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What’s New with
Metallic DES?
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation
Disclosures
• None
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
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
Polymer Integrity Issues in FDA
Approved DES
c/o Renu Virmani
Neoatherosclerosis may be the common final
denominator in many cases of late DES failure,
and is not decreasing in prevalence
Autopsy series
SES
PES
EES
40
35
P=NS
35%
29%
30
25
20
19%
15
10
5
0
Neoatherosclerosis
Otsuka F et al. Eur Heart J 2015;36:2147–2159
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
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
100
80
60
%
40
20
0
12 mo in-stent LL ~0.17 mm (n=31)
Sirolimus Zotarolimus Everolimus Biolimus
A9
±2.8% (valid for all drugs test)
Potential Advantages:
• Rapid drug transfer to vessel wall (98% within one month2)
• Avoid possible polymer-related adverse effects
• Safe to shorten DAPT?
1. Data on file at Biosensors Intl
2. Tada et al. Circ Cardiovasc Interv 2010;3;174-183
Leaders Free: Primary Efficacy
Endpoint (Clinically-Driven TLR)
12
DCS (n=1221)
CD-TLR (%)
BMS (n=1211)
9.8%
9
6
5.1%
3
P < 0.001
0
0
90
180
Days
270
390
1221
1211
1167
1131
1130
1072
1098
1034
1053
984
Number at Risk
DCS
BMS
Urban P et al. NEJM 2015;373:2038-47
Leaders Free: Components of the
Safety Endpoint (1-year)
10
8.9
9
DCS (n=1221)
BMS (n=1211)
8
7
6.1
6
%
5
5.3
4.2
4
3
2.0
2.2
2
1
0
Cardiac death
MI
ST (def /prob)
p = 0.19
p = 0.01
p = 0.70
Urban P et al. NEJM 2015;373:2038-47
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)
20 um
Drug
Tantalum
Cobalt alloy
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 16 - 25 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
Drug fills/coats
inner lumen
Drug elutes through
abluminal holes
Results in uniform drug
distribution to tissue
DFS: Pharmacokinetic Analysis
% Eluted from
Explanted DFS
% Eluted from
Explanted Xience
100
% Label Claim (100 % = 88µg)
% Label Claim (100 % = 96µg)
100
75
50
25
N = 6 stents per time point
(2 stents/animal)
0
75
50
25
Historical control1:
0
0
30
60
Time (days)
1
90
0
30
60
90
Time (days)
Perkins LE. et al. J Interv Cardiol. 2009;22:S28–S41
120
DFS: Radial Force and Radio-opacity
Stent Radial Stiffness
Stent Radiopacity Contrast
(3.0 mm stent, n=3)
5
P=0.05
P=0.90
4.4
4
3.6
3.5
3
2
Radiopacity contrast (arb unit)
Radial Stiffness per Unit Length
(N/mm per mm)
6
(Avg of 6 measures ± SD)
0.6
0.5
0.43
0.36
0.4
0.3
0.2
0.1
0.0
DFS
1
0
DFS
INTEGRITY
ONYX
Nicolas Foin, TCT 2015
0.47
ONYX
INTEGRITY
RevElution Study
9 Month Cohort
N=50
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
OCT Subgroup
N=30
N=20
9 mo
Angio/IVUS
N=20
1 mo OCT
Subgroup
N=15
3 mo OCT
Subgroup
N=15
9 mo
Angio/IVUS/OCT
N=30
24 Month Cohort
N=50
OCT Subgroup
N=30
2 mo OCT
Subgroup
N=15
6 mo OCT
Subgroup
N=15
24 mo
Angio/IVUS/OCT
N=30
Principal investigators: Alex Abizaid, Steve Worthley
Study chair: Gregg W Stone
N=20
24 mo
Angio/IVUS
N=20
RevElution: In-stent Late Loss at 9 Mo
Percent of lesions (%)
100
DFS
US Resolute ZES
historical control
(n=49 lesions)
(n=93 lesions)
0.26 ± 0.28
0.36 ± 0.52
80
Pnon-inferiority <0.001
60
40
20
0
–0.5
0.0
0.5
1.0
1.5
2.0
In-stent Late Loss (mm)
Worthley S et al. JACC Int 2017:on-line
2.5
RevElution: 9 Month QCA and IVUS
QCA (49 lesions)
In-stent
RVD (mm)
In-segment
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
0%
0%
Binary restenosis rate (%)
IVUS (49 lesions)
In-segment
Neointimal hyperplasia volume (mm3)
14.81 ± 8.96
Volume obstruction (%)
9.8 ± 5.6
Stent malapposition (%)
- Post-procedure
- Persistent at 9 months
- Late-acquired
Worthley S et al. JACC Int 2017:on-line
12.5%
4.1%
0%
RevElution: OCT at 1, 3 and 9 Months
100
Covered Struts
Malapposed Struts
per lesion, median %
per lesion, median %
91.4
99.0
95.6 99.5
10
75
%
P<0.001
50
P=0.001
%
5
P=0.03
P=0.08
25
0.3
0
0
1M 9M
1M OCT
Cohort
3M 9M
3M OCT
Cohort
0.0
1M 9M
1M OCT
Cohort
IQR
84.8 93.2
97.9
-99.8
90.3 97.2
98.3 100
IQR
98.1
± 2.7
92.9 ±
6.0
98.8
± 2.0
Mean
Mean
89.3
± 6.3
0.2
0.0
3M 9M
3M OCT
Cohort
0 - 2.3
0-0
0 - 7.0
0-0
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
RevElution: Representative case
Post-procedure: 2.9% malapposed struts
1-month follow-up: 91.4% strut coverage; 0.8% malapposed struts
9-month follow-up: 98.8% strut coverage; 0% malapposed struts
1.2 mm
10.6 mm
18.8 mm
25.0 mm
Worthley S et al. JACC Int 2017:on-line
RevElution: 9-Month Cinical Outcomes
- in 48/50 pts 15
10
Events (%)
%
5
2.1
2.1
0.0
0
TLF
Cardiac death
TV-MI
0.0
0.0
TLR
Stent thrombosis
(definite/probable)
While undergoing a CT-guided lung biopsy for lung cancer 263 days post DFS,
1 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
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