BackgroundData regarding management of patients with unprotected left main coronary artery in-stent restenosis (LM-ISR) are scarce.ObjectivesThis study investigated the safety and effectiveness of percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG) for the treatment of unprotected LM-ISR.MethodsConsecutive patients who underwent PCI or CABG for unprotected LM-ISR were enrolled. The primary endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE), defined as cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), and stroke.ResultsA total of 305 patients were enrolled, of which 203(66.6%) underwent PCI and 102(33.4%) underwent CABG. At 30-day follow-up, a lower risk of cardiac death was observed in the PCI group, compared with the CABG-treated group (2.1% vs. 7.1%, HR 3.48, 95%CI 1.01–11.8, p = 0.04). At a median of 3.5 years [interquartile range (IQR) 1.3–5.5] follow-up, MACCE occurred in 27.7% vs. 29.6% (HR 0.82, 95%CI 0.52–1.32, p = 0.43) in PCI- and CABG-treated patients, respectively. There were no significant differences between PCI and CABG in cardiac death (9.9% vs. 18.4%; HR 1.56, 95%CI 0.81–3.00, p = 0.18), MI (7.9% vs. 5.1%, HR 0.44, 95%CI 0.15–1.27, p = 0.13), or stroke (2.1% vs. 4.1%, HR 1.79, 95%CI 0.45–7.16, p = 0.41). TVR was more frequently needed in the PCI group (15.2% vs. 6.1%, HR 0.35, 95%CI 0.15–0.85, p = 0.02).ConclusionsThis analysis of patients with LM-ISR revealed a lower incidence of cardiac death in PCI compared with CABG in short-term follow-up. During the long-term follow-up, no differences in MACCE were observed, but patients treated with CABG less often required TVR.Visual overviewA visual overview is available for this article.Registrationhttps://www.clinicaltrials.gov; Unique identifier: NCT04968977.