Bioabsorbable Scaffolds - the future, Jacques Koolen

Transcription

1 Bioabsorbable Scaffolds - the future, a passing fad or somewhere in between? Jacques Koolen Amsterdam

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3 POBA Acute closure Restenosis 3 months 30-50% BMS DES First generation Subacute-late trombus very late stent trombosis Deliverability Subacute- late -very late stent trombosis, aneurysms?? Restenosis 6 months 20 % Restenosis <10 % DES Second generation Still late and very late stent Restenosis < 5 % trombosis Catch-up 10 yrs? Continuing 1-2 %/yr stent trombosis?? BVS Deliverability / visibility????????????????????????

4 Why implant a resorbable scaffold? Advantages of transient BRS vs. permanent DES Restoration of vessel anatomy Restoration of vessel functionality Restoration of low thrombogenic milieu Potential elimination of neoatherosclerosis Vessel angulation and curvature are anticipated to be restored by the time the scaffold loses its integrity. Liberation from the permanent metal cage will facilitate restoration of vessel pulsatility and vasomotion. Compensatory expansive remodeling and/or lumen enlargement will not be restricted. The risk of late or very late scaffold thrombosis will be eliminated as the foreign material (platform & coating) will be resorbed. Complete scaffold resorption, intact endothelium with restored vasomotion will potentially eliminate the risk of in-scaffold neoatherosclerosis. Vascular Restoration Therapy Gogas BD. Bioresorbable scaffolds for percutaneous coronary interventions, Global Cardiology Science and Practice 2014

5 CE Mark CE Mark

6 The current available technology The price to pay CE mark since June 2016 Abbott Vascular. Bulky stent struts Higher shear stress Less crossability Low or no visibility

7 SPIRIT III: Target ) TLF (% 30% 25% 20% 15% 10% 5% 0% Number at risk XIENCE V (n=669) TAXUS Express (n=332) 1-year HR 0.56 [0.34, 0.90] p= % Δ3.8% 5.4% 5-year HR 0.64 [0.46, 0.89] p= % Δ6.3% 12.7% ~1.8%/yr event rate after year Months XIENCE V TAXUS TLF = cardiac death, target vessel MI, or ischemic-driven TLR Stone GW et al. JACC 2011 (abstract)

8 Primary Composite Endpoint Target Lesion Failure to 3 Years 20% Resolute ZES (N = 1140) Cumulative Incidence of Events 15% 10% 5% Xience V EES (N = 1152) Log rank P = 0.65 HR 1.05 [0.84, 13.1% 12.4% 0% Time After Initial Procedure (Months) 36 TLF (Target Lesion Failure) is defined as cardiac death, TVMI, or clinically driven TLR.

9 OR 1.10, 95% CI % 16% Zotarolimus-eluting stent Sirolimus-eluting stent M Maeng Lancet 2014

10 OR 0.55, 95% CI % Zotarolimus-eluting stent 1.2% Sirolimus-eluting stent M Maeng Lancet 2014 In press

11 SO IV Stent Thrombosis Hazard Ratio = 0.18, 95% CI , p= Sirolimus-eluting stent 2.0% 0.4% 0.3% Everolimus-eluting stent Jensen LO J Am Coll Cardiol. 2016;67:751-62

12 Outcome 1-Year Clinical Outcomes BVS (N=355) EES (N=166) P value Target lesion failure 5% 3% 0.35 Target vessel failure 5% 5% 0.78 All Death 0 1% 0.33 Cardiac Death Any MI 4% 1% 0.06 Target-vessel revascularization 2% 5% 0.15 Target-lesion revascularization 1% 2% 0.69 Any revascularization 4% 7% 0.08

13 1-Year Clinical Outcomes BVS (N=355) EES (N=166) Difference (95% CI) P value 1-year definite ST 2 (0.6%) % (-1.72 to 2.19) 1.00 Acute (0-1 day) 1 (0.3%) % (-1.98 to 1.67) 1.00 Subacute (2-30 days) 1 (0.3%) % (-1.98 to 1.68) 1.00 Late ( days) % (NA) 1.00 Definite or probable ST 3 (0.9%) % (-1.45 to 2.65) 0.55

14 ABSORB II, ABSORB III, ABSORB Japan, ABSORB China 1-Year DoCE (TLF): Cardiac Death,TV-MI or ID-TLR Absorb Study BVS Absorb II 20/331 XIENCE CoCr-EES RR [95% CI] RR [95% CI] 7/ [0.61, 3.30] Absorb China 8/238 10/ [0.32, 1.98] 11/265 5/ [0.39, 3.11] Absorb Japan 102/ / [0.90, 1.82] 141/ / [0.91, 1.64] Test for overall effect: Z=1.36; P=0.18 Absorb III Test for heterogeneity: I 2 =0%; P=0.78 Summary Absorb BVS Better DoCE = Device-oriented composite endpoint Xience CoCr-EES Better

15 Serruys PW, Ormiston J, van Geuns RJ, de Bruyne B, Dudek D, Christiansen E, Chevalier B, Smits P, McClean D, Koolen J*, Windecker S, Whitbourn R, Meredith I, Wasungu L, Ediebah D, Veldhof S, Onuma Y A Polylactide Bioresorbable Scaffold Eluting Everolimus for Treatment of Coronary Stenosis: 5- Year Follow-Up J Am Coll Cardiol Feb 23;67(7):766-76

16 Results from the GHOST-EU registry demonstrated already a safety concern at 6-month follow-up Capodanno D. et al., GHOST-EU registry, EuroIntervention 2015

17 Appropriate use of Bioresorbable Vascular Scaffolds in percuteneous coronary interventions: A recommendation from experienced users Neth Heart J Mar; 23(3): Published online 2015 Jan 28. doi: /s PMCID: PMC A position statement on the use of bioresorbable vascular scaffolds in the Netherlands Bert Everaert, Cordula Felix, MD, Jacques Koolen, Peter den Heijer, Jose Henriques, Joanna Wykrzykowska, Rene van der Schaaf, Bart de Smet, Sjoerd Hofma, Roberto Diletti, MD, Nicolas Van Mieghem MD, Evelyn Regar MD, PhD, Peter Smits MD, PhD, Robert-Jan M. van Geuns 1, MD, PhD,

18 Fajadet J, Haude M, Joner M, Koolen J*, Lee M, Tölg R, Waksman R. Magmaris preliminary recommendation upon commercial launch: a consensus from the expert panel on 14 April 2016 EuroIntervention Sep 18;12(7):828-33

19 ABSORB III Procedural Outcomes Longer Procedure Times and Lower Device Success with BVS Procedural Outcomes Absorb (N=1322) XIENCE (N=686) P-value Procedure duration (min) 42.2± ±20.9 <0.001 Device success 94.3% 99.3% <0.001 Any Unassigned Devices 6.0% 0.6% <0.001 Only Unassigned Devices 4.4% 0.6% <0.001 Low device success compared to metallic stents Ellis, S. N Engl J Med Oct 12 [epub ahead of print]. 19

20 First Generation BVS: Limitations Becoming Apparent Malapposition, dislodgement, fracture, thrombosis 20

21 ABSORB III Device Thrombosis to 1-Year Higher Stent Thrombosis Rates with BVS 2.0% 1.6 Timing of Device Thrombosis 1.5% % % % Device Thrombosis (Def/Prob) P-value 0.13 Early (0 to 30 days) 0.46 Acute ( 24 hr) Subacute > 24 hr to 30 days Late > 30 days to 1 year 0.10 Ellis, S. N Engl J Med 2015;373:

22 ABSORB II Clinical Outcomes at 3 Year Follow-up DoCE/TLF: Higher Event Rate with BVS Driven by target vessel MI (6% vs 1%; p=0 0108) DoCE/TLF : Cardiac death, target-vessel myocardial infarction, and clinically indicated TLR Serruys PW et al. Lancet

23 ABSORB II Clinical Outcomes at 3 Year Follow-up Increased Stent Thrombosis Serruys PW et al. Lancet

24 20% RVD 2.25 mm RVD <2.25 mm (median 2.74 mm) (median 2.09 mm) Absorb 1--Year Year Events (%) 15% TLF: Pint diff = 0.31 TVMI: Pint diff = 0.09 ST: Pint diff = % 10.0% 10% 8.3% 6.7% 5.5% 5.2% 4.5% 4.6% 5% 4.6% 1.5% 0.9% 0.6% 0% TLF TVMI ST TLF TVMI ST # Event # At risk Median based on pooled Absorb and Xience

25 P S P Optimal implantation technique is imperative for good clinical outcomes OBJECTIVE Prepare lesion to receive scaffold Facilitate delivery Enable full expansion of pre-dilatation balloon to facilitate full scaffold expansion OBJECTIVE Accurately size the vessel Select appropriate scaffold for best fit OBJECTIVE Achieve <10% final residual stenosis Ensure full strut apposition PRESCRIBE DAPT In ABSORB III all patients were maintained on DAPT for a minimum of 12 months. Risks versus benefits should be considered for each patient, including judgment regarding risk of antiplatelet therapy. Antiplatelet therapy should be used per ACC/AHA guidelines, information from the ABSORB family of clinical trials, current literature on DES and scaffolds, and the specific needs of individual patients. Wright, RS, et al., Circulation. 2011; 123: / Wijns, W, et al., European Heart Journal. 2010; 31: / Levine, GN, et al., Circulation. 2011; 124: / Steg, PG, et al., European Heart Journal. 2012; 33: / O Gara, PT, et al., Circulation. 2012; 127: e368-e425.

26 PSP Analysis Def/Prob ST KM Through 3-Years (Absorb Patients, As-Treated Population) Stent/Scaffold Thrombosis Rate (%) 5% Non-PSP Log-rank p = 0.13 (PSP vs Non-PSP) Proper sizing Proper post-dil 4% PSP 3% 3.4 % 3.3 % 2% 0.8 % 0.7 % 1% 0% Time Post Index Procedure (Days) Non-PSP Proper Sizing Proper post-dil PSP days population: A-EXTEND, A-II, A-Japan, A-China, A-III days population: A-EXTEND, A-II, A-Japan, A-China days population: A-II

27 (As-Treated Population) ) EXTEND ABSORB-II ABSORB-Japan ABSORB-China ABSORB-III 108/772 21/324 35/258 32/237 96/1224 (14.0%) (6.5%) (13.6%) (13.5%) (7.8%)

28 Characteristics of 4 BVS VLST Cases in ABSORB ID ST Type A-J VLST 1 Day 494 A-J VLST 2 Day 536 Device Diameter (mm) 3.5 Undersized 3.5 Undersized A-J VLST 3 Day Undersized A-J VLST 4 Day Oversized Dmax OCA (mm) In-device MLD Post (mm) In-device %DS Post Postimaging % None Postdilatation Yes DAPT 13-month In-device %DS ASA: d/c 1 week prior Clop: d/c at 1-year 13% 22% % IVUS No ASA: Ongoing (d/c transiently at 2 months before) Clop: d/c at 1-year 2,45 11% None Yes DAPT on-going 8% % None No ASA: Ongoing Clop: d/c at 669-day 2% 3 / 4 ST had undersized scaffold selection

29 Optimal Implantation Technique Is Imperative for Good Clinical Outcomes Prepare the Lesion, Size Vessel Appropriately, and Post-Dilate Adoption of BVS specific strategy Hamm, C. GABI-R, EuroPCR / 2. Koning, R., France ABSORB Registry, EuroPCR / 3. Hernandez, F., REPARA, EuroPCR / 4. Cortese, B. RAI, EuroPCR / 5. Petronio, A.S., IT-DISAPPEARS, EuroPCR

30 Optimal Implantation Technique Is Imperative for Good Clinical Outcomes Pooled Absorb Outcome with PSP Analysis 8.0% 7.1% 6.3% Event Rate % 6.0% 4.8% 4.0% 3.3% 2.0% 0.5% 0.0% TLF (01y) TLF (12y) 0.0% TLF (13y) 1.3% 0.7% 2.0% 0.8% 0.0% 0.0% 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= y A-EXTEND, A-II, A-Japan, A-China N=1381 N= y A-II N=297 N=21

31 Significant improvement in ghost-eu outcomes at 1y with optimal implantation 25.0% 20.5% Event Rate % PSP No PSP 19.1% 20.0% 15.0% 10.0% 10.3% 8.8% 7.4% 5.7% 5.0% 3.7% 1.8% 1.5% 0.0% POCE All Death 1.5% 1.1% 0.0% 0.8% All MI All Revasc DOCE Cardiac Death 2.5% 0.0% TV-MI 1.5% 2.3% 0.0% TLR ST 31 Brugaletta, S., GHOST-EU PSP Analysis, TCT 2016.

32 4 Cities Registry: Reduction in Absorb Scaffold Thrombosis with Improved Technique 4 German and Swiss centers BVS specific protocol 0 Nitrates 1 Sizing with balloon (1:1:1), 2 angiographic planes Absorb-specific Protocol Thrombosis, KM Estimate (%) 2 3 Early Experience Low threshold for OCT 4 Implant following IFUs Log Rank p= NC postdilation (+0.5mm) Do not accept MLD<2.5/2.9mm MLA<4.9/6.6mm2 *For a mm and 3.5 mm scaffold respectively Puricel, S. et l. J Am Coll Cardiol. 2016; 67(8): Patients Early Experience Absorbspecific

33 PSP and It s Components: Putative Impact Early ST Very late ST Frequent type Underexpansion Often in small vessels (ex. A-III) Frequent type: Malapposition Often in mid-large vessels Ex. 2.5mm device in 2.0mm RVD Mitigation: RVD > 2.50mm and PSP In particular proper sizing to ensure full expansion of the device in an appropriately sized vessel Proprietary and confidential do not distribute Ex. 3.00mm device in 3.25mm RVD w/o High pressure postdil Mitigation: PSP In particular high pressure postdilation with properly sized non compliant balloon to ensure full wall apposition

34 Optimal Implantation Technique Is Imperative for Good Clinical Outcomes Implantation Guidance Has Evolved During Enrollment in ABSORB Trials Full PSP Was Not Used in Many Patients ABSORB Cohort B ABSORB EXTEND ABSORB II ABSORB JAPAN ABSORB III ABSORB CHINA ABSORB FIRST ABSORB IV Study enrollment period Guidance on technique in commercial practice Size the vessel (3Ps) Postdil (OUS: 4Ps) High Pressure Post Dil RVD 2.5mm (US: FDA IFUs)

35 Dmax for sizing, PSP-1, PSP-2, PSP-3 or OCT guidance: interventionalist s jargon or indispensable implantation techniques for short- and long-term outcomes of Absorb BRS? Published on 2 March 2017 Patrick W. Serruys1*, MD, PhD; Yoshinobu Onuma2, MD, PhD 1. NHLI, Imperial College London, London, United Kingdom; 2. Erasmus MC, Rotterdam, The Netherlands Introduction Recent reports of randomised trials (ABSORB II, ABSORB Japan and ABSORB China) have raised questions on the non non-inferiority of the acute and long-term performance of the Absorb bioresorbable scaffold (BRS) when compared to the XIENCE stent1,2 (both Abbott Vascular, Santa Clara, CA, USA). Furthermore, very late scaffold thrombosis has been perceived as a possible new unexpected enemy 3,4 unexpected because thrombosis occurred at a moment when the scaffold was expected to have disappeared

36 Post-procedural shear stress in underexpanded and overexpanded scaffold and its long-term evolution (at five years). The wall shear stress simulations in a case of an underexpanded (left) and overexpanded scaffold (right), combining three-dimensional angiography and optical coherence tomography. In the case of underexpansion (left), post-implantation lumen showed a step down and step up at the proximal and distal edges of the bioresorbable scaffold. The proximal underexpanded part of the device causes relatively high shear stress of >5 Pa on top of the proximal struts, whereas the part of the scaffold normally expanded exhibits low shear stress of Pa between the struts. The high shear stress initially observed in the proximal part of the scaffold was, at five years, no longer present as a result of dynamic remodelling and lumen enlargement. In the overexpanded scaffold case (right), the inter-strut shear stress was very low (<1 Pa). At five years, the very low shear stress was no longer observed69. In both cases at five years, the lumen exhibited a smooth endoluminal surface, and accordingly the shear stress distribution became more homogenous and physiological 56,70,71. Pa: pascal unit of shear stress.

37 Absorb BVS may have a higher risk of ST, but this can be overcome by the operator who is in charge to ensure optimal implantation. Colombo A. JACC 2016 Puricel S. et all. J Am Coll Cardiol. 2016

38 Is Absorb ready to be used in most patients and lesions? AGE <70 YEARS DM STEMI MVD LONG LESION BIFURCATIONS (PROVISIONAL) CTO SCAD BIFURCATIONS (2 STENTS) SEVERE CALCIFICATIONS ISR? Tarantini et al. G ITAL CARDIOL;17:28S-44S

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41 CONCLUSIONS personal view - At present, there are some differences between BVS and metallic stents. - The current BRS technology has some limitations and is really first generation (infancy) - BVS requires a dedicated technique for implantation: lesion preparation, sizing, post-dilatation. - Requires more time for implantation but this investment has potentially important long-term benefits

42 - Other systems with faster absorb rates, different struts, materials used and visibility can and will change the game. - So if we use it properly (willing and able to), have some patience and don t kill it to early: BVS is here to stay

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44 No differences in outcomes in simple lesions DOCE, device-oriented composite end point*doce corresponds to the primary end point. Patients with DES were treated 1:1 with either EES or biolimus-eluting stents. Score based on optical coherence tomography imaging.

45 RVD <2.25 mm (N=582) 20% 15% 1-Year Events (%) 10% RVD 2.25 mm (N=2787) =2.0% P=0.47 =1.2% 10.3% 8.3% =2.0% P= % 1.5% 5% Ab Xie P= % 4.6% =0.5% P= %0.4% 0% TLF ST TLF ST

46 Device Thrombosis to 1 Year: ITT Absorb (N=1322) Xience (N=686) p-value 1.54% 0.74% Early (0 to 30 days) 1.06% 0.73% Late (> 30 to 1 year) 0.46% 0.00% Definite* (1 year) 1.38% 0.74% Probable (1 year ) 0.15% 0.00% 0.55 Device Thrombosis (def/prob) *One definite ST in the Absorb arm by ITT was in a pt that was treated with Xience

47 Debate Final Thought Is Absorb ready to be used in most patients and lesions? YES Absorb is ready to be implanted in almost all patients, and in MOST BUT NOT ALL PATIENTS/LESIONS Lesion selection based on coronary anatomy is almost all. Coronary Angiography alone is not Anatomy BRS-Specific Implantation Protocol is mandatory to achieve procedural success and fovourable clinical outcomes Careful Planning- Proper technique - Intracoronary Tomographic Imaging

48 Current Generation BVS Ready for Prime Time? Best to wait! Potential BVS Benefits Potential BVS Benefits Current BVS BVS Limitations / Potential Risks BVS Limitations/ Potential Risks 48

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51 Differences between DES and BVS Different stent structure BVS have larger stent struts and less radial force Different implantation techniques Optimal lesion preparation Correct sizing of Scaffold to vessel Meticulous post dilatation Different anatomical indications The bulky structure of BVS limits their use in particular settings

52 POBA BMS DES BRS Acute occlusion Acute recoil Acute thrombosis Sub-acute thrombosis Late thrombosis Very late thrombosis Neointimal hyperplasia Constrictive remodelling Adaptative remodelling Restoration of vasomotion Late luminal enlargement Negative / no effect Iqbal J, et al. Eur Heart J 2014; 35: ? Positive / beneficial effect Neutral or uncertain effect

53 The Promise of New Technologies 30% Emerging New Technologies (Theoretical) XIENCE V (n=669) SPIRIT III TAXUS Express (n=332) TLF (%) 25% 19.0% 20% 15% 9.2% 12.7% 10% 5% 7.2% 5.4% 5.3% 0% Months Number at risk XIENCE V TAXUS TLF = cardiac death, target vessel MI, or ischemicischemic-driven TLR Spirit III: Gada H et al. J Am Coll Cardiol Intv 2013;6: ;6:1263 6

54 The reabsorption process Hydrolysis occurs via random chain scission of the ester bond Tie chains Initially, hydrolysis preferentially cleaves amorphous tie chains, leading to a decrease in molecular weight without altering radial strength When enough tie chains are broken, the device begins losing radial strength Support Molecular Weight Mass Loss Abbott Vascular Months

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