1. The Fourth Revolution Fully Bioresorbable Devices The Abbott Vascular BVS Program Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott Vascular Santa Clara, CA
CRT 2010

2. Charles A. Simonton, MD DISCLOSURES
Chief Medical Officer Abbott Vascular Santa Clara, CA

3. Miami, November 1976

4. First PTCA, Zurich September 16, 1977

5. First PTCA and Follow-Up (A. B.)
1977
2000
A.B. ,the 1st PTCA by Andreas Gruentzig on September 29, 1977, attended and spoke at the 30th Anniversary on September 30, 2007 in Zurich, an incredible tribute to the breakthrough made by Andreas 30 years ago

6. Performance Criteria for a Fully Bioabsorbable Device
Support
Leukocyte Recruitment - Inflammation
Re-endothelialization
Everolimus Elution
Platelet Deposition - Thrombosis
Matrix Deposition - Remodeling
SMC Proliferation and Migration
Vascular Function
Full Mass Loss & Bioabsorption
Mass Loss 1 3 6
Mos
2 Yrs
Data on file at Abbott Vascular
Forrester JS, et al. J Am Coll Cardiol 1991, 17(3):

7. Phases of Functionality
Revascularization
Restoration
Resorption
Support
Leukocyte Recruitment - Inflammation
Re-endothelialization
Everolimus Elution
Platelet Deposition - Thrombosis
Matrix Deposition - Remodeling
SMC Proliferation and Migration
Vascular Function
Full Mass Loss & Bioabsorption
Mass Loss 1 3 6
Mos
2 Yrs

8. Bioresorbable Device Components
MULTI-LINK VISION Stent Delivery System
Bioresorbable Device Platform
Bioresorbable Coating
Everolimus
Seven generations of MULTI-LINK success
Poly (Lactic Acid) (PLLA)
Resorbed, fully metabolized (2 years)
PDLA coating
Fully bioresorbable (3 months)
Similar dose and release rate to XIENCE V
In order to develop an optimal bioabsorbable DES, and to better our chances for success, we are leveraging technologies we have experience with – technologies that have proven themselves as some of the best technologies in the industry.
The delivery catheter we are using is from the Vision stent system. This catheter is recognized as having a high of deliverability.
The stent platform has evolved from technology developed by researchers at Duke University over 20 years ago. He stent is made from poly lactic acid, or PLA, a material that is absorbed by natural processes in the body.
The coating is also made from PLA. The polymer is mixed with everolimus to form a matrix.
The drug we are using on the BVS stent is everolimus – the same drug used in our Xience V stent. Although the drug is eluted from a bioabsorbable coating, the release rate is similar to that of Xience V.
All illustrations are artists’ renditions 8 8

9. Full Mass Loss & Bioabsorption
Revascularization
What if you could have a device that performs just like a standard stent during the acute period of recanalization, inhibits NIH and prevents restenosis just like a DES, and allows rapid re-endothelialization, but is fully bioresorbable?
Revascularization
Matrix Deposition - Remodeling
Support
Leukocyte Recruitment - Inflammation
Everolimus Elution
Re-endothelialization
Platelet Deposition - Thrombosis
SMC Proliferation and Migration
Vascular Function
Full Mass Loss & Bioabsorption
Mass Loss
Deliverability
Radial Strength 1 3 6
Duration of Radial Strength
Mos
2 Yrs
NIH Inhibition
Re-endothelialization

10. Deliverability in Simulated Arterial Model (SAM)
MORE
Deliverable
Diffuse Disease PVA Vessel
LESS
Deliverable
We tested the deliverability of the Xience V system extensively in our 3D synthetic arterial models with simulated tortuosity and lesions and demonstrated for the smallest and largest stent sizes that the deliverability was equivalent to the bare metal ML Vision stent.
Comparable deliverability in SAM.
Data on file at Abbott Vascular.

11. Addressing Vessel / Implant Compliance Mismatch
LESS
Conformable
Original PVA vessel curvature
MORE
Conformable
(permanent metallic stent)
(temporary implant)
Data on file at Abbott Vascular.

12. Addressing Vessel / Implant Compliance Mismatch
88° .
91°
BVS ABSORB Cohort B
Serruys, P. , TCT 2009 12

13. Radial Strength Radial strength comparable to metal stent at T=0
Flat Plate Compression Testing (3.0 x 18mm)
PSI
Xience V
BVS
Radial strength comparable to metal stent at T=0
Data on file at Abbott Vascular.

14. Radial Strength Over Time: BVS Cohort B Stent
In Vitro Degradation Testing (Cohort B)
3-4 months

15. Strut Coverage: ABSORB 6-Month OCT Results
Strut Coverage – 6 Mos. F/U 1%
99%
A subset of patients were studied using Optical Coherence Tomography (OCT) at 6 months. OCT provides very high resolution imaging, which is ideal for observing the interaction between the stent struts and the vessel over time.
At baseline, 91% of the stent struts were fully apposed in these patients. Most of the non-apposed struts were struts spanning across side branches. At 6-month follow-up, stent strut apposition remained very good, with 92% of struts apposed. Nearly all struts (99%) were covered with tissue at 6 months, which is an encouraging finding.
One of the more interesting findings was the change in optical appearance of the struts over time, which could be an early indication of bioabsorption.
N = 13 devices, 671 struts
Complete
Incomplete
Ormiston, J, et al. Lancet 2008; 371:

16. Full Mass Loss & Bioabsorption
Restoration
Restoration
What if a fully bioabsorbable device could provide unique benefits by gradually un-restraining the vessel?
Leukocyte Recruitment - Inflammation
Support
Platelet Deposition - Thrombosis
Everolimus Elution
Re-endothelialization
Matrix Deposition - Remodeling
SMC Proliferation and Migration
Vascular Function
Full Mass Loss & Bioabsorption
Mass Loss
Mechanical Conditioning 1 3 6
Mos
2 Yrs

17. Mechanical Conditioning
Gradual disappearance of supportive structure
Vessel recovers the ability to respond to physiologic stimuli
Support
Vascular Function
Shear stress & pulsatility
Tissue adaptation
Structure and functionality

18. Mechanical Conditioning
Organized tissue can only be generated in appropriate mechanical conditions. Culturing SMC-seeded PGA scaffolds with pulsatile flow for 8 weeks results in organization of SMCs into multilayer structures with orientated collagen fibrils between cells.
Xue, L, Greisler, H. J Vasc Surg. 2003;37:

19. Mechanical Conditioning
Static Pressure
Pulsatile Pressure
Histologic appearance of tissue-engineered constructs illustrating that rat SMCs are more highly oriented in mechanical conditioned constructs (B) as compared to statically grown constructs (A)
Seliktar, D. et al. Ann Biomed Eng. 2000;28:
Exposure of cellular structures to normal physiologic stimuli has a positive affect on cellular organization and function

20. Full Mass Loss & Bioabsorption
Resorption
What if a fully bioabsorbable device could completely disappear, leaving behind a more natural vessel?
Resorption
Leukocyte Recruitment - Inflammation
Everolimus Elution
Platelet Deposition - Thrombosis
Re-endothelialization
Matrix Deposition - Remodeling
Support
SMC Proliferation and Migration
Vascular Function
Benign Bioabsorption
Full Mass Loss & Bioabsorption
Return of Vascular Function
Mass Loss
Address Current DES Concerns
Expansive Remodeling 1 3 6
Mos
2 Yrs

21. Poly Lactide Acid - Hydrolysis
PLA – Poly Lactic Acid
PLA
H2O
 Molecular Weight
Hydrolysis
Lactide Units O O
Mass Loss R +
H2O R + HO R′ O R′ OH
carboxylic acid
alcohol
Mass Transport
CO2 + H2O
Krebs Cycle

22. Porcine Coronary Safety Study: Representative Photomicrographs (2x)
Porcine Coronary Artery Model.
BVS
1 month
6 months
1 year
2 years
3 years
4 years
CYPHER
1 month
6 months
1 year
2 years
3 years
4 years
Here are some representative histology slides from one of our safety studies in a porcine model. In this study, the BVS stent and a Cypher stent were implanted in each animal – we used the Cypher as a control since it is an approved DES.
The neointimal response was comparable between the two implants at 28 and 90 days in terms of neointimal composition and coverage. At later time points, however, the neointimal response to BVS stents was milder.
Representative photomicrographs 2X.
Photos taken by and on file at Abbott Vascular.
NOTE TO PRESENTERS: you may get a comment about the non-uniform strut distribution in the BVS 1 month image. This slice likely cut through part of a ring (from 11 o’clock to 5 o’clock) and one of the links (at 9 o’clock). Our next generation device has a new cell pattern that provides more uniform coverage. You might also hear a comment that it appears the struts are still there at 1 year. The material is fully absorbed in months, so it is not surprising to still see struts at 1 year. We know from additional porcine model testing that vasomotion in the BVS stented segment is restored by this 12-month timepoint (shown by intracoronary injection of acetylcholine causing vasoconstriction)

23. BVS: Minimal Inflammation
Porcine Coronary Artery Model
Inflammation Score (0-4)
BVS associated Inflammation markedly less than Cypher
Benign bioabsorption with minimal inflammation observed beyond 1 year
Inflammation score ≤ 1 = background
Data on file at Abbott Vascular.

24. ABSORB Vasomotor Function Testing: 24 Months
Stented Segment !
Potential clinical significance:
- Intact, functional endothelium  reduced thrombosis risk?
- Improved coronary reserve  improved perfusion/less angina?
- Glagov’s phenomenon, accommodative remodeling  fewer TLRs?
- Reduction in other MACE?
Serruys, P, et al. Lancet 2009; 373:

25. Address Current Concerns: Late Strut Fracture
DES
BMS
BMS fracture in SVG
Patient required repeat CABG
Strut fracture can occur with BMS or DES
Frequency of strut fracture reported at 1.7 – 3.2% (Kim, et al. Int J Cardiol. 2009;131: )
Fracture is associated with long lesions and overlapped stents (Yang, et al. Int J Cardiol. 2009;131: )
Chowdhury, P., et al. N Engl J Med. 2002;347:581.
Sianos, G., et al. Catheter Cardiovasc Interv. 2004;61: 25 25 25

26. ABSORB Thrombosis through 2 Years – Intent to treat
Per protocol and per ARC definition
0 – 2 Years
Acute (< 1 day)
0 (0.0%)
N = 30
Sub-Acute (1 – 30 days)
Late (> 30 days – 1 year)
N = 29
Very Late (> 1 year)
N = 28
No ‘stent’ thrombosis up to 2 years
One patient stopped Clopidogrel a few days after the 2-Year visit
All the other patients stopped before 2-Year
Serruys, P, et al. Lancet 2009; 373:

27. ABSORB Serial IVUS Results – Per Treatment
Post-PCI
6-month F/U
2-year F/U
% Diff (6M to 2Y)
p-value
n=16
Vessel (EEM) area (mm2)
13.17*
13.11*
12.56*
-4.89
0.055
Lumen area (mm2)
5.99
4.92
5.60
+11.53
0.034
Plaque area (mm2)
7.44*
8.60*
7.10*
-17.44
<0.001
Minimal Lumen area (mm2)
5.05
3.76
4.54
+18.32
0.005
*n=24
*n=15
Serruys, P, et al. Lancet 2009; 373:
P-values per Wilcoxon’s signed rank test 27

28. ABSORB OCT Images BL 2Y BL 2Y
Serruys, P, TCT 2008.

29. ABSORB: 3 Year Clinical Results
Hierarchical
6 Months
30 Patients
12 Months
29 Patients**
2 Years
28 Patients**
3 Years
Ischemia Driven MACE (%)
3.3% (1)*
3.4% (1)*
3.6% (1)*
Cardiac Death (%)
0.0% (0)
MI (%)
Q-Wave MI
Non Q-Wave MI
Ischemia Driven TLR (%)
by PCI
by CABG
No Stent Thrombosis Up to 3 Years
No new MACE events from 6 months and 3 years
*Same patient – this patient also underwent a TLR, not qualified as ID-TLR (DS = 42%) and died from a non-cardiac cause 888 days post-procedure.
**One patient missed the 9, 12, 18 month and 2 and 3 year visits. One patient died from a non-cardiac cause 706 days post-procedure
Product currently in development at Abbott Vascular. Not available for sale.

30. 3-Year Follow-Up: Example of Strut Resorption by OCT
Serruys, ICI 2009

31. Next Generation BVS Device: Objectives
More uniform strut distribution
More even support of arterial wall
Higher radial strength
Lower late ‘stent’ area loss
Storage at room temperature
Improved device retention
Unchanged:
Material, coating and backbone
Strut thickness
Drug release profile
Total degradation Time
Cohort A
Here you see images of the stent that was used in the first 30 patients in the ABSORB trial (BVS A), compared to the new stent design that will be tested in the next cohort of patients (BVS B).
Some of the improvements are obvious from these photos. The new design has a more uniform strut distribution, which should lend itself to a more even support of the vessel wall. The regions of unsupported surface area within the cells are also considerably smaller.
We have also made some processing enhancements that have contributed to yielding a stent that demonstrates less late stent area loss and higher radial strength, in bench and pre-clinical testing.
Cohort B
Photos taken by and on file at Abbott Vascular.

32. ABSORB Cohort B N = 101 pts; 12 sites (Europe, Australia, New Zealand)
Clinical follow-up schedule:
30 days, 6 months, 12 months, annually to 5 years
Imaging schedule:
Group B1 (n = 45)
QCA, IVUS, OCT, IVUS VH 12
Baseline 6 24
Months
Months
Months
Group B2 (n = 56) 32

33. First 3 COHORT B Patients: 6 Month Angiograms
Prior
Immediately Post
6 Months 33

34. Patient 2
Prior
Immediately
after
6 months 34

35. Immediately Post-Stent
Patient 3
Pre-Stent
Immediately Post-Stent
6-Month F/U 35

36. COHORT B Initial OCT Example: 6 Months
Serruys, ICI 2009

37. ABSORB EXTEND Study
Continued enrollment in ABSORB with expanded lesion complexity
1000 patients in up to 100 sites internationally outside the U.S. (P.I. = Alexander Abizaid MD)
Objective: Continue expanding experience with the COHORT B BVS device with the aim of substantiating confidence in the acute performance and late clinical outcomes with an expanded matrix of sizes in more complex patients

38. Summary
The Abbott Vascular Bioresorbable Vascular Scaffold (BVS) has shown encouraging acute, sub-acute and late (2-year) restoration of vessel patency and function in selected patients in the ABSORB study with minimal clinical events and no events after 6 months
The acute vessel conformability and late reduction in plaque area with restoration of vasomotor function in ABSORB opens up the potential for Vascular Restorative Therapy for patients undergoing PCI for obstructive CAD
ABSORB COHORT B registry with angiographic, IVUS and OCT follow-up and ABSORB EXTEND with clinical follow-up will greatly expand our understanding of the clinical outcomes and vascular responses to BVS therapy

39. BVS: Vascular Response (10X)
Porcine Coronary Artery Model
BVS
All struts incorporated within neointima
Minimal Inflammation
Complete Luminal Endothelialization
Strut degradation near complete and replaced with extracellular matrix & smooth muscle cells by 3 years
1 month
3 months
6 months
1 year
2 years
3 years
Here are some representative histology slides from one of our safety studies in a porcine model. In this study, the BVS stent and a Cypher stent were implanted in each animal – we used the Cypher as a control since it is an approved DES.
The neointimal response was comparable between the two implants at 28 and 90 days in terms of neointimal composition and coverage. At later time points, however, the neointimal response to BVS stents was milder.
Data on file at Abbott Vascular.
Photos taken by and on file at Abbott Vascular.
NOTE TO PRESENTERS: you may get a comment about the non-uniform strut distribution in the BVS 1 month image. This slice likely cut through part of a ring (from 11 o’clock to 5 o’clock) and one of the links (at 9 o’clock). Our next generation device has a new cell pattern that provides more uniform coverage. You might also hear a comment that it appears the struts are still there at 1 year. The material is fully absorbed in months, so it is not surprising to still see struts at 1 year. We know from additional porcine model testing that vasomotion in the BVS stented segment is restored by this 12-month timepoint (shown by intracoronary injection of acetylcholine causing vasoconstriction)

40. Inhibition of Neointimal Hyperplasia
ABSORB 6-Month IVUS Data
Post-PCI
Follow-Up
Difference
p-Value
Vessel Area (mm2)
13.55
13.49
-0.4% NS
EEM-’Stent’ Area (mm2)
7.47
8.08
+8.2%
0.003
‘Stent’ Area (mm2)
6.08
5.37
-11.7%
<0.001
NIH Area (mm2)
0.30 NA NA
Lumen Area (mm2)
6.08
5.07
-16.6%
<0.001
In this first animation, we look at IVUS measurements taken in the Vision bare metal stent arm of the SPIRIT First study. There was no change in vessel area. There also no change in stent area – as you would expect in a metal stent. All of the loss in lumen was due to neointimal hyperplasia within the stent, resulting in a late loss of 0.87mm.
In the Xience V arm of the SPIRIT First study, we again see no change in vessel area and no change in stent area. With Xience V, there is only a small amount of neointimal growth inside the stent due to everolimus inhibiting neointimal hyperplasia. As a result, the late loss is quite low and there is a widely patent lumen.
With the BVS stent in the ABSORB trial, we once again see no change in vessel area. But we see nearly a 12% reduction in stent area. The stent has become smaller. Siimilar to Xience V, there is only a small amount of neointimal growth inside the stent. The majority of late loss is due to a reduction in the stent area.
So, why is the stent getting smaller? There are two possible explanations. It could be that we are seeing signs that the stent is being bioabsorbed and is losing some of its strength, allowing vascular remodeling. It could also be that the stent gradually recoiled a bit.
BVS ‘Stent’ Percent Volume Obstruction = 5.5%
Xience V Stent Percent Volume Obstruction = 8.0%*
*SPIRIT-FIRST Trial
P.W.Serruys, ACC 2007
NOTE TO PRESENTERS: be careful not to confuse vascular remodeling with negative vessel remodeling. There is no change in vessel area – so this is not negative vessel remodeling (constriction) as was seen in balloon angioplasty. The stent apparently scaffolded effectively against vessel constriction. Rather, there is vascular remodeling – changes in the tissue behind the stent that is somehow encroaching on the stent as it is bioabsorbed. Our PIs think it is more likely chronic recoil of the stent. Our next generation device has less recoil in animal studies.

41. How Long is Radial Strength Needed
How Long is Radial Strength Needed? Restenosis Following Balloon Angioplasty
Absolute change in Minimal Luminal Diameter (mm) and Percent Diameter Stenosis (%) from Post-PTCA to Follow-Up
Quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months
N = 342 patients (N = 93 at 30-day F/U; N = 79 at 60-day F/U; N = 82 at 90-day F/U; N = 88 at 120-day F/U)
Most of the  MLD and  %DS occurred in the first 3 months, with a relative flattening from 3-4 months.
Serruys, PW, et al. Circulation. 1988; 77:

42. Device Flexibility LESS Flexible MORE Flexible STM2056533 Rev A
To compare the flexibility of the ML VISION® stent as crimped on a stent delivery system (SDS) and BVS V1.1 stent as crimped as crimped on a SDS using a three point bend test method.
MORE
Flexible
Data on file at Abbott Vascular.