10.2 Management of In-Stent Restenosis: Are DCBs the Answer?

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022 in Punta Cana, Dominican Republic

Faculty Disclosures     Vendor Acknowledgments

2022 IAGS Summary Document

Statement of the problem or issue

Drug-eluting stents significantly reduce restenosis compared with bare-metal stents, but when restenosis does occur, it is often more difficult to manage. Placement of additional drug-eluting stents inside the restenotic lesion reduces but does not eliminate the risk of more neointimal hyperplasia (NIH). Furthermore, this stent “sandwich” adds multiple metallic layers inside the vessel, further reducing the lumen and making it more rigid and difficult to dilate. These additional stent layers may jail or even occlude coronary side branches, resulting in angina or myocardial infarction. A more prolonged course of dual-antiplatelet therapy is required, increasing the risk of bleeding. Conversely, a drug-coated balloon (DCB) contains the active antiproliferative medication to reduce NIH and restenosis, but does not require a bulky, permanent stent to deliver this medication to the target coronary wall.

Several studies have shown DCBs can reduce restenosis and the need for subsequent coronary revascularizations, and the European Guidelines have given DCBs the highest (class 1A) recommendation. Importantly, DCBs are approved and in use in most other countries except the United States (US). The AGENT trial (NCT04647253), a multicenter, pivotal trial required for FDA approval in the US, will randomize patients with coronary in-stent restenosis to treatment with DCB compared with standard balloon angioplasty. This trial is scheduled to be completed in 2024.

Gaps in knowledge

Some intravascular imaging studies have shown the in-stent “restenosis” may be due to lack of full stent expansion rather than NIH. Other restenotic lesions may be due to neoatherosclerosis rather than NIH, and these new lesions can be more difficult to treat. Should operators routinely use OCT/IVUS in restenotic lesions to determine adequate stent expansion and the mechanism of the restenosis? Does the pattern of drug-eluting stents restenosis (edge, focal in-stent, diffuse, proliferative, or total occlusion) influence the risk of subsequent restenosis and thus the choice of treatment?

Although DCBs and drug-eluting stents are both considered class 1A for management of restenosis in the European guidelines, the RIBS IV randomized study found that drug-eluting stents were superior to DCBs.¹ However, this may be due, in large part, to suboptimal lesion preparation with DCB. Studies have shown if the DCB-to-stent ratio was at least 0.90, residual stenosis <20%, and >60 seconds DCB inflation time, then target-lesion failure occurred in only 8% of these optimized lesions.² In the ISAR DESIRE-4 study, use of a scoring balloon was superior to balloon angioplasty for lesion preparation prior to DCB.³ However, there is no standard agreement regarding optimal lesion preparation prior to DCB. This lack of consistency in preparation techniques may influence outcomes in the ongoing AGENT trial.

Other gaps

Although most of us would place a second stent to treat in-stent restenosis, when would one worry about the number of layers of stent before switching to DCB?

• Calcified vessels and multiple stent layers make subsequent stent expansion difficult. Which technique or device is best suited to safely expand old stents?

• What is the best drug for DCB? Can newer preparations allow drugs in the limus-family to be retained in the vessel wall and prolong their therapeutic effects?

• Should we worry about paclitaxel DCB given the scare from the peripheral DCB experience?

Possible solutions and future directions

Intravascular imaging may be essential, both during initial stent implantation to assure that the first stent is optimally deployed, but also if the patient returns to determine the mechanism of restenosis. Some argue that OCT is preferred over IVUS, given its ability to determine depth of calcium and neoatherosclerosis. It is also advocated that guidelines be revised to Class 1, Level of Evidence B, to strongly encourage imaging for in-stent restenosis, given that stent under-expansion is a significant cause of “restenosis.”

Calcified vessels or multiple layers of stent make subsequent stent expansion difficult. There is a wide variety of opinion regarding which technique or device is best suited to safely expand old stents. Initial ultra–high-pressure inflations with noncompliant balloons could be followed by laser “bomb,” intravascular lithotripsy, or atherectomy, and then additional high-pressure inflations performed. However, data are limited and multicenter registries and randomized trials would be necessary to determine risk-to-benefit ratio.

Although many interventional cardiologists would place a second stent to treat in-stent restenosis, there are concerns about adding subsequent stent layers. Restenosis tissue seems difficult to compress between stent sandwiches, and some advocate debulking of tissue. In addition, use of DCB seems promising, especially if the lesion could be adequately prepared with cutting or scoring balloons. Ultimately, randomized trials will be necessary to determine the best lesion preparation of restenosis lesions.

What is the best antiproliferative drug for DCB? Can newer preparations allow drugs in the limus family to have better retention in the vessel wall and prolong their therapeutic effects? Drug and device development in this area should be strongly encouraged.

References

1. Alfonso F, Pérez-Vizcayno MJ, Cuesta J, et al. 3-year clinical follow-up of the RIBS IV clinical trial: a prospective randomized study of drug-eluting ­balloons versus everolimus-eluting stents in patients with in-stent restenosis in coronary arteries previously treated with drug-eluting stents. JACC Cardiovasc Interv. 2018;11(10):981-991. doi:10.1016/j.jcin.2018.02.037

2. Lee HS, Kang J, Park KW, et al. Procedural optimization of drug-coated balloons in the treatment of coronary artery disease. Catheter ­Cardiovasc Interv. 2021;98(1):E43-E52. Epub 2021 Jan 25. doi:10.1002/ccd.29492

3. Kufner S, Joner M, Schneider S, et al. Neointimal modification with scoring balloon and efficacy of drug-coated balloon therapy in patients with restenosis in drug-eluting coronary stents: a randomized controlled trial. JACC Cardiovasc Interv. 2017;10(13):1332-1340. doi:10.1016/j.jcin.2017.04.024