1. 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

2. 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:

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

4. 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:e

5. 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% ( )
Mortality
7.5 vs. 7.9% ( ) MI
3.3 vs. 4.5% ( )
Stroke
2.1 vs. 3.4% ( )
Berger et al. JAMA 2009;301:

6. Clopidogrel Versus Aspirin in PAD
CAPRIE Steering Committee. Lancet 1996;348:

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

8. 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:

9. 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

10. 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:

11. 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:

12. 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:

13. 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

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

15. 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: , Mohler et al. Circulation 2003;108:1481-6, Aiello et al. J Vasc Surg 2012;55:371-80

16. 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:

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

18. 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

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

20. 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

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

22. 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:

23. 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)

24. 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