Is FFR a Substitute For Sound Clinical Judgement ?

1. Is FFR a Substitute For Sound Clinical Judgement ? Jeffrey W. Moses, MD Columbia University Medical Center/ NY-Presbyterian Hospital

2. Conflicts of Interest Consultant /SAB: BSC,Abbott

3. 74 y/o woman with effort and rest angina ETT ; ex time 3’ with ST changes. Anterior reversible perfusion defect FFR of LAD 0.9 ......... Med Rx

4. Continued Sx on Med Rx Repeat FFR 0.91 MLA=2.7mm2 PB=72% Vessel size=3.5mm

5. POST STENT MLA=5.9 mm2 Complete symptomatic relief !

6. Correllation Slide • If FFR is validated by MPI… • …how can it overrule an unequivocal MPI?

7. 15 Studies:FFR and MPI (0.75 Cutoff) n=996 Christou et al. Am. JCardiol 2007;99:450

8. Sensitivity Specificity FFR=0.75 0.80 FFR and the “Grey Zone” Sensitivity 100 80 Specificity 60 FFR=0.75 0.80 40 20 0 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 FFR De Bruyne, et al. Circulation 2001;104:157-62

9. “Grey Zone”

10. FFR Test Retest Reproducibility Petraco et al., J Am Coll Cardiol Intv 2013;6:222-5

11. What is Our Basis for Deferral?

12. DEFER: Patients with Intermediate Lesions with Equivocal or Negative StressTests: No Data With Unequivocal Ischemia 100 N=144 90 N=91 80 N=90 70 60 30 Stenosis Severity (%) 50 40 30 20 Defer Group Perform Group Reference Group FFR >0.75 FFR <0.75 Bech et al, Circ 2001;103:2928-34

13. Safety of Deferring PCI Based on FFR 5 Year Cardiac Death and MI rate in DEFER Trial P< 0.003 20 P< 0.005 15.7 15 P=0.20 % 10 7.9 5 3.3 0 DEFER PERFORM REFERENCE FFR ≥ 0.75 FFR < 0.75 Pijls, et al. J Am Coll Cardiol 2007;49:2105-11

14. FAME 2 : Trial Design Stable patients with 1, 2, or 3 vessel CAD evaluated for PCI with DES n=1220 FFR in all target lesions Registry Randomized Trial At least 1 stenosis with FFR ≤ 0.80 (n=888) All FFR > 0.80 (n=322) Randomization 1:1 MT MT PCI + MT 50% randomly assigned to follow-up Primary Endpoint: Death, MI, Urgent Revascularization at 2 years

15. FAME 2: Primary Outcomes PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001 30 PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61 25 MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001 20 15 Cumulative incidence (%) 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization No. at risk MT 441 414 370 322 283 253 220 192 162 127 100 70 37 PCI+MT 447 414 388 351 308 277 243 212 175 155 117 92 53 Registry 166 156 145 133 117 106 93 74 64 52 41 25 13 De Bruyne B et al. NEJM 2012:on-line

16. What a Difference a Decade Makes: 1 Year Outcomes 20% 8% 4.3 3.0 DEFER 2001 FAME II 2011 FAME II 2011 DEFER 2001 Deferral Perform Non ischemic Ischemic Circ 2012;201:2928

17. Possible Problems with FRR The flow impediment specific to the interrogated stenosis is underestimated as an opposite stenosis becomes more severe because maximal hyperemic flow is not achieved Branches between serial stenoses may inhibit maximal hyperemia because of “branch steal.” Left ventricular hypertrophy causes inadequate flow reserve because of a mismatch between the vasculature and myocardial mass Exercise induced vasoconstriction not accounted for

18. Chronic Microvascular Damage and FFR Old Myocardial Infarction Irreversible Microvascular Damage Maximum Achievable Flow is Less Smaller Gradient and Higher FFR across Any Given Stenosis

19. Systemic Adenosine Infusion and Maximum Hyperemia: Variable Responses • Routine set up for FFR measurement in my lab: venous sheath in the groin for adenosine infusion 140 μg/kg/min :FFR .98 • Repeat assessment by bolus injection of 100μg into RCA: short total AV block, then FFR 0.78 repeated with 50μg without AV block, then FFR 0.80 • Some patients may metabolize adenosine faster than others -> use a multipurpose catheter to deliver adenosine into the right atrium

20. FFR Gets Complex in Serial Stenosis Pijls et al. Circulation. 2000;102:2371-2377

21. FFR in MI/ACS NOT in acute INFARCT or ACS lesion These lesions ALL need treatment May use in chronic infarct lesion Does not predict viability Does correlate with residual ischemia May use in non-culprit ACS lesions Avoid “over-treatment” Avoid need for subsequent stress testing

22. PCI in ACS : Angiographically Driven PCI Saves Lives 50% Selective invasive Routine Invasive 45% 40% High 35% 30% Cumulative death and MI 25% 20% Intermediate 15% 10% Low 5% 0% 0 1 2 3 4 5 Follow-up time (years) Fox et al, JACC 2010;55:435-45

23. PRAMI: “Preventative” PCI of Non-culprit Lsns after Culprit Lesion Primary PCI in STEMI 465 non-shock pts at 5 UK sites with MVD; after successful primary PCI randomized to NCL PCI of non-LM DS 50-99% stenoses vs. conservative care 600 pts planned; DSMB stopped trial early after 465 pts enrolled (2008-2013) Primary endpoint: Cardiac death, MI or refractory angina Culprit PCI only 100 91% 80 77% Complete revasc 60 Freedom from Primary Outcome (%) HR 0.35 (95%CI 0.21-0.58) P<0.001 40 20 0 0 6 12 18 24 30 36 Months No. at Risk Preventive PCI 234 196 166 146 118 89 67 No Preventive PCI 231 168 144 122 96 74 50 Wald DS et al. NEJM 2013:on-line

24. PRAMI: “Preventative” PCI of Non-culprit Lsns after Culprit Lesion Primary PCI in STEMI 465 non-shock pts at 5 UK sites with MVD; after successful primary PCI randomized to NCL PCI of non-LM DS 50-99% stenoses vs. conservative care 600 pts planned; DSMB stopped trial early after 465 pts enrolled (2008-2013) Median FU 2.3 Years Wald DS et al. NEJM 2013:on-line

25. How Do Patients End up on the Cath Table? ACS Symptoms Significant ischemia Left ventricle dysfunction Atypical symptoms and equivocal non-invasives Anatomically driven (ie abnormal CTA)

26. How Do Patients End up on the Cath Table? ACS Symptoms Significant ischemia Left ventricle dysfunction Atypical symptoms and equivocal non-invasives Anatomically driven (ie abnormal CTA)

27. Recurrent Angina 9 Months Post Stent VD 4.8x5.0 VA 19.5 mm2 LD 1.4x2.3 LA 2.6 mm2

28. Recurrent Symptoms Post BMS 102 FFR = 0.83 Are you going to Defer? 83

29. How Do Patients End up on the Cath Table? ACS Symptoms Significant ischemia Left ventricle dysfunction Atypical symptoms and equivocal non-invasives Anatomically driven (ie abnormal CTA)

30. Cardiac Mortality in Medically Treated Patients According to Ischemic Risk – CSMC Database N=9,956 pts Cardiac Death Rate (%) (1.9 yr FU) N=7110 N=1331 N=718 N=545 N=252 0% 1- 5% 5-10% 11-20% >20% % Total Myocardial Ischemia Hachamovitch et al Circulation. 2003;107:2900-07

31. Rates of Death or MI by ResidualIschemia on 6-18m MPS p=0.002 p=0.023 p=0.063 Death or MI Rate (%) 0%(n=23) 1%-4.9% (n=141) 5%-9.9% (n=88) >10% (n=62) Shaw LA et al. Circulation 2008;117:1283-91

32. ACS “Classic” Symptoms Significant ischemia Left ventricle dysfunction Atypical symptoms +/- equivocal NI How to Treat Anatomic (culprit) Anatomic Anatomic Anatomic +/- viability FFR Location + severity+ / - FFR Anatomically driven Multivessel disease FFR for IL

33. Conclusions FFR needs to be put into the context of our overall understanding of coronary physiology , the prognosis of CAD and the influence of revascularization in various clinical and anatomic situations It has been validated in limited clinical trials and extending it to areas where other modalities (e.g., MPI , angiography ,viability studies) have demonstrated improvement of outcomes is simply not “evidence based”