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-25-00005 Mar 17, 2025
Unveiling the coronary acetylcholine test: can it help us predict future cardiovascular events?
Escaned J and Paolucci L
free

Flashlight

10.4244/EIJ-D-24-00248 Mar 17, 2025
Endovascular treatment of tandem lesions in a novel cadaveric stroke model
Grunwald I et al

Letter to the editor

10.4244/EIJ-D-24-00974 Mar 17, 2025
LETTER: An update on changes to the design of the ODIN trial
Sandner S et al
free
Trending articles
57.8

State-of-the-Art

10.4244/EIJ-D-24-00386 Feb 3, 2025
Mechanical circulatory support for complex, high-risk percutaneous coronary intervention
Ferro E et al
free
39.45

Clinical research

10.4244/EIJ-D-23-00725 Nov 19, 2023
A systematic algorithm for large-bore arterial access closure after TAVI: the TAVI-MultiCLOSE study
Rosseel L et al
free
39.45

Original Research

10.4244/EIJ-D-23-00725 Mar 18, 2024
A systematic algorithm for large-bore arterial access closure after TAVI: the TAVI-MultiCLOSE study
Rosseel L et al
free
36

State-of-the-Art

10.4244/EIJ-D-23-00448 Jan 15, 2024
Coronary spasm and vasomotor dysfunction as a cause of MINOCA
Yaker ZS et al
free
35.15

State-of-the-Art

10.4244/EIJ-D-23-00895 Apr 1, 2024
Percutaneous interventions for pulmonary embolism
Finocchiaro S et al
free
28.5

CLINICAL RESEARCH

10.4244/EIJV11I1A6 May 19, 2015
European expert consensus on rotational atherectomy
Barbato E et al
free
22.55

CLINICAL RESEARCH

10.4244/EIJV12I5A93 Aug 5, 2016
Longer pre-hospital delays and higher mortality in women with STEMI: the e-MUST Registry
Benamer H et al
free
X

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

EuroPCR EAPCI
PCR ESC
Impact factor: 7.6
2023 Journal Citation Reports®
Science Edition (Clarivate Analytics, 2024)
Online ISSN 1969-6213 - Print ISSN 1774-024X
© 2005-2025 Europa Group - All rights reserved