iFR vs FFR for guiding coronary revascularization –DEFINE-FLAIR Justin E Davies, MD, PhD on behalf of the DEFINE-FLAIR investigatorsHammersmith Hospital, Imperial College London

Functional Lesion Assessment of Intermediate stenosis to guide Revascularization

Disclosures

Volcano-Philips Consultant, Research grants, IP royaltiesMedtronic Consultant, Research grantsRECOR Consultant, Research grantsAstra Zeneca Research support

Study supported by an unrestricted educational grant from Volcano-Philips

Background

iFR is a pressure wire alternative to FFR

– Vasodilator-free  (e.g. Adenosine, ATP)

– Similar power to detect ischemia 

CFR, Coronary Flow Reserve; HSR, Hyperaemic Stenosis Resistance; ROC, receiver-operating characteristic; PET, positron emission tomography; SPECT, single-photon emission computed tomography 

1. Van de Hoef TP et al. Circ Cardiovasc Interv. 2012;5:508-14; 2. Sen S et al. J Am Coll Cardiol. 2013;61:1409-20; 3.  Van de Hoef TP et al. EuroIntervention. 2015;11:914-25; 4. Sen S et al. J Am Coll Cardiol. 2013;62:566; 5. Petraco R et al. Circ. Int. 2014;7:492-502; 6. de Waard G et al. J Am Coll Cardiol. 2014;63:A1692. 

iFR and FFR have similar diagnostic power in head-to-head studies

Aims and benefits of DEFINE-FLAIR

Strategy study comparing iFR- and FFR-guided revascularization in real world clinical decision-making

– safety and performance outcomes

– procedural symptoms – procedural characteristics 

and efficiencies 

Increased adoption of coronary physiology 

– Improved patient experience– Time / cost savings– Simplified serial lesion 

assessmentAvoid off-label use of adenosine in USAAvoid rare but serious complications

AIMS BENEFITS

Investigator team

Javier EscanedCo-Principal InvestigatorHospital Clinico San Carlos, Madrid

Justin DaviesCo-Principal InvestigatorImperial College, London

Manesh PatelCo-ChairmanDuke University Health System

Patrick SerruysCo-ChairmanImperial College, London

Investigator team

Principal hypothesis

iFR is non-inferior to FFR for major adverse cardiac events (MACE) at 1 year in patients undergoing physiological-guided revascularization. 

MACE definition

• MACE was defined as composite endpoint of –Death–Non-fatal myocardial Infarction–Unplanned revascularization 

Power calculations

• Assumed event rate 8.5%• Non-inferiority margin for risk difference 3.4%• Type 1 error rate of 5% and 90% power, the sample size was n=2305

• Target recruitment n=2500

Study design

DEFINE FLAIR. https://clinicaltrials.gov/ct2/show/NCT02053038. 

FFR >0.8Defer PCI

FFR ≤0.8Perform PCI

FFR-guided revascularizatio

n

iFR ≤0.89Perform PCI

iFR >0.89Defer PCI

Coronary stenosis in which physiological severity was in question

1:1 Randomization

iFR-guided revascularizatio

n

30 day, 1-, 2- and 5-year follow-upPrimary endpoint to be reported at 1-

year

MACE composite endpoint of:• Death• Non-fatal myocardial 

infarction• Unplanned 

revascularization

Non-inferiority margin for risk difference: 3.4%

Clinical iFR and FFR Cut-points

TREAT       DEFERiFR1.0

≤ 0.890.70.6

TREAT DEFERFFR

ADVISE 2 Study, JACC Cardiovasc Interv 2015;8(6):824–33. RESOLVE Study, JACC 2014 Apr 8;63(13):1253-61

≤ 0.80

Study governance

• Imperial College Trials Unit (ICTU)• 100% Clinical Record Form (eCRF) monitoring• On-site case record verification• Screenshot documentation of iFR/FFR traces• Blinding of patients / follow-up teams to study arm

Global recruitment

49 Centers19 Countries

Consort diagram

Patient demographics

* Non-culprit lesions only 

Procedural characteristics

FFR value distribution reflecting real world practice of physiology

3%

50%47%

DEFER*583/1250

PCI***625/1250

CABG**42/1250

Treatment allocation with iFR and FFR

2%

45%52%

DEFER*652/1242

PCI***565/1242

CABG**25/1242

iFR FFR

DEFER*  p=0.003CABG**   p=0.04PCI***      p=0.02

p for comparison between patients randomized to iFR and FFR

Significantly less revascularization based on iFR interrogation 

FFR (7.02%)

iFR (6.79%)

Primary endpoint (MACE) iFR equivalent to FFR with less PCI and CABG

FFR (7.02%)

iFR (6.79%)

Primary endpoint (MACE) iFR equivalent to FFR with less PCI and CABG

Primary endpoint components

Event rates in deferred patients

6/638 (0.94%

)

11/618 (1.78%

)

22/638 (3.45%

)

33/619 (5.33%

)

7/638 (1.10%

)4/618 (0.65%

)

30/638 (4.70%

)

38/619 (6.14%

)

p=0.26

p=0.20

p=0.10

p=0.39

iFR>0.89FFR>0.80

Rate %

DyspneaChest pain

Rhythm disturbanceHypotensionVomiting / NauseaBronchospasm/VTOther

13 (1.0%)       250 (20.0%)19 (1.5%)   90 (7.2%)

  2 (0.2%)     60 (4.8%)  4 (0.3%)   13 (1.0%)  1 (0.1%)    11 (0.9%)  1 (0.1%)     8 (0.6%)  4 (0.3%)    38 (3.0%)

iFR FFR

39 (3.1%)

385 (30.8%)

P<0.001

FFRiFR

10-fold fewer procedural symptoms and signs

% Procedural sym

ptom

s

39 (3.1%)

385 (30.8%)

P<0.001

DyspneaChest pain

Rhythm disturbanceHypotensionVomiting / NauseaBronchospasm/VTOther

13 (1.0%)       250 (20.0%)19 (1.5%)   90 (7.2%)

  2 (0.2%)     60 (4.8%)  4 (0.3%)   13 (1.0%)  1 (0.1%)    11 (0.9%)  1 (0.1%)     8 (0.6%)  4 (0.3%)    38 (3.0%)

iFR FFR

FFRiFR

10-fold fewer procedural symptoms and signs

% Procedural sym

ptom

s

iFR guided revascularization reduces procedure time

Time (minutes) 

iFR

4.5 minutes saved*

FFR

40.5min

45min

Median Time Saving

* Threshold for reduction in median time (p=0.001)

Conclusions (1)

– iFR is non-inferior to FFR for major adverse cardiac events (MACE) at 1 year in patients undergoing physiological-guided revascularization. 

DEFINE-FLAIR confirms that in stable and ACS patients with coronary stenoses: 

Conclusions (2)

– iFR or FFR can safely guide coronary revascularization

– iFR improves procedural safety and reduces time

DEFINE-FLAIR confirms that in stable and ACS patients with coronary stenoses: 

– Is the largest RCT of physiology-guided revascularization

–Was performed in a study population representative of real world clinical practice

Clinical interpretation (1)

DEFINE-FLAIR: 

– Supports the safety of physiological guided revascularization with either iFR or FFR

Clinical interpretation (2)

DEFINE-FLAIR: 

Special thanks

Elisa VorosMilaana JacobMichael MielewczikHakim-Moulay DehbiBruce SamuelsAlphonse Ambrosia

Sayan SenRicardo Petraco Rasha Al-LameeSukhjinder NijjerChris Buller 

Investigators

Sam Lehman Flinders University, Adelaide AustraliaJames Sapontis Monash Heart, Melbourne AustraliaDarren Walters The Prince Charles Hospital, Brisbane AustraliaRavinay Bhindi Royal North Shore Hospital, Sydney AustraliaChristiaan Vrints UZA - Antwerp University Hospital, 

AntwerpBelgium

Luc Janssens Imelda Hospital, Bonheiden BelgiumAhmed Khashaba  Al Dorrah Heart Care Hospital, Cairo EgyptMika  Laine Helsinki University Hospital, Helsinki FinlandOlaf  Göing Sana Klinikum Lichtenberg, Berlin GermanyWaldemar

BojaraGemeinschaftsklinikum Mittelrhein, Koblenz

Germany

Florian Krackhardt Charité Universitätsmedizin Berlin, Berlin Germany

Tobias HärleHerzzentrum Klinikum Oldenburg, Oldenburg Germany

Giampaolo Niccoli Catholic University of the Sacred Heart, Rome

Italy

Flavio Ribichini University Hospital Verona, Verona ItalyCiro Indolfi University Magna Graecia, Catanzaro ItalyHiroaki  Takashima Aichi Medical University Hospital, Aichi JapanHiroyoshi Yokoi Fukuoka Sanno Hospital, Fukuoka JapanNob Tanaka Tokyo Medical University Hospital, Tokyo JapanYuetsu Kikuta Fukuyama Cardiovascular Hospital, 

Fukuyama  JapanHitoshi Matsuo Gifu Heart Centre, Gifu JapanAndrejs Erglis Pauls Stradins Clinical Hospital, Riga LatviaSérgio Baptista Hospital Prof. Doutor Fernando Fonseca, 

AmadoraPortugal

Pedro Canas Da Silva

Hospital Santa Maria, Lisbon Portugal

Hugo Vinhas Hospital Garcia de Orta, Almada Portugal

Ali  Al-Ghamdi King Abdulaziz MedicalCity Cardiac Centre, Riyadh Saudi Arabia

Farrel Hellig Sunninghill Hospital, Johannesburg South AfricaBon-Kwon Koo Seoul National University Hospital, Seoul South KoreaChang-Wook

Nam Keimyung University Dongsan Medical Center, Daegu 

South Korea

Eun-Seok Shin Ulsan University Hospital, Ulsan South KoreaJoon-Hyung 

Doh Inje University Ilsan Paik Hospital, Goyang-si South Korea

Eduardo Alegria-Barrero 

Torrejon University Hospital, MadridSpain

Javier  Escaned Hospital Clinico San Carlos, Madrid SpainSalvatore Brugaletta Hospital Clinico Y Provincial, Barcelona SpainMartijn Meuwissen Amphia Hospital, Breda The NetherlandsJan Piek Academic Medical Centre, Amsterdam The NetherlandsNiels Van Royen VU University Medical Center, Amsterdam The NetherlandsMurat Sezer Istanbul University Hospital, Istanbul TurkeyCarlo Di Mario Royal Brompton Hospital, London UKRajesh Kharbanda John Radcliffe Hospital, Oxford UKAndrew  Sharp Royal Devon and Exeter University Hospital, 

ExeterUK

Bob Gerber Conquest Hospital, St Leonards on Sea UKIqbal Malik Hammersmith Hospital, Imperial College 

LondonUK

Kare Tang Basildon University Hospital, Basildon UKSuneel Talwar Royal Bournemouth Hospital, Bournemouth UKHabib Samady Emory University Hospital, Atlanta USAArnold  Seto UC Irvine VA/VA Long Beach, Long Beach USARichard Bach Washington University in St Louis, St Louis USAAllen Jeremias Stony Brook Medicine, New York USAJohn Altman Colorado Heart and Vascular, Lakewood USA

Published online today

http://www.nejm.org/doi/full/10.1056/NEJMoa1700445

Additional slides

Myocardial infarction

iFR > 0.89 iFR ≤0.89  FFR > 0.80 FFR ≤ 0.80MI, N (%)* 11 21 21 11

Peri-CABG (%9.1) 1 (%0) 0 (%0) 0 (%0) 0Peri-procedural (%27.3) 3 (%52.4) 11 (%47.6) 10 (%54.5) 6Re-stenosis (%0) 0 (%4.8) 1 (%0) 0 (%9.1) 1Secondary (%0) 0 (%9.5) 2 (%0) 0 (%0) 0Spontaneous (%54.5) 6 (%23.8) 5 (%47.6) 10 (%36.4) 4Stent thrombosis (%9.1) 1 (%9.5) 2 (%4.8) 1 (%0) 0

* Total number of myocardial infarction; some patients experienced >1 event

Unplanned revascularization

iFR > 0.89 iFR ≤0.89 FFR > 0.80

FFR ≤ 0.80

Unplanned revascularization, N (%) 27 23 49 19

non-target (%29.6) 8 (%30.4) 7 (%34.7) 17 (%31.6) 6target lesion (%59.3) 16 (%56.5) 13 (%51) 25 (%42.1) 8target vessel (%11.1) 3 (%13) 3 (%14.3) 7 (%21.1) 4unknown (%0) 0 (%0) 0 (%0) 0 (%5.3) 1* Total number of myocardial infarction; some patients experienced >1 event

           

iFR > 0.89 iFR ≤0.89 FFR > 0.80 FFR ≤0.80 

All cause death, N (%) 10 12 9 4CV death (%30) 3 (%33.3) 4 (%11.1) 1 (%75) 3Non CV death (%70) 7 (%66.7) 8 (%88.9) 8 (%25) 1

               

All cause death

Primary end point

0 1 2 3 4

<3.4% Margin

iFR Non-Inferior to FFR 

iFR not non-Inferior to FFR

95% CI 

95% CI 

Risk Difference (%)

Hypothesis confirmed

Hypothesis rejected

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Study design - Exclusion

• Previous CABG• LMS >50%• Tandem stenosis not 

amenable to continuous stenting

• Chronic total occlusion• Restenotic stenosis• Heart Rate < 50bpm, 

Systolic blood pressure <90 mmHg

• Known contraindication to vasodilator drugs

• Heavily calcified or tortuous vessels 

• Severe hepatic or lung disease

• Pregnancy• STEMI<48 hours• Severe vavlular heart 

disease• ACS patient in whom the 

target is unknown

iFR and FFR education

• Learn more about iFR and FFR– https://simpleeducation.co/moments/187

• Watch expert round table discussions DEFINE-FLAIR results– https://simpleeducation.co/moments/686/