advanced angioplasty 2008 hilton london metropole hotel january 25, 2008 josiah n. wilcox, ph.d....
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Advanced Angioplasty 2008
Hilton London Metropole Hotel
January 25, 2008
Josiah N. Wilcox, Ph.D.
Vice President and Resident Scholar Science & Technology
Medtronic CardioVascular
Overview of the Endeavor Resolute Overview of the Endeavor Resolute Preclinical and Clinical ProgramsPreclinical and Clinical Programs
Unmet Clinical Needsin the DES era
• TLR and MACE rates remain high in patients at the highest clinical risk of TLR
• Diabetics– 11.3% MACE @ 9 mo—DIABETES Trial, Sabate,
TCT 2004– 10.9% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005
• Small Vessels– 9.3% MACE @ 8 mo—SES SMART, Ardissino, JAMA, Dec 8,
2004– 14.2% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005
• Multi-Vessel Disease– 14.3% TLR—The Milan DES Experience, Columbo, ACC 2004
• Improve clinical outcomes in more complex lesions
• Maintain current safety profile seen with Endeavor™ DES
• Extended drug elution to match the potentially delayed healing times of complex lesions
• Combat the sustained stimulus to the proliferative response
Endeavor Resolute™Design Goals
Endeavor Resolute Incorporates the BioLinx™ Polymer System
Retains three components of the Endeavor Sprint™ Coronary Stent System with a new DES polymer
Driver Cobalt Alloy Stent Stent Delivery System Drug: zotarolimus
▫ Medtronic proprietary polymer design
▫ Hydrophobic/Hydrophilic polymer blend
▫ Extended release kinetics
▫ Biocompatibility equivalent to PC
▫ Compatible with multiple drug platforms
Novel Features of BioLinx Polymer System:
A hydrophilic polymer is compatible with water
A hydrophobic polymer is not compatible with waterEvidence that hydrophilic polymers are more biocompatibile
Polymers can either be hydrophilic or hydrophobic
Hydrophilic = water-lovingHydrophilic = water-lovingHydrophobic = water-hatingHydrophobic = water-hating
Body is approximately 70% waterBody is approximately 70% waterBody is approximately 70% waterBody is approximately 70% water
Hydrophilic vs Hydrophobic Polymers
θ1
Hydrophilic
θ2
Hydrophobic
Hydrophobic Polymer
Hydrophilic Polymer
Contact Angle
PC (Endeavor)
BioLinx (Endeavor Resolute)
83º
94o
PBMA 115º
SIBS 118º
Fluoro Polymer 129º
Water-loving Water-hating
• Angle formed when water drop applied to polymer surface
• Smaller angle = more hydrophilic
Hydrophilic vs HydrophobicContact Angles are used to determine if a polymer is hydrophilic or hydrophobic
θ1 < θ2
• C10 Polymer (Hydrophobic)Based primarily on hydrophobic butyl methacrylate to provide adequate hydrophobicity for zotarolimus
• C19 polymer (Hydrophilic) Manufactured from a mixture of hydrophobic hexyl methacrylate and hydrophilic vinyl pyrrolidinone and vinyl acetate monomers to provide enhanced biocompatibility
• Polyvinyl pyrrolidinone (PVP)Hydrophilic polymer increases initial drug burst and enhances biocompatibility
C O
O
C6H13
CH2 C
CH3
CH2 CH
N
O
CH2 CH
O
C O
CH3
x y z
C O
O
C4H9
CH2 C
CH3
CH2 CH
O
C O
CH3
a b
CH2 CH
N
O
a
C19
C10
PVP
Overall the BioLinx polymer blend displays a very hydrophilic surface
to the body for biocompatibility
The BioLinx Polymer SystemComposed of Hydrophilic and Hydrophobic Polymers
Vinyl pyrrolidinone groups
NO
[ ]
BioLinx
Phosphorylcholine(PC) Headgroup
PC Technology
O
P OO
ON
Hydrophilic outer surface
Cell Membrane
Hydrophobic layer
Medtronic Polymer TechnologiesPC and BioLinx Polymers Hydrophilic Surface Chemistry
Greater than 85% of zotarolimus is eluted at 60 daysComplete drug content exhausted by 180 days
100
80
60
40
20
0
% Z
otar
olim
us L
oadi
ng
0 50 100 150 200Days
<2% (LOQ)
% Eluted
% Remaining
Endeavor ResoluteBioLinx Polymer In Vivo Drug Elution
A Robust Durable Coating
• BioLinx is the first polymer system designed specifically for DES applications
• The BioLinx Polymer System provides a durable and robust coating
• The stent surface is primed to improve adhesion of the BioLinx Polymer System
Primer
BioLinx PolymerSystem
A deployed stent after tracking 3 times in a 5 Fr guide catheter
Atomic Force Microscopy (AFM) studies indicate that the interface between the BioLinx Polymer System and the primer is very strong
Endeavor ResoluteInhibition of Neointimal Development at 28 Days
Driver Control Endeavor Resolute Endeavor Resolute
Significant inhibition of neointimal development compared to Driver controls
28 day porcine study results
Endeavor Resolute Extended Efficacy out to 90 days
Significant inhibition of neointimal development at both 28 and 90 days in porcine coronary arteries
Ste
no
sis 40
50
30
10
20
60
0Day 28 Day 90
Endeavor Resolute
Driver (bare)
Developing a New Understanding of the Science of DES Polymer
Biocompatibility
ContactAngle: 83°
Negative Control PC
118° 115° 129°Hydrophobic
PBMASIBSFluoro Polymer
Positive Control
Hydrophilic
BioLinx
94°
Correlates With Polymer HydrophobicityMonocytic Adhesion
Low inflammatory scores seen with Endeavor and Endeavor RESOLUTE stents compared to DES containing hydrophobic polymers platforms in porcine coronary arteries
Endeavor Resolute with BioLinxBest in Class biocompatibility equivalent to Endeavor with PC
Comparison of Inflammation Scores
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
28 days 90 days 180 days 365 days
Time after stenting
Infl
am
ma
tio
n S
co
re
Endeavor*
Endeavor Resolute*
Fluro Polymer DES
PBMA DES
*Data on File Medtronic CardioVascularEndeavor not tested at 365 days **Data from Abbott US Physician presentation SE2924433D
The Design of DES Polymers Hydrophobic vs. Hydrophilic• First generation drug eluting stent (DES) coatings have been based on hydrophobic
polymers to hold and elute hydrophobic drugs
– SIBS– PBMA– Fluoro Polymer
• Hydrophobic polymers may stimulate inflammatory reactions
• Hydrophilic polymers may be more biocompatible in the aqueous body environment
• The phosphorylcholine (PC) based polymer used in the second generation Endeavor DES, is a hydrophilic polymer that shows good biocompatibility
• The next generation Endeavor Resolute DES coating based on the BioLinx Polymer System, is a unique blend of hydrophilic and hydrophobic polymers, that offers both biocompatibility and extended drug elution
• Hydrophobic polymers may contribute to the problem of Late Stent Thrombosis by increasing inflammation, endothelial dysfunction and/or expression of procoagulant proteins in the vessel wall
Endeavor RESOLUTE Clinical Update
Caution: Endeavor and Endeavor Resolute are investigational devices with an investigational drug, not approved for sale or commercial use.
RESOLUTEClinical Trial Design
Single De Novo Native Coronary Artery LesionsLesion Length: 14-27mm
Stent Diameters: 2.5, 3.0, 3.5mmStent Lengths: 18, 24, 30mm (8/9mm bailout)
Drug Dose: 1.6 g/mm2 stent surface areaAntiplatelet therapy for 6 months
Pre-dilatation required
130 Patients (9 additional PK Sub-Study Patients enrolled after original 130 patients)12 Sites (New Zealand and Australia)
Endeavor Resolute Stent
Clinical/MACE
Angio/IVUS30d 6mo 4 yr3yr2yr9mo 12mo 5 yr
Primary Endpoint: Late lumen loss (in-stent) at 9 mths by QCA
Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and
angiographic parameters at 9mths
30 pt Subset: 4mth MACE and angiographic, IVUS parameters*
4mo
N=30 N=100
*Meredith et al: EuroInterv 2007; 3:50-53
130 Patients Enrolled130 Patients Enrolled
4 Month4 MonthFollow-UpFollow-Up
Angiographic F/UAngiographic F/U30/3030/30
Clinical F/UClinical F/U30/3030/30
9Month9MonthFollow-UpFollow-Up
Angiographic F/UAngiographic F/U95/10095/100
Clinical F/UClinical F/U130/130130/130
12 Month12 MonthFollow-UpFollow-Up
Clinical F/UClinical F/U129/130129/130
99.2%99.2%100%100% 100%100%
95%95%100%100%
RESOLUTE Patient Flowchart
Male 75.4% (98/130)Age 61 +10yrs (130)Prior MI 45.7% (59/129)Prior PCI 18.5% (24/130)Diabetes Mellitus 17.7% (23/130) Insulin Dependent 2.3% (3/130)Unstable Angina 29.7% (38/128)Hyperlipidemia 94.6% (123/130)Current Smoker – within last 30 days
22.3% (29/130)
N=130
Meredith et al: EuroInterv 2007; 3:50-53
RESOLUTE Patient Demographics
LAD (%) 34.4% (45/131)
B2/C Lesions (%) 81.7% (107/131)
Pre-procedure RVD (mm) 2.81 ± 0.41
Lesion Length (mm) 15.49 ± 6.23
Pre-procedure MLD (mm) 0.82 ± 0.34
Pre-procedure DS (%) 70.50 ± 11.42
Device success 99.2% (130/131)
Procedure success 96.2% (125/130)
N=130 patients, 131 lesions
Meredith et al: EuroInterv 2007; 3:50-53
Device success <50% residual in-stent % ds with assigned stentProcedure success <50% residual in-stent % ds & without in-hospital MACE
RESOLUTE Procedural Characteristics
In-stent In-segment
Pre-procedure RVD (mm) 2.79 ± 0.40
Lesion Length (mm) 15.87 ± 6.51 MLD (mm) pre 0.82 ± 0.35
post 2.74 ± 0.41 2.33 ± 0.44
Acute Gain 1.91 ± 0.47 1.51± 0.50 9 mo f/u MLD (mm) 2.51 ± 0.48 2.21 ± 0.45
Late Loss (mm) 0.22 ± 0.27 0.12 ± 0.27
Late Loss Index 0.12 ± 0.16 0.08 ± 0.21
9 mo f/u % DS 10.13 ± 12.63 21.08 ± 10.62
ABR n (%) 1 (1%) 2 (2.1%)
n=96
RESOLUTE: 9 Month Follow Up Angiographic Results
9 months
n=130 patients
Death (all) - % (#) 1.5 (2)
Cardiac 0.8 (1)
MI (all) - % (#) 5.4 (7)
Q Wave 0
Non Q wave 5.4 (7)
Death (cardiac) + MI (all) - % (#) 6.2 (8)
Stent Thrombosis (all) - % () 0
0-30 days 0
31-360 days 0
TLR - % (#) 0
TVR (non-TL) - % (#) 0
TVR - % (#) 0
MACE - % (#/) 6.9 (9)
TVF - % (#/) 6.2 (8)
9-12 months
n=129
12 months
n=129
0.8 (1) 2.3 (3)
0 0.8 (1)
0 5.4 (7)
0 0
0 5.4 (7)
0 6.2 (8)
0 0 (0)
0 0 (0)
0 0 (0)
0.8 (1) 0.8 (1)
0 0.0
0.8 (1) 0.8 (1)
1.6 (2) 8.5 (11)
0.8 (1) 7.0 (9)
RESOLUTEClinical Events to 12 months
Comments
57 year old Prox RCA
Type C Lesion
Acute Marginal side branch of obstructed by lesion during post dilatation
67 year old Mid RCA
Type B2 Lesion
No reflow of PDA, prior to stenting
65 year old Mid RCA
Type C Lesion
RV Marginal branch has decreased flow after balloon dilatation prior to stenting
52 year old Mid LAD
Type C Lesion
Decreased flow in 1st diagonal side after post balloon dilatation
51 year old 1st OMA
Type C Lesion
Prior MI with MB still 2x baseline at time of intervention
50 year old Mid LAD Wire trauma leading to plaque rupture during follow- up angiography
75 year old Mid LAD Fully patent stent at follow-up. Non Q-wave MI due to lack of anti-coagulation during IVUS
RESOLUTENQMI to 12 months
History Index Procedural Info Time DAPT Event Description Outcome up to 12M FU
69 yo male Diabetic Mid RCA 3.5x30mm stent 1.3 months Laparoscopy; small bowel resection No MACE
38 yo female Non-diabetic Mid RCA 3.5x18 mm stent 3.0 months Pericardial window for pericarditis No MACE
66 yo male Non-diabetic 1st Obtuse Marginal 2.5x18 mm stent 3.0 months Anterior bowel resection for cancer No MACE
77 yo female Non-diabetic Mid RCA 3.0x24 mm stent 3.2 months Total hip replacementLaminectomy
No MACE
71 yo male Non-diabetic Prox Circumflex 2.5x18 mm stent 4.9 months Thoracentesis for right pleural effusion Yes : Death, non-cardiac, mesothelioma
75 yo male Non-diabetic Prox LAD 3.5x18 mm stent 4.9 months Elective resection of the prostate No MACE
76 yo male Non-diabetic Mid RCA 3.5x18 mm stent 5.6 months Catarct surgery No MACE
61 yo female Non-diabetic Dist Circumflex 2.5x18 mm stent 5.7 months Eye surgery to remove malignant nerve sheath tumor
No MACE
54 yo male Non-diabetic Prox Circumflex 2.5x24 mm stent 5.8 months Right knee medial menisectomy No MACE
59 yo male Non-diabetic 1st Obtuse Marginal 3.0x30 mm stent 5.8 months Total laryngectomy and neck dissection No MACE
58 yo, male Non-diabetic PDA 3.0x18mm stent 6.0 months Surgical repair of retinal detachment No MACE
68 yo female Non-diabetic Mid LAD 2.5x18 mm stent 6.0 months Arthroscopic surgery of shoulder No MACE
65 yo male Non-diabetic Mid RCA 3.5x30 mm stent 6.1 months Elective cholecystectomy No MACE
64 yo male Non-diabetic 1st Obtuse Marginal 3.0x18 mm stent 6.3 months Elective Cardioversion for atrial flutter No MACE
75 yo male Non-diabetic Mid LAD 2.5x18 mm stent 6.5 months Patient died Yes: Death, non-cardiac, melanoma with metastisis
RESOLUTE: DAPTPatients with a Surgical Procedure
15 Patients discontinued AP Therapy and had surgical procedures 5 females10 males1 diabetic
2 MACE Events by 12 months Both deaths due to Cancer
MelanomaMesothelioma
US Studies OUS Study
Angiographic/IVUS Studies
Randomized to Taxus n = ~430
RESOLUTE II
38 mm n=~100RESOLUTE Long
2.25 mm n=~150RESOLUTE Small
4.0 mm n=~100RESOLUTE Large
Pivotal Study
Randomized to Taxusn = ~1500
RESOLUTE IV
All Comers(CE Mark)
Randomized to Xience n = 2300
RESOLUTE III
Randomized to Xience n = 2300
RESOLUTE III
RESOLUTE Clinical ProgramCurrent Outline
All ComerDual APT ≥ 6 months
N = 230015-20 International Sites
Randomization 1:1
Endeavor ResoluteN=1150
Clinical Follow-up30d 6mo 4 yr3yr2yr 5 yr
Primary Endpoint: Non-inferiority TLF (Cardiac Death, TLR, MI) at 12 months
Secondary Clinical Endpoints: Cardiac death/MI or TLR
Secondary Angiographic Endpoints: (n=460)In-stent and In-segment DS%, In-stent and In-segment LL at 13 months
Secondary OCT Endpoints: (n=~50)Stent Strut Tissue Coverage, Stent Apposition at 13 months
XienceN=1150
1yr
RESOLUTE IIIInternational RCT vs Xience: PI: Patrick Serruys
Angiographic Follow-up 13 mo
Thank You
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
0 360 720 1080 1440
Endeavor 1301 1287 675
No. at Risk
Cypher 863 848 823
Taxus 1351 1300 1117
1 Year 2 Years 3 YearsPooled Data
*Xience 397 377 n/a
DES In Perspective DES In Perspective ARC Definite and Probable to 3 yearsARC Definite and Probable to 3 years
AR
C S
T %
Days
Mauri et al. N Engl J Med 2007;356:1020-9.Endeavor: Mauri et al. TCT. 2007Xience: FDA Panel Meeting Nov. 29, 2007
*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel
0%
3%
6%
9%
0 360 720 1080 1440
Car
dia
c D
eath
an
d M
I %
Days
DES In Perspective DES In Perspective Cardiac Death and MI to 3 yearsCardiac Death and MI to 3 years
Mauri et al. N Engl J Med 2007;356:1020-9.Endeavor: Mauri et al. TCT. 2007Xience: FDA Panel Meeting Nov. 29, 2007
*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel
Endeavor 1301 1287 675
Cypher 863 848 823
Taxus 1351 1300 1117
1 Year 2 Years 3 YearsPooled Data
*Xience 397 377 n/a