FFR Versus IVUS With Angiography-Derived FFR for Clinical Outcomes in Patients With Coronary Artery Disease

Comparison of Fractional Flow Reserve-Guided Strategy Versus Intravascular Ultrasound-Guided Stent Implantation After Angiography-Derived Fractional Flow Reserve-based Decision-Making (The FLAVOUR III Trial)

To compare the clinical outcomes of fractional flow reserve (FFR)-guided strategy versus intravascular ultrasound (IVUS)-guided stent implantation after angiography-derived FFR-based decision-making.

1. Hypothesis: The IVUS-guided stent implantation after angiography-derived FFR-based decision-making will show superiority in terms of a lower rate of patients-oriented composite outcomes (POCO) at 24 months after randomization compared with the FFR-guided PCI strategy in patients with coronary stenosis.

2. Research materials and indication for revascularization:

   2.1 Experimental group: PCI will be performed if angiography-derived FFR ≤0.80 and will be deferred if angiography-derived FFR >0.80; If PCI is performed, PCI optimization using IVUS will be performed following the recommended criteria: ① Plaque burden at stent edge ≤55%; ② Minimal stent area ≥ 5.5 mm2, or minimal stent area ≥ distal reference lumen area.

   2.2 Control group: PCI will be performed if FFR ≤0.80 and will be deferred if FFR >0.80; If PCI is performed, PCI optimization using FFR will be performed following the recommended criteria: ① Post-PCI FFR ≥ 0.88, or ② Post-PCI ΔFFR ([FFR at stent distal edge] - [FFR at stent proximal edge]) < 0.05.

3. Sample size: In the post-hoc analysis of the FLAVOUR I study applying QFR analysis, the 2-year POCO rate was 13.0% in the PCI group with FFR ≤0.80 and undergoing FFR-based PCI optimization and 7.1% in the PCI group with QFR ≤0.80 and undergoing IVUS-based PCI optimization. Meanwhile, the 2-year POCO rate was 5.8% and 6.5% in the deferral of PCI group with FFR >0.80 and QFR >0.80, respectively. Assuming a PCI rate of 70% in patients with coronary artery lesions with 50-90% stenosis that is the inclusion criteria for the current study, and considering event rates from historical studies evaluating FFR- and QFR-guided PCI strategies, the cumulative incidence rate of POCO at 24 months was estimated to be 13.0% in the control group (FFR group) and 9.0% in the experimental group (QFR-IVUS group).

   • Primary endpoint: POCO, defined as a composite of death from any cause, MI, or any revascularization at 24 months after randomization.
   • Design: superiority
   • Sampling ratio: experimental group : control group = 1:1
   • Type I error (α): One-sided 2.5%
   • Accrual time: 24 months
   • Total time: 4 years (accrual 24 months + follow-up 24 months)
   • Assumption: POCO 13.0% vs. 9.0% in control or experimental group, respectively
   • Statistical power (1- β): 90%
   • Primary statistical method: Kaplan-Meier survival analysis with log-rank test
   • Estimated attrition rate: total 10%
   • Stratification in randomization: Presence of diabetes mellitus

Based on the above assumption, we would need total 1,942 patients (971 patients in each group) with consideration of an attrition rate.

Inclusion Criteria:

• Subject must be ≥ 19 years.
• Subject is able to verbally confirm understanding of risks, benefits and treatment alternatives of receiving invasive physiologic or imaging evaluation and PCI with a drug-eluting stent (DES) and he/she or his/her legally authorized representative provides written informed consent.
• Subjects suspected with ischemic heart disease.
• Subjects with coronary artery diameter stenosis 50-90% by angiography-based visual estimation eligible for stent implantation.
• Target vessel size ≥ 2.5mm in visual estimation.

Exclusion Criteria:

• Known hypersensitivity or contraindication to any of the following medications: Heparin, Aspirin, Clopidogrel, Prasugrel, Ticagrelor
• Active pathologic bleeding.
• Gastrointestinal or genitourinary major bleeding within the prior 3 months.
• History of bleeding diathesis, known coagulopathy.
• Non-cardiac co-morbid conditions with life expectancy < 2 years.
• Target lesion located in coronary arterial bypass graft.
• Left main coronary artery stenosis ≥ 50%.
• Chronic total occlusion in the study target vessel.
• Culprit lesion of ST-elevation myocardial infarction (STEMI).
• Not eligible for angiography-derived FFR (ostial RCA ≥ 50% stenosis, severe tortuosity, severe overlap, poor image quality).