Brachytherapy Remains an Option for DES In-Stent Restenosis

For patients with in-stent restenosis (ISR) of a drug-eluting stent, intracoronary brachytherapy is a safe and effective treatment option, although its success decreases with the number of stent layers, according to new data.

Popular in the late 1990s and early 2000s when bare-metal stents were widely used, brachytherapy delivers high doses of radiation directly into the vessel wall via a catheter. After the introduction of DES, and a subsequent drop in ISR rates, brachytherapy fell largely out of favor, although several dozen US centers continue to offer it to patients in lieu of sending them for CABG or putting in another DES. Drug-coated balloons (DCBs) can also treat DES ISR, but they are not yet commercially available in the United States.

Senior study author Stephen Ellis, MD (Cleveland Clinic, Cleveland, OH), told TCTMD his institution currently performs brachytherapy about 60 to 80 times per year, mostly for patients with recurrent ISR. Limited data on the outcomes for these patients served as the impetus for conducting this study, he said.

While it’s likely that DCBs will “supplant” brachytherapy for the treatment of most ISR in the US, assuming they are approved, the latter will stick around for “niche applications” like DCB failure, Ellis predicted.

Commenting on the study for TCTMD, Ron Waksman, MD (MedStar Washington Hospital Center, Washington, DC), who was one of the original developers of the technology, said brachytherapy is currently “underutilized.”

The data are “reassuring,” he said, adding that “I think it's very good that we are now 25 years in and it's still helping patients. That is the most important part. There are many technologies that are good at what they do and then they are gone and replaced by something else.”

Three-year Outcomes

For the study, published online this month in the Journal of the Society for Cardiovascular Angiography & Interventions, Emily Ho, MS (Case Western Reserve University School of Medicine, Cleveland), Ellis, and colleagues looked at 330 consecutive patients (mean age 66 years; 70.3% men) presenting with 345 ISR lesions treated with intracoronary brachytherapy (Novoste Beta-Cath system; Best Vascular) at a single institution between 2012 and 2021. Just under two-thirds had previous CABG and 89% had at least two stents placed at the treated site.

Pre-brachytherapy treatment usually included high-pressure noncompliant balloons, often after debulking with laser or rotational atherectomy as well as angioplasty with cutting balloons. All patients had a DES as their innermost stent layer and were maintained on dual antiplatelet therapy (DAPT) after the procedure, with 92.5% still taking DAPT at 1 year, 86.0% at 2 years, and 75.4% at 3 years.

The rate of target lesion failure (TLF) at 3 years (the primary endpoint, defined as cardiac death, target lesion revascularization, target vessel occlusion without revascularization, or target vessel MI) was 46%, which jumped up from 18% at 1 year. The number of stent layers a patient had correlated with the risk of TLF at 3 years, with rates rising from 33.3% in patients with one layer to 47.0% in patients with two and 60.2% in patients with three or more layers (HR 1.39; 95% CI 0.25-1.53).

Diabetes, repeat brachytherapy, final percent stenosis, lesion length, and intravascular imaging use were not correlated with TLF.

At 3 years, all-cause and cardiac mortality rates were 19.8% and 12.3%, respectively.

Notably, after March 2015, the institution upped the standard radiation dose to 23 Gy (vessel diameter ≤ 3.35 mm) or 25 Gy (vessel diameter > 3.35 mm) from 18.4 Gy and 23 Gy, respectively, in response to anecdotal evidence suggesting a more-robust response. While the lower radiation dose did not have an effect on TLF at 3 years, it was linked with a lower risk of the endpoint at 1 year (P = 0.035), as was restenosis less than 1 year from previous PCI (P = 0.044).

Ellis said the results will lead him to be “a little less aggressive in terms of debulking because the final percent stenosis does not seem to matter.” Additionally, the findings provide “a very strong reminder not to put three layers of metal in,” he continued. Rather, these patients should be referred for DCB trials or brachytherapy.

Also, while some think that certain patients might benefit from brachytherapy for the first instance of ISR, the data remain inconclusive for that cohort, Ellis added.

His group plans to continue research in this space looking at the effect of a higher brachytherapy dose on ISR recurrence, but Ellis said it would be unlikely to see a head-to-head trial of brachytherapy and DCBs due to lack of resources from the manufacturers.

I think it's very good that we are now 25 years in and it's still helping patients. That is the most important part. Ron Waksman

Brachytherapy requires the involvement of radiation oncologists and physicists as well as interventional cardiologists: as a result, its cost is likely on par with DCBs, which, while relatively novel as a technology, are simpler in application, according to Ellis. “I think that is why brachytherapy will wane,” he said. “And we will probably return to a few institutions that do a lot of it and still get referrals.”

Future of Brachytherapy

Speaking with TCTMD, Samin Sharma, MD (Icahn School of Medicine at Mount Sinai, New York, NY), was not surprised by the data, saying he has noticed a “catch-up phenomenon” wherein a patient who received brachytherapy “looks very good at 1, 2 years and then after 3 years they come back. . . . Clearly, it is always dependent on how many layers of stenting you have already.”

The policy at his institution is that a patient with two layers of stent and ISR is sent for brachytherapy. After that, they are referred for CABG.

Because evidence has shown that DCBs, too, don’t work very well after three layers of stent have been implanted, Sharma said this element of practice is unlikely to change even if the devices are approved for coronary use. However, he could see DCBs being used as more of a “first-line therapy” followed by brachytherapy, if available.

Given the thinning pipeline of research into brachytherapy and no innovation with regard to radiation source at most institutions, Sharma agreed that the field is likely to continue to decline.

Waksman, however, noted that this research highlights an attractive treatment option for those “frequent flyers”—patients who come in with ISR every 3 to 4 months. “Brachytherapy gives them a longer interval of freedom from revascularization,” he said.

Waksman said there is a need for more research to understand why DES fail, and the mechanisms behind that. “It could be related to inflammation, it could be related to other mechanisms, but until we sort it out, brachytherapy is like a sledgehammer.”

An accompanying editorial by Michael P. Savage, MD, and David L. Fischman, MD (both Thomas Jefferson University Hospital, Philadelphia, PA), agreed, noting that “the demise of coronary restenosis has been greatly exaggerated. Recurrent restenosis after multiple DES presents a perplexing and frustrating clinical challenge.” While brachytherapy remains an “attractive option,” they continue, “the evidence basis is nascent and soft.