PCI & AimRadial 2018 | Lessons from iFR-SWEDEHEART and DEFINE-FLAIR - Hitoshi Matsuo

PCI & AimRadial 2018 | Lessons from iFR-SWEDEHEART and DEFINE-FLAIR - Hitoshi Matsuo

1. Lessons from iFR -SWEDEHEART and DEFINE-FLAIR Hitoshi Matsuo M.D.,PhD . Department of Cardiovascular Medicine Gifu Heart Center

2. Disclosures Speaker’s name: Hitoshi Matsuo I have the following potential conflicts of interest to report in the field of this presentation: Speaker at educational events and consultancies: PHILLIPS , BOSTON SCIENTIFIC, Abott Vascular, Zeon Medical, Kaneka

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 AIMRADIAL and PCI workshop 2018 Pa Pd Wave-free period

4. iFR validation studies 2011 2017 2012 2014 2013 2016 2015 “FFR as Gold Standard” studies ADVISE VERIFY RESOLVE JUSTIFY-CFR VU (PET) ADVISE II FORECAST AMC (MPI) ADVISE REG DEFINE FLAIR iFR SWEDEHEART SNUH (PET) TCT2011 April 23rd 2014 First enrollment in GHC

5. Rationale for iFR de Waard GA et al. EHJ 2017

6. AIMRADIAL and PCI workshop 2018 ESC Guideline of coronary revascularization (Neumann, Sousa- Uva et al. 2018) When evidence of ischemia is not available, FFR or iwFR are recommended to assess the hemodynamic relevance of intermediate grade stenosis.

7. iFR validation (against FFR) Johnson N et al. JACC Intv 2016;9:757–67

8. iFR validation studies 2011 2017 2012 2014 2013 2016 2015 “FFR as Gold Standard” studies “Head-to-head” studies ADVISE VERIFY RESOLVE JUSTIFY-CFR VU (PET) ADVISE II FORECAST AMC (MPI) ADVISE REG DEFINE FLAIR iFR SWEDEHEART SNUH (PET)

9. Similar Accuracy 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. *HSR: hyperemic stenosis resistance

10. iFR validation studies 2011 2017 2012 2014 2013 2016 2015 “FFR as Gold Standard” studies “Head-to-head” studies Clinical outcomes trials ADVISE VERIFY RESOLVE JUSTIFY-CFR VU (PET) ADVISE II FORECAST AMC (MPI) ADVISE REG DEFINE FLAIR iFR SWEDEHEART SNUH (PET)

11. 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) AIMRADIAL and PCI workshop 2018

12. iFR-Swedeheart 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) AIMRADIAL and PCI workshop 2018

13. 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 AIMRADIAL and PCI workshop 2018

14. 49 Centers 19 Countries Global Recruitment

15. DEFINE-FLAIR and iFR SwedeHeart in clinically meaningful patient distribution NEJM, (2017)

16. Natural history study of FFR has same distribution as DEFINE-FLAIR De Bruyne, Pijls, Johnson, JACC 2016 “A majority of the lesions were in the intermediate range of 50% to 69% diameter stenosis, and of moderate complexity”

17. Treatment allocations with iFR and FFR Significantly less revascularisation based on iFR interrogation (P < 0.01) iFR (n=2240) FFR (n=2246)

18. Similar MACE using either iFR or FFR to guide revascularization decision-making MACE similar and low at 1 year after iFR- and FFR-based revascularisation decision-making FFR 6.41% IFR 6.47% N=4486

19. MACE components in iFR and FFR guided revascularisation (DEFINE FLAIR + iFR SWEDEHEART) MACE components similar and low at 1 year after iFR - and FFR-guided revascularisation decision-making Outcome iFR Group N=2240 no.(%) FFR Group N=2246 no. (%) Hazard Ratio (95% CI) P value Primary outcome: death from any cause, nonfatal myocardial infarction, or unplanned revascularisation 145 (6.47) 144 (6.41) 1.03 (0.81-1.31) 0.81 Death from cardiovascular causes 15 (0.67) 10 (0.45) 1.52 (0.68-3.39) 0.3 Death from noncardiovascular causes 21 (0.94) 15 (0.67) 1.42 (0.73-2.76) 0.3 Nonfatal myocardial infarction 53 (2.37) 45 (2.00) 1.19 (0.76-1.85) 0.45 Unplanned revascularisation 93 (4.15) 109 (4.85) 0.91 (0.69-1.21) 0.53

20. iFR-guided strategy significantly reduces patient discomfort and procedural time AIMRADIAL and PCI workshop 2018 P < 0.001 3.1% 30.8% P < 0.001 45.0 40.5 90% Symptoms 10% Time iFR FFR iFR FFR Davies JE et al. NEJM 2017

21. Summary of clinical events in deferred patients, stratified into LAD and non-LAD Sen S , Davies JE et al. in submission AIMRADIAL and PCI workshop 2018

22. Summary of clinical events in LAD deferred patients Sen S , Davies JE et al. in submission AIMRADIAL and PCI workshop 2018

23. Kaplan-Meier for MACE in LAD deferred patients. Sen S , Davies JE et al. in submission AIMRADIAL and PCI workshop 2018

24. Kaplan-Meier for MACE in non-LAD patients. Sen S , Davies JE et al. in submission AIMRADIAL and PCI workshop 2018

25. ACS Management of non-culprit lesions ? Culprit Lesions PCI Non-culprit 40-70% FFR iFR Safe? Safe?

26. iFR FFR HR 0.74 (0.38-1.43); p=0.37 HR 0.52 (0.27-0.99); p<0.05 ACS 6.4% SCD 3.4% ACS 5.4% SCD 3.8% Safety of Deferral with FFR / iFR Escaned J , Tanaka N, Yokoi H, Takashima H, Kikuta Y, Matsuo H, Koo BK, Nam CW, SerruysPW , Götberg M, Davies JE et al. . JACC Cardiovasc Interv . 2018 Aug 13;11(15):1437-1449.

27. Improved Safety with iFR in ACS FFR iFR p<0.05 N=4529 N=674 p=0.026 Masrani Mehta et al. J Am Heart Assoc 2015;4:e002172. N=576 p<0.0001 Hakeem A, et al. J Am Coll Cardiol 2016;68:1181–91. Lee JM, Koo BK, et al. Eurointervention 2017;10:4244. N=1596 p=0.002 p=0.37 Escaned J , Tanaka N, Yokoi H, Takashima H, Kikuta Y, Matsuo H, Koo BK, Nam CW, SerruysPW , Götberg M, Davies JE et al. . JACC Cardiovasc Interv . 2018 Aug 13;11(15):1437-1449.

28. iFR is more Accurate for Hyperemic Flow indexes even when Hyperemic Pressure FFR Disagrees with Hyperemic Flow Cook, Jeremias, Kikuta , Shiono, Stone, Davies et al. J Am Coll Cardiol Cardiovasc Interv 2017. Jeremias A, Fearon WF, Pijls NHJ et al . RESOLVE. J Am Coll Cardiol 2014;63:1253–61. iFR ( 0.99 ) F FR ( 0.74 ) iFR ( 0.83 ) F FR ( 0.83 )

29. Health Economics of FFR vs. iFR

30. Significantly Lower Cost with iFR Lord J, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Koo BK, Nam CW, Matsuo H, Serruys PW, Escaned J, Patel M, Davie s J , et al. ACC.18 . Submitted shorter procedural duration hyperaemic medication PCI rates CABG procedures PCI Adjusted Δ $896 (p=0.006) $7442 FFR iFR $8243 Shorter procedural duration No hyperaemic medication Lower PCI rates Fewer CABG procedures Fewer Unplanned PCI (LAD) AIMRADIAL and PCI workshop 2018

31. iFR -SWEDEHEART: Two-year results Randomized Trial of Instantaneous Wave-Free Ratio vs Fractional Flow Reserve Guided PCI Ole Fröbert, MD, PhD - on behalf of the iFR SWEDEHEART investigators

32. Enrollment 22.0% mean use of iFR /FFR in stable angina in SCAAR - 2015 No patients were lost to follow-up

33. Composite Endpoint at 2 years (Death, MI, Unplanned revasc .) log-rank p = 0.93

34. Mortality at 2 years log-rank p = 0.88

35. Myocardial infarction at 2 years log-rank p = 0.758

36. Unplanned revasc . at 2 years log-rank p= 0.854

37. Mace deferred patients Escaned, J et al, JACC Cardiovasc Interv 2018, 11: 1437

38. Subgroup analysis at 2 years FFR iFR

39. Conclusions iFR -SWEDEHEART demonstrated overall similar clinical event rates between iFR and FFR at 2-year follow-up Subgroup analysis suggests increased event rates among diabetic patients evaluated with FFR iFR upgraded to class IA in newest European Society of Cardiology Guidelines on myocardial revascularization * ) * ) European Heart Journal 2018, doi:10.1093/ eurheartj /ehy394

40. AIMRADIAL and PCI workshop 2018 ESC Guideline of coronary revascularization (Neumann, Sousa- Uva et al. 2018) When evidence of ischemia is not available, FFR or iwFR are recommended to assess the hemodynamic relevance of intermediate grade stenosis.

41. iFR Installation in Japan ● 2018 ● 2017 ● 2016 ● 2015 ● 2014 ● 2013 (As of June 30, 2018)

42. Syntax II: results and implications for MVD revascularization . Hitoshi Matsuo MD, PhD, In favour of Javier Escaned MD, PhD, FESC Hospital Clínico San Carlos / Madrid / Spain on behalf of the SYNTAX II Investigators.

43. Background The management of patients with 3-vessel disease (3VD) according to ESC guidelines is largely influenced by the results of the pivotal SYNTAX trial. H o wever , since the completion of that trial major technical and procedural advances, influencing PCI outcomes, have taken place: New risk stratification tools. 2 nd generation DES. Physiology- and imaging PCI guidance. Improved CTO PCI techniques. Windecker S et al. EHJ 2014;35:2541-619 Escaned J et al. EuroIntervention . 2016 Jun 12;12(2):e224-34 3VD with a SYNTAX Score >32 3VD with a SYNTAX Score 23-32 3VD with a SYNTAX Score >32 I I I I III III A A A B B B Extent of CAD CABG PCI AIMRADIAL and PCI workshop 2018

44. SYNTAX 5 year follow -up / Mohr et al Lancet. 2013;381:629-38. Syntax II score in MVD disease / Farooq et al Lancet. 2013;381:639-50. Risk stratification in MVD AIMRADIAL and PCI workshop 2018

45. SYNTAX II study で検 証された最先端の PCI とは SYNTAX Score II score (incorporating clinical and anatomical variables) をガイドに Heart Team で血行再建適応を決定 . FFR と iFR に基づいた血行再建部位の決定　 (hybrid use of iFR and FFR). 第 3 世代の DES を使用 (thin strut, biodegradable polymer, everolimus-eluting Synergy™ stent [EES]). IVUS を用いた stent 最適化　 (modified MUSIC criteria). 最新の CTO 治療技術を用いる . ガイドラインに沿った薬物療法 Escaned J et al. EuroIntervention . 2016 Jun 12;12(2):e224-34 State of Art PCI AIMRADIAL and PCI workshop 2018

46. Study flowchart: patient inclusion Screening with SYNTAX Scores (SS) I & II SS II favours PCI SS II shows equipoise for PCI or CABG SS II favours CABG Heart Team Discussion Equivalent anatomic revascularisation achievable? Yes No CABG registry Patient “signed off” by Heart Team for PCI Informed Consent Patient included in the study AIMRADIAL and PCI workshop 2018

47. State of art PCI procedure Patient included in the SYNTAX II study iFR in all intended to treat stenoses iFR 0.86 – 0.93 FFR ≤ 0.80 FFR iFR < 0.86 iFR > 0.93 Stenosis treated with SYNERGY TM EES FFR > 0.80 Stenosis not treated IVUS optimization Optimal medical therapy with strict LDL control (≤ 1.8mmol/L=70mg/dl) Escaned J et al. EuroIntervention . 2016 Jun 12;12(2):e224-34 AIMRADIAL and PCI workshop 2018 虚血を生じさせる狭窄のみを Pressure wire で選択

48. Anatomic target lesions (n=1559) (3.49 lesions/patient) iFR performed (n=1150; 73.8%) Only FFR performed (n=27; 1.7%) Lesions not assessed with physiology (n=382; 24.5%) Pressure wire crossing not attempted/indicated*: 221 Unable to cross the lesion with a pressure wire**: 127 Other reasons: 26 *Use of pressure guidewire in CTOs was not indicated . ** Physiological interrogation was prompted irrespective of angiographic lesion severity . Physiological stenosis interrogation AIMRADIAL and PCI workshop 2018

49. Anatomic target lesions (n=1559) (3.49 lesions/patient) iFR performed (n=1150) iFR <0.86 (n = 603; 52%) iFR 0.86-0.93 (n = 264; 23%) iFR >0.93 (n = 283; 25%) Treated (n=600; 99.5%) Treated (n=179; 67.8%) Deferred (n=262; 92.6%) FFR 16 (2.6%) FFR 252 (95.4%) FFR 41 (14.4%) Only FFR performed (n=27) Physiological stenosis interrogation AIMRADIAL and PCI workshop 2018

50. Impact of intracoronary physiology on PCI Cases of three -vessel PCI (%) in SYNTAX II and SYNTAX I Lesion treatment after iFR/FFR interrogation (n=1177) P < 0.001 P < 0.001 Lesions treated per patient (n) in SYNTAX II and SYNTAX I PCI deferred 31% PCI performed 69% 2.64 4.02 37.2% 83.3% SYNTAX II Escaned J et al. European Heart Journal (2017) 38 , 3124–3134 AIMRADIAL and PCI workshop 2018

51. Treatment of chronic total occlusions (CTO) CTO PCI procedural success rate in SYNTAX II: 87% n =94 n =14 SYNTAX II CTO PCI CTO PCI procedural success rate in SYNTAX II and SYNTAX I 87% 53% p<0.0001 AIMRADIAL and PCI workshop 2018

52. Post-implantation IVUS led to further optimisation of the stented lesion in 30.2%. Patient level 84.1% 15.9% 23.6% 76.4% Lesion level SYNTAX II IVUS use in SYNTAX II and SYNTAX I ( patient level , % of cases) Use of intravascular ultrasound (IVUS) 84.1% p<0.0001 84.1% 4.8% AIMRADIAL and PCI workshop 2018

53. MACCE SYNTAX II and SYNTAX I PCI / CABG Vs. PCI Hazard ratio, 0.58 (95% CI 0.39-0.85) p- value =0.006 SYNTAX I PCI SYNTAX II SYNTAX I CABG 10.6% 11.2% 17.4% Escaned J et al. European Heart Journal (2017) 38 , 3124–3134 AIMRADIAL and PCI workshop 2018

54. SYNTAX II MACCE in SS I ≤22 and > 22 HR 0.26 (95% CI 0.0.7-0.97), p=0.045 SS ≤22 SS >22 SYNTAX II patients only SYNTAX SCORE ≤22 SYNTAX SCORE >22 AIMRADIAL and PCI workshop 2018

55. SYNTAX II: 2-Year Results MACCE vs. Historical PCI SYNTAX II strategy resulted in statistically significant improvement in MACCE* compared to SYNTAX I Trial at 2 years P. Serruys , MD., PCR 2018 MACCE (Primary Endpoint) 2 Year Follow-up Results (Compared to Historical PCI Cohort from SYNTAX-I Trial) HR 0.57 (95% CI 0.40-0.81, p=0.001) HR 0.59 (95% CI 0.40-0.86, p=0.007) 17.4% 10.7% 30 90 180 270 365 540 730 Days: SYNTAX I PCI Number at Risk SYNTAX II PCI 315 298 288 275 262 256 250 242 454 442 433 422 407 399 391 347 Patients (%) 21.9% 13.2% *All-cause death, stroke, any myocardial infarction or any revascularization

56. SYNTAX II: 2-Year Results MACCE PCI vs. CABG State-of-the-art Contemporary PCI demonstrated equivalent outcomes to CABG in patients with 3VD at 2 years* P. Serruys , MD., PCR 2018 MACCE (Secondary Endpoint) 2 Year Follow-up Results (Compared to Historical CABG Cohort from SYNTAX-I Trial) HR 0.85 (95% CI 0.58-1.25, p=0.42) HR 0.93 (95% CI 0.60-1.43, p=0.73) P <0.001 for non-inferiority 11.2% 10.7% 30 90 180 270 365 540 730 Days: SYNTAX I CABG Number at Risk SYNTAX II PCI 334 313 295 289 279 277 268 263 454 442 433 422 407 399 391 347 Patients (%) 15.1% 13.2% *Angiographically Detected

57. Syntax : 29 points Syntax II 4-year mortality : PCI 12%, CABG 11% Male 80 y.o . Diabetes, dyslipidaemia , hypertension A case example from SYNTAX II AIMRADIAL and PCI workshop 2018

58. AIMRADIAL and PCI workshop 2018

59. Syntax : 29 points / Syntax II 4-year mortality : PCI 12%, CABG 11% Male 80 y.o . Diabetes, dyslipidaemia , hypertension iFR 0.90 FFR 0.83 iFR 0.94 iFR 0.95 iFR 0.35 A case example from SYNTAX II AIMRADIAL and PCI workshop 2018

60. SYNTAX II study で検 証された最先端の PCI とは SYNTAX Score II score (incorporating clinical and anatomical variables) をガイドに Heart Team で血行再建適応を決定 . FFR と iFR に基づいた血行再建部位の決定　 (hybrid use of iFR and FFR). 第 3 世代の DES を使用 (thin strut, biodegradable polymer, everolimus-eluting Synergy™ stent [EES]). IVUS を用いた stent 最適化　 (modified MUSIC criteria). 最新の CTO 治療技術を用いる . ガイドラインに沿った薬物療法 Escaned J et al. EuroIntervention . 2016 Jun 12;12(2):e224-34 State of Art PCI AIMRADIAL and PCI workshop 2018

61. Pressure pullback using iFR Hitoshi Matsuo MD.PhD . Department of Cardiovascular Medicine Gifu Heart Center

62. AIMRADIAL and PCI workshop 2018

63. AIMRADIAL and PCI workshop 2018