Fractional FLow Reserve And IVUS for Clinical OUtcomes in Patients With InteRmediate Stenosis (FLAVOUR)

Comparison of Clinical Outcomes Between Imaging and Physiology-guided Intervention Strategy in Patients With Intermediate Stenosis: Fractional FLow Reserve And IVUS for Clinical OUtcomes in Patients With InteRmediate Stenosis (FLAVOUR)

Second Affiliated Hospital, School of Medicine, Zhejiang University, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ulsan University Hospital, Keimyung University Dongsan Medical Center, Inje University, KangWon National University Hospital, Ajou University School of Medicine

To compare the safety and efficacy of FFR (fractional flow reserve)-guided percutaneous coronary intervention (PCI) strategy with IVUS (intravascular ultrasound [IVUS])-guided PCI in patients with intermediate coronary stenosis.

Study overview This study is a prospective, open-label, randomized, multicenter trial to test the safety and efficacy of physiology- or imaging-guided PCI in patients with intermediate coronary stenosis. The primary hypothesis is that FFR-guided strategy will show non-inferior rate of patients-oriented composite outcomes (POCO) at 24 months after randomization, compared with IVUS-guided strategy in patients with intermediate coronary stenosis. Study population and sample size calculation Sample Size Calculation Based on the event rates of previous trials, investigators predicted the rates of POCO at 24 months after PCI will be 10% in the FFR-guided arm, and 12% in the IVUS-guided arm. Primary endpoint: patient-oriented composite outcome (a composite of all-cause death, MI, any repeat revascularization) at 24 months after PCI Design: non-inferiority , delta = 2.5% Sampling ratio: FFR-guided strategy : IVUS-guided strategy = 1:1 Type I error (α): One-sided 5% Accrual time : 2 years Total time : 4 years (accrual 2 year + follow-up 2 years) Assumption: POCO 10.0% vs. 12.0% in FFR or IVUS-guided strategy, respectively Statistical power (1- β): 90% Primary statistical method : Kaplan-Meier survival analysis with log-rank test Potential withdrawal rates : total 2% Stratification in Randomization: Presence of Diabetes Mellitus (600 patients (35%) will be Diabetic patients, with 300 patients in each group) Based on the above assumption, 1,700 patients (850 patients in each group) will be enrolled in this study with consideration of withdrawal rates. Research Materials and Indication for Revascularization For the FFR-guided strategy arm, a pressure-sensor wire system will be used and the criterion for revascularization is FFR ≤ 0.80. Hyperemia will be induced by intravenous infusion of adenosine (140ug/kg/min). For the IVUS-guided strategy arm, the criterion for revascularization is MLA ≤ 3mm2 or [3mm2 < MLA ≤ 4mm2 and plaque burden > 70%]. Funding This is an investigator-initiated study with grant support from Boston Scientific. Other than financial sponsorship, the company has no role in protocol development or the implementation, management, data collection, and analysis of this study.

Percutaneous coronaryintervention using drug-eluting stent(s) will be performed by FFR-guided strategy.

Percutaneous coronaryintervention using drug-eluting stent(s) will be performed by IVUS-guided strategy.

The percutaneous coronaryintervention using drug-eluting stent will be indicated according to following criteria in the FFR-guided strategy arm * Criteria for revascularization: The FFR ≤ 0.80 will be targeted for PCI

The percutaneous coronaryintervention using drug-eluting stent will be indicated according to following criteria in the IVUS-guided strategy arm * Criteria for revascularization: Minimum lumen area (MLA) ≤ 3mm2 or (MLA ≤ 4mm2 AND Plaque burden >70%)

medical expenses of treatment and follow-up. Cost estimates utilize micro-costing, the total cost by identifying the utilization of medical resources used, and macro-costing, medical expenses resulting from clinical events from health insurance data.

Target-vessel and all-cause nonfatal myocardial infarction without per-procedural myocardial infarction

Number of participants and vessels/lesions with ischemia-driven or any reavascularizations at target vessel/lesion

Number of participants and vessels/lesions with ischemia-driven or any reavascularizations at non-target vessel/lesion.

Number of participants and vessels/lesions with ischemia-driven or any revascularizations at any vessel/lesion

Device-related, lesion-related and procedure-related success of index procedure (residual diameter stenosis<50% and thrombolysis in myocardial infarction flow 3)

Seattle Angina Questionnaires (physical limitation and angina frequency were classified as minimal: 75-100, mild: 50-74, moderate: 25-49, severe: 0-24)

Seattle Angina Questionnaires (physical limitation and angina frequency were classified as minimal: 75-100, mild: 50-74, moderate: 25-49, severe: 0-24)

Inclusion Criteria Subject must be ≥ 19 years ② Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving invasive physiologic or imaging evaluation and PCI and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure. Patients suspected with ischemic heart disease ④ Patients with intermediate degree of stenosis (40-70% stenosis by visual estimation) eligible for stent implantation who need FFR or IVUS for further evaluation ⑤ Target vessel size > 2.5mm Target lesions located at the proximal to mid part of coronary artery Exclusion Criteria Known hypersensitivity or contraindication to any of the following medications: Heparin, Aspirin, Clopidogrel, Prasugrel, Ticagrelor, Adenosine. Active pathologic bleeding Gastrointestinal or genitourinary major bleeding within the prior 3 months. History of bleeding diathesis, known coagulopathy (including heparin-induced thrombocytopenia) ⑤ Non-cardiac co-morbid conditions with life expectancy < 2 years ⑥ Target lesion located in coronary arterial bypass graft ⑦ Target lesion located in the left main coronary artery

Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement

Koo BK, Hu X, Kang J, Zhang J, Jiang J, Hahn JY, Nam CW, Doh JH, Lee BK, Kim W, Huang J, Jiang F, Zhou H, Chen P, Tang L, Jiang W, Chen X, He W, Ahn SG, Yoon MH, Kim U, Lee JM, Hwang D, Ki YJ, Shin ES, Kim HS, Tahk SJ, Wang J; FLAVOUR Investigators. Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI. N Engl J Med. 2022 Sep 1;387(9):779-789. doi: 10.1056/NEJMoa2201546.