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

Conflicts of Interest Consultant /SAB: BSC,Abbott

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

Continued Sx on Med Rx MLA=2.7mm 2 PB=72% Vessel size=3.5mm Repeat FFR 0.91

Complete symptomatic relief ! POST STENT MLA=5.9 mm 2

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

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

FFR and the “Grey Zone” De Bruyne, et al. Circulation 2001;104: FFR Specificity Sensitivity FFR= Specificity Sensitivity FFR=

“Grey Zone”

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

What is Our Basis for Deferral?

DEFER: Patients with Intermediate Lesions with Equivocal or Negative Stress Tests: No Data With Unequivocal Ischemia Bech et al, Circ 2001;103: Stenosis Severity (%) Defer Group Perform Group Reference Group FFR >0.75FFR < N=90 N=91 N=144

% P=0.20 P< P< DEFER PERFORM REFERENCE FFR ≥ 0.75 FFR < 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:

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

Cumulative incidence (%) Registry PCI+MT MT No. at risk FAME 2: Primary Outcomes MT vs. Registry: HR 4.32 ( ); p<0.001 PCI+MT vs. Registry:HR 1.29 ( ); p=0.61 PCI+MT vs. MT: HR 0.32 ( ); p<0.001 Months after randomization De Bruyne B et al. NEJM 2012:on-line

What a Difference a Decade Makes: 1 Year Outcomes Deferral Perform Non ischemicIschemic DEFER % DEFER % FAME II FAME II Circ 2012;201:2928

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

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

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

FFR Gets Complex in Serial Stenosis Pijls et al. Circulation. 2000;102:

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

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

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 ) P<0.001 No. at Risk Preventive PCI No Preventive PCI 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 ( ) Complete revasc Culprit PCI only

Complete revasc (N=234) Culprit PCI only (N=231) HR (95%CI)P value Pre-specified outcomes Cardiac death, MI, or refractory angina ( )<0.001 Cardiac death or MI ( )0.004 Cardiac death ( )0.07 Nonfatal MI ( )0.009 Refractory angina w/o CD or MI ( )0.002 Secondary outcomes Noncardiac death ( )0.86 Repeat revascularization ( )<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 ( )

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)

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)

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

FFR = 0.83 Are you going to Defer? Recurrent Symptoms Post BMS

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)

Cardiac Mortality in Medically Treated Patients According to Ischemic Risk – CSMC Database Hachamovitch et al Circulation. 2003;107: % 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

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

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

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”