1. Medical Therapy for Intermittent Claudication

2. Benefit onPAD Cohort InterventionTreadmill/QoLLimitationsIndicated Exercise100% / ImprovedAvailability50%-85% Motivation Cilostazol50% / ImprovedCHF50%-85% Medication AEs AngioplastyImprovementProximal10%-15% arteries best Surgery150% / ImprovedGraft failure< 5% Morbidity, mortality Treatment of Claudication: Therapeutic Choice & Evidence

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;347:1941-1951.

4. Effects of Exercise Training on 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 Treadmill Walking Distance (%) Meta-analysis of 21 Studies * * * P < 0.05

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 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. Exercise Rest Exercise Cool Down Rest

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. 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.

10. 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.

11. PAD Guideline-Based Care: Claudication Treatment via Home Exercise The usefulness of unsupervised exercise programs is not well established as an effective initial treatment modality for patients 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.

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. In Favor of PlaceboIn 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 = 128 Scandinavian Study: n = 150 Effect of Pentoxifylline on Claudication Distance: Pooled Analysis of US and Scandinavian Studies ICD=intermittent claudication distance ACD=absolute claudication distance

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 Beebe, et al. Arch Internal Medicine. 1999;159:2041-50. 60 80 100 120 140 160 180 200 220 240 260 04812162024 Meters (mean) Weeks of Treatment * * * * * * * * * P < 0.05 vs. placebo * * * * * * * * * * * * Maximal Walking Distance Pain-Free Walking Distance Cilostazol 100 mg bid (n=140) Cilostazol 50 mg bid (n=139) Placebo (n=140)

17. Benefit of Cilostazol on Walking Distance in Patients With Claudication Hiatt WR. N Engl J Med. 2001;344;1608-21. Copyright © 2001 Massachusetts Medical Society. All rights reserved. 0.60.81.01.21.41.61.8 No. of Patients 698 516 239 81 Cilostazol, 200 mg/day Pentoxifylline, 1200 mg/day Cilostazol, 200 mg/day Cilostazol, 100 mg/day Cilostazol, 200 mg/day Four Randomized, Placebo Controlled Trials Relative Improvement Over Placebo

18. 0 10 20 30 40 50 04812162024 Treatment (weeks) 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) 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. *

19. Effect of Cilostazol on Quality of Life 0 5 10 15 20 25 30 Wk 4Wk 8Wk 16Wk 20Wk 24 Physical Summary Score Placebo Cilostazol 100 mg bid Medical Outcome Scale SF-36 * * ** *

20. BaseASAClopCiloASA + Cilo ASA + Clop ASA + Clop + Cilo Clop + Cilo Effect of Aspirin, Clopidogrel and Cilostazol on Average Bleeding Time 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. * * * * ** 20 18 16 14 12 10 8 6 4 2 0 Bleeding Time (minutes)

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

22. Contraindications to Cilostazol Use 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.

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. 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