Stent implantation is an effective therapy for coronary artery disease. However, ISR has always been one of the most common complications, even in the era of DES. Thus, establishing a predication model of ISR for risk-tailored screening and preventive measure implementation may be pivotal to improve clinical outcomes of patients undergoing PCI. In the present study, five clinical and angiographic characteristics including the history of prior PCI, glycemia, stents in LAD, the type of stent, and absence of clopidogrel were found to independently predict ISR in DES recipients. Moreover, the nomogram prediction model based on these independent factors was constructed and validated, which could provide clinicians with a simple-to-use clinical tool for individualized assessments of patients with high-risk of ISR. Notably, visually and prospectively informing patients of the benefits of risk factor control may improve the patient's understanding of treatment and compliance of therapies, which has great significance for reducing the risk of ISR after stent implantation.
Although the exact mechanism of ISR in DES is unclear and probably multifactorial, it is currently accepted that factors including biological, mechanical, and technical issues can facilitate the adverse neointimal hyperplasia and contribute to ISR after stent implantation . Several studies have attempted to identify the independent predictors of ISR. Stolker et al  developed a risk model for predicting restenosis of DES from the EVENT registry and identified age < 60, prior PCI, unprotected left main PCI, saphenous vein graft PCI, minimum stent diameter ≤ 2.5 mm, and total stent length ≥ 40 mm as the predictors of ISR. In another study evaluating the incidence and predictors of target vessel revascularization among 27,107 patients undergoing implantation of BMS or DES, significant predictors of restenosis included prior PCI, emergency or salvage PCI, prior coronary artery bypass grafting (CABG), peripheral vascular disease, diabetes mellitus (DM), and angiographic characteristics . Lately, Zheng et al  analyzed 944 stented lesions from 394 patients with 2nd-generation DES implantation. Factors including DM, previous PCI, postprocedural diameter stenosis and CRP levels were found to independently predict target lesion revascularization. A large patient data pooled analysis from 6 prospective and randomized trials, which included 10,072 patients undergoing DES implantation, suggested that vessel diameter, DM, prior CABG, and prior PCI were patient- and lesion-related predictors of target lesion failure .
Individual predictors likely vary between different studies on account of difference in the complexity of patients and candidate variables. However, the overlap in predictive factors, such as prior PCI, prior CABG, and DM, are strongly interlinked with accelerated ISR and repeated target lesion revascularization. Similar to those found in previous studies identifying predictors of ISR, our study also indicates that patient populations with prior PCI and history of DM are prone to ISR.
A history of PCI, which was a consistent and independent predictor of ISR, is closely related to the primary risk factors of atherosclerosis and represents the overall risk of severe coronary lesions requiring further intervention. It is also reported that repeated revascularization is more likely to occur for culprit lesions at a site of previous restenosis . As for DM, patients have a higher risk of developing ISR due to the higher inflammatory response, endothelial dysfunction, platelet hyperreactivity and more aggressive neointimal hyperplasia accompanied by elevated plasma glucose levels [20, 21]. Generally, DM is associated with complicated coronary artery disease characterized by multivessel lesions and diffuse lesions in small vessels, which requires multiple stents with small diameter during PCI. Thus, it can explain at least partly why variables like the total length and minimum diameter of stents were not included in the prediction model in this study. In addition, a noteworthy finding of our study is that uncontrolled glycemia in patients with DM has more predictive value for ISR rather than DM itself ignoring whether the glycemia level is controlled or not.
Although several of the factors associated with ISR in our study are concordant with previous findings, some key predictors including stents in LAD, type of stent, and absence of clopidogrel have not been reported consistently in literature. Most studies suggested that coronary artery intervention restenosis was more frequent for lesions in the LAD than other native coronary arteries, confirming that the LAD may be another potential risk factor for ISR [22–24]. However, different views have also been proposed by other researchers. To the contrary, lesions located in the LAD were also reported to have a decreased restenosis rate [25, 26]. In fact, in the present study the results observed after stent implantation for LAD lesions were very similar to those observed in most studies and we believe that stents located in the LAD were associated with an elevated incidence of ISR. For lesions in LAD and other complicated lesions, intravascular ultrasound (IVUS), optical coherence tomography (OCT) and other coronary imaging techniques are recommended for optimizing the treatment strategy. In addition, our findings figured out that sirolimus-eluting stent (SES) was associated with a lower risk of ISR than paclitaxel-eluting stent (PES). Sirolimus and its analogs have a cytostatic effect on coronary artery endothelial cells, while paclitaxel has a cytotoxic effect. Several studies have also indicated that use of SES has a less late luminal loss [7, 27, 28] and a lower rate of late stent thrombosis , as compared with use of PES, suggesting a better performance of SES in reducing restenosis. Finally, drugs and polymers of DES can inhibit the excessive neointimal hyperplasia. However, it delays the repair of endothelial cells. Therefore, antiplatelet drugs are still the cornerstone in the treatment of coronary heart disease, especially after PCI. Gianluca et al investigated the clinical outcome of patients undergoing PCI for ISR with short (6 months) or long (24 months) dual antiplatelet therapy (DAPT) . The main findings of this study were that patients receiving revascularization for ISR may benefit from long-term administration of aspirin plus clopidogrel. Similarly, our study showed that the absence of clopidogrel increased the risk of ISR after PCI, suggesting the benefit of appropriately prolonged DAPT duration for patients with high risk of ISR after DES implantation.
Predictors identification and risk assessment are essential and important to an effective medical decision making for preventing restenosis. However, the levels of prognostic utility of prediction models of ISR in prior studies remained less than totally satisfying with c-statistic below 0.7 [8, 9, 17, 31]. In the present study, the best c-statistic derived from the nomogram model in the development set was 0.706 and was confirmed to be 0.662 in the validation set as well, suggesting that the distinct predictors improved the overall discrimination of the models. Moreover, calibration plots and decision curve analysis for the nomogram-based predication model were also performed well, making our findings more convincing and providing broad applicability in clinical practice.