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

2. Jeff Chambers, MD Disclosures Consulting CSI Boston Scientific
ACIST Medical 

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

4. 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): doi: /j.jacc
Date of download: 4/30/2016

5. 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 Jan 15;360(3): doi: /NEJMoa

6. 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: /heartjnl

7. How to best access FFR
RESTING INDICES

8. 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

9. 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
Jeremias et al; JACC 2013

10. 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): doi: /j.jacc

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

12. 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):

13. Contrast FFR

14. 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):  

15. 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): doi: /j.jcin

16. 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):  

17. 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):  

18. 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):  

19. What Vasodilator to use?
Hyperemic FFR
What Vasodilator to use?

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

21. Comparative Hyperemia
J Am Coll Cardiol Intv. 2015;8(11):

22. 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 :
Wait for stable hyperemia
Pijls, van Son, Kirkeeide, DeBruyne, Gould.
Circulation :

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

24. 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

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

26. 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):

27. Medications and Doses to Produce Maximal Hyperemia
Fearon, W. CircCardiovascularInterv. 2015;j8:doi:

28. 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

29. 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):  

30. 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.