Direction of guidelines about drug-coated balloon angioplasty for in-stent restenosis of drug-eluting stents

Introduction

Coronary drug-coated balloon (DCB) has been used in the field of percutaneous coronary intervention (PCI) as a representative device of stent-less PCI (1-5). The advantages of DCB angioplasty were (I) a single touch of balloon to the plaque lumen enables to deliver the highly lipophilic anti-restenotic drug homogenously without the polymer and metal, and thus; (II) leave nothing behind to the vessel; (III) the possibility to shorten the duration of dual anti-platelet therapy (DAPT) to 1 month; and (IV) to develop the late lumen enlargement (LLE) in approximately a half lesions link to very small late lumen loss (LLL). Lesions of in-stent restenosis (ISR) of bare-metal stent (BMS) and drug-eluting stent (DES) have been the evidence-based target of DCB angioplasty from the beginning of clinical application (6). Paclitaxel-coated balloon (PCB) has been the evidence-based DCB (1-3), and a representative PCB is the SeQuent Please (Braun Melsungen AG, Berlin, Germany). However, in recent years, the efficacy of DCB for ISR lesions compared to DES has been reported to be inconsistent (7-11). Therefore, its recommendation rank in European Society of Cardiology (ESC) guidelines has been downgraded from IA (12,13) to IIA (14). Therefore, the present editorial commentary updated the important practical concepts of DCB angioplasty for ISR by referring to the pivotal meta-analyses of ISR of DES (15,16).

Management of ISR of DES by DCB angioplasty

In the Diagnostic Catheterization and Percutaneous Coronary Intervention (CathPCI) registry of the National Cardiovascular Data Registry (NCDR) between 2009 and 2017 in the United States, 10.6% of patients underwent PCI for ISR lesions in the whole 5 million patients, accompanying the significant and gradual increase in ISR of DES (16). The percentage of acute coronary syndrome (ACS) in the clinical presentation of patients with ISR was approximately 77%. Of them, ST-segment elevation myocardial infarction (STEMI) was approximately 15% of the whole, and ISR of DES was more likely to present after the first year of DES placement. Thus, continuous careful management is essential in patients after DES placement, particularly with several predictors of ISR (17).

The pathophysiological aspects of ISR of DES were more heterogeneous than the clinical implications of DES failure, combining not only the neo-intimal growth, but also the neo-atherosclerosis and in-stent calcification. ISR of BMS was relatively consisted by the neo-intimal growth (17), and the percentages has been decreased. The percentage of unsuccessful procedures of ISR of DES was significantly higher than the procedure of ISR of BMS (13). The Waksman ISR classification was proposed to correctly classify on the bases of intracoronary imaging by intravascular ultrasound (IVUS) and optical coherence tomography (OCT) to identify number of stent layers and mechanism and individualize the treatment of ISR of DES from Type I to V which link to the clinical outcomes: type I [mechanical: (i) under-expansion and (ii) stent fracture], type II [biologic: (i) neointimal hyperplasia, neoatherosclerosis; (ii) noncalcified; and (iii) calcified], type III (mixed pattern of types I and II), type IV (chronic total occlusion), and type V (>2 layers of stent) (17). Therefore, it is critical to define the superiority between DCB angioplasty and DES placement for ISR of DES.

In the first randomized study of DCB angioplasty in the United States, DCB angioplasty showed consistent superiority for ISR of DES compared to uncoated conventional plain old balloon angioplasty (POBA) with respect to the composite end point of target lesion failure (10). Thus, the evidence of DCB angioplasty has been anticipated to increase in the United States. In Europe, previous guidelines of ESC in 2014 (12) and 2018 (13) endorsed DCB angioplasty for ISR of DES as a class IA indication for revascularization. The major advantages of DCB angioplasty for ISR of DES were (I) to avoid the secondary metal layers by placing DES inside an existing DES and (II) to undergo 1-month DAPT after index PCI. As mentioned above about Waksman ISR classification (17), if DES was placed for ISR of DES, 2 layers of stent were developed. If it was implicated in recurrent ISR of DES as type V ISR, the probability to obtain the complete revascularization became low. Therefore, PCI operators are encouraged to treat ISR of DES by DCB alone. However, an issue arose for debate about the efficacy of DCB angioplasty in comparison to DES placement for ISR of DES (Table 1). Several randomized trials showed clinically insignificant efficacy and safety after DCB angioplasty and DES placement [PEPCAD China ISR (7), RESTORE (8), ISAR-DESIRE 3 (9)]. On the other hand, another randomized trial, RIBS IV (10), showed the superiority of DES placement to DCB angioplasty for ISR of DES, in terms of midterm cumulative frequency of target lesion revascularization (TLR). Therefore, the current guideline (14) lowered the class of recommendation about DCB angioplasty for ISR treatment from IA to IIA, because of the inferiority to DCB angioplasty in terms of the angiographic efficacy (15). The 2021 American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography & Interventions (SCAI) guideline recommended the use of DES for the treatment of ISR as IA (18), based on the results of studies revealing lower target vessel restenosis after DES placement compared to DCB angioplasty alone. The 2021 ACC/AHA/SCAI guideline did not mention the indication of DCB angioplasty owing to the practical reason as mentioned above. Thus, in the following paragraphs, two pivotal systematic reviews and meta-analyses (15,16) were examined to evaluate the efficacy between DCB angioplasty and DES placement for ISR of DES.

The Difference in Anti-restenotic Effectiveness of Drug-eluting stent and drug-coated balloon AngiopLasty for the occUrrence of coronary in-Stent restenosis (DAEDALUS) study (15) was an individual patient data meta-analysis including 10 available randomized clinical trials [RCTs: (I) BMS as a restenotic stent: PEPCAD Ⅱ, RIBS V, SEDUCE, TIS; (II) DES as a restenotic stent: PEPCAD China ISR, RIBS IV, RESTORE, ISAR-DESIRE 3; (III) BMS and DES combined as restenotic stents: BIOLUX-RCT, DARE] included with 1,976 patients (1,033 assigned to DCB and 943 to DES). At 3-year follow-up, DCB was associated with a significant increase in the risk of TLR compared with DES [hazard ratio (HR) 1.32, 95% confidence interval (CI): 1.02–1.70, P=0.03]. The primary safety endpoint of all-cause death, myocardial infarction, or target lesion thrombosis was comparable between treatments (HR 0.80, 95% CI: 0.58–1.09, P=0.15). Thus, in patients with coronary ISR, repeat stenting with DES is more effective than DCB angioplasty by reducing the need for TLR within 3 years. The incidence of a composite of all-cause death, myocardial infarction, or target lesion thrombosis was similar between DES and DCB groups. Thus, the clinical safety of DCB angioplasty for ISR of DES in terms of major adverse cardiovascular outcomes compared to DES placement was consistent. In addition, in the sub-analysis of the 3-year follow-up of the DAEDALUS study (19), DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment of DES-ISR, and is associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR (19). Therefore, since the frequency of BMS-ISR has been reduced clinically, it is very important to clarify the effectiveness of DCB for ISR of DES by comparing with repeat DES placement for ISR of DES.

More recent meta-analysis (16) including prospective randomized 5 studies [PEPCAD China ISR (7), BIOLUX (11), RESTORE (8), RIBS IV (10), and ISAR-DESIRE 3 (9) trials] comparing the impacts of DCB angioplasty versus DES placement for ISR of exclusive DES showed the consistent results with DAEDALUS study, where DES significantly reduced the frequency of TLR with the similar 2-year clinical safety compared with DCB angioplasty, such as all-cause mortality, cardiac death, non-cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), target lesion thrombosis, target vessel MI, stroke, and coronary artery bypass grafting (CABG) (16) (Table 1). Thus, the recent 2 systematic reviews and meta-analyses comparing the midterm clinical outcomes between DCB angioplasty and DES placement for ISR of DES showed the efficacy of DES placement in terms of reduced TLR with similar clinical safety compared to DCB angioplasty. This advantageous impact of DES placement compared to DCB angioplasty is reflected in the current guidelines, which favor DES for ISR of DES over DCB (14,18).

Several issues needed to be improved for DCB angioplasty for ISR of DES. First, to clarify the pathophysiology and the treatment of ISR of DES, a classification of ISR types based on the etiology is essential. Waksman ISR classification was the most up-to-date classification of ISR of DES (17) incorporated the previous classifications (20,21). Owing to the ISR etiologies, the treatment options were raised and recommended individually (17). Thus, the clinical implications of those treatments, including the prevalence of recurrent ISRs, needed to be evaluated to define the superiority between DCB angioplasty and DES placement for ISR of DES. Second, in relation to the definition of the type of ISR, the intravascular assessments for ISR of DES are also essential to obtain clear, insightful characteristics of ISR (20-22). The first generation ISR classification by Mehran et al. (20) was based on the angiographic assessment. Mehran’s classification has been widely used because of the simplicity in the visual estimation and good accordance with clinical practice. The first classification of ISR type by OCT showed 3 patterns of ISR, such as homogeneous, heterogeneous, and layered patterns (21). This classification was also straightforward and relevant to clinical outcomes, leading to the proper interventional approaches by either DCB or DES. Usually, with a full preparation of the ISR lesion by conventional ballooning and scoring balloons with the guidance of an intravascular assessment, the attachment of paclitaxel to the intimal tissues brought non-inferior clinical outcomes compared to the secondary DES placement inside DES. The Waksman ISR classification is based on the angiography and optical coherence tomography (OCT) (17). However, the most recent meta-analysis (15) including the comparative studies of DCB angioplasty and DES placement performed by visual estimation without intravascular assessment (Table 1). Thus, further studies based on the novel Waksman classification would warrant the improvement of the clinical outcomes of ISR of DES by defining the proper device to treat the ISR lesions.

In summary, the optimal PCI strategy for ISR inside DES is (I) to clarify the previous PCI procedures of the related vessel, such as used stent and the final angiographic and intravascular parameters; (II) to apply the ISR classifications by the intravascular aspects obtained by IVUS or OCT (21,22); and (III) to decide which device to use DCB or DES with the tailored approach.

Finally, in this editorial commentary, we briefly summarized the recent concept of DCB angioplasty for ISR of DES in comparison to DES placement by referring to the 5 pivotal trials and 2 meta-analyses (Table 2). At present, it is essential to compare the safety and efficacy of DCB angioplasty with those of contemporary 3^rd-generation ultra-thin strut DES placement for ISR lesions with the intravascular assessments.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-97/prf

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-97/coif). The authors have no conflicts of interest to declare.

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