Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels
Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
The evaluation of coronary artery disease (blocked arterial blood supply to heart muscle) by stress tests is functional: is there enough blockage to starve a region of muscle when demand is high? By starvation we mean ischemia – insufficient supply to meet metabolic demands as expressed by consequent functional impairment, e.g., metabolic, electric, mechanical. In the catheterization laboratory, the evaluation is primarily anatomic – is there a bite missing in the silhouette of a coronary artery consistent with a significant impediment to blood delivery beyond the lesion? Half of all heart attacks are due to such lesions. The other half derive from non-obstructive but unstable lesions that may crack, bleed into the vessel wall, and suddenly clot, blocking the blood flow. Coronary lesions that restrict blood delivery sufficient to cause demand ischemia (insufficient blood supply to meet high demands) cause angina pectoris.
The focus of flow reserve is to add an assessment of functional significance to anatomic lesions observed at catheterization. The widespread practice of deciding on intervention based on percent diameter reduction imposed by a lesion is obviously flawed. The flow limitation imposed by a lesion depends on its length and shape (entrance and exit effects on flow pattern), not merely the diameter reduction expressed as a percent, that is currently deemed the decision-making “degree of stenosis.” In the midst of a medical emergency heart attack, the target of intervention is the culprit lesion, the one that best explains why a region of muscle is dying. In that case, timely intervention is potentially life saving and does not depend on or wait for measurements. In the non-emergent setting, it is much harder to establish benefit from intervention. If a lesion is flow limiting and explanatory for angina pectoris, then intervention to relieve obstruction offers pain relief and may improve exertion tolerance. In relatively rare circumstances (3-vessel obstruction, left main obstruction) intervention may avoid heart attack and extend life expectancy, but with as good or better outcomes from bypass surgery. Most elective catheter interventions (balloon angioplasty, stent placement) have failed to establish improved life expectancy or even superiority over medication. Furthermore, stent placement obligates use of strong anti-platelet medications (e.g., aspirin plus clopidogrel) that elevate risk of serious bleeding and stroke. Therefore it is reasonable to require further evidence that a coronary lesion is obstructive and consequential that just percent stenosis (narrowing) as indication for intervention. Fractional flow reserve offers such confirmation of lesion significance.
Fractional flow reserve may prove useful also in the definition of heart attack (myocardial infarction): New Definition of MI Unveiled, Fractional Flow Reserve (FFR) CT for Tagging Ischemia
Recorded: May 23, 2013
The use of FFR is relatively widespread in Europe, while its usage is beginning to catch up in the US. But for what reasons? Drs Roxana Mehran,Justin Davies, and Ron Waksman gathered recently to share their thoughts on the role of functional assessment in the cath lab, to evaluate FFR and its alternatives, and discuss what testing the future might hold for the optimal detection of culprit lesions.
Roxana Mehran MD
Professor of Medicine, Divisions of Cardiology and Health Evidence and Policy
Director, Interventional Cardiovascular Research and Clinical Trials
The Zena and Michael A Wiener Cardiovascular Institute
Icahn School of Medicine at Mount Sinai
New York, NY
Dr Mehran has served as an advisor or consultant for AstraZeneca Pharmaceuticals, Regado Biosciences, Abbott Cardiovascular Systems, Janssen (Johnson & Johnson), Merck, and Maya Medical. She has received grants for clinical research from Bristol-Myers Squibb, Sanofi, the Medicines Company, and Lilly/DSI.
Justin Davies MBBS PhD
Consultant Interventional Cardiologist
London, United Kingdom
Dr Davies has served as an advisor or consultant for Volcano and Medtronic. He has served as a speaker or a member of a speakers’ bureau for Medtronic and has received grants for clinical research from Volcano, Medtronic, and Abbott.
Ron Waksman MD
Director, Clinical Research and Advanced Education
MedStar Cardiovascular Research Network/Cleveland Clinic Heart and Vascular Institute
Clinical Professor of Medicine (Cardiology)
Dr Waksman has served as a speaker or a member of a speakers’ bureau for AstraZeneca Pharmaceuticals, Boston Scientific, and Medtronic.
Roxana Mehran, MD: Hello. My name is Roxana Mehran from Mount Sinai
School of Medicine in New York. It’s my pleasure to welcome you to this editorial
program in which we will look into how FFR usage differs in Europe vs the United
I’m joined by my colleagues Justin Davies from Imperial College London and, of
course, Ron Waksman, an old friend, from the Washington Hospital Center in
Ron Waksman, MD: Thank you.
Dr Mehran: We thought today we’d have a conversation about fractional flow
reserve and the use of functional studies in guiding our interventional
procedures. This has become a very interesting and important modality that has
been incorporated, now, more and more into the cath lab.
Let’s begin, Justin. Maybe you could tell us: what is FFR? How do we use it?
What do you think about it? How important is it to have? Does every cath lab
need to have FFR?
Justin E Davies, MD: I think that it provides cath labs with an objective measure
of stenosis assessment that is quick and relatively easy to use. Often you find
people don’t come to cath labs with preprocedural ischemic assessment, so it
enables a physician in the lab to see if there is ischemia and to effectively
document that. It has clearly got a good, strong evidence base, which has been
developed over a number of years with the founding studies of DEFER and
FAME—and FAME-2, now, which has led to the technique getting into guidelines
and which has propelled its use to widespread practice.
Dr Mehran: There’s no question that functional assessment is quite important,
but what do you think about patients coming into the cath lab, especially in the
United States, without an ischemic assessment? How often are you seeing that
and would you even use [FFR] in a patient who has got a 90% stenosis or 80%
Dr Waksman: I think we are in a period of transformational culture, now, in terms
of appropriate-use criteria and justifying every lesion that we are doing. I think
that interventional cardiologists are on the defensive—because we have to justify
almost any angioplasty that we are doing, especially with an intermediate lesion.
I think physicians are more flexible in using FFR and looking it as guidance to
support their decision-making.
I would say, still, if it is a 90% lesion even without a functional test I don’t think it
is required, but the 90% is on the eyes of the beholder, so you know that if you
take it to the core lab it is not going to be probably 90%, it is usually going to be
less than that.
And as you know, we have been scrutinized by looking at films and, again, [we
need to] justify. It is true that in the past the algorithm was having a functional
test and going to the cath lab. But this [step] has delayed things, and now people
presenting with some chest discomfort, [who] have risk factors, they sometimes
would be sent to the cath lab as the first method of assessment. I think we have
to take this more carefully and incorporate a functional ischemic assessment in
the cath lab—especially when those lesions are not necessarily unambiguous,
we don’t clearly know that they would derive ischemia.
Dr Mehran: It seems like that is really the way to go. You talked to us about
FAME, FAME-2, [that FFR is] the only modality in the cath lab that actually
improves hard end points like death and MI. I think that was how it got into the
guidelines, obviously. Very important studies. But at what cost? Can we afford to
do this in every single patient who presents with, let’s say, multivessel disease,
as they did in FAME?
Dr Davies: I think, actually, that this is a tremendous opportunity because I think
for us as cardiologists, as Ron said, it is very easy to get yourself into a little bit of
a hole stenting lesions that are not as significant as you may think, and I think
this obviously provides a justification and a safety net for people to deploy stents.
But also I think increasingly going forward when you are taking on potentially
more challenging techniques and you have got three-vessel disease, [FFR]
enables us to assess multivessel disease and perhaps convert a three-vessel
PCI into a two- or [even] a single-vessel PCI, which may move them from getting
a CABG to angioplasty.
Dr Mehran: So actually decreasing the number of stents. Reducing your
devices—hopefully even radiation exposure and contrast media. If you actually
just do an FFR and say, okay, I am done. But you know that we have all
[discussed]: if you want to treat the lesion you use an IVUS; if you don’t want to
treat the lesion you use an FFR. What do you think about that, Ron? Is that
something that is going on in your lab?
Dr Waksman: No. We try to stay away [from that]. I know that is said. But I
would still think that FFR is oversold. For the controversy, I would [argue] that
those studies were investigator-sponsored studies and I don’t think the data are
so relevant today. In DEFER there was a balloon angioplasty. Even in FAME-1, it
was with first-generation stents, and it was not really practice to go after every
I think we have to take these [data] with a grain of salt. To my view, not
everything is definitive. Nevertheless, we do see uptake of the FFR usage in the
lab and for something that used to be under 3% in the US—only a couple of
years ago—it is now reaching up to 20%. More and more people are using [FFR].
There are other modalities that you can use. I think that we try to do a conversion
between the anatomical [minimum lumen area] (MLA) to the IVUS / FFR. It is
controversial, but it is another option. I think we need to learn to use the tool
when we really need it, not to be obsessed with it.
Often, we would have a scenario [where] a patient presents with chest pain. It is
classical angina. It is relieved by nitroglycerin. You have what you think is about
70% lesion in the proximal LAD and then you stick [in] the FFR wire and you get
0.81. Then you have a problem. You can repeat the study. You shoot another
adenosine and now it is 0.79. Then you shoot another one and it is 0.80. It is very
hard for me when you have a binary number to make a decision [based] on that
number. I don’t think we should lose our clinical judgment. It is a nice tool, but
don’t abuse it. Use it when it is really helpful.
Dr Davies: I will share my view. I have to say I agree wholeheartedly with Ron.
To me, if you ask them what are the most important numbers in FFR, people will
say: 0.80 or 0.75. Actually, I think the two most important numbers are 0 when it
is completely occluded and 1. As you get nearer to 0.80 you know that you are
approaching a place where it is going to be likely ischemia and a high probability
of events. Ron is absolutely right. If you have a type A, 90% lesion and you have
an FFR of 0.81—I know [that] in the US you are in difficulties, at the moment,
with these kinds of lesions. I think with the commonsense kind of medical
entirety/holistic approach that would say you should probably stent these people.
Dr Mehran: But isn’t that just so important? Those are really important points
because it is not about the dichotomous number of 0.80 or 0.75. It is about the
clinician and what they feel the scenario is and how it all fits together.
Dr Waksman: I would say even though it is getting very hard to support by
studies but I may not have an 80% or 70% lesion. I would rather have an FFR of
0.92 or 0.96 than 0.81.
Dr Davies: Absolutely.
Dr Mehran: Of course.
Dr Waksman: If I have the choice. You also have to realize that the stents of
today are not the stents of yesterday. I think we see [many fewer] events. I think
that the price of stenting and the likelihood that we would have events is much
lower than in the past. So even if we deviate a little bit, it I don’t think we do an
injustice to the patients [or] put them at high risk. I would challenge that if you
would [do] the same study today as DEFER, with the new second-generation
stents, I am not sure that the results would be the same—as robust—as they
were in the past. As a matter of fact, if you are looking even [at] FAME-2, at the
two groups—[those who] were medically treated and those who were
[interventionally] treated, the curves were actually very similar. I would challenge
that you [would not be replicating these results] with second-generation [stents].
You have to be taking [FFR] when you really need. I don’t think [that]
systematically you go [to] every lesion and if it meets the criteria of 0.80, you
don’t treat. If it is less, you treat.
Dr Davies: And there are some people who see this as a weakness, but we
don’t do that in any other form of medicine we practice, and I see it as a strength
that you get a continuous range of values. I think the one thing, which we have
also done, is using these techniques purely as an outcome base. But really if you
look back they were designed to describe ischemia and chest pain, so really it is
a very good tool for seeing if chest pain is genuine and if it is likely to benefit from
Dr Mehran: That’s right.
Dr. Davies: And that hasn’t been thoroughly explored since the original studies.
Dr Mehran: Those are really excellent points. Now, we have alternatives to FFR.
We talked a little bit about IVUS, but we also know now that, Justin, you have
done a lot of the work on [instantaneous wave-free ratio] iFR. Maybe you can just
tell us: what is iFR? How is it different from FFR and where are we in that? Do
you believe it will replace FFR?
Dr Davies: iFR is a technique which is very similar to perform as FFR. You use
the same pressure wire. It is a software change in the console that essentially
allows us to make a measurement of stenosis severity over a particular phase of
the cardiac cycle without the need for a drug. It typically takes a few seconds to
measure and is very quick.
There have been, to date, about 3000 patients studied, in five clinical trials,
which—with the exception of one study—have all shown, essentially, the same
And we know at the EuroPCR meeting this was, again, replicated this week. At
the moment, we are in a situation where we are advocating the use of a hybrid
approach, similar to the big RESOLVE study, which essentially says that if you
are above an iFR threshold of 0.93 you are safe to defer and below 0.86, to treat.
That gives you about a 90% to 95% agreement with FFR and overall
classification, and the ADVISE-II study shows it saves about 70% of adenosine.
There are potentially quite marked savings in the cath lab.
I think this is out there in clinical practice—in a limited release, in terms of certain
labs around the world on three continents. The general experience has been
very, very good from people in terms of just facilitating the use of physiology.
What I mean by that: I take centers that were relatively small users of FFR and
they found they have done the same number of cases in three months as they
would have done over the whole year. If you ask them why, it’s because it lowers
the burden of doing [the cases]. I think if we then move on to doing triple-vesseldisease
assessment I think it takes five seconds of each.
Dr Mehran: I think there is no question that taking away the adenosine is music
to a lot of people’s ears. We all know that adenosine is not being given perfectly
right in certain laboratories. It really should be an intravenous injection. There is
time needed for nurses to put it together, to put in the IV, the intra-arterial
[injection] has been refuted, etc.
But when I look at iFR I start to think that we are pushing ourselves toward what
Ron was just talking about. I think the validations need to take place. It would be
great to have technology that is well validated, studied, that actually correlates
with events without adenosine. I think that part of it is brilliant. But are we there
Dr Davies: We have had a very good response taking the stuff from the research
lab into the cath lab, so this is what we are using this as a tool, certainly, within
the framework of studies. I think now we are in a position to do large studies. I
will give you an example: we asked all of the investigators who have got these
machines if they are willing to contribute to analysis at the time of PCI. [In the
space of] for four weeks—most of them only had the device that length of time,
they managed to get together 400 cases. [This shows that] doing very large
studies of 1500 or 2000 patients is extremely feasible and very easy to do.
Dr Mehran: I hope you are designing them and actually performing them.
Ron, what do you think about iFR? I love to hear your scrutiny.
Dr Waksman: I think it hasn’t been validated, obviously. I [would] like to get rid of
the adenosine. But I like to see reproducibility of any test. Again, I would say, we
don’t have to lose our brains just because we have numbers. We have a patient
in front of us. He has symptoms and we have lesions that we have to treat.
Obviously if you have a proximal lesion, it’s going to behave differently than a mid
or distal vessel. We know that, for example, if you look at most of the studies, at
just a circumflex of FFR. Most of them will be above 8.0. But you take most
proximal LADs, they probably would fit more into the predictability of ischemia vs
nonischemia. We have to, again, use our brains when we use the numbers and
understand what they mean.
I think that there will be other technologies that [will] try to be alternatives to
FFR—not that FFR is necessarily bad, but there are other ways that you can do
it. There is the heart flow option with a CT. I still think that IVUS is an option.
Not all of them are ideal, but it gives you a variety of options. The message is: we
are trying to treat only the vessels that need to be treated. I think that can also
change the paradigm of treatment. For example, we may turn “three vessel” to
“one vessel” and change the whole syntax score and move patients from CABG
to PCI—which is very attractive for interventional cardiologists.
One other thing that is interesting: recently I heard that SJ Park was presenting a
systematic use on all patients with FFR—which is amazing! It is over 70%. It was
not a randomized study but what he did show by systematically using FFR in his
practice [is that] he reduced, by a lot, the number of PCIs, the number of stents,
and the outcome of those patients was good. You have to compare it in a
randomized fashion. What would be the alternative? And that is the challenge.
You really have to show [efficacy] in a randomized clinical trial. I recognize there
were studies in the past, but they have limitations. I think we [are] moving to
another phase that this has to be tested.
Dr Mehran: Quickly touching on what you just said about noninvasive functional
assessments. More and more we are getting patients who come in with a
multislice CT. Can we use that technology to actually do some of the functional
assessment right then and there? The DEFACTO trial, in my mind, is a negative
study. Where are we with that technology?
Dr Davies: You are absolutely right to say a lot of these patients have CTs and it
is a question of whether we can use information from that CT. As Ron said, there
is HeartFlow technology, which enables you to effectively get a noninvasive
preprocedural virtual FFR measurement. Certainly from a theoretical perspective,
it should be possible to do these calculations. I think the problem that the
HeartFlow team has is translating the computational flow dynamic theory in a
perfect research environment into the clinical practice of getting good-quality
CTs. I think there is probably more work in progress to see that really translate.
Dr Mehran: That’s right.
Dr Waksman: But what we are seeing in the US right now is [that] there is a
decline in the nuclear test and there is increased uptake in FFR. There is a
change in paradigm because of many reasons. Some of them have nothing to do
with medicine. It is more the reimbursement. Because reimbursement went down
on nuclear tests, we see less nuclear tests being performed. Now we are getting
the patients actually to be assessed in the lab and we get [to have] more
confidence with FFR or other technologies. I think we are shifting the traditional
assessment of ischemia, which was in the old days was nuclear or dobutamine
echo, more into those [tests performed] in the lab. And I do believe that the fact
that studies were negative is not the end of the story. We still have to fine-tune.
This is all about software validation and finding the sweet spot. What is the
window that allows you to get good matching? That you can feel comfortable
Dr Mehran: So great technology to look forward to in the future. We are looking
for that kind of noninvasive assessment of functional studies. Let’s now turn to
why we are really here, which is about the regional differences of FFR. In the UK,
in Europe, in the United States, are there regional differences? Let’s better
understand that. And, if so, why? Justin, maybe you could tell us about the UK
Dr Davies: I think [FFR penetration] is somewhere between 15% and 20% of
cases in the UK, which is very high on a worldwide basis. I think some of that has
to do with reimbursement and some of it is to do with the way that doctors are
reimbursed, as well. In terms of the UK, if we put a stent in or not, it has no net
effect on the income to ourselves. So it is very easy for us to follow guidelines
and, in fact, if we don’t, [we] get rapped around the knuckles and told off for not
doing so. I think that is a strong incentive to do it.
I think there are obviously differences from us in other parts of the world with
regard to the reimbursement—the cost of the bits of kit and the availability of the
kit. In some labs around the world, and some territories, getting adenosine is
simply not possible or it is [so] outrageously expensive that people would just say
I am not going to make this measurement and they defer to angiography or, as
Ron said, to IVUS.
Dr Mehran: It seems like the penetration is a little bit the same between the UK
and US? What do you think about the United States?
Dr Waksman: Not yet. I would actually take from what Justin just said. I think
that the main motivation in Europe for the penetration of FFR was monetary. It
was actually to save money to the operator, to the cath lab. This never was the
case in the US. I think the [explanation] in the US of the uptick is more related to
the appropriateness[-criteria guidelines] and to be on the defensive. The
interventionalist now has to defend himself for every procedure [he is] doing and
to have a backup [as to] why they did this procedure. That was not the case in
the European continent, [where] the main drive was to reduce overall costs on
the capitation system. I always had a problem with that because this is the way
that it was presented and I think that we should give the best to our patients.
We also have to realize that the reason for the uptick could be because of
appropriateness. We actually learned to turn this into a helpful tool for us [and] to
use it not just for those ancillary decisions—that probably should not be related to
the patient (whether it is a cost or whether it is appropriateness), but [also for]
what [it is] really good [for]: to see how we can utilize [it] to do the right procedure
to the right vessel. So it’s another tool.
But as I mentioned before, I think we are seeing an uptick. I don’t think we are
crossing the 20% and we are not as broad as in Europe. When are we going to
get there? It is a question of how much push we are going to see, but one thing
you see [now is] more companies providing FFR systems. That means that there
will be more reps in the labs and more opportunities, and that is usually what will
populate the usage of the device. I have no doubt that we are going to continue
to see an increase.
Dr Davies: It is interesting. I know from the US, and some of the data there,
there is a big difference between diagnostic use of FFR and actually the PCI use.
It is almost used in the US to justify PCI, and I think the angiography use is
somewhere around 3%. If you take that study that SJ Park has just done and you
compare that 70% percent that he was doing with the 3%, there is obviously a
Dr Mehran: Isn’t it interesting that maybe the driving force of doing a functional
assessment in the lab is different in the UK vs the US or Europe vs the United
States? I believe that at the end of the day they both will come to the same
conclusion of doing the right procedure to the right patient, making the correct
diagnosis, treating the right lesion for the right patient, but at the end of the day
actually decreasing costs. While maybe we are seeing in the United States that
appropriate-use criteria is why we are doing this, it has, perhaps, to do with
capitation, as well, for us in the United States, and enhancing the cost in the
system, hopefully, with this kind of functional assessment?
Dr Waksman: I think there is one more important collateral benefit from using
the FFR. That I would say is that we are changing the paradigm. In the old days
we thought we have to treat all the three vessels; we have to have complete
revascularization. I think FFR taught us that actually we may not need to treat all
the three vessels. That is a big advantage of technology. As we are using it we
are starting to see maybe we just have to treat the culprit lesion and move on
and then leave the others either on medical therapy or not treat them at all. That
is a huge change in paradigm.
Dr Mehran: This has been a fantastic conversation among the three of us, and I
just want to close and I want you each to close for me. What do you think is the
future of FFR? What should we be looking forward to as alternatives and what
incorporation of functional assessment in the cath lab as we move to the next
decade of interventional cardiology. Ron?
Dr Waksman: I think that the FFR will continue to grow. I think that there is a
good future for iFR without the adenosine, the wireless, and better wires that you
can use. I think you [could] incorporate an IVUS probe in them—FFR on an IVUS
probe, so you can do both. I think that the combination of anatomical and
physiological [testing] is important. We learned that with IVUS you can optimize
the outcome of the PCI, not only just determine whether you treat or not. So the
future is there. We are coming to do more sophisticated PCIs, and these data will
help us to get better outcomes and also to triage the patients to what should be
the treatment of choice. In the long run—even though the short run shows
reduction of the PCIs—if we use [FFR] carefully it will open us or enable us to do
more complex patients and meet the outcome that is expected.
Dr Mehran: That’s great. Justin?
Dr Davies: I would agree with Ron’s thoughts and also extend them to say I think
we will be doing more of these measurements, but I also think we should be
doing more smartly. As we discussed earlier, if you get these very borderline
lesions in patients who clearly have angina, then this is an indication for treating
your patient and looking at the patient as a whole.
I think we are really going to embrace technology. Medicine is always a little bit
behind the kind of technological leaps compared with smartphones, for instance.
I think techniques such as the HeartFlow technique, techniques such as the ones
we have been working on with iFR, I think will continue to move forward. I think
whereas we only today have discussed things from the purely diagnostic single
ischemic perspective, I think within one or two years you are going to have
techniques freely available in the cath lab that enable us to coregister the
FFR/iFR images onto angiogram in real time, enable you to plan PCI by selecting
which lesions may or may not benefit from therapy, even before you deploy a
stent. I think this, in the SYNTAX era, where we know the potential benefits of
minimizing angioplasty, like Ron said, will really facilitate our practice, and I
suppose the most important thing is lead to the better results for our patients.
Dr Mehran: I think that you both did a beautiful job telling us about the current
and the future technology and even if there are regional differences, at the end of
the day what we are trying to do is use the functional assessment to enhance
outcomes for our patients with cardiovascular disease, to make the right
diagnostic and therapeutic choices in these patients. And the combination of
these technologies that currently exists and hopefully will exist in the future will
absolutely get us there.
Thank you so much for your time this morning and I hope our audience enjoys
this conversation as I did. Thank you.
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