Methods for Hyperemic Assessment of FFR Jeff Chambers

Methods for Hyperemic Assessment of FFR Jeff Chambers, MD FSACI, FACC Director Cardiac Cath Lab Metropolitan Heart and Vascular Institute Mercy Hospital , Minneapolis, MN

Jeff Chambers, MD Disclosures Consulting CSI Boston Scientific ACIST Medical

Method To Assess Myocardial Ischemia in the Cath Lab • Angiography • Resting Indices – i. FR – Pd/Pa • Contrast FFR • Hyperemic FFR – Adenosine • Intravenous - IV • Intracoronary -IC

Why Does the Angiogram Fail to Predict Physiology? Pancake and Starfish Lesions From: Current Concepts of Integrated Coronary Physiology in the Catheterization Laboratory Why Does the Angiogram Fail to Predict Physiology? The angiogram is a 2 -dimensional image of 3 -dimensional structures. Most intermediate lesions are oval shaped with 2 diameters, 1 narrow and 1 wide dimension. The angiogram of an eccentric lesion cannot reliably indicate flow adequacy. Other lesions (lower right) may appear hazy but widely patent, only to be responsible for angina due to plaque rupture, as demonstrated by intravascular ultrasound cross-section (far right corner). Figure illustration by Rob Flewell. Morton J. Kern, MD? ; J Am Coll Cardiol. 2010; 55(3): 173 -185. doi: 10. 1016/j. jacc. 2009. 062 Date of download: 4/30/2016

FAME study: Event-free Survival FFR guide therapy is superior to angio -guided absolute difference in MACE-free survival FFR-guided 30 days 2. 9% 90 days 3. 8% 180 days 4. 9% Angio-guided 360 days 5. 3% p=0. 02 N Engl J Med. 2009 Jan 15; 360(3): 213 -24. doi: 10. 1056/NEJMoa 0807611.

Angiography-guided percutaneous coronary intervention (PCI) versus fractional flow reserve-guided PCI major adverse cardiac events/major adverse cardiac and cerebrovascular events. Dongfeng Zhang et al. Heart doi: 10. 1136/heartjnl-2014 -306578

How to best access FFR RESTING INDICES

i. FR Instantaneous pressure ratio (i. FR) is measured across a stenosis during the wavefree period when resistance is naturally constant and minimized in the cardiac cycle

Resting Indices - RESOLVE study No adeno , PCI FFR No adeno , No PCI i. FR 0. 86 - 0. 93 Jeremias et al; JACC 2013

Multicenter Core Laboratory Comparison of the Instantaneous Wave-Free Ratio and Resting Pd/Pa With Fractional Flow Reserve: The RESOLVE Study Association Between Use of Adenosine and Diagnostic Accuracy of i. FR and Pd/Pa An inverse relationship between use of adenosine and diagnostic accuracy is shown, such that with increasing accuracy the adenosine-free zone decreases in width for both i. FR and Pd/Pa. The blue line displays this association for i. FR and the red line for Pd/Pa. J Am Coll Cardiol. 2014; 63(13): 1253 -1261. doi: 10. 1016/j. jacc. 2013. 09. 060

Accuracy = (True Positive +True Negative) (True Positive+ False Positive + True Negative + False Negative)

Resolve Study - Accuracy i. FR Study/ Participating Site Pd/Pa No. of Lesions Cutoff Point AUC From ROC(C statistic) Overall Accuracy (%) Correlation (R 2) 1, 593 0. 90 0. 81 80. 4 0. 66 0. 92 0. 82 81. 5 0. 69 ADVISE∗ 432 0. 91 0. 82 81. 9 0. 71 0. 92 0. 82 81. 9 0. 75 VERIFY† 654 0. 89 0. 80 79. 4 0. 60 0. 92 0. 81 79. 8 0. 65 Seoul National University 179 0. 92 0. 83 82. 7 0. 68 0. 93 0. 82 82. 1 0. 70 Stony Brook University 149 0. 93 0. 81 79. 2 0. 54 0. 93 0. 83 83. 2 0. 61 Columbia University 95 0. 91 0. 84 82. 1 0. 62 0. 92 0. 87 89. 5 0. 70 AMC/VUMC/KCL 84 0. 90 0. 78 78. 6 0. 72 0. 93 0. 72 72. 6 0. 70 Total J Am Coll Cardiol. 2014; 63(13): 1253 -1261. ∗Includes data from the ADVISE study and ADVISE registry. †Includes data from the prospective and retrospective VERIFY cohorts. AMC = Academic Medical Center, University of Amsterdam KCL = King's College London ; VUMC = VU University Medical Center, Amsterdam.

Contrast FFR

CONTRAST Study: • Comparison of FFR with IV or IC adenosine to: c. FFR, Resting Pd/Pa and i. FR • Multicenter, international trial including ≈750 patients (1 lesion/patient) • Blinded, independent core lab Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016, 9(8): 757 -767

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment Example of Protocol Complete example from the study that demonstrates essentially no gradient at rest (high Pd/Pa and i. FR) with a clearly positive result by c. FFR then confirmed by both intracoronary and intravenous adenosine FFR. No significant drift was observed, and each metric was measured twice (#1 and #2). Aortic pressure (Pa) in red, distal coronary (Pd) in blue, and their ratio Pd/Pa in black. c. FFR = contrast-based fractional flow reserve; IC = intracoronary; i. FFR = instantaneous wave-free ratio; Pd/Pa = resting ratio of distal coronary pressure to aortic pressure J Am Coll Cardiol Intv. 2016; 9(8): 757 -767. doi: 10. 1016/j. jcin. 2015. 12. 273

Resting Indices Diagnostic Accuracy: True positives (%) 100% 80% 60% Pd/Pa = 80% accuracy i. FR = 79% accuracy same accuracy (p=0. 89) i. FR = 0. 879* Pd/Pa = 0. 874 40% 20% * = same AUC (p=0. 28) 0% 0% 20% 40% 60% 80% 100% False positives (%) Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016, 9(8): 757 -767

Diagnostic Accuracy: c. FFR = 86% accuracy Pd/Pa = 80% accuracy i. FR = 79% accuracy superior accuracy (p<0. 001) Optimal binary cutoff for c. FFR ≤ 0. 83 Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016, 9(8): 757 -767

n c. FFR is: q q q Easy, inexpensive, and safe Reproducible Available immediately does not depend on specific software platform or ECG Optimal binary cutoff for c. FFR ≤ 0. 83 Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016, 9(8): 757 -767

Hyperemic FFR What Vasodilator to use?

Dose Response Curves Adenosine Bolus Dose Response curve Adenosine Infusion Dose Response curve Wilson R et al. Circulation 1990; 82: 1595 -1606

Comparative Hyperemia J Am Coll Cardiol Intv. 2015; 8(11): 1422 -1430.

When to measure FFR Take the lowest value Automated software records the lowest Pd/Pa as the FFR. Take the Pd/Pa ratio at the lowest Pd Vranckx, Cutlip, Mc. Fadden, Kern, Mehran, Muller. Circ CV Interv 2012. 5: 312 -317 Wait for stable hyperemia Pijls, van Son, Kirkeeide, De. Bruyne, Gould. Circulation 1993. 86: 1354 -1367

FFR Patterns with IV Adenosine Fearon, W. Circ. Cardiovascular. Interv. 2015; j 8: doi: 10. 1161

Comparison of IC Versus IV Adenosine for FFR 80 μg adenosine (left coronary artery) or 40 μg adenosine (right coronary artery) 140 μg/kg per minute Christian Schlundt et al. Circ Cardiovasc Interv. 2015; 8: e 001781

Intracoronary Adenosine: Dose–Response Relationship With Hyperemia J Am Coll Cardiol Intv. 2015; 8(11): 1422 -1430.

Intracoronary Adenosine: Dose–Response Relationship With Hyperemia This dose-response study with flow measurements indicates that IC bolus injections of adenosine of 100 μg in the RCA and 200 μg in the LCA induce maximum hyperemia without affecting systemic hemodynamics and with minimal side effects. J Am Coll Cardiol Intv. 2015; 8(11): 1422 -1430.

Medications and Doses to Produce Maximal Hyperemia Fearon, W. Circ. Cardiovascular. Interv. 2015; j 8: doi: 10. 1161

Major Reasons for inaccurate FFR • Maximal hyperemia not achieved – Epicardial Artery spasm – 200 IC nitro – IV adenosine • Adenosine T ½ < 10 sec • Small distal IV – Adenosine metabolized before it reaches the coronaries – IC adenosine • Side hole guide • • Guide cath damping Drift Serial lesions AMI territory

Diagnosing Ischemia in the Cath Lab Contrast FFR 86% Inc r eas ing Acc ura cy (% ) FFR 95% Resting Measures (i. FR, Pd/Pa) 80% Coronary Angiography 70% Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016, 9(8): 757 -767

Conclusions • FFR guided therapy improves outcomes and should be used more often. • Resting indices are less accurate than Contrast FFR. • Contrast FFR may eliminate the need for adenosine is some cases. • IV and IC adenosine are both effective in inducing maximal hyperemia. • Attention to detail is required to avoid technical induced inaccuracies when performing FFR.