This document discusses restenosis of drug-eluting stents. It begins by introducing the topic and defining in-stent restenosis. It then discusses classifications of in-stent restenosis and the underlying mechanisms. Various treatment approaches are mentioned, including medical management, balloon angioplasty, cutting/scoring balloon angioplasty, and drug-eluting balloons. Imaging with IVUS and OCT can help identify factors associated with stent failure. Overall, the document provides an overview of in-stent restenosis and approaches to managing it.

1. RESTENOSIS OF DRUG ELUTING
STENT : CLASSIFICATION &
MANAGEMENT
Dr. Ajay Pratap Singh
Senior Resident
Dr. Ram Manohar Lohia Hospital, New Delhi.

2. INTRODUCTION
• Second-generation DESs have improved on prior technology with a modification of stent design, alloy composition
(including strut thickness), polymer, and drug that is eluted. These changes were associated with improved performance
of second generation DESs compared with their first-generation predecessors.
• Second- generation DES have failure rates at 1 year that average 5.7% and 8.7% in non-diabetic and diabetic patients,
respectively.
• Worse yet, DES TLF rates do not plateau at 1 year, and all modern DES trials show a gradual increase in major adverse
clinical events (MACE) over time, such that 5-year TLF rates are in the 9% to 12% range in generally noncomplex
lesions
• In real world use, modern DES fare even less well with 5-year TLF rates that exceed 15%. The cumulative rates of DES
failure have created a major clinical problem so that > 10% of all PCIs done in the United States (US) are to treat ISR,
and the number of ISR interventions appears to be increasing year over year

4. • The timing of DES-ISR presentation has shifted to a longer period that can extend several years beyond stent
implantation. This accumulation of ISR over the years, coupled with late neoatherosclerosis and slow healing,
may contribute to the relatively constant rate of ISR encountered in clinical practice despite recent
improvements in DES technology.
• Compared with revascularization of de novo lesions, the treatment of DES-ISR is associated with increased
complexity and worse clinical outcomes

5. DEFINITION
The definition of ISR
remains an angiographic
one:
recurrent diameter stenosis
>50% at the stent segment or its
edges (5-mm segments adjacent
to the stent)

6. CLASSIFICATION-Mehran et al (IVUS guided)
Angiographic Patterns of In-Stent Restenosis Classification and Implications for Long-Term OutcomeCirculation.1999; 100: 1872-1878

7. • Prognostically important, and it may be used for appropriate and early patient triage.
• Recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV
• as was the incidence of diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01).
• Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with
athero-ablation
• TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (P<0.001)
DRAWBACKS
• This criteria provide no insight into the mechanism of stent failure and do not dictate applicable treatment.
Angiographic Patterns of In-Stent Restenosis Classification and Implications for Long-Term OutcomeCirculation.1999; 100: 1872-1878

10. ISR is not a benign clinical entity

11. The Underlying Mechanisms of Restenosis With Drug-Eluting Stent
Biological
Factors
Arterial
Factors
Stent Factors
Implantation
Factors

12. Biological
Factors
Hypersensitivity
/Resistance to drug
Genetic
Hypersensitivity to Stent
polymer or metal platform
Serum
Metalloproteinase

13. Arterial
Factors
“Thromborestenosis”
Vessel remodeling
Small vessels and
progression of
atherosclerosis in a stented
segment.
Wall shear stress

14. Stent
&
Implantation
Factors
Polymer drug
release kinetics
Stent gap,
non- uniform strut
distribution,
and drug deposition
Polymer disruption,
peeling, and
cracking
Stent fractures
Incomplete stent
expansion
Geographical
miss
Barotrauma to
unstented
segments
Deployment of
DES in a clot-laden
arterial segment

15. Need for a newer classification
Shlofmitz E, Iantorno M, Waksman R. Restenosis of Drug-Eluting Stents: A New Classification System Based on Disease Mechanism to Guide Treatment and State-of-
the-Art Review. Circ Cardiovasc Interv. 2019 Aug;12(8):e007023. doi: 10.1161/CIRCINTERVENTIONS.118.007023. Epub 2019 Jul 26. Erratum in: Circ Cardiovasc
Interv. 2019 Oct;12(10):e000044. PMID: 31345066.

16. ROLE OF IMAGING
Peter Nguyen & Arnold Seto (2020): Contemporary practices using intravascular imaging guidance with IVUS or OCT to optimize percutaneous coronary intervention,
Expert Review of Cardiovascular Therapy, DOI: 10.1080/14779072.2020.1732207

17. • Intracoronary imaging with IVUS/OCT is helpful in identifying factors associated with Stent
failure (restenosis):
I. Minimal luminal area post stenting
II. Stent malapposition
III. Edge dissection
IV. Tissue protrusion/ thrombus
• Benefit of imaging has been extensively studied and established in many clinical trials for both
IVUS and OCT.

18. • Meta-analyses of 8 trials (3,276 patients, 1,635 IVUS-guided and 1,641 angiography-guided; with a mean follow-up 1.4 ±
0.5 years.) demonstrates a significant reduction in MACE, TVR, and TLR with IVUS-guided DES implantation in complex
coronary lesions.
Bavishi C, G. Stone, et al. Intravascular ultrasound–guided vs angiography-guided drug-eluting stent implantation in complex coronary lesions: Meta-analysis of
randomized trials. AHJ, 2017, Vol. 185, pp.26-34.

19. OCT-GUIDED PCI TO IMPROVE OUTCOMES

20. TREATMENT OF ISR

21. MEDICAL MANAGEMENT
• Several attempts to manage ISR using medical therapy failed to significantly reduce the recurrence rate and were
associated with adverse effects.
• Among these were abciximab, oral sirolimus, oral corticosteroids, and local delivery of paclitaxel, with limited efficacy
as a primary treatment approach.
Ribichini F, Tomai F, De Luca G, Boccuzzi G, Presbitero P, Pesarini G, Ferrero V, Ghini AS, Abukaresh R, Aurigemma C, De Luca L, Zavalloni D, Soregaroli D,
Marino P, Garbo R, Zanolla L, Vassanelli C; CEREA-DES investigators. Immunosuppressive therapy with oral prednisone to prevent restenosis after PCI. A multicenter
randomized trial. Am J Med. 2011 May;124(5):434-43. doi: 10.1016/j.amjmed.2010.11.027. PMID: 21531233.

22. Cassese S, De Luca G, Ribichini F, Cernigliaro C, Sansa M, Versaci F, Proietti I, Stankovic G, Stojkovic S, Fernandez-Pereira C, Tomai F, Vassanelli C, Antoniucci D,
Serruys PW, Kastrati A, Rodriguez AE. ORAl iMmunosuppressive therapy to prevent in-Stent rEstenosiS (RAMSES) cooperation: a patient-level meta-analysis of
randomized trials. Atherosclerosis. 2014 Dec;237(2):410-7. doi: 10.1016/j.atherosclerosis.2014.09.021. Epub 2014 Sep 30. PMID: 25463066.

23. Balloon Angioplasty
• Plain balloon angioplasty historically represents the initial intervention performed for both BMS-ISR and DES-ISR. The
procedure, however, was associated with edge-related complications and high recurrence of ISR (>50%).

24. • Patients with diabetes and those with a short time
interval from stenting to PTCA were independently
associated with a worse outcome. Cumulative
event-free survival at 12 and 24 months was 80%
and 77%, respectively, and was poorer for patients
with a short time from stenting to repeat
intervention and in diabetics

25. • In general, a balloon to artery ratio of 1.1 to 1 is recommended for sizing when treating ISR.
• One of the limitation of POBA is that sub-acute tissue re-intrusion back to the lumen tends to occur within
minutes of the last balloon inflation. This explains the “early lumen loss” phenomenon detected in POBA
studies in ISR, a finding also associated with subsequent recurrent restenosis .
• Balloon slippage outside the stent (“water-melon seeding” phenomenon), which occurs more often in severe
and diffuse narrowing when balloons are oversized, can lead to edge dissections and suboptimal outcomes.
Alfonso F, Pérez-Vizcayno MJ, Gómez-Recio M, et al. Implications of the “watermelon seeding” phenomenon during coronary interventions for in-stent
restenosis. Catheter Cardiovasc Interv. 2005;66:521–527.

26. Cutting & Scoring Balloon Angioplasty
• The cutting balloon is an attractive and simple technique for treatment
of ISR. Theoretically, the device deeply incises neointimal tissue and
may favor its subsequent extrusion. The lateral blades of the device
anchor the balloon within the target lesion, preventing balloon
slippage-related complications.
• Initial observational data suggested that cutting balloons may have
superior efficacy compared to POBA, a finding which was associated
with a lower rate of target lesion revascularization (TLR) (12.5% vs.
40%) at follow-up. [1]
1. Montorsi P, Galli S, Fabbiocchi F, Trabattoni D, Ravagnani PM, Bartorelli AL. Randomized trial of conventional balloon angioplasty versus cutting balloon for in-
stent restenosis. Acute and 24-hour angiographic and intravascular ultrasound changes and long-term follow-up. Ital Heart J. 2004 Apr;5(4):271-9. PMID: 15185885.

27. • In the largest randomized trial (Restenosis Cutting Balloon Evaluation Trial [RESCUT]), cutting balloon
angioplasty comparing POBA failed to show an improvement in angiographic restenosis or in the rate of
clinical events at late follow-up.
Albiero R, Silber S, Di Mario C, Cernigliaro C, Battaglia S, Reimers B, Frasheri A, Klauss V, Auge JM, Rubartelli P, Morice MC, Cremonesi A, Schofer J, Bortone A,
Colombo A; RESCUT Investigators. Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis: results of the restenosis cutting
balloon evaluation trial (RESCUT). J Am Coll Cardiol. 2004 Mar 17;43(6):943-9. doi: 10.1016/j.jacc.2003.09.054. PMID: 15028348.

28. • Scoring balloons are based on the same principle as cutting balloons but
are especially attractive in patients with ISR due to their superior flexibility
and deliverability
de Ribamar Costa J Jr, Mintz GS, Carlier SG, Mehran R, Teirstein P, Sano K, Liu X, Lui J, Na Y,
Castellanos C, Biro S, Dani L, Rinker J, Moussa I, Dangas G, Lansky AJ, Kreps EM, Collins M,
Stone GW, Moses JW, Leon MB. Nonrandomized comparison of coronary stenting under
intravascular ultrasound guidance of direct stenting without predilation versus conventional
predilation with a semi-compliant balloon versus predilation with a new scoring balloon. Am J
Cardiol. 2007 Sep 1;100(5):812-7. doi: 10.1016/j.amjcard.2007.03.100. Epub 2007 Jun 13.
PMID: 17719325.

29. Debulking Techniques
• Debulking techniques such as directional/rotational atherectomy and excimer laser are a novel treatment for
ISR through their physical removal of neointimal tissue or neoatherosclerotic plaque.
• Early observational studies suggested that the use of laser or rotational atherectomy, followed by a POBA post-
dilation, was superior to conventional POBA alone in ISR [1]
1. Mehran R, Dangas G, Mintz GS, Waksman R, Abizaid A, Satler LF, Pichard AD, Kent KM, Lansky AJ, Stone GW, Leon MB. Treatment of in-stent restenosis with
excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results. Circulation. 2000 May 30;101(21):2484-9. doi:
10.1161/01.cir.101.21.2484. PMID: 10831522.
Favors ROTABLATION
• Randomized Trial of Rotational
Atherectomy Versus Balloon
Angioplasty for Diffuse In-Stent
Restenosis (ROSTER),
rotational atherectomy reduced
the amount of residual tissue
within the stent and the rate of
TLR at follow-up, compared
with POBA alone
Neutral for ROTABLATION
• In the Angioplasty Versus
Rotational Atherectomy for
Treatment of Diffuse In-
StentRestenosis Trial
(ARTIST), which compared
rotational atherectomy with
POBA alone, lower restenosis
rates, an improved safety profile
and superior clinical outcomes
were seen in the POBA group

30. • Recently, the value of debulking techniques in patients with DES-ISR has been re-evaluated with the latest
study showing greater acute luminal gain after percutaneous coronary intervention with excimer laser
atherectomy [1]
• Debulking techniques can be considered as a pre-treatment option for un-dilatable ISR lesions, especially
those as a result of severely under-expanded stents or calcified intrastent neo-atherosclerosis [2]
1. Ichimoto E, Kadohira T, Nakayama T, De Gregorio J. Long-Term Clinical Outcomes after Treatment with Excimer Laser Coronary Atherectomy for In-Stent
Restenosis of Drug-Eluting Stent. Int Heart J. 2018 Jan 27;59(1):14-20. doi: 10.1536/ihj.16-638. Epub 2018 Jan 15. PMID: 29332914.
2. Her AY, Shin ES. Current Management of In-Stent Restenosis. Korean Circ J. 2018 May;48(5):337-349. doi: 10.4070/kcj.2018.0103. PMID: 29737639; PMCID:
PMC5940640.

31. Excimer Laser Coronary Atherectomy
• However, it is to be noted that
use of ELCA was associated
with formation of intracoronary
microbubbles and was
associated with higher
incidence of periprocedural MI.
• Considering the limited data
and lack of randomized trials,
use of ELCA is still reserved
for selected lesions only.
Ichimoto E, Kadohira T, Nakayama T, De Gregorio J. Long-Term Clinical Outcomes after Treatment with Excimer Laser Coronary Atherectomy for In-Stent Restenosis
of Drug-Eluting Stent. Int Heart J. 2018 Jan 27;59(1):14-20. doi: 10.1536/ihj.16-638. Epub 2018 Jan 15. PMID: 29332914.

32. Vascular Brachytherapy
• Brachytherapy was one of the most promising treatment options for patients with neointimal hyperplasia
related to BMS-ISR. It involved temporary intracoronary deposition of a radioactive isotope within the
diseased segment, which led to significantly reduced clinical and angiographic restenosis rates. Randomized
clinical trials in patients with ISR showed it to be more effective in preventing ISR progression and improving
clinical outcomes than either POBA or debulking procedures with laser or atherectomy.
• However, the advent of DES signaled the end of brachytherapy.
• Finally, the complexity of the procedure, as well as issues with radioprotection/radiation dosing, led to the
virtual abandonment of this strategy.
Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-
radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001 Jan 25;344(4):250-6. doi: 10.1056/NEJM200101253440402. PMID:
11172151.

33. Sirolimus-Eluting Stents
versus Vascular
Brachytherapy for In-
Stent Restenosis Within
Bare-Metal Stents (SISR)
Paclitaxel-Eluting Stents
versus Vascular Brachytherapy
for In-Stent Restenosis Within
Bare-Metal Stents (TAXUS V
ISR).

34. • This may be related to incompetent and dysfunctional endothelial coverage of the stented segment, which allows a greater
number of lipoproteins to enter the subendothelial space. This process can be accelerated with the combination of VBT and
DES

35. Repeat stenting with BMS
• Early studies suggested that the problem of early tissue loss, which was seen with POBA, was virtually eliminated with the
use of BMS, which gave credence to the possible superiority of stenting over POBA in the treatment of ISR.
• In the Restenosis Intra-stent Balloon Angioplasty Versus Elective Stenting (RIBS I) trial, patients with BMS-ISR, were
randomized to receive either POBA or repeat BMS implantation, with acute angiographic results being significantly better
after BMS placement due to a larger acute gain
• However, at 6-month follow-up, significant late lumen loss in the BMS group resulted in the final angiographic appearance
being similar in both groups.

36. Repeat stenting with DES
• In de novo lesions, DES produce a profound inhibition of
neointimal proliferation. Therefore, the use of DES has
become an attractive option in the treatment of
neointimal hyperplasia in BMS-ISR.
• The Intracoronary Stenting or Angioplasty for Restenosis
Reduction-Drug-Eluting Stents for In-Stent Restenosis
(ISAR-DESIRE) trial was the first randomized study
assessing the value of DES in patients with BMS-ISR.
The rate of recurrent restenosis was significantly lower
with sirolimus- (14.3%) and paclitaxel-DES (21.7%)
compared with POBA alone (44.6%)
Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, Schühlen H, Schmitt C, Dirschinger J, Schömig A; ISAR-DESIRE Study Investigators.
Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized
controlled trial. JAMA. 2005 Jan 12;293(2):165-71. doi: 10.1001/jama.293.2.165. PMID: 15644543.

37. • Restenosis Intrastent: Balloon Angioplasty Versus
Elective Sirolimus-Eluting Stenting (RIBS II)
trial, which compared sirolimus-DES versus
POBA in patients with BMS-ISR, patients with
sirolimus-DES had a significantly lower restenosis
rate (11%) and superior long-term clinical
outcomes
Alfonso F, Pérez-Vizcayno MJ, Hernandez R, Bethencourt A, Martí V, López-Mínguez JR, Angel J, Mantilla R, Morís C, Cequier A, Sabaté M, Escaned J, Moreno R, Bañuelos C, Suárez A,
Macaya C; RIBS-II Investigators. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon
Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial. J Am Coll Cardiol. 2006 Jun 6;47(11):2152-60. doi: 10.1016/j.jacc.2005.10.078. PMID: 16750678.
Alfonso F, Pérez-Vizcayno MJ, Hernández R, Bethencourt A, Martí V, López-Mínguez JR, Angel J, Iñiguez A, Morís C, Cequier A, Sabaté M, Escaned J, Jiménez-Quevedo P, Bañuelos C, Suárez
A, Macaya C; RIBS-II Investigators. Long-term clinical benefit of sirolimus-eluting stents in patients with in-stent restenosis results of the RIBS-II (Restenosis Intra-stent: Balloon angioplasty vs.
elective sirolimus-eluting Stenting) study. J Am Coll Cardiol. 2008 Nov 11;52(20):1621-7. doi: 10.1016/j.jacc.2008.08.025. PMID: 18992651.

38. • However, the treatment of DES-ISR is more challenging, and overall, the outcomes in patients requiring
treatment for DES-ISR are worse compared with patients with BMS-ISR
• It is proposed that DES-ISR that results from a mechanical complication (such as stent under-sizing, edge
dissection or stent fracture) can be successfully overcome by placing another DES.
• However, debate regarding whether to use a DES eluting the same or a similar type of drug (homo-DES
approach) versus a switch to a different type of drug (hetero-DES approach) has continued.
• The benefits of a switch approach are based on the hypothesis that it might overcome drug resistance or
polymer-related problems
• Overall, results remain inconclusive, and the evidence favoring a switch strategy is weak.
Kastrati A, Byrne R. New roads, new ruts: lessons from drug-eluting stent restenosis. JACC Cardiovasc Interv. 2011 Feb;4(2):165-7. doi: 10.1016/j.jcin.2010.11.008.
PMID: 21349454.

39. The Restenosis Intra-Stent: Balloon
Angioplasty vs Drug-Eluting Stent
(RIBS III) trial concluded that in
patients with DES-ISR (Sirolimus)
implantation with switch strategy
provides superior late clinical and
angiographical results than other
modalities.
The ISAR-DESIRE 2 (Intracoronary
Stenting and Angiographic Results:
Drug Eluting Stents for In-Stent
Restenosis 2) study concluded that
treatment with either repeat SES or
switch to PES was associated with a
comparable degree of efficacy and
safety

40. • The findings from this analysis of the ISAR-DESIRE and ISAR-DESIRE 2
trials shows that the efficacy of sirolimus-eluting but not paclitaxel-eluting
stents is significantly reduced when used for treatment of SES restenosis as
compared to bare metal stent restenosis. The lower antirestenotic efficacy
following SES implantation in patients with SES restenosis lends support
to the hypothesis that drug resistance plays a role in restenosis within these
stents..
Byrne RA, Cassese S, Windisch T, King LA, Joner M, Tada T, Mehilli J, Pache J, Kastrati A. Differential relative efficacy between drug-eluting stents in patients with bare metal and drug-eluting
stent restenosis; evidence in support of drug resistance: insights from the ISAR-DESIRE and ISAR-DESIRE 2 trials. EuroIntervention. 2013 Nov;9(7):797-802. doi: 10.4244/EIJV9I7A132. PMID:
23687095.

41. Despite these benefits of repeat stenting with DES in the management of DES-ISR,
current data suggests that 10–20% of these patients will go on to develop recurrent
ISR.
Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, Schühlen H, Schmitt C, Dirschinger J, Schömig A; ISAR-DESIRE Study Investigators.
Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized
controlled trial. JAMA. 2005 Jan 12;293(2):165-71. doi: 10.1001/jama.293.2.165. PMID: 15644543.

42. Bioresorbable Vascular Scaffolds
• BVS have also been proposed as
treatment for patients with ISR. The
main advantages are that the device
eventually disappears from the vessel
wall, avoiding the presence of multiple
stent layers, and prevents early lumen
loss associated with tissue retraction
seen in balloon angioplasty.
• Further clinical data are needed to
assess the role of bioresorbable
vascular scaffold in ISR.
Moscarella E, Tanaka A, Ielasi A, Cortese B, Coscarelli S, De Angelis MC, Piraino D,
Latib A, Grigis G, Bianchi R, Buccheri D, Calabrò P, Tespili M, Silva Orrego P, Colombo
A, Varricchio A. Bioresorbable vascular scaffold versus everolimus-eluting stents or drug
eluting balloon for the treatment of coronary in-stent restenosis: 1-Year follow-up of a
propensity score matching comparison (the BIORESOLVE-ISR Study). Catheter
Cardiovasc Interv. 2018 Oct 1;92(4):668-677. doi: 10.1002/ccd.27473. Epub 2018 Jan 22.
PMID: 29356269.

43. Drug Coated Balloons
• The development of DCB enabled deliver of anti-proliferative drug to the area of ISR without leaving behind
an additional layer of stent strut
• Although the value of DCB in de novo lesions remains controversial, the use of DCB has been to proven to be
very effective in patients with both BMS-ISR and DES-ISR
• DCBs, while not commercially available for use in coronary arteries in the United States, are widely available
worldwide. DCBs are recommended by European Society of Cardiology guidelines as a treatment option
(Class I, Level of Evidence: A)
Her AY, Shin ES. Current Management of In-Stent Restenosis. Korean Circ J. 2018 May;48(5):337-349. doi: 10.4070/kcj.2018.0103. PMID: 29737639; PMCID:
PMC5940640.

44. Her AY, Shin ES. Current Management of In-Stent Restenosis. Korean Circ J. 2018;48(5):337-349. doi:10.4070/kcj.2018.0103

45. In patients with coronary ISR, repeat
stenting with DES is moderately more
effective than angioplasty with DCB at
reducing the need for TLR at 3 years.
The incidence of a composite of all-
cause death, myocardial infarction, or
target lesion thrombosis was similar
between groups.
Giacoppo D, Alfonso F, Xu B, et al. Paclitaxel-coated balloon angioplasty vs. drug-eluting stenting for the treatment of coronary in-stent restenosis: a comprehensive,
collaborative, individual patient data meta-analysis of 10 randomized clinical trials (DAEDALUS study). Eur Heart J. 2020;41(38):3715-3728.
doi:10.1093/eurheartj/ehz594

46. DCB v/s DES
Kokkinidis DG, Prouse AF, Avner SJ, Lee JM, Waldo SW, Armstrong EJ. Second-generation drug-eluting stents versus drug-coated balloons for the treatment of coronary in-stent restenosis: A
systematic review and meta-analysis. Catheter Cardiovasc Interv. 2018 Aug 1;92(2):285-299. doi: 10.1002/ccd.27359. Epub 2017 Oct 10. PMID: 29024274.

47. Integrated Approach- DEB+ELCA
• At six-month follow-up the average
diameter stenosis had increased to 60 ±
26% (p=0.001)
• There were 28 patients with a moderate
degree of restenosis between 50% and
69% and 45 patients with a high grade
of restenosis between 70% and 99%.
• Further studies including DES
implantation along with this approach
are required.

48. Integrated Approach- DEB + Scoring Balloon
Neointimal
Modification With
Scoring
Balloon and Efficacy
of Drug-Coated
Balloon Therapy in
PatientsWith
Restenosis in Drug-
Eluting Coronary
Stents
[ISAR-DESIRE 4]

49. Integrated Approach- IVL & RA
• Combined IVL and RA for the treatment of in-stent neo-atherosclerosis with severe neointimal
calcification.
• Rotational atherectomy allows adequate lesion preparation and delivery of the IVL balloon-
catheter, the latter aiming to the circumferential treatment of in-stent coronary calcium deposits.
Chen G, Zrenner B, Pyxaras SA. Combined Rotational Atherectomy and Intravascular Lithotripsy for the Treatment of Severely Calcified in-Stent Neoatherosclerosis:
A Mini-Review. Cardiovasc Revasc Med. 2019 Sep;20(9):819-821. doi: 10.1016/j.carrev.2018.10.007. Epub 2018 Oct 27. PMID: 30409500.

50. Surgical Treatment of ISR- CABG
• One may consider CABG in the absence of satisfactory results with interventional therapies in
cases of multivessel DES with multivessel ISR, especially in diffuse or even single-vessel ISR at a
very critical location.

51. Bioengineered Stents ?
Role of Endothelial Progenitor Cells
The beneficial effects seen with most of the antiproliferative medications are found to
be hampered by the potential of late thrombotic events that seem to be related to
delayed vascular healing
Stent endothelialization after acute vascular injury results from either the local
recruitment of adjacent endothelial cells or blood-derived endothelial progenitor
cells (EPC) that adhere, differentiate, and populate the surface of the device
Hypothesized that by combining drug partitioning (abluminal delivery) with a cell-
capturing surface (anti-cd34), the antiproliferative effect of sirolimus could be
maintained while enhancing surface endothelialization.

52. • This was an animal study, which showed that
combined technology may promote a more
organized and appropriate vascular healing, a key
factor associated with favorable clinical outcomes
• Till date only REMEDEE trial has evaluated its
efficacy showing non-inferiority to PES.
Granada JF, Inami S, Aboodi MS, Tellez A, Milewski K, Wallace-Bradley D, Parker S, Rowland S, Nakazawa G, Vorpahl M, Kolodgie FD, Kaluza GL, Leon MB, Virmani R. Development of a novel prohealing
stent designed to deliver sirolimus from a biodegradable abluminal matrix. Circ Cardiovasc Interv. 2010 Jun 1;3(3):257-66. doi: 10.1161/CIRCINTERVENTIONS.109.919936. Epub 2010 May 4. PMID: 20442358.

53. Haude M, Lee SWL, Worthley SG, Silber S, Verheye S, Rosli MA, Botelho R, Sim KH, Abizaid A, Mehran R; REMEDEE Trial Investigators. The REMEDEE trial: 5-
Year results on a novel combined sirolimus-eluting and endothelial progenitor cells capturing stent. Catheter Cardiovasc Interv. 2020 May 1;95(6):1076-1084. doi:
10.1002/ccd.28483. Epub 2019 Sep 5. PMID: 31489742.

54. Why is COMBO stent not used in practice?
• Only one human study done with small sample size, which was under powered and with low-risk lesions only
hence conclusions of REMEDEE cannot be extrapolated to other patient populations.
• An extensive study program is underway to investigate the benefits of the Combo stent in comparison with
contemporary DES.
Jakobsen L, Christiansen EH, Maeng M, Kristensen SD, Bøtker HE, Terkelsen CJ, Madsen M, Raungaard B, Jensen SE, Christensen MK, Hansen HS, Jensen LO.
Randomized clinical comparison of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent with the sirolimus-eluting Orsiro stent in patients treated
with percutaneous coronary intervention: Rationale and study design of the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) X
trial. Am Heart J. 2018 Aug;202:49-53. doi: 10.1016/j.ahj.2018.04.019. Epub 2018 May 5. PMID: 29807307.

55. Role of Antioxidants?
• Probucol (A metanalysis showed beneficial effect on prevention of ISR after BMS implantation,
lacks randomized trials and no comparison done with DES in view of clear superiority.)
• Colchicine (micro particle delivery system has been evaluated which failed to show any beneficial
effect but was associated with nearby musculature toxicity in animal model hence abandoned)

56. Current Guidelines
Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Jüni P, Kastrati A Koller A, Kristensen SD,
Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R, Zembala MO; ESC Scientific Document Group. 2018 ESC/EACTS guidelines
on myocardial revascularization. Eur Heart J. 2019;40:87–165. doi: 10.1093/eurheartj/ehy394

57. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R,
Moussa ID, Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation.
2011 Dec 6;124(23):e574-651. doi: 10.1161/CIR.0b013e31823ba622. Epub 2011 Nov 7. Erratum in: Circulation. 2012 Feb 28;125(8):e412. Dosage error in article text.
PMID: 22064601.

58. Proposed treatment algorithm for in-stent restenosis
Shlofmitz E, Iantorno M, Waksman R. Restenosis of Drug-Eluting Stents: A New Classification System Based on Disease Mechanism to Guide Treatment and State-of-
the-Art Review. Circ Cardiovasc Interv. 2019 Aug;12(8):e007023. doi: 10.1161/CIRCINTERVENTIONS.118.007023. Epub 2019 Jul 26. Erratum in: Circ Cardiovasc
Interv. 2019 Oct;12(10):e000044. PMID: 31345066.

59. THANK YOU