Intravascular Ultrasound- and Angiography-Derived Fractional Flow Reserve-Guided Drug-Coated Balloon for Large Coronary Artery De Novo Lesions

Intravascular Ultrasound- and Angiography-Derived Fractional Flow Reserve-Guided Drug-Coated Balloon for Large Coronary Artery De Novo Lesions

Trial name Intravascular Ultrasound- and Angiography-Derived Fractional Flow Reserve-Guided Drug-Coated Balloon for Large Coronary Artery De Novo Lesions Objectives To compare the safety and efficacy of Drug-Coated Balloons (DCB) versus Drug-Eluting Stents (DES) in large de novo coronary lesions guided by intravascular ultrasound (IVUS) and Angiography-derived fractional flow reserve (AngioFFR).

Study design Investigator-initiated, open-label, multicenter, non-inferiority randomized controlled trial Patient enrollment 2,492 patients enrolled in China and Republic of Korea. Duration Anticipated recruitment is 2 years. Follow-up will be performed at 1, 3, 6, 12, 36, and 60 months.

Inclusion Criteria

1. Patients must require PCI based on clinical condition (angiographic stenosis ≥ 75% or angiographic stenosis ≥ 50% with AngioFFR≤0.80) and have signed the informed consent form.
2. Coronary angiography shows a single non-left main lesion, with a reference vessel diameter between 2.75mm and 4.00mm, and an estimated lesion length < 40mm.
3. Following adequate intraoperative lesion preparation, the following must be met: IVUS shows MLA≥ 4.0mm² and/or AnioFFR > 0.80.
4. Absence of flow-limiting dissection or hematoma (angiographic Type A or B dissection; IVUS dissection not involving the media) and TIMI flow grade 3
5. Patients must be able to be followed up for more than 1 year and be willing to cooperate with the trial follow-up requirements.

Exclusion Criteria

1. Patients are younger than 19 or older than 80 years of age.
2. High-Risk Clinical/Anatomical Factors: Cardiogenic shock, left main disease, severely tortuous lesions, complex bifurcation lesions, severe calcification, total occlusion of the target vessel, or bypass grafts.
3. Recent major surgery (within 1 month pre-procedure) or clear gastrointestinal bleeding events.
4. Known allergy or contraindication to heparin, aspirin, clopidogrel, prasugrel, ticagrelor, or contrast media (patients with clear contrast allergies such as rash may be included if controlled beforehand with effective medication like glucocorticoids or diphenhydramine).
5. Women who are currently pregnant or breastfeeding.
6. Non-cardiac comorbidities indicating an expected life expectancy of less than 1 year.
7. Any other factors that may affect follow-up or participation in other clinical studies.

Patient follow-up Clinical follow-up will perform 1, 6, 12, 36 and 60 months after the procedure by telephone contacts or office visits.

Primary endpoint

The study employs a hierarchical testing (sequential testing) approach, following the logical order below:

1.12-Month Net Adverse Clinical Events (NACE): Defined as a composite endpoint consisting of all-cause death, stroke, myocardial infarction (MI), ischemia-driven revascularization, and bleeding (BARC 3 or 5).

2.Ischemic Endpoint - Major Adverse Cardiac and Cerebrovascular Events (MACCE): Defined as the composite of death, MI, ischemia-driven revascularization, and ischemic stroke.

3.Bleeding Endpoint: Defined as 12-month major bleeding or clinically relevant non-major bleeding, categorized as BARC 2, 3, or 5.

Secondary endpoint

1. Target Vessel Failure (TVF): A composite of cardiac death, target vessel MI, or target vessel revascularization.
2. NACE, major bleeding or clinically relevant non-major bleeding, and MACCE at 36 and 60 months.
3. All-cause death and cardiac death.
4. MI, spontaneous MI, peri-procedural MI, and target vessel MI.
5. Any revascularization of the target vessel/target lesion.
6. Any revascularization of a non-target vessel/ non-target lesion.
7. Any revascularization (ischemia-driven or all-cause).
8. Stent Thrombosis: Classified as definite, probable, or possible.
9. Stroke: Including both ischemic and hemorrhagic stroke.
10. Bleeding Events: BARC 3 or 5 bleeding, and BARC 2 bleeding.
11. Evaluation of cost-effectiveness.

Background Coronary artery disease (CAD) remains a leading cause of death and disability worldwide. While the widespread use of percutaneous coronary intervention (PCI) and drug-eluting stents (DES) has significantly improved patient outcomes, long-term follow-up studies indicate that stent-related complications, such as late restenosis, very late thrombosis, decreased vascular compliance due to metal residue, and high bleeding risks associated with long-term dual antiplatelet therapy (DAPT), remain significant concerns.

In this context, the drug-coated balloon (DCB) has emerged as a "metal-free" alternative strategy. By expanding the balloon to release anti-proliferative drugs directly into the vessel wall, DCBs aim to reduce metal residue, improve vascular healing, and lower the incidence of long-term events. "Intervention without implantation" represents the future direction of coronary intervention.

Internationally, multiple high-quality studies have validated the safety and efficacy of DCB in treating in-stent restenosis (ISR) and small vessel de novo lesions. For instance, international DCB consensus clearly includes ISR and small vessel disease within mature indications. Recent research has shown that in small vessel disease, DCB is comparable to second-generation DES in terms of target lesion revascularization (TLR) and major adverse cardiovascular events (MACE), while offering lower long-term stent-related risks.

Current DCB research is gradually expanding toward "large coronary artery de novo lesions". These lesions typically involve a reference vessel diameter ≥2.75-3.0 mm, high plaque burden, and poor vascular compliance. Some international studies have found that under conditions of adequate lesion preparation (residual stenosis < 30%, absence of severe dissection, and sufficient expansion), DCB treatment for large vessel de novo lesions can achieve satisfactory results. However, a multicenter randomized controlled trial of 2,272 patients showed a 3-year composite endpoint of 8.2% for DCB (plus rescue stenting) versus 5.0% for DES, suggesting that in unselected patient populations, DCB did not meet non-inferiority standards compared to DES. Currently, there is a lack of large-scale randomized controlled trials specifically investigating DCB intervention for large de novo lesions.

Previous studies have demonstrated that Intravascular Ultrasound (IVUS) and Angiography-Derived Fractional Flow Reserve (AngioFFR) effectively improve patient outcomes, with both technologies receiving Class I recommendations in multiple international guidelines. Our research team previously analyzed 610 cases of DCB treatment guided by IVUS combined AngioFFR. For coronary arteries with a diameter ≥2.75 mm, patients who achieved a post-preprocessing minimal lumen area (MLA) ≥ 4.0 mm2 and AngioFFR > 0.80, without flow-limiting dissection, showed favorable outcomes with a 1-year follow-up event rate of less than 10%. Therefore, exploring the efficacy of DCB in large coronary artery de novo lesions guided by coronary imaging and functional physiology is of great significance.

Currently, for DCB treatment of small vessels and ISR, DAPT is typically maintained for only 1-3 months. However, there is no clear guideline-recommended antiplatelet strategy for large de novo lesions. Based on the regenerative and repair functions of the vascular endothelium, endothelialization of the treated lesion can be completed within 1 month post-procedure, supporting a de-escalation antiplatelet strategy. Consequently, further exploration of antiplatelet strategies for large de novo lesion patients treated with DCB is highly important.

Hypothesis

This study employs a hierarchical testing (sequential testing) approach. The hypotheses will be tested in the following order:

In patients with large coronary artery de novo lesions, under the guidance of IVUS and AngioFFR:

H1: The DCB treatment group is non-inferior to the DES treatment group regarding Net Adverse Clinical Events (NACE) at 12 months.

H2: The DCB group is non-inferior to the DES group regarding Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 12 months.

H3: The DCB group is superior to the DES group regarding major bleeding or clinically relevant non-major bleeding (BARC 2, 3, or 5) at 12 months.

1. DCB Treatment Group Patients receive Dual Antiplatelet Therapy (DAPT) for 1 month. After 1 month, therapy is switched to Single Antiplatelet Therapy (SAPT), with Clopidogrel as the preferred agent.

   Oral Anticoagulants: If the patient is concurrently taking oral anticoagulants, they will receive SAPT plus anticoagulation for 1 month, followed by anticoagulation alone.

2. DES Treatment Group Patients receive DAPT for at least 6 months following DES implantation. Subsequent antiplatelet regimens are determined by the operator's discretion. Oral Anticoagulants: If the patient is concurrently taking oral anticoagulants, they will receive DAPT plus anticoagulation for 1 month, followed by SAPT plus anticoagulation.

DCB or DES Used in PCI Device Selection: The specific type of DCB or DES used is at the operator's discretion.

Medication Selection: The specific types of drugs used for DAPT or SAPT are determined by the operator.

Study Period Seven years after IRB approval

Inclusion Criteria:

1. Patients must require PCI based on clinical condition (angiographic stenosis ≥ 75% or angiographic stenosis ≥ 50% with AngioFFR≤0.80) and have signed the informed consent form.
2. Coronary angiography shows a single non-left main lesion, with a reference vessel diameter between 2.75mm and 4.00mm, and an estimated lesion length < 40mm.
3. Following adequate intraoperative lesion preparation, the following must be met: IVUS shows MLA≥ 4.0mm² and/or AnioFFR > 0.80.
4. Absence of flow-limiting dissection or hematoma (angiographic Type A or B dissection; IVUS dissection not involving the media) and TIMI flow grade 3
5. Patients must be able to be followed up for more than 1 year and be willing to cooperate with the trial follow-up requirements.

Exclusion Criteria:

1. Patients younger than 19 or older than 80 years of age.
2. High-Risk Clinical/Anatomical Factors: Cardiogenic shock, left main disease, severely tortuous lesions, complex bifurcation lesions, severe calcification, total occlusion of the target vessel, or bypass grafts.
3. Recent major surgery (within 1 month pre-procedure) or clear gastrointestinal bleeding events.
4. Known allergy or contraindication to heparin, aspirin, clopidogrel, prasugrel, ticagrelor, or contrast media (patients with clear contrast allergies such as rash may be included if controlled beforehand with effective medication like glucocorticoids or diphenhydramine).
5. Women who are currently pregnant or breastfeeding.
6. Non-cardiac comorbidities indicating an expected life expectancy of less than 1 year.
7. Any other factors that may affect follow-up or participation in other clinical studies.