BIOABSORBABLE VASCULAR SCAFFOLD

WHERE ARE WE?

I.TAMMI RAJU

overview

• History & evolution of BVS

• Advantages

• Types of BVS

• Physiology of BVS

• Clinical trails of BVS

• Future perspectives of BVS

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• First revolution- balloon angioplasty

• The invention of balloon angioplasty as a percutaneous treatment for obstructive coronary disease by Andreas Gruntzig in 1977 was a huge leap forward in cardiovascular medicine and undoubtedly will always be remembered as a revolution in the field of revascularization

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• In 1964, Charles Theodore Dotter and Melvin P. Judkins described the first angioplasty

• 1977, Andreas Grüntzig performed the first balloon coronary angioplasty

Plain Old Balloon

Angioplasty(POBA)

Dissections – Focal to threatened dissection

Acute recoilChronic constrictive remodeling

• second revolution -BMS• The advent of BMS and the landmark Belgian-Netherlands

Stent Study (BENESTENT) and Stent Restenosis Study (STRESS) trials have established BMS as the second revolution in interventional cardiology.

• A solution to acute vessel occlusion by– sealing the dissection flaps and – preventing recoil &– making emergency bypass surgery a rare occurrence.

– Serruys PW, de Jaegere P, Kiemeneij A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease: Benestent Study Group. N Engl J Med. 1994;331:489–495.

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Plain Old Balloon

Angioplasty(POBA)

Bare Metal Stent(BMS)

• In 1986, first coronary stent by Sigwart et al

• Gianturco-Roubin first FDA – BES – 1993

• Palmaz-schartz first STENT VS POBA

• Restenosis rates were further reduced from 32% to 22% at 7 months, but this rate was still high, and neointimal hyperplasia inside the stent was even more prominent than with angioplasty.

• Disadvantages (Because the vessel was now caged with metal) – late luminal enlargement and – advantageous vascular remodeling could no longer

occur. – late stent thrombosis (ST), was also first described. – Serruys PW, Daemen J. Late stent thrombosis: a

nuisance in both bare metal and drug-eluting stents Circulation. 2007;

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• Third revolution-DES• The first 45 patients implanted with the

sirolimuseluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ) were found to have negligible neointimal hyperplasia at follow-up.

• This was confirmed in the randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization (RAVEL) study.– Morice MC, Serruys PW A randomized comparison of a

sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:

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The RAVEL Study

A RAndomised (double blind) study with the Sirolimus coated BX™ VElocity balloon

expandable stent (CYPHER™) in the treatment of patients with De Novo native coronary

artery LesionsM.C. Morice, P.W Serruys, J.E. Sousa, J. Fajadet, M. Perin, E. Ban

Hayashi, A. Colombo, G. Schuler, P. Barragan, C. Bode

A RAndomised (double blind) study with the Sirolimus coated BX™ VElocity balloon

expandable stent (CYPHER™) in the treatment of patients with De Novo native coronary

artery LesionsM.C. Morice, P.W Serruys, J.E. Sousa, J. Fajadet, M. Perin, E. Ban

Hayashi, A. Colombo, G. Schuler, P. Barragan, C. Bode

The treatment of a de novo lesion with CYPHER™ appears feasible and safe : no acute, subacute (30 days) or late occlusion occurred although clopidogrel / ticlopidine was administered for only 2 months

Virtual elimination of neo-intimal in-stent proliferation: MLD post deployment (2.43 mm) remains essentially unchanged at 6 months (2.42 mm) with no measurable late loss (-0.05 mm) Restenosis (0%) and no evidence of edge effect

• Disadvantages• Increased risk of late and very late ST.• late ST rates of 0.53%/y, with a continued increase to 3%

over 4 years. – Late thrombosis in drug-eluting coronary stents after

discontinuation of antiplatelet therapy. Lancet. 2004• In the (ARTS II) trial,with complex multivessel disease, the

rate of combined definite, probable, and possible ST was as high as 9.4% at 5 years, accounting for 32% of major adverse cardiovascular events (MACEs). – J Am Coll Cardiol. 2009

• Postmortem specimens of DES revealed significant numbers of uncovered struts with persistent inflammation around the stent struts.

• Vasomotion testing demonstrated vasoconstriction to Ach. – Vascular responses to drug eluting stents: importance of

delayed healing. Arterioscler Thromb Vasc Biol. 2007BVS , WHERE ARE WE

ANGIOPLASTY

• Fully Bioresorbable Scaffold: The Fourth Revolution in Interventional Cardiology?

POTENTIAL ADVANTAGE OF BRS

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ADVANTAGES of BVS• 1. A reduction in adverse events such as ST. • Because drug elution and scaffolding are

temporary and are provided by the device only until the vessel has healed, no foreign material such as nonendothelialized struts and drug polymers (potential triggers for ST) can persist long term.

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• 2.The removal, through bioabsorption, of the rigid caging of the stented vessel.

• This can facilitate the return of vessel vasomotion, adaptive shear stress, late luminal enlargement, and late expansive remodeling.

• Furthermore, this might reduce the problems of jailing of the ostium of side branches as seen with permanent metallic stent struts.

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• 3.A reduction in bleeding complications.• No requirement for long-term dual antiplatelet therapy. • This is particularly pertinent given that the elderly, who are

at the greatest risk of bleeding.• Furthermore, early discontinuation of dual antiplatelet

therapy with current metallic DES,for whatever indication, has consistently been shown to be an independent predictor of ST.– Development and validation of a prognostic risk score for

major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J. 2007;

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• 4.An improvement in future treatment options. • The treatment of complex multivessel disease frequently

results in the use of multiple long DES; for example, in the synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) trial, the average number of stents was 4, and one third of patients had 100 mm of stent implanted.

• In such cases, repeat revascularization is potentially challenging.

• The use of a BRS would mean that there would potentially be no restriction on any future percutaneous or surgical revascularization should they be needed.

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• 5.Allowing noninvasive imaging (CT/MR angio.) • Metallic stents can cause a blooming effect with these

imaging modalities, making interpretation more difficult. • The (PLLA) scaffold should not restrict the use of CT or MRI

because it is nonmetallic; once bioabsorption has been completed with a BRS, it should also not restrict the use of CT or MRI

• Noninvasive imaging follow-up could therefore become an alternative to invasive imaging followup.– Artifact-free coronary magnetic resonance angiography and

coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent. Circulation. 2005

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• 6.Reservoir for the local delivery of drugs and genes.

• Because the duration of bioresorption is modifiable, according to the type of polymers/copolymers, a tuned elution of multiple drugs can potentially be achievable (eg, early elution of antiproliferative agent from a coated polymer and long-term elution of an antiinflammatory or other agent from the backbone polymer).

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• 7.Elimination of the concern that some patients have at the thought of having an implant in their bodies for the rest of their lives.(young individuals)– Ormiston JA, Serruys PW. Bioabsorbable

coronary stents. Circ Cardiovasc Interv. 2009;2:255–260.

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• VASCULAR REPARATIVE THERAPY • On Premise that scaffolding & drug are only required on a

temporary basis following coronary interventions. • Several studies support this concept and indicate that there

is no incremental clinical benefit of a permanent implant over time.

• The use of Absorb eliminates the presence of a mechanical restraint and offers the potential of restoring natural vessel reactivity. – Incidence of restenosis after successful coronary angioplasty: a

time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation, 1988.

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• While stent performance is characterized by a single phase (Revascularization), the performance of Absorb is governed by three distinct phases: – Revascularization– Restoration– Resorption.

• Together, these phases of Absorb performance deliver VRT

© 2010 Abbott Laboratories Pipeline product. Currently in development at Abbott Vascular. Not available for sale.

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What is Required of a Fully Bioresorbable Scaffold to Fulfill the Desire for ‘Vascular Restoration Therapy’?

Revascularization Restoration Resorption

0 to 3 months 3 to ~6-9 months + ~9 months +

Performance should mimic that of a standard DES

Transition from scaffolding to discontinuous structure

Implant is discontinuous and inert

• Good deliverability

• Minimum of acute recoil

• High acute radial strength

• Controlled delivery of drug to abluminal tissue

• Excellent conformability

• Gradually lose radial strength

• Struts must be incorporated into the vessel wall (strut coverage)

• Become structurally discontinuous

• Allow the vessel to respond naturally to physiological stimuli

• Resorb in a benign fashion

© 2010 Abbott Laboratories Pipeline product. Currently in development at Abbott Vascular. Not available for sale.

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What is Required of a Fully Bioresorbable Scaffold to Fulfill the Desire for ‘Vascular Restoration Therapy’?

1 3 6 2 Yrs

Full Mass Loss & Bioresorption

Mos

Platelet Deposition

Leukocyte Recruitment

SMC Proliferation and Migration

Matrix Deposition

Re-endothelialization

Vascular Function

Forrester JS, et al., J. Am. Coll. Cardiol. 1991; 17: 758.

Revascularization Restoration Resorption

Everolimus ElutionMass Loss

Support

Oberhauser JP, et al., EuroIntervention Suppl. 2009; 5: F15-F22.

• Vessel Remodeling • Through the use of the imaging modality intravascular

ultrasound (IVUS), data from the ABSORB Cohort B trial, reveals an increase in lumen area between 6 months and 2 years.

• As Absorb resorbs, the vessel segment becomes unconstrained and there is the potential for lumen gain.

• Vasomotion • As Absorb resorbs, the treated vessel segment is able to

react to changes in blood flow and physiological stimuli that may occur with exercise or certain drugs.

• By no longer supporting or caging the vessel, there is the potential for allowing the vessel to respond naturally to physiological stimuli, which could provide unique benefits.

• Restoration to a More Natural State with Absorb

• Another appealing long-term benefit of Absorb is the possibility of progressive restoration of Absorb-treated vessel segments to a more natural state as the polymeric scaffold undergoes degradation. – Restore vasomotor tone for regulation of coronary blood

flow – Restore vessel compliance and cyclic strain in response to

pulsatile flow – Enable adaptive shear stress, allowing the vessel to regain

its ability to maintain quiescent homeostasis – Permit accommodative, beneficial remodeling

Importance of Respecting Natural Vessel Curvature

Long-term flow disturbances and chronic irritation can contribute to adverse eventsGyöngyösi, M. et al. J Am Coll Cardiol. 2000;35:1580-1589.

Wentzel, J. et al. J Biomech. 2000;33:1287-1295.

91°

88°

Stiff Metal Stents BVS (Cohort B case)

Pre BVS Post BVS

Serruys, P. , TCT 2009

BVS appears to maintain natural vessel curvature at implantation; long-term, scaffold is fully resorbed

MECHANICAL CONDITIONING IN PRE-CLINICAL MODEL (PORCINE)

Tests were performed by and data are on file at Abbott Vascular.

Transmission Electron Microscopy (TEM) Smooth Muscle -Actin

Dense bodies

At 36 months, SMCs are well organized and have undergone transformation to a functional, contractile phenotype

Mechanical conditioning

• Fourth revolution • All these problems promise to be solved with the advent of

fully biodegradable scaffolds.• Offers the possibility of

– Transient scaffolding of the vessel to prevent acute vessel closure and recoil &

– Transiently eluting an antiproliferative drug to counteract the constrictive remodeling and excessive neointimal hyperplasia

• Development of BRS• The efforts to create BRS started 20 years ago. • The first experimental studies using a nonbiodegradable

polyethylene-terephthalate braided mesh stents in porcine animal models were published in 1992.

• In 1996, it was reported in porcine coronary arteries negative consequences after implantation of the Wiktor stent coated with 5 different types of biodegradable polymers ,all resulting in marked inflammation leading to neointimal hyperplasia and/or thrombus formation. – Development of a polymer endovascular prosthesis and its

implantation in porcine arteries. J Interv Cardiol. 1992;5:175–185.

• Lincoff et al -- high-molecular-weight (321 kDa) PLLA was well tolerated and effective, where as a stent coated with low-molecular-weight (80 kDa) PLLA was associated with an intense inflammatory neointimal response.

• They also proved the feasibility of drug elution from the PLLA, although no suppression of neointimal hyperplasia was reported. -Lincoff AM, Schwartz RS, van Beusekom HM. Circulation. 1996;94:1690 –

1697.

• In 1998, Yamawaki et al reported that in the porcine model the fully biodegradable PLLA stent with tyrosine kinase inhibitor efficiently suppressed proliferative stimuli caused by balloon injury. – Yamawaki T, Shimokawa H, Kozai T. J Am Coll Cardiol. 1998;32:780 –

786.

The technology failed to develop an ideal polymer that could limit inflammation and restenosis and secondarily because of the growing

interest in metallic DES.

• The key mechanical traits for ideal material :

– High -elastic moduli to impart radial stiffness,– Large -break strains to impart the ability to withstand

deformations from the crimped to expanded states, and– Low -yield strains to reduce the amount of recoil and

overinflation necessary to achieve a target deployment.

• Numerous different polymers are available, each with different chemical compositions, mechanical properties, and subsequently bioabsorption times

• TYPES OF BVS

• first absorbable stent implanted in humans,is constructed from poly-L-lactic acid (PLLA).

• In the absorption process, hydrolysis of bonds between repeating lactide units produces lactic acid that enters the Krebs cycle

• first-in-man prospective, nonrandomized clinical trial that enrolled 50 patients a 4yr follow-up of all the patients (100%) revealed a low complication rate.

• loss index (late loss/acute gain) was 0.48 mm, which was comparable to BMS, and demonstrated for the first time that

• BRS did not induce an excess of intimal hyperplasia Focus is now on a peripheral application

Tamai H, Igaki K, Kyo E. Initial and 6-month results of biodegradable

poly-L-lactic acid coronary stents in humans. Circulation. 2000

IGAKI-TAMAI BIOABSORBABLE STENT

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• Despite these impressive results, the failure of the stent to progress was related primarily to the use of heat to induce self-expansion. There were concerns that this could cause necrosis of the arterial wall, leading to excessive intimal hyperplasia or increased platelet adhesion, leading to ST.

• Biodegradable peripheral Igaki-Tamai stents PERSEUS study,the stent became available in Europe for peripheral use;– Biamino G, Schmidt A, Scheinert D. Treatment of SFA lesions

with PLLA biodegradable stents: results of the PERSEUS Study. J Endovasc Ther. 2005;12:5.

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• The degradation of Mg produces an electronegative charge that results in the stent being hypothrombogenic.

• Although the stent was completely absorbed within 2 months, radial support was lost much earlier so that, perhaps within days, there was an insufficient radial strength to counter the early negative remodeling forces after PCI.

• In addition, it did not release an antiproliferative drug to counter the intimal hyperplastic response to stenting.

• Consequently, there was a high restenosis rate at 4 months of almost 50% and target vessel revascularization at 1 year was 45%

PROGRESS AMS trial: Lancet. 2007;369:1869 –1875.

BIOABSORBABLE MAGNESIUM STENT

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• It provides prolonged mechanical stability, which has been achieved by using a different magnesium alloy that has not only a higher collapse pressure of 1.5 bar compared with 0.8 bar for AMS-1 but also a slower degradation time.

• In addition, the stent surface has been modified; the stent strut thickness has been reduced

• and the shape of the strut in cross section has been altered from rectangular to square (improving radial strength).

• These changes have prolonged scaffolding and stent integrity, improved radial strength, and reduced neointima proliferation in animal models.

AMS-2

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• The AMS-3 stent (drug-eluting AMS) is designed to reduce neointimal hyperplasia by incorporating a bioresorbable matrix for controlled release of an antiproliferative drug onto the AMS-2 stent.

• Research is currently focused on establishing the ideal drug kinetics; initial animal trials have demonstrated a sustained antiproliferative effect at 1 month.

• A new clinical program resumed in July 2010.

AMS-3 stent

Stent: Bioabsorbable

Magnesium AlloyDiscrete Drug

Delivery Reservoirs

Drug:Pimecrolimus

Carrier:

Bioresorbable Matrix

Modifications

BIOTRONIK DREAMS

Pimecrolimus-Eluting Stent System

REVA Endovascular Study of aBioresorbable Coronary Stent (RESORB)

study

• More robust polymer, a spiral slide-and-lock mechanism to improve clinical performance, and a coating of sirolimus (80% is eluted by 30 days and 95% by 90 days.)

• The RESTORE Trial (Pilot Study of the ReZolve Sirolimus-Eluting Bioresorbable Coronary Scaffold) is evaluating the safety and performance of the first-generation ReZolve scaffold in 26 patients that were enrolled 2011 & 2012-F/u-5yrs.

• The ReZolve2 scaffold, a lower profile and sheathless version of the original ReZolve scaffold, is being evaluated clinically in the RESTORE II TriaL (IN 2013)

ReZolve stent.

Poly (Anhydride Ester) Salicylic Acid: The IDEAL Stent

both antiinflammatory and antiproliferative properties.

• Whisper trial, a stent with strut thickness of 200 m and a crossing profile of 2.0 mm with a stent-toartery coverage of 65% was implanted in 8 patients.

• Because of higher-than-expected intimal hyperplasia, a subsequent design iteration will have thinner struts, a higher dose of sirolimus, and a lower percent wall coverage.

• The BVS stent design is characterized by a crossing profile of 1.4 mm with circumferential hoops of PLLA.

• The struts are 150 m thick and are either directly joined or linked by straight bridges.

• Both ends of the stent have 2 adjacent radiopaque platinum markers. The radial strength = BMS.

• The backbone of the BVS device is made of semicrystalline polymer called PLLA.

• The coating consists of poly D,L-lactide acid (PDLLA), which is a random copolymer of D and L-lactic acid with lower crystallinity than the BVS backbone.

• The coating contains and controls the release of the antiproliferative drug everolimus.

Everolimus-Eluting PLLA Stent: BVS Scaffold

BIORESORBABLE POLYMER

Everolimus/PDLLA Matrix Coating

• Thin coating layer• Amorphous (non-

crystalline)• 1:1 ratio of

Everolimus/PLA matrix• Conformal Coating, 2-4

m thick• Controlled drug release

PLLA Scaffold• Highly crystalline• Provides device

integrity• Processed for increased

radial strength

Polymer backbone

Drug/polymer matrix

Absorb Design Elements

• Two versions of the stent have been developed.• The design of the BVS stent Revision 1.0 consists of

circumferential out-of-phase zigzag hoops of PLLA with a strut thickness of 150 μm, linked either directly or by straight bridges, with two radiopaque markers at each end which enable a good visualization on angiography.

• The BVS Revision 1.1 consists of the same polymer, but different process refinements allow the stent to increase its radial force, provide radial support for a longer time, and, consequently, avoid the slightly higher, but nonsignificant, recoil shown by QCA.

• MCUSA- This stent version has a different strut distribution, reducing the maximum circular unsupported cross-sectional area, in contrast to BVS Revision 1.0.

• It is currently under evaluation in the Cohort B of the non-randomized ABSORB trial (NCT00856856) in 80 patients.

•Elixir’s proprietary fabrication and processing technology allows for excellent flexibility, deliverability, and well-apposed struts that provide substantial radial strength with low recoil. •Performance has been evaluated in clinical studies and has been shown to provide excellent mechanical support, even in highly tortuous vessels.•More sizes.

• Bioresorption Process of PLLA• In the PLA family of polymers, molecular-weight

degradation occurs in vivo predominantly through hydrolysis, which is a bimolecular nucleophilic substitution reaction that can be catalyzed by the presence of either acids or bases.

• The hydrolysis reaction in which water catalyzes a chain scission event at an ester bond.

• From chemical standpoint, resorbable implants undergo 5 stages

• First stage is hydration of polymer.Starting at Hydrophilic (carboxylic acid )end .

• second phase is depolymerization by hydrolysis. reduction in molecular weight.

• Third stage- loss of mass (starts to fragment into segments of low-weight polymer (radial strength reduces) .

• The fourth phase is assimilation or dissolution of the monomer by Phagocytes

• Fifth-L-lactate is changed into pyruvate, which eventually enters the Krebs cycle and is further converted into carbon dioxide and water.

– Handbook of Biodegradable Polymers. Boca Raton, FL: CRC

Press; 1998.

REACTION PATHWAY FOR HYDROLYTIC DEGRADATION OF THE PLA FAMILY OF POLYMERS.

• Poly-L-lactide is a semicrystalline polymer. The ordered polymer chains constitute the crystalline component of the semicrystalline polymer, and the random polymer chains form the amorphous segment

• In other words, the semicrystalline PLLA polymer is made of crystal lamella (regions with high concentrations of polymer with crystalline structure) interconnected by amorphous tie chains binding the crystallites

• Because the amorphous regions are less packed and therefore are more accessible to water, more susceptible to hydration.

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Echogenicity analysis of BVS 1.0 after the procedure (BL) and at the 6-month follow-up (FU). The polymeric strut was highly echogenic at baseline and thus colored green by the dedicated echogenicity software. At 6 months, most struts are no longer hyperechogenic (absence of green spots and prevalence of red background), suggesting that the bioresorption has already occurred

Sequential changes in strain assessed by IVUS palpography. Prestenting shows a long area of high strain (color coded for strain ranging from 1% to 2%); on a single cross section, the high-strain region is located at the shoulder (7 to 8 o’clock) of the plaque. After scaffolding, abolition of this high strain spot is documented. At 6 months and 2 years after scaffolding, high strain remained absent.

IVUS virtual histology (IVUS-VH) images after the procedure and at 6 and 24 months after implantation of BVS 1.0, respectively. With IVUS-VH, the struts were misclassified as dense calcium after the procedure and at 6 months, whereas at 24 months, they were no longer visible.

• Regulatory Status • Absorb received CE Mark on December 14, 2010

for a limited number of sizes. Additional sizes have received CE Mark on August 13, 2012

• Implantation of Absorb • Absorb is implanted into the patient’s coronary arteries via

a percutaneous intervention. The procedure of implanting an Absorb should only be performed by physicians who have received appropriate training. The implantation procedure of an Absorb is similar to a metallic stent; however, additional attention is needed to ensure:

• Careful selection of the scaffold diameter for the target lesion reference vessel diameter

• Thorough lesion preparation prior to scaffold implantation to optimize scaffold deployment

• Safe advancement of Absorb across the lesion.

• Clinically Tested BRS

• ABSORB Cohort A • A prospective, open-labeled, non-randomized, multi-center

trial .• The First in Man ABSORB trial represents the first clinical

evaluation of the safety and performance of the BVS Cohort A device. (n=30)

• In the ABSORB Cohort A trial, among 29 patients, the 5-year MACE rate was low at 3.4%, due to only one ischemic MACE event (non-Q wave MI.) that was reported within the first 6 months of the trial.

• There were no incidences of (ID-TLR). • Additionally, there were no incidences of scaffold

thrombosis or cardiac death out to 5 years

ABSORB Trial Designs

ABSORB Cohort A

• N = 30; 6 sites* (Europe, New Zealand)

• Clinical follow-up schedule:– 30 days, 6 months, 12 months, annually to 5 years

• Imaging schedule:

QCA, IVUS, OCT, IVUS VH Baseline6 18 24

MonthsMonthsMonths

MSCT(optional)

*Patients were enrolled in only 4 of 6 sites

Derived from Serruys, PW., AHA 2009.

BaselineM2 1.0 mm/s

6 Month Follow UpM3 1.0 mm/s

2 Year Follow UpC7 20 mm/s

ABSORB Cohort A Side Branch Preservation by Angio, and OCT

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ABSORB Cohort ATemporal Lumen Dimensional Changes, Per Treatment

ABSORBCohort A

Scaffold Area

11.8% 17.2%

Post-PCI 6 Mos. 24 Mos.n = 25

Late Loss = 0.43 mm

MLA = 5.09mm2 3.92mm2 4.34mm2

Late lumen loss at 6 months mainly due to reduction in scaffold area

Very late lumen enlargement noted from 6 months to 2 years

n = 25 n = 19

BVS Device Optimization Objectives

Cohort A

Cohort B Photos taken by and on file at Abbott Vascular.

• More uniform strut distribution

• More even support of arterial wall

• Lower late scaffold area loss―Maintain radial strength for at least 3

months

• Storage at room temperature

• Improved device retention

• Unchanged:– Material, coating and backbone– Strut thickness– Drug release profile– Total degradation Time

• More uniform strut distribution

• More even support of arterial wall

• Lower late scaffold area loss―Maintain radial strength for at

least 3 months

• Storage at room temperature

• Improved device retention

• Unchanged:– Material, coating and

backbone– Strut thickness– Drug release profile– Total degradation Time

• ABSORB Cohort B • The ABSORB Cohort B trial had two subgroups (B1 and B2)

for follow-up purposes as determined by protocol.• 3-year follow-up data is available for Group B1 (n=45), and

was recently reported at the TCT 2012 meeting in Miami, Florida, USA

• In the ABSORB Cohort B trial, among 100 patients There has been no reported scaffold thrombosis or cardiac death in the ABSORB Cohort B trial to date, the 2-year ischemic driven MACE rate was 9.0%, due to 3 non-Q wave MIs and 6 ischemia driven target lesion revascularizations .

KM estimate of MACE rate in patients treated with Absorb BVS (ABSORB Cohort B, n=101) vs. patients treated with a single 3.0x 18 mm metallic XIENCE V

(SPIRIT FIRST+II+III, n=227)

• Clinical Procedure Success 98% • ABSORB B Group 1 –MACE rate of 6.8% at 2 and 3

years (1 peri-procedural MI & 2 TLR)• No additional MACE between 1 year and 3 years• No scaffold thrombosis event• Clinical data very comparable to Xience-V data

from SPIRIT I-III

CONCLUSION

• ABSORB EXTEND • The ABSORB EXTEND trial is a continuation in the

assessment of the safety and performance of Absorb in a larger study.

• The lesions are longer than in the ABSORB Cohort A and Cohort B trials.

• Planned overlap of Absorb scaffolds during the procedure • ABSORB EXTEND is a prospective, single-arm, open-label

clinical study that is planned to enroll up to 1,000 subjects at up to 100 global sites.

• Clinical follow-up is being planned on all subjects enrolled in the trial for up to 3 years.

• ABSORB II: European Randomized Control Trial • ABSORB II is a randomized, active-controlled, single-

blinded, multicenter clinical trial and will enroll approximately 501 subjects in 40 sites in Europe.

• Aim: primary endpoints of vasomotion and change in lumen diameter.

• Subjects will be clinically followed at 30 days, 180 days, 1, 2, and 3 years post-procedure

• Imaging studies will include angiography, IVUS/IVUS-virtual histology, Lipiscan, (MSCT), all at 2 years with the option of 3 years pending 3-year results from the ABSORB Cohort B trial.

• ABSORB III: US Randomized Controlled Trial for US Approval

• The ABSORB (RCT) is designed to evaluate the clinical safety and efficacy of Absorb for US approval. in comparision with the XIENCE family.

• The ABSORB III is a prospective, randomized, active-control, single-blind, multi-center clinical trial that will register approximately 2,250 subjects in up to 220 sites in the US and outside the US.

• A cohort of approximately 2,000 patients will be used for approval of Absorb by the United States Food and Drug Administration (FDA). Enrollment is planned for 2012/2013, pending US FDA approval.

• ABSORB IV: Randomized Controlled Trial for Landmark Analysis

• The ABSORB IV trial is similar in design to ABSORB III, and designed to enroll approximately 2,500 to 3,000 patients with clinical follow-up out to 5 years.

• Clinical data from both ABSORB III and IV will be pooled to enable a landmark analysis for 4,500 to 5,000 subjects to show superior safety and benefits of Absorb compared to XIENCE.

• ABSORB Japan: Randomized Controlled Trial • ABSORB Japan is a prospective, single-blind, multi-center

randomized 2:1 trial of Absorb: XIENCE V involving up to 400 subjects in up to 35 Japanese sites to seek Japanese approval.

• The patient eligibility criteria are similar to the ABSORB III study.

• The primary endpoint is 1 year target lesion failure (TLF) showing non-inferiority to XIENCE, with each subject returning for at least one imaging follow-up involving one of the following modalities: angiography, IVUS, and/or OCT.

• ABSORB China: Randomized Controlled Trial • ABSORB China is a prospective, single-blind, multi-center

randomized 1:1 trial of Absorb: XIENCE V involving approximately 400 subjects in up to 25 Chinese sites.

• The patient eligibility criteria are similar to ABSORB III.• The primary endpoint is 9 months angiographic

endpoint of in-segment late loss, showing non-inferiority to XIENCE, for Chinese approval.

• Patients will subsequently return only for clinical follow-up out to 5 years.

• ABSORB FIRST: International Post-Market Registry • The ABSORB FIRST Registry is designed to evaluate the safety

and clinical outcomes of Absorb in daily use in patients with de novo lesions in previously untreated vessels.

• The ABSORB FIRST Registry is a single arm, prospective, international post-market registry of patients with de novo lesions in previously untreated vessels treated with Absorb per IFU (on-label use).

• The ABSORB FIRST Registry will enroll a minimum of 10,000 patients in approximately 300 sites throughout multiple countries worldwide where Absorb has regulatory approval and is commercially available. Enrollment will be initiated in phases distributed over various regions/geographies worldwide. One year follow-up will be conducted on all patients. Annual follow-up visits will be conducted in subgroups of 1,000 patients each from 2 to 4 years.

TCT 2013

• First, the optimal duration of scaffolding with drug-elution should be further elucidated.

• In both AMS-1 magnesium stent and BVS 1.0 scaffolds, late scaffold shrinkage was one of major contributors to luminal loss.

• In a previous study with serial IVUS imaging after angioplasty or directional coronary atherectomy,some positive remodeling occurred early after the procedure up to 1 month, whereas the negative remodeling (eg, decrease in external elastic lamina) occurred at 1 to 6 months

Future Perspectives

• This suggests that the need to prevent negative remodeling is necessary at least until 6 months.

• This could be achieved by tuning the biodegradation speed in changing the molecular weight of the polymer and increasing its crystallinity,thereby prolonging the mechanical integrity of the scaffold.

• 2.BRS technologies without drug elution such as REVA and AMS-1 were associated with high TLR rates.

• More specifically, in the AMS-1 trial, 45% of late luminal reduction was attributed to neointimal hyperplasia at 6 months.

• These results suggest that the elution of antiproliferative agents might be indispensable to make the BRS clinically applicable and efficient at medium term.

• 3.The clinical advantage of BRS technology over the currently available DES needs to be further investigated.

• BVS and Mg stents showed the recovery of responsiveness of the treated vessel to vasoactive agents such as nitroglycerin.

• The restoration of vasomotion can indirectly stand for the completeness of vessel healing; however, it is still unclear what the real clinical advantage of this phenomenon is.

• In patients with early atherosclerosis, the presence of abnormal endothelial function was associated with poor outcomes or more frequent angina.

• 4.A potential drawback of this new technology is strut fracture.

• Unlike metallic stents, the polymeric devices have inherent limit of expansion and can break as a result of overdilatation.

• In an anecdotal case from the ABSORB cohort A, a 3.0-mm scaffold was overexpanded with 3.5-mm balloon, which resulted in strut fracture as documented with OCT.

• The clinical significance of such a case, evidenced only by OCT, needs to be further elucidated, but undoubtedly fracture should be avoided by respecting the nominal size of the scaffold.

• 5.Data transferability might be another issue from the regulatory perspective.

• In conventional metallic stents, the essential component was platform, coating, and drug.

• When it comes to BRS polymeric stents, even with the same PLLA and design, the speed of biodegradation/bioresorption can be different according to the manufacturing process of PLLA.

• For example, molecular weight can influence the degree of inflammation, as shown in a previous preclinical study.

• Although the safety of PLLA is inferred from other medical application such as orthopedics, orbital floor defects, and spinal surgery, each scaffolding device implanted in the coronary circulation still needs to be tested in terms of biocompatibility.

conclusion• This technology is currently still in its

infancy. • However, the return of normal vascular

function after bioabsorption has opened a new horizon aimed at promoting “vascular restoration therapy.”

• This therapy is an exciting development and certainly worthy of the accolade of being the fourth revolution in interventional cardiology

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