Authors: Timothy P Murphy, Donald E. Cutlip, Judith G. Regensteiner, Emile R. Mohler III, David J. Cohen, Matthew R. Reynolds, Beth A. Lewis, Joselyn Cerezo, Niki C. Oldenburg, Claudia C. Thum, Alan T. Hirsch. Presenter: Alan T. Hirsch, Chair, on behalf of the CLEVER Study Investigators Claudication Treatment Comparative Effectiveness: Primary (6 Month) Outcomes from the CLEVER Study

Acknowledgements and Disclosures Acknowledgements: The CLEVER Study was sponsored by the National Heart Lung and Blood Institute (grants HL77221 and HL081656), and also received financial support from Cordis/Johnson & Johnson (Warren, NJ), eV3 (Plymouth, MN), and Boston Scientific (Natick, MA). Otsuka America, Inc., (San Francisco, CA) donated cilostazol for all study participants throughout the study. Omron Healthcare Inc., Lake Forest, IL donated pedometers. Krames Staywell, San Bruno, CA, donated print materials for study participants on exercise and diet. Disclosures: Timothy P. Murphy, M.D.: Research grant support - Abbott Vascular, Cordis/Johnson&Johnson, Otsuka Pharmaceuticals; consultant - Microvention/Terumo, Inc.; David Cohen, M.D.: Research grant support - Medtronic. Boston Scientific, Abbott Vascular, Medrad; consultant - Medtronic, Inc.; Matthew R. Reynolds, M.D., M.Sc. : Consultant - Medtronic, Inc.; Alan T. Hirsch, MD..: Research Grant Support - Cytokinetics, Viromed, Abbott Vascular; consultant - Merck, Pozen, Novartis, AstraZeneca.

Background  Claudication is the most frequent symptom of peripheral artery disease (PAD), and is experienced by an estimated 2 million Americans  Current therapeutic options include home exercise; supervised exercise; claudication pharmacotherapy (cilostazol); or endovascular procedures  Invasive stent procedures have not been shown to offer better claudication improvement than supervised exercise; stenting is reimbursed, but supervised exercise is not  Patients with proximal (aortoiliac) PAD are often highly symptomatic, and are generally considered ideal for stent revascularization

Study Objectives 1.To test whether aortoiliac stenting (ST) and supervised exercise therapy (SE) are superior to optimal medical care (OMC) ­- as measured by peak walking time (PWT) at 6 months -- in patients with claudication due to aortoiliac peripheral arterial disease (PAD). 2.If these comparisons are positive, to test whether stenting is superior to supervised exercise for the same endpoint.

Population  Moderate to severe claudication (2-11 min on Gardner treadmill protocol or up to 5.5 METS)  Hemodynamically significant aortoiliac PAD confirmed by non-invasive vascular lab testing or advanced imaging  No other co-morbid diseases that limited walking  No critical limb ischemia (rest pain, non-healing wound or gangrene)  SFA disease allowed and endovascular treatment permitted by protocol, but not required in any patients

Treatment Strategies Optimal Medical Care (OMC):  Cilostazol 100 mg bid as tolerated, written and oral advice about exercise and diet, with monthly coordinator contact Supervised Exercise (SE):  OMC plus 78 sessions of supervised exercise, 3x/wk, for 1 hr sessions Stenting (ST):  OMC plus stent revascularization of aortoiliac PAD

Endpoints Primary Endpoint:  Peak Walking Time (PWT) on a graded treadmill test (Gardner protocol) Secondary Endpoints:  Claudication Onset Time (COT)  Community-based walking by pedometer  Quality of life (QOL) by WIQ, PAQ, SF-12  Atherosclerosis biomarkers Primary Endpoint Assessed at Six (6) Months  Eighteen (18) months long-term follow-up pending

Demographic and Medical History Characteristics OMC N=22 SE + OMC N=43 ST + OMC N=46 P-value Age, years62.4 ± ± ± Male (%) Diabetes (%) Hypertension (%) Current smoking (%) Hypercholesterolemia (%) Prior stroke (%) Prior myocardial infarction (%) Prior use of cilostazol (%)

Baseline Physiologic, Biochemical, and Anthropomorphic Characteristics OMC N=22 SE + OMC N=43 ST + OMC N=46 P-value Blood Pressure and ABI SBP (mmHg)136±14135±22136± DBP (mmHg)77±1074± Ankle-Brachial Index0.73± ± Biochemical Profile LDL (mg/dl)105± ± HDL (mg/dl)48±1249±1648± Triglycerides (mg/dl)135±70147±82147± HbA1c (%)6.3±1.36.1±1.16.4± Anthropomorphic Characteristics BMI28.1± ± ± Waist Circumference (cm)100±1497±14102±150.27

Baseline Performance Characteristics OMC N=22 SE + OMC N=43 ST + OMC N=46 P-value Treadmill Walking PWT (minutes)5.5±2.55.3±2.35.2± COT (minutes)1.7±0.71.6±0.91.7± Community-based Walking Hourly Free-Living Steps343±411264±216291±

Treatment Delivery Cilostazol Compliance:  >90% in all treatment groups Exercise Compliance:  71% Technical Success of Stenting:  All ST patients successfully stented  Pre-procedure mean lesion length 3.9±3.4 cm  Mean stenosis 83±19%; post-procedure stenosis 5±8%  ABI 0.66±0.2 at baseline, improved by 0.29±0.33 Crossover Rates:  None at six months

Primary Endpoint: Peak Walking Time Pair-Wise Comparisons Difference (minutes)P Value Exercise vs. OMC4.6 (95% CI, )<0.001 Stenting vs. OMC2.5 (95% CI, )0.02 Exercise vs. Stenting2.1 (95% CI, )0.04 Change from Baseline to Six (6) Months Minutes

Claudication Onset Time Pair-Wise Comparisons Difference (minutes)P Value Exercise vs. OMC 2.2<0.003 Stenting vs. OMC Exercise vs. Stenting Change from Baseline to Six (6) Months

Community Walking Pair-Wise Comparisons Difference (steps)P Value Exercise vs. OMC Stenting vs. OMC Exercise vs. Stenting Change from Baseline to Six (6) Months

Walking Impairment Questionnaire Change from Baseline to Six (6) Months P Value SE vs. OMC ST vs. OMC< ST vs. SE

Peripheral Artery Questionnaire Change from Baseline to Six (6) Months P Value SE vs. OMC ST vs. OMC< <0.001 ST vs. SE

Conclusions  In patients with moderate to severe claudication and hemodynamically significant aortoiliac disease, supervised exercise offers better treadmill walking performance outcomes than stent revascularization  Both supervised exercise and stenting are more effective at increasing walking distance compared to pharmacotherapy alone  Aortoiliac stent revascularization was associated with better QOL scores than patients treated with supervised exercise, which is unexplained  Ongoing 18 month follow-up will provide greater insight into the relative durability of these treatments, as well as the health economic impact

CLEVER Study Sites  Rhode Island Hospital in Providence, RI (Tim Murphy)  Henry Ford Hospital in Detroit, MI (Jonathan Ehrman)  VA Ann Arbor in Ann Arbor, MI (Venkat Krishnamurthy)  Aiyan Diabetes Center in Evans, GA (Janaki Nadarajah)  University of Minnesota & Abbott Northwestern Hospital in Minneapolis, MN (Alan T. Hirsch)  Jobst Vascular Center in Toledo, OH (Anthony Comerota)  Torrance Memorial Medical Center in Torrance, CA (Mark Lurie)  Vascular and Endovascular Specialist of Ohio in Mansfield, OH (William Miller)  Ochsner Clinic in Metairie, LA (Olusegun Osinbowale)  Spokane-Providence Medical Center in Spokane, WA (Stuart Cavalieri)  St. Joseph Hospital in Orange, CA (Mahmood Razavi)  Forsyth - Salem Surgical in Salem, NC (Ray Workman)  Capital Health in Halifax, NS (Robert Berry)  Johns Hopkins Hospital in Baltimore, MD (Elizabeth Ratchford)  Stony Brook Hospital in Stony Brook, NY (Apostolos Tassiopoulos)  University of Pennsylvania in Philadelphia, PA (Emile Mohler)  Oregon Health Science University in Portland, OR (John Kaufman)  Iowa Clinic in Des Moines, IA (John Matsuura)  Peripheral Vascular Associates in San Antonio, TX (Jeffrey Martinez)  Central Arkansas Veterans Health Care in Little Rock, AR (Mohammed Moursi)