Medical Therapy for Peripheral Artery Disease Beau M. Hawkins, MD, FSCAI University of Oklahoma Health Sciences Center, Oklahoma City, OK Sahil A. Parikh, MD, FSCAI Columbia University Medical Center, New York, NY

Medical Therapy in PAD- The Problem Aspirin Use in Incident PAD Population Medical therapy is under- prescribed despite the excess cardiovascular risk associated with PAD Under-utilization is greater in the PAD population than it is in other forms of cardiovascular disease Subherwal et al. Circulation 2012;126:1345-54

Guideline-Directed Medical Therapy (GDMT) Antiplatelets Antithrombotics Exercise Program Statins GDMT Nicotine Cessation Comorbidity Treatment

Antiplatelets Aspirin reduces cardiovascular events in patients with coronary and cerebrovascular disease The benefits of antiplatelets in patients with PAD are less well established Monotherapy with aspirin or clopidogrel is a guideline recommendation Symptomatic patients- Class I, LOE A Asymptomatic patients- Class IIa, LOE C-EO Gerhard-Herman et al. Circulation 2017;135:e686-725

Risk Reduction with Aspirin in PAD Meta-analysis of 18 randomized trials involving 5,269 patients with PAD Non-significant decrease in events with aspirin compared to placebo (8.9 vs. 11.0%, P=NS) Aspirin significantly reduced stroke risk Endpoint Event rate (CI), aspirin vs. placebo Composite of mortality, MI, or stroke 8.2 vs. 9.6% (0.48-1.18) Mortality 7.5 vs. 7.9% (0.75-1.22) MI 3.3 vs. 4.5% (0.36-2.14) Stroke 2.1 vs. 3.4% (0.42-0.99) Berger et al. JAMA 2009;301:1909-19

Clopidogrel Versus Aspirin in PAD CAPRIE Steering Committee. Lancet 1996;348:1329-39

Miscellaneous Therapies- Cilostazol P= NS Dawson et al. Am J Med 2000;7:523-30

Dual Antiplatelet Therapy (DAPT) in PAD Substudy of 3,096 patients with PAD from CHARISMA trial 92% had symptomatic PAD DAPT consisting of aspirin plus clopidogrel compared to aspirin monotherapy MI rates reduced with DAPT Minor but not severe bleeding increased in DAPT arm Event DAPT (%) Aspirin (%) P value Death, MI, stroke 7.6 8.9 0.183 Death 6.7 7.5 0.387 MI 2.3 3.7 0.028 Stroke 3.0 0.275 Major bleed 1.7 0.901 Minor bleed 34.4 20.8 <0.001 Cacoub et al. Eur Heart J 2009;30:192-201

Newer Antiplatelets- EUCLID Trial 13,885 patients with symptomatic PAD randomized to ticagrelor or clopidogrel Primary endpoint- CV death, MI, or stroke Mean follow up of 30 months No difference in outcomes between groups Hiatt et al. NEJM 2017;376:32-40

PEGASUS PAD Sub-study Does DAPT with ticagrelor reduce events compared to aspirin monotherapy? 1,143 patients (5% of total) from PEGASUS-TIMI 54 analyzed post- hoc Significant event reduction in ticagrelor arm at 3 years (NNT=25) Bonaca et al. J Am Coll Cardiol 2016;67:2719-28

PEGASUS PAD Sub-study Ticagrelor associated with lower rates of acute limb ischemia and peripheral revascularization Excess bleeding not evident at both 60 mg BID and 90 mg BID dosing Bonaca et al. J Am Coll Cardiol 2016;67:2719-28

Vorapaxar- TRAP2⁰P-TIMI 50 Study 5,845 patients with PAD 16% of patients received peripheral revascularization over mean f/u 2.5 years Vorapaxar associated with reductions in need for revascularization Vorapaxar increased moderate/severe bleeding Bonaca et al. J Am Coll Cardiol Intv. 2016;9:2157-64

Rivaroxaban in PAD- COMPASS Results 7,470 patients with leg PAD or carotid disease Patients randomized to aspirin, rivaroxaban, or combo therapy Primary endpoints included MACE (death/MI/CVA) and MALE (ALI/CLI/amputation) Combo treatment reduced MACE compared to aspirin alone Anand et al. Lancet 2018;391:219-29

Adverse limb events reduced with rivaroxaban Anand et al. Lancet 2018;391:219-29

Statins Statins should be prescribed to all patients with PAD- class I, LOE A Statins increase walking distance and physical activity in claudicants Statin use is associated with improved patency following lower extremity revascularization Statins improve limb salvage rates in patients who have undergone peripheral revascularization Statins reduce rates of stroke, myocardial infarction, and death in patients with PAD Vogel et al. Circ Interv. 2013;6:694-700, Mohler et al. Circulation 2003;108:1481-6, Aiello et al. J Vasc Surg 2012;55:371-80

Smoking Cessation Programs Work 124 smokers with PAD randomized to usual nicotine cessation counseling vs. intensive program Intensive program included counseling and education on pharmacologic methods to aid cessation Group Abstinent (%) P Value 3 month follow up - Minimal 6.8 Intensive 21.3 0.023 6 month follow up 10.2 31.2 Hennrikus et al. JACC 2010;56:2105-12

Cessation Medications- Varenicline Rigotti et al. Circulation 2010;121:221-9

Exercise Therapy Meta-Analysis 200 Exercise training 180 Control 160 140 Exercise prescriptions come in one of two forms Supervised exercise Home-based exercise program Randomized trials support both types of programs to improve quality-of-life and walking distance in claudicants 120 Change in treadmill walking distance (%) 100 80 60 40 20 Onset of claudication pain Maximal claudication pain Gardner and Poehlman. JAMA 1995;274:975-80

Types of Structured Exercise Programs Gerhard-Herman et al. Circulation 2017;135:e686-725

CMS Coverage of Supervised Exercise Programs 30-60 min sessions in outpatient hospital or physician office setting Coverage of up to 36 sessions over 12 week period Sessions must be supervised by qualified personnel (physician, physician assistant, nurse practitioner) Exercise prescription must occur after face-to-face visit between patient and provider that includes counseling on cardiovascular disease prevention Available at CMS.gov, Decision memo for supervised exercise therapy (SET) for symptomatic peripheral artery disease (PAD), accessed February 22, 2018

Exercise Versus Revascularization- ERASE Trial Fakhry et al. JAMA 2015;314:1936-44

Exercise Versus Revascularization- CLEVER Trial Peak Walking Distance (m) 18 month f/u data of patients randomized to exercise, stenting, or medical therapy Only patients with aorto-iliac disease included Sustained improvement with stenting and exercise relative to medical therapy alone Murphy et al. J Am Coll Cardiol 2015;65:999-1009

Summary Antiplatelets, statins, nicotine cessation, and exercise are recommended as first-line therapies for treatment of PAD Clopidogrel monotherapy is more effective that aspirin at reducing composite adverse cardiovascular events (MACE) in patients with PAD DAPT utilizing either clopidogrel or ticagrelor reduces MACE compared to aspirin alone DAPT with ticagrelor is associated with reductions in adverse limb events (MALE)

Summary (continued) Vorapaxar use is associated with reduced rates of peripheral revascularization Rivaroxaban plus aspirin reduces MACE and MALE in patients with PAD Exercise therapy with or without revascularization improves functional outcomes in claudicants