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.

Background and Objectives: Percutaneous coronary intervention (PCI) has markedly improved outcomes in coronary artery disease through the implantation of bare-metal stents (BMS) or drug-eluting stents (DES). However, in-stent restenosis (ISR) remains a significant complication, often necessitating repeat interventions. This study aimed to identify risk factors associated with ISR in patients with ST-elevation myocardial infarction (STEMI) who underwent PCI. Materials and Methods: We conducted a retrospective, non-randomized observational study of 107 STEMI patients treated with PCI between January 2016 and December 2019 who subsequently underwent clinically indicated (predominantly symptom-driven) follow-up coronary angiography within 12 months. ISR was defined as ≥50% luminal narrowing at follow-up angiography. Time-to-event analysis was performed using Cox regression models, incorporating clinical, biochemical, and angiographic variables. Results: In this selected cohort of patients undergoing follow-up angiography, ISR of any degree was identified in 87% of patients, and 52% had restenosis >70%. Advanced age, prior cardiovascular events, diabetes mellitus, chronic kidney disease, and history of stroke significantly increased the hazard of ISR. Smoking, dyslipidemia, and hypertension were prevalent in patients with severe ISR. Women presented with more severe clinical profiles (higher Killip class and troponin levels). DES showed slightly better TIMI flow than BMS, but stent type, dimensions, and number did not significantly impact restenosis risk. Thrombolytic therapy was associated with a significantly reduced ISR hazard. Mortality was 6% in patients with severe ISR. The highest restenosis incidence occurred in the LAD and RCA territories. Conclusions: ISR is a multifactorial process influenced by demographic, clinical, and procedural factors. Despite technological advances, ISR remains a prevalent issue, particularly in high-risk groups undergoing clinically indicated follow-up angiography. Secondary prevention strategies, optimized stent deployment, and targeted therapies addressing inflammation and vascular remodeling are essential to improving long-term PCI outcomes.