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Νεότερα DES stents. Δεδοµένα εφαρµογής των και προοπτικές
Δηµήτρης Γ. Σιώνης Αιµοδυναµικό Τµήµα Επεµβατικής
Καρδιολογίας Σισµανόγλειο-Αµ. Φλέµιγκ ΓΝ Αθήνα
Δήλωση συµφερόντων
• None for the presentation • Potential conflicts of interest
– Institutional research grant : Elpen, Sanofi, Boehringer Ing
– Honoraria : Medtronic, Sanofi
• Thick struts • Thick, durable coating (~15 µm)
• High drug dose
• High polymer load
1st-Generation DES was not ideal for healing
✓Uncovered struts ✓Hypersensitivity ✓Malapposition ✓Late stent thrombosis ✓Neoatherosclerosis
Th ThTh
NeoatherosclerosisUncovered struts Hypersensitivity reaction Malapposition from excessive fibrin
deposition
Th
Virmani, CRT 2014
2nd gen DES perm polymer: Improved efficacy and safety
Data from Spirit II,III,IV and COMPARE trials (6789)
RESOLUTE All Comers
Windecker PCR 2014
Event rates persist beyond 1 year with 2nd gen PERMANENT Polymer DES
Resolute ZES (N=1140) Xience V EES (N=1152)
Log rank P=0.65
17.1%
16.3%
Primary endpoint Pnon-inferiority <0.0018.3%
8.2%TLF
Rate
(%
)
Years
0
10
20
30
40
0 1 2 3 4 5
2% event rate per year
Etiology of metallic stents eventsWithin 1 year Early thrombosis and restenosis
• Early DAPT discontinuation • Suboptimal implantation (under –
expansion, malapposition, geographic miss, edge dissections)
• Longitudinal stent deformation • Strut fracture • Polymer defects or stripping during
delivery • Inflammation/hypersensitivity from
the polymer/drug • Non responsiveness to drug
Beyond 1 year Very late thrombosis and restenosis
• Uncovered struts (thrombosis) • Abnormal shear stress from
protruding struts and/or loss of cyclic strain relief
• Strut fracture • Persistent stimulation of SMC’s from
adherent fibrin and/or loss of normal vessel curvature
• Chronic inflammation due to late foreign body reactions and polymer hypersensitivity
• Positive remodeling with strut malapposition
• Neoatherosclerosis
Approaches to improve Next Generation metallic DES outcome
No Stent Thrombosis
Low TLR, Low Clinical Symptom Recurrence
Deliverable, Visible, Trackable Conformable
Improved Stent Delivery System Stent Material Thinner Struts Modified Stent Geometry Enhanced side-branch access Surface Coating
Facilitating re-endothelialization Polymer facilitating endothelialization
Durable, but more biocompatible
Reduced Polymer Load Abluminal Polymer No Polymer Bioabsorbable Polymer
Reduced Drug Load
Less/no effect on endothelial function
Short DAPT duration
Approaches to improve early and late DES outcomes
• Metallic DES with thinner struts
Thin Struts Restenosis and Thrombosis
1. ISAR STEREO 1, Circulation 2001 2. ISAR STEREO 2 JACC 2003 3. Kolandaivelu et al Circulation 2011
Approaches to improve early and late DES outcomes
• Metallic DES polymer-free • Metallic DES with bioabsorbable polymers • Bioresorbable scaffolds (BRS)
HYPOTHESIS: Polymers play a role in phenomena observed with DES
Illustration based on Beckmann JA et al. JAMA. 2002;287(19):2570-2581 and Roesen P et al. Exp Clin Endocrinol Diabetes. 2001;109(supp 12):S474-S486. aTongi et al. Int J Cardiol. 2007;120:212. bJoner et al. J Am Coll Cardiol. 2006;48:193-202. cAwata et al. ACC. 2008.
ANEURYSMS, HYPERSENSITIVITY, LATE RESTENOSIS, LISA
DELAYED HEALINGc
PRO- THROMBOGENICb
INCREASEDINFLAMMATIONb
VASO- CONSTRICTIONa
Decreased Endothelial Function
Polymer Free Design Types
1.Bioactive agent in “pure” form, impregnated in porus surface or stent body
•Nano/micro can use metal sieve structure to control release kinetics
•Macro or wells-diffusion depends primarily on pharmacokinetic properties
of the agent Biosensors
2.Bioactive agents dissolved in a non-polymeric biodegradable carrier.
•On surface of stent
•In a nano-micro structure
3.Bioactive agent attached to stent surface
•Covalent bonding
•Chemical precipitation or crystalization
on stent surface
Setagon Medronic
Translumina Ziscoat
Amazonia PAX
Leaders Free trial
• Age>75 years • OAC planned after PCI • Baseline Hb <11g/dl or transfusion
prior 4 weeks • Planned major surgery • Cancer diagnosed or treated <3 years • Creatinine clearance <40ml/min • Hospital admission for bleeding during
past year • Thrombocytopenia (<100.000/mm3) • Any prior intra-cerebral bleed • Any stroke during the past year • Severe liver disease • NSAID or steroids planned after PCI • Anticipated poor DAPT compliance for
other medical reason
Primary Efficacy Endpoint –Clinically Driven TLR
Primary Safety Endpoint – Cardiac Death, MI, ST
Urban F et al, NEJM 2015
• Drug (sirolimus) is protected and contained inside the stent
• Drug releases through multiple laser-drilled holes on the abluminal side of the stent
• Drug elution is controlled and sustained through natural diffusion via direct interaction with the vessel wall. Elution profile is similar to durable polymer DES
Drug coats inner lumen
Drug elutes through abluminal holes
Uniform distribution in stented area
The Drug Filled Stent-Concept (Medtronic)
RVD (mm) 3.0
Lesion Length (mm)
46
Lesion location
Mid RCA
Age (yrs) 60
Gender (M/F)
F
Diabetes (Y/N)
Y(ID)
Post-Procedure
1-Month Follow-up
0.6 mm 14 mm 17 mm 17.8 mm 42.2 mm
Case by Prof. Stephen Worthley. OCT Analysis by Daniel Chamié, MD, OCT Core Laboratory, Cardiovascular Research Center, Sao Paulo, Brazil
DFS case, Early Healing of Overlapping Struts
Approaches to improve early and late DES outcomes
• Metallic DES polymer-free • Metallic DES with bioabsorbable polymers • Bioresorbable scaffolds (BRS)
Vascular Response to Durable Polymers
Virmani et al TCT 2012
Newer generation durable polymers are still a source of inflammation, neoatherosclerosis and thrombosis risk
Time Course For Polymer Bioabsorption
Time (Months)
BioMime (PLLA+PLGA)
SYNERGY (PLGA)
Ultimaster (PLLA - CL)
MiStent (PLGA)
ABLUMINUS (PLA)
ELIXIR DESyne BD (PLA)
FIREHAWK (PLA)
BIOMATRIX (PLA)
NOBORI (PLA)
SVELTE (Amino Acid)
ORSIRO (PLLA)
DREAMS 2 (Mg w/PLA coat)
ART (PDLLA)
ELIXIR DESolve (PLLA)
BVS (PLLA)
REVA ReZolve (Polycarb)
0 5 10 14 19 24 29 34 38 43 48
42
36
24
18
9
15
12
9
9
9
9
8
3
4
4
2
3
3
3
3
2
6
6
1
3
8
9
4
3
1
Drug Release Bioabsorbable Polymer Bioresorbable Scaffold (BRS)
(no drug)
Arterial Wall
Vessel Lumen
Strut
An abluminally coated bioabsorbable polymer DES may be optimal for healing?
Freedom from long-term polymer
exposure once coating is absorbed
Targeted drug delivery reduces risk of restenosis and inflammation
Uncoated surface on luminal side to promote cell coverage and
adhesion
SYNERGY OCT Results in All Comers Patients Understanding healing from 30 Days – 6 Months
30 days 6 Months3 Months
72.2% Covered
99.3% Covered*
94.5% Covered
96.6% Covered
N=30 N=37 N=22 N=20
SORT-OUT VIII PCR 2015
TIMELESS CRT 2015
De la Torre CCI 2015
De la Torre CCI 2015
0% Thrombosis Rate
No. at risk
0 6 12 24PE+ 838 790 772 538
SYNERGY 846 807 794 553
PROMUS Element Plus vs SYNERGY
Months
ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; log-rank P values
EVOLVE II TLF at 2 years
TLF
(%)
0
16
12
4
8 8.5%9.4%
6.5%
6.7%
2 years HR 1.10 [0.79, 1.52]
P=0.57
1° Endpoint: 12 months ITT
Pnoninferiority=0.0005
Kereiakes, ACC 2016
3rd generation
Approaches to improve early and late DES outcomes
• Bioresorbable scaffolds (BRS) Absence of metallic cage
- Drug elution complete
- Mechanical support to maintain
patency
RESTORATION
- Drug elution to reduce risk
of restenosis
- Mechanical support to
maintain patency
REVASCULARIZATION
Drug Elution
4th Evolution in Coronary Angioplasty Bioresorbable Scaffold –Lifecycle
Forrester, et al. J Am Coll Cardiol. 1991:758-69. Oberhauser, et al. EuroInterv. 2009: F15-22.
30 6Months
Scaffold Support
Scaffold Mass
RESORPTION
- Polymer exposure
complete
- Scaffold support no longer
required
- Natural vasomotion and
positive remodeling
enabled
Available and upcoming Bioresorbable Scaffolds
First Generation BVS – The Absorb Series
Everolimus/PDLLA (1:1) matrix coating •7µm •Conformal coating •Controlled drug release similar to Xience CoCr-EES
-Impressive results of pivotal trials -Non inferior to 2nd gen DES
-First signs of safety issues in GHOST trial (2.1% thrombosis)
Absorb (%)
Xience (%)
Odds Ratio (95% CI) P value
Target Lesion FailureCassese et al, 2015 6.3% 5.1% 1.20 [0.9, 1.6] 0.21
Stone et al, 2016 6.6% 5.1% 1.25 [0.92, 1.70] 0.18
Myocardial InfarctionCassese et al, 2015 5.2% 3.5% 1.36 [0.98, 1.89] 0.06
Stone et al, 2016 5.7% 4.0% 1.34 [0.97, 1.85] 0.07
Lipinski et al, 2016 3.2% 1.5% 2.06 [1.31, 3.22] 0.002
Stent Thrombosis (def/prob)Cassese et al, 2015 1.2% 0.5% 1.99 [1.00, 3.98] 0.05
Stone et al, 2016 1.3% 0.6% 2.09 [0.92, 4.75] 0.08
Lipinski et al, 2016 1.4% 0.7% 2.06 [1.07, 3.98] 0.03
1st gen BVS Meta-Analyses Comparison
Absorb better Xience better
Cassese, et al. The Lancet 2016; 387:537-44. Lipinski, et al. JACC Cardiovasc Interv 2016;9:12-24. Stone, et al. The Lancet 2016 [epub ahead of print].
0 1 2 3 4 5
Poor Lesion Preparation Thick Struts (157µm overlapping 354µm) Non-laminar Flow Inadequate Post-dilatation Malapposition Delayed Healing Fractures
Possible Causes of Increased ST Rates with ABSORB
Strut Fracture Malapposition Thick StrutsUnderexpansionThrombosis
1Jaguszewski, M. Eur Heart J. Feb 2015 [Epub ahead of print]. 2Ormiston, et al. Circ Cardiovasc Interv. 2011;4:535-538. 3RadcliffeCardiology.com, September 2014. 4Sipotz, J. presented at TCT2014. Capodanno, et al. EuroIntervention 2015 Feb;10(10):1144-53.
• Use in >2.5mm vessels • Need for proper
preparation • Adequate post-
dilatation • Avoid overlapping
scaffolds
Proposed solutions
Verheye et al, JACC Interv 2014
3.4mm
3.8mm
4.0mm
4.75mm
0 28 180 360 720
DESolve Bioresorbable Coronary Scaffold- elutes for 3 months absorbs in 2 years
Hierarchical Events (n,%) 6M (N=122)
12M (N=122)
24M (N=122)
36M (N=122)
Major Adverse Cardiac Events 3.3% 5.7% 7.4% 8.2%
Cardiac Death 1(0.8%) 2 (1.6%) 3 (2.5%) 4 (3.3%)
Target Vessel MI •Q wave •Non Q wave MI
1(0.8%) 0(0,0%) 1(0.8%)
1 (0.8%) 0 (0,0%) 1 (0.8%)
1 (0.8%) 0 (0,0%) 1 (0.8%)
1 (0.8%) 0 (0,0%) 1 (0.8%)
Clinically Indicated TLR 2 (1.6%) 4 (3.3%) 5 (4.1%) 5 (4.1%)
Definite Stent Thrombosis 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
BIOTRONIK Mg BRS results
Magmaris
Bioresorbable Scaffolds dataThe Idea…. the Data….. the Future
• Preservation of targets for CABG
• Restoration of vasomotion
• Late luminal enlargement
• Strut thickness ↓
• Fracture resistance ↑
• Visibility ↑
• Absorption time↓
• Radial force↑
• Clinical data ↑↑
• Significantly longer procedure time
• Significantly lower acute gain and post procedure MLD
• Numerically high adverse event rates even in relatively simple lesions
• Signal for high rates of late events
• More than 8 studies with >2% ST at 1 year in real-world populations
Absence of Permanent Rigid Metallic Cage
Future (near) BRS
Bioresorbable scaffolds Next Gen
Puricel et al, JACC 2016;67:921-931
Absorb
NG Absorb
BOSTON’s RENUVIA Bioresorbable ScaffoldBioresorbable Microfiber Scaffold (BRMS)- MIRAGEMedtronic Mg Absorbable Scaffold
120
2 Magmaris
Conclusions • Current metallic DES (either with durable or
bioabsorbable polymer) have shown excellent safety and efficacy, therefore remain the default treatment for CAD either SIHD or ACS.
• Bioabsorbable polymer DES seem to offer advantages over durable polymer DES but are not a homogenous class
• Novel technologies include advantages on stent design and platform (DFS, polymer-free) may show further advantages of metallic DES .
• 1st generation BRS use face problems short and long term as far as the efficacy and safety of the devices
• Possible overcome of these limitations can be achieved with the development of 2nd generation BRS and the refinement of the deployment procedure
• Till then, the Operator is a major factor in the efficacy and safety of 1st generation BRS, being an “unforgiving” device.
Orsiro (N=298)
Xience Prime (N=154)
Acute (0-48h) 0 % 0 %
Subacute (48h-30d) 0 % 0 %
Late (>30d) 0 % 0 %
Very late (>12m) 0 % 0 %
Overall 0 % 0 %
Orsiro (N=298)
Xience Prime (N=154)
Acute (0-48h) 0 % 0 %
Subacute (48h-30d) 0 % 0 %
Late (>30d) 0 % 0 %
Very late (>12m) 0 % 0.7 %
Overall 0 % 0.7 %*
Stent Thrombosis at 36 months
Definite ST Definite, Probable or Possible ST
Source: T. Slagboom, Poster, EuroPCR 2015
* One possible very late ST occured in a diabetic patient in the Xience Prime arm
Bioresorbable Scaffolds dataThe Idea…. the Data….. the Future
• Restoration of vasomotion
• Late luminal enlargement
• Preservation of targets for CABG
• Appeal to physician/patient
• Freedom from long-term polymer exposure
• Angina relief
• Strut thickness ↓
• Fracture resistance ↑
• Visibility ↑
• Absorption time↓
• Radial force↑
• Clinical data ↑↑
• Significantly longer procedure time
• Significantly lower acute gain and post procedure MLD
• Numerically high adverse event rates even in relatively simple lesions
• Signal for high rates of late events
• More than 8 studies with >2% ST at 1 year in real-world populations
Absence of Permanent Rigid Metallic Cage
Future (near) BRS
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