This trial is designed to test the hypothesis that IVUS-guided DCB will result in a lower incidence of major adverse cardiac events (MACE)—including cardiac death, target vessel-related myocardial infarction, and ischemia-driven target lesion revascularization—compared to angiography-guided DCB for de novo small-vessel coronary lesions over a 12-month follow-up period. Additionally, the trial aims to identify the optimal critical values of lumen parameters (such as minimum lumen area, plaque burden, dissection length, and thickness) through the use of IVUS prior to DCB application in de novo small-vessel coronary lesions.

This trial is a prospective, multicenter, randomized controlled study involving 998 patients across at least 10 hospitals in China. The overall study flow chart is presented in Figure . Conducted in accordance with the guidelines outlined in the Declaration of Helsinki, the trial is registered with the China Clinical Trial Registry (ChiCTR2300073877). All enrolled patients are required to sign written informed consent prior to participation. The study’s Data Management System is secured by password protection and accessible only to authorized users with designated research credentials. While operators in the cardiac catheterization laboratory are not blinded, individuals responsible for data analysis remain unaware of the treatment strategies to ensure impartial evaluation. The results of this clinical trial will be published in peer-reviewed journals and shared during international conferences.

Flowchart depicting the design of the clinical trial. In cases where residual stenosis exceeds 30%, decreased blood flow (TIMI flow grade ≤2) or a flow-limiting dissection is observed following predilation or DCB angioplasty, DES implantation is recommended as a rescue treatment strategy. DCB, drug-coated balloon; IVUS, intravenous ultrasound.

A total of 998 eligible patients, each with an indication for PCI due to de novo coronary lesions suitable for DCB, are randomly assigned in a 1:1 ratio to either the research group (IVUS-guided group) or the control group (angiography-guided group). Random sequence numbers for patient allocation are generated using an Interactive Web Randomization System, which also manages the randomization serial numbers for each participating hospital. The specific inclusion and exclusion criteria are outlined below.

• (1)

  Age 18-80 years old.

• (2)

  Asymptomatic myocardial ischemia, stable or unstable angina, or acute myocardial infarction with an onset exceeding 1 week.

• (3)

  The vessel diameter visually estimated stenosis in the target lesion is ≥ 70%, with a reference vessel diameter of 2-2.75 mm. The target lesion is required to be a de novo lesion possessing a visual lesion length not exceeding 25 mm and is to be treated using only 1 DCB.

• (4)

  Suitable for PCI.

• (5)

  The subject (or legal guardian) comprehends the requirements of the trial and the treatment process.

• (6)

  The subject (or their legal guardian) must provide a signature on the written informed consent form before undergoing the examination or procedure outlined in the protocol.

• (7)

  The subject willingly agrees to comply with all follow-up evaluations required by the protocol.

• (1)

  Inability to perform dual antiplatelet therapy (DAPT).

• (2)

  Allergies to the balloon, stent system or accompanying drugs used in the study.

• (3)

  Expected life is less than 12 months.

• (4)

  Pregnant or lactating women.

• (5)

  The subject is currently participating in another clinical trial that has not yet reached the study endpoint.

• (6)

  Cardiogenic shock, severe congestive heart failure (LVEF <35% or NYHA grade IV), severe renal insufficiency (serum creatinine >2.0 mg/dL).

• (7)

  In-stent restenosis.

• (8)

  Chronic total occlusion lesions.

• (9)

  Left main trunk lesion.

• (10)

  The target vessel has extensive thrombosis.

• (11)

  PCI ever done or planned within 10mm of the edge of the area covered by the DCB of the target lesion.

• (12)

  Severe calcification or distortion of target vessels hinders the passage of instruments.

• (13)

  The target lesion in bypass graft blood vessels.

• (14)

  There is an aneurysm involved in the target lesion, or the target lesion is positioned within 5 mm next to an aneurysm.

• (15)

  The target lesion with severe calcification requires rotational atherectomy.

All procedures adhere strictly to current guidelines and local practices. Our protocol necessitates meticulous predilation of lesions. Starting predilation with a smaller balloon is considered a reasonable approach. A recommended final predilation balloon can be achieved using semi-compliant balloons, noncompliant balloons, cutting balloons, or scoring balloons Predilation is deemed successful when the residual stenosis is visually observed to be ≤30%, the TIMI (Thrombolysis In Myocardial Infarction) flow grade is 3, and no flow-limiting dissections are present, thereby allowing the use of DCB angioplasty DCB angioplasty is performed using a commercially available biolimus-coated balloon (BA9, JW Medical Systems). The DCB must extend 2 to 3 mm beyond the prepared lesion on both sides and should be inflated at the minimum nominal pressure for a minimal time of 30 seconds, unless severe ischemia occurs. Angiographic success is defined as a residual stenosis of ≤30%, TIMI flow grade 3, and the absence of flow-limiting dissections, as assessed visually. In cases where residual stenosis exceeds 30%, decreased blood flow (TIMI flow grade ≤2) or a flow-limiting dissection is observed following predilation or DCB angioplasty, DES implantation is recommended as a rescue treatment strategy.

In the angiography-guided group, the selection of the predilation balloon size, DCB size, and dilation pressure is determined through visual assessment of angiographic images The maximum diameter of predilation balloon-to-distal reference artery diameter ratio of 1:1 is recommended, and the recommended DCB-to-distal reference artery diameter ratio ranges from 0.8 to 1.0.

In the IVUS-guided group, after administering nitroglycerin (100-200 μg) into the coronary artery, the IVUS catheter is positioned at least 10 mm distal to the lesion. IVUS images are then acquired using an automated pullback mechanism with a 40-MHz commercially available imaging system (iLab, Boston Scientific). It is recommended to utilize IVUS at specific stages: prior to predilation, as well as before and after DCB angioplasty. If the IVUS catheter is anticipated to be unable to traverse the lesion, a small balloon (2.0 mm) can first be employed for low-pressure predilation. Several essential parameters are assessed on-site via IVUS, including the minimal lumen diameter, minimal lumen area, reference lumen area, plaque burden, and the length and depth of any dissection. Lesion length was defined as the distance between the distal and proximal reference segments, with the reference segment identified as a cross-sectional image adjacent to the lesion with <50% plaque burden. Based on the IVUS data, the predilation balloon size, DCB size, and dilation pressure are selected accordingly. The maximum diameter of predilation balloon and DCB are determined according to the distal reference artery, with a ratio of 0.8 to the media diameter or 1:1 to the lumen diameter. Following the procedure, IVUS images are archived onto a DVD for subsequent offline analysis.

Patients participating in this trial are treated in accordance with contemporary guidelines and local practices. It is advised to administer loading doses of aspirin (300 mg) and clopidogrel (300 mg, or alternatively, 180 mg of ticagrelor) at least 6 hours prior to PCI. During the procedure, heparin or other antithrombotic agents, such as bivalirudin, are employed. Following the PCI, DAPT is recommended, consisting of aspirin at a daily dose of 100 mg and clopidogrel at a daily dose of 75 mg (or alternatively, 90 mg of ticagrelor, taken twice daily). The duration of DAPT is determined by the attending physician’s assessment. For patients with stable conditions where DCB is used alone, DAPT duration of 1 to 3 months is suggested. If DES is implanted alongside the DCB, antiplatelet therapy should align with the stent’s specific requirements. For patients with acute coronary syndrome, DAPT is recommended for a minimum of 12 months’ postprocedure. However, for those with high bleeding risks, the DAPT duration may be shortened, or single antiplatelet therapy may be employed instead. Once patients have completed the postprocedure DAPT regimen, they should transition to at least 1 antiplatelet drug or a novel oral anticoagulant, such as rivaroxaban or dabigatran, with no specified time limit for continuation.

Clinical follow-up for outcome evaluation is conducted by the enrolling site through office visits or telephone communications at 30 days, 3 months, 6 months, 9 months, and 12 months. Angiographic follow-up is advised to take place 9 months after PCI, unless clinical circumstances necessitate an earlier evaluation.

Shaanxi Provincial People’s Hospital will serve as the core laboratory, overseeing the off-site quantitative coronary angiographic analysis during 4 stages: baseline, intra-operative, postprocedural, and follow-up. The coronary angiography images will be independently reviewed by 2 experienced interventional cardiologists blinded to the assigned intervention. For angiography performed at the baseline and postprocedural stages of the target lesions, a minimum of 2 injections following intracoronary nitroglycerin administration (100–200 μg, unless clinically contraindicated) is required. Additionally, the 2 injections must exhibit an angulation difference of at least 30°.