In-stent restenosis (ISR) is the most frequent late complication of stent implantation and occurs when there is a reoccurrence of stenosis in a lesion that was previously treated with a stent. In stent restenosis results from exaggerated neointimal formation. The lesion is primarily composed of smooth muscle cells and extracellular matrix. Intravascular ultrasound studies demonstrate that in stent restenosis is not due to extrinsic compression of the stent by scar tissue (i.e. there is not compression of the stent).
In the drug-eluting stent era the mechanisms of in-stent restenosis are recognized to be multiple rather than single. Neointimal hyperplasia remains one mechanism, but neoatherosclerosis developing within the stented segment, stent underexpansion and stent fracture each account for a substantial share of cases, and these mechanisms cannot be distinguished from one another on angiography. Intracoronary imaging with intravascular ultrasound or optical coherence tomography is therefore used to establish the mechanism before the lesion is treated, and the treatment selected follows from what the imaging shows. Repeat implantation of a drug-eluting stent is the reference percutaneous treatment. Drug-coated balloon angioplasty, which leaves no additional metal in the vessel, became available in the United States for this indication in 2024 and is an alternative where further stent layers are undesirable. Coronary artery bypass grafting and intracoronary brachytherapy have defined roles in recurrent, diffuse and multilayer disease.
Epidemiology and Demographics
Although ISR has traditionally occurred in 30-40% of treated lesions, its incidence has been dramatically reduced by the development of drug-eluting stents.
After drug-eluting stent implantation, in-stent restenosis and the resulting need for repeat revascularization continue to occur at a rate of 1% to 2% per year.[2]
With second-generation drug-eluting stents the restenosis rate is 5.7% in patients without diabetes and 8.7% in patients with diabetes, and the 5-year restenosis rate is 9% to 12% in non-complex lesions.[1]
In-stent restenosis should not be regarded as a benign process: approximately one quarter of cases present as acute myocardial infarction, with a 30-day mortality of 10% to 25%.[1]
Classification
The angiographic pattern of restenosis should be recorded, because it predicts recurrence: pattern I is focal disease 10 mm or less in length, pattern II is disease longer than 10 mm confined within the stent, pattern III is disease longer than 10 mm extending beyond the stent margins, and pattern IV is a totally occluded stent.[3]
The need for repeat target lesion revascularization rises steeply from the focal to the occlusive pattern, so diffuse and occlusive patterns should prompt consideration of a strategy other than repeat balloon angioplasty alone.[3]
Restenosis within a drug-eluting stent should additionally be classified by mechanism on intracoronary imaging as mechanical (stent underexpansion or stent fracture), biological (neointimal hyperplasia, or non-calcified or calcified neoatherosclerosis), mixed, occlusive, or occurring in a segment already carrying more than two stent layers, because each mechanism calls for a different treatment.[4][1]
An increased number, overlap, and length of stents
Implantation without intracoronary imaging guidance; image-guided stenting at the index procedure should be used to minimize the occurrence of stent failure[1]
Treatment
The major goal of treating in-stent restenosis is to minimize the chance of recurrent restenosis. If a bare metal stent develops ISR, then a drug eluting stent should be placed. If ISR develops in a drug eluting stent, there is no data to suggest that a different type of drug eluting stent will prevent a recurrence (e.g. switching from sirolimus to paclitaxel). While use of a cutting balloon may improve acute angiographic results, there is no data to suggests that the use of a cutting balloon reduces the risk of a recurrence. Radiation treatment or brachytherapy was used in the past to treat ISR, but this procedure was associated with a higher rate of late stent thrombosis, and had fallen out of favor.
Imaging should be used to separate stent underexpansion and stent fracture from neointimal hyperplasia and from neoatherosclerosis, and to establish how many stent layers are present at the lesion.[1][4]
Where imaging demonstrates underexpansion, the stent should be expanded before any antiproliferative treatment is delivered, because an antiproliferative device does not correct a mechanical problem.[1]
Lesion Preparation
An underexpanded stent should first be treated with an appropriately sized high-pressure non-compliant balloon.[1]
Neointimal modification with a scoring balloon before drug-coated balloon angioplasty improves the angiographic antirestenotic result compared with predilatation using a standard balloon, although the randomised evidence was not powered for clinical events.[6]
Repeat stenting adds a further layer of metal, and the number of layers already present should be weighed before restenting, since accumulating layers reduce the available lumen and are associated with a higher rate of further recurrence.[1][2]
A drug-coated balloon should not be delivered until predilatation has produced a satisfactory result, taken as a residual stenosis of 50% or less.[7]
Because it leaves no additional metal behind, drug-coated balloon angioplasty is favoured where several stent layers are already present, where a side branch would be jailed by a further stent, or where prolonged dual antiplatelet therapy is undesirable.[1]
For restenosis occurring within a drug-eluting stent, repeat drug-eluting stenting is moderately more effective than paclitaxel-coated balloon angioplasty at preventing target lesion revascularization to three years, while death, myocardial infarction and target lesion thrombosis occur at similar rates with the two strategies.[8]
The evidence is not uniformly one-sided. At ten years, the randomised comparison of paclitaxel-coated balloon against paclitaxel-eluting stent for drug-eluting stent restenosis showed broadly comparable clinical outcomes, so the choice between the two strategies remains unsettled and should be made lesion by lesion.[10]
Vascular Brachytherapy
Intracoronary brachytherapy may be considered for recurrent in-stent restenosis to improve symptoms, and is used in particular where the lesion already carries several stent layers.[5][1]
Establish whether the mechanism is mechanical, biological, or mixed, and count the stent layers present
Routine intracoronary imaging is strongly recommended for every ISR lesion, since angiography alone cannot reliably distinguish stent underexpansion from neointimal hyperplasia or neoatherosclerosis; imaging is used both to select the treatment strategy and to confirm an effective result after treatment.[1]
Target an IVUS-optimized minimal stent area >5.0 mm² or an OCT-optimized minimal stent area >4.5 mm², since a suboptimal minimal stent area is a major predictor of subsequent stent failure.[1]
Neointimal hyperplasia → lesion preparation, then an antiproliferative treatment
Calcified neoatherosclerosis → calcium modification before any antiproliferative treatment
For focal neointimal hyperplasia, a high-pressure or scoring/cutting balloon alone may be sufficient, with excimer laser coronary atherectomy or atherectomy reserved for selected cases; for diffuse neointimal hyperplasia, atherectomy or scoring/cutting balloon angioplasty followed by repeat drug-eluting stent implantation is typically advised.[1]
Any major edge dissection (>60°, >3 mm in length, or penetrating the media) should be treated with additional stenting.[1]
When imaging identifies a peri-stent calcium arc >270° or >0.67 mm in thickness, atherectomy vessel preparation should be considered to optimize lesion and stent expansion.[1]
Repeat drug-eluting stent implantation is recommended (Class I, Level of Evidence A) when the anatomy is suitable and the patient can comply with prolonged dual antiplatelet therapy.[5]
Drug-coated balloon angioplasty and repeat drug-eluting stent implantation produce similar outcomes for restenosis of a bare-metal stent, but repeat drug-eluting stent implantation is more effective than drug-coated balloon angioplasty for restenosis of a drug-eluting stent.[11]
More recent comparative meta-analyses report broadly similar clinical outcomes between drug-coated balloon angioplasty and repeat drug-eluting stent implantation, although guideline recommendations continue to favor repeat drug-eluting stent implantation where anatomy and dual antiplatelet therapy tolerance permit.[12]
Adverse events with drug-coated balloon angioplasty are increased when treating a segment with more than two existing stent layers, but not with one or two prior stents.[1]
Step 5: Manage recurrence after repeated failure[5]
Symptomatic recurrent diffuse restenosis with suitable anatomy and acceptable operative risk → coronary artery bypass grafting
Repeated recurrence not amenable to surgery → intracoronary brachytherapy
Multilayer (more than two stents) underexpanded ISR is particularly recalcitrant to standard treatment; intracoronary brachytherapy is often reserved for this setting.[1]
Surgical revascularization should be considered in discussion with the patient once several interventional procedures have failed.[1]
2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)[13]
"1. In patients who develop clinical in-stent restenosis (ISR) for whom repeat PCI is planned, a DES should be used to improve outcomes if anatomic factors are appropriate and the patient is able to comply with DAPT. (Level of Evidence: A)"
"1. In patients with symptomatic recurrent diffuse ISR with an indication for revascularization, CABG can be useful over repeat PCI to reduce recurrent events. (Level of Evidence: C-EO)"
↑ 3.03.1Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, Pichard AD, Kent KM, Stone GW, Leon MB (1999). "Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome". Circulation. 100 (18): 1872–8. doi:10.1161/01.cir.100.18.1872. PMID10545431. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑ 4.04.14.2Shlofmitz E, Iantorno M, Waksman R (2019). "Restenosis of Drug-Eluting Stents: A New Classification System Based on Disease Mechanism to Guide Treatment and State-of-the-Art Review". Circulation: Cardiovascular Interventions. 12 (8): e007023. doi:10.1161/CIRCINTERVENTIONS.118.007023. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑ 5.005.015.025.035.045.055.065.075.085.095.10Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, Don CW, Fremes SE, Gaudino MF, Goldberger ZD, Grant MC, Jaswal JB, Kurlansky PA, Mehran R, Metkus TS, Nnacheta LC, Rao SV, Sellke FW, Sharma G, Yong CM, Zwischenberger BA (2022). "2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Journal of the American College of Cardiology. 79 (2): e21–e129. doi:10.1016/j.jacc.2021.09.006. PMID34895950Check |pmid= value (help). Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑Kufner S, Joner M, Schneider S, Tölg R, Zrenner B, Repp J, Starkmann A, Xhepa E, Ibrahim T, Cassese S, Fusaro M, Ott I, Hengstenberg C, Schunkert H, Abdel-Wahab M, Laugwitz KL, Kastrati A, Byrne RA (2017). "Neointimal Modification With Scoring Balloon and Efficacy of Drug-Coated Balloon Therapy in Patients With Restenosis in Drug-Eluting Coronary Stents: A Randomized Controlled Trial". JACC: Cardiovascular Interventions. 10 (13): 1332–1340. doi:10.1016/j.jcin.2017.04.024. PMID28683939. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑ 7.07.17.2Yeh RW, Shlofmitz R, Moses J, Bachinsky W, Dohad S, Rudick S, Stoler R, Jefferson BK, Nicholson W, Altman J, Bateman C, Krishnaswamy A, Grantham JA, Zidar FJ, Marso SP, Tremmel JA, Grines C, Ahmed MI, Latib A, Tehrani B, Abbott JD, Batchelor W, Underwood P, Allocco DJ, Kirtane AJ (2024). "Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial". JAMA : the Journal of the American Medical Association. 331 (12): 1015–1024. doi:10.1001/jama.2024.1361. PMID38460161Check |pmid= value (help). Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑Giacoppo D, Alfonso F, Xu B, Claessen BE, Adriaenssens T, Jensen C, Pérez-Vizcayno MJ, Kang DY, Degenhardt R, Pleva L, Baan J, Cuesta J, Park DW, Schunkert H, Colleran R, Kukla P, Jiménez-Quevedo P, Unverdorben M, Gao R, Naber CK, Park SJ, Henriques JP, Kastrati A, Byrne RA (2020). "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)". European Heart Journal. 41 (38): 3715–3728. doi:10.1093/eurheartj/ehz594. PMID31511862. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, Banning AP, Budaj A, Buechel RR, Chiariello GA, Chieffo A, Christodorescu RM, Deaton C, Doenst T, Jones HW, Kunadian V, Mehilli J, Milojevic M, Piek JJ, Pugliese F, Rubboli A, Semb AG, Senior R, Ten Berg JM, Van Belle E, Van Craenenbroeck EM, Vidal-Perez R, Winther S (2024). "2024 ESC Guidelines for the management of chronic coronary syndromes". European Heart Journal. 45 (36): 3415–3537. doi:10.1093/eurheartj/ehae177. |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑Giacoppo D, Alvarez-Covarrubias HA, Koch T, Cassese S, Xhepa E, Kessler T, Wiebe J, Joner M, Hochholzer W, Laugwitz KL, Schunkert H, Kastrati A, Kufner S (2023). "Coronary artery restenosis treatment with plain balloon, drug-coated balloon, or drug-eluting stent: 10-year outcomes of the ISAR-DESIRE 3 trial". European Heart Journal. 44 (15): 1343–1357. doi:10.1093/eurheartj/ehad026. PMID36807512Check |pmid= value (help). Unknown parameter |month= ignored (help); |access-date= requires |url= (help)CS1 maint: Multiple names: authors list (link)
↑Giacoppo D, Alfonso F, Xu B, Claessen BEPM, Adriaenssens T, Jensen C, Pérez-Vizcayno MJ, Kang DY, Degenhardt R, Pleva L, Baan J, Cuesta J, Park DW, Kukla P, Jiménez-Quevedo P, Unverdorben M, Gao R, Naber CK, Park SJ, Henriques JPS, Kastrati A, Byrne RA (2020). "Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis". Journal of the American College of Cardiology. 75 (21): 2664–2678. doi:10.1016/j.jacc.2020.04.006. PMID32466881Check |pmid= value (help). Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
↑Maqsood MH, Zhang RS, Rawal N, Sella G, Kleiman NS, Bangalore S (2025). "Drug-Eluting Stent, Drug-Coated Balloon, or Plain Old Balloon Angioplasty for In-Stent Coronary Restenosis: Insights From a Mixed Treatment Comparison Meta-Analysis of Randomized Trials". Circulation: Cardiovascular Interventions. 18 (12): e015161. doi:10.1161/CIRCINTERVENTIONS.125.015161.CS1 maint: Multiple names: authors list (link)