history, advances in the development of biovascular scaffolds

1. BIOABSORBABLE
SCAFFOLDS/ STENT
Dr Siva Subramaniyan
PGIMER &Dr.RML Hospital
New Delhi

3. 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 will always be
remembered as a revolution in the field of revascularization
• However, the outcomes of POBA were compromised by re-narrowing
of the coronary arteries due to elastic recoil, acute closure secondary
to dissection, constrictive remodelling, and neointimal proliferation.

4. 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 interventional
cardiology
• This technology provided a solution to acute vessel occlusion by sealing the
dissection flaps and preventing recoil. The rate of subacute occlusion was
reduced to 1.5%, making emergency bypass surgery a rare occurrence.
• high incidence of in-stent restenosis

5. • Neointimal hyperplasia inside the stent was even more prominent
than with angioplasty, necessitating repeat treatment in numerous
patients.
• Because the vessel was now caged with metal, late luminal
enlargement and advantageous vascular remodeling could no longer
occur. Another problem, namely late stent thrombosis (ST), was also
first described

6. 3 revolution -DES
• Drug-eluting stents have significantly reduced in-stent restenosis and
target lesionrevascularization (TLR) compared with BMS
• These stents still leave a permanentmetal implant inside the vessel
with potential future problems

7. • Vasomotion testing demonstrated abnormal vasoconstriction
responses to acetylcholine distal to the deployed stent, suggesting
that the structure and function of the endothelium remained
abnormal
• Geometry and vasomotion altered.

8. BIOABSORBABLE STENT

9. BIOABSORBABLE STENT DESIGN
• The ideal design should have mechanical properties that are able to
provide the necessary vessel support during the required period.
• must be biocompatible, and should have an adequate degradation
time, disappearing without creating an intense inflammatory
response.
• Apart from that, the device has to have good deliverability, and,
ideally, it should be able to carry an antiproliferative drug in order to
reduce restenosis.

10. • Both the selection of the material and the design are going to
influence the success of the device.
• Regarding the material, there are two possibilities that are being
tested:
- 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 is
polylactide (PLLA), which degrades via the Krebs cycle to water and
carbon dioxide

11. • Both polymers and magnesium alloys are less stiff than conventional
metallic 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) are
required to obtain an adequate radial support.
• In order to avoid inflammation or a toxic response in the vessel wall
during degradation, the device should have as little material as
possible, and the process should not occur too fast to allow an
adequate response of the tissue to the products of degradation

12. • in order to be introduced in the catheterization laboratories,
bioabsorbable devices should be easy to store (avoiding, the need for
refrigeration), should have good deliverability, an should be easy to
position in the coronary artery.
• The majority of bioabsorbable materials have low radio-opacity, but
the visualization of the device under fluoroscopy can be increased by
the use of radio-opaque markers in the balloon or in the device itself.

13. TYPES
• Polymer based metal based
- BVS (abbot) DREAMS 1, 2
- igaki tamai iorn
- REVA stent
- ART
- IDEAL

15. ABSORB BVS

17. 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

22. 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

27. 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

29. Igaki-Tamai stent
• The Igaki-Tamai PLLA coronary stent was the first fully bioresorbable
stent to be implanted in humans in 1998 with complete degradation
taking 18 to 24 months.
• Tamai stent is a self- expandable when heated, consequently contrast
dye at 80C is used for balloon inflation. Expansion continues at body
temperature until dilation and vessel wall resistance reach
equilibrium.
• In 2000, Tamai et al. reported initial results from 15 patients in whom
25 stents were successfully implanted.

30. • During the first 6 months, minimal lumen diameter decreased and then
constantly 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 from
5.44 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 thrombosis
and 1 very late scaffold thrombosis, 1 lesion-related myocardial infarction,
and 1 cardiac death were noted.

31. • 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.

33. METAL STENTS

35. Magnesium-based metallic bioresorbable
scaffolds
• The PROGRESS-AMS clinical trial was a non-randomized, prospective,
multi-center trial that was designed to assess the efficacy and clinical
safety of the absorbable magnesium stent (AMS-1)
• 63 patients underwent revascularization with an AMS in vessels with
reference diameters of 3 to 3.5 mm and average lesion lengths of <13
mm.
• Coronary angiography and intravascular ultrasound imaging was
completed 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 4
months

36. MACE - 24%
TLR - 39.7% at 4 months.
• There were no events of cardiac death, myocardial infraction, or stent
thrombosis.
• The angiographic in-stent lumen loss was 1.08 + 0.49 mm at 4
months, and IVUS imaging suggested that most of the struts were
fully resorbed with only strut remnants being visibly embedded into
the intima

37. • Although this study demonstrated the safety of AMS-1 with no
reported death, myocardial infarction or stent thrombosis, imaging
and clinical results raised concerns over the further use of this
generation in coronary interventions as increased neo-intimal
formation and vessel recoil became evident.
• AMS 1 - metal
• AMS 2 – modified structure
• AMS 3 or DREAMS 1 - pacitaxel
• DREAMS 2 - sirolimus

39. DREAMS stents
• It is a drug-eluting absorbable metal scaffold (DREAMS, Biotronik,
Bülach, Switzerland) is made of a magnesium alloy, coated with a
matrix of absorbable polymer PLLA carrier
• antiproliferative drug paclitaxel
• The paclitaxel was completely released in a controlled manner for 3
months. The scaffold absorption is complete within 1 year post device
implantation

40. BIOSOLVE-I
• The BIOSOLVE-I clinical trial was a prospective, non-randomized,
multicenter, first-in-man trial assessing the safety and efficacy of
DREAMS in non-complex coronary lesions.
• Forty-six patients with stable/unstable angina or silent ischemia were
treated with 47 stents.
• Imaging follow-up included angiography and IVUS at 6 and 12 months
with clinical assessment scheduled at 1, 6, 12, 24 and 36 month

41. 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% reduction
compared to the 4-month results of AMS-1.
• Serial IVUS imaging confirmed the angiographic observations showing
in-scaffold area obstruction of only 6.24% (p , 0.0001) at 1 year,
attributed to neo-intimal formation with extra-scaffold plaque area
increase.
• TLR rates reached 7% with no reported episodes of stent thrombosis
throughout the 3-year follow-up

44. • 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 resorption
rate compared to the previous generation.
• The BIOSOLVE-II study was designed to assess the safety, efficacy and
feasibility of this generation in 120 patients

45. CONCLUSION FROM BIOSOLVE
• BIOSOLVE-I and -II added to the ever-expanding evidence to support
BVS by assessing the safety and efficacy of two generations of drug
eluting metallic scaffolds.
• The first drug eluting magnesium based metallic scaffold in BIOSOLVE-
I showed similar safety findings to PROGRESS-AMS in that it could be
safely and successfully implanted in patients without an associated
risk for cardiac death or stent thrombosis.
• The addition of drug-elution with paclitaxel further improved the
rates of target lesion revascularization from 26.7% to 4.7%.

46. Tyrosine Polycarbonate: The REVA Stent
• The ReZolve devices (REVA Medical) are made of desaminotyrosine
polycarbonate, 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 and
gets locked to preventing it from going back.

48. RESORB trail
• RESORB Study (REVA Endovascular Study of a Bioresorbable Coronary
Stent) 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

49. • 6 months follow up showed absence of any significant vessel recoil.
• Unfortunately higher-than-anticipated rate of TLR (66.7%) were seen
between 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-generation
ReZolve stent

50. • More robust polymer, a spiral slide-and-lock mechanism to improve
clinical 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 the
original ReZolve scaffold evaluated clinically in the RESTORE II Trial
ReZolve stent

51. IDEAL stent
• The IDEAL BRS is a sirolimus-eluting device with the backbone of
polylactide anhydride mixed with a polymer of salicylic acid and sebacic
acid linker.
• The presence of salicylic acid provides anti-inflammatory properties to the
device. The IDEAL BRS was tested in the WHISPER FIM trial in 2008. The
first-generation device required an 8-Fr guide catheter and poorly
supressed neointimal proliferation due to inadequate drug dosing and
rapid release of the sirolimus.
• The second-generation IDEAL BioStent with a higher sirolimus dose, slower
drug-release, and a 6-Fr compatible delivery system is currently undergoing
preclinical evaluation

55. BENEFITS

56. 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.

57. • 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

58. • Metallic stents do not seem to fully protect the vessel from
neoatherosclerosis or plaque progression.
• It is postulated that BRS implantation may provide a symmetrical
uniform fibrous neointimal layer which along with late lumen
enlargement and lack of any permanent vascular prosthesis may help
to stabilize and passivate vulnerable plaques and thus prevent future
cardiovascular events

59. Preservation of vascular geometry
• The metallic stents can alter vessel geometry and biomechanics, and
resultant chronic irritation and flow disturbances may contribute to
neointimal proliferation and adverse events.
• Bioresorbable scaffolds offer the potential to preserve vascular
geometry. ABSORB BVS is more conformable than metallic stents and
produces less alteration in vessel angulation and curvature.
• It has also been shown that, at 6- to 12-month follow-up, ABSORB
BVS tends to restore the coronary configuration to pre-implant level,
whereas coronary geometry remains permanently altered after
implantation of permanent metallic stents

60. Restoration of vascular physiology
• A number of studies using metallic DES have reported abnormal
vasomotion in the segment distal to the DES, which may restrict the
distal flow and predispose to late stent thrombosis.
• Bioresorbable scaffold technology has been described as vascular
reparative therapy
• after complete bioresorption, BRSs promise the return of dynamic
vasomotion, pulsatility, distensibility, and mechanotransduction, i.e.
the ability to translate mechanical forces into chemical signals (e.g.
nitric oxide and prostacyclins).

61. • In the ABSORB Cohort A, evaluation of the scaffolded segment
following intraluminal administration of acetylcholine suggested that,
at 2 years, the scaffolding function of the polymeric struts had
completely disappeared and the scaffolded segment could exhibit
vasomotion.

62. 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.

63. • In such cases, repeat revascularization, by means of either
percutaneous or surgical revascularization, is potentially challenging
because of the metallic cages formed by previously implanted DES
• 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.

64. REDUCTION IN BLEEDING
• Once bioabsorption of the temporary scaffold has been completed,
there will potentially be no requirement for long-term dual
antiplatelet therapy.
• This is particularly pertinent given that the elderly, who are at the
greatest risk of bleeding, are increasingly receiving invasive treatment
for ischemic heart disease.
• 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.

65. IMAGING
• Allowing the use of noninvasive imaging techniques such as
computed tomography (CT) angiography or magnetic resonance
imaging for follow-up.
• Presently, metallic stents can cause a blooming effect with these
imaging modalities, making interpretation more difficult.
• The poly-L-lactic acid (PLLA) scaffold should not restrict the use of CT
or magnetic resonance imaging

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

68. 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.

69. • 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.
• Safety of PLLA
• Duration of antiplatelets ?

75. CONCLUSION
• Treatment of noncomplex coronary lesions with the absorb
everolimus-eluting bioresorbable vascular scaffold was within the
prespecified range for noninferiority to the xience everolimus-eluting
cobalt–chromium stent with regard to target-lesion failure at 1 year

76. 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 promote
and achieve faster endothelialisation. The drug eluted is sirolimus.
• The xinsorb br (huaan biotechnology group, laiwu, china) is made of plla
and elutes sirolimus
• The SAHAJANAND BRS (sahajanand medical technologies, pvt, ltd, india),
the avatar brs (s3v; vascular technologies pvt. Ltd., Bangalore, karnataka,
india)

77. CONCLUSION
• There is no doubt that after percutaneous coronary intervention the
injured vessel requires scaffolding
• However, there is no consensus on how long this scaffolding is
required.
• The currently available metallic DES have demonstrated their ability
to provide a permanent scaffolding and to prevent restenosis, but
legitimate safety concerns have emerged

78. • 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
award of being the fourth revolution in interventional cardiology

79. July 5, 2016
• “The FDA’s approval of the Absorb GT1 BVS offers a new treatment
option for individuals who are candidates for angioplasty, but would
prefer an absorbable device rather than a permanent metallic
coronary stent,”

80. THANK YOU