1. *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

2. 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

3. 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 Go AS, et al. Circulation. 2014;129(3):e28-e American Diabetes Association 2015 Fast Facts—Data and Statistics About Diabetes (Accessed December 8, 2015) American Kidney Fund Website. Accessed July 30, Howlader N, et al. SEER Cancer Statistics Review, Accessed April 17, Schiavetta A, et al. Stem Cells Transl Med. 2012;1(7): Sage Report Généreux P, et al. J Am Coll Cardiol. 2014;63(18): Bourantas CV, et al. Heart. 2014;100(15):

4. 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:
10. Parikh K, et al. CCI. 2013;81:
2. Bourantas CV, et al. Heart ;100:
11. Mintz G, et al. Circulation. 1995;91(7):
3. Zimoch W, et al. Presented at EuroPCR 2016.
12. Cavusoglu E, et al. CCI ;62:
4. Fitzgerald PJ, et al. Circulation. 1992;86:64-70.
13. Gilutz H, et al. CCI. 2000;50:
5. Kawaguchi R, et al. CRM. 2008;9:2-8.
14. Moussa I, et al. Circulation. 1997;96:
6. Ko MC, et al. Clinics. 2013;68:
15. Mosseri M, et al. CRM. 2005;6:
7. Gijsen R, et al. J Clin Epidem. 2001;54:
16. Nakano M, et al. Eur Heart J. 2013;34:
8. Madhavan MV, et al. JACC. 2014;63:
9. Meerkin D, et al. JIC. 2002;14:

5. 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:

6. 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

7. 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

8. 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 Hours
Follow-up Visits
As available
Any CK-MB elevated to >3X Upper Limit Normal classified as MI

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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

15. 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.

16. 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.

17. 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.

18. 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.

19. 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)

20. 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)

21. 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:

22. 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)

23. 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)

24. 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.

25. 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)

26. 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