DOI:

Serial assessment of tissue growth inside and outside the stent after implantation of drug-eluting stent in clinical trials. - Does delayed neointimal growth exist?

Jiro Aoki1, MD; Alexandre C. Abizaid2, MD, PhD; Andrew.T.L. Ong1, MBBS, FRACP; Keiichi Tsuchida1, MD, PhD; Patrick W. Serruys*1, MD, PhD.

Although long term follow-up after drug-eluting stent (DES) implantation shows a sustained clinical benefit in several randomized trials, delayed neointimal growth beyond the first 6 to 9 months has been reported in serial intravascular ultrasound (IVUS) analyses in some trials. The issue of a delayed restenosis which was observed after brachytherapy has not been thoroughly evaluated with DES.

Tissue growth inside the stent (Neointima)

Drug-eluting stents (DES) dramatically reduce neointimal growth at 6 or 9 months compared to bare metal stents (BMS).1-3 Although long term follow-up after DES implantation shows a sustained clinical benefit in several randomised trials,4,5 little is known about neointimal growth beyond the first 6 to 9 months. The issue of a “late catch up phenomenon” (delayed restenosis) which was observed after brachytherapy has not been fully investigated with DES.6

In porcine models, the inhibition of neointimal hyperplasia after deployment of polymer-coated sirolimus-eluting stents was not sustained at 90 and 180 days due to delayed cellular proliferation, and neointimal suppression after deployment of chondroitin sulfate and gelatin coated paclitaxel-eluting stents was also not maintained at 90 days.7,8

In humans, neointimal tissue does not keep growing after BMS implantation. During long-term angiographic follow-up, compaction of neointima has been described in several reports.9-11 Histological analyses of post-mortem coronary arteries demonstrate that compaction of neointima occurs due to the replacement of water-trapping proteoglycans by decorin and type I collagen.11 Following DES implantation, neointima continues to grow during the follow-up period in some trials in which serial IVUS analyses were performed (Table 1).

A chronic arterial response towards the durable polymer and to the remaining drug within the polymer has been imputed to explain this phenomenon. However, this was also observed with Conor paclitaxel-eluting stents in which neither polymer nor drug is retained at the end of the programmed release period.12 The precise reason for this observation is thus still unclear, but may be related to the delayed healing response and persistent biological reaction caused by the drug soon after the implantation of DES. In view of the results of animal studies and clinical studies, DES may delay restenosis, instead of halting definitively the process of neointimal hyperplasia. Further follow-up is warranted to evaluate the long-term efficacy of DES.

Tissue growth outside the stent (Vessel remodeling)

Polymer based sirolimus-eluting stents (Cypher) and polymer based paclitaxel-eluting stents (Taxus) are used in daily practice, and several types of drugs and durable or erodable polymers have been tested in clinical trials.1,3,13,14 After BMS implantation, expansive vessel remodeling (i.e. increasing plaque outside the stent) was reported.15 In the TAXUS II trial, the increased plaque outside the stent 6 months after BMS implantation had regressed completely at 2 years (Table 2).16

Thus, it is likely that mechanical injury and biological reaction against the stainless steel stent that may have induced the inflammation, had subsided by 2 years. After sirolimus and everolimus-eluting stents implantation, increasing plaque area outside the stent was insignificant in both the First In Man (sirolimus)17 and SPIRIT FIRST (everolimus) trials18, whereas a significantly increasing plaque area behind the stent was observed with paclitaxel-eluting stents in the TAXUS II15 and PISCES trials19, and tissue growth exceeded the vessel reaction observed with BMS in both trials. The EPC capture stents induce the rapid establishment of a functional endothelial layer early in the healing response and the mean plaque volume outside the stent was similar immediately post procedure and at 6-month follow-up, demonstrating that overall expansive remodeling did not occur with this device.20

The vessel reaction outside the stent differs from the reaction observed inside the stent, and the different drugs, polymers, and pharmacokinetics result in various effects on tissue growth not only in the intrastent neointima but also on vessel remodeling outside the stent. Interestingly, the timing of regression of the plaque outside the stent was also different. For sirolimus-eluting stents, significant expansive plaque outside the stent was not observed during follow-up and shrinkage of plaque outside the stent occurred at 4 years.17 For paclitaxel-eluting stents, complete regression of expansive plaque outside the stent was observed at 2 years in the slow release group in TAXUS II trial, and partial regression was observed at 1 year in the PISCES and at 2 years in the moderate release group in the TAXUS II trial.12,16 The exact reason for these variant vascular responses is unknown. The tissue growth outside the stent may be more complex and heterogeneous, compared to tissue growth inside the stent. The tissue growth inside the stent consists of smooth muscle cell and a proteoglycan rich matrix, whereas the tissue growth outside the stent consists of several components; 1) cell proliferations and intracellular matrix, 2) oedema caused by mechanical injury and chemical injury due to drug, polymer and stent, 3) growth or regression of existing atherosclerotic plaque. Studies involving larger sample sizes and more detailed analyses with novel in vivo techniques of tissue characterisation may be necessary to assess and better understand the process of vessel remodeling after DES implantation.


References

Volume 1 Number 3
Nov 20, 2005
Volume 1 Number 3
View full issue


Key metrics

Suggested by Cory

Editorial

10.4244/EIJ-E-25-00027 Jul 7, 2025
Antithrombotic strategies after TAVI in light of cerebral microembolism
Dangas G and Nicolas J
free

Editorial

10.4244/EIJ-E-25-00028 Jul 7, 2025
The challenge of interpreting comparative TAVI studies
Rosseel L et al
free

Research Correspondence

10.4244/EIJ-D-24-01113 Jul 7, 2025
Restenosis patterns after percutaneous coronary intervention with drug-coated balloons for de novo coronary lesions
Matsuda K et al

Debate

10.4244/EIJ-E-25-00019 Jul 7, 2025
Colchicine benefits are overestimated and current recommendations are too strong: pros and cons
Bainey K and Rossello X

Expert Review

10.4244/EIJ-D-24-01003 Jul 7, 2025
Current and future applications of robotics in structural heart interventions
Chen X et al

Editorial

10.4244/EIJ-E-25-00024 Jul 7, 2025
The new balloon-expandable Myval transcatheter heart valve: only good news?
Pibarot P and Van Belle E
free
Trending articles
172.05

Focus article

10.4244/EIJY19M08_01 Jan 17, 2020
EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion – an update
Glikson M et al
free
79.55

State-of-the-Art

10.4244/EIJ-D-24-00066 Apr 21, 2025
Management of complications after valvular interventions
Bansal A et al
free
42

Original Research

10.4244/EIJ-D-25-00331 May 21, 2025
One-month dual antiplatelet therapy followed by prasugrel monotherapy at a reduced dose: the 4D-ACS randomised trial
Jang Y et al
open access
X

The Official Journal of EuroPCR and the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

EuroPCR EAPCI
PCR ESC
Impact factor: 9.5
2024 Journal Citation Reports®
Science Edition (Clarivate Analytics, 2025)
Online ISSN 1969-6213 - Print ISSN 1774-024X
© 2005-2025 Europa Group - All rights reserved