Drug-coated ballons finally land in the United States: an appraisal of the agent IDE randomized clinical trial
Editorial Commentary

Drug-coated ballons finally land in the United States: an appraisal of the agent IDE randomized clinical trial

Filippo Luca Gurgoglione1,2, Bernardo Cortese2,3,4,5

1Division of Cardiology, University of Parma, Parma University Hospital, Parma, Italy; 2DCB Academy, Milano, Italy; 3Fondazione Ricerca e Innovazione Cardiovascolare, Milano, Italy; 4University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 5Case Western Reserve University School of Medicine, Cleveland, OH, USA

Correspondence to: Bernardo Cortese, MD, FESC, FSCAI. Fondazione Ricerca e Innovazione Cardiovascolare, via E. Ponti, 49 Milan, Italy; DCB Academy, Milan, Italy; University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Case Western Reserve University School of Medicine, Cleveland, OH, USA. Email: bcortese@gmail.com.

Comment on: Yeh RW, Shlofmitz R, Moses J, et al. Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial. JAMA 2024;331:1015-24.


Keywords: Drug-coated balloons (DCBs); in-stent restenosis (ISR); target lesion failure


Received: 17 June 2024; Accepted: 29 October 2024; Published online: 10 December 2024.

doi: 10.21037/actr-24-102


Drug-eluting stents (DES) are the most common strategy for revascularization of obstructive coronary artery disease (CAD). Despite improvements in DES technology, in-stent restenosis (ISR) still occurs in nearly 5% to 10% of percutaneous coronary interventions (PCIs) with DES within the first year, according to the complexity of the treated lesion (1,2). Several often coexisting mechanisms, including stent-related, procedure-related, and biological factors, subtend ISR and its management is challenging (3,4). The key paradigm is the identification and targeted treatment of the underlying pathophysiology (5). It’s worth noting that PCI of ISR confers a higher risk of failure, as compared to revascularization of de novo lesions (2,6). In particular, the implantation of an additional DES often results in the so-called “onion skin phenomenon”. This phenomenon is characterized by the histological presence of multiple stent struts surrounded by concentric layers of neointimal hyperplasia, resembling the layers of an onion. The underlying pathology involves the recruitment of inflammatory cells and the release of growth factors that stimulate smooth muscle cell proliferation and migration, resulting in the gradual accumulation of neointimal tissue (7). The “onion-skin phenomenon” could induce a vicious cycle with progressively reduced minimal stent area, increased risk of stent under-expansion and of ISR recurrence (3).

Drug-coated balloons (DCB) are a valuable therapeutic option for the management of coronary ISR (8). The advantage of treating coronary lesions while avoiding an additional scaffold, coupled with the opportunity to blunt long-term coronary inflammation (9) and preserve endothelial vasomotion (10) is particularly appealing (11), laying the foundation for several head-to-head comparisons between DCB and other interventional strategies. The RIBS IV (restenosis intra-stent of drug-eluting stents: drug-eluting balloons vs. everolimus-eluting stents) trial (12) demonstrated the superiority of DES over paclitaxel DCB in the treatment of DES-ISR. In a cohort of 309 patients, the 3-year follow-up results showed a significantly lower incidence of major adverse cardiovascular events in the DES group compared to the DCB group (12.3% vs. 20.1%, P=0.04). DAEDALUS (the difference in anti-restenotic effectiveness of drug-eluting stent and drug-coated balloon angioplasty for the occurrence of coronary in-stent restenosis) individual patient-data meta-analysis (13) gathered all these trials having investigated the role of paclitaxel DCB vs. coronary stents and concluded that the latter strategy was moderately more effective at reducing the rate of target lesion revascularization (TLR) at 3 years, with no difference as regards all-cause death, myocardial infarction (MI), or target lesion thrombosis between DES and DCB. The 10-year follow-up of the ISAR-DESIRE 3 trial (14), which involved 402 patients with ISR, compared the long-term outcomes of three treatment strategies: plain balloon angioplasty, paclitaxel DCB and DES. The incidence of TLR was found to be comparable between the paclitaxel DCB and DES groups. Interestingly, the initial advantage of DES in reducing restenosis rates diminished over time, with the occurrence of TLR becoming similar between paclitaxel DCB and DES after the first year following the index PCI. Later, also the role of a sirolimus DCB was investigated for this type of lesions, showing a rate of TLR of 10.5% and 14% at 1 and 2 years, respectively (15,16). All these studies laid the groundwork for the clinical use of DCB in Europe since more than a decade and current European Society of Cardiology guidelines endorse DCB revascularization for treating coronary ISR with a class I recommendation, like for DES (17). However, none of these RCT was conducted in the United States (US). Therefore, the Food and Drug Administration (FDA) precluded so far the use of DCB is the country for this indication.

The AGENT IDE [a clinical trial to assess the agent paclitaxel coated percutaneous tranluminal coronary angioplasty (PTCA) balloon catheter for the treatment of subjects with in-stent restenosis] trial was designed to overcome this lack of scientific evidence (18). Yeh and colleagues compared the clinical performance of the agent paclitaxel-coated balloon (Boston Scientific, USA) vs. an uncoated balloon for treating coronary ISR in a cohort of 600 patients enrolled in 40 centers in the US. The inclusion of a high ischemic risk population, with a high burden of cardiovascular risk factors and multivessel CAD involvement, is a strength of the study. In particular, up to one third of the patients presented with acute coronary syndrome (ACS) and 43% of patients harbored multiple stent layers in the target lesion. Patients were randomized in a 2:1 ratio to agent DCB or uncoated balloon after successful lesion predilatation. Importantly, several devices (directional or rotational coronary atherectomy, laser, cutting/scoring balloons) could be employed to achieve adequate lesion preparation and the procedural guidance with intracoronary imaging was frequent (73.8%). Furthermore, the rate of procedural success was high, while the need for bailout stenting was uncommon. The primary endpoint of this study was the occurrence of target lesion failure (TLF), defined as the composite of ischemia-driven TLR, target vessel-related MI and cardiac death. At 12-month follow-up, patients treated with DCB experienced a significantly lower occurrence of the primary endpoint, mainly driven by a reduction of TLR and target vessel MI as compared to those who received uncoated balloons. In detail, the absolute risk reduction was 10.7% and the number needed to treat was 10. The present study is the largest RCT conducted so far for evaluating the safety and efficacy of DCB for coronary ISR. In view of the large sample size, authors were able to perform subgroups analyses. Interestingly, the superiority of DCB was particularly pronounced among high-risk subsets, such as males [hazard ratio (HR) 0.60, P=0.01], elderly patients (HR 0.42, P=0.01) and those with multiple stent layers at target site (HR 0.55, P=0.009). On the other hand, we have to acknowledge in the DCB arm a high rate of TLF at 1 year, occurring in 17.9% of the population, a rate higher than expected. Interesting, if we compare this with the 7.9% rate of 1-year TLF after optical coherence tomography-guided DES implantation for ISR in a subgroup analysis of the ILUMIEN IV sub-study we understand that the path toward an optimal DCB is still long (Z.A. Ali, oral presentation, CRT 2024). So far, the best mix for a successful DCB-angioplasty in ISR must have all the following ingredients: (I) correct understanding of the cause(s) of previous stent failure by means of interpretation of intravascular imaging; (II) usage of all the tools deemed appropriate for an effective lesion preparation; (III) re-assessment of the result with intravascular imaging; and (IV) usage of an effective, well studied DCB as the last step of coronary angioplasty.

In conclusion, the AGENT IDE trial represents a pillar in the field of PCI with DCB because it gave the lead for the first DCB being marketed in the US for coronary indications. However, a direct comparison between DES and DCB for the treatment of ISR is lacking in the US and it remains challenging for surgeons to choose between DCB and DES in the US. Finally, this trial also showed how this is still a restless field and new technological improvements should be pursued in order to reach a similar outcome to DES at 1 year, hoping for lower events on the very long term.


Acknowledgments

Funding: 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-24-102/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-102/coif). The authors have no conflicts of interest to declare.

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doi: 10.21037/actr-24-102
Cite this article as: Gurgoglione FL, Cortese B. Drug-coated ballons finally land in the United States: an appraisal of the agent IDE randomized clinical trial. AME Clin Trials Rev 2024;2:95.

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