Coronary DCB Works Well in Multilayer In-Stent Restenosis: AGENT IDE Subanalysis

In patients with in-stent restenosis (ISR) affecting two or more drug-eluting stents, treatment with a drug-coated balloon (DCB) offers better efficacy than plain old balloon angioplasty (POBA), according to a prespecified subgroup analysis of the AGENT IDE trial.

The paclitaxel-coated device was associated with a lower 1-year risk of target lesion failure (TLF), the composite of ischemia-driven TLR, target vessel-related MI, or cardiac death. While the TLF rate was nearly double in those with multilayer versus single-layer ISR (P < 0.0001), less TLR and target-vessel MI drove the benefit in those with multilayer ISR who received the DCB instead of POBA, the analysis showed.

Another important aspect of the study, published online ahead of the August 19, 2025, issue of JACC, is that the results favoring DCB over POBA were consistent in both the multilayer and single-layer groups, lead author Ajay J. Kirtane, MD, SM (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), told TCTMD. The P value for interaction was a nonsignificant 0.66.

“When we designed the trial, we had concern that in the multilayer group, nothing would be effective,” he said. “To be able to show that not only was this device effective without putting in a third layer or more of stents, but it was much more effective than the conventional approach, was really reassuring. And I think for me, it shows that if you have multilayer stent stenosis and you’re going to use an interventional therapy, then you really should be using a drug-coated balloon.”

When we designed the trial, we had concern that in the multilayer group, nothing would be effective. Ajay Kirtane

In an editorial accompanying the study, Angelo Oliva, MD (Icahn School of Medicine at Mount Sinai, New York, NY), and colleagues say other takeaways from this analysis are the need for a lifetime management strategy for patients with ISR undergoing PCI, as well as the importance of choosing the optimal revascularization strategy at the first ISR occurrence.

“Although DES implantation may provide better acute outcomes than DCB angioplasty, adding another stent layer increases the risk of future multilayer ISR and its complications,” they write. “A tailored, mechanism-guided approach ideally supported by intravascular imaging should be adopted, with repeat DES implantation reserved for cases with clear evidence of underexpansion or inadequate lesion preparation.”

Outcomes, Lesion Preparation, and Beyond

The DCB used in the trial (Agent; Boston Scientific), which is coated with a low dose of paclitaxel, became the first coronary DCB in the United States to be approved for the treatment of ISR, with the Food and Drug Administration basing their decision on early data from the AGENT IDE trial.

A significant barrier to using the device for many US operators, however, is the cost of the DCB, which until now hasn’t been reimbursed by the US Centers for Medicare & Medicaid Services (CMS) or other major payers, Kirtane said. However, CMS is attempting to improve access to and adoption of the technology by granting a Transitional Pass-Through (TPT) payment, which took effect at the beginning of 2025, and a New Technology Add-On Payment (NTAP) that will be put in place October 1, 2025. Additionally, the company says new CPT I codes for procedures involving the Agent DCB will take effect on January 1, 2027.

AGENT IDE randomized 600 patients to treatment with the DCB or POBA. Patients were enrolled if they had ISR of a lesion previously treated with BMS or DES that was < 26 mm in length and between 2.0 and 4.0 mm in reference vessel diameter. Symptomatic patients were enrolled if they had target lesion stenosis < 100% but greater than 50%, and asymptomatic patients were enrolled if they had target lesion stenosis > 70%.

For the current subanalysis, researchers compared outcomes among the 258 patients (mean age 68 years; 24% female) who had multilayer ISR and the other 341 patients (mean age 68 years; 27% female) with single layer ISR; information on stent layer was not available for one patient.

Diabetes was present in more than 50% of patients and a history of MI in approximately 50%. Compared with the single-layer ISR group, those with multilayer ISR were more likely to have multivessel CAD and previous CABG. Those in the multilayer group treated with the DCB had slightly longer lesions than those treated with POBA (13.7 vs 11.5 mm; P = 0.01).

At 1 year, TLF had occurred in 23.8% of patients with multilayer ISR who were treated with the DCB and in 40% of those treated with POBA (HR 0.55; 95% CI 0.34-0.87). Corresponding TLR rates in the multilayer group were 17.4% and 37.8%, respectively (P = 0.0003), and target-vessel MI rates were 5.9% and 17.2% (P = 0.005). Additionally, rates of cardiac death were 4.6% and 1.2% in the multilayer group treated with DCB and POBA, respectively (P = 0.17).

Six patients (7.4%) in the multilayer group who were treated with POBA experienced definite stent thrombosis, as compared with none in the DCB group (P = 0.0003).

In the paper, Kirtane and colleagues say the lower rates of TLR, target-vessel MI, and stent thrombosis indicate “that the mechanism of benefit of DCB extends beyond solely preventing repeat revascularization procedures to further include the prevention of clinical events with important sequelae.” They add that three of the six stent thromboses in the multilayer group treated with POBA occurred after a TLR, which they say further emphasizes “the recurrent and longitudinal nature of stent failure in multilayer ISR.”

In their editorial, Oliva and colleagues point out that lesion preparation in the AGENT IDE trial was fairly conservative and speculate that more aggressive strategies, such as intravascular lithotripsy and stent ablation, might be important considerations for improving outcomes in those with complex disease.

To TCTMD, Kirtane said while ablation has never been demonstrated to be any more efficacious than other lesion preparation that is routinely done, the points are well taken. AGENT IDE randomized patients only with optimal lesion preparation, Kirtane added, and intravascular imaging was used in more than 70% of the study cohort.

“The lesion preparation part is super important. But how you do it, honestly, I don’t think there’s a lot of comparative data that would demonstrate that one way is any better than another,” he said.

Newer-generation sirolimus- and paclitaxel-based coronary DCB trials, including SELUTION4ISR, MAGICAL ISR, and the Prevail Global study, are ongoing and expected to shed more light on how these devices perform across a broader range of ISR phenotypes, Oliva and colleagues say.

“Future studies comparing DCBs with contemporary DES platforms and integrating optimal lesion preparation and intravascular imaging will further help define the best contemporary practices in the management of ISR,” they add.