BIOABSORBABLE SCAFFOLDS/ STENT

Dr Siva SubramaniyanPGIMER &Dr.RML HospitalNew Delhi

BALLOON ANGIOPLASTY

• The invention of balloon angioplasty as a percutaneous treatment forobstructive coronary disease by andreas gruntzig in 1977 was a hugeleap forward in cardiovascular medicine and will always beremembered as a revolution in the field of revascularization

• However, the outcomes of POBA were compromised by re-narrowingof the coronary arteries due to elastic recoil, acute closure secondaryto dissection, constrictive remodelling, and neointimal proliferation.

2ND REVOLUTION- BMS

• The advent of bare metal stenting (BMS) and the landmark Belgian-Netherlands Stent Study (BENESTENT) and Stent Restenosis Study (STRESS)trials have established BMS as the second revolution in interventionalcardiology

• This technology provided a solution to acute vessel occlusion by sealing thedissection flaps and preventing recoil. The rate of subacute occlusion wasreduced to 1.5%, making emergency bypass surgery a rare occurrence.

• high incidence of in-stent restenosis

• Neointimal hyperplasia inside the stent was even more prominentthan with angioplasty, necessitating repeat treatment in numerouspatients.

• Because the vessel was now caged with metal, late luminalenlargement and advantageous vascular remodeling could no longeroccur. Another problem, namely late stent thrombosis (ST), was alsofirst described

3 revolution -DES

• Drug-eluting stents have significantly reduced in-stent restenosis andtarget lesionrevascularization (TLR) compared with BMS

• These stents still leave a permanentmetal implant inside the vesselwith potential future problems

• Vasomotion testing demonstrated abnormal vasoconstrictionresponses to acetylcholine distal to the deployed stent, suggestingthat the structure and function of the endothelium remainedabnormal

• Geometry and vasomotion altered.

BIOABSORBABLE STENT

BIOABSORBABLE STENT DESIGN

• The ideal design should have mechanical properties that are able toprovide the necessary vessel support during the required period.

• must be biocompatible, and should have an adequate degradationtime, disappearing without creating an intense inflammatoryresponse.

• Apart from that, the device has to have good deliverability, and,ideally, it should be able to carry an antiproliferative drug in order toreduce restenosis.

• Both the selection of the material and the design are going toinfluence the success of the device.

• Regarding the material, there are two possibilities that are beingtested:

- polymer-based materials that are degraded by hydrolysis, and

- absorbable metals such as magnesium-based alloys.

• Among the polymers, the one that has been used more frequently ispolylactide (PLLA), which degrades via the Krebs cycle to water andcarbon dioxide

• Both polymers and magnesium alloys are less stiff than conventionalmetallic stents, and several modifications in the material processing(such as polymer chain orientation, increases in the molecular weight,or length of the polymer chain) and strut design (thickness) arerequired to obtain an adequate radial support.

• In order to avoid inflammation or a toxic response in the vessel wallduring degradation, the device should have as little material aspossible, and the process should not occur too fast to allow anadequate response of the tissue to the products of degradation

• in order to be introduced in the catheterization laboratories,bioabsorbable devices should be easy to store (avoiding, the need forrefrigeration), should have good deliverability, an should be easy toposition in the coronary artery.

• The majority of bioabsorbable materials have low radio-opacity, butthe visualization of the device under fluoroscopy can be increased bythe use of radio-opaque markers in the balloon or in the device itself.

TYPES

• Polymer based metal based

- BVS (abbot) DREAMS 1, 2

- igaki tamai iorn

- REVA stent

- ART

- IDEAL

ABSORB BVS

ABSORB A

BVS stent (Abbott Vascular)• PLA backbone, releases everolimus (80% by 30 days)

• Struts are 150µm, radiopaque markers at either end

• ABSORB cohort A FIM trial

• 3x12 then 3x18mm BVS

• Simple lesions

ABSORB B

• Prospective, open label, single arm study

• 101 patients enrolled at 12 sites

• Device sizes: 3.0 x 18 mm

• Treatment: up to 2 de novo lesion

CONCLUSIONS

• At 2 years there were no significant differences in the clinical outcomes between the two arms:

– PoCE (all death, all MI and all revascularization)

Absorb BVS: 11.6% vs XIENCE: 12.8%, p=0.70

– DoCE/TLF (cardiac death, and TLR)

Absorb BVS: 7.0% vs XIENCE: 3.0%, p=0.07

Igaki-Tamai stent

• The Igaki-Tamai PLLA coronary stent was the first fully bioresorbablestent to be implanted in humans in 1998 with complete degradationtaking 18 to 24 months.

• Tamai stent is a self- expandable when heated, consequently contrastdye at 80C is used for balloon inflation. Expansion continues at bodytemperature until dilation and vessel wall resistance reachequilibrium.

• In 2000, Tamai et al. reported initial results from 15 patients in whom25 stents were successfully implanted.

• During the first 6 months, minimal lumen diameter decreased and thenconstantly increased to 2.22 ±0.56 mm at the 3-year follow-up.

• IVUS analysis showed almost constant stent cross-sectional area after 1, 2,and 3 years, whereas minimal lumen cross sectional area decreased from5.44 mm2 immediately after the procedure to 3.64 mm2 after 6 months,then increased to 5.18 mm2 after 3 years.

• During the follow-up period, a total of 14 TLRs, 1 acute scaffold thrombosisand 1 very late scaffold thrombosis, 1 lesion-related myocardial infarction,and 1 cardiac death were noted.

• Accordingly, cumulative TLR rates per patient were

- 16% after 1 and 3 years,

- 18% after 5 years, and

- 28% after 10 year

Limitations

• Implantation requires an 8-French guiding catheter.

• The heated contrast dye may cause vessel wall injury.

METAL STENTS

Magnesium-based metallic bioresorbablescaffolds• The PROGRESS-AMS clinical trial was a non-randomized, prospective,

multi-center trial that was designed to assess the efficacy and clinicalsafety of the absorbable magnesium stent (AMS-1)

• 63 patients underwent revascularization with an AMS in vessels withreference diameters of 3 to 3.5 mm and average lesion lengths of <13mm.

• Coronary angiography and intravascular ultrasound imaging wascompleted post-procedure and at 12-month follow-up.

• The primary endpoint of this feasibility study was cardiac death, non-fatal myocardial infraction, or target lesion revascularization at 4months

MACE - 24%

TLR - 39.7% at 4 months.

• There were no events of cardiac death, myocardial infraction, or stentthrombosis.

• The angiographic in-stent lumen loss was 1.08 + 0.49 mm at 4months, and IVUS imaging suggested that most of the struts werefully resorbed with only strut remnants being visibly embedded intothe intima

• Although this study demonstrated the safety of AMS-1 with noreported death, myocardial infarction or stent thrombosis, imagingand clinical results raised concerns over the further use of thisgeneration in coronary interventions as increased neo-intimalformation and vessel recoil became evident.

• AMS 1 - metal

• AMS 2 – modified structure

• AMS 3 or DREAMS 1 - pacitaxel

• DREAMS 2 - sirolimus

DREAMS stents

• It is a drug-eluting absorbable metal scaffold (DREAMS, Biotronik,Bülach, Switzerland) is made of a magnesium alloy, coated with amatrix of absorbable polymer PLLA carrier

• antiproliferative drug paclitaxel

• The paclitaxel was completely released in a controlled manner for 3months. The scaffold absorption is complete within 1 year post deviceimplantation

BIOSOLVE-I

• The BIOSOLVE-I clinical trial was a prospective, non-randomized,multicenter, first-in-man trial assessing the safety and efficacy ofDREAMS in non-complex coronary lesions.

• Forty-six patients with stable/unstable angina or silent ischemia weretreated with 47 stents.

• Imaging follow-up included angiography and IVUS at 6 and 12 monthswith clinical assessment scheduled at 1, 6, 12, 24 and 36 month

RESULTS• The angiographic in-stent lumen loss was 0.64 + 0.50 mm at 6-months

and 0.52 + 0.49 mm at 1 year, which represents a 61% reductioncompared to the 4-month results of AMS-1.

• Serial IVUS imaging confirmed the angiographic observations showingin-scaffold area obstruction of only 6.24% (p , 0.0001) at 1 year,attributed to neo-intimal formation with extra-scaffold plaque areaincrease.

• TLR rates reached 7% with no reported episodes of stent thrombosisthroughout the 3-year follow-up

• The second-generation DREAMS device has been recently developed.- sirolimus instead of paclitaxel,

- carries two tantalum radiopaque markers at both ends

- delivers higher bending flexibility with slower resorptionrate compared to the previous generation.

• The BIOSOLVE-II study was designed to assess the safety, efficacy andfeasibility of this generation in 120 patients

CONCLUSION FROM BIOSOLVE

• BIOSOLVE-I and -II added to the ever-expanding evidence to supportBVS by assessing the safety and efficacy of two generations of drugeluting metallic scaffolds.

• The first drug eluting magnesium based metallic scaffold in BIOSOLVE-I showed similar safety findings to PROGRESS-AMS in that it could besafely and successfully implanted in patients without an associatedrisk for cardiac death or stent thrombosis.

• The addition of drug-elution with paclitaxel further improved therates of target lesion revascularization from 26.7% to 4.7%.

Tyrosine Polycarbonate: The REVA Stent

• The ReZolve devices (REVA Medical) are made of desaminotyrosinepolycarbonate, which is bioresorbable and radio-opaque polymer.

• REVA’s ‘slide & lock’ mechanism is based on a ratchet system where,as the stent is deployed in an artery by use of a balloon catheter, each‘tooth’ on the sliding part passes through a bracket in the stent andgets locked to preventing it from going back.

RESORB trail

• RESORB Study (REVA Endovascular Study of a Bioresorbable CoronaryStent) trial enrolled 30 pts at multiple sites in Germany and Brazil

• Non-randomized study

• Endpoints

• Primary – 30 days MACE

• Secondary – 6 mths QCA & IVUS derived parameters for restenosis.

• Clinical follow up

- At discharge, 2 wks, 1, 6, 12, 24, 36, 48, 60 months.

- Subset of pts will be returning for long term angiographic follow up

• 6 months follow up showed absence of any significant vessel recoil.

• Unfortunately higher-than-anticipated rate of TLR (66.7%) were seenbetween 4 and 6 months.

• The degree of neointimal hyperplasia was similar to that of a BMS

• Redesigning of the stent ensued, resulting in the second-generationReZolve stent

• More robust polymer, a spiral slide-and-lock mechanism to improveclinical performance, and a coating of sirolimus

• The RESTORE Trial evaluating the safety and performance of the 1st-generation ReZolve scaffold

• One yr follow up showed late lumen loss comparable to that of DES.

• The ReZolve2 scaffold, a lower profile and sheathless version of theoriginal ReZolve scaffold evaluated clinically in the RESTORE II TrialReZolve stent

IDEAL stent

• The IDEAL BRS is a sirolimus-eluting device with the backbone ofpolylactide anhydride mixed with a polymer of salicylic acid and sebacicacid linker.

• The presence of salicylic acid provides anti-inflammatory properties to thedevice. The IDEAL BRS was tested in the WHISPER FIM trial in 2008. Thefirst-generation device required an 8-Fr guide catheter and poorlysupressed neointimal proliferation due to inadequate drug dosing andrapid release of the sirolimus.

• The second-generation IDEAL BioStent with a higher sirolimus dose, slowerdrug-release, and a 6-Fr compatible delivery system is currently undergoingpreclinical evaluation

BENEFITS

Prevention of very late thrombotic events

• One of the major hopes with BRS is that, after bioresorption, the treated segment of the vessel will return to normal function.

• will be free of a permanent foreign body, thus minimizing the risk of very late thrombotic events and need for long-term DAPT.

• Bioresorbable scaffolds can potentially eliminate certain factors contributing to the late stent thrombosis including

- delayed endothelialization,

- chronic inflammatory response, and localized hypersensitivity reaction.

- return of vessel vasomotion,

- adaptive shear stress,

- late luminal enlargement, and late expansive remodelling

- reduce the problems of jailing of the ostium of side branches as seen with permanent metallic stent struts

• Metallic stents do not seem to fully protect the vessel fromneoatherosclerosis or plaque progression.

• It is postulated that BRS implantation may provide a symmetricaluniform fibrous neointimal layer which along with late lumenenlargement and lack of any permanent vascular prosthesis may helpto stabilize and passivate vulnerable plaques and thus prevent futurecardiovascular events

Preservation of vascular geometry

• The metallic stents can alter vessel geometry and biomechanics, andresultant chronic irritation and flow disturbances may contribute toneointimal proliferation and adverse events.

• Bioresorbable scaffolds offer the potential to preserve vasculargeometry. ABSORB BVS is more conformable than metallic stents andproduces less alteration in vessel angulation and curvature.

• It has also been shown that, at 6- to 12-month follow-up, ABSORBBVS tends to restore the coronary configuration to pre-implant level,whereas coronary geometry remains permanently altered afterimplantation of permanent metallic stents

Restoration of vascular physiology

• A number of studies using metallic DES have reported abnormalvasomotion in the segment distal to the DES, which may restrict thedistal flow and predispose to late stent thrombosis.

• Bioresorbable scaffold technology has been described as vascularreparative therapy

• after complete bioresorption, BRSs promise the return of dynamicvasomotion, pulsatility, distensibility, and mechanotransduction, i.e.the ability to translate mechanical forces into chemical signals (e.g.nitric oxide and prostacyclins).

• In the ABSORB Cohort A, evaluation of the scaffolded segmentfollowing intraluminal administration of acetylcholine suggested that,at 2 years, the scaffolding function of the polymeric struts hadcompletely disappeared and the scaffolded segment could exhibitvasomotion.

FUTURE TREATMENT

• 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, by means of eitherpercutaneous or surgical revascularization, is potentially challengingbecause of the metallic cages formed by previously implanted DES

• The use of a BRS would mean that there would potentially be norestriction on any future percutaneous or surgical revascularizationshould they be needed.

REDUCTION IN BLEEDING

• Once bioabsorption of the temporary scaffold has been completed,there will potentially be no requirement for long-term dualantiplatelet therapy.

• This is particularly pertinent given that the elderly, who are at thegreatest risk of bleeding, are increasingly receiving invasive treatmentfor ischemic heart disease.

• Furthermore, early discontinuation of dual antiplatelet therapy withcurrent metallic DES, for whatever indication, has consistently beenshown to be an independent predictor of ST.

IMAGING

• Allowing the use of noninvasive imaging techniques such ascomputed tomography (CT) angiography or magnetic resonanceimaging for follow-up.

• Presently, metallic stents can cause a blooming effect with theseimaging modalities, making interpretation more difficult.

• The poly-L-lactic acid (PLLA) scaffold should not restrict the use of CTor magnetic resonance imaging

PSYCHOLOGICAL EFFECT

• Elimination of the concern that some patients have at the thought ofhaving an implant in their bodies for the rest of their lives.

DRAWBACKS

• BVS – still in infant level

• All BVS scaffolds tested in uncomplicated lesion, not in

- angulated - complex

- post cabg graft

- left main, bifurcation, chronic total occlusion, small vessel, long lesion and calcific lesion.

• A potential drawback of this new technology is strut fracture. Unlikemetallic stents, the polymeric devices have inherent limit ofexpansion and can break as a result of overdilatation.

• Safety of PLLA

• Duration of antiplatelets ?

CONCLUSION

• Treatment of noncomplex coronary lesions with the absorbeverolimus-eluting bioresorbable vascular scaffold was within theprespecified range for noninferiority to the xience everolimus-elutingcobalt–chromium stent with regard to target-lesion failure at 1 year

Drug-Eluting BRS Under Preclinical Investigation

• ON-AVS - differs from other drug-eluting BRS as it incorporates CD34+antibodies for endothelial progenitor cell capture. This aims to promoteand achieve faster endothelialisation. The drug eluted is sirolimus.

• The xinsorb br (huaan biotechnology group, laiwu, china) is made of pllaand elutes sirolimus

• The SAHAJANAND BRS (sahajanand medical technologies, pvt, ltd, india),the avatar brs (s3v; vascular technologies pvt. Ltd., Bangalore, karnataka,india)

CONCLUSION

• There is no doubt that after percutaneous coronary intervention theinjured vessel requires scaffolding

• However, there is no consensus on how long this scaffolding isrequired.

• The currently available metallic DES have demonstrated their abilityto provide a permanent scaffolding and to prevent restenosis, butlegitimate safety concerns have emerged

• However, the return of normal vascular function after bioabsorptionhas opened a new horizon aimed at promoting “vascular restorationtherapy.”

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

July 5, 2016

• “The FDA’s approval of the Absorb GT1 BVS offers a new treatmentoption for individuals who are candidates for angioplasty, but wouldprefer an absorbable device rather than a permanent metalliccoronary stent,”

THANK YOU