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