1. The ABSORB III trial and Beyond
Everolimus-eluting Bioresorbable Vascular Scaffolds in Patients with Coronary Artery Disease:
The ABSORB III trial and Beyond
Dean J. Kereiakes, MD, Stephen G. Ellis, MD, D. Christopher Metzger, MD, Ronald P. Caputo, MD, David G. Rizik, MD, Paul S. Teirstein, MD, Marc R. Litt, MD, Annapoorna Kini, MD, Ameer Kabour, MD, Steven O. Marx, MD, Jeffrey J. Popma, MD, Robert McGreevy, PhD, Zhen Zhang, PhD, Charles Simonton, MD and Gregg W. Stone, MD for the ABSORB III Investigators

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.
Affiliation/Financial Relationship
Company
Modest Consulting Fees
Significant Consulting Fees
Major Stock Shareholder/Equity
HCRI
Boston Scientific
Abbott Vascular
Svelte Medical Systems, Inc.
Janssen Research & Development LLC
Sanofi-Aventis U.S. LLC
Ablative Solutions, Inc.

3. Absorb Program Objectives A Series of Randomized Trials Designed to:
Demonstrate similar (non-inferior) results with ABSORB BVS compared to Xience CoCr-EES at 1 year
Demonstrate superior results with ABSORB BVS compared to Xience CoCr-EES between 1 and 5 years

4. ABSORB III Study Design Prospective, multicenter, single-blind, trial
~2,000 patients randomized
2:1 Absorb BVS vs. XIENCE CoCr-EES
Clinical follow-up:
30 days
6 months
12 months
24 months
36 months
48 months
60 months
No routine angiographic follow-up
Primary Endpoint: Target Lesion Failure (non-inferiority)
Cardiac death, or
Myocardial infarction attributed to the target vessel (TV-MI), or
Ischemia-driven target lesion revascularization (ID-TLR)
Powered Secondary Endpoints (superiority)
Angina
All revascularization
Ischemia-driven target vessel revascularization (ID-TVR) 4

5. Statistical Design Primary Endpoint
Non-inferiority analysis for TLF at 1 year with the following assumptions:
1-year TLF rate of 7%
Non-inferiority margin of 4.5%
“Putative placebo”, preserving ≥ 50% of the treatment effect of Xience vs. BMS
1-sided alpha of (equivalent to 2-sided 0.05)
95% 1-year follow-up
2000 subjects → 96% power
Maximum observed absolute difference between devices in order to pass non-inferiority = 2% 5

6. Derivation of NI Margin Based on Meta-analysis1 of Historical Trials
BMS
Treatment Effect Estimate
Xience vs BMS (sum 90% LCL)
9.0%
11.6% (7.8%, 15.4%)2*
1st Gen DES
TAXUS/CYPHER
At the time of ABSORB III trial design, Xience had not been directly compared to BMS outside the context of ST elevation myocardial infarction.
Therefore we first performed meta-analysis of trials comparing BMS to first generation DES,
[CLICK]
as well as meta-analysis of trials comparing 1st generation DES to Xience for the composite endpoint of cardiac death, all MI, and TLR. In each comparison, we took the lower bound of the two-sided 90% confidence interval as a conservative estimate of the treatment effect
We then combined the individual estimates to get the overall treatment effect estimate of 9% for Xience over BMS.
Therefore, the non-inferiority margin was selected to be 50% of 9% -- or 4.5%.
2.5% (1.2%, 3.7%)3
50% Treatment Effect = 4.5%
Xience
1. Random effect meta-analysis (Dersimonian and Laird method)
2. Two-sided 90% confidence interval. Based on results from clinical trials SIRIUS and TAXUS IV
3. Two-sided 90% confidence interval. Based on results from clinical trials SPIRIT IV and ISAR TEST IV
* CD, MI, TLR

7. Key Patient Eligibility Criteria
>18 years old
Evidence of myocardial ischemia (stable/unstable/post- infarction angina or silent ischemia)
No elevation of CK-MB
1 or 2 de novo target lesions in up to 2 native coronary arteries (max 1 lesion per artery)
Diameter stenosis ≥50% and <100% with TIMI flow ≥1
If <70%, abnormal functional test (including FFR ≤0.80), unstable angina or post-infarct angina
RVD ≥2.50 mm and ≤3.75 mm (site-determined)
Lesion length ≤24 mm (site-determined) 7

8. Study Flow and Follow-up
Randomized 2:1
N=2008 (ITT)
ABSORB N=1322
ABSORB
N=1312
Xience
N=677
99.2% Complete
98.7% Complete
N=4 lost to follow-up
N=6 withdrew consent
N=6 lost to follow-up
N=3 withdrew consent
N=686
12-month Follow-up

9. Baseline Characteristics
Absorb
(N=1322)
Xience
(N=686)
p-value
Age (mean)
63.5 ±10.6
63.6±10.3
0.75
Male
70.7%
70.1%
0.80
Race (Caucasian)
87.1%
88.3%
0.44
Current tobacco use
21.3%
20.7%
0.77
Hypertension
84.9%
85.0%
0.95
Dyslipidemia
86.2%
86.3%
0.97
Diabetes
31.5%
32.7%
0.60
Insulin-treated
10.5%
11.2%
Prior MI
21.5%
22.0%
0.79
Prior coronary intervention
38.7%
38.0%
Stable angina
57.3%
60.8%
0.13
Unstable angina
26.9 %
24.5%
0.25
Silent ischemia
10.0%
10.2%
0.88
Single vessel disease
69.5%
67.2%
0.29

10. Baseline Lesion Characteristics (QCA)
Absorb
(N=1322)
(L=1385)
Xience
(N=686)
(L=713)
p-value
ACC/AHA lesion class B2/C
68.7%
72.5%
0.08
# of target lesions treated
1.0 ± 0.2
0.38
One
95.1%
96.1%
0.32
Two
4.8%
3.9%
0.36
Target lesion
LAD
44.5%
42.2%
0.31
RCA
29.2%
27.2%
0.35
Circumflex
26.2%
30.6%
0.03
Lesion length, mm
12.60 ± 5.41
13.12 ± 5.82
0.05
RVD, mm
2.67 ± 0.45
2.65 ± 0.46
RVD <2.25 mm
18%
19%
0.39
MLD, mm
0.92 ± 0.37
0.90 ± 0.34
0.11
%DS
65.3 ± 12.5
65.9 ± 11.7
0.24
N= number of subjects
L= number of lesions

11. Procedural Characteristics
Absorb
(N=1322)
(L=1385)
Xience
(N=686)
(L=713)
p-value
Per Subject
Bivalirudin use
60.7%
58.7%
0.39
GP IIb/IIIa inhibitor use
10.1%
12.4%
0.11
Only unassigned devices implanted
4.4%
0.6%
<0.001
Unplanned overlapping devices
6.2%
8.5%
0.06
Post-dilatation performed
65.5%
51.2%
Intravascular imaging guidance
11.2%
10.8%
0.81
Procedure duration (min)
42.2 ± 23.1
38.3 ± 20.9
Per Lesion
Total study device length (mm)
20.5 ± 7.2
20.7 ± 9.0
0.56
Max device/balloon diameter (mm)
3.18 ± 0.43
3.12 ± 0.45
0.007
Max device/balloon to vessel diameter ratio
1.21  0.15
1.19  0.14
0.05
Maximum device/balloon pressure (atm.)
15.4 ± 3.0
15.4 ± 3.2
0.83
N= number of subjects
L= number of lesions

12. Post-procedural QCA Measurement Absorb (N=1322) (L=1385) Xience
p-value
RVD
2.70 ± 0.45
2.68 ± 0.47
0.33
In-Device
MLD
2.37 ± 0.40
2.49 ± 0.40
<0.0001
Acute gain
1.45 ± 0.45
1.59 ± 0.44
%DS
11.6 ± 8.77
6.4 ± 8.91
In-Segment
2.15 ± 0.41
2.14 ± 0.43
0.58
1.23 ± 0.46
1.24 ± 0.44
0.50
20.0 ± 7.94
19.8 ± 8.20
0.55
N= number of subjects
L= number of lesions

13. Acute Success Absorb (N=1322) (L=1385) Xience (N=686) (L=713) p-value
Device Success
94.3%
99.3%
<0.0001
Procedural Success
94.6%
96.2%
0.12
Device Success (lesion basis)
Successful delivery and deployment of study scaffold/stent at intended target lesion
Successful withdrawal of delivery system and final in-scaffold/stent DS <30% (QCA)
Procedure Success (patient basis)
Successful delivery and deployment of at least one study scaffold/stent at intended target lesion
No in-hospital (maximum 7 days) TLF

14. Non-inferiority margin
Primary Endpoint
1 Year TLF
Non-inferiority margin
= 4.5%
1-Year TLF
AbsorbTM vs. XIENCE
7.8% (102/1313) vs. 6.1% (41/677)
Difference = 1.7% [-0.5%, 3.9%]
PNI = 0.007
No confusion on p-value
% Difference (ABSORB - XIENCE)

15. Months Post Index Procedure
Target Lesion Failure
100%
Absorb BVS (n=1322)
Xience CoCr-EES (n=686)
Diff [95% CI] =
1.7% [-0.5% to 3.9%]
Psuperiority=0.16
20%
15%
10% 5% 0% 1 2 3 4 5 6 7 8 9 10 11 13
7.7%
6.0% 12
80%
60%
TLF (%)
40%
20% 0% 1 2 3 4 5 6 7 8 9 10 11 12 13
Months Post Index Procedure
No. at Risk:
Absorb
1322
1254
1230
1218
1196
Xience
686
661
651
643
634

16. 1-Year TLF: Subgroup analysis
Absorb
(N=1322)
Xience
(N=686) RR
(95% CI)
Relative Risk
p-value (interaction)
Age ≥64 years
8.1%
5.9%
1.37 ( )
0.69
Age <64 years
7.4%
6.2%
1.19 ( )
Female
8.5%
1.16 ( )
0.68
Male
5.5%
1.36 ( )
Diabetes
10.7%
9.1%
1.18 ( )
No diabetes
6.3%
4.6%
1.38 ( )
Unstable angina/recent MI
6.5%
6.6%
0.98 ( )
0.35
Stable CAD
8.3%
5.8%
1.42 ( )
Single TL/TV treated
7.7%
1.32 ( )
0.50
Dual TL/TV treated
9.4%
11.5%
0.81 ( )
Clopidogrel
8.0%
6.8%
1.17 ( )
0.43
Prasugrel or ticagrelor
7.1%
4.3%
1.63 ( )
ACC/AHA class A or B1
2.2%
3.05 ( )
0.07
ACC/AHA class B2 or C
8.2%
7.5%
1.10 ( )
Lesion length <11.75 mm
7.9%
4.8%
1.64 ( )
0.23
Lesion length ≥11.75 mm
7.3%
1.06 ( )
RVD <2.63 mm
9.8%
7.8%
1.27 ( )
0.90
RVD ≥2.63 mm
5.7%
1.34 ( )
1.0
Favors Absorb
Favors Xience

17. 1-Year TLF Components
P=0.16
P=0.18
P=0.50
P=0.29

18. Myocardial Infarction to 1 Year
P=0.28
P=0.40
P=0.18
P=0.31
P=0.56
P=0.35

19. Peri-Procedural MI by Definition
CK-MB threshold
Absorb
(N=1322)
Xience
(N=686)
Difference
p-value
>3x ULN
6.8%
6.6%
0.2
0.89
>5x ULN (protocol)
3.0%
2.8%
0.75
>8x ULN
1.3%
0.0
0.96
>10x ULN
0.9%
1.2%
-0.3
0.58
SCAI definition*
*>10x ULN or >5x ULN with new Q waves or new persistent LBBB
J Am Coll Cardiol 2013;62:

20. Device Thrombosis to 1 Year
Absorb
(N=1322)
Xience
(N=686)
p-value
Device Thrombosis (def/prob)
1.54%
0.74%
0.13
- Early (0 to 30 days)
1.06%
0.73%
0.46
- Late (> 30 to 1 year)
0.46%
0.00%
0.10
- Definite* (1 year)
1.38%
0.21
- Probable (1 year )
0.15%
0.55
*One “definite ST” in the Absorb arm by ITT
was in a pt that was treated with Xience

21. 1-Year Device Thrombosis
Subgroup
Absorb
(N=1322)
Xience
(N=686) RR
(95% CI)
Relative Risk
p-value (interaction)
Age ≥64 years
1.8%
0.6%
3.22 (
0.38
Age <64 years
1.2%
0.9%
1.33 ( )
Female
1.6%
2.0%
0.79 ( )
0.07
Male
1.5%
0.2%
7.21 ( )
Diabetes
3.2%
1.4%
2.34 (0.67-8,13)
0.78
No diabetes
0.8%
0.4%
1.79 ( )
Unstable angina/recent MI
1.0%
1.88 ( )
0.91
Stable CAD
1.7%
2.16 ( )
Single TL/TV treated
2.09 ( )
n/a
Dual TL/TV treated
0.0% -
Clopidogrel
0.7%
2.69 ( )
0.33
Prasugrel or ticagrelor
0.96 ( )
ACC/AHA class A or B1
1.36 ( )
0.67
ACC/AHA class B2 or C
1.9%
2.32 ( )
Lesion length <11.75 mm
1.58 ( )
0.56
Lesion length ≥11.75 mm
2.82 ( )
RVD <2.63 mm
2.3%
2.65 ( )
0.48
RVD ≥2.63 mm
1.28 ( )
Favors Absorb
Favors Xience

22. Powered Secondary Endpoints
Absorb
(N=1322)
Xience
(N=686)
p-value
Angina
18.3%
18.4%
0.93
All Revascularization
9.1%
8.1%
0.50
ID-TVR
5.0%
3.7%
0.21

23. Limitations
ABSORB III enrolled patients with stable ischemic heart disease and/or stabilized ACS, and excluded specific complex lesions (e.g. CTO, LM, large bif); results may therefore not be generalizable to higher- risk patients and more complex disease
Underpowered for low frequency events
Results must be viewed in context that Xience was the control device which has been associated with the lowest rates of ST and other events
BVS is a first generation device and was used for the first time by most operators within this trial 23

24. Outcomes of Absorb Bioresorbable Scaffold in Patients with Coronary Artery Disease: One-Year Results from Patient-Level, Pooled Meta-Analysis
Gregg W. Stone, MD, Runlin Gao, MD, Takeshi Kimura, MD, Dean Kereiakes, MD, Stephen G. Ellis, MD, Yoshinobu Onuma, MD, PhD, Wai-Fung Cheong, PhD, Jennifer Jones-McMeans, PhD, Xiaolu Su, MS, Zhen Zhang, PhD, Patrick W. Serruys, MD, PhD
Lancet 2016 Jan26,ePub

25. ABSORB 1-Year Meta-analysis Objectives and endpoints
Objective: To evaluate the 1-year relative outcomes of the AbsorbTM BVS compared to the XIENCE CoCr-EES for the treatment of simple and moderately complex lesions in pts with stable CAD and stabilized ACS
Primary endpoints:
The patient-oriented composite endpoint (PoCE) of death, all MI or all revascularization
The device oriented composite endpoint (DoCE) of cardiac death, TV-MI or ID-TLR (=TLF)
Secondary endpoints:
Safety: Death, MI, and device thrombosis
Efficacy: Revascularization, ID-TVR, ID-TLR

26. * EVERBIO (9mos); TROFI II (6mos) STEMI **Maximum 1 lesion per vessel
4 ABSORB RCTs*, 3389 patients
ABSORB II
ABSORB Japan
ABSORB China
ABSORB III
ClinicalTrials.gov
NCT
NCT
NCT
NCT
N centers 46 38 24
193
N randomized pts
501
400
480
2,008
- assigned to BVS
335
266
241
1,322
- assigned to CoCr-EES
166
134
239
686
N study lesions
1 or 2
N study vessels**
* EVERBIO (9mos); TROFI II (6mos) STEMI
**Maximum 1 lesion per vessel

27. ABSORB 1-Year Meta-analysis
ABSORB II, ABSORB III, ABSORB Japan, ABSORB China
1-Year PoCE: Death, MI, or Revascularization
Absorb
BVS
XIENCE
CoCr-EES
Study
Absorb II
Absorb China
Absorb Japan
Absorb III
Summary
27/331
19/238
26/265
184/1313
256/2147
17/165
23/237
11/133
78/677
129/1212
RR [95% CI]
0.76 [0.43, 1.36]
0.82 [0.46, 1.47]
1.19 [0.60, 2.33]
1.22 [0.95, 1.56]
1.09 [0.89, 1.34]
RR [95% CI]
Fixed: MH
Random: DL
Test for overall effect: Z=0.88; P=0.38
0.1
0.5
1.0
5.0
10.0
Test for heterogeneity: I2=5.1%; P=0.37
Absorb
BVS Better
Xience CoCr-EES
Better
PoCE = Patient-oriented composite endpoint

28. ABSORB 1-Year Meta-analysis
ABSORB II, ABSORB III, ABSORB Japan, ABSORB China
1-Year DoCE (TLF): Cardiac Death,TV-MI or ID-TLR
Absorb
BVS
XIENCE
CoCr-EES
Study
Absorb II
Absorb China
Absorb Japan
Absorb III
Summary
20/331
8/238
11/265
102/1313
141/2147
7/165
10/237
5/133
41/677
63/1212
RR [95% CI]
1.42 [0.61, 3.30]
0.80 [0.32, 1.98]
1.10 [0.39, 3.11]
1.28 [0.90, 1.82]
1.22 [0.91, 1.64]
RR [95% CI]
Fixed: MH
Random: DL
Test for overall effect: Z=1.36; P=0.18
0.1
0.5
1.0
5.0
10.0
Test for heterogeneity: I2=0%; P=0.78
Absorb
BVS Better
Xience CoCr-EES
Better
DoCE = Device-oriented composite endpoint

29. ABSORB 1-Year Meta-analysis
ABSORB II, ABSORB III, ABSORB Japan, ABSORB China
DoCE (TLF):Cardiac Death,TVMI or ID-TLR (pooled)
20%
Absorb BVS (n=2161)
XIENCE CoCr-EES (n=1223)
15%
Difference [95%CI] = 1.2% [-0.4%, 2.7%]
HR [95%CI] = 1.25 [0.92,1.70]
P=0.16
Target lesion failure (%)
10%
6.0% 5%
4.9% 0% 1 2 3 4 5 6 7 8 9 10 11 12
Months Post Index Procedure
Number at risk
Absorb BVS
XIENCE CoCr-EES
2161
1223
2065
1188
2037
1174
2022
1161
2003
1150
DoCE = Device-oriented composite endpoint

30. ABSORB 1-Year Meta-analysis 1-Year Device Thrombosis (Def/Prob)
ABSORB II, ABSORB III, ABSORB Japan, ABSORB China
1-Year Device Thrombosis (Def/Prob)
Absorb
BVS
XIENCE
CoCr-EES
Study
Absorb II
Absorb China
Absorb Japan
Absorb III
Summary
3/329
1/238
4/262
20/1301
28/2130
0/164
0/232
2/133
5/675
7/1204
RR [95% CI]
N/A
1.02 [0.19, 5.47]
2.08 [0.78, 5.51]
2.09 [0.92, 4.75]
RR [95% CI]
Fixed: MH
Random: DL
Test for overall effect: Z=1.77; P=0.08
0.1
0.5
1.0
5.0
10.0
Test for heterogeneity: I2=0%; P=0.40
Absorb
BVS Better
Xience CoCr-EES
Better

31. ABSORB 1-Year Meta-analysis
ABSORB II, ABSORB III, ABSORB Japan, ABSORB China
Device Thrombosis (Def/Prob) (pooled)
20%
Absorb BVS (n=2161)
XIENCE CoCr-EES (n=1223)
15%
Device thrombosis (%)
10%
Difference [95%CI] = 0.7% [0.0%, 1.3%]
HR [95%CI] = 2.11 [0.92,4.83]
P=0.08 5%
1.3%
0.6% 0% 1 2 3 4 5 6 7 8 9 10 11 12
Months Post Index Procedure
Number at risk
Absorb BVS
XIENCE CoCr-EES
2161
1223
2128
1213
2114
1207
2108
1200
2098
1197

32. ABSORB Meta-analysis- ABSORB III
Conclusions from 4 trials and 3,389 randomized patents
For treatment of simple and moderately complex lesions in pts with stable CAD and stabilized ACS, the Absorb BVS, compared to the XIENCE CoCr-EES, provided:
Similar rates of the patient-oriented and device-oriented composite endpoints, consistent with comparable overall outcomes at 1 year
Non-significantly different rates of major safety outcomes, including death, MI, and device thrombosis
No significant difference in peri-procedural MI, but a small increase in TV-MI (p=0.04 meta-analysis)
Comparable measures of efficacy, including ID-TLR, ID- TVR and all revascularization