FDA Approves Coronary Drug-Coated Balloon Specifically for In-Stent Restenosis

By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

SYNOPSIS: This trial randomized 600 U.S. patients with restenosis of a previously placed stent 2:1 to treatment with the AGENT drug-coated balloon or with regular balloon angioplasty. Target lesion failure at one year was significantly lower with the drug-coated balloon, as were target vessel myocardial infarction and stent thrombosis.

SOURCE: Yeh RW. Primary outcomes of a pivotal multicenter randomized trial comparing the AGENT paclitaxel-coated balloon with conventional balloon angioplasty for in-stent restenosis. Presented at TCT 2023. San Francisco; Oct. 25, 2023.

In-stent restenosis (ISR) remains a significant problem even in the modern drug-eluting stent (DES) era, with intervention for ISR currently accounting for up to 10% of all percutaneous coronary interventions (PCIs) performed, according to some estimates. Implantation of an additional DES remains the most commonly used tactic for dealing with these cases, with efficacy that is greater than plain balloon angioplasty alone. However, this approach results in additional layers of metal being deployed in the artery, and still has a significant target lesion failure rate. When these lesions continue to recur, then, the added stent layers can further complicate treatment. Drug-coated balloons (DCB) have been advocated to treat ISR lesions efficiently and effectively, without the need for additional scaffolding. Although coronary DCB have been available elsewhere in the world for years, the U.S. Food and Drug Administration (FDA) has, until now, reserved judgment on these devices for U.S. use, based on a lack of compelling data.

The AGENT IDE trial was a prospective, randomized controlled trial designed to evaluate the efficacy and safety of a commercial DCB for treatment of ISR lesions. Forty U.S. sites enrolled 600 patients, who were randomized 2:1 to DCB or to plain balloon angioplasty after initial successful pre-dilation of the lesion. One-year data from the initial 480 patients (321 randomized to the AGENT DCB, 159 to balloon angioplasty) were presented in October and subsequently were evaluated by the FDA.

The primary endpoint of one-year target lesion failure — a composite of target lesion revascularization, myocardial infarction (MI), or cardiac death — was significantly lower in the DCB group (17.9% vs. 28.7%; P = 0.0063), which represents a 38% relative risk reduction. Some of the individual components of the primary endpoint also were significantly reduced in the DCB group. Target lesion revascularization is the biggest component of this endpoint and was reduced by 51% (12.4% vs. 24.0%; P = 0.002). Target vessel MI similarly was reduced by 49% (6.4% vs. 12.3%; P = 0.03). Interestingly, stent thrombosis also appeared to show an advantage to the DCB group, with six events (3.9%) in the balloon angioplasty group and zero events in the DCB group.

The trial was reported by the principal investigators as demonstrating a marked superiority of DCB over balloon angioplasty for in-stent restenosis. The FDA apparently agreed, granting approval for this device on March 1, 2024. This is the first coronary DCB to be approved for U.S. use.

COMMENTARY

AGENT is not the first trial to address the efficacy of DCB in treating coronary in-stent restenosis. In fact, the first randomized trial of DCB in coronary ISR was published in the New England Journal of Medicine in 2006. That trial (PACCOCATH ISR) enrolled only 52 patients, and yet reported a significant advantage to DCB for this indication. Several subsequent international trials have since been published (PACCOCATH ISR II, PEPCAD II, PEPCAD-DES), all with relatively small numbers of subjects. However, the strength of this evidence resulted in changes to the European Society of Cardiology guidelines in 2014, elevating the use of DCB for coronary ISR to a IA recommendation. Some observers have taken issue with the plain balloon angioplasty comparator in this trial, given that 85% of cases of ISR in the United States are treated with repeat stenting.

However, AGENT is the largest trial of its kind to investigate this problem, and the results illustrate both the advantages of this technology and the remaining challenges. Specifically, a target lesion failure rate of nearly 18% in the DCB group shows that patients with restenosis lesions continue to have high event rates regardless of the technology applied. Much of the focus in the field in recent years has been on improving the quality of stenting interventions performed, with improved options for lesion preparation and emphasis on the use of intravascular imaging, which can reduce the occurrence of ISR.

While DCB does not represent a panacea for ISR treatment, this trial suggests a high degree of safety and enough efficacy to justify its use as first-line therapy in a majority of such cases. Other options, such as intracoronary radiation (brachytherapy), remain poorly available and are niche use only. Whether DCB ultimately will also gain traction in the treatment of de novo coronary disease will depend on the results of further trials in this space.