Clinical Outcome of Paclitaxel-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation for the Treatment of Coronary Drug-Eluting Stent In-Stent Chronic Total Occlusion

The main findings of our study are as follows:

1)

With the increase in the number of previous stent layers in DES IS-CTO lesions, the proportion of PCB gradually increased.

2)

After successful revascularization with PCB or DES in patients with DES IS-CTO, MACEs occurred in approximately one-fourth of patients during the median follow-up of 3 years and were mainly driven by TLR.

3)

No significant difference in long-term clinical outcomes was observed between patients who underwent PCB angioplasty and those who underwent DES repeat stenting in the treatment of DES IS-CTO.

4)

CKD and ≥ 3 stent layers in the lesion were independent predictors of adverse prognosis, while switching to another antiproliferative drug was an independent protective factor.

For a long time, ISR has been a problem for operators despite the evolution of stents [25]. In the era of DES, CTO occurring within stents has become a unique type of coronary artery disease. Unlike bare-metal stent (BMS) IS-CTO, the main cause of DES IS-CTO is acute thrombotic occlusion followed by neointimal hyperplasia-related restenosis, hypersensitivity, neointimal erosion, neoatherosclerotic rupture, and edge-related disease [26].

In our study, patients with DES IS-CTO were observed to have a high incidence of long-term adverse events. Previous studies have shown that regardless of the therapeutic modality, the clinical outcomes of DES-ISR were worse than those of BMS-ISR [27]. A study of 11,961 CTO PCI cases at 107 centers worldwide reported that interventions for IS-CTOs and de novo CTOs had similar rates of technical success, procedural success, and in-hospital adverse events, but poorer prognosis [28]. Other contemporary studies also confirmed that compared to de novo CTO, IS-CTO was associated with poorer long-term outcomes despite similar procedural success rates [29,30,31]. The objective of our study was the intersection of the two adverse lesions, DES-ISR, and IS-CTO. Especially in the era of widespread application of DES, DES IS-CTO has become a troublesome type of lesion that operators have to face. However, the poor prognosis, which was not parallel to the high success rate, was an unacceptable fact for operators. Vasodilation is severely impaired after IS-CTO PCI, which leads to hemodynamic changes and promotes the progression of thrombosis or atherosclerosis [32]. The phenomenon of multilayered stents at lesions was observed in nearly half of the cases in our study. Previous studies have found that multilayer stent implantation may be associated with an increased risk of abnormal vascular response and stent recoiling leading to underexpansion, which in turn leads to a worse long-term prognosis [30, 33].

In the published literature, few studies have specifically explored the long-term outcomes of PCB or DES treatment with IS-CTO. Basavarajaiah et al. [34] compared the long-term outcome of 403 IS-CTO patients treated with balloon angioplasty (BA), drug-coated balloon (DCB), or DES. During the 4-year median follow-up period, MACEs occurred in about half of the patients, of which the BA group had the worst outcome. Compared with the other two treatment modalities, the DCB group had a lower rate of revascularization, but the difference was not statistically significant. In our study, no significant difference in long-term clinical events was observed between PCB angioplasty group and DES repeat stenting group for DES IS-CTO. As the two most effective treatments for ISR, the question about PCB angioplasty and DES repeat stenting which one is better has always been the focus of academic attention. In the 2018 European Society of Cardiology/European Association for Cardiothoracic Surgery Guidelines on Myocardial Revascularization, both DESs and DCBs were recommended for the treatment of ISR, whether BMS-ISR or DES-ISR (Class I, Level of Evidence: A) [10]. A large meta-analysis of 10 randomized clinical trials showed that angioplasty with PCB was less effective than repeat stenting with DES in reducing TLR in the treatment of DES-ISR [11].

As an alternative implant, DCBs are coated with antiproliferative drugs based on a lipophilic matrix, such as paclitaxel, which homogeneously transfers the drug to the coronary artery wall during balloon dilatation. The obvious advantage of DCBs is that they do not require additional metal layers, and they prevent the risks associated with permanent implants and reduce the incidence of inflammation and thrombosis. However, the disadvantages of intervention without implantation are the reduction in acute gain and occurrence of acute recoil [12]. As the other choice of the two main treatment options, DES stenting seems to be the more common and widely accepted treatment for CTO. However, repeated stenting in IS-CTO may again trigger previous stent restenosis factors, such as local abnormal inflammation, adverse reactions to the stent polymer, resistance to antiplatelet agents, stent malapposition or underexpansion, and even immune diseases [29, 35]. Therefore, in the intervention of DES IS-CTO, especially in the treatment of complex lesions with multiple stent layers, there is a dilemma that every operator must face. Although the placement of PCBs can prevent the need for additional stent placement, it does not bring satisfactory long-term outcomes. Similarly, although DES can bring good acute and midterm outcomes, it constitutes a part of the vicious circle of ISR in the long run [36].

A phenomenon of routine intervention for DES IS-CTO has been observed: as the number of stent layers increased in the lesions, operators preferred PCB angioplasty as an emerging alternative option to additional stent implantation. The current theory holds that stent overlap increases the risk of restenosis and recurrent ISR, and additional stenting at ISR lesion can further impair muscle reactivity and endothelial function [37]. In a number of large multicenter registries published in recent years, stenting has been found to be less used in the interventions of IS-CTOs than in de novo CTOs [28]. This may represent the operator’s concern that repeated stenting may be associated with poor prognosis. Our study confirmed the operator’s concern that the long-term outcomes of IS-CTO with multilayer metal stents were worse than those with single-layer metal stents. Yabushita et al. [33] presented data from the New Tokyo Registry that evaluated the clinical outcome of DCBs for the treatment of ISR based on the number of previous metallic layers. MACEs and TLR at 1 year after DCB treatment were significantly higher in patients with ≥ 3 stent layers than in those in the 1 and 2 stent layer groups, and ≥ 3 metallic layers were independent predictors of MACEs. For multimetal layer ISR, previous stent underexpansion or stent fracture may be more difficult to correct, which may be a possible reason for the poor prognosis of multimetal layer ISR. Since multilayer metal stents are associated with poor prognosis, operators should avoid placing stents with more than 2 layers. For patients with symptomatic recurrent restenosis, other alternative treatments may be considered, such as DCB, brachytherapy, or bypass grafting [38].

In this study, CKD was independently associated with poor prognosis, which was expected, as a higher incidence of MACEs was also observed in a subset of patients with CKD complicated with ISR in previous studies [39]. In the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease trial, revascularization did not reduce the risk of death and nonfatal MI in patients with stable coronary heart disease and advanced CKD [40]. Since each intervention causes additional damage to renal function, current guidelines recommend that the contrast load greater than 4 times estimated glomerular filtration rate should be used as an indication for terminating CTO-PCI attempts [41], leaving very limited room for physicians to operate in patients with CKD. Therefore, operators should carefully weigh the risks and benefits and be cautious when considering interventions for such patients. It must be emphasized that the effective treatment cannot be achieved without comprehensive and integrated management of individuals. Therefore, for patients with DES IS-CTO complicated with CKD, in addition to the necessary interventional therapy and antiplatelet therapy, active control of clinical complications and guideline-directed medical therapy may be helpful for improving prognosis [38].

We observed that switching to another antiproliferative drug was associated with better clinical outcomes. In our study, almost all PCB angioplasties adopted a switching strategy, which may be because fewer patients were previously implanted with paclitaxel-eluting stents in our study. Therefore, we analyzed limus-DES as a subgroup and confirmed that the switching to another antiproliferative drug was still significantly associated with a better prognosis in the DES repeat stenting group. In the Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent trial, a prospective multicenter study evaluated the angiographic and clinical outcomes of DES with different drug or alternative interventional modalities in the treatment of DES-ISR [42]. The main finding was that treatment of DES-ISR with different DESs (switch strategy) was associated with better angiographic and clinical long-term results. When compared in the cohort that underwent repeat stenting, the angiographic results of different DES approaches were superior to those of the same DES approach, which also showed a better trend in clinical results. The theoretical basis of DESs with different antiproliferative drugs in the treatment of DES-ISR is based on the different mechanisms of action of their active pharmacologic agents. Tissues respond differently to different DESs, so the factors involved in previous stent failure may be corrected by switching to DESs with different antiproliferative drugs [43]. Although there are many different mechanisms involved in ISR, when the previous DES fails, operators should be cautious in developing new intervention strategies, in which case switching to another antiproliferative drug may be an attractive treatment strategy.

The classification of ISR has been updated in recent years. In the past, Mehran et al. [44] developed a classification of ISR based on BMS according to the characteristics of angiography. With the promotion of DES and an in-depth understanding of the restenosis mechanism, Waksman et al. [45] based on the mechanism of restenosis proposed a new classification for DES-ISR. Sekiguchi et al. [46] proposed four occlusion patterns of IS-CTO and found differences in the technical success rate, guidewire crossing times, and crossing strategy among different patterns. In the DES era, both the correct classification and individualized treatment of DES IS-CTO based on the mechanism and occlusion patterns of restenosis are crucial to improve clinical efficacy. It is challenging to infer the mechanism of stent failure by angiography alone, and intracoronary imaging can effectively identify the mechanical and biological mechanisms of ISR [22]. Intravascular ultrasound (IVUS)-guided IS-CTO PCI can assist in the selection of appropriate stents, optimize the final result, and provide acceptable long-term clinical outcomes [8]. In addition, optical coherence tomography (OCT) has been recommended by the European Association of Percutaneous Cardiovascular Interventions, as the preferred imaging technique for studying ISR [47]. OCT can provide higher resolution images for the evaluation of morphological features, thus helping to correct factors related to past failures and optimize the intervention [48]. Although previous stents can serve as a roadmap for intervention, tracking through the stented segment theoretically reduces the risk of dissection or injury during the procedure, further improving the procedure success rate [30]. In routine recanalization practice, however, conditions such as stent underexpansion or stent rupture often make wiring more difficult, and the complexity of the IS-CTO means presence of subintimal or extra-stent wire passage, difficulty in device delivery, and even crushing the occluded stent, which increases the risk of adverse events [28, 49, 50]. Recently, the IS-CTO score system was established to predict the technical success of IS-CTO PCI via antegrade approach, which reflects the academic circle’s attention to this special type of coronary artery disease [50]. We are pleased to see that with the improvement of technology, the innovation of CTO PCI devices, and the accumulation of experience, the success rate of contemporary IS-CTO PCI is increasing [28]. Of course, the best way to solve DES IS-CTO is to prevent it. Once the DES IS-CTO happens, trying to identify the cause behind it, correct the undesirable factors, and avoid repeating the same mistakes is the direction we should strive for.

Limitations

This study has several limitations. First, this was a single-center, retrospective study of a small cohort with inevitable shortcomings. Second, because the choices of implants were determined by the operators or interventional cardiologist teams, there was selection bias in this real-world study. Although we performed propensity score to minimize possible bias, larger multicenter randomized controlled trials are still needed to clarify the clinical outcome of DES IS-CTO. Third, the proportion of intracoronary imaging used in our study was much lower than in other large IS-CTO studies conducted at the same period [28], so it was not possible to carefully evaluate the pathological features and potential mechanism of DES IS-CTO, and the lack of an IVUS- or OCT-optimized intervention may be associated with poor clinical outcomes; therefore, the results of this study should be interpreted carefully. Fourth, this study only recorded the medication of patients at discharge, but the medication of patients after discharge, including dose, frequency, and duration, has not been well evaluated. Therefore, it was not clear whether drug factors affect the long-term prognosis of patients. Last, this study excluded patients with unknown data on previous interventional procedures, so the conclusions of this study may not be extended to all patients with DES IS-CTO.

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