Instent chronic total occlusion (IS-CTO) is defined as complete occlusion for at least 3 months at a stent site or within 5 mm proximal or distal to the stent. The pathophysiology of instent restenosis (ISR) is incompletely understood, but potential mechanisms include significant neointima formation, thrombus, stent under-expansion, stent deformation, vessel calcification, and/or neo-atherosclerosis [1]. The incidence of IS-CTO ranges between 5 and 25% of CTOs with a large multicenter registry that included 11,728 patients with CTOs from 107 medical centers reporting an incidence of IS-CTO of 15% [2]. Percutaneous procedural success rates in IS-CTO using current techniques are generally similar to success rates in de novo CTO, but there are higher rates of MACE in long-term follow-up, mainly driven by target lesion revascularization (TLR) [2,3,4].

While there are numerous treatment options for ISR including intravascular brachytherapy, rotational atherectomy, bare metal stents, drug-eluting stents (DES), drug-coated balloons (DCB), and coronary artery bypass grafting, DES and DCB are the most common treatments for ISR with the use of paclitaxel-coated balloons (PCB) gaining popularity in the past decade [5, 6]. The theoretical benefit of PCB is the deposition of paclitaxel into the vessel wall thus providing the anti-proliferative effects of drug-eluting stents without necessitating another layer of metal. European guidelines currently recommend either DES or DCB to treat ISR with a class 1 indication [7] while the most recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines include DES as a class 1A indication for the treatment of ISR since DCB are not FDA-approved for coronary artery interventions in the USA [8].

The study by Zhang et al. published in Cardiovascular Drugs and Therapy adds to the database on IS-CTO [9]. The authors performed a retrospective analysis of 219 patients with IS-CTO who underwent successful revascularization from January 2016 to December 2019 with either PCB or DES. Approximately 84% of all participants in the study were male, and the mean age was 59.1 ± 8.9 years. This population overwhelmingly had sirolimus drug-eluting stents in their previous PCI (70%) with less frequent use of everolimus- (10%), zotarolimus- (16%), or paclitaxel- (4%) eluting stents. The mean follow-up was 72 months with no difference in MACE rates or TLR rates between PCB and DES.

There are several strengths of the study including the relatively large number of patients with IS-CTO, that only 8% of patients were lost to follow-up and a median follow-up of 72 months. Chronic kidney disease and ≥ 3 stent layers were associated with higher rates of MACE whereas a switch in anti-proliferative drug during IS-CTO PCI was associated with a lower rate. The hazard ratio of MACE was 1.6 with 2 layers of stents (p = 0.15) and 4.5 with 3 layers of stents (p < 0.001). These results are consistent with data from the New Tokyo Registry of patients with ISR (12.6% with IS-CTO) which reported that 3 layers of stent were associated with a hazard ratio for MACE of 3.2 compared to one layer of metal [10].

Limitations of the current study include those common to retrospective, single-center, observational studies (e.g., differences in the groups including PCB being used more often in the left anterior descending artery and DES in the right coronary artery), no data on whether complete revascularization was performed, no data on medication adherence, and a low rate of females (16.4%) in the study population. There was also a low rate of intracoronary imaging (15.4%) compared to most studies of CTO which limits insight into mechanisms and what role under-sizing and/or deformation of the original stent played. Both the European and US guidelines recommend, with a class IIa indication, the use of intracoronary imaging to elucidate the mechanisms of ISR [7, 8].

There are several take home messages from this study. One is that IS-CTO is associated with long-term TLR rates and MACE rates of approximately 20% and 30%, respectively. These numbers can inform discussions with patients about available treatment options. Stated another way, however, is that > 70% of the patients in the study did well with IS-CTO PCI. Second is that interventional cardiologists can use either PCB or DES for treatment of IS-CTO as long-term clinical outcomes were similar. And lastly, it might make sense to use a different antiproliferative drug as these patients had a lower risk of MACE in this study, although these data are confounded by different delivery mechanisms as well as different drugs.