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 MLA=2.7mm 2 PB=72% Vessel size=3.5mm Repeat FFR 0.91

5. Complete symptomatic relief ! POST STENT MLA=5.9 mm 2

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. J Cardiol 2007;99:450 TPFNFPTN 331100143422

8. FFR and the “Grey Zone” De Bruyne, et al. Circulation 2001;104:157-62 FFR Specificity 100 80 60 40 20 0 0.20.30.40.50.60.70.80.91.0 Sensitivity FFR=0.750.80 Specificity Sensitivity FFR=0.750.80

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 Stress Tests: No Data With Unequivocal Ischemia Bech et al, Circ 2001;103:2928-34 Stenosis Severity (%) Defer Group Perform Group Reference Group FFR >0.75FFR <0.75 20 30 40 50 3060 70 80 90 100 N=90 N=91 N=144

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

14. Primary Endpoint: Death, MI, Urgent Revascularization at 2 years 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 At least 1 stenosis with FFR ≤ 0.80 (n=888) Randomization 1:1 PCI + MT MT Randomized Trial All FFR > 0.80 (n=322) MT Registry 50% randomly assigned to follow-up

15. 0 5 10 15 20 25 30 Cumulative incidence (%) 16615614513311710693746452412513Registry 4474143883513082772432121751551179253PCI+MT 4414143703222832532201921621271007037MT No. at risk 0123456789101112 FAME 2: Primary Outcomes MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001 PCI+MT vs. Registry:HR 1.29 (0.49-3.39); p=0.61 PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001 Months after randomization De Bruyne B et al. NEJM 2012:on-line

16. What a Difference a Decade Makes: 1 Year Outcomes Deferral Perform Non ischemicIschemic DEFER 2001 20% DEFER 2001 8% FAME II 2011 3.0 FAME II 2011 4.3 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 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. Old Myocardial Infarction Irreversible Microvascular Damage Maximum Achievable Flow is Less Smaller Gradient and Higher FFR across Any Given Stenosis Chronic Microvascular Damage and FFR

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 Fox et al, JACC 2010;55:435-45 Selective invasive Routine Invasive High Follow-up time (years) Intermediate Low Cumulative death and MI 012345 0% 5% 10% 15% 20% 25% 30% 35% 50% 45% 40%

23. Primary endpoint: Cardiac death, MI or refractory angina Wald DS et al. NEJM 2013:on-line 91% 77% Freedom from Primary Outcome (%) Months HR 0.35 (95%CI 0.21-0.58) P<0.001 No. at Risk Preventive PCI No Preventive PCI 0 231 6 234 1218243036 168 196 144 166 122 146 96 118 74 89 50 67 0 20 40 60 80 100 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) Complete revasc Culprit PCI only

24. Complete revasc (N=234) Culprit PCI only (N=231) HR (95%CI)P value Pre-specified outcomes Cardiac death, MI, or refractory angina21530.35 (0.21-0.58)<0.001 Cardiac death or MI11270.36 (0.18-0.73)0.004 Cardiac death4100.34 (0.11-1.08)0.07 Nonfatal MI7200.32 (0.13-0.75)0.009 Refractory angina w/o CD or MI12300.35 (0.18-0.69)0.002 Secondary outcomes Noncardiac death861.10 (0.38-3.18)0.86 Repeat revascularization16460.30 (0.17-0.56)<0.001 Median FU 2.3 Years Wald DS et al. NEJM 2013:on-line 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)

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. VD 4.8x5.0 VA 19.5 mm 2 LD 1.4x2.3 LA 2.6 mm 2 Recurrent Angina 9 Months Post Stent

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

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 Hachamovitch et al Circulation. 2003;107:2900-07 % Total Myocardial Ischemia 0%1- 5%5-10%11-20%>20% Cardiac Death Rate (%) (1.9 yr FU) N=7110N=1331N=718N=545N=252 N=9,956 pts

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

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

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”