Since the release of the FAME1 study [Fractional flow reserve vs. Angiography in Multivessel Evaluation] and new interest in the long-term fractional flow reserve (FFR) outcome studies,2-6 appreciation and use of FFR has risen. Many former skeptical interventionalists have now begun to use FFR. Of course, and as one could expect when beginning a new procedure, some common and frequently asked questions (FAQ) arise. Since I often get emails or calls asking about both basic and advanced use of FFR, I thought it would be a good time to address some of these questions.
Use of NTG before FFR
Q: My physician is concerned with the use of nitroglycerin (NTG) either just prior to or during the measurement of FFR. He feels that most of the FFR trials use some form of NTG [intracoronary (IC) or even paste] during FFR measurement and thus he MUST use this protocol as well in order to derive an accurate FFR value. Is this right?
A: NTG dilates and fixes the diameter of the epicardial vessel for 10-15 minutes after 100-200 mcg IC. It has no effect on FFR, unless the stenosis is vasotonically constricted and opens up after NTG. This is unusual for an atherosclerotic narrowing. NTG is useful to reduce guidewire-induced vasospasm and relieve vessel tonus. NTG can be given before inserting any intracoronary equipment, but it is not mandatory for an accurate FFR measurement.7
FFR in Patients with Myocardial Infarction and Diabetes
Q: I attended a presentation at which they presented the data below (Figure 1) as justification to use intravascular (IVUS) rather than FFR in certain cases. I thought I understood FFR, but this data doesn't make sense to me from a physiologic standpoint. In patients with prior myocardial infarction (MI), the FFR results are different because coronary blood flow is limited in infarcted regions and the pressure drop across the stenosis during hyperemia may be smaller than expected. The study included consecutive patients with ‘significant’ stenotic lesions. The patients were divided into 2 groups; 20 patients without prior MI (25 lesions) and 35 patients with a documented MI of a target artery (41 lesions). The FFR was calculated, and the minimal lumen diameter and the % stenosis were evaluated by quantitative coronary analysis (QCA). The conclusion from this study is that FFR tends to be higher in patients with prior MI compared with patients without MI, but the same degree of coronary artery stenosis. Is this correct?
A: FFR represents the percent of normal flow across a stenosis. Flow is determined by the myocardial bed beyond the stenosis. For example, a small diagonal branch with an 80% stenosis supplying a tiny territory of muscle needs little flow, and hence an FFR of 0.84 might be just fine and certainly be considered clinically insignificant. Since the perfusion bed is related to flow and to FFR, a severe angiographic lesion supplying a territory that is infarcted and not need much flow can produce a high FFR, not corresponding to the visual estimate of narrowing. Dr. Iqbal and colleagues have presented a very interesting and important illustration of this fact.8
It is important to remember that the first principle of FFR is that the angiogram and the flow for most lesions between 40-70% do not correlate at all. Figure 2 is an illustration of the well-known lack of relationship between % diameter stenosis and functional stress testing. Overall, the concept of this paper does not make much sense for 2 reasons: 1) The authors were comparing FFR to QCA in two different groups of patients with different myocardial beds; and 2) the authors apparently did not understand that infarction can reduce the bed and the corresponding flow, and hence have high FFR despite a similar degree of stenosis (whatever that means).
Q: The Caymaz study (Figure 1) also examined patients with acute MI. This study demonstrated that patients with significant vascular dysfunction have a higher FFR measurement than those without. Do these types of studies demonstrate that in these patient subsets something is going on to cause inconsistent FFR measurements? If so, is additional validation needed in these subsets of patients?
A: As noted above, FFR in acute MI can change as the bed recovers.7,8 This is consistent with physiology and not a reason to consider FFR unreliable. FFR is not used in the acute coronary syndromes because steady state has not been achieved in the target bed. We treat the ACS lesion for active biology, not physiology. However, remote lesions and late, stabilized MI lesions9 may be assessed by FFR and decisions regarding treatment are valid.
Regarding lesion assessment using IVUS in this setting, there are no validated IVUS thresholds for significant lesions in ACS patients either. For elective PCI, Nam et al10 found that the use of IVUS produced three times as many percutaneous coronary interventions (PCIs) compared with FFR with no better clinical results, demonstrating that IVUS was likely associated with excess and some unnecessary stenting. I hope that you can appreciate the limitations of the common but incorrect dictum, “if you want to stent, use IVUS; if not, use FFR.” (See CLD July 2010, “Apples, Oranges, FFR and IVUS”). If you believe this, then you don’t even need IVUS, just stent it and save yourself the trouble.11 I say this partly facetiously, but conscientious operators use FFR to decide whether to treat, then use IVUS for how to treat.
Q: I have a question about the Tamita study (Figure 1), where FFR values are higher in diabetics. If FFR measures pressure, why would diabetes mellitus (DM) make a difference? What is the effect of vascular dysfunction on FFR measurements, especially in diabetics? In this study with similar stenotic lesions, FFR measurements were slightly different. In patients with DM, higher FFR values were observed than in those without DM, and a higher FFR threshold value may be necessary in patents with DM, because of abnormal distal vasodilation. Is this true?
A: FFR is independent of changing hemodynamics and independent of the status of the microvascular bed for that individual. If there is a stenosis and microvascular dysfunction, then for whatever maximal amount of flow can occur through the bed, the FFR will accurately give the resistance and ischemic potential of the stenosis. While some postulate a higher FFR threshold for ischemia in patients with microvascular disease, no studies have been done to date to challenge the current ischemic threshold of 0.80 (top end of the gray zone from greater than 15 ischemia studies and the cut point used for best outcomes in the FAME study). In addition, it is hard to be sure even a diabetic patient has microvascular dysfunction. Measurement of the index of the microcirculatory resistance may assist in this regard.12
Other studies have not shown a difference in FFR in diabetic patients.13 Because the value of FFR in diabetic patients is thought to be controversial in light of microvascular dysfunction, Sahinarslan et al investigated 121 patients with an intermediate (QCA) lesion who had undergone FFR measurement. The patients were divided into groups according to the presence (group 1) or absence (group 2) of DM. There was no difference between the FFR values of diabetic and non-diabetic patients who had coronary lesions with similar degree of luminal narrowing (0.87+/-0.08 vs. 0. 0.85+/-0.07; 0.81+/-0.08 vs. 0.82+/-0.10; 0.81+/-0.10 vs. 0.83+/-0.09, p = 0.957). In grouping patients by reference vessel diameter, there was no difference. From this study, DM does not have a significant impact on FFR values in coronary stenoses of intermediate severity.
Serial Lesions, Coronary Aneurysms, and FFR
Q: Is there any data on FFR and coronary aneurysms that lie proximal to lesions? Of course, I know a physician that has had 2 patients with this finding. Wouldn’t the FFR value be false positive due to the turbulent flow?
A: FFR reflects the summed resistance across any artery segment: narrowed, wide, or irregular. FFR registers the net pressure loss. The ratio of the distal pressure to aortic pressure at maximal hyperemia is the FFR and provides the ischemic potential of any narrowed segment.
It is true that turbulence in aneurysms can produce pressure loss, but it will be accounted for across the narrowing. If the aneurysms are serial lesions, then the pull back method will be best to assess both the sum of all the lesions on FFR. The pressure gradients between lesions will show which is the more significant.
Q: I have a question regarding FFR in vessels that have diffuse disease or serial lesions. For example, you are presented with a left anterior descending coronary artery (LAD) that has three lesions. If you do a pullback while infusing IV adenosine and the distal FFR measurement is 0.65, your FFR measurement between the distal and mid lesion is 0.75, and your FFR measurement between the mid and proximal lesion is 0.90, how do you treat this patient? Do you treat the mid lesion first and reassess the FFR of the distal lesion? Do you treat the distal and mid lesion?
A: The technique to assess serial lesions involves 2 steps with 2 different measurements.
Step 1. Measure the FFR across all lesions. In the example above, the FFR across lesions 1+2+3 was 0.65, a significant value. If this had been 0.84, then none of the lesions would need treatment.
Step 2. To assess which of the lesions was contributing the most resistance to flow, perform pressure pull back during IV adenosine. The next measurement is NOT FFR; it is the pressure gradient (aortic minus distal pressure means). The largest gradient between lesions indicates the degree of severity (Figures 3a-b). Treatment would then start with the lesion with the most significant gradient. After treating this lesion, reassess the remaining lesion(s), repeating the standard FFR technique to make a decision about another stent.
In practical terms, it may be judicious to treat the distal lesion first, then reassess more proximal lesions of lesser severity. Alternatively, if the two lesions can be covered by one DES that is not excessively long, then treat both with one stent.
Alternatives to Adenosine
Q: Our physician uses IC nitroprusside (Nipride) 100mcg bolus. He says it’s cheaper and it’s already mixed in the lab.
A: Adenosine either IC or IV is the standard for FFR measurements.14 It is also true that IC nitroprusside produces similar hyperemia to IC adenosine.15 Higher doses (>150mcg) produce transient hypotension. I agree it is probably cheaper and if mixed up already, there is no objection to using this method. However, I wasn’t aware he had to pay for the adenosine.
Q: I have used FFR routinely, until arriving in a new town. Apparently, IVUS is the only local method for “assessing” coronary lesions. I have finally succeeded in having two of the hospitals here upgrade to the pressure wire. As there is considerable resistance among my colleagues, I was hoping you might share your lab protocols for FFR. Specifically, is IC better than IV adenosine? Do you use peripheral venous at 170/mcg/kg or always central venous at 140/mcg/kg?
A: IC and IV adenosine induce equivalent hyperemia. There have been a couple of studies suggesting higher FFRs with IV than IC adenosine, but the differences were very small.14 In general, and in my lab, I recommend IV adenosine at 140mcg/kg/min for several reasons. It is weight-based. It is hands-free, i.e., the operator does not need to switch stop cocks and flush. It measures FFR at a steady state. IV adenosine is the standard everywhere in the world and was used by the developers of the technique, Drs. Pijls and DeBruyne. Central venous infusion is optimal, but a large peripheral arm vein (not hand vein) is adequate.7
It is curious that some FFR operators want to use very high IC bolus doses of adenosine (100, 200mcg etc). It seems to me that those who insist on using multiple higher doses when the FFR is 0.84 and unchanging are non-believers who want to treat the stenosis despite the non-ischemic value and keep raising the dose in hopes of lowering the FFR. The same might be said for IV adenosine at 170mcg/min/kg, which does not produce lower FFRs, but more side effects.
Q: I have not seen Lexiscan (regadenoson) in a comparative trial with adenosine. Do you have any experience with this drug in assessing FFR?
A: I have not seen the results of the ongoing trials of regadenoson and adenosine for FFR. Although our lab contributed to the flow velocity comparison studies of several A2A receptor blockers, we did not perform FFR in these patients, since they did not have significant coronary artery disease.16
One concern was that multiple A2A agonist dosing could minimize subsequent hyperemia. This issue has not yet been resolved. For the moment, I cannot recommend regadenoson replace adenosine.
I hope this discussion on FFR is helpful. I’ll look for more of your questions on this or any important cath lab topic in the coming year.
1. Pijls NHJ, Fearon WF, Tonino PAL, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56:177-184.
2. Tonino PAL, DeBruyne B, Pijls NHJ, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. (FAME). New Engl J Med 2009;360:3:213-224.
3. Pijls NHJ, Van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally non-significant stenoses: 5 year follow-up of the DEFER study. J Am Coll Cardiol 2007; 49: 2105-2111.
4. Tonino PAL, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation). J Am Coll Cardiol 2010;55:2816–2821.
5. Kern MJ, Samady H. Current concepts integrated coronary physiology in the cath lab. J Am Coll Cardiol 2010;55:173–185.
6. Hamilos M, Muller O, Cuisset T, et al. Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 2009;120:1505-1512.
7. Pijls NHJ, Kern MJ, Yock PG, DeBruyne B. Practice and potential pitfalls of coronary pressure measurement. Cath Cardiovasc Interv 2000;49:1-16.
8. Iqbal MB, Shah N, Khan M, Wallis W. Reduction myocardial perfusion territory and its effect on the physiological severity of a coronary stenosis. Circ Cardiovasc Interv Feb 2010; 3: 89-90.
9. DeBruyne B, Pijls NHJ, Bartunek J, et al. Fractional flow reserve in patients with prior myocardial infarction. Circulation 2001;104:157-162.
10. Nam C-W, Yoon H-J, Cho Y-K, et al. Outcomes of percutaneous coronary intervention in intermediate coronary artery disease: fractional flow reserve-guided versus intravascular ultrasound–guided. J Am Coll Cardiol Intv 2010;3:812-817.
11. Magni V, Chieffo A, Colombo A. Evaluation of intermediate coronary stenosis with intravascular ultrasound and fractional flow reserve: its use and abuse. Catheter Cardiovasc Interv 2009;73:441-448.
12. Fearon WF, Shah M, Ng M, et al. Predictive value of the index of microcirculatory resistance in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2008;51:560-565.
13. Sahinarslan A, Kocaman SA, Olgun H, et al. The reliability of fractional flow reserve measurement in patients with diabetes mellitus. Coron Artery Dis 2009;20(5):317-321.
14. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140(4):651-657.
15. Parham WA, Bouhasin A, Ciaramita JP, et al. Coronary hyperemic dose responses to intracoronary sodium nitroprusside. Circulation 2004; 109:1236-1243.
16. Hodgson JMcB, Dib N, Kern MJ, et al. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist. Am J Cardiol 2007;99:1507-1512.
Disclosure: Dr. Kern reports that he is a speaker for Volcano Therapeutics and St. Jude Medical, and is a consultant for Merit Medical and InfraReDx, Inc.
Check out Dr. Kern’s latest book, “Notes from the Editor’s Corner of Cath Lab Digest” at www.mortonkernmd.com