Lessons from DEFINE-FLAIR - Hitoshi Matsuo

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iFR outcome study
-DEFINE FLAIR-
• Hitoshi Matsuo M.D.,
• The Department of Cardiovascular
Medicine,
• Gifu Heart Center
• Japan
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Disclosure Statement of Financial Interest
I have no financial conflicts of interest related to this presentation
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Definition of iFR:
Instant wave-free ratio across a stenosis during the wave-free period, when
resistance is naturally constant and minimized in the cardiac cycle
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Pa
Pd
0 100 200 300 400 500 600 700 800 900
70
120
Pressure(mmHg)
Time (ms)
Wave-free period

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ADVISE study
Oct 2011
• Over 3000 stenoses evaluated, core lab analysis, using the Philips Volcano algorithm
ADVISE Registry
May 2012
HYBRID strategy
Aug 2012
RESOLVE study4
Oct 2012
Algorithm is critical for
accurate calculation of iFR
Confirmed previous studies
VERIFY was the clear outlier
iFR compared to FFR has been well validated
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Best cutoff : 0.90, AUC:0.89
Diagnostic accuracy 81%

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What we know about iFR:
Vasodilators do not improve physiological diagnostic accuracy
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.
p=ns p<0.01
p=ns p=ns
p<0.01
100
80
60
40
0
Accuracy(%)orROC(%)
20
FFR
IFR
HSR HSR SPECT PET CFR

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DEFINE FLAIR
Primary objective
• Assess safety and efficacy of decision-
making on coronary revascularisation
based on iFR vs FFR
• Assess if iFR is non-inferior to FFR
when used to guide treatment of
coronary stenosis with PCI
Primary endpoint
• Major adverse cardiac events (MACE)
rate in the iFR and FFR groups at 30
days, 1 and 2 years.
• MACE (combined endpoint of death,
non-fatal MI, or unplanned
revascularisation)
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From the largest global physiology studies
• DEFINE FLAIR and iFR Swedeheart are
the new landmark physiology studies
• 4500+ patients, more than twice
the combined patient population of
previous landmark physiology studies
– DEFINE FLAIR: n = 2492 patients
– iFR Swedeheart: n = 2037 patients
• 2 prospective, randomized, controlled
trials
• Published in New England Journal of
Medicine
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The NEW ENGLAND
JOURNAL of MEDICINE

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Investigator team
Javier Escaned
Co-Principal Investigator
Hospital Clinico San Carlos, Madrid
Justin Davies
Co-Principal Investigator
Imperial College, London
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Manesh Patel
Co-Chairman
Duke University Health System
Patrick Serruys
Co-Chairman
Imperial College, London
Investigator team
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Clinical iFR and FFR Cut-points
TREAT DEFERiFR
1.0
≤ 0.89
0.70.6
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
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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
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Global recruitment
49 Centers
19 Countries
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FFR value distribution reflecting real world
practice of physiology
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FFR values reflect interrogation of
predominantly intermediate stenoses
Patients in FFR arm = 2246
Mean 0.83 (0.10)
Median 0.84
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3%
50%47%
DEFER*
583/1250
PCI***
625/1250
CABG**
42/1250
Treatment allocation with iFR and FFR
2%
45%53%
DEFER*
652/1242
PCI***
565/1242
CABG**
25/1242
iFR FFR
DEFER* p=0.003
CABG** p=0.04
PCI*** p=0.02
p for comparison between
patients randomized to
iFR and FFR
Significantly less revascularization based on iFR interrogation
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Consistent patient outcome
• An iFR guided strategy is statistically comparable to an FFR-Guided Strategy
for patient outcome*
– Primary endpoint: major cardiovascular adverse event rates, assessed at 1-year
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* p-values are for non-inferiority of an iFR-guided strategy versus an FFR-guided strategy with respect to 1-year MACE rates; pre-
specified non-inferiority margins were 3.4% in DEFINE FLAIR.

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Primary endpoint (MACE)
iFR equivalent to FFR with less PCI and CABG
FFR (7.02%)
iFR (6.79%)
Davies JE et al. NEJM 2017
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H.K 81 y.o M, ID:289302 Jan/19/2015

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Pressure study iFR
iFR(RCA far distal)=0.99
H.K 81 y.o M, ID:289302 Jan/19/2015

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0
2
4
6
8
10
MACE Myocardial infarction Unplanned
revascularization
Death
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>0.89
FFR>0.80
Rate%
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What happened after 2 years?
2017 Jan.2015 Jan.
H.K 81 y.o M, ID:289302

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Pressure study iFR
iFR(RCA far distal)=1.0
H.K 81 y.o M, ID:289302 Jan/24/2017

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Published online NEJM
http://www.nejm.org/doi/full/10.1056/NEJMoa1700445
Online now at nejm.org
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An iFR-guided strategy
significantly reduces patient discomfort
• DEFINE FLAIR reported that without the need of hyperemia, you can achieve a 90%
reduction of patient discomfort during procedures
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iFR
(n = 1242)
FFR
(n=1250)
Patient reported adverse
symptoms
Dyspnoea 13 250
Chest pain 19 90
Patient reported adverse signs
Rhythm disturbance 2 60
Significant Hypotension 4 13
Vomiting or nausea 1 11
Serious symptoms or
bronchospasm 1 8
other 4 38
Total adverse procedural
symptoms or signs 39 385
0
5
10
15
20
25
30
35
iFR FFR
Total adverse procedural
symptoms or signs (%)
P < 0.001
3.1%
30.8%

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An iFR-guided strategy
significantly reduces procedural time and cost
• DEFINE FLAIR reported an average procedural time of 40.5 minutes in the iFR arm,
vs. 45.0 minutes in the FFR arm (p < 0.001)
• This means a 10% reduction in procedural time
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38
39
40
41
42
43
44
45
46
iFR FFR
Procedural time (mins)
P < 0.001
45.0
40.5

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An iFR-guided strategy
significantly reduces procedural time and cost
• DEFINE FLAIR reported significantly fewer
stents used in the iFR arm patients
undergoing PCI, vs. FFR arm (p < 0.05)
• This means reduced procedural cost
• Similarly, iFR Swedeheart reported 10%
fewer stents used in iFR arm patients,
although the difference is non-significant
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0
0.2
0.4
0.6
0.8
1
1.2
1.4
DEFINE FLAIR iFR Swedeheart
# of stents used in patients
undergoing PCI
iFR FFR
P < 0.05
0.72
0.66
1.19
1.08

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Management of CAD
Deepak Bhatt, NEJM 2017
“ FFR has been the evidence-based standard for
invasive evaluation of such lesions, but it now
appears that iFR may be the new standard.”
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29. D000134437 Patel M et al. JACC 2017
Management of CAD:AUC update
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30. AUC update 2017
iFR measurements may be substituted for FFR

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AUC update 2017
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iFR measurements may be substituted for FFR

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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:
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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:
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–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:
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– Supports the safety of physiological guided
revascularization with either iFR and FFR
Clinical interpretation (2)
DEFINE-FLAIR:
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Thank you for your attention
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