The Changing Landscape of Managing Patients with PAD- Update on the Evidence and Practice of Care in Patients with Peripheral Artery Disease

Interventional Cardiology and Cath Labs The Changing Landscape of Managing Patients with PAD- Update on the Evidence and Practice of Care in Patients with Peripheral Artery Disease Manesh R. Patel MD Chief, Division of Cardiology Co-Director Duke Heart Center Duke University All Rights Reserved, Duke Medicine 2008

Disclosures Member of Appropriate Use Criteria Task Force: 2005-2016 Current AUC Chair Research Support: AstraZeneca, CSI, HeartFlow, Janssen Research & Development, Johnson & Johnson, Bayer, Medtronic, National Heart, Lung, & Blood Institute Consulting/Advisory Board: AstraZeneca, CSI, Bayer Corporation, Janssen Research & Development,Merck & Co.

PAD is Common NHANES 1 Aged >40 years San Diego 2 Mean age 66 years NHANES 1 Aged 70 years Rotterdam 3 Aged >55 years Diehm 4 Aged 65 years 4.3% 11.7% 14.5% PARTNERS 5 Aged >70 years, or 50 69 years with a history diabetes or smoking 19.1% 19.8% In a primary care population defined by age and common risk factors, the prevalence of new and established PAD was approximately one in three patients 29% 0% 5% 10% 15% 20% 25% 30% 35% NHANES=National Health and Nutrition Examination Study; PARTNERS=PAD Awareness, Risk, and Treatment: New Resources for Survival [program]. 1. Selvin E, Erlinger TP. Circulation. 2004;110:738-743. 2. Criqui MH, et al. Circulation. 1985;71:510-515. 3. Diehm C, et al. Atherosclerosis. 2004;172:95-105. 4. Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192. 5. Hirsch AT, et al. JAMA. 2001;286:1317-1324.

Noninvasive Diagnosis Interpretation of ABI >1.30 Noncompressible 0.91-1.30 Normal 0.41-0.90 Mild/moderate PAD 0.40 Severe PAD/critical limb ischemia Jan08MP

2 Major Issues in Peripheral Arterial Disease PAD Management Symptom Improvement* Cardiovascular Risk Reduction* *In symptomatic patients only (atypical or classical?) All Rights Reserved, Duke Medicine 2007

Consequences of PAD Amputation/Tissue Loss Myocardial infarction (MI) Stroke Death Functional capacity Quality of Life 13

Goals of Therapies for PAD All PAD patients Patients with IC Patients with CLI Improve functional status Prevent leg amputation Reduce cardiovascular morbidity & mortality Restore mobility Reduce morbidity & mortality Reduce mortality 14

Cumulative Event Rate (%) Efficacy of Clopidogrel vs. Aspirin in MI, Ischemic Stroke, or Vascular Death 8.7%* 16 Overall Relative Risk Reduction ASA 12 5.83% 8 5.32% Clopidogrel 4 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of Follow-Up N=19,185 ASA=aspirin. Mean follow-up=1.91 years. *ITT analysis. Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

Risk Reduction of Clopidogrel vs. Aspirin in Patients With Atherosclerotic Vascular Disease Aspirin favored Clopidogrel favored Stroke N=19,185 MI PAD All patients -30-20 -10 0 10 20 30 40 Effect in PAD patients drive results Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

Cumulative Event Rate* (%) CHARISMA: Affect of Clopidogrel Plus Aspirin vs. Aspirin Alone on MI, Stroke, or CV Death 8 6 4 First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death Placebo + ASA 7.3% Clopidogrel + ASA 6.8% 2 RRR 7.1% (95% CI: -4.5%, 17.5%) P=0.22 0 0 6 12 18 24 30 Months Since Randomization ASA=aspirin; CI=confidence interval; MI=myocardial infarction; RRR=relative risk ratio. *All patients received ASA 75-162 mg/day; The number of patients followed beyond 30 months decreases rapidly to zero; only 21 primary efficacy events occurred beyond this time (13 clopidogrel and 8 placebo). Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706.

Overall Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17 Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08)<0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

In PAD population, treatment with vorapaxar resulted in: Reduced rates of hospitalization for ALI Reduction in urgent vascular hospitalization Reduced rates of peripheral revascularization All Rights Reserved, Duke Medicine 2007

EUCLID Study Design Key exclusion criteria: Poor metabolizer for CYP2C19 Patients requiring dual anti-platelet therapy Patients with symptomatic PAD Ticagrelor 90 mg bid Double-blind Double-dummy 1:1 N=13,885 Clopidogrel 75 mg od Duration: Event Driven Trial Approximately 14-month recruitment and 26-month follow-up Inclusion criteria: Symptomatic PAD AND one of the following: A. ABI 0.80 at Visit 1 0.85 at Visit 2 OR B. Prior lower extremity revascularization > 30 days Primary Endpoint: cardiovascular death, myocardial infarction, or ischemic stroke Primary Safety Endpoint: TIMI major bleeding

Medical History Ticagrelor (N=6930) Clopidogrel (N=6955) History of stroke, no. (%) 576 (8.3) 567 (8.2) History of TIA, no. (%) 279 (4.0) 228 (3.3) CAD, no. (%) 2019 (29.1) 2013 (28.9) MI, no. (%) 1242 (17.9) 1280 (18.4) Number of vascular beds, no. (%) 1 3874 (55.9) 3930 (56.5) 2 2333 (33.7) 2355 (33.9) 3 723 (10.4) 670 (9.6) Diabetes mellitus (Type I & II), no. (%) 2639 (38.1) 2706 (38.9) Hypertension, no. (%) 5437 (78.5) 5420 (77.9) Hyperlipidemia, no. (%) 5229 (75.5) 5251 (75.5) CAD is defined as prior MI, prior PCI, or prior CABG. A vascular bed is defined as either PAD, prior CAD (prior MI, prior PCI, or prior CABG), or prior cerebrovascular disease (prior stroke, prior TIA, prior carotid artery stenosis or prior carotid revascularization). ABI indicates ankle-brachial index; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; MI, myocardial infarction, PAD, peripheral artery disease; SD, standard deviation; TBI, toe-brachial index; TIA, transient ischemic attack.

Primary Efficacy Endpoint (CV Death, MI, or Ischemic Stroke)

Efficacy Outcomes Ticagrelor (N=6930) Clopidogrel (N=6955) HR (95% CI) P Value Primary outcome: Composite of CV death, MI, or ischemic stroke, no. (%) 751 (10.8) 740 (10.6) CV death, no. (%) 363 (5.2) 343 (4.9) MI, no. (%) 349 (5.0) 334 (4.8) Ischemic stroke, no. (%) 131 (1.9) 169 (2.4) Key secondary efficacy outcome: Composite of CV death, MI, ischemic stroke, or ALI requiring hospitalization, no. (%) 839 (12.1) 833 (12.0) 1.02 (0.92 1.13) 1.07 (0.92 1.23) 1.06 (0.91 1.23) 0.78 (0.62 0.98) 1.02 (0.92 1.12) 0.65 0.40 0.48 0.03 0.74 ALI indicates acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.

Anti-platelet therapy conclusions - PAD: PAD is common, and patients with PAD have high risk for cardiovascular events Clopidogrel is equivalent to ASA in prevention of CV events in patients with broadly defined vascular disease but nominally superior in PAD In patients with broadly defined vascular disease, dual anti-platelet therapy provided no clinical benefit Vorapaxar on top or ASA or Clopidogrel benefit in PAD patients Ticagrelor was similar to clopidogrel for PAD clinical event reduction All Rights Reserved, Duke Medicine 2007

PAD Patients Dual Pathway therapy (oral anticoagulant at the right dose) with low dose ASA (anti-platelet) therapy seems to provide clinical benefit Test strategy in PVI patients (VOYAGER PAD) Test understanding individual CV risks in patients with PAD All Rights Reserved, Duke Medicine 2007

MACE + ischaemic limb risk Compared with COMPASS, VOYAGER PAD targets a patient population at high risk of cardiovascular events Early risk Late risk VOYAGER 1 EUCLID 3 ATLAS ACS 2 COMPASS 4 Acute event (ACS, limb revascularization) Time Chronic disease (stable PAD, CV disease) 1. www.clinicaltrials.gov/ct2/show/nct02504216; 2. Mega JL et al, N Engl J Med 2012;366:9 19; 3. Hiatt WR et al, N Engl J Med 2017;376:32 40; 4. Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118 39