Balloon-based percutaneous coronary intervention in multilayer in-stent restenosis

In-stent restenosis (ISR) remains an important clinical challenge in contemporary interventional cardiology. Despite the widespread adoption of newer-generation drug-eluting stents (DES) and substantial improvements in stent platforms, polymers, and antiproliferative agents, ISR continues to account for a meaningful proportion of repeat coronary interventions (1). Current percutaneous management strategies for ISR are heterogeneous and include DES implantation, plain old and drug-coated balloon (DCB) angioplasty, and intravascular brachytherapy. Each option carries trade-offs, and none fully eliminates the potential for recurrence, particularly when restenosis develops repeatedly within the same coronary segment. Brachytherapy, while effective in recurrent and multilayer ISR, remains limited by restricted availability and logistical constraints, largely confining its use to specialized centers in the setting of refractory disease (2).

Current guidelines recommend DES as first-line therapy for the first occurrence of ISR (3,4). Although repeat DES implantation may provide greater acute results than DCB angioplasty, further metal layering may worsen the disease and amplify the cycle of vessel injury and recurrent neointimal response, particularly in patients with an aggressive restenotic substrate (Figure 1). Among ISR phenotypes, the multiple-layer restenosis represents a distinct scenario. In these patients, the vessel has already undergone repeated mechanical injury and repeated metal implantation, resulting in progressive luminal compromise and reduced compliance for future treatment. In this context, DCB offer an appealing therapeutic concept: delivery of an antiproliferative drug without leaving an additional permanent implant (5,6).

Figure 1 Multilayer ISR as a vicious cycle and the role of DCB-enabled lifetime management. CABG, coronary artery bypass grafting; DCB, drug-coated balloon; DES, drug-eluting stent; ISR, in-stent restenosis; IVI, intravascular imaging.

In The Journal of the American College of Cardiology, Kirtane and colleagues published a prespecified subgroup analysis from AGENT IDE comparing a low-dose paclitaxel-coated balloon (PCB) with plain old balloon angioplasty (POBA) in patients with single-layer and multilayer ISR (7). By stratifying randomization according to stent-layer complexity, the investigators provided evidence directly relevant to a patient population that frequently challenges routine algorithms and remains only partially addressed by guideline recommendations (2-4).

A notable observation from AGENT IDE is the substantial representation of multilayer ISR, with approximately 43% of enrolled patients presenting restenosis within more than one stent layer, a finding consistent with the broader clinical burden of ISR as a major driver of repeat coronary interventions in the United States. In this context, multilayer ISR may represent a marker of cumulative coronary interventions and heightened susceptibility to recurrent stent failure over time.

Understanding ISR as a clinical syndrome requires recognition that the mechanism of failure is not uniform. Mechanical contributors, including stent underexpansion, incomplete lesion coverage, or stent fracture, may be relevant in some cases, while technical factors such as inadequate lesion preparation or residual plaque burden may also contribute. However, in many patients with recurrent ISR, the dominant mechanism may reflect exuberant neointimal hyperplasia or neoatherosclerosis, sometimes with limited responsiveness to prior antiproliferative therapy. When restenosis occurs after DES implantation, the lesion has already “failed” an effective antiproliferative strategy. Although an additional DES may improve acute lumen gain through scaffolding and tissue compression, it may not mitigate the underlying propensity for recurrent neointimal growth and may further compromise luminal dimensions, making subsequent ISR increasingly difficult to treat. Consistent with clinical experience, outcomes in multilayer ISR were substantially worse than in single-layer ISR. The rate of 1-year target lesion failure (TLF)—a composite of ischemia-driven target lesion revascularization (TLR), target-vessel myocardial infarction (TV-MI), or cardiac death—was nearly doubled in multilayer ISR compared with single-layer ISR (29.0% vs. 15.7%). This observation reinforces that multilayer ISR identifies a subgroup with more advanced and aggressive coronary artery disease, and likely a more refractory restenotic substrate.

Within this framework, the pharmacologic properties of paclitaxel remain relevant. The marked lipophilicity of paclitaxel favors rapid uptake from the balloon surface and preferential partitioning into lipid-rich layers, resulting in transmural penetration (8). This concept may be further supported by the fact that contemporary DES predominantly elute limus-family drugs, making paclitaxel a mechanistically attractive alternative in patients with recurrent and multilayer ISR.

Accordingly, multilayer and recurrent ISR may represent a niche in which balloon-based local antiproliferative delivery is mechanistically attractive. In AGENT IDE, among patients with multilayer ISR, PCB reduced 1-year TLF from 40.0% to 23.8%, [hazard ratio (HR): 0.55; 95% confidence interval (CI): 0.34–0.87; P=0.01], a reduction driven by both TLR (17.4% vs. 37.8%; P=0.0003) and TV-MI (5.9% vs. 17.2%; P=0.005). While the overall treatment effect appeared consistent across multilayer and single-layer ISR, the absolute clinical impact was inherently larger in those with multilayer ISR, reflecting their higher baseline risk. More broadly, these findings highlight the following: in ISR with a more aggressive phenotype, such as multilayer ISR, higher event rates may allow treatment differences to emerge earlier. Conversely, in single-layer ISR, where event rates are lower, longer-term follow-up may be needed to determine whether differences between strategies become apparent over time.

Given the absence of durable scaffolding and radial support with balloon-only strategies, achieving the same acute luminal gain as repeat stenting may be challenging; accordingly, a key translational lesson of the DCB era is that outcomes depend not only on the device, but also on the overall procedural strategy. Appropriate plaque modification may therefore be critical not only to optimize luminal gain, but also to enhance drug transfer and tissue penetration, a particularly relevant consideration for DCB therapy in which the more drug that reaches the vessel wall, the greater the antiproliferative effect may be (2).

As such, DCB therapy requires careful attention to lesion preparation and an upfront commitment to achieving an optimal procedural result. Contemporary DCB practice increasingly emphasizes: (I) systematic use of intravascular imaging is essential to differentiate biological (neoatherosclerosis and patterns of neointimal hyperplasia) from mechanical mechanisms of ISR, particularly by identifying stent underexpansion, deformation and fracture; (II) lesion modification tools such as cutting or scoring balloons when appropriate; and (III) stricter criteria for acceptable residual stenosis in absence of flow-limiting dissection (9,10). In AGENT IDE, the criterion for successful predilation (residual stenosis <50%) was more permissive than thresholds proposed in consensus documents (11). Although this does not undermine the core findings, it highlights the need for continued refinement of procedural standards as DCB-based strategies become more integrated into routine practice.

Kirtane et al. reinforce several clinically relevant themes. PCB therapy seems to improve outcomes compared with POBA in both strata, with a larger absolute benefit in multilayer ISR. These findings support a broader ISR management framework focused on minimizing iterative metal layering and preserving long-term vessel treatability. At the same time, perspective is warranted. Even with PCB therapy, event rates in multilayer ISR remained substantial, underscoring that recurrent ISR continues to represent an important unmet need. Moreover, POBA was the only comparator, and other contemporary strategies were not evaluated. This limitation is particularly relevant in light of the recently published SELUTION4ISR trial, in which a sirolimus-eluting balloon met non-inferiority for 1-year TLF compared with contemporary standard care, composed predominantly of repeat DES implantation and to a lesser extent balloon angioplasty. However, the trial also highlights the complexity of ISR treatment: outcomes numerically favored standard care overall, the benefit of the sirolimus-eluting balloon appeared more evident against balloon angioplasty than against repeat DES, and patients with more than two stent layers were excluded. While awaiting additional evidence, DCB-based treatment represents a reasonable approach in patients with multilayer ISR, particularly when avoidance of further metal implantation is clinically desirable. More broadly, contemporary PCI strategies should prioritize minimizing additional stent layering whenever feasible, given the potential to perpetuate the cycle of vessel injury and recurrent restenosis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0015/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0015/coif). A.L. reports consulting fees from Medtronic, Abbott, Boston Scientific, Edwards Lifesciences, Philips, Anteris, and Tresquare; and participation on Data Safety Monitoring Boards or Advisory Boards for the same entities. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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