1. Peripheral Arterial Disease Mehul Bhatt, MD Interventional Cardiology / Vascular Medicine Athens Heart Center

2. Two Major Goals in Treating Patients With PAD Improved ability to walk Improved ability to walk Increase in peak walking distance Increase in peak walking distance Improvement in quality-of- life (QoL) Improvement in quality-of- life (QoL) Prevention of progression to critical limb ischemia and amputation Prevention of progression to critical limb ischemia and amputation Treatment of critical limb ischemia and amputation Treatment of critical limb ischemia and amputation Decrease in morbidity from non-fatal MI and stroke Decrease in morbidity from non-fatal MI and stroke Decrease in cardiovascular mortality from fatal MI and stroke Decrease in cardiovascular mortality from fatal MI and stroke Limb outcomes Cardiovascular morbidity and mortality outcomes

3. Medical Treatment Smoking cessation Smoking cessation Statin therapy Statin therapy Blood pressure control Blood pressure control Oral antiplatelet therapy Oral antiplatelet therapy Exercise therapy Exercise therapy Pentoxifylline / Cilostazol Pentoxifylline / Cilostazol

4. Effect of Smoking Cessation on Survival Years Postoperative Faulkner KW, et al. Med J Aust. 1983;1:217-219. 133 Patients observed after bypass graft or lumbar sympathectomy Cumulative Survival (%)

5. Heart Protection Study: Vascular Event by Prior Disease CBD=cerebrovascular disease; CHD=congestive heart disease. Reprinted with permission from Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22 from Elsevier. Previous MI 23.529.4 Other CHD 18.924.2 No prior CHD or CBV disease 18.723.6 Diabetes 13.818.6 All patients 19.825.2 1.0 1.2 1.4 0.8 0.60.4 24% Reduction (P<.0001) Existing disease StatinControl Incidence of events (n=10,269)(n=10,267) Statin favoredPlacebo Risk vs Control PAD 24.730.5

6. Considerations for the Treatment of Hypertension in PAD Blood pressure lowering is indicated to reduce the risk of stroke, MI, CHF, CRF, and death. Blood pressure lowering is indicated to reduce the risk of stroke, MI, CHF, CRF, and death. Only major reductions in perfusion pressure may worsen claudication (21 mm Hg decrease in SBP resulted in a 9% decrease in absolute claudication distance). Only major reductions in perfusion pressure may worsen claudication (21 mm Hg decrease in SBP resulted in a 9% decrease in absolute claudication distance). Individuals with PAD should receive hypertension treatment according to current national guidelines (e.g., JNC-7). Individuals with PAD should receive hypertension treatment according to current national guidelines (e.g., JNC-7). CRF=chronic renal failure; CHF=congestive heart failure.

7. - Blockers Are Not Contraindicated in PAD - Blockers Are Not Contraindicated in PAD In a meta analysis of 11 randomized controlled trials beta-blocker therapy did not worsen claudication in patients with PAD. In a meta analysis of 11 randomized controlled trials beta-blocker therapy did not worsen claudication in patients with PAD. Beta blockers had no significant effect on pain-free walking distance compared with placebo in pooled analysis. Beta blockers had no significant effect on pain-free walking distance compared with placebo in pooled analysis. Radack K. Arch Intern Med. 1991;151:1769.

8. N=9214. Data from 197 randomized trials comparing an antiplatelet agent (APT; aspirin, clopidogrel, dipyridamole, or a glycoprotein IIb/IIIa antagonist) vs control or another antiplatelet agent. APT=antiplatelet; CRTL=control. Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86. CategoryAPTCTRLReduction (%) Intermittent 6.4% 7.9% 23±9 claudication Peripheral artery 5.4% 6.5% 22±16 bypass graft Peripheral 2.5% 3.6%29±35 angioplasty All high-risk patients 22±2 (P<.001) (P<.001) 1.00.50.01.52.0 Antithrombotic Trialists Collaboration (ATC): Meta-Analysis of Vascular Events in Antiplatelet Trials in Patients With PAD

9. Risk Reduction of Clopidogrel vs. Aspirin in Patients With Atherosclerotic Vascular Disease Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:1329-1339. Stroke 01020-10-20 MI PAD All patients Aspirin favored -303040 Clopidogrel favored N=19,185

10. Intermittent Claudication: Exercise Therapy (Supervised) Frequency: 3–5 supervised sessions/week Frequency: 3–5 supervised sessions/week Duration: 35–50 minutes of exercise/session Duration: 35–50 minutes of exercise/session Type of exercise: treadmill or track walking to near-maximal claudication pain Type of exercise: treadmill or track walking to near-maximal claudication pain Length: 6 months Length: 6 months Results: 100%–150% improvement in maximal walking distance and associated improvement in quality-of-life 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.

11. 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

12. Pharmacotherapy for Claudication FDA Approved Drugs: Pentoxifylline (Trental) Pentoxifylline (Trental) Cilostazol (Pletal) Cilostazol (Pletal) Anecdotal Treatments: Ranolaxine (Ranexa) Ranolaxine (Ranexa) Enhanced external counter-pulsation (EECP) Enhanced external counter-pulsation (EECP)

13. 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. *

14. Contraindications to Cilostazol Use Provisos: CHF of any severity (systolic dysfunction) CHF of any severity (systolic dysfunction) Any known or suspected hypersensitivity to any of its components 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.