The persisting challenge of recurrent in-stent restenosis: a systematic review and meta-analysis of prevalence and prognostic risk factors

BACKGROUND: Recurrent in-stent restenosis (R-ISR) after percutaneous coronary intervention remains a clinically important failure mode, yet reported rates and predictors vary widely. We aimed to quantify the pooled incidence of R-ISR and synthesize multivariable risk factors. METHODS: A comprehensive literature search of the electronic database was updated on May 3, 2025. Studies reporting the incidence or analyzing the risk factors of R-ISR were eligible. Study quality was assessed using the Newcastle-Ottawa Scale. Data synthesis was achieved via random-effects meta-analysis using the R studio (version 4.4.3). Subgroup analyses considered region, treatment, and follow-up, with leave-one-out sensitivity analyses. The systematic review is reported in accordance with the PRISMA 2020 checklist. RESULTS: Twenty-three studies were included. The overall pooled incidence of R-ISR was 21.7% (95%CI 17.1%-27.2%), with variations by region (highest in Europe), treatment type (lowest with DES), and follow-up duration (highest within 6 months). Significant risk factors included renal disease (OR 3.90; 95%CI 1.87-8.11), non-focal restenosis (OR 3.29; 95%CI 2.41-4.49), lesion length (OR 1.15; 95%CI 1.06-1.24), heterogeneous tissue pattern (OR 3.36; 95%CI 1.69-6.67), stent fracture (OR 2.21; 95%CI 1.29-3.79), and higher percentage diameter stenosis (OR 1.05; 95%CI 1.03-1.06). Age showed non-significant association (OR 0.96; 95%CI 0.93-1.00). CONCLUSIONS: To our knowledge, this is among the first systematic reviews and meta-analyses specifically focused on recurrent ISR after treatment of ISR lesions. Renal disease, non-focal morphology, lesion length, heterogeneous tissue pattern, stent fracture and greater post-procedural percentage diameter stenosis were consistently associated with higher risk of R-ISR. These findings support individualized treatment selection with intensified secondary prevention and closer surveillance during the first six months after the recent percutaneous coronary intervention performed for ISR. PROSPERO REGISTRATION NUMBER: CRD420251043520.