Download - Dreams & papyrus
DREAMS and BIOSOLVE Trials Bioabsorbable scaffolds
Update
Dr. Rumoroso
28 Noviembre 2014
BIOTRONIK // Coronary Intervention Innovation
Key characteristics of absorbable scaffold materials
Material PLLA Iron Magnesium Alloy
Tensile Strength (MPa) ~30-45 300 280
Elongation (%) 2 – 6 25 23
Total Degradation Time 2-3 Years > 4 years 9-12 months
Iron @ 28dMagnesium @ 28d
1 Ratner DB, et al. Biomaterials Science: Introduction to Materials in Medicine, 2nd Edition. Elsevier Academic Press, 2004. 2/3 Hermanwan H, et al. “Developments in metallic biodegradable stents. Acta Biometerialia. 6 (2012):1693-1697. 4 “A Cautionary Tale”, Ormiston, J., Serruys, P., et al., Circ Cardiovasc Interv 2011;4;535-538, Oct. 2011
PLLA @ 1m4
Biocompatibility
! Mechanics
!Absorption
Absorbablescaffolds
For coronary scaffolds, tailor-made Magnesium alloys provide the best balance
Iron @ 28d
AMS
165µm80µm
28-‐day histology
AMS 1.0: Absorbable Magnesium Scaffold from BIOTRONIK (2004)
No drug coating
!▪ Proprietary Mg-alloy
Low crossing profile (1.2 mm) High radial strength (~1 bar) Low bending stiffness Low recoil (<5%) !
▪ Excellent biocompatibility !
▪ 4-crown design !!
Clinical Study: !!
Clinical studyPROGRESS-AMS
Study design ▪ Prospective, multi-center, consecutive,
non-randomized First In Man (FIM) trial !
Primary endpoint (reached) ▪ MACE *at 4 months <30 % !
Results (at 4 months) ▪ LLL 1.08 mm ▪ TLR 23.8% !
Conclusion ▪ Bare AMS (Absorbable magnesium
Scaffold) concept is safe and feasible ▪ Need for prolonged scaffolding time and
an anti-proliferative drug
Long-term FUP (~7 yrs) Clinical, angiographic, IVUS
4-month FUP Clinical, angiographic, IVUS
63 patients enrolled at 8 international clinical sites
6-month clinical FUP (n=61)
12-month clinical FUP (n=60)
Source: Erbel et al. Lancet 2007; 369: 1869–75. Waksman et.al, JACC Cardiovasc Interv 2009;2:312-320
* Composite of cardiac death, nonfatal MI, ischemia driven TLR
Lessons learned from the bare AMS
PROGRESS-I showed the bare AMS concept to be safe and feasible
Optimization of device with prolonged scaffolding time and an anti-proliferative drug
Improvements for future AMS
Loss of scaffolding area (55%)
In-stent neointima (45%)
Post implantation 4 month follow-up
Contribution to lumen loss
! Source: Erbel R. et al., Lancet 2007;369:1869-75.
Waksman et.al, JACC Cardiovasc Interv 2009;2:312-320.
Results: ▪ LLL 1.08 mm ▪ TLR 23.8%
From AMS to DREAMS G1Device evolution
AMS (Absorbable magnesium Scaffold)
165µm80µm
28-‐day histology
No drug/polymer coating
130µm120µm
DREAMS G1 (Drug Eluting AMS 1st Generation )
28-‐day histology
Paclitaxel + PLGA
▪ Refined Mg-alloy High radial strength (~1 bar) Normal ‘stent like’ deployment behavior
▪ Excellent biocompatibility ▪ 6-crown, 3-link design !Clinical Study: !!
1 6 pts withdrew consent for imaging FUP (2 at 6-‐month and 4 at 12-‐month FUP) 2 1 pt died a non-‐cardiac death (Cohort 1). 2 pts withdrew consent (1 Cohort 1 and 1 Cohort 2) 3 1 pt died of a non-‐cardiac death 1 pt withdrew consent
46 patients with de novo coronary artery stenosis
Mandatory 6mo:Clinical FUP (n = 22)Imaging FUP (n = 201)
Cohort 1 (n = 22) Cohort 2 (n = 24)Optional 6mo:
Clinical FUP (n = 24)Imaging FUP (n = 16)
Mandatory 12mo:Clinical FUP (n = 232)Imaging FUP (n = 201)
Optional 12mo: Clinical FUP (n = 202)Imaging FUP (n = 13)
Mandatory 24mo:Clinical FUP (n = 202)
Mandatory 24mo:Clinical FUP (n=24)
Clinical studyBIOSOLVE-I
Study design ▪ Prospective, multi-center First In Man
(FIM) trial. Single, de novo lesions 3.0-3.5mm and ≤ 12mm long !
Primary endpoints
Cohort 1: TLF at 6 months Cohort 2: TLF at 12 months
!
Source: M Haude. et al. Lancet 2013; 381:836-‐44.
Mandatory 36mo:Clinical FUP (n = 203)
Mandatory 36mo:Clinical FUP (n=24)
BIOSOLVE-I study results 6-and 12-month late lumen loss (LLL)
6-‐month LLL 0.64 ± 0.50 mm
12-‐month LLL 0.52 ± 0.39 mm
LLL of the bare AMS in the PROGRESS study at 4-‐month: 1.08 ± 0.49 mm
Cumulative Freq
uency (%
)
In-‐scaffold LLL (mm)
M Haude. et al. Lancet 2013; 381:836-44.
BIOSOLVE-I study results Six to 36-month clinical & angiographic follow-up
Device Success 100% (47/47)
Procedure Success 100% (46/46)
Clinical Results 6-Month 12-Month 24-Month 36-Month
TLF 4.3% (2/46) 6.8% (3/44) 6.8% (3/44) 6.8% (3/44)
Cardiac death 0.0% 0.0% 0.0% 0.0%
MI2 0.0% 2.3% (1/44) 2.3% (1/44) 2.3% (1/44)
Scaffold Thrombosis 0.0% 0.0% 0.0% 0.0%
TLR (clinically driven) 4.3% (2/46) 4.5% (2/44) 4.5% (2/44) 4.5% (2/44)
In-scaffold LLL 0.64 ± 0.50 mm 0.52 ± 0.39 mm NA NA
1 M Haude. et al. Lancet 2013; 381:836-44. 2 Target vessel peri-procedural MI. 3 TLR occurred during 6M FUP, both pts had angina. 1 pt received an additional DREAMS during the initial procedure due to a flow-limiting bailout. 4 LLL not available at 24-month as no imaging FUP was performed 5 M Haude, oral presentation EuroPCR 2013. 6 R Waksman, oral presentation EuroPCR 2014.
Post-implantation 12M FUP
Side Branch
Side Branch
Guide wire
shadow
Guide wire
shadowCalcium
Calcium
**
*
*
Source: Garcia-Garcia HM et al. Work in progress. Data presented at the EuroPCR 2014
Serial OCT analysis in DREAMS
* Strut Remnants
Conclusions
▪ DREAMS demonstrates an excellent safety profile up to 12 months
▪ A TLF rate of 7.0% at 12 months after DREAMS implantation is similar to the results of ABSORB (7.1%; Cohort B)
▪ DREAMS demonstrated significantly improved efficacy at 12 months compared to the bare AMS:
▪ Reduction in LLL of 61% compared to the 4-month data of the bare AMS (1.08 vs. 0.52 mm)
▪ Reduction of TLR rate by 82% (26.7 vs. 4.7%)
▪ The late lumen loss remained stable between 6-and 12-month follow-up
▪ Vasomotion and natural vessel angulation were completely restored at 6-month follow-up
study&name BIOFLOW1I BIOFLOW1IIIidentifier NCT01214148 NCT01553526
date4(main4end4point) 2010 2013study4type FIM,4single4arm all4comers4registry
PI Dr4Hamon Prof.4Waltenberger
number4of4centers 2 42geography Romania international
primary4end4point inLstent4LLL TLFsecondary4end4point TLR,4ST,4MACE... TVR,4ST,4sucess,4MACE...
41st4FUP 30d 6m2nd4FUP 4m 12m3rd4FUP 9m 36m
Other4FUP 12,4244&436m 60m
product&name Orsiro Orsiro Xience&Prime Orsiro Orsiro Xience
N 30 298 154 1356 1063 1056
InLstent4LLL4(mm) 0.054±40.224(9m)0.104±40.324
(9m)0.141±40.294(9m)
ST4(%)4(cumulative,4probable4&4definitive)
04(9m) 0.04(12m) 0.04(12m) 0.44(12m) 2.84(12m) 3.44(12m)
TLF4(%) 6.54(12m) 8.04(12m) 5.14(12m) 6.74(12m) 6.74(12m)CILTLR4(%) 6.74(9m) 3.54(12m) 4.74(12m) 3.04(12m) 3.44(12m) 2.44(12m)TVR4(%) 4.54(12m) 4.64(12m) 3.04(12m)TVF4(%) 8.14(12m) 7.84(12m)
cardiac4death4(%) 0.74(12m) 0.74(12m) 1.34(12m) 1.94(12m) 2.14(12m)TVMI4(%) 2.74(12m) 2.64(12m) 2.34(12m) 2.94(12m) 3.04(12m)
Binary4Restenosis4(%)4(inLstent)
04(9m) 2.164(9m) 1.344(9m)
All4MI4(%) 04(9m) 3.94(12m) 4.44(12m)
publicationHamon4et4al,4
EuroIntervention42013;8:1006L1011
other internal internal
primary4end4point
24m36,460m
results
source
Pilgrim4et.4al,4The4Lancet,4doi:10.1016/S0140L6736(14)61038L2
internal
TVR,4TLR,4ST,44MACE...9m 30d12m 12m
Prof.4Windecker
24 9international Switzerland
LLL TLF
BIOFLOW1II BIOSCIENCE
design
NCT01356888 NCT014431042013 2014RCT RCT4all4comers
Prof4WindeckerDr4Lefevre
Programa clínico DES Orsiro
The Lancet, published online September 1, 2014
BIOSCIENCE publicado en the Lancet, incluye un metaanálisis con BIOFLOW-‐II
META-‐ANALYSIS OF BIOSCIENCE AND BIOFLOW II
Risk ratio (95% CI)Favours BP SES Favours DP EES
Target lesion failure Bioflow-‐II Bioscience Overall
Cardiac death Bioflow-‐II Bioscience Overall
Target vessel myocardial infarction Bioflow-‐II Bioscience Overall
Target lesion revascularisation Bioflow-‐II Bioscience Overall
BP SES DP EES
0.82 (0.41-‐1.64) 0.98 (0.71-1.35) 0.95 (0.71-1.27)
19/298 69/1,063
12/154 70/1,056
1.03 (0.09-11.31) 0.90 (0.50-1.64) 0.91 (0.51-1.63)
2/298 20/1,063
1/154 22/1,056
1.03 (0.32-3.38) 0.96 (0.59-1.58) 0.97 (0.62-1.53)
8/298 30/1,063
4/154 31/1,056
0.74 (0.29-1.90) 1.51 (0.90-2.54) 1.18 (0.61-2.30)
10/298 35/1,063
7/154 23/1,056
0.25 0.5 1 2 4
Risk ratio (95% CI)
BIOSCIENCE confirma los resultados de BIOFLOW-‐II en una gran población de pacientes más compleja. Especialmente para los criterios de valoración más dificiles: IM y muerte .
DREAMS G1 (Drug Eluting AMS 1st Generation )
120µm
90-Day Faxitron, porcine explant
Paclitaxel + PLGA
DREAMS G2 (Drug Eluting AMS 2nd Generation )
150µm
Sirolimus + PLLA (BIOlute)
90-Day Faxitron, porcine explant
DREAMS evolution from 1st to 2nd generation
▪ Optimized design: 6-crown 2-link ▪ 120-150µm strut thickness* ▪ Addition of 2x markers at each end ▪ Improved delivery system !!!!! Clinical Study:
*3.0 and 3.5 scaffolds :150µm strut thickness 2.5 scaffold: 120µm strut thickness
At the beginning T = 0: Immediately following scaffold deployment ▪ Drug starts to elute ▪ No signs of degradation in coating or metalT = 0
Vascular restoration therapy: Bioabsorption in single steps
Vascular restoration therapy: Bioabsorption in single steps
Second phaseT = 1 month ▪ Drug elutes from the polymer ▪ Healing begins with minimal tissue growth ▪ The magnesium core starts to corrode and converts
gradually to Mg-‐oxide
T = 1 month
Vascular restoration therapy: Bioabsorption in single steps
T = 3 months
Third phaseT = 3 months ▪ Drug elution is completed ▪ Magnesium is further corroded and converted to Mg-‐
oxide. Bioabsorption of Mg has not yet started ▪ Struts are mostly covered with tissue
Vascular restoration therapy: Bioabsorption in single steps
T = 9 months ▪ Magnesium core is fully converted into Mg oxide.
Mg oxide converts to hydroxyapatite ▪ Cracks appear and are infiltrated by SMCs; material is
getting bioabsorbed
T = 9 months
Fourth phase
Vascular restoration therapy: Bioabsorption in single steps
T = 1 year ▪ Most of the scaffold material has been bioabsorbed
T = 1 year
Fifth phase
Vascular restoration therapy: Bioabsorption in single steps
T = 1.5+ years
▪ All foreign material is gone, only cells are left
▪ Vessel has returned to its natural, healed state
T = 1.5 years
Completed
121 patients with de novo coronary artery stenosis
1 month Clinical FUP
6 month Clinical FUP Angiographic FUP (mandatory) IVUS / OCT (Subgroup only)
Vasomotion (if patient consents)
12 month Clinical FUP Angiographic FUP (voluntary) IVUS / OCT (Subgroup only)
Vasomotion (if patient consents)
3 year, Clinical FUP
2 year, Clinical FUP
DESIGN
▪ Prospective, multi-center, FIM. Single de novo coronary artery lesions in up to two coronary arteries, RVD between 2.2-3.8 mm and ≤ 21 mm long
!PRIMARY ENDPOINT
▪ In-scaffold late lumen loss @ 6-month !
COORDINATING CLINICAL INVESTIGATOR
▪ Prof. M.Haude, Lukaskrankenhaus GmbH, Neuss, Germany !
CORELAB
▪ Cardialysis, Rotterdam, The Netherlands
BIOSOLVE-II Study Design
Post-dilatation capability of DREAMS scaffold
DREAMS crimped (3.0mm nominal) Expansion to 3.0mm
Over expansion to 5.0mm
Potential for side branch access
Kissing balloon inflation: MB 3.0 mm / SB 2.5 mm
D = 1.3mm
5.5mm
*Experimental, N=1
Experimental* post-dilatation of DREAMS shows potential side-branch access
Coating integrity of DREAMS
SEM images of expanded 3.0 mm DREAMS (expansion diameter 3.5 mm)
SEM images of expanded 3.0 mm DREAMS (expansion diameter 4.25 mm)
Summary
▪ Magnesium offers an ideal balance between biocompatibility, mechanical performances and absorption
▪ The Biotronik absorbable Mg program is most advanced: - BIOSOLVE-I has proven safety of DREAMS 1. generation with
Paclitaxel elution and improved efficacy compared to the bare AMS version
- BIOSOLVE-II is currently testing safety and efficacy of DREAMS 2. generation with Sirolimus elution
!▪ In about a year we will have the DREAMS-2 available in our shelfs
if the BISOLVE II trial gets the primary endpoint in terms of efficacy and safety
PK Papyrus Covered coronary stent systemIndicated for acute coronary artery perforations
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1.571.19
Crossing profile [mm diameter]
Data on file at BIOTRONIK; * Ø 2.5-4.0 mm
6F 5F
24% reduction
Guide catheter compatibility*
Jostent Graftmaster 3.0/16 Sandwich design
PK Papyrus 3.0/15Covered single stent design
Covered single stent design allows for low crossing profile and 5F guide catheter compatibility*
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High flexibility and low crossing profile for exceptional deliverability – allowing you to seal perforation with confidence
Nmm²
0 27,5 55 82,5 110
Bending stiffness of crimped stent
58% reduction
Jostent Graftmaster 3.0/16
PK Papyrus 3.0/15
Data on file at BIOTRONIK
Expect PK Papyrus to deliver like a conventional stent
Track Force in coronary artery model [N]
0,0
0,6
1,3
1,9
2,5
Distance [mm]
0 50 100 150 200
53% reduction in maximum track force
PK Papyrus 3.0/20Jostent Graftmaster 3.0/19PRO-Kinetic Energy 3.0/20
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PK Papyrus Compliance Chart
Pressure (ATM) Ø (mm)
2.5 3.0 3.5 4.0 4.5 5.05 2.38 2.85 3.33 3.86 4.33 4.826 2.42 2.90 3.39 3.93 4.41 4.91
NP 7 2.46 2.95 3.44 4.00 4.50 5.00NP 8 2.50 3.00 3.50 4.07 4.59 5.09
9 2.54 3.05 3.56 4.14 4.67 5.1810 2.58 3.10 3.61 4.21 4.76 5.2711 2.62 3.15 3.67 4.28 4.84 5.3612 2.67 3.20 3.72 4.36 4.93 5.4513 2.71 3.25 3.78 4.43 5.02 5.54
RBP 14 2.75 3.29 3.83 4.50 5.10 5.6315 2.79 3.34 3.89 4.57
RBP 16 2.83 3.39 3.94 4.64
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Control 11 meses
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Conclusión
▪ Papyrus es un dispositivo que se convierte en un MUST en las estanterías de las salas de hemodinamica para evitar complicaciones graves, ya que tiene una alta capacidad de sellado coronario
▪ Es un dispositivo cuyo performance es equivalente al BEST IN CLASS de los DES de última generación
▪ No hay que utilizar catéteres guía de mayor perfil
▪ Pasa perfectamente por un GuideLiner de 6F
▪ El performance del stent queda patente en los casos testados
▪ La comprobación al año da idea de la eficacia y seguridad del dispositivo
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