MACE Trial Rationale, Study Design, and Current Status David J. Cohen, MD, MSc Director of Cardiovascular Research Saint-Luke’s Mid America Heart Institute Missouri Endowed Professor of Medicine University of Missouri-Kansas City School of Medicine DJC-CRT 2015

Disclosures Grant Support/Drugs Grant Support/Devices Daiichi-Sankyo - Eli Lilly Astra-Zeneca - Merck Grant Support/Devices Edwards Lifesciences - Abbott Vascular Medtronic - Boston Scientific CSI, Inc. - Covidien Consulting/Advisory Boards Medtronic - Astra-Zeneca Eli Lilly DJC: 2/15

Challenges in Treating Calcified Coronary Lesions Prone to dissection with POBA and other standard PTCA techniques Inability to dilate Incomplete stent expansion increased stent thrombosis and restenosis Inhibition of drug delivery/absorption

Impact of Severe Calcification on DES Outcomes Cardialysis Study Pooled data from 7 DES trials (6296 pts) Presence of severe coronary calcification determined by angiographic core lab Severe calcification present in 20% of pts associated with worse outcomes across full spectrum of endpoints P<0.01 for all comparisons Bourantas C, et al. EuroPCR 2014

Rationale for the MACE Study Previously, no device was specifically FDA approved for treatment of coronary calcification Recently, the Diamondback 360 catheter was approved for the indication of “facilitating stent delivery in patients with CAD… due to severely calcified coronary lesions” Nonetheless, there remain numerous gaps in knowledge about the treatment of CAD in this challenging patient population

MACE Study Multicenter Prospective Study to Evaluate Outcomes of Moderate to Severely Calcified Coronary Lesions

MACE Study: Organization Study Sponsor: Cardiovascular Systems, Inc. Principal Investigator Samin K. Sharma, MD Mount Sinai Medical Center, New York Angiographic Core Laboratory Jeffrey J. Popma, MD Beth Israel Deaconess Medical Center, Boston Economic Core Laboratory Saint Luke’s Mid America Heart Institute, Kansas City MO

MACE Study: Objectives To determine the impact of both moderate and severe coronary calcification on the outcomes of PCI using contemporary devices and pharmacotherapy To evaluate the impact of coronary calcification on the short- and long-term costs of PCI To serve as a virtual “control group” to better understand the benefits of orbital atherectomy in patients with severe coronary calcification

MACE Study: Design Enroll up to 500 subjects 2002 subjects with: Moderate calcification 1001 subjects with: None/mild calcification Severe calcification All patients biomarker negative at entry ensures accurate assessment of periprocedural MI Real-world design Treatment using any FDA approved device(s) per operator discretion 3 year follow-up for all patients for both clinical and economic outcomes

Assessment of Calcification  Ca++ Severity Angiographic Appearance* IVUS/OCT None/Mild Absence of readily apparent radiopacities at the site of stenosis ≤ 180° of calcium at one (1) cross section Moderate Presence of radiopacities only during cardiac cycle before contrast injection 181° to 269° of calcium at 1 cross section Severe Presence of radiopacities noted without cardiac motion Involves both sides of the arterial wall in at least one location Total length of calcium at least 15mm and extend partially into the target lesion, or ≥ 270° of calcium at 1 cross section. * Assessed by core laboratory

Study Endpoints Primary Endpoint 30-day MACE: composite of cardiac death, MI (CKMB >3x ULN), or TVR Secondary Endpoints MACE at 1 year TLR Procedural and device success Cardiovascular Related Costs: In-hospital (billing data), 1-year, 3-years

Study Update (as of 1/19/15) 34 activated sites 293 subjects enrolled First 50 Patients 34 activated sites 293 subjects enrolled Calcification None/Mild 93 pts Moderate 100 pts Severe 98 pts Characteristic Mean Value Male 64% Age (yrs) 67 yrs Diabetes 40% Prior CABG 6% Target Vessel LAD/LM LCx/Ramus 32% RCA 28%

Summary (1) MACE is the first study that will prospectively assess short and long-term PCI outcomes according to the extent of coronary calcification as assessed by a centralized core laboratory Patients from MACE will also serve as a “virtual control group” for the ORBIT II trial in order to better understand the benefits of orbital atherectomy in contemporary practice for patients undergoing PCI for treatment of calcified coronary lesions

Summary (2) Detailed health economic data will be collected to better understand the cost-effectiveness of alternative strategies for managing calcified coronary lesions Preliminary results for 30 day outcomes are expected in late 2015