Hermiller_DES_Current_Data_2013

Report
Hilton La Jolla Torrey Pines
La Jolla, California - Oct 3rd, 2013
Drug-Eluting Stents 2013:
Current Data and Future
Advances
B
L
2
Y
James Hermiller, MD, FACC, FSCAI
The St Vincent Medical Group
The St Vincent Heart Center of Indiana
Indianapolis, IN
Disclosures
Affiliation/Financial Relationship
• Consulting Fees/Honoraria
• Speaker Bureau
Company
• Abbott, BSC, Medtronic
and St Jude
• Medicines Company
Outline
• Introduction
• Current Data
•
Advances to Date
• Future Directions
•
Metallic DES Bioabsorbable Polymer
•
Metallic DES with No Polymer
•
Completetly Bioabsorbable DES
• Conclusions and Summary
Introduction: DES Talks
PES
First Generation DES
Paclitaxel
Express2
Polymer
Stent
PEVA + PBMA blend
BX Velocity
SES
Drug
Polyolefin derivative
Sirolimus
1st Gen Drug-Eluting Stents
The good, the bad, and the ugly!
Late loss = 0
BMS
DES
Giant cells
DES
Angioscopy
BMS
7 years
Eos
Inflammation
Delayed Healing!
Incomplete
apposition
Late stent
thrombosis
Abn Vasomotion
Sirolimus
Control
*P<0.001 vs. control
40 mos
*
IVUS
*
ZES
Second Generation DES
EES
HO
Zotarolimus
BioLinx copolymer
Integrity
Drug
Polymer
Stent
O
O
O
O
O
N
O
HO
O
O
O
HO
Vision
O
O
Everolimus
VDF + HFP copolymer
Omega
Current Stent Attributes
Stent
EES PROMUS
ZES Resolute
EES - Xience
Expedition
Underlying Stent
PtCr –
Element
(Omega)
CoCr –
Integrity
CoCr – Modified
Vision
Strut Thickness
0.0032”
0.0036”
0.0032”
9,12,15,18,22,26,
30, 34 and 38 mm
(34 and 38 for
>3.0 mm
diameter)
8,12,15,18,23,28,
33, and 38 mm
(33 and 38 mm for
>2.5 mm
diameter)
Strut Pattern
Lengths (mm)
8,12,16,20,24,2
(Diameters 2.25 to 8, 32, and 38
4.0 mm)
mm
(38 for >2.75
mm diameter)
Current Stent Attributes
Stent
EES –
PROMUS
ELEMENT
ZES - Resolute EES –
Expedition
Max Expansion
(mm)
2.25 to 2.75
2.5 & 2.75 to 3.5
3.0 & 3.5 to 4.25
4.0 to 5.25
2.25 – 2.75 to 3.25
3.0 – 4.0 to 4.75
2.25 & 2.5 to
3.25
2.75 &3.0 to 3.75
3.5 & 4.0 to 4.75
Sidebranch Cell
Size (Max
Expansion)
2.25 to 4.18
2.5 & 2.75 to 4.7
3.0 & 3.5 to 5.75
4.0 to 7.44
2.25 to 4.0 to 9.24
mm
6 Cresst -- 2.25
to 3.0 to 3.5mm
9 Crest – 3.5 &
4.0 to 4.2 mm
Polymer Drug
Fluorinated
Copolymer EES
Biolinx Polymer
ZES
Fluorinated
Copolymer EES
<0.2 mm
<0.2 mm
In Stent Late Loss <0.2mm
Bern-Rotterdam Cohort Study
Räber L, ESC 2011
EES vs. SES Hazard Ratio* = 0.41, 95% CI 0.27–0.62, P<0.0001
EES vs. PES Hazard Ratio* = 0.33, 95% CI 0.23-0.48, P <0.0001
Cumulative incidence (%)
5
ARC Definite ST @ 4 Years
4
Paclitaxel Stent 4.4%
3
Sirolimus Stent 2.9%
2
1
Everolimus Stent 1.4%
0
0
6
12
4214
3784
4135
3916
3617
3913
3797
3569
3793
18
24
30
Months after index PCI
36
42
48
1880
2521
1041
1077
2118
514
686
1734
208
No. at risk
PES
SES
EES
3176
3499
3284
2905
3404
2604
2344
3080
1856
Bern-Rotterdam Cohort Study
Very Late ST (1-4 yrs)
Cumulative incidence (%)
5
EES vs. SES HR* = 0.33, 95% CI 0.15 – 0.72,
P=0.006
EES vs. PES HR* = 0.24, 95% CI 0.13-0.47,
P <0.0001
4
3
Paclitaxel Stent 2.4%
2
1
Sirolimus Stent 1.6%
Everolimus Stent 0.6%
0
0
6
12
*from Cox proportional hazards model
18
24
30
Months after index PCI
36
42
48
Räber L, ESC 2011
SPIRIT II, III, IV and COMPARE trials
Pooled database analysis (n=6,789)
Ischemic TLR
EES (n=4,247)
PES (n=2,542)
Ischemic TLR (%)
10
HR: 0.60 [0.48, 0.75]
P<0.001
6.6%
∆=2.5%
4.7%
5
4.1%
∆=2.4%
2.3%
0
0
3
6
9
12
15
18
21
24
Time in Months
Number at risk
XIENCE
TAXUS
4247
2542
4143
2416
4004
2328
3891
2260
Kereiakes DJ et al. EuroIntervention 2011:7:74-83
3363
2018
SPIRIT II, III, IV and COMPARE trials
Pooled database analysis (n=6,789)
Stent thrombosis (ARC definite/probable)
Stent thrombosis
ARC def or prob (%)
HR: 0.30 [0.19, 0.47]
p<0.001
EES (n=4,247)
PES (n=2,542)
3
2.3%
2
1
0.7%
0
0
3
6
9
12
15
18
21
24
Time in Months
Number at risk
XIENCE
TAXUS
4247
2542
4177
2463
4082
2408
3998
2350
Kereiakes DJ et al. EuroIntervention 2011:7:74-83
3479
2110
RESOLUTE All Comers
Target Lesion Failure to 2 Years (Cardiac Death, TV-MI, CD-TLR)
Cumulative Incidence of Events
20%
Resolute ZES (N = 1140)
Xience V EES (N = 1152)
Log rank P = 0.73
15%
11.2%
10.7%
10%
5%
0%
0
6
12
18
Time after Initial Procedure (Months)
Silber S, et al. Lancet. 2011;377:1241-47.
24
TWENTE (n=1,387)
Target Vessel Failure at 2-Year Follow-up
30
Xience V (n=692)
Resolute (n=695)
25
P = 0.67
TVF (%)
20
15
11.6%
10.9%
10
5
0
0
60
120
180
240
300
360
420
480
Follow-up (days)
Von Birgelen C. TCT 2012
540
600
660
720
EES Pt-Cr vs EES Co-Cr
3-Year Clinical Results
10
p = 0.40
Incidence Rate (%)
8
6
p = 0.21
p = 0.27
p = 0.81
p= 0.40
p= 0.30
p= 0.75
7.1
5.9
4.9
4
3.5
2.5 2.3
1.9
2
1.2
2.1
1.5
0.8
0.4
0.5 0.7
0
TLF
TLR Cardiac Death
Xienca CoCr EES
MI
TV MI Q-Wave MI
Promus PtCr EES
Presented by Ian T Meredith MBBS, PhD at ACC 2013
ST
Longitudinal stent deformation:
Angiographic patterns
Longitudinal
elongation with
pseudo-fracture
Longitudinal
compression
Longitudinal
compression
Longitudinal
compression
• Longitudinal stent compression: Manifests itself as a dark
band in the region of compression (also called stent “accordion”,
“concertina”, “wrinkling”, etc.)
• Longitudinal stent elongation: Appears like a fracture in the
stent (pseudo-fracture)
Retrospective analysis of longitudinal stent
deformation in the “real world”: Study
2,936 Promus Element stents implanted in 2,839
lesions in 1,295 pts at a single center over 22 months
LSD occurred in:
1.4% (n=20) of pts (95%CI 0.9%-2.2%)
0.7% of lesions (95%CI 0.4%-1.1%)
0.7% of Promus Element stents (95%CI 0.4%-1.1%)
Multivariable predictors of LSD:
# and length of stents, ostial and bifurcation lesions
30 Day MACE in pts with LSD = 5.0% (1 NQMI)
Leibundgut G et al. CCI 2012: doi: 10.1002/ccd.24472
Promus PREMIER Everolimus-Eluting Stent
Customized Platinum Chromium (PtCr) Stent Architecture
Additional connectors on
proximal end
Provide increased axial strength
2 connectors throughout body
Enhanced Stent Delivery System
PTFE Coating on hypotube to reduce friction
Shorter tip to
improve flexibility
SCAAR Registry (94,384 pts)
Adjusted Risks of Adverse Events at 2 yrs
Restenosis
Restenosis
ST
Definite Definite
Stent Thrombosis
BMS
BMS
“Old DES”
“New DES”
“Old DES”
“New DES”
Old DES = SES, PES, ZES-Endeavor; New DES = EES, ZS-Resolute
Sarno et al, Eur Heart J 2012
Network Meta-analysis
Endpoints: Death, MI, ST, TVR early (<1 yr) and late
77 RCTs, 57,138 pts, 117,762 pt-yrs of FU
BMS
24
25
Sirolimus-Eluting
Evidence
network
11
8
7
Paclitaxel-Eluting
4
2
1
Everolimus-Eluting
1
7
Zotarolimus-Eluting
2
Zotarolimus-ElutingResolute
Bangalore S et al. Circulation 2012:On-line
Network Meta-analysis: 1-year TLR
77 RCTs, 57,138 pts, 117,762 pt-yrs of FU
Control
BMS (Ref)
Treatment
Favors
Treatment
OR
(95% Crl)
Favors
Control OR [95% CrI]
Sirolimus
Paclitaxel
Everolimus
Zotarolimus-E
Zotarolimus-R
0.20 (0.16, 0.25)
0.39 (0.31, 0.49)
0.21 (0.14, 0.29)
0.46 (0.32, 0.65)
0.29 (0.15, 0.60)
Paclitaxel
Everolimus
Zotarolimus-E
Zotarolimus-R
1.95 (1.60, 2.38)
1.03 (0.75, 1.45)
2.30 (1.67, 3.22)
1.47 (0.74, 3.04)
Everolimus
Zotarolimus-E
Zotarolimus-R
0.53 (0.38, 0.73)
1.18 (0.85, 1.64)
0.76 (0.38, 1.53)
Zotarolimus-E
Zotarolimus-R
Zotarolimus-E (ref)
Zotarolimus-R
2.23 (1.45, 3.47)
1.43 (0.78, 2.71)
Sirolimus (Ref)
Paclitaxel (Ref)
Everolimus (Ref)
0.10
0.64 (0.30, 1.37)
1.00
Bangalore S et al. Circulation 2012:On-line
10.00
EXAMINATION Trial
1504 pts with STEMI undergoing PCI within 48 (85% primary PCI within 12)
were randomized to Xience V EES vs. Vision BMS
Stent thrombosis (Def/prob) within 1 year
Acute
Subacute
Late
2.6%
Vision
p = 0.01
0.9%
Xience V
0
1
2
3
Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01
Sabate M. ESC 2011
EES CoCr vs BMS: Lower Def. Stent Thrombosis
Evidence from 5 RCT Network Meta-Analyses.
ARC Definite Stent Thrombosis:
EES CoCr vs. BMS
Favors EES CoCr
Subsequent Late ST (ARC Def/Prob) (%)
Late ST Rates (30 Days - 1 Year)
After DAPT Interruption
Overall
Standard Risk
13/3500 2/1272
No Interruption
2/435 0/157
Interruption
After 30 Days*
1/378 0/147
0/292 0/120
Interruption
Interruption
After 90 Days* After 180 Days*
Hermiller, JB, PCR 2010 – In Press JACC Int 2011
EES Co-Cr Demonstrates 0% Stent Thrombosis
Rate After DAPT Interruption from 3 to 12 Months1
Timing of First DAPT Interruption and Stent Thrombosis Through 12 Months
6%
Subsequent Stent Thrombosis ARC Def/Prob (%)
1 in every 6
patients who
receive stents
may interrupt or
discontinue
DAPT
within 12 months
post-PCI
Never Interrupted3
5%
DAPT Interrupted
4%
N=11,156
3%
2%
1%
1.64%
0.68%
0.21%
0%
60/8,996
0-3 Months
11/700
18/8,996
0.00%
0/919
3-12 Months
Palmerini, T. Stent Thrombosis and DAPT Interruption in XIENCE V Real-World Patients. PCR 2012
Combined XIENCE USA, SPIRIT V, XIENCE India. SPIRIT women
DES Progress
Evolution of Drug-Eluting Stents:
Better than Man’s
TCFA Development in Neointimal Hyperplasia is
More Common with DES than BMS, and can Rupture
Causing Stent Thrombosis and Occlusion
Nakazawa G et al. J Am Coll Cardiol 2011;57:1314–22
Late Incomplete Apposition in SIRTAX
Late ISA at 8 month IVUS was seen in 39/221 lesions (18%) treated with
SES or PES, and was more common with SES
p<0.001
Cook et al Eur Heart J 2012
SPIRIT IV: Target Lesion Failure @3 years
Target lesion failure (%)
25
XIENCE V (n=2,458)
TAXUS Express (n=1,229)
20
HR [95%CI] =
0.61 [0.46, 0.81]
p=0.001
15
HR [95%CI] =
0.78 [0.63, 0.97]
p=0.02
HR [95%CI] =
0.71 [0.56, 0.90]
p=0.004
11.7%
Δ 2.5%
10
6.7%
9.2%
Δ 2.7%
5
~2.6%/yr event rate after year 1
4.0%
0
0
3
6
9
12
15 18 21
Months
24
27
30
33
36
Number at risk
XIENCE V
2458
2390
2364
2323
2281
2238
2212
2187
2162
2132
2116
2095
2074
TAXUS
1229
1166
1138
1119
1095
1069
1060
1049
1029
1019
1008
994
979
TLF = cardiac death, target vessel MI, or ischemic-driven TLR
Stone GW et al. JACC 2011 (abstract)
Outline
• Introduction
• Current Data
•
Advances to Date
• Future Directions
•
Metallic DES Bioabsorbable Polymer
•
Metallic DES with No Polymer
•
Completetly Bioabsorbable DES
• Conclusions and Summary
Persistent Limitations
• Uncovered stent struts with or without late
malapposition (thrombosis)
• Chronic inflammation due to late foreign
body reactions and polymer hypersensitivity
• Strut fracture
• Lack of vasomotion
• Neoatherosclerosis
Biolimus-A9 Eluting Stent
• Biolimus is a semi-synthetic sirolimus
analogue with 10x higher lipophilicity and
similar potency as sirolimus.
• Biolimus is immersed at a concentration of
15.6 g/mm into a biodegradable polymer,
polylactic acid, and applied solely to the
abluminal stent surface by a fully
automated process.
• Biolimus is co-released with polylactic acid
and completely desolves into carbon dioxide
and water after a 6-9 months period.
• The stainless steel stent platform has a strut
thickness of 120 m with a quadrature link
design.
LEADERS 5-Year Results
Serruys P, et al. J Am Coll Cardiol Intv 2013;6:777–89
LEADERS: Definate Stent Thrombosis
Serruys P, et al. J Am Coll Cardiol Intv 2013;6:777–89
LEADERS: Definate Stent Thrombosis
Landmark Analyses at 0-1 and 1-5 years
RR (95%CI); p value
0-1 yr: 0.99 (0.51-1.95); p= 0.98
1-5 yrs: (0.20-0.68); p=0.003
%
Serruys P, et al. J Am Coll Cardiol Intv 2013;6:777–89
Drug-Eluting Technology Progression
Current DES
SYNERGY DES
Conformal Biostable Polymer
Abluminal Bioabsorbable Polymer
Vessel Wall
Polymer + Drug
Polymer + Drug
Platinum
Chromium
Abluminal
Thin strut
(0.0029”) PtCr
stent
Polymer + Drug
Platinum
Chromium
BMS on luminal side
PLGA bioabsorbable
polymer + everolimus on
abluminal side of stent
Coating weight on 16 mm
stent ~200 µg (vs ~675 µg
for Xience / Promus)
Everolimus elutes over
~3 months (similar to
Xience / Promus)
PLG absorbs by
~4 months, leaving
behind a BMS
BioFreedom Stent (Biosensors)
Hypothesis: Polymer-free drug
release via porous-eluting
stents may reduce late events
caused by polymer stent
coatings.
Selectively micro-structured surface
holds drug in abluminal surface
structures
Potential advantages
• Avoid long term late adverse
effects that might be attributable
to the polymer
• Improved surface integrity since
there is no polymer to be
sheared or pealed away from the
stent struts
• Possible shorter need of dual
antiplatelet therapy
Biolimus A9 - lipophilic
DFS: Drug Filled Stent (Medtronic)
Drug elution controlled by diffusion physics
Elution Holes
Bioresorbable Vascular Scaffolds (BVS)
Igaki-Tamai
PLLA
Abbott Absorb
PLLA (w/PDLLA coat
eluting everolimus)
Reva ReSolve
Iodinated tyrosinederivative (eluting
sirolimus)
Elixir DESolve
Biotronik Dreams
PPLLA (eluting
myolimus)
Magnesium (eluting
paclitaxel)
What is the Minimum Duration of Radial
Scaffolding?
After DES Placement, Scaffolding of the Vessel is Only a Transient Need
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)
p < 0.00001
p < 0.00001
The lumen appears to stabilize
approximately three months after PTCA.
Serruys PW, et al., Circulation 1988; 77: 361.
ABSORB Extend
Clinical Results - MACE
Similar Rates of MACE Compared to Historical XIENCE Data
Intent to Treat (ITT) Analysis; Interim Snapshot
Dudek D. ABSORB Cohort B 2-year data, ACC 2012.
Absorb Trial (BVS cohort A): OCT Results
Post-stenting
Complete strut
apposition
6-month
Late acquired incomplete
stent apposition with
tissue bridges between
fractured struts
Corrugated endolumen
Serruys PW et al. Lancet 2009;373:897-910.
24-month
Smooth endoluminal
lining
Struts largely
disappeared although
remnant just visible
(arrow)
6 months
Sealing and shielding of plaques as a result of scaffold implantation :
can the scaffold cap the plaque? … and Late lumen enlargement
60 months
The Final Golden tube
Presented by PW Serruys at TCT2012, accessed at www.tctmd.com
ABSORB Cohort B
Temporal Lumen Dimensional Changes
Post-PCI
6 Months
2 Years
n = 33
n = 33
n = 33
ABSORB
Cohort B
Serial Analysis*
Lumen Area
6.53 mm2
Scaffold
Area
 1.7%
6.36
mm2
Lumen
Area
6.85 mm2
 7,2%
 Very late lumen enlargement noted from 6 months to 2 years
*Serruys, PW., TCT 2011
6 Months1
12 Months2
24 Months3
ABSORB Cohort B1
ABSORB Cohort B2
ABSORB Cohort A
(n=15)
(n=6)
(n=19)
(n=13)
(n=9)
0.5
(n=7)
Vasodilation
1
0
-0.5
Acetylcholine
-1
Methergine
1.
2.
3.
Adapted from Serruys, PW. ACC 2011
Adapted from Serruys, PW. ACC 2011
Adapted from Serruys, PW, et al. Lancet 2009; 373: 897-910.
Vasoconstriction
(pre-drug infusion to post-drug infusion)
 in Vessel Diameter (mm)
ABSORB Vasomotor Function
Testing
Outline
• Introduction
• Current Data
•
Advances to Date
• Future Directions
•
Metallic DES Bioabsorbable Polymer
•
Metallic DES with No Polymer
•
Completetly Bioabsorbable DES
• Conclusions and Summary
Conclusions: Current and future
directions in stenting
• Current DES have appreciably improved safety
and efficacy profiles in ACS and stable CAD
compared to first generation devices
• By utilizing small amounts of a bioabsorbable
polymer, polymer-free systems, or fully
bioresorbable scaffolds, future generation DES
will likely further reduce stent thrombosis and
improve late outcomes
The Bar is High – For Advanced Devices
Thanks for your attention!

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