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 iFR 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 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.2009.06.062 Date of download: 4/30/2016

absolute difference in MACE-free survival FAME study: Event-free Survival FFR guide therapy is superior to angio -guided FFR-guided absolute difference in MACE-free survival 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/NEJMoa0807611.

Angiography-guided percutaneous coronary intervention (PCI) versus fractional flow reserve-guided PCI major adverse cardiac events/major adverse cardiac and cerebrovascular events. 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

iFR Instantaneous pressure ratio (iFR) is measured across a stenosis during the wave-free period when resistance is naturally constant and minimized in the cardiac cycle

Resting Indices - RESOLVE study VUmc Basispresentatie Resting Indices - RESOLVE study Several studies investigated the iFR to see if it was comparable to FFR for the assessment of hemodynamic significance of a coronary artery stenosis. I would like to highlight the RESOLVE and CLARIFY study. The RESOLVE study was a collaborative study between several centers worldwide and pooled pressure traces to investigate the correlation between FFR and iFR. They found a strong correlation between FFR and iFR with a AUC of 0.81. When interpreting these results it can be argued that the advantage of avoiding adenosine administration does not weigh up to the decrease in diagnostic accuracy. However, in this study FFR was appointed as reference standard and while it has a large body of evidence and thus often considered the golden standard for lesion assesment, a different index is a priori unable perfectly match this reference standard. No adeno ,PCI FFR No adeno , No PCI iFR 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 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 iFR and Pd/Pa. The blue line displays this association for iFR 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 Accuracy = (True Positive +True Negative) (True Positive+ False Positive + True Negative + False Negative)

Resolve Study - Accuracy Participating Site No. of Lesions iFR Pd/Pa Cutoff Point AUC From ROC(C statistic) Overall Accuracy (%) Correlation (R2) Total 1,593 0.90 0.81 80.4 0.66 0.92 0.82 81.5 0.69 ADVISE∗ 432 0.91 81.9 0.71 0.75 VERIFY† 654 0.89 0.80 79.4 0.60 79.8 0.65 Seoul National University 179 0.83 82.7 0.68 0.93 82.1 0.70 Stony Brook University 149 79.2 0.54 83.2 0.61 Columbia University 95 0.84 0.62 0.87 89.5 AMC/VUMC/KCL 84 0.78 78.6 0.72 72.6 ∗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. J Am Coll Cardiol. 2014;63(13):1253-1261.

Contrast FFR

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 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 Complete example from the study that demonstrates essentially no gradient at rest (high Pd/Pa and iFR) with a clearly positive result by cFFR 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. cFFR = contrast-based fractional flow reserve; IC = intracoronary; iFFR = 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: 100% Pd/Pa = 80% accuracy iFR = 79% accuracy  same accuracy (p=0.89) True positives (%) 80% iFR = 0.879* Pd/Pa = 0.874 60% 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: Optimal binary cutoff for cFFR ≤ 0.83 cFFR = 86% accuracy Pd/Pa = 80% accuracy iFR = 79% accuracy  superior accuracy (p<0.001) Optimal binary cutoff for cFFR ≤ 0.83 Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016,9(8):757-767 

Optimal binary cutoff for cFFR ≤ 0.83 cFFR is: Easy, inexpensive, and safe Reproducible Available immediately does not depend on specific software platform or ECG Optimal binary cutoff for cFFR ≤ 0.83 Nils P. Johnson. J Am Coll Cardiol Intv. April 25, 2016,9(8):757-767 

What Vasodilator to use? 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, McFadden, Kern, Mehran, Muller. Circ CV Interv 2012. 5:312-317 Wait for stable hyperemia Pijls, van Son, Kirkeeide, DeBruyne, Gould. Circulation 1993. 86:1354-1367

FFR Patterns with IV Adenosine Fearon, W. CircCardiovascularInterv. 2015;j8: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:e001781

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. CircCardiovascularInterv. 2015;j8: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 FFR 95% Contrast FFR 86% Resting Measures (iFR, Pd/Pa) 80% Coronary Angiography 70% Increasing Accuracy (%) 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.