1. What’s New with Metallic DES?
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation

2. Disclosures
None

3. 2017: Why do we Need Better Stents?
To further eliminate early and late stent thrombosis and restenosis
To reduce dependency on long-term DAPT
To improve lifelong prognosis

4. Principal Causes of Adverse Events with Current Metallic DES
Early and late inflammatory and hypersensitivity reactions to the drug or polymer
Polymer irregularities that result in inconsistent drug delivery or serve as a nidus for thrombus
Mechanical issues: Strut fracture >> longitudinal deformation

5. Polymer Integrity Issues in FDA Approved DES
c/o Renu Virmani

6. Otsuka F et al. Eur Heart J 2015;36:2147–2159
Neoatherosclerosis may be the common final denominator in many cases of late DES failure, and is not decreasing in prevalence
P=NS
Otsuka F et al. Eur Heart J 2015;36:2147–2159

7. Polymer-Free Metallic Stents
Once the drug is eluted, a BMS is left behind
Potential advantages
More uniform drug delivery
Removes nidus for thrombosis
No adverse polymer reactions
Potentially more rapid healing and shorter mandatory duration of DAPT
Potential disadvantages
Difficult to control drug dose and elution rate

8. BioFreedom Drug Coated Stent (DCS)
120 um thick stainless steel stent
Selectively micro-structured surface holds drug in abluminal surface structures
Biolimus A9 is 10x more lipophilic than sirolimus1
Sirolimus
Zotarolimus
Everolimus
Biolimus A9 20 40 60 80
100 %
±2.8% (valid for all drugs test)
12 mo in-stent LL ~0.17 mm (n=31)
Potential Advantages:
Rapid drug transfer to vessel wall (98% within one month2)
Avoid possible polymer-related adverse effects
Safe to shorten DAPT?
Data on file at Biosensors Intl
Tada et al. Circ Cardiovasc Interv 2010;3; 8

9. Leaders Free: Primary Efficacy Endpoint (Clinically-Driven TLR)12
DCS (n=1221)
BMS (n=1211)
9.8% 9
CD-TLR (%) 6
5.1% 3
P < 0.001 90
180
270
390
Days
Number at Risk
DCS
BMS
1221
1211
1167
1131
1130
1072
1098
1034
1053
984
Urban P et al. NEJM 2015;373: 9

10. Leaders Free: Components of the Safety Endpoint (1-year)10 5 6 7 %
p = 0.19
p = 0.01
p = 0.70
4.2
6.1
2.0
5.3
8.9
2.2
Cardiac death MI
ST (def /prob) 9 8 4 3 2 1
DCS (n=1221)
BMS (n=1211)
Urban P et al. NEJM 2015;373: 10

11. Drug-Filled Stent: Concept
DFS is made from a polymer-free tri-layer wire
Outer cobalt alloy layer for strength
Middle tantalum layer for radiopacity
Inner layer core material is removed and becomes a lumen that is filled with drug (sirolimus)
Cobalt alloy
Tantalum
Drug
20 um
Evolution of the Continuous Sinusoid Technology and Core Wire Technology using a tri-layer wire
Drug elutes through natural diffusion via direct interaction with the vessel wall
Fluid (extracellular fluid and serum elements) fills inner lumen
Drug solubilizes and diffuses with the concentration gradient (high to low)
Controlled and sustained elution profile
Elution is controlled through drug formulation, drug load, number of holes and size of holes
Drug diffuses into the tissue resulting in a uniform tissue response throughout stented area
Extended elution similar to current durable polymer DES

12. Drug-Filled Stent: Concept
Sirolimus is protected and contained inside the stent (drug density ~1.1 μg/mm2, based on circumferential outer stent surface area)
Drug is released through multiple laser-drilled holes on the abluminal side of the stent (average 5/strut, fenestration diameter μm, median 20 μm)
Drug elution is controlled and sustained through natural diffusion via direct interaction with the vessel wall; the elution profile is similar to durable polymer DES
Evolution of the Continuous Sinusoid Technology and Core Wire Technology using a tri-layer wire
Drug elutes through natural diffusion via direct interaction with the vessel wall
Fluid (extracellular fluid and serum elements) fills inner lumen
Drug solubilizes and diffuses with the concentration gradient (high to low)
Controlled and sustained elution profile
Elution is controlled through drug formulation, drug load, number of holes and size of holes
Drug diffuses into the tissue resulting in a uniform tissue response throughout stented area
Extended elution similar to current durable polymer DES
Drug fills/coats inner lumen
Drug elutes through abluminal holes
Results in uniform drug distribution to tissue

13. DFS: Pharmacokinetic Analysis
% Eluted from Explanted DFS
% Eluted from Explanted Xience
100
100 75 75
% Label Claim (100 % = 96µg) 50
% Label Claim (100 % = 88µg) 50 25 25
N = 6 stents per time point (2 stents/animal)
Historical control1: 30 60 90
120 30 60 90
Time (days)
Time (days)
1 Perkins LE. et al. J Interv Cardiol. 2009;22:S28–S41 13

14. DFS: Radial Force and Radio-opacity
Stent Radiopacity Contrast
(Avg of 6 measures ± SD)
P=0.05
P=0.90
Nicolas Foin, TCT 2015

15. RevElution Study N = 100 at 15 sites in Australia, Brazil, Singapore
1-2 de novo native coronary lesions per pt;
RVD: 2.25 mm – 3.5 mm
Lesion length: ≤27 mm
9 Month Cohort
N=50
24 Month Cohort
N=50
OCT Subgroup
N=30
1 mo OCT Subgroup
N=15
3 mo OCT Subgroup N=15
9 mo Angio/IVUS/OCT N=30
OCT Subgroup
N=30
2 mo OCT Subgroup N=15
6 mo OCT Subgroup N=15
24 mo
Angio/IVUS/OCT
N=20
N=20
9 mo Angio/IVUS N=20
24 mo Angio/IVUS N=20
Principal investigators: Alex Abizaid, Steve Worthley Study chair: Gregg W Stone

16. RevElution: In-stent Late Loss at 9 Mo
100 80 60 40 20
Percent of lesions (%)
–0.5
0.0
0.5
1.0
1.5
2.0
2.5
In-stent Late Loss (mm)
0.36 ± 0.52
0.26 ± 0.28
DFS
(n=49 lesions)
US Resolute ZES historical control
(n=93 lesions)
Pnon-inferiority <0.001
Speaker note: the major difference is the absence of the rightward tail – meaning fewer bad results, likely due to elimination of issues with polymer inconsistency
Worthley S et al. JACC Int 2017:on-line

17. RevElution: 9 Month QCA and IVUS
QCA (49 lesions)
In-stent
In-segment
RVD (mm)
2.68 ± 0.39
MLD (mm)
2.30 ± 0.41
 2.05 ± 0.36
% Diameter stenosis
13.7 ± 12.1
 23.3 ± 8.0
Late loss (mm)
0.26 ± 0.28
0.11 ± 0.22 
Binary restenosis rate (%) 0%
0% 
IVUS (49 lesions)
In-segment
Neointimal hyperplasia volume (mm3)
14.81 ± 8.96
Volume obstruction (%)
9.8 ± 5.6
Stent malapposition (%)
- Post-procedure
12.5%
- Persistent at 9 months
4.1%
- Late-acquired 0%
Worthley S et al. JACC Int 2017:on-line

18. RevElution: OCT at 1, 3 and 9 Months
Covered Struts
per lesion, median %
Malapposed Struts
per lesion, median % %
P<0.001
P=0.001 %
P=0.03
P=0.08 1M 9M 3M 9M 1M 9M 3M 9M
1M OCT Cohort
3M OCT Cohort
1M OCT Cohort
3M OCT Cohort
IQR
Mean
89.3 ± 6.3
98.1 ± 2.7
92.9 ± 6.0
98.8 ± 2.0
IQR
0 - 0
Mean
1.5 ± 2.3
0.1 ± 0.4
1.1 ± 2.2
0.3 ± 0.8
1M: n=14 patients, 17 lesions, 19 stents, 605 cross-sections and 7403 struts analyzed
3M: n=15 patients, 17 lesions, 19 stents, 651 cross-sections and 7451 struts analyzed
9M: n=25 patients, 29 lesions, 32 stents, 1102 cross-sections and 12,819 struts analyzed

19. RevElution: Representative case
Post-procedure: 2.9% malapposed struts
1-month follow-up: 91.4% strut coverage; 0.8% malapposed struts
Case
OCT images of 3.0 x 26 mm DFS stent in the mid LAD presented serially at post-procedure, 1-month, and 9-month follow-up. OCT images were taken from matched positions along the treated segment, and are presented from distal (left) to proximal (right). The position of matched OCT cross-sections along the stented segment is indicated in millimeters at the bottom of the image.
At post-procedure, 2.90% of the struts were malapposed. At 1 month, a favorable healing profile was observed, with 91.4% of all struts already covered, and only 0.80% persisting malapposed. At 9 months, all struts are virtually covered (98.8%) with no malapposed struts.
1.2 mm
10.6 mm
18.8 mm
25.0 mm
9-month follow-up: 98.8% strut coverage; 0% malapposed struts
Worthley S et al. JACC Int 2017:on-line

20. RevElution: 9-Month Cinical Outcomes - in 48/50 pts -%
Events (%)
While undergoing a CT-guided lung biopsy for lung cancer 263 days post DFS, patient developed ischemic symptoms with elevated troponin levels with no ECG changes (adjudicated as non-Q-wave MI)
Worthley S et al. JACC Int 2017:on-line

21. RevElution: Conclusions at 9 Months
The drug-filled stent (DFS) is a novel polymer-free DES with sirolimus contained inside the stent and eluted through abluminal holes
DFS was safe and effective with late lumen loss non-inferior to historical control, with minimal neointima hyperplasia and 0% binary restenosis at 9 months
DFS implantation resulted in a high degree of early stent strut coverage and 0% late incomplete malapposition, indicative of rapid early healing
The 9-mo TLF rate was low (2.1%), with no stent thrombosis
Follow-up in the 2-year cohort is ongoing, and large-scale RCTs are being planned