The Starting Point: Translesional Pressure versus Flow Morton J. Kern, MD Professor of Medicine Chief of Cardiology, LBVA Associate Chief Cardiology, UCI University California Irvine Orange, California Slides to accompany document on FFR and AUC – meeting and Beating Guidelines 021817@1230-1240

Disclosure: Morton J. Kern, MD Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Company Name Relationship St. Jude Medical Inc. Speakers’ Bureau Volcano Therapeutics Speakers’ Bureau Merit Medical Inc. Consultant Acist Medical Inc. Consultant Opsens Consultant Heartflow Consultant

What is Gold Standard of Ischemia in Man? Biomarkers, Troponin Exercise ECG Wall motion abnormalities, thickening and shortening Transmyocardial Lactate PET 1ml/gram flow, Radionuclide perfusion imaging, Coronary blood flow velocity

Limitations of Angiography to reflect physiology: Flow is effected by >6 morphologic features. The PV curve determines ischemia. At hyperemia, P and Flow are linearly related. Ischemia 2 length 3 exit angle 1 entrance ΔP No Ischemia 1 2 3 4,5,6 7 Fig 3. Coronary Pressure and Flow measurements and the Relationship determines the ischemic potential of a stenosis Top right translesional pressure measurements, bottom right Doppler flow velocity measurements. Bottom left, pressure-flow relationships across mild stenosis (B) and severe stenosis (A). 5

Physiology (CFR) can predict Anatomy but not vice versa

Risk Continuum of Noninvasive CFR (Ischemia) Ischemia is Important Risk Continuum of Noninvasive CFR (Ischemia) Johnson N and Gould KL. J Am Coll Cardiol. 2016;67(23):2772-2788. Montage of supporting data from cardiac PET. ∗p = 0.028 for SSS≥4 to 7 and CFR<1.5 versus CFR≥2. ∗∗p = 0.002 for SSS≥8 and CFR<1.5 versus CFR≥2. Adapted with permission from (A) Murthy et al. (59); (B) Fukushima et al. (57); (C) Ziadi et al. (56); and (D) Herzog et al. (55). CFR = coronary flow reserve; CT = computed tomography; CV = cardiovascular; MFR = myocardial flow reserve; PET = positron emission tomography; SSS = summed stress score. other abbreviations as in Figure 1.

Relationship between Flow (CFR) or (MFR) and Pressure (invasive FFR) Danad et al19 Valenta et al20 Lee et al7 Relationship between coronary or myocardial flow reserve (CFR or MFR) and invasive fractional flow reserve (FFR). A triangular relationship exists between CFR and invasive FFR, as summarized here in 1199 lesions from 489 subjects using cardiac PET but also seen using every other tool to assess flow reserve. A, Conceptual Figure 3 describes the mechanisms for CFR vs FFR discordance. Reprinted from Johnson et al11 with permission of the publisher. Copyright ©2012, Elsevier. B, Figure 7C with 863 lesions in 330 subjects. Reprinted from Danad et al19 with permission of the publisher. Copyright ©2014, Elsevier. C, Figure 4D with 29 lesions in 29 subjects. Reprinted from Valenta et al20 with permission of the publisher. Copyright ©2016, Oxford University Press. D, Figure 1A with 307 lesions in 130 subjects. Reprinted from Lee et al7 with permission of the publisher. Copyright ©2016, Wolters Kluwer Health, Inc. Nils P. Johnson, and K. Lance Gould Circ Cardiovasc Imaging. 2016;9:e005435

FFR has durable Outcome Studies 2000-2015 FFR Outcome Studies N= Study Design Question Outcome Journal DEFER (2000-2015) 325 Prospective MC RCT Is it safe to defer stenting intermediate lesions with FFR>0.75 Less MACE, med rx when FFR >0.75 JACC FAME (2009-2015) 750 Does FFR guided PCI vs. angio guided for MVD improve outcomes? Less MACE*, lower cost w FFR NEJM FAME II (2012) 1,220 Does FFR guided PCI + OMT vs. OMT alone improve outcomes? Less MACE w FFR, cost effective Mayo (2013) 7,358 Retro SC Registry Does FFR vs angio-guided PCI improve outcomes in routine practice? Less MACE w FFR EHJ R3F (France) (2014) 1.075 Prospective MC Registry “” FFR reclass revasc decision in 47% Circulation Ripcord FFRCT (UK) (2015) 200 Prospective MC Registry FFR reclass revasc decision in 36% EHJ, In press Asan FFR (Korea) (2013) Prospective SC Registry Fewer stents and less MACE w FFR

FFR Outcome Studies DEFER 15yr FAME I – 5yr FAME II – 2 yr Fractional flow reserve was 0.86+0.06 in the Defer group, 0.87+0.07 in the Perform group, and 0.57+0.16 in the Reference group. The rate of MI was significantly lower in the Defer group (2.2%) compared with the Perform group (10.0%), RR 0.22, 95% CI: 0.05–0.99, P ¼ 0.03. This was almost exclusively due to less target vessel-related infarctions. Patients with a baseline FFR ≥ 0.75 had a significantly lower rate of MI compared with patients with an FFR , 0.75 (6.1 vs. 12.5%, RR 0.49, 95% CI: 0.24–1.00, P ¼ 0.044). De Bruyne, et al. NEJM 2014;371:1208-17. Pijls NHJ et al. ESC, August 2015. EHJ 2015; 36, 3182–3188

The lower FFR, the worse event rate. There is an ischemic dose response relationship of FFR to Ischemic events. The lower FFR, the worse event rate. Patient-level meta-analysis of a broad outcomes literature through February 2014 on the relation of fractional flow reserve (FFR) to adverse events. FFR has a continuous relation to events that differs between medical therapy and revascularization.12 The crossover point of these curves marked by the black dot indicates where potential risk associated with the procedure is greater than the potential benefit of eliminating the stenosis. Potentially low FFR threshold for intervention would be expected to show the greatest benefit from revascularization because of the highest event rates potentially reduced by the procedure. A high FRR threshold would be expected to incur greater risk because of the procedure than from such mild disease. MACE indicates major adverse coronary events; and MI, myocardial infarction. Adapted from Johnson et al12 with permission of the publisher. Copyright @ 2014, the American College of Cardiology. K. Lance Gould et al. Circ Cardiovasc Imaging. 2015;8:e003099

CFR, FFR Outcomes Conflict: High flow can produce a low FFR. High CFR vs. Low FFR outcomes tbd Nl CFR Abn FFR Study: Define Flow N,N FFR >0.80 / CFR<2.0 microvascular treat microvascc Van de Hoef et al. Circ Cardiovasc Interv 2014 Meuwissen M et al. Circulation 2001;103:184-187

Pressure gradient vs distal AVP Hypermic CFR and FFR: Pressure gradient vs distal AVP Hypermic Basal Meuwissen M et al. Circulation 2001;103:184-187

Difference between iFR and FFR – PV curves DeWaarde G et al, Eurointervention, Jan 2017 ahead of print

What are valid comparators to ischemia? All Indices will correlate for severe and minimal lesions. But accuracy? iFR v FFR vs. MPI Pd/Pa v FFR Head-to-head comparison of basal stenosis resistance index, instantaneous wave-free ratio, and fractional flow reserve: diagnostic accuracy for stenosis-specific myocardial ischaemia EuroIntervention 2015;11:914-925

Current Physiologic Measurement Tools for Pressure and Flow 0 mm Hg 50 mm Hg 100 mm Hg Flush Off FFR = 0.96 iFR Pd/Pa FFR IMR=Pa*Tmn [(Pd–Pw)/(Pa–Pw)] FFR=0.78 CVR IC Doppler BSRv=Pa-Pv/APVrest HSRv=Pa-Pv/APVhyp Flow velocity

Pressure Flow