Drug eluting stents (DES) widely used in clinical practice have dramatically reduced subsequent repeat target lesion revascularizations (TLR) after percutaneous coronary intervention (PCI) [1, 2]. Nevertheless, it is far away from completely eliminating in stent restenosis (ISR). Current therapeutic strategies to address ISR include plain balloon angioplasty, cutting balloon angioplasty, repeat DES implantation, radiation therapy, and drug coated balloon (DCB) angioplasty. Among these strategies, repeat DES implantation and DCB angioplasty are the most effective methods for treatment of ISR [3]. Repeat DES implantation is the most preferred modality because DCB is not available in our hospital.

Diabetes mellitus (DM) has been an established predictor of TLR and major adverse cardiac events (MACEs) after PCI for coronary de novo lesions [4, 5]. The biologic effects of DM include leading to plaque growth, vascular instability and risk of thrombosis [4]. However, in DES era some studies have suggested that DM has no longer correlated with ISR [6, 7], while others still identify DM as a predictor of TLR [8]. Overall it is likely that DM is not a predictor of ISR for vein grafts and simple lesions (ACC/AHA type A/B1 lesions) and unprotected left main coronary artery lesions [5, 9, 10].

In the 2^nd generation DES era, whether DM remains a predictor of long-term adverse clinical outcomes after repeat DES implantation for DES-ISR is controversial [6‐8]. Resolving this question would help cardiologists choose the optimal therapy for these patients.

In order to evaluate the effect of DM on the long-term clinical outcomes in a consecutive series of patients undergoing repeat DES implantation for DES-ISR lesions, we compared 2-year MACEs between patients with DM and patients without DM from our PCI registry. The aim of this study was to discover whether DM is a predictor for MACEs in patients undergoing repeat DES after DES-ISR.

A dedicated data coordinating center performed all data management and analyses. Pre-specified clinical and demographic data, as well as clinical events during hospitalization, were collected from the hospital charts, reviewed by qualified personnel blinded to the objectives of the study, and entered prospectively into the database. Long-term clinical outcomes were conducted by clinic visit.

Data was collected for the occurrence of MACEs, defined as the combined incidence of death, MI, and TLR [12]. Death was defined as mortality from cardiac cause. MI was defined as typical ischemic chest pain and/or ST-segment and/or T-wave abnormalities with a creatine kinase isoenzyme-MB increase 2 times the reference values. We defined TLR as clinically driven revascularization of index lesion. A residual stenosis of <30% with TIMI-3 flow was defined as PCI angiographic success. Angiographic success without TLR, Q wave MI, or death prior to hospital discharge was defined as clinical success. We defined Chronic renal insufficiency (CRI) as patients receiving medical therapy or dialysis for chronic renal failure or have a creatinine level 2.0 mg/dL on admission.

All statistical analyses were performed using the SPSS statistical software package (version 17.0; SPSS Inc., Chicago, Illinois, USA). A normality test demonstrated a normal distribution of the data. We presented continuous variables as mean ± SD while categorical variables as frequencies (%). Unpaired Student’s t-test was used for comparison of continuous variables and categorical variables was compared using χ ² or Fisher’s exact tests. A Kaplan–Meier curve was plotted for the MACE-free survival of both groups using GraphPad Prism (version 5; GraphPad Software Inc., La Jolla, California, USA). Difference between groups was evaluated by a log-rank test. A censored data indicated the loss of follow up. A Cox regression analysis was performed to identify whether there is independent association between DM and higher incidence of MACEs. Variables were selected on the basis of overall clinical relevance, according to the previously published literature with particular attention paid to clinical and procedural factors that would make MACE more likely and included age, sex, hypertension, diabetes mellitus, chronic renal insufficiency, calcification lesion, bifurcation lesions, no-focal lesion and early restenosis. Statistical significance was defined as a P value less than 0.05.

The results reveal that there were no differences in the rate of 2-year MACEs in DM and non-DM groups in our study population (30.9% in DM group vs. 26% in non-DM group, P = 0.453).It indicates that DM is not a risk factor of poor long-term prognosis in patients undergoing repeat 2^nd generation DES implantation for DES-ISR (HR 1.531, 95%CI 0.882-2.658, P = 0.130).

Clinical use of DES has reduced the incidence of ISR, but treatment of DES-ISR is still challenging. [3, 13] The etiology of ISR remains unclear. Smooth muscle cell proliferation and neoatherosclerosis are the probable causes [14]. Clinical studies have proved that repeat DES implantation could acquire acceptable clinical and angiographic results for DES-ISR treatment [8‐18]. Intravascular ultrasound (IVUS) or optical coherence tomography (OCT) can give us more important details of lesion characteristics of DES-ISR, which may improve the clinical results of repeat DES for DES-ISR treatment [19, 20]. Unfortunately, IVUS or OCT was not used for every patient enrolled in our study. During the 2-year follow-up of our study, 25 MACEs including 20 TLR were observed in the DM group and 45 MACEs including 34 TLR in the non-DM group. More TLRs occurred in the current study than previous studies [15‐18]. In current study, follow-up period was 2 years which is relatively longer than that in previous studies [17, 18], which indicated that a longer follow-up period may contribute to the higher occurrence of TLR than before [14]. In addition, multivariable model analysis showed that non-focal and early ISR were the only two independent predictors of MACEs over the 2-year follow-up. Therefore, the angiographic type of DES-ISR, especially the non-focal type, and early phase of DES-ISR were highly associated with the TLR after repeat DES implantation. When our data was analyzed in terms of early and late occurrence of ISR we found that the differences in the rate of MACEs and TLR and TLR-free survival were significant only in the non-DM group. It is not clear why the occurrence of early ISR was not important for MACEs and in particular TLR in the DM group, but the DM subgroups were smaller than the non-DM subgroups so this may have influenced the analysis. Further studies are needed to investigate the mechanisms and better treatment methods for non-focal and early phase DES-ISR and whether these are influenced by DM.

It is well known that DM is a risk factor for MACE after PCI, but whether DM is still an independent predictor of ISR after PCI for all lesions is unknown in the DES era, especially in the 2^nd generation DES era. Previous studies have reported conflicting results [6‐8]. Some of them comparing outcomes after PCI with 2^nd DES suggest that DM no longer correlates with ISR [6, 7], whereas others confirm that DM is still a risk factor of TLR [8]. Therefore, some investigators have concluded that DM is no longer a predictor of ISR after DES implantation for specific populations, such as patients with vein graft lesions, simple lesions (ACC/AHA type A/B1 lesions) and unprotected left main [5, 9, 10]. This study suggests that in 2^nd generation DES era, DM is not an independent risk factor of MACE in patients accepting repeat DES implantation for DES-ISR. The 2^nd generation DES is better in reducing ISR than the 1^st generation DES and BMS, which correlates with similar 2-year rates of TLR and overall MACE between DM and non-DM patients with ISR lesions in this study. On the other hand, ISR lesions are different from coronary de novo lesions [21], which maybe in part contribute to these results in these special patients. At the same time, our study reveals that non-focal type and early ISR independently predict the adverse outcomes after PCI for DES-ISR with 2^nd generation DES, which indicates that mechanical factors underlying non-focal type or early ISR other than DM maybe play important roles in the repeat occurrence of ISR after PCI for DES-ISR lesions [22‐24].

Long term outcomes equate between DM and non-DM groups of patients when a 2^nd generation DES was used for treatment of DES-ISR. DM is not a predictor of long-term prognosis in patients undergoing repeat 2^nd generation DES for DES-ISR.