Intracoronary Stenting And Restenosis – randomized trial of Drug-Eluting Stent Implantation or drug-coated balloon angioplasty according to neointima morphology in drug-eluting stent REstenosis 5 (ISAR-DESIRE 5, ClinicalTrials.gov: NCT05544864) is an investigator-initiated, multicenter, prospective, stratified, randomized controlled trial (RCT), designed to investigate a potential interaction between different restenotic tissue patterns and treatment modality (DCB or DES) of ISR lesions in patients presenting with DES-ISR.

The hypothesis being tested is that a significant interaction between OCT-defined tissue patterns (homogeneous or non-homogeneous) and treatment modality with the currently recommended ISR treatment strategies (DES or DCB) exists.

A total of 376 patients will be prospectively enrolled in Germany, Spain, and Belgium. The study started in September 2022 and is expected to conclude in 2026.

This trial will be conducted in accordance with the Declaration of Helsinki, ISO 14155, and applicable local laws and regulations. The protocol, amendments, and the subject's informed consent were approved by all participating sites'independent ethics committees (IEC).

Before enrollment in the study, investigators will inform patients orally and in writing about the scope, purpose, and possible risks/benefits of the study and his/her rights and duties in lay language. Signed informed consent must be collected before randomization. All patient data will be protected and anonymized by a specific identification code and entered into an electronic case reporting form (eCRF).

Study Population

Patients ≥ 18 years old who have signed the written informed consent for participation in the study will be considered eligible for inclusion if they have ischemic symptoms and/or evidence of myocardial ischemia (including non-invasive or invasive functional tests), angiographic evidence of ≥ 50% diameter stenosis (visual estimation) in a native coronary vessel previously treated with DES, as well as availability of an OCT pullback of the target lesion. Key exclusion criteria are represented by cardiogenic shock, acute ST-elevation myocardial infarction (MI) within 48 h from symptoms onset, target lesion location in the left main coronary artery or in a bypass graft, or unsuccessful treatment of other lesion(s) during the same procedure. Multiple stent layers will not be considered an exclusion criterion. The complete list of inclusion and exclusion criteria is shown in Table 1.

Table 1 Complete list of inclusion and exclusion criteriaRandomization and Study Procedures

Patients meeting all inclusion and none of the exclusion criteria will be considered eligible for participation in the study. Eligible patients will be randomized using an electronic randomization system in the chronological order in which they qualify. Patients will first be characterized during the procedure according to the OCT-defined restenotic pattern (homogeneous or non-homogeneous). Then, they will be randomized to either DES or DCB treatment in a 1:1 stratified way based on OCT-defined restenotic tissue in order to obtain an equal distribution of treatment modality within OCT patterns (Graphical Abstract). Patients randomized to repeat DES implantation will be treated with a permanent-polymer everolimus-eluting stent (Xience, Abbott Vascular), while those randomized to DCB angioplasty will undergo treatment with any CE-approved, commercially available DCB. Particular care will be paid to ensure optimal lesion preparation. It is strongly recommended to consider OCT findings when determining the PCI strategy (e.g.: choice of device size and length) (Supplemental Methods S1).

Additional lesions must be treated before the study lesion. In the case of multiple ISR lesions, the highest-grade ISR will represent the target lesion. Baseline clinical and interventional procedures will be performed according to standard clinical practice before randomization (Supplemental Methods S2 and Fig. 2).

Fig. 2

Scheduled activities during different periods of the ISAR-DESIRE 5 Trial. *: PCI will be performed only after randomization. †: Within 24 h after randomization. Hs: High sensitivity; OCT: Optical Coherence Tomography; PCI: Percutaneous Coronary Intervention

In the case of sub-occlusive ISR, precluding sufficient blood clearance through contrast medium and insufficient OCT image quality, lesion predilation with a 1.5 mm balloon will be performed to allow adequate vessel opacification and optimal OCT image quality.

A comprehensive description of peri-interventional and post-interventional therapies is provided in the Supplemental Methods S3.

OCT Assessment

Real-time assessment of the intravascular OCT pullback will be performed by the operator in order to confirm the presence of ISR at the target lesion as well as to conduct qualitative characterization of restenotic tissue at the site of minimum luminal area (MLA) within the restenotic segment, which will ultimately guide stratification during the randomization process [25, 26].

The restenotic pattern will be defined as predominantly homogeneous (≥ 50% uniform optical proprieties that don’t show any focal variation in backscattering patterns) or non-homogeneous (focally changing optical properties with various backscattering patterns or a layered appearance) (Fig. 1). This classification was adapted from that originally proposed by Gonzalo et al. [24]. Detailed definitions are provided in the Supplemental Methods S4. Based on its optical properties at intravascular OCT imaging, restenotic tissue has been subdivided into several patterns that correlate with different histological substrates. Previous histopathological validation studies of intravascular OCT findings have shown homogeneous patterns to consistently correlate with an abundance of smooth muscle cells. In contrast, the remaining neointimal patterns are typically characterized by a multitude of histological findings, including myxomatous extracellular matrix, proteoglycans, organized fibrin and neoatherosclerosis [25,26,27]. Based on the findings of the aforementioned OCT-histology correlation studies and aiming to apply a pragmatic, clinically oriented, and easily applicable algorithm, restenotic tissue will be categorized as predominantly homogenous or non-homogenous.

Subsequently, a detailed offline analysis of OCT pullbacks, including morphometric measurements and qualitative tissue characterization, will be performed in a blinded way at the ISAResearch Center (German Heart Center, Munich, Germany), which will serve as the core laboratory for the present trial (Supplemental Figure S1). Following the enrollment of the first few patients, the core laboratory will provide feedback to participating centers on the qualitative tissue characterization.

Patient Follow-up

Patients will be prospectively clinically monitored for endpoint-relevant clinical events throughout the study period. Furthermore, the concomitant medication will be reviewed. Patients will be clinically monitored daily during their in-hospital stay and contacted by phone or visited in-office at 30 ± 7 days, 12 months ± 30 days, and 24 months ± 30 days (Fig. 2).

Study Endpoints

The primary endpoint of the study is represented by the composite of major adverse cardiac events (MACE) defined as all-cause death, MI, and target lesion revascularization (TLR) after 24 months of clinical follow-up. The prespecified secondary endpoints are represented by the individual components of the primary composite endpoint, target lesion failure (TLF), defined as a composite of cardiac death, target vessel MI and TLR, stent thrombosis (ST) according to the academic research consortium (ARC) criteria as well as the composite safety endpoint represented by of all-cause death and MI. Detailed definitions of the single endpoint components are provided in the Supplemental Methods S5.

Statistical Analysis and Sample Size Calculation

According to current evidence, the incidence of homogeneous and non-homogeneous ISR patterns is comparable [25, 26], and thus, both arms are sized equally. We used a z-Test for the interaction effect of homogeneous morphology (yes/no) and stent treatment (yes/no) in a proportional hazard regression model. Based on the results of our previous explorative observational analysis [27], we assume a proportion of primary endpoint events of 12.5% in the group with non-homogeneous morphology and PCI with DES, of 40% in the group with non-homogeneous morphology and PCI with DCB and 27% in both groups (treated with DCB or DES) with homogenous morphology. With a power of 80%, a two-sided 5% significance level, and assuming a 25% drop-out due to patients lost to follow-up, the total estimated sample size of the study is 376 patients.

The analysis will be based on the intention-to-treat (ITT) population. The full analysis set (FAS) consists of all randomized patients. According to the ITT principle analysis, the FAS will allocate patients to treatment groups as randomized. The per-protocol (PP) population includes all patients of the FAS without protocol deviations. The primary endpoint will be analyzed using a Cox proportional hazards regression model, including the interaction effect of restenotic morphology (homogeneous vs. non-homogeneous) and treatment strategy (DES vs. DCB). Both factors will be included as binary (dummy-coded) variables. This approach will allow assessment of whether the effect of treatment differs according to the underlying OCT-defined restenotic morphology. The exploratory hypothesis of the primary and secondary endpoints will be performed similarly to the confirmatory analysis of the primary endpoint using ITT and PP populations. Event-times distribution will be estimated using the Kaplan–Meier method and tested for group differences by exploratory long-rank tests.

Descriptive statistics will be computed for baseline variables as appropriate.

Prespecified subgroup analysis will be performed for each of the following subgroups: age, sex, body mass index, diabetes mellitus, renal function, clinical presentation, angiographic classification of ISR, vessel size, and use of advanced lesion preparation devices (modified balloon, super-high pressure balloon, intravascular lithotripsy, and atheroablative techniques). Results will also be analyzed according to the OCT tissue appearance according to the central core lab analysis.

Study Organization

The ISAR-DESIRE 5 Trial is an investigator-initiated trial financed by the Munich German Heart Centre and additionally supported by an unrestricted educational grant from Abbott Vascular. The steering committee is responsible for overseeing the good execution and administrative progress of the protocol. The clinical trial documents will be made available by the principal investigator upon request by monitors, auditors, and other representatives of the sponsor or authorities, provided that the data are kept confidential and the patient’s privacy is guaranteed.

Clinical Event Adjudication Committee

The Clinical Event Committee (CEC) will review and decide on all clinical endpoints. The CEC will create clear rules and processes for classifying a clinical event, using specific criteria based on the definitions in the study protocol. All committee members will be blinded to the randomized treatment assignments for all adjudicated patients.