1. Medical Therapy for Intermittent Claudication

2. Treatment of Claudication: Therapeutic Choice & Evidence
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

3. 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:

4. Effects of Exercise Training on Claudication
Meta-analysis of 21 Studies
200 *
Exercise Training
180
Control
160
140 *
120
Change in Treadmill Walking Distance (%)
100 80 60 40 20
* P < 0.05
Onset of Claudication Pain
Maximal Claudication Pain
Gardner AW, Poehlman ET. JAMA. 1995;274:
Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA. 1995;274:

5. 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.

6. The PAD Exercise Training Prescription
Warm-up
Exercise
Rest
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.

7. 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.

8. 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.

9. 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.

10. 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 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).
Also see Table 18 of Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192.

11. PAD Guideline-Based Care: Claudication Treatment via Home Exercise
IIa
IIb
III B
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:

12. 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.

13. Pentoxifylline Drug Class: Methylxanthine Approved: August 1984
Dosing: 400 mg tid
Pharmacologic Hemorheologic agent Properties: Some vasodilation Weak antiplatelet activity

14. 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
ICD=intermittent claudication distance
ACD=absolute claudication distance
Lindgarde, et al. Vascular Medicine. 1996;1:
Porter, et al. Am Heart J. 1982;104:66-72.
Lindgarde, et al. Circulation. 1989;80:

15. Cilostazol Drug Class: Phosphodiesterase III inhibitor derivative
Approved: January 1999
Dosing: 100 mg bid
Pharmacologic Platelet aggregation inhibitor
Properties: Vasodilation
 HDL-cholesterol (10%)
 Triglycerides (15%)
Inhibits smooth muscle cell proliferation in vitro

16. Effect of Cilostazol on Walking Distance in Patients With Claudication*
260
Maximal Walking Distance *
240 *
220
Cilostazol 100 mg bid
(n=140)
Cilostazol 50 mg bid
(n=139)
Placebo (n=140) *
200 * * *
180 *
Meters (mean)
160 * * *
140 *
120 * * *
Pain-Free Walking Distance * *
100 * * * 80
* P < 0.05 vs. placebo 60 4 8 12 16 20 24
Weeks of Treatment
Beebe, et al. Arch Internal Medicine. 1999;159:

17. 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
Cilostazol, 200 mg/day
516
Cilostazol, 100 mg/day
239
Cilostazol, 200 mg/day 81
Cilostazol, 200 mg/day
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Relative Improvement Over Placebo
Hiatt WR. N Engl J Med. 2001;344; Copyright © 2001 Massachusetts Medical Society. All rights reserved.

18. Percentage Change From Baseline MWD (mean)
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) 50 * 40 30
Percentage Change From Baseline MWD (mean) 20 10 4 8 12 16 20 24
Treatment (weeks)
MWD=maximal walking distance. *P<0.001 vs pentoxifylline.
Reprinted from Dawson DL, et al. Am J Med. 2000;109: with permission from Elsevier.

19. Effect of Cilostazol on Quality of Life30
Placebo
Cilostazol 100 mg bid * 25 * * * 20
Physical Summary Score 15 * 10 5
Wk 4
Wk 8
Wk 16
Wk 20
Wk 24
Medical Outcome Scale SF-36

20. Effect of Aspirin, Clopidogrel and Cilostazol on Average Bleeding Time20 18 16 14 12 10 8 6 4 2 ** ** * *
Bleeding Time (minutes) * *
Base
ASA
Clop
Cilo
ASA + Cilo
ASA + Clop
ASA + Clop + Cilo
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:

21. Medications for Patients With PAD
Therapeutic Goal
To Reduce Ischemic Events
To Improve Claudication Symptoms
Drug
Clopidogrel Yes No (Plavix®)
Cilostazol No Yes (Pletal®)

22. 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.

23. 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).

24. Pharmacotherapy of Claudication
IIa
IIb
III A
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. I
IIa
IIb
III C