Fractional Flow Reserve: Clinical Trials Update

3/22/2013 Fractional Flow Reserve: Clinical Trials Update William F. Fearon, MD Associate Professor Director, Interventional Cardiology Stanford University Medical Center Conflict of Interest Advisory Board for HeartFlow Research support from St. Jude Medical Research and salary support from National Institutes of Health: 1 R01 HL093475 (PI) FFR: Gold Standard for Identifying Ischemia Proximal Pressure (Pa) Distal Pressure (Pd) FFR = P d / P a during maximal flow P a P d / P a = 60 / 100 FFR = 0.60 P d 1

3/22/2013 Validation of FFR Fractional Flow Reserve Exercise Test Thallium Scan Stress Echo 0.75 FFR < 0.75 : Sensitivity = 88% Specificity = 100% Pijls et al., New Engl J Med 1996;334:1703 What is FAME 1? Fractional Flow Reserve versus Angiography for Multivessel Evaluation Tonino, et al. New Engl J Med 2009;360:213-24 FAME 1 Trial: FFR-Guided PCI performed on indicated lesions only if FFR 0.80 Lesions warranting PCI identified Randomized Angio-Guided PCI performed on indicated lesions Primary Endpoint Composite of death, MI and repeat revasc. (MACE) at 1 year Tonino, et al. New Engl J Med 2009;360:213-24. 2

3/22/2013 Angio- Guided n = 496 FFR- Guided n = 509 P Value Indicated lesions / patient 2.7±0.9 2.8±1.0 0.34 Stents / patient 2.7 ± 1.2 1.9 ± 1.3 <0.001 Angio- Guided n = 496 FFR- Guided n = 509 P Value Indicated lesions / patient 2.7±0.9 2.8±1.0 0.34 Stents / patient 2.7 ± 1.2 1.9 ± 1.3 <0.001 Procedure time (min) 70 ± 44 71 ± 43 0.51 Contrast agent used (ml) 302 ± 127 272 ± 133 <0.001 Equipment cost (US $) 6007 5332 <0.001 Length of hospital stay (days) 3.7 ± 3.5 3.4 ± 3.3 0.05 FAME Study: One Year Outcomes % 20 Angio-Guided FFR-Guided ~30% 18.3 15 10 5 ~40% 3 1.8 ~35% 8.7 5.7 ~30% 9.5 6.5 ~35% 11.1 7.3 13.2 0 Death MI Repeat Revasc Death/MI p=0.04 MACE p=0.02 Tonino, et al. New Engl J Med 2009;360:213-24. 3

3/22/2013 FAME: Economic Evaluation Bootstrap Analysis FFR-guided PCI saved >$2,000 per patient at one year compared to Angioguided PCI Circulation 2010;122:2545-50. FAME Study: Two Year Outcomes Death/MI was significantly reduced from 12.9% to 8.4% (p=0.02) Survival Free of MACE FFR-Guided Angio-Guided 730 days 4.5% Pijls, et al. J Am Coll Cardiol 2010;56:177-184 Functional SYNTAX Score Reclassifies > 30% of Cases Without FFR Nam CW, et al. J Am Coll Cardiol 2011;58:1211-8 4

3/22/2013 Functional SYNTAX Score Reclassifies > 30% of Cases Without FFR With FFR Nam CW, et al. J Am Coll Cardiol 2011;58:1211-8 Functional SYNTAX Score Discriminates Risk for Death/MI P < 0.01 20% 32% 34% 59% Nam CW, et al. J Am Coll Cardiol 2011;58:1211-8 Implications of FAME Death and MI in the COURAGE study FAME 2 Boden et al., New Engl J Med 2007;356:1503-16. 5

3/22/2013 FAME 2 Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI N = 1220 Randomized Trial FFR in all target lesions Registry At least 1 stenosis with FFR 0.80 (n=888) When all FFR > 0.80 (n=332) Randomization 1:1 PCI + MT 73% MT 27% MT 50% randomly assigned to FU Primary Endpoint: Death, MI or urgent revascularization at 2 Yr 69 yo man with chest pain and apical ischemia on NPS FFR of RCA = 0.89 6

3/22/2013 FFR of LAD = 0.51 LAD after PCI Baseline Characteristics Randomized Trial Registry p Patients, N PCI+MT=447 MT=441 with FU=166 Demographic Age (y) 63.5±9.3 63.9±9.6 63.6±9.8 0.90 Male sex - (%) 79.6 76.6 68.1 0.005 BMI 28.3±4.3 28.4±4.6 27.8±3.9 0.14 Risk factors for CAD Positive family history CAD - (%) 48.3 46.9 45.8 0.65 Smoking - (%) 19.9 20.4 21.1 0.79 Hypertension - (%) 77.6 77.8 81.9 0.23 Hypercholesterolemia - (%) 73.9 78.9 71.1 0.15 Diabetes mellitus - (%) 27.5 26.5 25.3 0.65 Insulin requiring diabetes - (%) 8.7 8.8 6.0 0.24 De Bruyne, et al. New Engl J Med 2012;367:991-1001 7

Cumulative incidence (%) 3/22/2013 Angiographic Characteristics Randomized trial N=888 Registry N=322 Patients, N PCI+MT=447 MT=441 with FU=166 P* Angiographically significant stenoses - no. per patient 1.87±1.05 1.73±0.94 1.32±0.59 <0.001 No of vessels with 1 significant stenoses - (%) 1 56.2 59.2 81.9 2 34.9 33.1 15.7 3 8.9 7.7 2.4 <0.001 Prox- or mid- LAD stenoses - (%) 65.1 62.6 44.6 <0.001 De Bruyne, et al. New Engl J Med 2012;367:991-1001 Patients with Angina Class II to IV % p<0.001 p=0.002 De Bruyne, et al. New Engl J Med 2012;367:991-1001 Primary Endpoint: Death, MI, Urgent Revasc 30 PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001 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 10 5 No. at risk MT PCI+MT Registry 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization 441 414 370 322 283 253 220 192 162 127 100 70 37 447 414 388 351 308 277 243 212 175 155 117 92 53 166 156 145 133 117 106 93 74 64 52 41 25 13 8

Cumulative incidence (%) Cumulative (%) 3/22/2013 Landmark Analysis of Death or MI 30 25 7 days: HR 7.99 (0.99-64.6); p=0.038 > 8 days: HR 0.42 (0.17-1.04); p=0.053 p-interaction: p=0.003 20 15 10 5 0 2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 5 6 7 Days after randomization >8 days PCI plus MT MT alone 7 days 07days 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization MT alone PCI plus MT Patients with urgent revascularization 21.4% Myocardial Infarction 51.8% 26.8% Unstable angina +evidence of ischemia on ECG Patients with urgent revascularization Urgent revascularization driven by MI or unstable angina with ECG changes FFR-Guided PCI + MT 51.8% MT 0.9% vs. 5.2% p<0.001 83% Relative Risk Reduction 21.4% 26.8% Myocardial Infarction Unstable angina +evidence of ischemia on ECG 9

3/22/2013 Cost-Effectiveness in FAME 2 Cumulative Costs during first 12 months $2,508 $5,485 Late Breaking Trial: TCT 2012 Cost-Effectiveness of FAME-2 Quality of Life at 1 Month Angina (%) FFR-Guided PCI MT p-value Class 0-1 89 71 <0.001 Class 2-4 11 29 <0.001 Utility Change 0.054 0.003 <0.001 Late Breaking Trial: TCT 2012 Cost-Effectiveness of FAME-2 In-trial results $2,500 / 0.047 QALY = $53,000 / QALY Three Year Projection $2,500 / 0.079 QALY = $32,000 / QALY Late Breaking Trial: TCT 2012 10

3/22/2013 Conclusions FFR-Guide PCI improves outcomes and saves resources compared to angio-guided PCI in stable and unstable patients with multivessel CAD. In patients with stable coronary artery disease, FFR-guided PCI improves patient outcome as compared with medical therapy alone. In patients with functionally non-significant stenoses, medical therapy alone resulted in an excellent outcome, regardless of the angiographic appearance of the stenoses. 11

Time to to Retool Your Interventions 3/25/2013 Use of I.V.U.S. and F.F.R. in the Treatment of Complex Multivessel Coronary Artery Disease David G. Rizik, M.D., F.A.C.C. Director of Heart & Vascular Medicine Scottsdale Heart Group at Scottsdale Healthcare Hospitals Disclosure Cordis Scientific Advisory Panel Abbott Medical Advisory Board Boston Scientific: Research Support TherOx Scientific Panel InfraRed X Advisory Panel TriReme Medical Scientific Advisory Board IVUS and FFR Use of IVUS. Applying those lessons learned from use of IVUS. Applying FFR in complex decision making. 1

3/25/2013 Acute MI in the Setting of Multi-Vessel CAD 66 year non-diabetic with a history of hypertension, hypercholesterolemia and a family of CAD. He presented with his first episode of chest pain to the ER. As he was naïve to DAPT, he received loading doses ASA and a thienopyridine in the ER 2

3/25/2013 Lessons Learned From Use Of IVUS 2.5 Balloon for Initial Dilation of the RCA 3

3/25/2013 3.0 Xience Stent Following Implantation of a 3.0 Stent 4

3/25/2013 4.0 NC Balloon at 20 atm Use of IVUS 5

3/25/2013 Double Wire 2.5 MB Balloon, 2.0 SB Balloon 6

3/25/2013 2.5 MB Baloon, 2.25 SB Stent 3.0 MB Xience Stent x 2 Final Result??? 7

3/25/2013 What Did We Learn in This Case From Utilizing IVUS MB Stent grossly undersized. SB Stent grossly undersized Residual disease in SB ostium mandates both MB and SB direct IVUS imaging 2.5 NC SB, 4.0 NC MB 8

3/25/2013 Three Studies Have Suggested that Patients with Bifurcation Lesions Treated with IVUS Guidance Do Better Long-term than Patients with Bifurcation Lesions Treated with Angiographic Guidance Kim et al. Am Heart J 2011;161:180-7 Bifurcation lesions, propensity score matching (n=487 in each group) Kim et al. Am J Cardiol 2010;106:612-8 Bifurcation lesions, propensity score matching (n=303 / n=111) Patel et al. Am J Cardiol, Bifurcation lesions, propensity score matching (n=247 / n=202) Incomplete Crush Apposition Optimal Imaging techniques MV MV Incomplete crushing incomplete apposition of the SB or MV stent struts against the MV wall proximal to the carina was found in >60% of non-lm lesions Costa et al. J Am Coll Cardiol. 2005;46:599-605 Serial IVUS (post-intervention and follow-up) analysis of the main and side-branches in 73 bifurcation lesions treated with T-stenting Stent expansion was significantly less in the SB than in the MV (87.1±20.4% vs. 97.0±29.1%, p=0.007). The SB ostium was the most frequent site of the post-procedural MSA. At the SB ostium, follow-up MLA correlated with post-procedural MSA (r=0.805, p <0.001). The percentage of neointimal area was higher at the SB ostium than at the MV proximal, MV distal, and SB distal stent (p<0.0001). Hahn et al. J Am Coll Cardiol 2009;54:110-7 9

3/25/2013 Percentage of Neointimal Hyperplasia in the Sidebranch and Main Vessel %IH Hahn et al. J Am Coll Cardiol 2009;54:110-7 An important Principle of IVUS Imaging Image Both Parent & Daughter Vessel Definitive IVUS study of bifurcation lesions EEM and lumen areas, remodeling, and plaque burden requires direct imaging of the both the main branch to the main vessel as well as the side branch to the main vessel. IVUS imaging of only the main branch of the main vessel is, at best, inferential and at worst misleading. Most of the available IVUS data is from LMCA and LAD/D1 bifurcations. Gary Mintz Personal Communication October 2012 LAD LAD 10

3/25/2013 Diagonal Tangential Imaging Direct Imaging Diagonal n=471 89% Medina Class 1,1,1 A wide variety of stenting techniques were used. Clinical outcomes: death, myocardial infarction (MI), periprocedural MI, stent thrombosis, target vessel revascularization (TVR), and target lesion revascularization (TLR) were compared between patients undergoing PCI with and without IVUS. Use of IVUS was associated with significantly lower rates death and/or MI, periprocedural MI and TLR-TVR compared to no IVUS use. In addition, 50% of the time IVUS led the interventionalist to modify his treatment strategy 11

3/25/2013 Current Medical Therapy DAPT Oral nitrates ARB Beta-Blockers Statin therapy Staging of LAD Use of IVUS and FFR 12

3/25/2013 FFR of the LAD 0.61 Double Wire IVUS Pre-Procedure 13

3/25/2013 IVUS Pre Intervention Proximal LAD Disease 14

3/25/2013 IVUS Confirms Length of Lesion in MB IVUS Post PCI of the LAD MB Intervention Complete What About SB Ostium? 15

3/25/2013 Utilizing FFR for Assessment of the S.B. Physiologic Assessment of Jailed Side Branch Lesions Using Fractional Flow Reserve 97 jailed side branch lesions (vessel size >2.0 mm, percent stenosis >50% by visual estimation) after stent implantation at main branches were consecutively enrolled. FFR was measured using a pressure wire at 5 mm distal and proximal to the ostial lesion of the jailed side branch. FFR measurement was successful in 94 lesions. Koo et al. JACC Vol. 46, No. 4, 2005 Utilizing FFR for Assessment of the S.B. Physiologic Assessment of Jailed Side Branch Lesions Using Fractional Flow Reserve 78% of the lesions were located in the diagonal branches Mean percent stenosis 79+11% Reference vessel diameter 2.23+0.45 mm Lesion length of jailed SB.. 7.0+3.3 mm Mean FFR in jailed SB. 0.85+0.11 (after intracoronary 80-g bolus adenosine administration and 0.84+0.12 with 240-g/min adenosine continuous Infusion) Koo et al. JACC Vol. 46, No. 4, 2005 Utilizing FFR for Assessment of the S.B. Physiologic Assessment of Jailed Side Branch Lesions Using Fractional Flow Reserve Among 73 lesions with >75% stenosis, only 20 lesions (27%) had functionally significant stenosis (by FFR). In relatively large side branches (>2.5 mm) with >75% stenosis (n 21), 8 lesions (38%) had FFR < 0.75. 16

3/25/2013 Using FFR to Guide S.B. Treatment The best available data shows that there is discordance between the functional significance and the conventional morphologic stenosis severity measured by QCA. FFR is a lesion-specific parameter that can measure the functional significance of a stenotic lesion AND may be useful in the decision to treat a jailed side branch lesion. SB FFR 0.78 Repeat FFR 0.94 Post SB PCI 17

3/25/2013 Closing Thoughts IVUS and FFR can (and should) be used to guide the treatment strategy in complex CAD. 18

3/25/2013 Making the most important Lesion Decision: FFR in Left Main Morton J. Kern, MD Professor of Medicine Chief of Cardiology Associate Chief Cardiology University California Irvine Orange, California 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 St. Jude Medical Inc. Volcano Therapeutics Merrit Medical Inc. Opsens Relationship Speakers Bureau Speakers Bureau Consultant Consultant 79 yo M ESRD pre op for renal tx. Asymptomatic LAO RAO 1

3/25/2013 LAO caudal RAO caudal FFR=0.94 IVUS FFR=0.94 2

3/25/2013 Assessment of LM by FFR- When? Equivocal or Intermediate LM Stenoses Caveat: LM + LAD/CFX involvement is special case, Courtesy of Bernard De Bruyne Technical Notes on FFR for LM assessment 1. Equilibrate wire and guide pressure in aorta, not LM 2. Advance wire across lesion(s) 3. Unseat guide from ostium 4. Use IV adenosine (140mcg/kg/min) FFR CFX with Pull back to ostium CFX wire position ostial wire position 3

% Survival 3/25/2013 FFR in Ramus Wire in Ramus FFR in LAD Wire in LAD FFR Criteria for INTERMEDIATE LEFT MAIN CORONARY DISEASE Medical Therapy Surgical Therapy Study FFR Threshold N N (%) MACE Death n(%) MACE Death Follow-up Time (mo) Hamilos (2009) 0.8 213 136(65%) 26% 9(6.5%) 73 (35%) 17% 7 (9.6%) 35 ± 25 Courtis (2009) 0.75 surg 0.8 med 142 82(58%) 13% 3 (3.6%) 60 (42%) 7% 3 (5%) 14 ± 11 Lindstraedt (2006) 0.75 surg 0.8 med 51 24 (47%) 31% 0 27 (53%) 34% 5(19%) 29 ± 16 Suemaru (2005) 0.75 15 8 (53%) 0 0 7 (47%) 29% 0 33 ± 10 Legutko (2005) 0.75 38 20 (53%) 10% 0 18 (46%) 11% 2 24 (mean) Jimenez-Navaro 0.75 27 20 (74%) 10% 0 7 (26%) 29% 2 2 ± 12 Bech (2001) 0.75 54 24 (44%) 24% 0 30 (56%) 17% 1 29 ± 15 Source: Lokhandwala, Juzar MD ; Hodgson, John MD, Cardiac Interventions Today/ October 2009 Clinical Outcome Data after FFR-Guided Revascularization in Patients with LM Equivocal LM Stenosis SURVIVAL RATE All LM Stenoses 100 Pure LM Stenoses 80 60 40 p=0.19 FFR 0.80 FFR<0.80 FFR 0.80 No CABG FFR <0.80 CABG FFR 0.80 No CABG 20 FFR <0.80 CABG 0 0 12 24 36 48 60 Months No at risk FFR 0.80 52 41 32 25 19 13 FFR<0.80 19 17 15 12 10 7 4

3/25/2013 Correlation Between MLA and FFR Kang, S.-J. et al. J Am Coll Cardiol Intv 2011;4:1168-1174 A, Correlation between IVUS MLD and FFR (r=0.79, P Jasti, V. et al. Circulation 2004;110:2831-2836 Assessment of the LM 63 yo M w recent CP, 2y of fatigue. Cath 2005 100% RCA, 50% LAD, 50% CFX with collaterals to RCA. Normal LV function. LM now significant? 5

3/25/2013 Normalized inside guide FFR across LAD ostium FFR across CFX, transient HB 1. FFR OK 2. FFR OK, check both LAD and CFX 3. FFR LM? FALSE Positive (<0.80). Distal Lesion reduces bed. Apply if LAD+LM FFR <0.60 4. FFR LM? FALSE Negative (>0.80). Distal lesions blocks max hyperemia. Go to #3 6

3/25/2013 Take Home Points Left Main Angiography not a good standard for determining significance FFR assessment is a direct assessment of physiologic significance Make sure guide catheter pressure waveform no damped (may need to disengage) Use IV adenosine for hyperemia FFR for LM Decisions Improves Outcomes and Appropriateness FFR is in-lab marker of specific ischemic lesion. FFR Reduces Uncertainty If you re not using FFR Retool or Retire 7

3/25/2013 Is FFR, IVUS, or OCT the Right Tool in Acute Coronary Syndromes? Intravascular Imaging in ACS Monday, March 25 th,, 2013 Habib Samady MD FACC Professor of Medicine Director, Interventional Cardiology and Cardiac Cath Lab Emory University Hospital, Atlanta, Georgia FFR, IVUS, or OCT in Acute Coronary Syndromes Non-Culprit Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days FFR, IVUS, or OCT in Acute Coronary Syndromes Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days 1

3/25/2013 Is FFR, IVUS, or OCT the Right Adjunct To Angiography to Assess Culprit Lesion in Acute Phase of ACS? Any doubt about culprit lesion location? Any doubt about culprit lesion severity? Any relevant questions about culprit lesion morphology? Does everyone receive thrombectomy? In STEMI? How about NSTEMI? Does anyone receive a distal protection device? How well have we reperfused the myocardium? What is the microvascular status? What is the likelihood of functional recovery versus remodeling? Case 1: Inferior STEMI 73 yr old male Dyslipidemia HTN 2 hrs of severe central chest pain HR 100 BP 140/83 + S4, no CHF Culprit Lesion Location, Severity, Morphology in ACS? Stent or no stent? Stent where? 2

3/25/2013 Ongoing Chest Pain What is the Culprit Lesion? Stent or no stent? Stent where? MLA 5.5 mm 2 MLA 4.3 mm 2 MLA 2.6 mm 2 OCT Plaque Rupture IVUS Thrombus 3

3/25/2013 OCT for Assessing Underlying Lesion Morphology in ACS cap cavity thrombus Plaque Rupture Plaque Erosion Courtesy of Dr. Giulio Guagliumi Courtesy Dr. Ryan Madder 4

3/25/2013 Is FFR, IVUS, or OCT the Right Adjunct To Angiography to Assess Culprit Lesion in Acute Phase of ACS? Any doubt about culprit lesion location? OCT Any doubt about culprit lesion severity? OCT/IVUS Questions about culprit lesion morphology? OCT/NIRS Does everyone receive thrombectomy? In STEMI? Mostly How about NSTEMI? Occasionally? OCT Does anyone receive a distal protection device? Currently rarely.? NIRS/OCT/VH How well is myocardium reperfused? What is status of microvascular? What is likelihood of functional recovery versus remodeling? ST resolution, angiographic blush scores, IMR, HMR, MCE, CMR. FFR, IVUS, or OCT in Acute Coronary Syndromes Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days Case: FFR for Assessment Of Culprit Lesions in STEMI subacute reperfused phase 67-year-old was transferred in from an outside facility for anterior STEMI after thrombolytics 5

3/25/2013 Right Coronary Artery Left Coronary Artery FFR in Culprit Lesions: Subacute Setting Flow = Pressure Gradient / Resistance Normal microvasculature Recently Infarcted microvasculature Cell death Edema Reperfusion injury Microembolism Vasospasm Is flow proportional to pressure in recently infarcted microvasculature? 6

3/25/2013 Validation of FFR in Recent MI N=48 after stabilized STEMI and NSTEMI, underwent SPECT, MCE, FFR, PCI, f/uspect 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 Specificity Sensitivity 0.20 0.78 0.10 0.00 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Figure 6 Samady et al. JACC 2006 FAME Trial: Substudy: ACS versus Stable Angina ACS, FFR, N= 150 ACS, Angio, N=178 Data suggest that like the overall population, a 30% reduction in MACE when FFR is used to guide revascularization in ACS Sels et a. JACC Intv. 2011;4:1183-9 7

3/25/2013 Position of MLA in relation to Plaque Rupture not necessarily coincident: prox or distal Plaque Rupture MLA site Proximal Reference Courtesy of Dr. Giulio Guagliumi Is FFR, IVUS, or OCT the Right Adjunct To Angiography to Assess Culprit Lesion in Subacute Phase of ACS? Any doubt about culprit lesion severity? FFR (if there is TIMI 3 flow) particularly for stabilized NSTEMI Questions about culprit lesion location or morphology? OCT 8

3/25/2013 FFR, IVUS, or OCT in Acute Coronary Syndromes Non-Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days FFR in Non-Culprit Bed Acute Setting N=101 patients undergoing PCI for AMI (75 STEMI and 26 N-STEMI) N= 112 lesions FFR of non-culprit lesions was measured at time of culprit vessel PCI and repeated 35+4 days later In a subgroup of 14 patients, IMR was also measured at time of culprit vessel PCI and repeated 35+4 days later Ntalianis et al. JACC Int. Volume 3, Issue 12, December 2010, Pages 1274-1281 FFR in Non-Culprit Bed Acute Setting Acute Phase (n = 101) Follow-Up (n = 101) p Value LVEF (%) 59 ± 15 61 ± 14 NS LVEDP (mm Hg) 18 ± 7 17 ± 7 NS FFR nonculprit 0.77 ± 0.13 0.77 ± 0.13 NS IMR nonculprit (IU) 20 ± 3 24 ± 6 NS DS nonculprit (%) 56 ± 14 55 ± 14 NS MLD nonculprit (mm) 1.32 ± 0.46 1.31 ± 0.50 NS RD nonculprit (mm) 2.9 ± 0.70 2.7 ± 0.70 NS TIMI flow nonculprit 2.93 ± 0.30 2.97 ± 0.20 NS ctfc nonculprit 15 ± 6 15 ± 6 NS Values are mean ± SD. ctfc = corrected TIMI frame count; DS = diameter of stenosis; FFR = fractional flow reserve; IMR = index of microcirculatory resistance; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction; MLD = minimum lumen diameter; RD = reference diameter. Ntalianis et al. JACC Int. Volume 3, Issue 12, December 2010, Pages 1274-1281 9

3/25/2013 FFR, IVUS, or OCT in Acute Coronary Syndromes Non-Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days FAME Trial: Substudy: ACS versus Stable Angina ACS, FFR, N= 150 ACS, Angio, N=178 Data suggest that like the overall population, a 30% reduction in MACE when FFR is used to guide revascularization in ACS Sels et a. JACC Intv. 2011;4:1183-9 FFR, IVUS, or OCT in Acute Coronary Syndromes No use for FFR Culprit OCT, IVUS, NIRS, VH can help identify culprit lesion location, severity, morphology to guide PCI IMR, HMR, CME, CMR can predict functional recovery and remodeling to potentially guide adjunctive pharmacologic or cell therapy Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days 10

3/25/2013 FFR, IVUS, or OCT in Acute Coronary Syndromes FFR < 0.78 shown to be predictive of ischemia on SPECT and MCE in stabilized reperfused STEMI and NSTEMI Culprit FAME data in stabilized USA/NSTEMI Suggest effective role for FFR in this setting as adjunct to angiography Can use OCT, IVUS NIRS, VH to identify culprit lesion location, severity, morphology to guide PCI Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days FFR, IVUS, or OCT in Acute Coronary Syndromes FFR < 0.80 shown to accurately reflect lesion severity IMR also shown to be relatively preserved lending support for FFR s accuracy in this setting Because PCI not recommended for non culprit lesions would avoid other intravascular imaging except to help identify culprit lesion when in doubt Non-Culprit Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days FFR, IVUS, or OCT in Acute Coronary Syndromes FFR < 0.80 may be superior to angiography for guiding revascularization of non culprit lesions in stabilized USA/NSTEMI Non-Culprit OCT and IVUS are not ideal for assessment of non culprit lesion severity but may be helpful for optimal stent deployment Acute < 1 day Sub-acute 1-3 days Timeline Chronic > 7days 11

3/25/2013 Is FFR, IVUS, or OCT the Right Tool in Acute Coronary Syndromes? Intravascular Imaging in ACS Monday, March 25 th,, 2013 Habib Samady MD FACC Professor of Medicine Director, Interventional Cardiology and Cardiac Cath Lab Emory University Hospital, Atlanta, Georgia 12

Using Fractional Flow Reserve to Aid in Decision Making in Tandem Lesions The FFR Pullback William M. Suh, MD Assistant Clinical Professor Ronald Reagan UCLA Medical Center David Geffen School of Medicine at UCLA Financial Disclosures: None Case 63 yo man presents with acute onset dyspnea which awoke him from sleep. Associated with racing heart beat. No angina, orthopnea, PND, edema. PMHx: Dx d with Hyperlipidemia in his 20s, but has not taken anti-hyperlipidemic therapy due to multiple reported intolerances (atorvastatin - palpitations, simvastatin - transaminitis, niacin - transaminitis). 1

ECG Labs 8.2 11.7 34.5 251 138 3.7 105 21 15 0.96 109 Biomarkers: CK-MB Negative Troponin <0.01 NT-BNP 2026 Lipids: TC 375 HDL 37 LDL 312 TG 129 Echo Echocardiogram: EF 20% with diffuse hypokinesis Trace AI, mild MR, moderate TR RVSP 40 mmhg RV dilated, RV hypokinesis 2

3

??? Stent the mid RCA, ostial RCA, or both? 4

FFR of Two Lesions in Series How to Predict FFR of Individual Lesion [FFR predicted = (P d -[(P m /P a )*P w ])/((P a -P m )+(P d -P w )) This calculation requires pressure distal (Pd), pressure proximal (Pa), pressure between lesions (Pm), and coronary occlusion wedge pressure (Pw). Shown in animal models, but impractical for clinical use. How to Perform FFR Pullback Step 1 Position pressure wire with the sensor past the most distal lesion Perform standard FFR with IV adenosine at 140 mcg/kg/min If FFR > 0.80, no treatment is necessary If FFR < 0.80, move to step 2 5

How to Perform FFR Pullback Step 2 With IV adenosine still being infused, pullback the pressure wire until the sensor is proximal to the distal lesion. Note the change in pressure (DP). Continue pullback for each lesion again noting the DP Treat the lesion with the largest DP How to Perform FFR Pullback Step 3 After stenting the most severely narrowed lesion, repeat FFR of the remaining lesions. Repeat step 1 and step 2. Pressure sensor 6

IV adenosine 140 mcg/kg/min Sensor pullback between lesions, FFR 0.94 Pullback into guide, FFR 1.0 Maximal hyperemia What does this mean? The FFR of both lesions in sum is physiologically significant with FFR 0.64 The largest DP was across the mid RCA lesion indicating that this lesion is the more stenotic of the two The value of 0.94 between the ostial lesion and the mid lesion does not necessarily mean that the ostial lesion is not significant Pijls and DeBruyne demonstrated in an animal model the effect of increasing the severity of the distal lesion on the serial FFR measurements of a proximal lesion in series. As the distal lesion becomes more severe with a larger gradient, the hyperemic flow across the first lesion becomes less and the FFR of the proximal lesion goes up (i.e., becomes less severe). FFR of the ostial lesion needs to be repeated after mid RCA stenting Repeat FFR after mid RCA stent 0.90 7

Conclusions In tandem lesions, FFR pullback has the spatial resolution to be able to determine specifically where DP is the largest FFR pullback is a useful tool in assisting decision making in complex coronary lesions and can simplify revascularization strategies. In minimizing unnecessary PCI, immediate and late complications of stenting can be avoided. 8