Fractional Flow Reserve: How to use FFR in 2015 William F. Fearon, MD Associate Professor of Medicine Director, Interventional Cardiology Stanford University Medical Center

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest /arrangement or affiliation with the organization(s) listed below Affiliation/Financial Relationship Company Grant/ Research Support: St. Jude Medical/Medtronic Grant/ Research Support: NIH-R01 HL093475 (PI) Consulting Fees/Honoraria: Medtronic Major Stock Shareholder/Equity Interest: Royalty Income: Ownership/Founder: Salary: NIH-R01 HL093475 (PI) Intellectual Property Rights: Other Financial Benefit (minor stock options): HeartFlow

How to use FFR in 2015: When to measure FFR How to measure FFR

When to measure FFR: All angiograms? Multivessel CAD ACS Left main disease Stable angina patients When not to FFR

When to measure FFR: 200 stable patients referred for coronary angiography underwent routine FFR in all patent vessels. Treatment plan pre and post FFR compared. Curzen, et al. Circ Cardiovasc Interv 2014;7:248-55.

FFR for All Angiograms? Curzen, et al. CircCardiovasc Interv 2014;7:248-55. 200 stable patients referred for coronary angiography underwent routine FFR in all patent vessels. Treatment plan pre and post FFR compared. Overall the management plan was changed in 26% of cases.

FFR for All Angiograms? 1,075 consecutive patients undergoing FFR at 20 French centers Van Belle, et al. Circulation 2014;129:173-185.

FAME Study: One Year Outcomes 1,005 patients with multivessel CAD randomized to FFR or Angio-guided PCI p=0.02 p=0.04 % ~40%  ~35%  ~30%  Tonino, et al. New Engl J Med 2009;360:213-24.

FAME: Economic Evaluation Bootstrap Analysis FFR-guided PCI saved >$2,000 per patient at one year compared to Angio-guided PCI Circulation 2010;122:2545-50.

Anatomic vs. Functional CAD Angiographic 3 Vessel Disease 0VD (9%) 3VD (14%) 1VD (34%) 2VD (43%) Tonino, et al. J Am Coll Cardiol 2010;55:2816-21

Functional SYNTAX Score Discriminates Risk for Death/MI P < 0.01 32% of patients 20% of 34% of patients 59% of Nam CW, et al. J Am Coll Cardiol 2011;58:1211-8

FAME 3 Trial: All Comers with 3 V CAD (not involving LM) Heart team identifies lesions for PCI/CABG and then patient is randomized FFR-Guided PCI with DES Stent all lesions with FFR ≤ 0.80 (n=750) Perform CABG based on coronary angiogram (n=750) One Year follow-up for MACCE Three Year follow-up for death/MI/CVA ClinicalTrials.gov Identifier: NCT02100722

FFR in Acute Coronary Syndromes Comparison of MACE in FAME patients with and without ACS Tonino, et al. J Am Coll Cardiol Intv 2011;4:1182-9.

FFR in STEMI (Non-Culprit Vessels) Ntalianis, et al. J Am Coll Cardiol Intv 2010;3:1274. 101 patients with an acute coronary syndrome (75 STEMI, 26 NSTEMI) 112 non culprit stenoses FFR measured acutely and 3524 days later In only 2/112 stenoses was the FFR >0.80 during the ACS and <0.75 at follow-up.

FFR for Assessing Left Main Disease FFR in 209 patients with intermediate LM disease followed for 5 years Medical Therapy Revascularization Hamilos, et al. Circulation 2009;120:1505

Left Main Stem Stenoses are Rarely Isolated The influence of a distal stenosis on the FFR of the LM depends on the extent to which hyperemic flow across the LM stenosis will be decreased by this distal lesion Severity Myocardial mass Courtesy Bernard De Bruyne, MD, PhD

Left Main Stem Stenoses are Rarely Isolated The influence of a distal stenosis on the FFR of the LM depends on the extent to which hyperemic flow across the LM stenosis will be decreased by this distal lesion Severity Myocardial mass Courtesy Bernard De Bruyne, MD, PhD

Left Main Stem Stenoses are Rarely Isolated The influence of a distal stenosis on the FFR of the LM depends on the extent to which hyperemic flow across the LM stenosis will be decreased by this distal lesion Severity Myocardial mass Courtesy Bernard De Bruyne, MD, PhD

Effect of Downstream Stenosis on LM FFR: Human Validation Un-inflated balloon used to simulate LM stenosis Balloons inflated within stent to simulate downstream stenosis This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 2 pressure wires with sensors in the distal LAD and LCX Yong, et al. JACC Intervent 2015; in press. 19 19

Effect of Downstream Stenosis on LM FFR: Human Validation 91 paired measurements obtained in 25 patients This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Yong, et al. JACC Intervent 2015; in press. 20 20

Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI FAME 2 Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI N = 1220 FFR in all target lesions Randomized Trial 73% Registry 50% randomly assigned to FU 27% At least 1 stenosis with FFR ≤ 0.80 (n=888) Randomization 1:1 PCI + MT MT When all FFR > 0.80 (n=332) MT This slide shows the study design. Patients scheduled for 1, 2 or 3 vessels DES PCI were included. The first step was measure FFR in all lesio,ns considered for stenting. If at least one of these stenoses appeared to be hemodynmically significant stenosis as defined by an FFR lower than 0.80, only then the patient were randomized to receive PCI + medical therapy or med therapy alone. In contrast patients in whom all stenoses appeared to be hemodynamically non significant were NOT randomized, were treated with the best available medical therapy and followed up in a registry. Thus importnat to realize that in the FALME 2 study there is a randomized trial with patients with ischemia and a registry with patients without ischemia. Primary Endpoint: Death, MI or Urgent Revascularization at 2 Yr

FAME 2: Two Year Follow-Up 51% of urgent revascularizations were triggered by myocardial infarction or ischemic ECG changes (3.4 vs 7.0%, p=0.01, PCI vs OMT) >80% of urgent revascularizations were triggered by myocardial infarction, ischemic ECG changes, or Class IV angina De Bruyne, et al. NEJM 2014;371:1208-17.

FAME 2: Two Year Follow-Up Landmark Analysis of Death/MI after 7 days 4.6 vs. 8.0%, p=0.04 5 10 15 20 Cumulative incidence (%) 2 4 6 8 12 14 16 18 22 24 Months after randomisation .5 1 1.5 2.5 3 7 Days after randomisation 0-7days: HR 9.01 (95%CI 1.13-72.0) 8 days-2years: HR 0.56 (95%CI 0.32-0.97) P for interaction 0.002 PCI+MT vs MT PCI+MT MT alone De Bruyne, et al. NEJM 2014;371:1208-17.

Spontaneous vs. Procedural MI 5 year F/U in 5,467 patients from RITA-3, ICTUS, and FRISC-II Cumulative CV Death (%) Spontaneous MI 22.2% Procedural MI 5.2% 5 Years Damman, et al. Circulation 2012;125:568-576.

FAME 2: Cost-Effectiveness The Incremental Cost-Effectiveness Ratio was $36,000 per QALY 80% of the 10,000 replications were below the $50,000/QALY willingness-to-pay threshold and 99.5% were below the $100,000/QALY threshold The difference in the primary endpoint in FAME 2 was driven by an increased rate of hospitalization requiring urgent revascularization and not due to a difference in death and MI. Because this may be considered a softer endpoint, it is critical to evaluate the cost-effectiveness of this approach. We found that patients treated with PCI not surprisingly, had higher up front costs, but there were significant improvements in quality of life as well as a narrowing of the cost difference over time as the medical therapy arm incurred higher event rates. This resulted in an attractive cost-effectiveness ratio of $36,000/QALY and with most of the bootstrap simulations falling under the $50,000/QALY threshold. Circulation 2013;128:1335-40.

When Shouldn’t We FFR? Patient with typical angina and ischemia on non-invasive testing in a region supplied by a vessel with an angiographically significant lesion Culprit vessel of a STEMI in the acute phase If the FFR result is not going to change your treatment plan

How to perform FFR? Should we measure resting Pd/Pa and/or iFR? How about “contrast” FFR (cFFR)? New FFR devices How do we deal with the “grey zone”?

Resting Pd/Pa and iFR versus FFR Resting Pd/Pa , iFR and FFR were measured in 1,678 patients Diagnostic Accuracy of Resting Pd/Pa = 81.5% Jeremias, et al. J Am Coll Cardiol 2014;63:1253-61.

Resting Pd/Pa and iFR versus FFR Resting Pd/Pa , iFR and FFR were measured in 1,678 patients Diagnostic Accuracy of iFR = 80.4% Jeremias, et al. J Am Coll Cardiol 2014;63:1253-61.

How about “contrast” FFR (cFFR)? Resting Pd/Pa = 0.98 and iFR > 0.90 across a moderate circumflex lesion

How about “contrast” FFR (cFFR)? cFFR = 0.79 (6 ml Isovue) across a moderate circumflex lesion

How about “contrast” FFR (cFFR)? FFR = 0.77 (240 mcg IC Adenosine) across a moderate circumflex lesion

CONTRAST Study: Comparison of FFR with IV or IC adenosine to: cFFR, Resting Pd/Pa and iFR Multicenter, international trial including ≈750 patients (1 lesion/patient) Blinded, independent core lab Results expected this Spring ClinicalTrials.gov Identifier: NCT02184117

New FFR Devices: Design Goals Integrated POLARIS display Wireless from bed-to-POLARIS Targeting improved wire performance Workhorse-like feel ‟Invisible” connection Accurate (no drift) Reliable (re)connection POLARIS Display Wireless Bedside Disposable Cable FFR Wire Courtesy: Boston Scientific

New FFR Devices: Optowire Optomonitor Opsensmedical.com

New FFR Devices: Acist.com

“Grey Zone”

FFR Meta-Analysis “Ischemia is not a dichotomous state, but a graded continuum” Johnson, et al. J Am Coll Cardiol 2014;64:1641-54

Conclusions: Fractional flow reserve is an indispensable tool for guiding decisions regarding coronary revascularization which leads to better resource utilization and most importantly improved patient outcomes.