09 FFR Matsuo aimradial2017 - DEFINE-FLAIR

Lessons from DEFINE-FLAIR - Hitoshi Matsuo

1. iFR outcome study -DEFINE FLAIR- Hitoshi Matsuo M.D., The Department of Cardiovascular Medicine, Gifu Heart Center Japan PCI workshop 2017

2. Disclosure Statement of Financial Interest I have no financial conflicts of interest related to this presentation PCI workshop 2017

3. 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 PCI workshop 2017 Pa Pd Wave-free period

4. 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 study 4 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 PCI workshop 2017

5. PCI workshop 2017 Best cutoff : 0.90, AUC:0.89 Diagnostic accuracy 81%

6. 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 .

7. 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 ) PCI workshop 2017

8. 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 PCI workshop 2017 The NEW ENGLAND JOURNAL of MEDICINE

9. Investigator team Javier Escaned Co-Principal Investigator Hospital Clinico San Carlos, Madrid Justin Davies Co-Principal Investigator Imperial College, London PCI workshop 2017

10. Manesh Patel Co-Chairman Duke University Health System Patrick Serruys Co-Chairman Imperial College, London Investigator team PCI workshop 2017

11. Clinical iFR and FFR Cut-points TREAT DEFER iFR 1.0 ≤ 0.89 0.7 0.6 TREAT DEFER FFR ADVISE 2 Study, JACC Cardiovasc Interv 2015;8(6):824–33. RESOLVE Study, JACC 2014 Apr 8;63(13):1253-61 ≤ 0.80 PCI workshop 2017

12. 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 PCI workshop 2017

13. Global recruitment 49 Centers 19 Countries PCI workshop 2017

14. FFR value distribution reflecting real world practice of physiology PCI workshop 2017

15. FFR values reflect interrogation of predominantly intermediate stenoses Patients in FFR arm = 2246 Mean 0.83 (0.10) Median 0.84 PCI workshop 2017

16. DEFER* 583/1250 PCI*** 625/1250 CABG** 42/1250 Treatment allocation with iFR and FFR DEFER* 652/1242 PCI*** 565/1242 CABG** 25/1242 iFR F FR 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 PCI workshop 2017

17. 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 PCI workshop 2017 * 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 .

18. Consistent patient outcome PCI workshop 2017 In DEFINE FLAIR, the hazard ratio was 0.95 in favour of iFR , with a risk difference of minus 0.23% and 95% confidence intervals within the pre-specified non-inferiority margin, thus confirming non-inferiority of iFR .

19. Primary endpoint (MACE) iFR equivalent to FFR with less PCI and CABG FFR (7.02%) iFR (6.79%) Davies JE et al. NEJM 2017 PCI workshop 2017

20. H.K 81 y.o M, ID:289302 Jan/19/2015

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

22. 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 % PCI workshop 2017

23. What happened after 2 years? 2017 Jan. 2015 Jan. H.K 81 y.o M, ID:289302

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

25. Published online NEJM http:// www.nejm.org / doi /full/10.1056/NEJMoa1700445 Online now at nejm.org PCI workshop 2017

26. 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 PCI workshop 2017     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 P < 0.001 3.1% 30.8%

27. 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 PCI workshop 2017 P < 0.001 45.0 40.5

28. 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 PCI workshop 2017 P < 0.05 0.72 0.66 1.19 1.08

29. 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 .” PCI workshop 2017

30. Patel M et al. JACC 2017 Management of CAD:AUC update PCI workshop 2017

31. AUC update 2017 iFR measurements may be substituted for FFR

32. AUC update 2017 PCI workshop 2017 iFR measurements may be substituted for FFR

33. 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 : PCI workshop 2017

34. 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 : PCI workshop 2017

35. 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: PCI workshop 2017

36. Supports the safety of physiological guided revascularization with either iFR and FFR Clinical interpretation (2) DEFINE-FLAIR: PCI workshop 2017