This was a prospective, open-label, single-arm trial. The patients were enrolled from nine sites in Japan. This study was conducted in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines for medical devices. The study was registered with the Japan Registry of Clinical Trials (jRCT) under the registration number jRCT2032220438 and was conducted with the approval of the institutional review board at each participating site.

The KCB01 (KIZASHI™) is a cutting-type balloon catheter with nylon blades integrally formed with the balloon. The nominal pressure is 20 atm and the rated burst pressure (RBP) is 24 atm. The balloon is designed to be low-compliance, meaning that its outer diameter does not significantly increase, even under high pressure. The blades are arranged circumferentially at 120-degree intervals, and the blade height is adjusted according to the balloon diameter. The compatible guiding catheter is 5 Fr for balloon diameters of 3.0 mm or less, and 6 Fr for balloon diameters of 3.25 mm or more. The compatible guidewire size is 0.014 inches (Fig. 1).

The main inclusion criteria were as follows: (1) patients with stenotic lesions with > 90% stenosis, or lesions that are considered the cause of stable exertional angina classified as Class II or higher according to the Canadian Cardiovascular Society classification, or lesions that have been confirmed through functional testing to be the cause of functional ischemia; (2) patients with a target lesion located in a vessel with a diameter between 2.0 and 4.0 mm; (3) patients with a target lesion length of 38 mm or less; and (4) patients with a target lesion with residual indentation by conventional balloon nominal pressure dilation. The main exclusion criteria were as follows: (1) patients with a left ventricular ejection fraction of less than 40% within 30 days prior to the procedure; (2) patients with New York Heart Association Class III or IV heart failure; (3) patients with a target lesion in the unprotected left main coronary artery; 4) patients whose target lesion is in a vessel that can only be reached through the saphenous vein or arterial bypass graft; (5) patients with a target lesion located at or distal to a vessel bend greater than 45 degrees; (6) patients with excessive tortuosity in the target vessel; (7) patients with thrombus or ulceration in the target vessel; and (8) patients with angiographic evidence of severe dissection in the target vessel after conventional balloon dilation. All inclusion and exclusion criteria are listed in the Supplemental Table S1.

Information. Only one target lesion was treated with the KCB01; if multiple lesions met the criteria, the physician selected the target lesion. Patients who met the inclusion criteria and did not violate the exclusion criteria were considered eligible, and enrollment occurred when the KCB01 was inserted into the guiding catheter. Patients judged by the independent data monitoring committee (IDMC) to have no residual indentation by conventional balloon nominal pressure dilation after core lab analysis were excluded from the efficacy analysis.

Access sites (transradial approach or transfemoral approach) were not specified and left to the physician’s discretion. The selection of the KCB01 size was also at the discretion of the physician, and the use of a guide extension catheter was not restricted. If crossing the lesion with the KCB01 was difficult, pre-dilation with the conventional balloon used for the indentation check or a conventional balloon of the same or smaller size than the KCB01 was allowed. The dilation pressure of the KCB01 was set within the RBP range at the physician’s discretion, and there was no limit on the number of dilations.

No other device treatment was allowed for revascularization of the target lesion between patient enrollment and post-KCB01 angiography. After dilation with the KCB01, the use of any device or therapy other than conventional balloons, DCBs, or stents was prohibited. If pre-dilation with the KCB01 was insufficient, the residual stenosis was severe, and the physician judged that completing the procedure was difficult, the use of a device such as a rotational atherectomy or orbital atherectomy system was permitted, but the procedure was judged as unsuccessful.

There were no specific regulations regarding the selection of DES or DCB after KCB01 dilation, and the physician selected the device according to the extent of the dissection. Patient follow-up was carried out until the time of discharge.

Angiographic analysis was performed at pre-procedure, during conventional balloon dilation for eligibility assessment (at the time of indentation check with a conventional balloon), during KCB01 dilation (at the time of indentation check with the KCB01), after KCB01 dilation, and after the procedure (Fig. 2).

Procedure flow chart, detailing the steps from consent to discharge, including eligibility assessment, pre-dilation, stent implantation, and post-procedure examination. CAG #1 pre-procedure; CAG #2 at the time of indentation check with a conventional balloon; CAG #3 at the time of indentation check with the KCB01; CAG #4 after KCB01 dilation; CAG #5 upon completion of the procedure.CAG coronary angiography; DCB drug-coated balloon

All angiographic images were analyzed by the core laboratory (CARDIOCORE JAPAN, Tokyo, Japan) for qualitative lesion and quantitative coronary angiography (QCA) analyses (Supplemental Table S2). The main evaluations at the core lab included target lesion site, lesion morphology (e.g., American Heart Association [AHA] lesion classification, in-stent restenosis [ISR] lesion, ostial lesion, bifurcation lesion, calcification, and presence of dissection), dissection after KCB01 dilation, in-segment minimum lumen diameter, and in-segment residual stenosis rate. Calcification was classified as none/mild (not visible on CAG), moderate (radiopacities noted only during the cardiac cycle before contrast injection), and severe (radiopacities noted without cardiac motion before contrast injection generally compromising both sides of the arterial lumen) [9]. The evaluation results from the core lab, including judgments on the presence or disappearance of indentations impacting eligibility and procedural success, were reviewed by the IDMC for final determination. The evaluations at the core lab and IDMC are shown in Fig. 3.

Core lab and independent data monitoring committee (IDMC) indentation judgement, showing the process of quantitative coronary angiography (QCA) analysis, procedural success judgement, clinical success judgement, and final judgement of major adverse cardiac event (MACE)

The primary endpoint was the procedural success rate, defined as the KCB01 crossing the target lesion, no residual indentation, and a < 50% residual stenosis rate after KCB01 dilation (assessed by QCA). Secondary endpoints included the clinical success rate, major adverse cardiac event (MACE) incidence, in-segment minimum lumen diameter, in-segment residual stenosis rate, grade of dissection based on National Heart, Lung, and Blood Institute (NHLBI) classification, incidence of cardiac death, incidence of myocardial infarction, and target vessel revascularization (TVR) incidence. Clinical success was defined as successful dilation with the KCB01, residual stenosis less than 50% at the end of the procedure (evaluated by QCA), and the absence of MACE until discharge. MACE included cardiac death, nonfatal myocardial infarction, and revascularization based on clinical findings. The definitions of the other endpoints are provided in the Supplemental Table S3.

The final determinations of procedural success, clinical success, NHLBI classification, and MACE were performed using the IDMC.

Safety endpoints included the nature and incidence of adverse events and device deficiencies, laboratory data, vital signs, and 12-lead electrocardiograms (ECGs).

Continuous variables were presented as mean ± standard deviation, and binary data for efficacy evaluation were expressed as percentages and 95% confidence intervals (CIs; Clopper-Pearson).

The performance goal was set at 76.5% based on the procedural completion rate for cutting balloons from a previous domestic clinical study [10] and the percutaneous coronary intervention (PCI) success rate reported before the standardization of stent treatment [11]. Differences in the target lesions (such as the proportion of calcified lesions) between those reports and the target lesions expected in this study were considered.

For the primary endpoint of the procedural success rate, the efficacy of the KCB01 was confirmed if the lower limit of the two-sided 95% CI by Clopper-Pearson exceeded the set performance goal. Assuming an expected procedural success rate of 90% for the KCB01, a one-sided significance level of 2.5%, and a power of 80%, the required sample size was determined to be 63. Considering a dropout margin of approximately 10%, the target number of patients was set to 70.

The primary analysis set for efficacy evaluation was the full analysis set (FAS). Cases deemed not to meet the inclusion criteria of the IDMC, with no efficacy evaluation data obtained, were excluded from the FAS. The data management and statistical analysis were conducted by the contract research organization (RPM Co., Ltd., Tokyo, Japan). The software used for the statistical analysis included SAS Release 9.4 TS1M4 (× 64 version) and Microsoft Excel for Microsoft 365 (version 2301). The aggregation of adverse events and device deficiencies included all cases in which the KCB01 was inserted into the guiding catheter.