*Mount Sinai Medical Center, New York, NY Impact of Calcification on Percutaneous Coronary Intervention Outcomes: Insights from the MACE Study Samin K. Sharma, MD*, Roxana Mehran, MD, Jon Resar, MD, John Lasala, MD, PhD, David Cohen, MD, Ron Waksman, MD, Jeffrey Popma, MD, on behalf of the MACE investigators *Mount Sinai Medical Center, New York, NY EN-3886.A

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Samin K. Sharma, MD   Speaker’s Bureau: Abbott Vascular, Inc. Boston Scientific Corporation Cardiovascular Systems, Inc. TriReme Medical The Medicines Company

Coronary Artery Disease Prevalence Prevalence of Arterial Calcium: CAD: 6-20% severe calcium8,9 Key predictors include advanced age, diabetes & kidney disease *Includes myocardial infarction and angina pectoris 1.Dolor RJ, et al. Comparative Effectiveness Review No. 66. Agency for Healthcare Research and Quality. August 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. 2. Go AS, et al. Circulation. 2014;129(3):e28-e292. 3. American Diabetes Association 2015 Fast Facts—Data and Statistics About Diabetes http://www.diabetes.org/diabetes-basics/statistics/ (Accessed December 8, 2015). 4. American Kidney Fund Website. Accessed July 30, 2013. 5. Howlader N, et al. SEER Cancer Statistics Review, 1975-2010. Accessed April 17, 2014. 6. Schiavetta A, et al. Stem Cells Transl Med. 2012;1(7):572-8. 7. Sage Report 2010. 8. Généreux P, et al. J Am Coll Cardiol. 2014;63(18):1845-54. 9. Bourantas CV, et al. Heart. 2014;100(15):1158-64..

Coronary Artery Calcification Patients with Calcified Lesions More complications and worse outcomes1-8 Longer treatment time, more resources, longer hospital stay, and higher costs9,10 Severely Calcified Lesions Angiography underestimates severity of calcification11 Technically challenging4, 11-15 Stent underexpansion, asymmetric expansion, and malapposition Higher procedural complication rates8 Higher incidence of major adverse cardiovascular events1, 2, 5 Insufficient drug penetration and subsequent restenosis16 More costly to treat9, 10 1. Genereux P, et al. JACC. 2014;63:1845-54. 10. Parikh K, et al. CCI. 2013;81:1134-1139. 2. Bourantas CV, et al. Heart. 2014;100:1158-64. 11. Mintz G, et al. Circulation. 1995;91(7):1959-65. 3. Zimoch W, et al. Presented at EuroPCR 2016. 12. Cavusoglu E, et al. CCI . 2004;62:485-49. 4. Fitzgerald PJ, et al. Circulation. 1992;86:64-70. 13. Gilutz H, et al. CCI. 2000;50:212-214. 5. Kawaguchi R, et al. CRM. 2008;9:2-8. 14. Moussa I, et al. Circulation. 1997;96:128-136. 6. Ko MC, et al. Clinics. 2013;68:1109-1114. 15. Mosseri M, et al. CRM. 2005;6:147-53. 7. Gijsen R, et al. J Clin Epidem. 2001;54:661-674. 16. Nakano M, et al. Eur Heart J. 2013;34:3304-13 8. Madhavan MV, et al. JACC. 2014;63:1703-14. 9. Meerkin D, et al. JIC. 2002;14:547-551.

Coronary Calcium is a Predictor of Worse Outcomes 6,855 Patients Enrolled: 3,268 STEMI and 3,587 N-STEMI HORIZONS-AMI and ACUITY Coronary Calcium and Outcomes 1-Year Post-PCI Genereux P, et al. JACC. 2014;63:1845-54.

MACE Study Design MACE is a prospective, multi-center, non-randomized PCI study evaluating cardiovascular outcomes of patients with/without coronary calcification Subjects stratified into one of three arms based on Core Lab assessment of degree of calcification (none/mild, moderate, and severe) PCI strategy was at the discretion of the study physician with commercially available devices that included, but were not limited to: balloon angioplasty, laser atherectomy, rotablation, etc., followed by stent placement Thrombectomy, investigational devices, embolic protection devices, and CSI’s coronary orbital atherectomy system (OAS) were not allowed 350 subjects were enrolled at 33 sites with up to 3-year follow-up Angiographic Core Laboratory and CEC were utilized for independent assessment Endpoints include: Procedural and lesion success, and Major Adverse Cardiac Events (MACE) at 1-year post-procedure Angiographic Core Laboratory: Beth Israel Deaconess Medical Center Clinical Events Committee: Icahn School of Medicine at Mount Sinai

MACE Key Inclusion/Exclusion Criteria Key Inclusion Criteria 1. Age ≥ 18 years. 2. Subject scheduled for PCI involving stent deployment in de novo coronary lesions. 3. Subject CK-MB (or Troponin if CK-MB is not available) must be less than or equal to the ULN within 8 hours prior to the start of treatment. Key Exclusion Criteria 1. Diagnosed with chronic renal failure unless under hemodialysis or has a serum creatinine level > 2.5 mg/dL. 2. Evidence of current LVEF ≤ 25%, NYHA class III or IV, or clinical evidence of heart failure. 3. History of major cardiac intervention within 30 days of the treatment procedure, not including a PCI procedure for a staging purpose. 4. History of uncontrolled insulin dependent diabetes. 5. Angiographically confirmed evidence of three or more lesions within one vessel or more than one vessel requiring intervention, unless treatment is staged. In ORBIT II, only 1 lesion/vessel treated during index procedure. In MACE, 2 lesions/vessel allowed during index procedure—potentially decreases TVR rate

Any CK-MB elevated to >3X Upper Limit Normal classified as MI MACE Study Definition of MI and Surveillance Required CK-MB Collection Times Pre-procedure Required ≤ 8 hours Post-procedure Required 5 – 8 Hours Post-procedure Required 16 - 20 Hours Follow-up Visits As available Any CK-MB elevated to >3X Upper Limit Normal classified as MI

MACE Angiographic Core Lab Calcification Definitions MACE Angiographic Core Lab Calcium Definitions MACE Angiographic Core Lab Calcification Definitions None/Mild Presence of readily apparent radiopacities within the vascular wall at the site of stenosis Moderate Presence of radiopacities only during cardiac cycle before contrast injection with calcium extended partially into target lesion Severe Presence of radiopacities noted without cardiac motion prior to contrast injection involving both sides of the arterial wall in at least one (1) location, total length of calcium (including segmented) must be at least 15 mm and extend partially into the target lesion Subjects were enrolled based on investigator assessed calcium via angiography, IVUS, or OCT. Subject stratification (None/Mild, Moderate, Severe) was based on Angiographic Core Lab assessment.

Enrollment and 1-Year Follow-up 350 Subjects Enrolled at 33 sites Angiographic Core Lab assessment of calcium None/Mild Lesion Calcification 133 Subjects* Moderate Lesion Calcification 99 Subjects* Severe Lesion Calcification 114 Subjects* 1-year Follow-up 123 Subjects 88 Subjects 102 Subjects Validator Source: Tables A6, A8 3.0% withdrawal/lost to follow-up 3.0% missed 1-year follow-up 1.5% died 7.1% withdrawal/lost to follow-up 3.0% missed 1-year visit 1.0% died 4.4% withdrawal/lost to follow-up 3.5% missed 1-year visit 3.5% died *Due to lack of recorded baseline angiography for Core Lab review, 4 subjects excluded.

Subject Demographics Lesion Calcification p-value None/Mild Moderate Severe Subjects N=133 N=99 N=114 Male 72.2% 74.7% 74.6% 0.917 Age 64.6 ± 10.6 69.2 ± 10.7 68.9 ± 9.1 <0.001 BMI 31.2 ± 6.6 29.4 ± 5.3 28.9 ± 5.3 0.004 eGFR 87.8 ± 37.3 78.2 ± 26.2 79.7 ± 27.1 0.039 History of diabetes mellitus 37.6% 33.3% 36.8% 0.796 History of smoking tobacco 55.6% 62.6% 62.3% 0.468 Validator Source: Tables B7, B8 (Standard Deviation Version) P-value calculated via Fisher’s exact test or t-test. Values presented % or Mean ± Standard Deviation.

Subject History Lesion Calcification p-value None/Mild Moderate Severe Subjects N=133 N=99 N=114 History of: Hyperlipidemia 85.7% 90.9% 93.9% 0.104 Hypertension 88.7% 85.9% 89.5% 0.726 Renal Disease 10.5% 15.2% 14.9% 0.474 Renal Disease on Hemodialysis 0% 2.0% 3.5% 0.066 Coronary Artery Disease (CAD) 65.4% 75.8% 78.9% 0.044 Myocardial Infarction (MI) 30.1% 30.3% 34.2% 0.749 Coronary Artery Bypass Graft (CABG) 7.5% 11.1% 12.3% 0.399 Percutaneous Coronary Intervention (PCI) 51.1% 48.5% 44.7% 0.612 Validator Source: Tables B8 (Standard deviation version) P-value calculated via Fisher’s exact test.

Target Lesions Treated P=0.046 P=0.662 P<0.001 P=0.687 P=0.194 Validator Source: Tables B9 P-value calculated via Fisher’s exact test.

Target Lesion Baseline Characteristics P<0.001 P<0.001 P=0.103 P=0.779 Validator Source: Tables B9, B10 P-value calculated via t-test. None/Mild Moderate Severe

Target Lesion Balloon Use P<0.001 Balloons Used as Proportion of Subjects None/Mild Moderate Severe P-value N=133 N=99 N=114 Balloons, Mean ± SD 1.5 ± 1.3 2.1 ± 1.4 2.6 ± 1.6 <0.001 Conventional Balloon 72.9% 87.9% 96.5% Cutting Balloon 9.0% 12.1% 9.6% 0.750 Focal Force Balloon 0.0% 2.0% 0.081 Balloons Used as a Proportion of Balloon Use None/Mild Moderate Severe P-value N=99 N=88 N=111 Balloons, Mean ± SD 2.0 ± 1.1 2.3 ± 1.2 2.7 ± 1.6 <0.001 Conventional Balloon 98.0% 98.9% 99.1% 0.835 Cutting Balloon 12.1% 13.6% 9.9% 0.708 Focal Force Balloon 0.0% 2.3% 0.087 Validator Source: Tables B11 P-value calculated via Fisher’s exact test or t-test.

Target Lesion Atherectomy Use Atherectomy Used as Proportion of Subjects None/Mild Moderate Severe P-value N=133 N=99 N=114 Atherectomy, Mean ± SD 0.0 ± 0.2 0.3 ± 0.6 0.5 ± 0.8 <0.001 Rotablator 2.3% 21.2% 32.5% Laser 0.8% 1.0% 0.9% 1.000 OAS* 0.0% P<0.001 Atherectomy Used as a Proportion of Atherectomy Use None/Mild Moderate Severe P-value N=5 N=22 N=39 Atherectomy, Mean ± SD 1.2 ± 0.4 1.3 ± 0.6 1.4 ± 0.7 0.633 Rotablator 60.0% 95.5% 94.9% 0.049 Laser 20.0% 4.5% 2.6% 0.247 OAS* 0.0% 0.147 Validator Source: Tables B11 P-value calculated via Fisher’s exact test or t-test. * Use of OAS was not permitted in the MACE study; however, the initial protocol allowed any FDA approved device for treatment. Due to the timing of device approval, there were 2 subjects treated with OAS prior to a protocol revision explicitly excluding OAS. Both subjects had severely calcified lesions as reported by the Investigator.

Procedural Parameters Lesion Calcification p-value None/Mild Moderate Severe Subjects N=133 N=99 N=114 Lesions treated during index procedure 0.163 1 87.2% 81.8% 78.1% 2 12.8% 18.2% 21.9% Total procedure time (minutes) 33.7 ± 19.5 38.7 ± 25.8 51.9 ± 33.5 <0.001 Total fluoroscopy time (minutes) 12.6 ± 8.1 15.6 ± 9.0 21.3 ± 14.6 Total contrast volume (mL) 161.0 ± 72.9 149.2 ± 79.0 178.7 ± 91.7 0.030 Target Lesion final Minimum Lumen Diameter (MLD) 2.5 ± 0.5 2.6 ± 0.5 0.180 Validator Source: Tables B12 (Standard Deviation Version) P-value calculated via Fisher’s exact test or t-test. Values presented as % or Mean ± Standard Deviation.

Procedural Success Protocol Definition: Successful stent delivery Final post-procedural result of <50% residual stenosis as determined by Core Lab No in-hospital Major Adverse Cardiac Events (MACE): cardiac death, MI (CK-MB > 3X ULN), TVR 97.7% 97.0% Validator Source: Tables C42 86.8% Point estimate and Clopper-Pearson Exact two-sided 95% confidence intervals.

Procedural Success P<0.001 P=0.454 P=0.210 P<0.001 Validator Source: Tables C22, C49 P-value calculated via Cochran-Armitage test for trend. Fisher’s exact test indicates significance between arms (p<0.05)

In-Hospital MACE Rate Components P=N/A Validator Source: Tables C22, C49 Approx 0.9% Q-wave MI in Severe Arm P-value calculated via Cochran-Armitage test for trend. Fisher’s exact test indicates significance between arms (p<0.05)

Clinically Relevant MI1 SCAI Definition of Clinically Relevant MI SCAI definition includes a threshold level of cardiac biomarker elevation which has been strongly linked to subsequent adverse events1 SCAI Definition of Clinically Relevant MI1 Definition of clinically relevant MI after PCI in patients with normal baseline CK-MB2 Peak CK-MB measured within 48 hours of the procedure rises to ≥10 X ULN, or to ≥5 X ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent LBBB, OR In the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured within 48 hours of the PCI rises to ≥70 X ULN, or ≥35 X ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent LBBB P-Value from Fisher’s Exact Test. 1. Moussa ID, et al. J Am Coll Cardiol. 2013;62:1563-70.

Lesion Success Protocol Definition: Successful stent delivery Final post-procedural result of <50% residual stenosis as determined by Core Lab No severe angiographic complications: Type C-F dissection, coronary perforation, abrupt coronary closure, and persistent slow flow/no reflow. P=0.003 Validator Source: Tables C23, C49 P-value calculated via Cochran-Armitage test for trend. Fisher’s exact test indicates significance between arms (p<0.05)

Severe Angiographic Complications Validator Source: Tables C23, C24, C49 P-value calculated via Cochran-Armitage test for trend. Fisher’s exact test indicates significance between arms (p<0.05)

1-Year MACE Rates Protocol Definition: Cardiac death Myocardial Infarction (defined as CK-MB > 3x ULN) Events resulting in a TVR P<0.001 Validator Source: Tables C21, C49 Subjects At-Risk 30 45 180 270 365 None/Mild 126 124 122 121 Moderate 92 87 84 82 80 Severe 93 91 86 P-value calculated via Log-rank trend test on data through 1-year. Cardiac death and TVR as reported by CEC.

1-Year MACE Rate Components Validator Source: Tables C21, C49, “C20andC25” Approx 0.9% Q-wave in severe P-value calculated via Log-rank trend test on data through 1-year. Cox proportional hazards model at 1-year indicates significance between arms (p<0.05)

Conclusions The MACE study is the first to prospectively evaluate PCI standard of care treatment in patients with varied degrees of coronary calcification. Procedural success rate was lower in subjects with severely calcified coronary lesions compared to subjects with none/mild or moderate calcification. This difference was driven by a higher rate of in-hospital MI. The 1-year MACE rate was higher in subjects with severely calcified coronary lesions compared to subjects with none/mild or moderate calcification. The difference in none/mild compared to severe was driven by a higher rate of both MI and TVR. PCI strategy may need to change since this study indicates that severe calcium, not moderate calcium, is associated with short/long-term MACE. Validator Source: Tables C23, C49