Over the past two decades, percutaneous coronary intervention (PCI) with the placement of metallic drug-eluting stents (DES) has revolutionized the management of coronary artery disease and has become one of the most commonly performed treatments in modern medicine. Masu. However, the use of metal stents has inherent limitations due to the permanent retention of foreign bodies within the coronary artery, most notably thrombus formation and vascular inflammation, both of which result in the growth of new tissue (neointimal hyperplasia). , leading to some degree of vascular restenosis.¹ Despite the thinning of the stent struts and the administration of antiproliferative drugs, this process continues with either early extensive neointimal tissue formation (restenosis) or later atherosclerosis ( (neo-atherosclerosis) can sometimes become pathological.^2,3 Although the latest generation drug-eluting stents have a low incidence of in-stent restenosis (6% to 8%), which occurs primarily in the first year, drug-eluting stents are associated with adverse ischemic events after one year. Estimated. 2% per year without a noticeable plateau.^Four As a result, interventions to treat in-stent restenosis account for nearly 10% of all PCIs performed in the United States, potentially presenting therapeutic challenges with suboptimal long-term outcomes. there is.^Five Although the best management strategy remains controversial, in-stent restenosis in the United States is most commonly treated with repeated placement of drug-eluting stents (i.e., stent-within-a-stent placement).^Five

Drug-coated balloons (DCBs) have emerged as a potential alternative to drug-eluting stents in the treatment of in-stent restenosis. This leave-nothing strategy can deliver antiproliferative drugs directly to the vessel wall via a lipophilic matrix, eliminating the need for permanent metal prostheses using durable polymers.⁶⁷ DCBs are widely used in Europe and have received a class 1A recommendation in the European Society of Cardiology guidelines for the management of in-stent restenosis since 2014.⁸ Although multiple randomized trials and meta-analyses have established the efficacy and safety of DCB for in-stent restenosis of coronary arteries;⁷ None of these trials were conducted in the United States. Although DCBs can be used in the United States to treat peripheral vascular disease, they are not currently approved by the Food and Drug Administration for use in coronary artery lesions.

In this issue, jam, Ye et al.⁹ The AGENT IDE study is the first randomized clinical trial in the United States to evaluate the efficacy and safety of drug-coated versus uncoated balloons in the treatment of in-stent restenosis of coronary arteries. The study included 600 patients with in-stent restenosis who underwent paclitaxel-coated balloon (n = 406) or conventional (uncoated) balloon angioplasty (n = 194) after successful predilatation. They were randomized in a 2:1 manner. Visually estimated reference vessel diameter greater than 2.0 mm and up to 4.0 mm, lesion length less than 26 mm, target lesion diameter stenosis less than 100% and greater than 50% (for symptomatic patients) Patients were included. More than 70% (for asymptomatic patients). Key exclusion criteria include unprotected left main disease, recent ST-elevation or Q-wave myocardial infarction, saphenous vein or artery graft lesions, left ventricular ejection fraction <25%, or thrombus within the target vessel. included. The primary endpoint was target lesion failure, defined as a composite of cardiac death, target vessel-related myocardial infarction, and ischemic target lesion revascularization. At 1-year follow-up, paclitaxel-coated balloons were superior to uncoated balloon angioplasty for target lesion failure (hazard ratio, 0.59) [95% CI, 0.42-0.84]; P= .003), and the secondary endpoint of target lesion revascularization (hazard ratio, 0.50) [95% CI, 0.34-0.74]; P= .001) and target vessel-related myocardial infarction (hazard ratio, 0.51). [95% CI, 0.28-0.92]; P= .02). Cardiac death and quality of life outcomes were similar between the two groups.⁹

The researchers who conducted this important and long-overdue trial evaluating the effectiveness of coronary DCBs in the United States should be congratulated. This study raises several important questions that merit further consideration. First, this study was primarily conducted to obtain Food and Drug Administration approval for the DCB, and while its design directly tests the effectiveness of the drug coating, the use of uncoated balloons as a control It does not represent the current standard of care for treating in-stent restenosis. Practice. In fact, a previous study, ISAR-DESIRE 3, which compared uncoated balloons with DCB and drug-eluting stents for the treatment of in-stent restenosis, found that uncoated balloons were the least effective (i.e., had the highest rate of restenosis recurrence). high) was shown.^Ten Nevertheless, a significant number of in-stent restenosis patients in the United States are still treated with uncoated balloons for localized lesions, and the availability of DCBs would be a welcome addition to the arsenal. Second, DCBs are particularly useful in cases of in-stent restenosis where placing an additional metal layer may be problematic, such as bifurcation lesions or in-stent restenosis lesions that already have two or more stent layers. attractive. In the current study by Yeh et al.⁹ More than 40% of treated lesions had multilayer stents, and half had diffuse in-stent restenosis. It is known that there is a high risk of recurrence of in-stent restenosis after conventional treatment. DCB was clearly effective in these patients, with an absolute risk reduction of target lesion failure of 10.7% for every 9 patients with in-stent restenosis treated with drug-coated versus uncoated balloons. suggests that one target lesion failure is prevented. Despite this superior efficacy, the financial implications and availability of DCBs require further consideration, given their high cost compared to widely available drug-eluting stents. Sho.

A third point to consider with additional economic implications is that endovascular imaging is used in nearly three-quarters of AGENT IDE patients. This rate of intravascular imaging is 5 to 10 times higher than what is commonly performed in practice in the United States, and the use of intravascular imaging has been shown to improve PCI outcomes, resulting in lower event rates. may have influenced.³ Additional data on the mechanisms of in-stent restenosis, not detailed in this study, are also potentially important, particularly the rate of mechanical causes of stent failure such as underexpansion, where DCB may be less effective. Fourth, more than half of the patients in this trial received intervention for stable angina, and the absolute benefit of PCI compared with optimal medical therapy is questionable. An unfortunate trade-off of intervention strategies is the infrequent but observable adverse PCI outcomes, such as stent thrombosis, myocardial infarction, and cardiac death, even in otherwise stable patients. Fifth, although this trial required dual antiplatelet therapy for a minimum of 1 month after intervention, most patients continued dual antiplatelet therapy for 1 year. There is a lack of consensus and a paucity of data regarding the optimal duration and strategy of antiplatelet therapy for DCB. Recent studies in Europe have shown good results with single antiplatelet therapy after DCB-PCI, which may be highly advantageous for patients at high bleeding risk.¹¹

In summary, AGENT IDE provides strong evidence for regulatory approval of coronary DCBs in the United States and has the potential to provide access to this established technology to a large number of patients. The use of DCB may also be extended to other clinical scenarios such as de novo lesions, bifurcation lesions, small vessels, and patients at high bleeding risk. This study undoubtedly lays a solid foundation for future clinical trials of coronary DCB in the United States, and additional data on its efficacy and safety are eagerly awaited by the intervention community.

Corresponding author: David J. Moliterno, MD, Department of Cardiology, University of Kentucky, 900 S Limestone Ave, 326A Wethington Building, Lexington, KY 40536-0200 (Moliterno@uky.edu).

Published online: March 9, 2024. doi:10.1001/jama.2024.0813

Conflict of interest disclosure: There were no reports.