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)

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

• Status: Active, not recruiting
• Conditions: Stable Angina
• Intervention / Treatment: Procedure: FFR-guided stenting; Procedure: IVUS-guided stenting

Detailed Description

1. 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.

2. 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.

3. 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%].
4. 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.
5. Extended Outcome Follow-Up Following the 2-year follow-up period, clinical outcomes will also be collected until September 30, 2024, to assess the long-term outcomes of each treatment group.

• Study Type: Interventional
• Enrollment (Actual): 1700
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Zhejiang, China
    • The Second Affiliated Hospital, School of Medicine, Zhejiang University
• Korea, Republic of
  • Daegu, Korea, Republic of
    • Keimyung University Dongsan Medical Center
  • Goyang, Korea, Republic of
    • Inje University Ilsan Paik Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center, Sungkyunkwan University School of Medicine
  • Seoul, Korea, Republic of
    • Seoul National University Hospital, Seoul, Korea

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. 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

2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FFR-guided stenting; Percutaneous coronaryintervention using drug-eluting stent(s) will be performed by FFR-guided strategy.	Procedure: FFR-guided stenting; 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
Active Comparator: IVUS-guided stenting; Percutaneous coronaryintervention using drug-eluting stent(s) will be performed by IVUS-guided strategy.	Procedure: IVUS-guided stenting; 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%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-oriented composite outcome	a composite of all death, myocardial infarction (MI) or any revascularization	24 months
Long-term patient-oriented composite outcome	A composite of all death, myocardial infarction [MI, including peri-procedural MI] or any revascularization during the extended follow-up period after randomization according to the ARC consensus.	Up to 7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-oriented composite outcome	a composite of all death, myocardial infarction (MI) or any	12 months
Stent-oriented composite endpoint	a composite of cardiac death, target-vessel MI, or target lesion revascularization	12 months
Stent-oriented composite endpoint	a composite of cardiac death, target-vessel MI, or target lesion revascularization	24 months
Cost-effectiveness analysis	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.	24 months
All-cause death	death from any cause	24 months
Cardiac death	death from cardiaccause	24 months
Target-vessel and all-cause nonfatal myocardial infarction without per-procedural myocardial infarction	Myocardial infarction during 24 months follow-up without periprocedural myocardial infarction	24 months
Target-vessel and all-cause nonfatal myocardial infarction with per-procedural myocardial infarction	Myocardial infarction during 24 months follow-up with periprocedural myocardial infarction	24 months
Peri-procedural MI using referred definitions	Number of participants with peri-procedural myocardial infarction after PCI	At discharge (1 week after index procedure)
Target vessel/lesion revascularization	Number of participants and vessels/lesions with ischemia-driven or any reavascularizations at target vessel/lesion	24 months
Non-target vessel/lesion revascularization	Number of participants and vessels/lesions with ischemia-driven or any reavascularizations at non-target vessel/lesion.	24 months
Any revascularization	Number of participants and vessels/lesions with ischemia-driven or any revascularizations at any vessel/lesion	24 months
Academic Research Consortium defined - Stent thrombosis	Number of participants with definite/probable/possible stent thrombosis	24 months
Stroke	Number of participants with ischemic or hemorrhagic stroke	24 months
Acute success of procedure	Device-related, lesion-related and procedure-related success of index procedure (residual diameter stenosis<50% and thrombolysis in myocardial infarction flow 3)	immediately after the intervention
Angina severity measured with Seattle Angina Questionnaires	Seattle Angina Questionnaires (physical limitation and angina frequency were classified as minimal: 75-100, mild: 50-74, moderate: 25-49, severe: 0-24)	12 months
Angina severity measured with Seattle Angina Questionnaires	Seattle Angina Questionnaires (physical limitation and angina frequency were classified as minimal: 75-100, mild: 50-74, moderate: 25-49, severe: 0-24)	24 months
Long-term patient-oriented composite outcome in subgroups by use of anti-platelet agent and lipid-lowering agents	A composite of all death, myocardial infarction [MI, including peri-procedural MI] or any revascularization during the extended follow-up period in subgroups stratified by use of anti-platelet agent and lipid-lowering agents	Up to 7 years
Long-term patient-oriented composite outcome in subgroups by lipid profiles	Long-term patient-oriented composite outcome in subgroups stratified by changes in LDL-cholesterol, HDL-cholesterol, and triglyceride during the extended follow-up period	Up to 7 years
Long-term mortality	All-cause and cardiac death during the extended follow-up period	Up to 7 years
Long-term myocardial infarction	Myocardial infarction during the extended follow-up period	Up to 7 years
Long-term any revascularization	Any revascularization during the extended follow-up period	Up to 7 years
Long-term target vessel failure	Target vessel failure (cardiac death, target vessel MI, target vessel revascularization) during the extended follow-up period	Up to 7 years
Long-term target vessel myocardial infarction	Target vessel myocardial infarction during the extended follow-up period	Up to 7 years
Long-term target vessel revascularization	Target vessel revascularization during the extended follow-up period	Up to 7 years
Long-term target lesion revascularization	Target lesion revascularization during the extended follow-up period	Up to 7 years
Long-term non-target lesion revascularization-target vessel revascularization	Non-target lesion revascularization-target vessel revascularization during the extended follow-up period	Up to 7 years
Long-term stent thrombosis	Stent thrombosis (definite/probable/possible) during the extended follow-up period	Up to 7 years
Long-term stroke	Stroke (ischemic and hemorrhagic) during the extended follow-up period	Up to 7 years
Landmark analysis for patient-oriented composite outcome	A 2 year landmark analysis of patient-oriented composite outcome and its individual outcome components	Up to 7 years
Long-term patient-oriented composite outcome in the medical treatment group	Patient-oriented composite outcome and individual components of outcomes in the medical treatment group	Up to 7 years
Long-term patient-oriented composite outcome in the PCI group	Patient-oriented composite outcome and individual components of outcomes in the PCI group	Up to 7 years
Long-term patient-oriented composite outcome according to PCI optimization	Patient-oriented composite outcome and individual outcome components among patients in the PCI group, comparing those who received PCI optimization to those who did not.	Up to 7 years
Landmark analysis for target vessel failure	A 2 year landmark analysis of target vessel failure and its individual outcome components	Up to 7 years
Long-term target vessel failure in the medical treatment group	Target vessel failure and individual components of outcomes in the medical treatment group	Up to 7 years
Long-term target vessel failure in the PCI group	Target vessel failure and individual components of outcomes in the PCI group	Up to 7 years
Long-term target vessel failure according to PCI optimization	Target vessel failure and individual outcome components among patients in the PCI group, comparing those who received PCI optimization to those who did not.	Up to 7 years
Long-term target vessel failure according to IVUS-derived plaque characteristics	Target vessel failure (cardiac death, target vessel MI, target vessel revascularization) during the extended follow-up period according to IVUS-derived plaque characteristics	Up to 7 years
Long-term target vessel failure according to QFR values	Target vessel failure (cardiac death, target vessel MI, target vessel revascularization) during the extended follow-up period according to QFR values	Up to 7 years

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Samsung Medical Center, Sungkyunkwan University School of Medicine; Ulsan University Hospital; Second Affiliated Hospital, School of Medicine, Zhejiang University; Ajou University School of Medicine; Inje University; Keimyung University Dongsan Medical Center; KangWon National University Hospital
• Investigators: Principal Investigator: JianAn Wang, MD, PhD, Second Affiliated Hospital, School of Medicine, Zhejiang University; Principal Investigator: Seung-Jea Tahk, MD, PhD, Ajou University School of Medicine; Principal Investigator: Bon-Kwon Koo, MD, PhD, Seoul National University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: February 1, 2016
• First Submitted That Met QC Criteria: February 2, 2016
• First Posted (Estimated): February 3, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 5, 2025
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Myocardial Ischemia; Chest Pain; Angina Pectoris; Angina, Stable
• Other Study ID Numbers: NCT02673424

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The deidentified data will be shared after publication of first manuscript
• IPD Sharing Time Frame: Data will be available within 12 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL