*
*
*
*
Maximal
Walking Distance
Cilostazol 100 mg bid
(n=140)
Cilostazol 50 mg bid
(n=139)
Placebo (n=140)
Pain-Free
Walking Distance
* P < 0.05 vs. placebo
60
0
4
8
12
16
20
Weeks of Treatment
24
Beebe, et al. Arch Internal Medicine. 1999;159:2041-50.
Benefit of Cilostazol on Walking
Distance in Patients With Claudication
Four Randomized, Placebo Controlled Trials
No. of Patients
Cilostazol, 200 mg/day
698
Pentoxifylline, 1200 mg/day
516
Cilostazol, 200 mg/day
239
Cilostazol, 200 mg/day
81
Cilostazol, 200 mg/day
0.6
Cilostazol, 100 mg/day
0.8
1.0
1.2
1.4
1.6
1.8
Relative Improvement Over Placebo
Hiatt WR. N Engl J Med. 2001;344;1608-21. Copyright © 2001 Massachusetts Medical Society. All rights reserved.
Cilostazol vs. Pentoxifylline:
Relative 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)
Percentage Change From
Baseline MWD (mean)
50
40
*
30
20
10
0
0
4
8
12
16
Treatment (weeks)
20
24
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.
Physical Summary Score
Effect of Cilostazol on Quality of Life
30
Placebo
25
Cilostazol 100 mg bid
*
20
15
*
*
*
*
10
5
0
Wk 4
Wk 8
Wk 16
Wk 20
Medical Outcome Scale SF-36
Wk 24
Bleeding Time (minutes)
Effect of Aspirin, Clopidogrel and
Cilostazol on Average Bleeding Time
20
18
16
14
12
10
8
6
4
2
0
**
**
*
*
*
*
Base
ASA
Clop
Cilo
ASA + Clop + ASA + ASA +
Cilo
Cilo
Clop Clop +
Cilo
Error bars demonstrate SE.
*P0.05 versus baseline.
**P0.05 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.
Medications for Patients With PAD
Therapeutic Goal
Drug
To Reduce
Ischemic
Events
To Improve
Claudication
Symptoms
Clopidogrel
(Plavix®)
Yes
No
Cilostazol
(Pletal®)
No
Yes
Contraindications to Cilostazol Use
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.
Provisos:
• “CHF of any severity” (systolic dysfunction)
• Any known or suspected hypersensitivity to any of its
components
CHF=congestive heart failure.
Pletal® (cilostazol) Package Insert. Rockville, Md: Otsuka America Pharmaceutical, Inc; 1999.
Pharmacotherapy of Claudication
I IIa IIb III
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).
Pharmacotherapy of Claudication
I IIa IIb III
I IIa IIb III
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.