Updated BRS Data: Safety Issues and Long-Term Benefit
Seo Suk Min
Seoul St. Mary’s Hospital Cardiovascular Center
1 PCI and DES have revolutionized cardiovascular care
1977 1988 2001 - 2003 Andreas Gruentzig perfor Julio Palmaz and Richard Schatz de Drug-eluting stents are introduc ms the first PTCA in Zurich velop a stainless steel stent for cor ed to the European and U.S. ma , Switzerland onary applications rkets
Balloon Angio Bare Coronary Drug- plasty1977 (PTCA) Metal Stents ( Eluting Stents BMS) (DES)
• Continuous PCI technology advancements improved clinical outcomes for CAD • BVS represents a new approach transient vessel support with drug delivery capability without the long-term limitations of the metallic drug-eluting stents (DES)
*Additional sizes received CE Mark in August 2012.
2
2 Potential Fate of Vessels Stented with DESs
Delayed Healing Stent Thrombosis?
* uncovered struts1 Benign, low grade, Non-occlusive
Neo-Atheroma Stent Thrombosis?
In-Stent Restenosis (symptomatic or asymptomatic)
Late Acquired Malapposition Stent Thrombosis?
3 Information contained herein for distribution outside the U.S. only. AP2940435-OUS Rev. A 09/14
Despite improvements in PCI, there is evidence of unmet need with current treatment options
Long-term BMS event rate1 Long-term DES event rate2
1. Yamaji K, et al. Very long-term (15 to 20 years) clinical and angiographic outcome after coronary bare metal stent implantation. Circ Cardiovasc Interv 2010;3(5):468-75. 2. SPIRIT III: Ischemia-driven TLR through 5 years. Stone GW, TCT 2011.
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4 Three Approaches to Improve Early and Late DES Outcomes
1. Metallic DES with bioabsorbable polymers
2. Metallic DES, polymer-free
3. Bioresorbable scaffolds (BRS) =(BVS)
5 Bioresorbable Vascular Scaffolds (BRS)
Igaki-Tamai PLLA (poly-L-lactic acid)
PLLA Abbott Absorb (eluting everolimus)
PLLA Elixir DESolve (eluting novolimus)
Iodinated tyrosine- Reva Fantom derivative (eluting sirolimus)
Magnesium Biotronik Dreams (eluting sirolimus) Absorb Bioresorbable Vascular Scaffold System
Bioresorbable Bioresorbable XIENCE V Everolimus Scaffold Coating Delivery System
All illustrations are artists’ renditions *Except for platinum markers
7 Novel Attributes of Other BRS Elixir DESolve • Self-correcting property PLLA • Over-expansion w/o fracture (eluting novolimus) • More rapid bioresoption / • Lumen growth after 6 mo
Reva Fantom
Iodinated tyrosine- • Able to rapidly deploy derivative • Over-expansion w/o fracture (eluting sirolimus) • Radio-opaque
Biotronik Dreams
Magnesium • Greater stretchable strength (eluting sirolimus) 8 Status of BRS
• Either a polymer or metallic alloy • Polymeric BRS are mainly made of Poly-L-lactic acid (PLLA) or Poly- DL-lactic acid (PDLLA) • Iron and magnesium based alloys
• CE mark in Europe • PLLA based Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascula, Temecula, CA) • PLLA based DESolve (Elixir. Sunnyvale, CA) • PLLA based Fantom (Reva medical) • Magnesium based DREAMS-2 (Biotronik SE, Berlin, Germany)
9 10 PCI and DES have revolutionized cardiovascular care
? 1977 1988 2001 - 2003 2010* Andreas Gruentzig perfor Julio Palmaz and Richard Schatz de Drug-eluting stents are introduc First Absorb Bioresorbable Vascular S ms the first PTCA in Zurich velop a stainless steel stent for cor ed to the European and U.S. ma caffold (BVS) approved for use in Eur , Switzerland onary applications rkets ope and Asia-Pacific
Bioresorbable
Balloon Angio Bare Coronary Drug- Vascular Scaff plasty1977 (PTCA) Metal Stents ( Eluting Stents olds BMS) (DES) (BRS)
*Additional sizes received CE Mark in August 2012.
11
11 Bioresorbable Vascular Scaffold (BRS): The ideal of leaving nothing behind
After implantation After resorption
12 Vascular Reparative Therapy: Potential for Improved Long-Term Outcomes
Substantial lumen enlargement due to plaque regression and adaptive remodeling
IVUS OCT ABSORB Cohort A MLA 6.35 mm2 6 month f/u
MLA 8.77 mm2 5 year f/u The ‘final golden tube’
R.J. van Geuns, PCR 2012. Images courtesy of Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands
13 Expected Advantages of BRS When First Introduced in the Market
• Restoring physiologic vasomotor function • Late luminal gain late expansive remodeling • Overcome ‘jailing’ of the side branches • Ability to graft the stented segment • Reduce(?) the risk of stent thrombosis and the duration of dual antiplatelet therapy (DAPT)
14 Global Clinical and Commercial Experience Comprehensive Abbott-Sponsored Clinical Program
2011 2012 2014 2014 2015 2016
ABSORB Cohort A 5 Y n = 30; FIM
ABSORB Cohort B 1 Y 2 Y 3 Y 4 Y 5 Y n = 101; FIM
ABSORB EXTEND Enrollment & Follow-Up 1 Y 2 Y 3 Y n = 814, Registry
ABSORB II Enrollment & Follow-Up 1 Y 2 Y 3 Y n = ~501, International RCT
ABSORB FIRST Enrollment & Follow-Up 1 Y n = ~2,000, International Registry
ABSORB III Enrollment & Follow-Up 1 Y 2 Y n = 2,235, US Pivotal RCT
ABSORB Japan Enrollment & Follow-Up 1 Y 2 Y n = 400, Japan Pivotal RCT
ABSORB China Enrollment & Follow-Up 1 Y 2 Y n = 440, China Pivotal RCT ABSORB IV* n = ~3,000, US RCT
UK Registry Enrollment & Follow-Up 1 Y n = 1,000, UK Registry
Total Patients Studied n=~599 n~965 n~5,709 n~7,609 n~8,709 n~9,709
15 Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease – ABSORB III trial • Objectives: to evaluate TLF of BVS or EES • Methods • 2008 pts c stable or unstable angina • randomly assigned in a 2:1 ratio to BVS or EES • 1’ end point: target lesion failure at 1 yr • a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven targetlesion revascularization
Safety and Efficacy Outcomes at 1 Year
Treatment of noncomplex obstructive CAD with BVS was within the prespecified margin for noninferiority with respect to target-lesion failure at 1 year. 16 N Engl J Med 2015;373:1905-15. TLF by 2 Years
Overall QCA RVD ≥ 2.25 mm HR [95%CI]=1.42 [1.04, 1.94] HR [95%CI]=1.35 [0.93, 1.96] p=0.03 p=0.12 30% 30% Absorb BVS (N=1322) Absorb BVS (N=1074) 25% 25% Xience CoCr-EES (N=686) Xience CoCr-EES (N=549) 20% 20%
15% 15% 10.9% 10% 10% 9.3%
5% 7.8% 5% 7.0%
0% 0% 0 13 25 0 13 25 Time Post Index Procedure (Months) Time Post Index Procedure (Months) No. at Risk: Absorb 1322 1193 1141 1074 982 943 Xience 686 634 608 549 512 496
Note: The 2-year window allowed follow-up through 25 months ACC 2017 Clinical Endpoints by 2 Years
Overall QCA RVD ≥ 2.25mm
Absorb XIENCE Absorb XIENCE (N=1322) (N=686) (N=1074) (N=549)
TLF 11.0% (143)* 7.9% (53)* 9.4% (99) 7.0% (38)
Cardiac Death 1.1% (14) 0.6% (4) 0.9% (10) 0.4% (2)
TV-MI 7.3% (95)** 4.9% (33)** 6.5% (68) 4.8% (26)
ID-TLR 5.3% (69) 4.3% (29) 4.1% (43) 3.0% (16)
ST (Def/Prob) 1.9% (24) 0.8% (5) 1.3% (13) 0.6% (3)
* P-value=0.03. ** P-value=0.04. P-value >0.05 for all other comparisons Note: The 2-year window allowed follow-up through 25 months ACC 2017 19 Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II) : a 3 year
• Objectives: to evaluate long-term vasomotor function of BVS • Methods • 501 pts c myocardial ischemia and 1 or 2 vessel disease • randomly assigned in a 2:1 ratio to BVS or EES • 1’ : angiographic vasomotor reactivity after IC NTG (IVUS) • 2’ : angiographic late luminal loss
Thrombosis endpoint
The trial did not meet its co-primary endpoints of superior vasomotor reactivity and non- inferior late luminal loss for BVS 20 Lancet 2016; 388: 2479–91. Absorb vs EES: a meta-analysis
• 6 RCTs • 3738 pts • At 1 yr • 1’ efficacy outcome: target lesion revascularisation • 1’ safety outcome: definite or probable stent (scaffold) thrombosis
Absorb similar rates of repeat revascularisation at 1 year of follow-up an increased risk of subacute stent thrombosis.
Lancet 2016; 387: 537–44. 21 In total, definite/probable scaffold thrombosis occurred in 31 patients (3.5%) who received the Absorb device while stent thrombosis was documented in 8 patients (0.9%) who received the Xience stent (hazard ratio 3.87; 95% CI 1.78-8.42).
Wykrzykowska JJ, et al. N Engl J Med 2017 22 23 DESolve Cx Bioresorbable Coronary Scaffold System • 120 µm strut thickness Improved deliverability • System crossing profile (0.053” - 1.3mm*) • 6 Fr (0.71” – 1.8mm) guide cat heter compatible • 0.014” wire compatible
Alexandre Abizaid, TCT 2016 24 DESolve Bioresorbable Coronary Scaffold Expansion Capability
. DESolve scaffold can be expanded up to 0.5 mm above nominal (per I FU) for optimal results
. DESolve scaffold designed with a substantial margin for expansion to reduce the risk of strut fracture
3.4 mm 3.8 mm 4.0 mm 4.75 mm
DESolve over-expa nded scaff DESolve 3.0 mm expans old ion capability compared to metallic stent Xience over-expan ded metal st ent
25 Data on file at Elixir Medical DESolve Nx Clinical Trial Pre-specified 6m and 36m QCA Analysis Paired Results
6 months 36 months In-Scaffold Analysis p-value N = 19 N = 19
RVD (mm) 2.94 ± 0.30 2.95 ± 0.33 0.76
MLD (mm) 2.56 ± 0.36 2.45 ± 0.45 0.20
LLL (mm) 0.12 ± 0.14 0.22 ± 0.33 0.20
Median Late Loss (mm) 0.09 [0.04; 0.13] 0.16 [0.04; 0.31]
Diameter Stenosis (%) 13.06 ± 6.56 16.40 ± 13.47 0.37
Values are mean ± SD; % (n), or Median (interquartile range 25%, 75%) MLD – Minimum luminal diameter; LLL – late lumen loss.
Site: ZNA Middelheim, Antwerpen, Belgium 2015 TCT DESolve Cx Clinical Study
Single Arm Registry 50-pt imaging study ~15 to 20 sites 100-pt post market study Europe and Brazil Coordinating Investigators: A. Abizaid, S. Verheye
Inclusion Criteria Treat up to 2 de novo native coronary artery lesions Reference vessel diameters of 2.5 – 3.5 mm, lesion length ≤ 24 mm Clinical: MACE 30d 6m 1yr 2yr Imaging: QCA, IVUS, OCT Study Purpose: To assess performance of DESolve Cx Scaffold System through clinical and imaging endpoints
Primary Imaging Endpoint: 6-month in-scaffold late lumen loss Primary Clinical Endpoint: Major Adverse Cardiac Events (MACE), a composite of Cardiac Death, Target Vessel MI a nd Clinically-Indicated TLR at 6 months
Secondary Endpoints MACE: At 30 days, 1 and 2 years; scaffold thrombosis QCA: In-segment late lumen loss, binary restenosis, and percent diameter stenosis IVUS: In-scaffold percent volume obstruction, malapposition OCT: In-scaffold percent obstruction, strut coverage
Alexandre Abizaid, TCT 2016 27 Fantom Bioresorbable Scaffold
Key Scaffold Features • Complete scaffold visibility under x-ray • Single-step continuous inflation • Clinically significant expansion range • Adequate radial strength at 125 µm thickness Vasomotion restoration ~1 year(Preclinical) Fantom® (REVA Medical) Sirolimus-Eluting Bioresorbable Scaffold • No special storage or handling Desaminotyrosine Polycarbonate
Visibility Deliverability Vessel Patency
J Ribamar Costa Jr., TCT 2016 28 Fantom Radiographic Visibility
Fantom
• Fantom’s (x-ray) visibility Allows for: • Precise scaffold placement • Accurate lesion coverage Absorb Xience • Full structural assessment after deploy ment • Less reliance on invasive imaging com pared to other BRS (IVUS/OCT)
Fantom
J Ribamar Costa Jr., TCT 2016 29 FANTOM II – Cohort A & B Study Overview and Baseline Characteristics
Study Population N= 240 Patients Patient Characteristics (N=240) 28 Clinical Centers Patient Age (mean ± SD) 62.7 ± 10.1 6 & 9 Month Follow- up Male 70.4% Imaging Angiographic (cohort A N=100) Diabetes 23.8% (cohort B ongoing)
OCT Current/Former Smoker 59.6% (cohort A N=73) (cohort B ongoing) Hypertension 73.3%
IVUS Hyperlipidemia 70.4% (cohort A N=45) (cohort B ongoing) 6 Month Follow-up Prior PCI 43.8% Clinical Prior CABG 2.9% Prior MI 26.3% Long Term Follow-up Clinical Recent LVEF <40% 0.4% (N=231) (annual through 5 years)
J Ribamar Costa Jr., TCT 2016 30 FANTOM II – Cohort A & B Safety Results
Components of the 6-Month Primary N=240 Endpoint (modified ITT): non-Hierarchical N, (%)
MACE* 5 (2.1%)
Cardiac Death 1 (0.4%)
Target vessel MI 3 (1.3%)
Clinically Driven TLR 2 (0.8%)
6 Month MACE Results Event Timeframe N, (%)
In-Hospital 2 (0.8%) (Post Procedure MI)
30-Day Follow-up 1 (0.4%) (MI/TLR/SAT) 90-Day Follow-up 0 (0%)
6-Month Follow-up 2 (0.8%) (1 cardiac death, 1 TLR) * As adjudicated by an independent Clinical Events Committee Note: Excludes 3 Non-Clinically Driven TLRs
J Ribamar Costa Jr., TCT 2016 31 FANTOM II – Cohort A Angiographic – QCA Results*
In-Scaffold Analysis Baseline Post Procedure 6 Months (n=115) (n=112) (n=100)
RVD (mm) 2.68 ± 0.37 2.75 ± 0.40 2.70 ± 0.36 MLD (mm) 0.79 ± 0.29 2.47 ± 0.37 2.23 ± 0.41
Diameter Stenosis (%) 70.3 ± 10.4 7.6 ± 9.7 15.3 ± 15.2
Acute Gain (mm) 1.67 ± 0.41 Acute Recoil (%) 2.9 ± 8.8 Mean LLL (mm) 0.250.5 ±+ 0.38 0.40
Median LLL (mm) 0.2 (-0.43, 2.62) In-Segment Analysis Mean LLL (mm) 0.17 ± 0.34
Median LLL (mm) 0.15 (-0.43, 2.47)
Notes: Binary restenosis at 6 months follow-up = 2.0% Data analyzed by an independent QCA core lab (Yale Cardiovascular Research Group, New Haven, US)
J Ribamar Costa Jr., TCT 2016 32 Drug Eluting Mg Scaffold - MAGMARIS -
Sirolimus + PLLA (BIOlute)
. 6-crown 2-link design, 150µm strut thickness . Optimized scaffold design for . Higher bending flexibility . Higher acute radial force . Sirolimus drug elution & PLLA ( ORSIRO BIOlute coating) . Tantalum radiopaque markers . Absorption time: 12 months
33 Study Design
121 Patients with de novo coronary artery st enosis and successful DREAMS 2G implant DESIGN ation (2.5x20, 3.0x20, 3.5x25 mm) . Prospective, multi-center, FIM. 1 Month, Clinical FUP PRIMARY ENDPOINT 6 Month . In-segment late lumen loss @ 6-month • Clinical FUP (mandatory) • Angiographic FUP (mandatory) • IVUS / OCT (Subgroup only) COORDINATING CLINICAL INVESTIGATOR • Vasomotion (Subgroup only) . Prof. M. Haude, Lukaskrankenhaus, Neuss, Germany 12 Month • Clinical FUP (mandatory) • Angiographic FUP (voluntary) • IVUS / OCT (voluntary) CORELAB • Vasomotion (voluntary) . Cardialysis, Rotterdam, the Netherlands
2 Year, Clinical FUP
3 Year, Clinical FUP
34 M Haude et al., Lancet 2016; 387:31-39. Clinical Outcome Until 12-month Follow-up
6-Month 12-Month N=120 % N=118 %
TLF1 4 3.3 4 3.4
Cardiac death 12 0.8 12 0.8
Target vessel MI 1 0.8 1 0.8
Clinically driven TLR 2 1.7 2 1.7
CABG 0 0.0 0 0
Definite-or-probable 0 0.0 0 0.0 scaffold thrombosis
1. Composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization or CABG 2. A 58-year old man (CV RF: smoking, hypertension and hyperlipidemia, stable angina CCS Class II) was treated with a DREAMS 2G 3.0x20 mm in the dis tal RCA. The patient experienced an unwitnessed death 134 days after the procedure. Since a cardiac cause could not be ruled out, the independent Clinical Event Committee adjudicated the event as a cardiac death.
Haude M et al Lancet 2016; 387:31-39 35 Haude M et al Eur Heart J 2016; 37(35): 2701-9; Primary Endpoint In-segment LLL at 6-month 100
80
LLL: 0.27±0.37mm 60 95% CI: 0.20-0.33
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20 Cumulative Frequency (%) FrequencyCumulative
0 -1.00 -0.50 0.00 0.50 1.00 1.50 2.00 In-segment Late Lumen Loss (mm) 36 M Haude et al., Lancet 2016; 387:31-39. Summary Highlighting Some of the Current BRS Technologies
International Journal of Cardiology 228 (2017) 931–939 37 Clinical data
Small Strut thickness Resistance to fracture
Ideal BRS
Radial force Resorbsion time
Visibility
38 Alexandre Abizaid, TCT 2016 Clinical data Absorb Strut Thickness Desolve Cx, MeRes Fracture Resistance Absorb Falcon Desolve
The ideal BRS Absoption time Desolve Radial Force Fantom Dreams
MeRes Visibilty Dreams Fantonm Mirage 39 Alexandre Abizaid, TCT 2016 Limitations of BRS
• Thick strut • Weak radial force • Stent fracture • Technique more critical than metallic DES • Accurate sizing essential; need for imaging • Fewer clinical experience
40 Absorb Registry GABI-R trial (11/2013-01/2016)
Segeberger Kliniken Herzzentrum
93 sites in Germany Elisabethkrankenhaus and Austria Essen Universitätsklinikum Giessen Universitätsklinikum Mainz Kerckhoff-Klinik Bad Nauheim Universitätsklinikum Mannheim Universitätsklinikum Rems-Murr-Kliniken Erlangen Winnenden
Herz- und Gefäßzentrum Universitätsklinikum Oberallgäu Kempten Ulm
Alexandre Abizaid, TCT 2016 41 effective event rates in % Comparison of Endpointsat 6mo FU 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 TVR 4.2* *
2.9* GABI-R 2014 GABI-R -
TVF (Card.TVF Death, in 2014vs2015 TV - MI, MI, TVR) 4.6
3.7
TLR 2.2* * GABI-R 2015 GABI-R -
1.1*
TLF 3.2
Holger M. Holger 2.3
(definite/probable) * GABI P < 0.05 P BVS Nef thrombosis 2.2 - , TCT, 2016 R 1.3
42
GABI-R trial
• Real-world registry shows safety and efficacy of the bioresorbable scaffold system ABSORB • Preliminary analysis after 6 mo with 3196 pts. showed low TLF and TVF rate • Scaffold thrombosis rate remained low • Adapted guidelines for implantation of ABSORB resulted in significantly better treatment results (TLR, TVR) implicating a learning curve • Long-term FU analysis has to be awaited for final conclusions
43 Holger M. Nef, TCT 2016 Optimal Implantation Technique is Imperative for Good Clinical Outcomes P1. PPrep: Prep the the Lesion Lesion: NC balloon sized 1:1 For calcified lesions: scoring balloons, cutting balloon (rotablator/CSI) Goal: alter the compliance of the lesion 1.S SSize: Size the the Lesion Scaffold: Guide catheter (eye), pre-dil balloon, on- line QCA, or invasive imaging (IVUS, OCT) P2. PPost: Post-Dilate-Dilate with with NC NC Balloon Balloon Sized 0.5mm up to high pressure (>16A) **MANDATORY**
44 David G. Rizik. Nef, TCT 2016 Optimal Implantation Technique Is Imperative for Good Clinical Outcomes Pooled Absorb Outcome with PSP Analysis
8.0% 7.1% 7.0% 6.3% 6.0% 4.8% 5.0% 4.0% 3.3% 3.0% 2.0% Event Rate% Event 2.0% 1.3% 0.7% 0.8% 1.0% 0.5% 0.0% 0.0% 0.0% 0.0% TLF (0-1y) TLF (1-2y) TLF (1-3y) ST (0-1y) ST (1-2y) ST (1-3y)
Non-PSP PSP
0-1y A-EXTEND, A-II, A-Japan, A-China, A-III N=2540 N=294 1-2y A-EXTEND, A-II, A-Japan, A-China N=1381 N=194 1-3y A-II N=297 N=21 45 David G. Rizik. Nef, TCT 2016 Destiny of Absorb
Thrombosis Risk: ABSORB IV 12 month data (late 2018)
Complex Anatomy: AIDA 12 month data (Spring 2018) ABSORB IV 12 month data (late 2018)
Long Term Benefit: ABSORB II 5 year (late 2018) ABSORB III+IV 5 year (2022?)
46 Stephen G, Ellis. Nef, TCT 2016 Conclusions
. BRS is evolving despite recent concern about stent thrombosis.
. Development of new BRS and implementation of technical deployment recommendation might allow BRS implantation closer to current DES efficacy and enhancing the safety profile in near future.
47 Thank You For Your Attention !
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