NOW YOU SEE IT, NOW YOU DON’T STENT UPDATE

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NOW YOU SEE IT, NOW YOU DON’T
STENT UPDATE
GAGAN D. SINGH, MD
Division of Cardiovascular Medicine
UC Davis Medical Center
Sacramento CA
Outline
§ A Brief History of Coronary Interventions
§ Rationale Behind Coronary Stents
§ Evolution to Bioabsorbable Vascular Scaffolds
§ Case Examples
§ Future Directions
Outline
§ A Brief History of Coronary Interventions
§ Rationale Behind Coronary Stents
§ Evolution to Bioabsorbable Vascular Scaffolds
§ Case Examples
§ Future Directions
A Brief History
§ 1700’s: Catheterization:
ú Procedures where catheters are inserted into cardiac chambers for sampling of blood
§ 1940: Cournand, Forssmann, and Richards
A Brief History
§ 1958: An Accident
A Brief History
§ 1977 – A poster presentation that changed the world – 1st Revolution
First PTCA and 23-­‐Year Follow Up
1977
2000
A.B. ,the 1 st PTCA by Andreas Gruentzig on September 2 9, 1 977, a ttended a nd s poke a t the 3 0 th Anniversary on September 3 0, 2 007 in Zurich, a n incredible tribute to the breakthrough made by Andreas 3 0 y ears a go1
Restenosis
PTCA - 1977
•
Percutaneous Transluminal Coronary Angioplasty
•
Non-compliant balloon Angioplasty
•
Abrupt and threatened closure
•
~50% Restenosis - A new disease
•
Elastic recoil
•
Vascular negative remodeling
•
Neointimal hyperplasia - NIH
POBA
4 Months
The 2nd Revolution in Coronary Intervention
Bare Metal Coronary Stent - 1994
The 2nd Revolution in Coronary Intervention
Bare Metal Coronary Stent - 1994
•
Coronary Stent
•
Restenosis reduce to ~25-50%
•
Prevents elastic recoil
•
Prevents negative vascular remodeling
•
Increase Neointimal hyperplasia - NIH
What to Do Next?
•
Pathophysiology of restenosis defined
•
Smooth muscle cell migration
•
Smooth muscle cell proliferation
•
Extracellular matrix formtion
•
Sirolimus, Paclitaxel, Everolimus,
Zotarolimus
•
Polymer coating to bind drug, control release,
vascular biocompatible
The 3rd Revolution in Coronary Intervention
Drug Eluting Stents - 2003
Progression in Stent Platform Design
Strut Thickness and Biomaterials
2nd
Generation
1st
Generation
Cypher®
Stent
TAXUS®
Express®
Stent
TAXUS®
Liberté®
Stent
Endeavor®
Stent
3rd
Generation
Xience V® ION™ / and
TAXUS®
Xience
Element™ Prime®
Stent
Stents
PROMUS Element™ Stent
4th
Generation
SYNERGY™
Stent
current benchmark for lowest strut thickness
0.140 μm
(0.0055” ) 0.132 μm
(0.0052”)
Stainless Steel
0.096 μm (0.0038”)
0.091 μm (0.0036”)
Cobalt Alloys
0.081 μm (0.0032”) 0.081 μm (0.0032”)
0.081 μm (0.0032”)
0.074 μm (0.0029”)
Platinum Chromium
Drug Eluting Stent
­Pre
UC Davis
Post
1 Year
DES: Technological Advancement
Meta-­‐Analysis of DES vs. BMS with 180,749 patients
22 RCTs (9,470 patients) randomized to DES or BMS and followed for ≥1 year
DES resulted in:
Non-­Significant
3% Reduction in Mortality
HR 0.97 (0.81,1.15)
Significant Non-­Significant 55% Reduction in TVR
6% Reduction in MI
HR 0.94 (0.79,1.13)
HR 0.45 (0.37,0.54)
30 Registries (171,279 patients) treated with DES or BMS and followed for ≥1
year DES resulted in:
Significant Significant Significant 20% Reduction in Mortality
11% Reduction in MI
55% Reduction in TVR
HR 0.80 (0.72,0.88)
HR 0.89 (0.80-­0.98)
HR 0.53 (0.47-­0.61)
Issues with Drug Eluting Stents
Longer Duration
DAPT
New Disease Definitions Emerge
•
In-Stent Restenosis - ISR
•
Acute Stent Thrombosis - AST
•
Sub-acute Stent Thrombosis – SST
•
Late Stent Thrombosis – LST
•
Very Late Stent Thrombosis – VLST
Impact of Second Generation DES in ST
Cumulative incidence (%)
The Bern Rotterdam Cohort Extended – ARC Definite ST
5
EES vs. S ES Hazard Ratio* = 0.41, 95% CI 0.27–0.62, P<0.0001
EES v s. PES Hazard Ratio* = 0.33, 95% CI 0.23-­‐0.48, P <0.0001
4
Paclitaxel Stent 4.4%
3
Sirolimus Stent 2.9%
2
1
Everolimus Stent 1.4%
0
0
No. at risk
PES
SES
EES
4214
3784
4135
6
12
18
24
30
Months after index PCI
36
3797
3569
3793
2905
3404
2604
1880
2521
1041
Raber, L. et al, data presented at the ESC 2011
42
48
686
1734
208
Compensatory Expansive Remodeling of EEM
IT
PIT
+
FA
1Y
5Y
BL
-
Lumen Reduction
Late acquired malapposition
Lumen Reduction
Struts
Metallic Struts
SE2935049 Rev. A
Information contained herein intended for healthcare professionals from outside the US only. “Caged” (Stented) Vessel
Lumen Reduction by Intrastent Growth of tissue
Ruptured intra-­‐
stent plaque
-
Trends in PCI: Improvement in Patient Outcomes with the Opportunity for Further Advances
Balloon Angioplasty
Bare metal Stent
Drug Eluting Stent
Decade
1980s
1990s
2000s
Acute Success rate
70-­85%
>95%
>95%
Restenosis
40-­45%
20-­30%
<10%
Early Thrombosis
<30 days
3-­5%
1-­2%
1-­2%
Late Thrombosis
>30 days
NA
<0.5%
1-­2%
Very Late Thrombosis (>1y)
NA
≈0%
1-­2%
Metallic Stents
§ Permanent rigid scaffold
§ Interferes with shear stress
§ Interferes with late luminal enlargement
§ Interferes with compensatory expansive remodeling
§ Loss of physiologic response
§ Vessel distortion – lack of conformability
§ Compromises CT Angiography
The 4th Revolution in Coronary Intervention
Bioresorbable Vascular Scaffold
BVS
(Everolimus)
ART
BTI
Amaranth
Elixir
Orbus
REVA
Biotronik
Bioresorbable Scaffold – Rationale and Goals
Rationale: Vessel scaffolding is only needed transiently*
Goal: Revascularize the vessel like a metallic DES, then resorb naturally into the body.
Potential benefits:
§
Restoration of natural physiologic vasomotor function in some patients
§
Enable vascular remodeling and tissue adaptation
§
Elimination of chronic sources of vessel irritation and sources for chronic inflammation
§
Possibly avoid current challenges with leaving a metal implant behind
§
Potentially reduce the need for prolonged DAPT
§
No permanent implant to complicate future interventions and re-­interventions, particularly in younger patients
§
Non-­invasive imaging with MSCT or MRA without ‘blooming artifact’
*Serruys PW, et al., Circulation 1988;; 77: 361. Serial s tudy s uggesting v essels s tabilize 3-­4 months f ollowing PTCA.
Compensatory Expansive Remodeling of EEM
-
PIT
FA
2Y
6M
BL
+
Lumen Enlargement by Plaque Regression
Struts
Scaffolding
Lumen Enlargement By Bioresorbable Scaffolding
Bioresorbable Scaffold – A new treatment Paradigm for Atherosclerotic Plaque
-
SE2935049 Rev. B
-
Lumen Reduction
IT
Design Requirements of a Fully Bioresorbable Scaffold:
Three Phases of Functionality
Revascularization
Restoration
Resorption
0 to 3 months
3 to 12 months +
~12 months +
Transition from scaffolding to d iscontinuous structure
Implant is d iscontinuous and inert
Performance should mimic that o f a standard DES
•Good deliverability
•Gradually lose radial strength
•Resorb in a benign fashion
•Minimum of acute recoil
•Struts must be incorporated into the vessel wall (strut coverage)
•Allow the vessel to respond naturally to physiological stimuli
•Sufficient acute radial strength
•Controlled delivery of drug to abluminal tissue
•Excellent conformability
•Become structurally discontinuous
Bioresorbable Vascular Scaffold Components
Bioresorbable Scaffold
• Poly (L-­lactide) (PLLA)
• Naturally resorbed, fully metabolized
All illustrations are artists’ renditions
Bioresorbable Coating
• Poly (D,L-­lactide) (PDLLA) coating
• Naturally resorbed, fully metabolized
Everolimus
• Similar dose density and release rate to XIENCE V XIENCE V Delivery System
• World-­class deliverability Bioresorbable Polymer
Everolimus/PDLLA Matrix Coating
Drug/polymer matrix
Polymer backbone
•
Thin layer
•
Amorphous (non-­crystalline)
•
1:1 ratio of Everolimus/PDLLA matrix
•
Conformal coating, 2-­4 µm thick
•
Controlled drug release
PLLA Scaffold
•
Semi-­crystalline
•
Provides device structure
•
Processed for required radial strength
TCT 2014 13 Sep 2 014 -­ 17 Sep 2 014 , Washington, DC -­ U.S.A
Five Year Angiographic Results of the ABSORB Everolimus Eluting Bioresorbable Vascular Scaffold
B De Bruyne1, MD, PhD;; G.G Toth1, MD;; Y Onuma2,3, MD, PhD;; HM Garcia Garcia3, MD, PhD;; PW Serruys2, MD, PhD
B 1OLV Hospital, Aalst, Belgium;; 2 Thorax Centre, Erasmus MC, Rotterdam, The Netherlands;; 3 Cardialysis BV, Rotterdam, The Netherlands
on behalf of the ABSORB Cohort B Investigators
Saturday September 13, 5:00 PM
Results
OCT ImagesOver Time Showing Complete Resorbtion of the Scaffold Struts
Baseline
6 Months
2 Years
5 Years
Courtesy of Dr RJ v Geuns, Rotterdam, The Netherlands
Absorb Cohort B1 5 Year Results; B de Bruyne, TCT 2014
ABSORB III + IV Randomized Trials ~5,000 pts with up to 3 de novo lesions in different epicardial vessels randomized to ABSORB v XIENCE, with FU for at least 5 years, at up to 130 sites
Primary ABSORB IV endpoints (superiority):
1. Angina at 1 year (n=3,000 from ABSORB IV)
2. TLF between 1 and 5 yrs (n=5,000, landmark analysis)
Absorb IV PRO (baseline, 1, 3, 6, 9 months, 1, 2 and 3 years)
Detailed angina CRF, + validated instruments: Seattle Angina Questionnaire (SAQ), Rose Dyspnea Scale (RDS), EuroQoL 5D (EQ5D)
Detailed assessment of hospitalizations, revascularizations, MACE
Detailed resource utilization and cost data through 5 years
Ischemia substudy (RESOLVE): CTA, CT perfusion, CTFFR and SPECT at multiple time points PI: GW Stone
Co-­‐PIs: SG Ellis, DJ Kereiakes
Case Examples
PATIENT 1
PATIENT 2
Case Examples
PATIENT 1
PATIENT 2
Case Examples
PATIENT 1
PATIENT 2
Future Directions
§ 2nd and 3rd generation of BVS
ú Different drugs, different polymers, strut design, etc.
§ Drug Filled Stents
ú BMS Surface
ú Drug sits in a hollow core and elutes through surface holes
SYNERGY™ Stent Platform Abluminal Bioabsorbable Polymer
Bioabsorbable polymer (PLGA) Applied only to the abluminal surface (rollcoat)
Thin strut PtCr Stent
Durable Permanent
Polymer
+
Drug
360 Around
Stent
Current Durable Polymer Abluminal Bioabsorbable
Polymer
PLGA Bioabsorbable
Polymer (3 µm)
+
Everolimus*
on Abluminal Side of Stent *2 doses of everolimus evaluated: one similar to PROMUS™ stent and one that is half the dose
Presented by Ian Meredith, MBBS, PhD at TCT 2010 Ÿ Study sponsored by Boston Scientific Corporation. Not for sale. See glossary for prescriptive information.
Drug Filled Stent (DFS) Technology
Polymer Free Drug Delivery
Innovative DES Design
• Essentially a BMS surface
• Designed to address drug carrier issues such as:
§ Polymer biocompatibility
§ Inflammation upon polymer degradation
§ Surface coating durability
CAUTION: Design concepts not approved for sale or clinical use Paclitaxel Coated Balloon Technology
Acute Tissue Transfer of Paclitaxel
University of California Davis Medical Center
THANK YOU
Polylactide Degradation by Hydrolysis
Primary mode of degradation is by hydrolysis of ester bonds
§ Water preferentially penetrates amorphous regions of the polymer matrix
§ Hydrolysis initially results in a loss of molecular weight, but not radial strength, as the strength comes from crystalline domains
§ Once polymer chains are sufficiently short to diffuse from struts or become soluble, mass loss occurs
§
Pietrzak WS, et al. J. Craniofaxial Surg, 1997;; 2: 92-­96. Middleton JC, Tipton AJ, Biomaterials, 21 (2000) 2335-­2346.
1
Polylactide Degradation vs. Radial Support
Hydrolysis occurs via random chain scission of the ester bond
U
U
•⊗ •⊗ •⊗ •⊗
•⊗ •⊗ •⊗ •⊗
•⊗ •⊗ •⊗ •⊗
Tie chains
U
Hydrolysis randomly cleaves amorphous tie chains, leading to a decrease in molecular weight without altering radial strength
U
U
U
U
U
Support
When enough tie chains are broken, the device begins losing radial strength
U
U
U
U
Molecular Weight
Mass Loss
1
3
6
Illustration is a rtist’s rendition. Data o n file a t A bbott V ascular.
12
18
⊗ ⊗
⊗
⊗
⊗ ⊗
24 Mos
‘Caged’ (Stented) Vessel
Delayed Healing → Stent T hrombosis?
* uncovered struts1
Benign NIH
Neo-­Atheroma →
Stent T hrombosis?
In-­Stent Restenosis
Late Acquired Malapposition → Stent T hrombosis?
1. Virmani, R. CIT 2010
Design Requirements of a Fully Bioresorbable Scaffold:
Aligning Device Engineering with Vascular Biology
Revascularization
Restoration
Resorption
Support
Full Mass Loss & Bioresorption
Everolimus Elution
Mass Loss
1
3
6
Months
Platelet Deposition
Matrix Deposition
Leukocyte Recruitment
Re-­endothelialization
SMC Proliferation and Migration
Vascular Function
Forrester J S, et al., J . Am. Coll. Cardiol. 1991;; 17: 758.
Oberhauser J P, et al., EuroIntervention Suppl. 2009;; 5: F15-­F22.
2 Years
Potential of a Fully Bioresorbable Vascular Scaffold
Benign NIH
In-­Scaffold Restenosis
Expansive Remodeling
Late Lumen Enlargement
Plaque Regression
Since struts disappear, issues related to very late persistent strut malapposition and chronically uncovered struts become irrelevant
Bioresorption and vessel wall integration are a reality
BL
ISA incomplete stent apposition
Apposed
6M
Persistent ISA Late
acquired ISA 2Y
Resolved ISA
Non Discernible
Resolved ISA
Non Discernible
Serruys, PW, PCR, 2010
Bioresorption at jailed side branch is a real phenomenon Okamura et al., EHJ, 2010
Potential Causes for Less Angina and Ischemia with Absorb Compared to Metallic Stents Metallic Stent
Absorb
Baseline
At 6 months, Absorb begins to resorb
1 year
At 1 year, the vessel is no longer mechanically constrained
• Lumen gain allows for blood flow
• “Caging” inhibits natural vessel movement • Vasomotion allows the vessel to accommodate and remodeling
increased flow demand
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