Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR)

Prospective, Multi-center, Double Blind, Randomised Study to Test the Safety of Deferral of Stenting in Physiological Non-significant Lesions in a Clinical Population of Intermediate Stenoses Using iFR and FFR

Narrowing of coronary arteries interferes with blood flow and can cause chest pain. But patients may have more than one narrowing and studies have shown that not all narrowings need to be treated. To identify the narrowings that need treating cardiologists sometimes quantify the extent of the narrowing by measuring fractional flow reserve (FFR, the ratio of the pressure in the aorta to the pressure downstream of the narrowing).This technique requires the administration of drugs that add cost and time to the procedure and in some countries are simply unavailable. As a result despite the clear health and healthcare costs benefits of FFR its use is limited to less than 5% of procedure. We have developed a new technique called the instantaneous wave-free ratio (iFR) that does not require the administration of drugs for its accurate assessment. It has been approved for use in this indication. This study aims to compare clinical outcomes of patients whose treatment has been guided by iFR to those whose treatment has been guided by FFR. If iFR is found to provide the same clinical outcomes as FFR its adoption will permit the clear benefits of this approach of identifying the coronary narrowings that really need treatment to be applicable to a much larger patient population and further improve healthcare costs.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Device: iFR; Device: FFR

Detailed Description

Design:

Patients with one or more coronary stenoses, in which the physiological severity from coronary angiography is in question, will be randomised 1:1 to use of the instantaneous wave free ratio (iFR) or fractional flow reserve (FFR) to guide the treatment strategy for percutaneous coronary intervention (PCI).

Aims:

To assess whether the iFR is non-inferior to FFR when used to guide treatment of coronary stenosis with PCI.

Outcome measures:

The primary endpoint will be major adverse cardiac event rate in the iFR and FFR groups at 30 days, 1, 2, and 5 years.

Population:

This will be an international multi-centre study of 2500 patients. From population estimates, 35% of the total study population will present with stable angina and 65% will have acute coronary syndrome.

Eligibility:

Patients will be eligible when the physiological severity of a stenosis within a vessel is in question. In the cases of stable angina this will be confined to the target vessel, or with acute coronary syndrome assessment this will be made in the non-culprit vessel.

Duration:

Anticipated recruitment is 12 months. Follow-up will be performed at 30 days, 1, 2 and 5 years.

Results:

Primary outcome results will be reported in Spring 2017.

• Study Type: Interventional
• Enrollment (Anticipated): 2500
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Sam Lehman
  • Brisbane, Australia
    • Darren Walters
  • Melbourne, Australia
    • James Sapontis
  • Sydney, Australia
    • Ravinay Bhindi
• Belgium
  • Antwerp, Belgium
    • Christian Vrints
  • Bonheiden, Belgium
    • Luc Janssens
• Egypt
  • Cairo, Egypt
    • Ahmed Khashaba
• Finland
  • Helsinki, Finland
    • Mika Laine
• Germany
  • Berlin, Germany
    • Florian Krackhardt
  • Berlin, Germany
    • Olaf Going
  • Koblenz, Germany
    • Waldemar Bojara
  • Oldenburg, Germany
    • Tobias Haerle
• Italy
  • Catanzaro, Italy
    • Ciro Indolfi
  • Rome, Italy
    • Giampaolo Nicolli
  • Verona, Italy
    • Flavio Ribichini
• Japan
  • Aichi, Japan
    • Hiroaki Takashima
  • Fukuoka, Japan
    • Hiroyoshi Yokoi
  • Fukuyama, Japan
    • Yuetsu Kikuta
  • Gifu, Japan
    • Hitosh Matsuo
  • Tokyo, Japan
    • Nob Tanaka
• Korea, Republic of
  • Daegu, Korea, Republic of
    • Chang-Wook Nam
  • Daehwa, Korea, Republic of
    • Joon-Hyung Doh
  • Seoul, Korea, Republic of
    • Bon-Kwon Koo
  • Ulsan, Korea, Republic of
    • Eun-Seok Shin
• Latvia
  • Riga, Latvia
    • Andrejs Erglis
• Netherlands
  • Amsterdam, Netherlands
    • Jan Piek
  • Amsterdam, Netherlands
    • Niels Van Royen
  • Breda, Netherlands
    • Martijn Meuwissen
• Portugal
  • Almada, Portugal
    • Hugo Vinhas
  • Amadora, Portugal
    • Sergio Baptista
  • Lisbon, Portugal
    • Pedro Canas Silva
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • Ali Alghamadi
• South Africa
  • Johannesburg, South Africa
    • Farrel Hellig
• Spain
  • Barcelona, Spain
    • Salvatore Brugaletta
  • Madrid, Spain
    • Clinico San Carlos
  • Madrid, Spain
    • Eduardo Alegria
• Turkey
  • Istanbul, Turkey
    • Murat Sezer
• United Kingdom
  • Basildon, United Kingdom
    • Kare Tang
  • Bournemouth, United Kingdom
    • Suneel Talwar
  • Exeter, United Kingdom
    • Andrew Sharp
  • London, United Kingdom
    • Imperial College London
  • London, United Kingdom
    • Ranil De Silva
  • Oxford, United Kingdom
    • Rajesh Kharbanda
  • St Leonards, United Kingdom
    • Robert Gerber
• United States
  • California
    • Long Beach, California, United States
      • Arnold Seto
  • Colorado
    • Lakewood, Colorado, United States
      • John Altman
  • Georgia
    • Atlanta, Georgia, United States
      • Habib Samady
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Stony Brook, New York, United States
      • Allen Jeremias
  • North Carolina
    • Durham, North Carolina, United States
      • Manesh Patel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 18 years of age
2. Willing to participate and able to understand, read and sign the informed consent document before the planned procedure
3. Eligible for coronary angiography and/or percutaneous coronary intervention
4. Coronary artery disease with at least 1 or more native major epicardial vessels or their branches by coronary angiogram with visually assessed de novo coronary stenosis in which the physiological severity of the lesion is in question (typically 40-70% diameter stenosis).
5. Stable angina or acute coronary syndrome (non-culprit vessels only and outside of primary intervention during acute STEMI)

Exclusion criteria:

1. Previous Coronary Artery Bypass surgery with patent grafts to the interrogated vessel
2. Significant left main stenosis (>50% narrowing)
3. Tandem stenoses separated by more than 10 mm that require separate pressure guide wire interrogation or percutaneous coronary intervention (PCI) (not to be interrogated or treated as a single stenosis)
4. Total coronary occlusions (CTOs). NOTE: Patients with CTOs can be included if i) treatment of the CTO is completed first, ii) the CTO PCI is successful, iii) the CTO PCI is successful and iii) the physiological lesion is in another vessel
5. Restenotic lesions
6. Hemodynamic instability at the time of intervention (heart rate<50 beats per minute, systolic blood pressure <90mmHg), balloon pump
7. Significant contraindication to adenosine administration (e.g. heart block, severe asthma)
8. Contraindications to PCI (percutaneous coronary intervention) or drug-eluting stent (DES) implantation
9. Heavily calcified or tortuous vessels
10. Significant hepatic or lung disease (chronic pulmonary obstructive disease), and/or malignant disease with unfavourable prognosis that may influence survival within the next 5 years
11. Pregnancy
12. STEMI (ST elevation myocardial infarction) within 48 hours of procedure
13. Severe valvular heart disease
14. ACS patients in whom more than one target vessel is present

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: iFR; Treatment guided by iFR	Device: iFR; Treatment guided by instantaneous wave-free ratio
Active Comparator: FFR; Treatment guided by FFR	Device: FFR; Treatment guided by Fractional Flow Reserve

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Adverse Cardiac Events	Composite of death, myocardial infarction, unplanned revascularisation	30 days, 1, 2 and 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death (all cause)		30 days, 1, 2 and 5 years
Death (cardiovascular)		30 days, 1, 2 and 5 years
Myocardial Infarction		30 days, 1, 2 and 5 years
Repeat revascularisation		30 days, 1, 2 and 5 years
Cost associated to iFR or FFR measurement	Cost associated to iFR or FFR	30 days, 1, 2 and 5 years
Quality of life assessed by EQ-5D-5L and Seattle Angina Questionnaire		30 days, 1, 2 and 5 years
Cost savings of removing secondary investigations	7) Cost savings of removing secondary investigations, by assessing/treating non-culprit acute coronary syndrome (ACS) at the time of index presentation.	30 days, 1, 2 and 5 years

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Justin ER Davies, MD, Imperial College London; Principal Investigator: Javier Escaned, MD, Clinico San Carlos; Study Chair: Patrick Serruys, MD, Imperial College London; Study Chair: Manesh Patel, MD, Duke University; Study Director: Sayan Sen, MD, Imperial College London

Publications and helpful links

General Publications

• Kim CH, Koo BK, Dehbi HM, Lee JM, Doh JH, Nam CW, Shin ES, Cook CM, Al-Lamee R, Petraco R, Sen S, Malik IS, Nijjer SS, Mejia-Renteria H, Alegria-Barrero E, Alghamdi A, Altman J, Baptista SB, Bhindi R, Bojara W, Brugaletta S, Silva PC, Di Mario C, Erglis A, Gerber RT, Going O, Harle T, Hellig F, Indolfi C, Janssens L, Jeremias A, Kharbanda RK, Khashaba A, Kikuta Y, Krackhardt F, Laine M, Lehman SJ, Matsuo H, Meuwissen M, Niccoli G, Piek JJ, Ribichini F, Samady H, Sapontis J, Seto AH, Sezer M, Sharp ASP, Singh J, Takashima H, Talwar S, Tanaka N, Tang K, Van Belle E, van Royen N, Vinhas H, Vrints CJ, Walters D, Yokoi H, Samuels B, Buller C, Patel MR, Serruys PW, Escaned J, Davies JE. Sex Differences in Instantaneous Wave-Free Ratio or Fractional Flow Reserve-Guided Revascularization Strategy. JACC Cardiovasc Interv. 2019 Oct 28;12(20):2035-2046. doi: 10.1016/j.jcin.2019.06.035.
• DEFINE-FLAIR Trial Investigators, Lee JM, Choi KH, Koo BK, Dehbi HM, Doh JH, Nam CW, Shin ES, Cook CM, Al-Lamee R, Petraco R, Sen S, Malik IS, Nijjer SS, Mejia-Renteria H, Alegria-Barrero E, Alghamdi A, Altman J, Baptista SB, Bhindi R, Bojara W, Brugaletta S, Silva PC, Di Mario C, Erglis A, Gerber RT, Going O, Harle T, Hellig F, Indolfi C, Janssens L, Jeremias A, Kharbanda RK, Khashaba A, Kikuta Y, Krackhardt F, Laine M, Lehman SJ, Matsuo H, Meuwissen M, Niccoli G, Piek JJ, Ribichini F, Samady H, Sapontis J, Seto AH, Sezer M, Sharp ASP, Singh J, Takashima H, Talwar S, Tanaka N, Tang K, Van Belle E, van Royen N, Vinhas H, Vrints CJ, Walters D, Yokoi H, Samuels B, Buller C, Patel MR, Serruys P, Escaned J, Davies JE. Comparison of Major Adverse Cardiac Events Between Instantaneous Wave-Free Ratio and Fractional Flow Reserve-Guided Strategy in Patients With or Without Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2019 Sep 1;4(9):857-864. doi: 10.1001/jamacardio.2019.2298.
• Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khashaba A, Laine M, Van Belle E, Krackhardt F, Bojara W, Going O, Harle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Hellig F, Koo BK, Nam CW, Shin ES, Doh JH, Brugaletta S, Alegria-Barrero E, Meuwissen M, Piek JJ, van Royen N, Sezer M, Di Mario C, Gerber RT, Malik IS, Sharp ASP, Talwar S, Tang K, Samady H, Altman J, Seto AH, Singh J, Jeremias A, Matsuo H, Kharbanda RK, Patel MR, Serruys P, Escaned J. Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J Med. 2017 May 11;376(19):1824-1834. doi: 10.1056/NEJMoa1700445. Epub 2017 Mar 18.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Anticipated): January 19, 2021
• Study Completion (Anticipated): January 19, 2021

Study Registration Dates

• First Submitted: November 26, 2013
• First Submitted That Met QC Criteria: January 31, 2014
• First Posted (Estimate): February 3, 2014

Study Record Updates

• Last Update Posted (Actual): August 14, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease
• Other Study ID Numbers: 13SM1797

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No