Transcript Endeavor Resolute

Sustained Polymer Technology
Should Remain the Gold Standard
Martin B. Leon, MD
Columbia University Medical Center
Cardiovascular Research Foundation
New York City
SOLACI 2009
June 10-12, Rio de Janeiro, Brazil
Presenter Disclosure Information for
SOLACI 2009
Martin B. Leon, M.D.
Scientific Advisory Board or Consultant:
Abbott, Boston Scientific, Cordis,
and Medtronic
Optimal DES
The Holy Grail?
• no restenosis!
• no inflammation & normal healing
• no clinical safety issues!!!
TAXUS
Drug-eluting Stents 2003 - 2007
Paclitaxel
Express2
Polymer
Stent
PEVA + PBMA blend
BX Velocity
Cypher
Drug
Polyolefin derivative
Sirolimus
The Sirolimus-Eluting Stent
Bx VELOCITYTMStent
• Balloon expandable
stainless steel stent
• Blend of components:
2 polymers (PEVA +
PBMA) and sirolimus in a
fixed ratio
• Thin uniform coating
(~ 10um thick)
Controlled Sirolimus Elution
from CypherTM
Topcoat
Stent
Basecoat
Basecoat = polymer/sirolimus
+
Topcoat = polymer only
(diffusion barrier)
Fractional Release
In Vivo Release Kinetics
1.0
85%
0.8
50%
0.6
0.4
0.2
0
0
5
10
15
20
25
Time (days)
Sirolimus is released in a controlled manner from a
polymer matrix (PEVA + PBMA) bound to the stent;
ALL of the drug is released within 3 months
30
The First Generation TAXUS Stent
Drug
Paclitaxel
Polymer
TransluteTM
• Binds tubulin
• Polyolefin derivative
• Stabilizes microtubular • Uniform
• Biocompatible
deconstruction
• Elastomeric
• Multi-cellular
• Provides controlled
• Multi-functional
release
• Cytostatic at low dose
Stent
Express2
• Tandem
architecture
• Maverick balloon
system
• Flexible
• Deliverable
In vivo PTx Release From Explanted Stents
1 ug/mm2
80
Mean ± SD
% PTx released
70
fast release
60
50
40
30
moderate release
20
slow release
10
0
0
20
40
60
80
100
120
Time (days)
140
160
180
200
Sustained Polymer DES
Advantages
• Long history of bio-medical applications…
•
•
generally biocompatible
Favorable mechanical properties… usually
integrates well with stent and balloon delivery
systems
Precise elution kinetics
optimal anti-restenosis efficacy
controls drug toxicity
SIRIUS – TLR Events @ 5 Years
Sirolimus Control
Overall
Male
Female
Diabetes
No Diabetes
LAD
Non-LAD
Small Vessel (<2.75)
Large Vessel
Short Lesion
Long Lesion (>13.5)
Overlap
No Overlap
9.4
10.1
7.5
13.7
8.0
11.5
7.7
13.3
5.6
9.3
9.7
11.0
8.6
Odds Ratio 95% CI
24.3
24.9
22.8
33.1
20.8
28.4
21.4
26.0
22.6
21.8
26.8
30.1
21.6
# pts needed
to prevent
P-value 1 restenosis
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3
Sirolimus better
6.7
6.7
6.5
5.2
7.8
6.0
7.3
7.9
5.9
8.0
5.9
5.2
7.7
TLR up to 5 Years: Subgroup Summary
TAXUS I, II-SR, IV & V Meta-analysis
HR [95% CI]
HR TAXUS Control
0.51 12.1% 21.0%
0.54 19.5% 30.0%
0.49 12.5% 23.1%
0.52
8.3% 14.1%
0.54 10.7% 18.3%
0.58 16.7% 24.5%
0.38 14.2% 31.3%
0.52 11.3% 19.5%
0.49 14.6% 26.5%
0.51 16.0% 24.3%
0.53 10.9% 18.5%
0.39 18.2% 35.7%
0.51 11.7% 20.4%
0.52 13.1% 22.6%
All (n=2797)
RVD ≤2.5 (n=635)
RVD 2.5-≤3.0 (n=1071)
RVD >3.0 (n=1030)
LL <18 (n=1758)
LL 18-26 (n=621)
LL >26 (n=357)
Non-DM (n=2082)
DM-Oral (n=494)
DM-Insulin (n=221)
Sing. Stent (n=2293)
Mult. Stents (n=469)
Male (n=2003)
Female (n=794)
0
0
0.5
0.5
1
1.0
1.5
1.5
P Value
<0.001
<0.001
<0.001
0.001
<0.001
0.004
<0.001
<0.001
<0.001
0.045
<0.001
<0.001
<0.001
<0.001
Network meta-analysis: 38 trials, 18,023 pts
TLR Frequency
Stettler C et al. Lancet 2007;370:937- 48
Drug-Eluting Stents
First Generation
Stent design and delivery system
“Off the shelf” outdated
stent and delivery system
Pharmacologic
agent
Known FDA-approved
drugs with approximated
release kinetics
DrugEluting
Stent
Drug carrier
vehicle
Available, FDA-approved
biostable polymers
LaST – Late DES Stent Thrombosis
After 3 Years
Baseline
Late Stent Thrombosis
at 3.5 yrs
After 2 DES
Hype and Hysteria: “If it Bleeds it Leads”
Studies linking drug-eluting stents to
increased mortality/MI spark impassioned
pleas for reason and calls for calm
September 3, 2006
September 5, 2006
Cardiologists Question the Risks
in Using Drug-Coated Stents
September 7, 2006
Boston Scientific
Acknowledges Risks
Tied to Stent
Stent Safety Concerns
Near Boiling Point
09.08.06
Cumulative Incidence of ARC Def/Prob ST
over 4 yrs after DES (CYPHER & TAXUS)
Bern-Rotterdam2
5
Cumulative Incidence, %
5.7% [95% CI]
CYPHER & TAXUS
(n=8,146)
4
3
Cypher & Taxus
Pooled Analyses1
2.1% (17)
— CYPHER Stent (n=878)
2
2.1% (26)
—TAXUS Stent (n=1401)
1
0
0
1
1
2
2
3
Time since PCI in years
4
Mauri et al; N Engl J Med 2007;356:1020-9
Wenaweser et al; J Am Coll Cardiol 2008;52:1134-40
1st Generation DES….
the good, the bad, and the ugly!
Late loss = 0
BMS
DES
Giant cells
DES
Angioscopy
BMS
48 months
Eos
Inflammation
Delayed Healing!
Incomplete
apposition
25
20
Abn Vasomotion
15
10
5
0
Late stent
thrombosis
-5
-10
-15
40 mos
IVUS
-20
*P<0.001 *vs. control
Prox. Ref.
Prox.
Stent
*
Distal
Distal Ref.
Sirolimus
Control
Vascular Impact of DES:
Procedure, Product, Patient
Procedure
Post Dilation
Full Apposition
Product
Polymer
Drug
Clinical
Events
Patient
Higher Risk
AP Compliance
DES: Stent, Drug, Polymer
What can Impact the Vessel Long Term?
Drug is exhausted by 6 months to 1 year
Potential Vessel Impact
Stent has shown minimal long term impact in BMS
Polymer is permanent and may have an increase
impact long term when drug is exhausted
0
6 months
1 year
2 years
Time
3 years
4 years
5 years
Sustained Polymer DES
Disadvantages
• Some durable polymers can cause
•
inflammation (acute and chronic) and can
induce hypersensitivity reactions… delayed
healing, abnormal vasoreactivity
causes
very late stent thrombosis
Erratic mechanical properties… flaking,
peeling, webs/bonds, and inhomogeneous
drug distribution (reduced effectiveness +
reduced safety)
1st Generation DES Polymers
Polymer-related problems which can
have clinical consequences…
Non uniform
polymer coating
“Webbing and
Bonding” of the
polymer surface
Polymer delamination
Conclusions—Compared
with bare metal stents,
drug-eluting stents
further delay arterial
healing and promote
inflammation
Circulation. 2005;112:270-278
Delayed Endothelialization
Rabbit Model of Coverage at 28 days
BMS
Cypher
Overlap
BMS
Taxus
Overlap
Conclusions:
•
BMS showed far greater endothelialization than DES
•
Lack of coverage highlighted in areas of overlap
Finn et al. Circulation. 2005;112:270-278.
Percent Struts Endothelialized
Human Analysis: DES vs BMS out to 3 years
Percentage Endothelialization
100
90
80
70
60
50
40
30
20
Taxus and Cypher
BMS
10
0
1
2
3
4
5
6 7 8 9 11 15 16 17 20 >40
Duration in months
Conclusions:
•
•
DES (solid line) consistently show less endothelialization
compared with BMS (dashed line) regardless of time point.
DES are not fully endothelialized even beyond 40 months
whereas BMS are completely covered by 6 to 7 months
Joner, Virmani et al. Circulation. 2005;112:3210.
Hypothesis: Polymer Inflammation
Potential Impact on Long term Safety and Efficacy
 Polymer Inflammation
 Dysfunctional Endothelium
VASOCONSTRICTION
INCREASED
INFLAMATION
PROTHROMBOGENIC
DELAYED
HEALING
Efficacy
Safety
TLR
VLST
?
?
Xience V*
Endeavor
Drug-eluting Stents 2008
HO
Zotarolimus
Phosphorylcholine
Driver
Drug
Polymer
Stent
VDF + HFP copolymer
Vision
O
O
O
O
O
N
O
HO
O
O
O
HO
O
O
Everolimus
*AKA Promus
Endeavor Polymer Technology
• The PC Technology hydrophilic polymer mimics
the outside surface of a red blood cell
Outer membrane
N
Inner membrane
The PC
Headgroup
• Highly biocompatible - originally
designed for ocular implants

O
O P O
O
More than 16 years of clinical
experience
Hayward JA et al., Biomaterials, 1984;5:135–142
ENDEAVOR Technology Considerations
Design Features
Biocompatible PC
Histopathology
% Drug Eluted
Stent design = reduced injury
(rounded thin struts)
100
87
98
Drug Layer
90% Zotarolimus
10% PC (≈ 2-4μm)
PC Basecoat
(≈ 1μm)
99
65
75
50
25
0
0
5
10
15
Time (Days)
Rapid drug elution
20
25
Stent
Strut
Safe
formulation
ENDEAVOR Technology Considerations
Human Results
Angioscopy
ZES (n=14) vs. SES (n=16)
@ 8 mos FU
ZES improved neointimal coverage
(P=0.0004) and fewer thrombi
OCT
44 overlapped ZES in 17 pts
@ 6 mos FU (24,076 struts analyzed)
ZES no malapposed or uncovered
struts; no intraluminal thrombus
Guagliumi et al; ESC 2008
Awata et al; J Am Coll Cardiol 2008;52;789-90
541 ZES pts @ 8 mos FU
0.4% late incomplete apposition; no
positive remodeling; homogeneous
neointimal distribution
Fitzgerald et al;IVUS
Stanford IVUS core lab
Distal
Proximal
ZES (n=20) vs. SES (n=20) vs.
BMS (n=10); Ach infusions
@ 6 mos; ZES improved
endothelial function cw SES
Endothelial
(P<0.001)
and similar to BMS
Kim et al; ACC 2008
Function
DES In Perspective: VLST
ARC Def/Prob ST Landmark Analysis
ARC (Def/Prob
No. at Risk
3.0%
Pooled Data
2.5%
Endeavor
Cypher
Taxus
1 Year
2 Years
3 Years
4 Years
2068
863
1351
2036
848
1300
1650
824
1117
1087
789
715
Xience V /Promus 892
865
NA
NA
There
are very significant
differences
in
stent thrombosis rates among 1st
generation DES cw Endeavor beyond the
first year after stent implantation
2.0%
1.5%
1.0%
0.5%
0.0%
0
360
Days
720
1. Mauri et al. TCT 2008.
2. Mauri L et al. N Engl J Med. 2007;356:1020-1029.
3. Serruys PW et al. ACC 2008
3. Stone GW et al. PCR 2008.
1080
1440
Coating Integrity – XIENCE™ V
Fluoropolymer (7.8 um thick)
Dilated to 3.5 mm
• Uniform, consistent coating integrity upon deployment
• Good adhesion to stent – no bonding, webbing, tearing
• Non-tacky drug matrix prevents “unwanted” adhesions
Photos taken by and on file at Abbott Vascular
14 Day Endothelialization: Rabbit Iliac Model
XIENCE™ V
CYPHER®
TAXUS®
Joner and Virmani, JACC 2008
ENDEAVOR™
SPIRIT II + III Pooled Meta-analysis
Late Loss
mm
Diff [95%CI]
-0.19 [-0.25,-0.12]
P<0.0001
Diff [95%CI]
-0.11 [-0.18,-0.05]
P=0.0004
±0.48
±0.44
±0.36
±0.37
SPIRIT II + III Pooled Meta-analysis
Binary Restenosis
%
XIENCE V (n=581)
10
8
RR [95%CI]
0.39 [0.17,0.86]
P=0.02
6
4.9
4
2
TAXUS (n=244)
RR [95%CI]
0.53 [0.30,0.95]
P=0.039
7.8
4.1
1.9
0
In-stent
In-segment
SPIRIT II + III: Ischemic TLR
Ischemic TLR (%)
10
PROMUS
TAXUS
8
1-year HR
0.53 [0.30, 0.92]
p=0.02
2-year HR
0.59 [0.36, 0.96]
p=0.03
6.8%
5.8%
6
Δ2.7%
Δ2.8%
4.1%
4
3.0%
2
0
0
3
6
9
12
15
18
21
24
Months
Number at risk
XIENCE V
892
880
869
852
840
819
816
808
801
TAXUS
409
397
392
375
366
354
349
348
346
SPIRIT II + III: All Death or MI
All Death or MI (%)
10
XIENCE V
TAXUS
8
1-year HR
0.62 [0.35, 1.09]
p=0.09
2-year HR
0.61 [0.39, 0.95]
p=0.03
8.3%
Δ3.2%
4.4%
6
5.1%
Δ1.3%
4
3.1%
2
0
0
3
6
9
12
15
18
21
24
Months
Number at risk
XIENCE V
892
876
871
859
848
826
824
814
810
TAXUS
409
390
388
381
375
361
357
355
352
Endeavor RESOLUTE DES
Drug
•
Zotarolimus – cytostatic limus analog
•
Powerful antiproliferative with broad therapeutic window
•
Lipophilic limus drug that aims to minimize proliferation of restenotic cells while
preserving healthy endothelial cells
Polymer
•
Proprietary polymer to provide extended elution kinetics
•
Hydrophobic characteristics for uniform drug release
•
Hydrophilic characteristics to provide biocompatibility equivalent to Endeavor
Extended elution
designed to
provide physicians
with more options
to treat patients
Stent
•
Medtronic Driver BMS platform
•
Cobalt Alloy stent with highly conformable design
Stent Delivery System
•
Advanced, highly trackable delivery system incorporating Sprinter
balloon technology
Increased
deliverability
for tortuous
anatomy
The BioLinx Polymer
Cell Membrane
BioLinx Polymer
Hydrophilic
Zotarolimus
Hydrophobic
Hydrophobic and hydrophilic groups
Hydrophilic polymer: Polyvinyl pyrrolidinone (PVP) for initial drug burst and
enhanced biocompatibility
Hydrophobic polymer: based upon hydrophobic butyl methacrylate (C10) for
combining with zotarolimus and uniform drug dispersion
Combination polymer: hydrophobic hexyl methacrylate, hydrophilic vinyl
pyrrolidinone and vinyl acetate (C19) to support delayed drug elution and
biocompatibility
Endeavor RESOLUTE
BioLinx Polymer in vivo Elution
% Zotarolimus Loading
100
80
60
% Remaining
% Eluted
40
20
<2% (LOQ)
0
0
50
100
Days
150
Greater than 85% of the drug is eluted at 60 days
Complete drug content exhausted by 180 days
Carter et al TCT 2006
200
Requirements of Polymer Safety
Biocompatibility
Non-thrombogenic
Hydrophilic
Non-inflammatory
Less Pro-thrombotic
genes expressed
Fewer platelets sticking
Healed Vessel
Rapid, complete, and
functioning endothelial cells
Excellent Safety Profile
Hydrophilic vs Hydrophobic
Contact Angles determine if a polymer is
hydrophilic or hydrophobic
• Angle formed when water drop applied to polymer surface
• Smaller angle = more hydrophilic
Contact Angle
Hydrophilic
Polymer
θ1
θ1 < θ2
Hydrophilic
Hydrophobic
Polymer
θ2
Hydrophobic
PC (Endeavor)
83º
PBMA (Cypher)
115º
BioLinx (Endeavor Resolute)
94o
SIBS (Taxus)
118º
Fluoro Polymer (Xience V)
129º
Water-loving
Water-resistant
Monocytic Adhesion to Polymers
Correlates With Hydrophobicity
200
Less
Biocompatible
Relative % Adhesion
160
120
80
40
0
Negative
control
Positive
control
PC
Contact Angle
83
More
Biocompatible
BioLinx
PBMA
S-IB-S
Fluoro
Polymer
94
115
118
129
More
Biocompatible
Less
Biocompatible
PBMA: Polybutyl methacrylate [Cypher cap coat]
SIBS: Styrene-Isobutylene-Styrene Triblock Copolymer [Taxus]
Fluoro Polymer: [Xience polymer]
Up-Regulation of Prothrombotic
Genes by PBMA and SIBS
compared with BioLinx
Tissue Factor
PAI-1
12
Fold Induction over Calibrator
Fold Induction over Calibrator
18
16
14
12
10
8
6
4
2
0
BioLinx
PBMA
SIBS
10
8
6
4
2
0
BioLinx
PBMA
SIBS
Biocompatibility of the
BioLinx Polymer
Porcine Coronary Artery Implants at 28 Days
Polymer
Inflammation score 0.10 ± 0.21
Bare Driver
Inflammation score 0.11 ± 0.38
Both BioLinx coated and bare metal
Driver stents had low inflammation scores
Endeavor RESOLUTE and Endeavor PC
vs. other DES
5
Comparison of Inflammation Scores
4.5
Inflammation Score
4
3.5
Endeavor*
3
Endeavor Resolute*
2.5
Xience**
2
Cypher**
1.5
1
0.5
0
28 days
90 days
180 days
365 days
Time after stenting
Endeavor not tested at 365 days
* Data on File Medtronic CardioVascular
** Data from Abbott XIENCEV US Physician presentation SE2924433D
Consistently low inflammations scores with Endeavor
and Endeavor Resolute across all time points
Endeavor RESOLUTE
Porcine coronary artery
CONTROL
ENDEAVOR
RESOLUTE
ENDEAVOR
RESOLUTE
Significant inhibition of neointimal development
compared to Driver controls
Endeavor RESOLUTE
Extended Efficacy in Porcine Coronary Arteries
60
Driver
Endeavor Resolute
% Stenosis
50
40
30
20
10
0
Day 28
Day 90
Significant inhibition of neointimal development at both 28* and 90 days^
*p=0.0006
^p=0.05
Requirements of Polymer Safety
Biocompatibility
Non-thrombogenic
Hydrophilic
Non-inflammatory
Less Pro-thrombotic genes
Fewer platelets sticking
Healed Vessel
Rapid, complete, and
functioning endothelial cells
Endeavor Resolute
Complete Endothelialization Present After 28 Days
% Endothelial Healing
ENDEAVOR RESOLUTE
Bare Driver
125
100
75
50
25
0
7 days
28 days
90 days
180 days
365 days
Full endothelialization achieved by 28 days with no aneurysms, incomplete
apposition, medial necrosis, late thrombosis or filling defects
Endeavor RESOLUTE Endothelial Healing:
SEM Analysis
28 day Small Vessel Safety
Study (FS144)
180 day Safety Study (FS129)
Endothelial Function:
ACH Challenge
28 Days After Stenting in Porcine Coronary Arteries
Endeavor Resolute
Lumen Diameter (mm)
Xience
2.06 ± 0.58
Relative eNOS Expression
0.27 ± 0.26
0.67 ±1.52
Inflammation Scores
1.89 ± 1.95
RESOLUTE Clinical Program
Enrollment Complete in Follow Up
RESOLUTE
Single Arm First-in-Human (n=139)
2yr
RESOLUTE AC
1:1 RCT vs. Xience® (R=1,150,X=1,150)
30d
Activating Sites / Enrolling
RESOLUTE Intl
Non-RCT Observational (R=2,200)
RESOLUTE US
2.25 – 3.5 Clinical Non-RCT vs. Hx Control (R=1,241)
2.25 – 3.5 Angio / IVUS Non-RCT vs. Hx Control (R=100)
4.0 Angio Non-RCT vs. Hx Control (R = 58)
38 mm – Long Lesion Non-RCT (R = TBD)
RESOLUTE Japan
2.5 – 3.5 Non-RCT (R = 100) vs. Hx. Control
Program Focus is on initial & expanded indications and pooled safety analyses
Sustained Polymer DES
Alternatives
• Bioabsorbable polymers…
 sounds nice – polymer gone, only BMS left
 bioabsorption can cause inflammation
There are
no meaningful
long-term
clinical
 difficult
to control
elution kinetics
precisely
outcomes
datadifferent
indicating
safety
advantage
 each
uniquely
(? aclass
effect)
associated with either bioabsorbable or
• Polymer-free
deliveryDES
systems…
polymer-free
systems!!!
 sounds even nicer – NO polymer (=BMS)
 rapid drug elution is the rule (reduced antirestenosis efficacy)
each uniquely different (? class effect)
Bioabsorbable Polymers - Preclinical Insights
Marked Inflammatory Sequelae to Implantation of
Biodegradable and Nonbiodegradable Polymers in
Porcine Coronary Arteries
Willem J. van der Giessen, MD, PhD; A. Michael Lincoff, MD; Robert S. Schwartz, MD;
Heleen M.M. van Beusekom, PhD; Patrick W. Serruys, MD, PhD; David R. Holmes, Jr, MD;
Stephen G. Ellis, MD; Eric J. Topol, MD
(1) All polymer implants were associated with
a significant inflammatory and
proliferative response
(2) Observed with both biodegradable and
nonbiodegradable polymer implants
(3) In some groups, implants were
complicated by acute thrombotic
vessel occlusion, although with no
more frequency than that experienced
with stainless steel coronary stents.
Circulation. 1996;94:1690-1697.)
Sustained Polymer DES
Final Thoughts
• Durable polymer DES systems have defined
•
•
the genre for a decade with > 10 million
implants and significant long-term FU!
The major purpose of a DES polymer carrier
is to precisely control extended drug release.
This function is best accomplished by a
durable polymer system!
1st generation DES polymers were flawed…
Too much inflammation
Inconsistent mechanical integrity
Stent thrombosis complications
Sustained Polymer DES
Final Thoughts
• 2nd generation DES polymers (Endeavor and
•
•
Xience ) are clearly improved…
More biocompatible (similar to BMS)
Improved mechanical integrity
Fewer complications (incl. stent thrombosis)
In the future, dedicated DES durable polymer
systems will continue to evolve (e.g. Resolute)
to achieve optimal safety-efficacy balance!
Alternatives (bioresorbables and polymer-free)
require far more intensive and long-term data
analysis to claim superior clinical outcomes.