Revascularization of chronic total occlusion (CTO) is still one of the most challenging types of percutaneous coronary intervention (PCI) procedures. Among PCIs for CTO, PCI for in-stent restenosis (ISR) CTO is thought to be the most difficult. ISR CTO is developed as a consequence of late thrombotic stenosis and/or slow diffuse restenosis [1] and has a reported incidence of 8% of all CTOs with bare metal stents (BMSs), with the overall CTO incidence estimated to be 5–10% [1, 2]. Even though ISR CTO is rare, it causes a considerable therapeutic burden, because PCI became the standard therapy for a considerable number of coronary artery diseases; thus, the absolute quantity of ISR CTOs is currently increasing.

Several studies have reported lower PCI success rate for BMS ISR CTO as compared to de novo CTO paired with BMS [1, 3, 4]. However, there are few data regarding the procedural success rate and clinical outcomes of ISR CTO PCI in the drug-eluting stent (DES) era. Furthermore, most studies about ISR CTO in the BMS era did not have enough data to evaluate long-term clinical outcomes of ISR CTO. Therefore, in the present study, we compared the procedural success rate and long-term clinical outcomes of ISR CTO and de novo CTO when paired with DES.

The present study has two major findings. First, procedural success rate was higher in the ISR CTO group than in the de novo CTO group in the propensity-matching analysis. Second, irrespective of successful revascularization of CTO, the long-term clinical prognosis of the ISR CTO group was significantly worse than that of the de novo CTO group, especially in terms of TLR.

ISR CTO lesions is still a challenging subset for successful CTO revascularization. In earlier period, the reported success rate of PCI for ISR CTO was lower than that of PCI for de novo CTO. Abbas reported a revascularization success rate for BMS ISR CTO of 63% (49 of 78 patients) and for de novo CTOs of 75% (164 of 235 patients) from 2002 to 2003 [3]. Werner et al. reported a success rate of 70% for DES ISR CTO and one of 85% for de novo CTO between 2005 and 2007 [1]. Along with the advancement of technique and devices for CTO PCI in the later period, the procedural success rate for DES ISR CTO between 2008 and 2010 was improved up to 86% in a separate study by Christopoulos et al. [7]. Herein, success rate of PCI in our study was high in DES ISR CTO and low in BMS ISR CTO, which are similar to the result of previous studies, and overall success rate of PCI for ISR CTO was higher than those of de novo CTO in propensity score-matching analysis. Mean J-CTO score, fluoroscopic time, and contrast volume was not different significantly between the two groups after propensity-matching, which demonstrate that the difficulty level of the procedure was similar between the groups.

Contrary to a previous BMS ISR CTO investigation [3], our study estimated a superior success rate for ISR CTO as compared to de novo CTO, which could be attributed to our larger number of DES ISR CTO cases. The mechanism for ISR development is different between DES and BMS [8, 9]. BMS ISR develops over a long period with smooth-muscle, cell-rich homogeneous tissue [10, 11]. Inside the stent, intimal hyperplasia is densely organized without fissuring, leading to ISR. This results in difficult guidewire penetration and balloon dilatation. In contrary to BMS ISR, DES ISR is made of hypo-cellular and proteoglycan-rich tissue [12, 13]. Thrombosis, the main mechanism of DES ISR, produces relatively softer ISR lesions than does BMS ISR. The current study showed that DES ISR CTO accounted for 79.3% of total ISR CTO, which might partially explain why success rate of PCI for ISR CTO was higher than that of de novo CTO. Therefore, the selection strategy for optimal wire passage of CTO segments should be different between BMS ISR CTO and DES ISR CTO.

The duration of ISR formation was also different between the two stent types [14]. Intimal hyperplasia formation in BMS usually peaks at 6 months and continues slowly afterward, while thrombosis in DES cases occurs within a relatively short period [15]. DES ISR can occur suddenly up to several years after implantation [12]. It is not clear how the formation time of CTO influences the difficulty of the procedure; however, when abundant collateral vessels are formed over a longer ISR period in BMS cases, the target vessel route can be confirmed and a retrograde procedure may be simpler to perform in these instances [16, 17].

As compared to PCI for de novo CTO, ISR CTO has both technical advantages and disadvantages. While wiring during PCI for de novo CTO frequently fails because of difficulty in finding the precise vessel route, it can be easier during PCI for ISR CTO, because the previous stent acts as a road map of the target vessel [18]. Furthermore, a previously implanted stent prevents vessel dissection or injury during PCI for ISR CTO.

Although vessel routes can be easily found in ISR CTO cases, the wire frequently gets caught by the strut of the initial stent or is undermined by the previous stent. Subintimal tracking and wire reentry to the true lumen are also not easily performed in ISR CTO cases, and it can be hard to advance a new stent in cases in which a deformity in the previous stent developed during balloon passage. Balloon and stent under expansion can also occur in ISR CTO cases. In addition, a newly implanted stent is often in conflict with a previous stent [4, 19].

Clinical outcomes of ISR CTO were worse than those of de novo CTO after successful revascularization with respect to MACEs, which was mainly driven by higher incidence of TLR and tended to be associated with higher incidence of MI, in our data. ISR has been shown not to be a benign clinical condition [8, 20, 21]. Rathore et al. [8] reported that approximately 18% of patients in their study with ISR presented with ACS, with 2% presenting with MI. Additionally, MI incidence of BMS and first-generation DES was about 10% in the study by Magalhaes et al. [21]. Our results showed that the TLR rate of ISR CTO group at 5 years of follow-up was higher than in the de novo CTO group, a finding which was deemed to be associated with a higher incidence of MI of the ISR CTO group.

We also found that stenting for ISR CTO was an important risk factor of MI and TLR. Very long or multiple stent implantations for full lesion coverage are known to be risk factors of restenosis after PCI [22, 23]. Therefore, the most likely explanation for our findings is that multi-layered stenting is associated with abnormal vessel reaction and thrombus formation. In addition, stent recoiling generated from two stent layers might increase the risk of underexpansion. As there are concerns about worse clinical outcomes due to multi-layered stent as we found, so interventionist might consider using of drug-coated balloons rather than DES in the treatment of ISR CTO lesions [24, 25]. Severe impairment of vasomotor tone occurs after PCI for CTO [26], which results in changes in blood-flow dynamics and subsequent high susceptibility to thrombus formation and/or atherosclerotic progression. Therefore, precise analysis of tissue characteristics such as calcium distribution and anatomical morphology of CTO segments such as lumen size, vessel size, lesion length, plaque burden, and optimal lesion preparation is extremely important for successful wiring and optimal stenting, which might be relevant to long-term stent patency. Modern imaging techniques, including coronary computed tomography angiogram, intravascular ultrasound, and optical coherence tomography, enable us to conduct examinations prior to and during PCI for ISR CTO [27, 28]. Due to the guidance using these advanced imaging technologies, results of wire passage and optimal stent implantation are improving [29‐31].

The procedural success rate was higher in the ISR CTO than in the de novo CTO, especially in DES ISR CTO. However, irrespective of successful revascularization, the long-term clinical prognosis of the ISR CTO was significantly worse than that of the de novo CTO, in terms of MI and TLR.