brief review of coronary artery stents

1. CORONARY STENTS
Dr Abhishek Sakwariya
Cardiology Department
MDM Hospital SNMC

2. Introduction
• Coronary artery disease is a major cause of mortality and
morbidity worldwide
• CAD is characterized by the narrowing of the artery due to
plaque deposits beneath the endothelium. Cells, fats, calcium,
cellular debris, and other substances may accumulate in these
deposits.
• Minimally invasive percutaneous angioplasty is the standard
treatment procedure for CAD at present
• Stenting involves placing a non collapsing scaffold in the
vessel to ensure blood flow.

3. Background
• Initially balloon angioplasty was the standard procedure after
its introduction by Andreas Gruentzig on 16 sept 1977 in
Zurich Switzerland.
• Stand alone balloon angioplasty had unpredictable
experience.
• majority of vessels tolerate the focal plaque dissections
caused by balloon dilatation and heal sufficiently to result in
an adequate lumen
• The injury to the vessel wall may unpredictably result in
severe dissections.

4. • Balloon angioplasty had two major limitations:
– Abrupt closure and restenosis.
• Therefore stent was designed as endoluminal
scaffold to create a larger initial lumen, seal
dissections, an to resist recoil and late vascular
remodelling.
• First implantation of stents in human coronary
arteries occurred in 1986 when Ulrich Sigwart and
Jacques Puel and colleagues.

5. • Further it was demonstrated high rates of thrombotic
occlusion and late mortality, although patients
without thrombosis had a 6-month angiographic
restenosis rate of only 14%, suggesting that stenting
could improve late patency.
• FDA approved it in 1993 to reverse post angioplasty
acute or threatened vessel closure.

7. Classification(s)
Based on
• composition: metallic or polymeric
• Configuration: slotted tube vs coiled wire, vs
modular.
• Bioabsorption: stable vs degradable
• Coating: none, passive(PTFE, Heparin) or
bioactive(sirolimus, everolimus etc)
• Mode of implantation: self expanding or balloon
expandable.

8. • Platform
• Earlier 316 L stainless steel
• Cobalt chromium and platinum chromium alloys
have been employed to allow lower-profile thin stent
struts (60 to 82 μm vs. 100 to 150 μm in most
stainless steel stents) that maintain strength and
visibility.
Stent components

9. • Most self-expanding stents utilize nitinol, a nickel-
titanium alloy, which, after being baked at a high
temperature, maintains shape memory for a
predetermined size and configuration.
• There is little evidence that thrombosis or restenosis
rates vary with the specific stent metal, though the
final stages of surface finishing, smoothing, and
purification or passivation may affect early
thrombotic and late restenotic processes

10. • Stent Configuration and Design
• Three distinct subcategories: wire coils, slotted tubes/
multicellular and modular.
• Vast majority are slotted tubes/ multicellular and modular.
• Open cell vs Closed cell design
Open-cell designs tend to have
varying cell sizes and shapes,
which provide increased
flexibility deliverability, and side
branch access,
with staggered cross-linking
elements to provide radial
strength.
Closed-cell designs typically
incorporate a repeating,
unicellular element that provides
more uniform wall coverage with
less tendency for plaque
prolapse,
But at the expense of flexibility
and side branch access.

13. • Stents that possess better conformability, less
rigidity, and greater circularity experimentally
produce less vascular injury, thrombosis, and
neointimal hyperplasia
• Clinical studies have suggested that thin stent struts
may be associated with reduced neointimal
hyperplasia and lower rates of restenosis
• Longitudinal integrity of the stent depends on the
number of connectors between hoops.
• Longitudinal distortion may manifest as length
change, strut overlap, or strut separation which may
obstruct the lumen, predisposing to stent thrombosis
or restenosis

14. • Stent coating
• Purpose of coating is to reduce thrombogenicity or restenosis
of metallic stents.
• Likewise coating can be of:
– Inert polymer; to reduce thrombogenicity, eg, heparin,
phosphorylcholine, activated protein C, hirudin,
bivalurudin etc
– Stable polymer; to bind a antiproliferative agent to reduce
restenosis,
– Bioabsorbable polymer; degrades with time after releasing
the antiproliferatinve agent.
• Most polymers found to cause intense inflamation,
necessitating DAPT .
• Covered stents with PTFE membrane to cover perforations

15. Bare metal stents
• These devices reduced rates of restenosis compared
with balloon angioplasty, in-stent restenosis (ISR),
narrowing within the stented segment, continued to
develop in 20%-30% of lesions.
• Although stent insertion prevents arterial recoil and
stabilizes vascular dissections, ISR might still occur
because of exuberant neointimal accumulation much
akin to “scar formation”

16. Limitations of BMS
• Though improvements in stent deliverability and
reductions in rates of subacute stent thrombosis to less
than 1%.
• Restenosis is major persistent limitation of coronary
stenting
• Stents cause better acute luminal gain compared to
balloon angioplasty but cause greater vascular injury and
thus greater neointimal hyperplasia.
• However, mean incremental gain in luminal dimensions
with stenting is statistically greater than the mean
incremental increase in late loss

17. • Even with optimal stent implantation, restenosis
after BMS implantation still occurred in
approximately 20% to 40% of patients within 6 to 12
months, in part due to stenting more complex
patient and lesion subsets than in the balloon
angioplasty era.

20. Drug eluting stents

21. Components of DES
1. Platform
– First gen DES had stainless steel platform
– second gen had CoCr, PtCr platform
2. Polymer
– 3 phases of response seen after stenting
1. Inflamatory reaction within 3-7 days, the intimal
thickness increase significantly in 4 weeks.
2. Second phase, within 1-3 months, stent surface
exposed to blood and endothelization starts,
3. Third phase, stent fully covered by endothelium
after 3 months

22. • For better loading drug molecules on the stent
surface and for enhancing an engineered control
over drug release, polymeric coatings have been
developed.
• Roles of polymer coating
– Inhibit drug from being washed off,
– Provide suitable scaffold for drug loading
– Provide engineered control over drug release
– Biocompatibility once drug washed off.
• There should be sufficient balance between drug
release and drug uptake by surrounding tissues

24. 3. Drug
– Characteristics of drug
– Capable of inhibiting platelet aggregation,
inflammation, SMC proliferation and migration.
– Promote appropriate healing and fast
endothelialisation.
• Commonly used drugs
– Sirolimus;
• highly lipophilic, naturally occurring macrocyclic
lactone, first isolated from Streptomyces hygroscopicus
• bind to FK binding protein-12 , the complex inhibit
mTOR and late G1 to S transition in cell cycle.

25. –Paclitaxel;
• highly lipophilic diterpenoid compound
• from the pacific yew tree (Taxus brevifolia),
• potent antineoplastic properties
• Paclitaxel is insoluble in water, and thus was
combined with an intravenous oil-based
cremophor for intravenous injection as the
oncologic compound Taxol
• interfere with microtubule dynamics, preventing
depolymerization

26. • Paclitaxel has antiproliferative and
antiinflammatory properties, prevents smooth
muscle migration, blocks cytokine and growth
factor release and activity, interferes with
secretory processes, is antiangiogenic, and
impacts signal transduction
• paclitaxel affects the G0 to G1 and G1 to S
phases (G1 arrest) resulting in cytostasis
without cell death
– Newer analogues of sirolimus
• Zotarolimus, everolimus, biolimus

27. • Generational Classification of Drug-Eluting
Stents

29. • First generation DES
Cypher SES and Taxus PES
– Several RCT and meta-analysis and observational
registries compared Cypher to BMS. Showed that
Cypher nearly abolished in-stent late loss (averaging
∼0.15 mm across studies, compared to 0.8 to 1.0 mm
with most BMS), with an approximate 70% to 80%
reduction in angiographic restenosis and clinical
recurrence.
– Longer-term follow-up with this device in RAVEL
SIRIUS, C-SIRIUS, and E-SIRIUS trial has shown
sustained reductions in clinical restenosis end points
with similar rates of death and MI found in both SES
and BMS arms

30. • Limitations of first gen DES
– Increased risk of late stent thrombosis after stopping
DAPT
– delayed endothelialisation caused by the locally
delivered drugs.
– inherent thrombogenicity of the stent as a foreign
device to the immune system
– Hypersensitivity and inflammatory reactions as a
result, either due to the metal-based framework
and/or polymeric coatings
– insufficient drug amount in addition to lack of
sustained drug release
– SES but not PES was associated with a reduction of
stent thrombosis during the first year compared to
BMS, which was offset by an increased risk of very late
stent thrombosis with SES after the first year

31. Second gen DES
• Superior stent platforms and more biocompatible
durable polymers or BP.
• Polymer-free stents have also been developed, which
offer the potential of controlled drug release without
the vascular toxicity associated with the presence of
the polymer.
• The introduction of BRS represents a novel approach
providing drug-elution and a temporary vascular
scaffolding function for 6 to 12 months, followed by
complete bioresorption within the next 1 to 3 years
depending on the device.

33. Durable Polymer-Based Second-Generation Drug-
Eluting Stents
CoCr- Everolimus stents(Xience)
• Contains everolimus (100 µg/cm2)
• Released from a thin (7.8 μm), nonadhesive, durable,
biocompatible fluorinated copolymer consisting of
vinylidene fluoride and hexafluoropropylene
monomers, coated onto a low-profile (81 μm strut
thickness), flexible cobalt chromium stent.
• Release kinetics, ∼80% of the drug released at 30
days, with none detectable after 120 days.
• polymer is elastomeric, experiences minimal
bonding, webbing, or tearing upon expansion.

34. • Fluoropolymers resist platelet and thrombus
deposition likely related to the capacity to attract
and bind albumin which passivates the stent surface,
avoiding fibrinogen binding.
• EES fluoropolymer has also been demonstrated to be
noninflammatory
• Low profile stent struts facilitate rapid re-
endothelialization and are fracture resistant
• To date, CoCr-EES has been the second-generation
DES that has received the most extensive
investigation

35. • To date, CoCr-EES has been the most
extensively investigated stent with at least 43
RCT and 61,228 patients.
• CoCR EES vs First gen DES
• PES
– With PES SPIRIT IV trial and COMPARE trial shown
lower rates of TLF( cardiac death, target vessel MI,
ischemia driven TLR composite.) and MACE
(death, MI, TVR) respt..
– Also reduced rates of stent thrombosis in both.

36. • SES
– Three large scale trials
– SORT OUT IV trial
• Comparable rates of composite of cardiac death, MI
and TVR or definite stent thrombosis at 9 months
• Less definite ST incidence in CoCr ERS.
– RESET trial
• Comparable rates of TLF
• Similar incidences of ST
– BASKET PROVE trial.
• 2 yr rates of composite of death and MI were lower in
CoCR ERS

37. • Summary, CoCr-EES have shown marked
improvements in safety and efficacy outcomes
compared with PES, and modest improvements with
SES.
• Meta-analysis including 11 trials with 16,775 patients
for the risk of definite stent thrombosis, CoCr-EES
was associated with significantly lower rates of early,
late, 1-year, and 2-year definite stent thrombosis
compared with pooled PES, SES, and Re-ZES.

38. Platinum-Chromium ERS( Promus
element/premier)
• Platinum-chromium alloy. Strut 81µm, high radial
strength and moderate radiopacity ( >CoCr ERS)
• Stable polymer Flouropolymer 7µm thick.
• Everolimus 100µg/cm2.
• Modified scaffold design improved deliverability,
vessel conformability, side branch access, radial
strength and fracture resisrance.

39. • In stent acure loss and percentage volume
obstruction were comparable to CoCr ERS in SPIRIT
series of trials.
• PLATINUM trial; 1530 patients, compared with CoCr
ERS , non-inferior for composite of cardiac death, MI
and TLR.
• Also no difference when compared for individual
parameters in primary outcome.

40. • PLATINUM PLUS: prospective, multicenter
noninferiority trial enrolled 2980 all-comer patients
to either PtCr-EES or CoCr-EES
• Non inferior for TLF ( MI, TLR, cardiac death)
• Similar rates of ST.
• Caution:
– Promus Element susceptible to longitudinal
deformation, appearing as decrase or increase in
stent length.
– Can predispose to thrombosis or restenosis.

41. – Distortion can occur at any stage i,e., after
deployment during positioning, post dilation,
thrombectomy device , IVUS or due to guide
compression.
– Problem is more with Promus Element compared
to other second gen DES due to fewer connectors
between hoops to increase longitudinal flexibility
and deliverability.
– Addition of additional connectors in hoops in
proximal segment lesd to new DES Promus
Premier.
– In bench testing, deformation with Promus
Premier was significantly less than Promus
Element, and similar to other stent platforms

42. • Zotarolimus eluting stent (Endeavor)
– Low profile CoCr stent with strut thickness 91µm
– Stable Polymer phosphorylcholine,5.3 µm thick
– Zotarolimus 10µg/mm stent length
– Potencies of zotarolimus, everolimus, and
sirolimus are roughly comparable, and zotarolimus
is some what more lipophilic.
– Release rate of zotarolimus from Endeavor (90%
within 7 days, 100% within 30 days) is significantly
faster

43. Important studies
• ENDEAVOR III: rates of late loss and restenosis higher
compared to SES, but lower 5 yr rates of all cause death,
MI. TVR and definite ST rates were comparable
• ISAR TEST II and KOMER; no difference between PC-ZES
and SES in terms of death, MI, and definite ST
• NAPLES and ZEST, shown higher MACE and higher rates
of ST with PC ZES
• Finally adequately powered large trial SORT OUT III
shown PC Zes to be significantly better than SES for all
cause mortality, MI definite ST for short term 1 Yr follow
up, but similar results for 5 yr follow up.

44. Zotarolimus eluting stent Re-ZES (Resolute)
• Thin strut cobalt-alloy BMS platform
• Instead of the phosphorylcholine coating of the
Endeavor stent, the Resolute stent employs a
proprietary BioLinx tri-polymer coating (4.1 μm
thickness)
• Consisting of a hydrophilic endoluminal component
and a hydrophobic component adjacent to the metal
stent surface
• Serves to slow the elution of zotarolimus relative to
the Endeavor phosphorylcholine polymer, such that
60% of the drug is eluted by 30 days and 100% by
180 days, making this the slowest rapamycin analog-
eluting DES

45. • RESOLUTE all comers, TWENTE and ISAR LEFT MAIN
compared resolute with CoCr-EES; RE-ZES was non
inferior
• DUTCH PEERS and HOST ASSURE evaluated RE-ZES
with PtCr- EES; RE-ZES non inferior.

46. Biodegradable polymer
• The long-term presence of non-biodegradable
materials in stents leads to late complications
such as thrombosis, neointimial hyperplasia,
and chronic inflammation.
• Biodegradation implies the dispersion of
polymeric materials as a consequence of
macromolecular degradation
• PLA and PGA are of two most ubiquitous
polymers that have been exploited in the
second-generation DES

47. BP based second gen stents
• Biolimus-eluting bioabsorbable polymer stent (BES-
BP), is the most studied one.
• Biomatrix (by Biosensors) or Nobori (by Terumo)
elute Biolimus, a semi-synthetic rapamycin analog
with similar potency but greater lipophilicity than
sirolimus, from the stainless steel S-Stent platform
(120 to 125 μm strut thickness)

48. • Biomatrix and Nobori have similar stent platforms,
polymers, and drugs, with slight differences in the
delivery system, delivery balloon, and the stent
coating process
• The delivery polymer is made of PLLA, which is
applied solely to the abluminal stent surface (11 to
20 μm thick), and is metabolized via the Krebs cycle
into carbon dioxide and water after a 6-to-9 month
period

49. Improtant trials
• With first gen DES
• Nobori and Biomatrix have been compared with first-
generation DES in a total of five randomized
controlled trials, and although some of them have
shown improved safety with similar efficacy of BP-
BES compared to either PES or SES, others have not
confirmed this association

50. Comparision with second gen DES
• With CoCr-EES in three randomized controlled trials
COMPARE II, NEXT, and BASKET-PROVE II.
– Although no major differences emerged between
BP-DES and CoCr-EES in these three trials, there
was no evidence that BP-DES provided any late
safety advantages compared to CoCr-EES
– In a pooled analysis of COMPARE II and NEXT trial,
BP-BES had significantly higher rates of target-
vessel MI compared to CoCr-EES

51. • With Re-ZES in one randomized trial (SORT OUT VI.
– At 1-year follow-up, no significant difference was
apparent between the two stents for the
composite primary end point of cardiac death, MI,
or TLR
– Similar results were apparent at 3-year follow-up,
with no significant difference in safety and efficacy
outcomes
• With PtCr-EES in one randomized trial, LONG DES V
– At 9-month follow-up, the primary end point of
the study, in-segment late luminal loss, was
comparable between the two groups
– The incidence of in-segment and in-stent binary
restenosis was also similar between the groups.

52. • Novel BP-BASED Drug-Eluting Stents
– Orsiro is a novel bioabsorbable polymer-based
DES releasing sirolimus from biodegradable poly-l
lactic acid polymer, which completely degrades
during a period of 12 to 24 months.
– Metallic stent platform consists of ultrathin (60
μm) cobalt-chromium struts covered with an
amorphous silicon carbide layer. The passive
coating seals the stent surface and reduces
interaction between the metal stent and the
surrounding tissue by acting as a diffusion barrier.

53. • Synergy PtCr PLGA-based everolimus
(100µg/cm2)eluting stent, very thin struts (74 μm)
and a 4 μm thick abluminal coating of PLGA polymer
which is completely absorbed within 4 months.
• EVOLVE trial, noninferior to durable polymer PtCr-
EES for the primary end point of angiographic late
lumen loss.
• Other BP based Stents

59. Polymer-free drug-eluting stents
• Polymer lead inflammatory reaction is the chief
cause of stent thrombosis and thus for the
requirement of DAPT
• An option to completely get rid of polymers as the
drug-carrier is to develop a polymer-free stent.
• This alternative should be able to preserve functions
of polymeric DESs including carrying drug molecules,
binding the drug to the stent, controlling the drug
release rate at a suitable rate
• Carrier-free stents need to be biocompatible to be
adapted to the tissue surrounding

60. • In comparison to polymeric coating as the drug-
loading platform, polymer-free stents are expected
to have a faster drug elusion rate which might have
adverse therapeutic effect.

63. Biodegradable scaffolds
• Loading drugs on first-generation DES was achieved
through polymer coating on the stent surface.
• Polymers were considered to initiate inflammatory
response contributing to instent restenosis (ISR)/.
• Newer stents coated with bioidegradable polymer
were introduced to address this, but they still had a
permanent backbone.
• Term scaffold indicates the temporary nature of BRS
which is in opposition to the permanent implant

64. • Biodegradable scaffolds provide support to the
vessel wall and later degrade and allow vessel to
revert back to its original condition.
• Fully degradable stent not only allows the artery to
revitalize, but also it makes any other re-intervention
or treatment to the affected site easier.

66. • Undesirable effects of metallic stents
– Disruption of the pulsatile flow
– More stress at the vessel wall causing more injury
and therefore more neointimal hyperplasia
– Straightening of the vessel and thereby disruption
in vessel’s natural geometry
– Permanent nature interfere with any future
intervention distal to the stent.
– Interference with imaging.
Delayed endothelialisation therefore longer DAPT
requirement

67. • Benefits of BRS
– Prevented constrictive remodeling
– Reduced risk of very late polymer reactions
– Avoidance of late vessel wall inflammation
– Prevented late ST
– Unjailing of side branches
– Avoidance of stent malapposition
– Normalizing shear stress and cyclic strain

68. • Drawbacks of BRS
– Lack of radiopacity;
• There are recently new polymers that have been found
to be inherently radio-opaque which are based on the
iodination of the tyrosine ring in tyrosine-derived
polycarbonates.
– Reduced radial strength compared to their
metallic counterparts
• Lower elastic moduli, lower break strain and higher
yield strain.
– Reduced flexibility of the stent
• As strut thickness is more to compensate for reduced
strength

69. • Increased thickness in struts to compensate for
reduced mechanical strength leads to
unfavorable events such as vessel injury, non-
laminar flow within the stent, making the stent
into a favorable scaffold for platelet deposition
and a diligent implantation
– During degradation of some polymer based stents
such as PLGA-based stent, the significant pH
change of the medium due to the acid-nature of
the polymer could lead to the necrosis of the cells
in contact

70. – Longer time of pre-dilatation.
• For BRSs, due to insufficient radial strength and
diligent deliverability especially in complex
lesions, prolonged and time-consuming pre-
dilatation is required compared to conventional
stents
– Unsuitable release profile for drug delivery system
– Difficulty in delivery to the site of action because
of thicker struts with larger crossing profile

71. • Mechanism of BRS function
Three overlapping phases
– Revascularization; Revascularization deals with the
problem of narrowing vessels to re-open them
– Restoration; loss in total mass of the molecule
which emerges in the reduction of molecular
weight.
– Resorption; final metabolism of the monomer.

75. THANK YOU