Highlight
The SELUTION4ISR trial evaluated a novel sirolimus-eluting balloon (DEB) against regular care strategies comprising predominantly repeat drug-eluting stents (DES) and balloon angioplasty (BA) for coronary in-stent restenosis (ISR). Results showed the sirolimus DEB was noninferior to usual care overall in preventing target lesion failure (TLF), but was not noninferior to DES in single-layer ISR. This highlights the nuanced role of sirolimus DEB, with potential benefits compared to BA but limitations versus DES in certain ISR subsets.
Study Background
Coronary in-stent restenosis remains a challenging complication following percutaneous coronary intervention (PCI) with stenting. Although drug-eluting stents have improved outcomes relative to bare-metal stents, restenosis occurs in a subset of patients requiring repeat revascularization. Treatment options traditionally include repeat stenting with DES or balloon angioplasty. However, DES reuse is not always feasible or utilized in over 20% of ISR cases due to anatomical, clinical, or operator factors. Drug-eluting balloons offer a potential alternative delivery platform for antiproliferative therapy without permanent implants, potentially reducing risks associated with additional stent layers and facilitating vessel healing. The clinical utility of sirolimus-eluting balloons in ISR, particularly compared to established DES therapies, remains to be established in randomized clinical trials.
Study Design
SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) was an open-label randomized controlled trial enrolling 418 patients with coronary ISR from July 2020 to July 2024. After successful lesion predilation, patients were randomized to receive either the sirolimus drug-eluting balloon (SELUTION Sustained Limus Release, MedAlliance) or a control strategy consisting of usual care as chosen by the operator prior to randomization—primarily repeat DES or balloon angioplasty. To maintain clinical equipoise, balloon angioplasty as the control arm was limited to 20% of patients. The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (MI), or clinically driven target lesion revascularization, assessed at 1 year in the per protocol population. The trial tested noninferiority of the DEB compared to control, with a 10% noninferiority margin for the upper bound of the 95% credible interval. As a secondary analysis, TLF in patients with single-layer ISR receiving DEB was compared to those receiving DES control.
Key Findings
Among 390 patients analyzed per protocol (197 DEB, 193 control: 154 DES, 39 BA), 1-year TLF rates were 16.2% for the DEB group and 14.5% for the control group. The difference of 1.7% (95% credible interval -5.5% to 8.9%) met the criterion for noninferiority with a 98.8% posterior probability. These results demonstrate that sirolimus DEB performs comparably to an operator-chosen strategy mainly involving repeat DES at 1 year, validating it as a safe and effective alternative for ISR management.
However, in the prespecified secondary analysis comparing DEB with DES in patients with single-layer ISR, TLF occurred in 14.2% versus 6.5%, respectively (difference 7.7%, 95% credible interval 0.6% to 14.6%). The posterior probability for noninferiority was 76.07%, indicating that DEB did not achieve noninferiority compared to DES in this subgroup. This suggests that repeat DES remains superior for single-layer ISR when feasible.
Breaking down control treatments by operator choice revealed significant interaction. TLF was higher in the DEB group compared with the DES subgroup (15.3% vs. 7.1%; difference 8.1%, credible interval 1.4% to 15.0%), but the DEB had significantly lower TLF rates than balloon angioplasty alone (23.6% vs. 43.6%; difference 23.7%, credible interval -41.4% to -1.5%; P for interaction = 0.0026). These findings reinforce that DEB offers clear advantages over BA but falls short of the efficacy of repeat DES in certain contexts.
Safety data showed no excess cardiac deaths or target vessel MIs attributable to the DEB compared to the control strategies, supporting the safety profile of sirolimus-eluting balloons in ISR treatment.
Expert Commentary
The SELUTION4ISR trial provides important insights into the evolving landscape of ISR management. While drug-eluting stents have set the benchmark for reducing restenosis, concerns about layering multiple stents—leading to impaired vessel compliance, complex reintervention, and longer dual antiplatelet therapy—point to the potential appeal of drug-coated balloons.
Sirolimus, a potent antiproliferative agent, had been less studied in balloon-based delivery compared to paclitaxel. The SELUTION DEB’s sustained release formulation suggests an effective and safe means to inhibit neointimal hyperplasia without adding a permanent implant. The trial’s demonstration of overall noninferiority to standard care including 80% DES is encouraging.
However, the inferior outcomes with DEB versus repeat DES in single-layer ISR underscore the nuanced decision-making needed. Repeat DES likely remain preferred when anatomy, stent characteristics, and patient factors allow. Conversely, DEB might be the optimal strategy in patients unsuitable for further stent implantation or when avoiding additional metal layers is prioritized.
Limitations include the open-label design and operator-driven control selection that could introduce bias. The 1-year follow-up, while standard, may underrepresent late restenosis or stent thrombosis patterns. Future trials with longer follow-up, additional ISR subsets, and mechanistic imaging could clarify optimal therapy selection.
Conclusion
The SELUTION4ISR trial establishes that sirolimus-eluting balloons are a safe and effective alternative to repeat drug-eluting stenting or balloon angioplasty for coronary in-stent restenosis at one year. Although noninferior to usual care strategies dominated by DES, they did not meet noninferiority criteria versus DES in single-layer ISR patients. Clinical decision-making should consider patient-specific lesion characteristics and the relative risks and benefits of further stenting versus drug-eluting balloon therapy. Sirolimus DEBs may be particularly useful for patients in whom repeat stenting is undesirable or contraindicated, expanding the interventional cardiologist’s armamentarium for ISR management.
Funding and ClinicalTrials.gov
The SELUTION4ISR trial was supported by MedAlliance, the manufacturer of the SELUTION Sustained Limus Release drug-eluting balloon. The trial is registered on ClinicalTrials.gov under identifier NCT04280029.
References
Cutlip DE, Mehran R, Sharma S, et al. Sirolimus-Eluting Balloon vs Repeat Drug-Eluting Stent or Balloon Angioplasty for Coronary In-Stent Restenosis. J Am Coll Cardiol. 2026;88(1):62-72. PMID: 41984017.
Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical efficacy of drug-eluting stents for in-stent restenosis: evidence from a comprehensive meta-analysis. J Am Coll Cardiol. 2013;62(22):2084–2092.
Ezechieli O, Landmesser U. Drug-coated balloons for coronary artery disease and in-stent restenosis – From concept to clinical reality. Front Cardiovasc Med. 2021;8:761565.