What does this research mean for the field?

In-stent restenosis (ISR) is associated with worse outcomes than PCI for de novo lesions, with diabetes, chronic kidney disease, and small vessel caliber being key risk factors. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

This review examines the complex mechanisms and risk factors associated with in-stent restenosis to improve management outcomes.

February 11, 2026Open Access

In-Stent Restenosis Pathophysiology and Risk Factors: A Comprehensive Review

Q: What is the clinical evidence from this study?

Study design: Review. Population: Patients with in-stent restenosis presenting for evaluation of ISR clinical presentation (n=909). Primary outcome: Incidence of clinical presentation modes of ISR including acute coronary syndrome and non-acute coronary syndrome and their associated outcomes.

Key Result

In-stent restenosis presented as acute coronary syndrome in over 60% of patients, with 44% unstable angina, 44% non-ST-elevation MI, and 12% ST-elevation MI, and exhibited higher 6-month mortality despite early revascularization.

Key Points

This review examines the complex mechanisms and risk factors associated with in-stent restenosis to improve management outcomes.
Comprehensive literature review of in-stent restenosis pathophysiology and risk factors.
Analysis of clinical outcomes related to different stent types.
Examination of patient-level and lesion/procedural risk factors.
In-stent restenosis frequently presents as acute coronary syndrome.
Patient-level risk factors include diabetes, chronic kidney disease, and hypertension.
Intravascular imaging is vital for identifying the mechanisms of restenosis and guiding therapy.

PICO

Population

Patients with in-stent restenosis presenting for evaluation of ISR clinical presentation (n=909)

Primary Outcome

Incidence of clinical presentation modes of ISR including acute coronary syndrome and non-acute coronary syndrome and their associated outcomes

Main Result

Absolute Event Rate: 61% vs 40%

Limitations

Narrative non-systematic review without exhaustive literature retrieval
Selection and publication bias cannot be fully excluded
No new statistical analysis or meta-analysis performed
Lack of formal risk-of-bias appraisal for included studies
Insufficient data to support efficacy of intravascular imaging due to small ISR incidence and unclear use of imaging data

Abstract

In-stent restenosis (ISR) remains a clinically relevant cause of recurrent ischemia and repeat revascularization despite progressive refinements in stent design and implantation technique. Contemporary data indicate that restenosis-related target lesion revascularization (TLR) has declined from bare-metal stent (BMS) to early- and newer-generation drug-eluting stents (DESs), yet ISR continues to accumulate over long-term follow-up and is associated with worse outcomes than PCI for de novo lesions. Mechanistically, ISR is a time-dependent, heterogeneous process dominated early by neointimal hyperplasia—triggered by mechanical endothelial injury, delayed re-endothelialization, inflammation/oxidative stress, vascular smooth muscle cell phenotypic switching, and extracellular matrix deposition—and later by in-stent neoatherosclerosis, which may confer a higher-risk plaque substrate and overlap with thrombotic complications. Clinically, ISR frequently presents as an acute coronary syndrome (ACS) rather than stable symptoms, underscoring the prognostic relevance of prompt recognition and mechanism-informed management. Patient-level risk determinants repeatedly reported across cohorts include diabetes mellitus, chronic kidney disease, dyslipidemia, hypertension, and smoking, while lesion/procedural factors include small vessel caliber, long/complex or bifurcation lesions, multiple stent layers, and suboptimal stent expansion. Intravascular imaging (OCT/IVUS) is central to phenotyping ISR mechanisms (e.g., underexpansion, calcific neoatherosclerosis, stent fracture, homogeneous hyperplasia) and can guide targeted prevention and therapy. This review synthesizes current evidence on ISR biology and risk factors to support risk stratification, preventive strategies, and individualized management.

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