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William Fearon, MD

William Fearon, MD, is an Associate Professor of Cardiovascular Medicine at Stanford University School of Medicine. He received his undergraduate degree in English at Dartmouth University in 1990 and his MD in 1994 from Columbia University. Dr. Fearon's chief research interest is in the coronary physiology, particularly invasive methods for evaluating the coronary microcirculation.

Dr. Fearon has been published in over 40 journals and was co-principal investigator on the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study, presented in 2008 at the 20th annual Transcatheter Cardiovascular Therapeutics scientific symposium and subsequently published in January 2009 in the New England Journal of Medicine. He is currently the co-principal investigator at Stanford for the FAME II study which will be recruiting over 1,800 patients worldwide. Dr. Fearon speaks at numerous scientific symposia about the technique and impact on interventional cardiology of Fractional Flow Reserve (FFR).



William Fearon, MD
William Fearon, MD

Q: The FAME study for many people was game-changing. Suddenly you had Fractional Flow Reserve (FFR), a way to measure internally the actual functional obstruction in a coronary artery, as opposed to just looking at a shadow image of the angiogram and making a guess. And even though FFR has been upgraded to a higher level of evidence in the national Guidelines, the use of FFR is still only around 15%.

Fractional Flow Reserve (FFR) Wire
Fractional Flow Reserve
(FFR) wire in artery

Dr. Fearon: Like any relatively new technology, it takes time for people to adopt it and especially, when data come out, it takes time for that data to get disseminated and for the technique to start being used.

There's a perception that FFR decreases the number of interventions and, because physicians are paid for interventions, that may be a financial dis-incentive. There's also a perception that it takes extra time to do it and that may discourage people to use it. But, if we can just keep generating data showing that it's beneficial and then trying to educate our colleagues, hopefully with time people will start using it more and more.

Q: Does using FFR really add time to the procedure?
Dr. Fearon: If you have a single vessel and you're deciding whether to do FFR and stent vs. just stenting, likely it would be quicker to just stent. But most cases we're dealing with are multivessel disease and in that setting, we studied that in FAME, and we found that there was no additional time, that the procedure time was identical between the FFR-guided group and the angio-guided group. And likely that's because, although almost every patient in the FFR-guided arm that got at least one stent, there were significantly fewer stents placed in that arm and that saved time, while measuring FFR might add some time, so it was a wash. I should say that, as people get more experienced using it and if you have your cath lab set up so that you're prepared to use it, it's just like doing IVUS. It adds a few minutes, but it's not like it greatly prolongs the procedure. It's certainly less than say doing Rotablator.

Q: You mentioned that using FFR results in doing less interventions, but as Nico Pijls pointed out to me in his interview, in the case of multivessel disease, where you might be thinking about sending the patient to open heart bypass surgery instead of PCI, FFR may show that only one or two blockages are significant, and so stenting would be indicated, and you’d actually be adding procedures.
Dr. Fearon: Yes, that's exactly right. That's why I was saying why it hasn't been adopted more, is that there is a perception that it decreases the number of interventions. But I would argue, just as Nico was arguing, that in fact it may add interventions in some cases, like the one you described.

Q: For those that have taken the plunge and are using FFR, how has FAME changed their PCI practice?
Dr. Fearon: I think people have really come to realize how limiting or how misleading the angiogram can be at times. There will be very modest lesions that in many cases, based on the angiogram, we would ignore and treat medically and which are actually causing significant ischemia. And then there are also tighter lesions that surprisingly are not causing ischemia. I think from FAME and other studies what we have learned is the importance of identifying ischemia-producing lesions and treating those and in that way maximizing the benefit of our stent -- and identifying lesions that aren't producing ischemia and treating those medically, and therefore minimizing the risk of putting in stents.

Q: For many patients, who are told that they have a 60% or 70% blockage -- and they can see a picture of it -- it is sort of counterintuitive for them to be told that, according to FFR, that is definitely not an ischemia-producing stenosis. You can see it; you want to do something to it: it's the oculo-stenotic reflex. But how can you see something on angiography that clearly looks like a blockage, but in fact it's not really causing ischemia?
Dr. Fearon: You have to remember that the angiogram is a two-dimensional image of a three-dimensional structure. You can have a very tight eccentric lesion that on the angiogram looks very mild. Likewise, if you're at the right angle, you can have a narrowing that looks quite severe, yet the lumen is actually quite large. Or even if the lumen is compromised, the amount of muscle that's supplied by that vessel is a small amount, so the size of the lumen is adequate to bring blood to that area. Or the patient's had a prior infarct in that region, so they don’t need that much blood flow. There are so many different factors that contribute to whether or not a patient has ischemia beyond just what the lesion looks like on the angiogram.

Q: An interesting aspect of FAME was that stenting a lesion that does not need it, a lesion that's not ischemic, actually seemed to have worse outcomes, although perhaps not as a cause and effect thing.
Dr. Fearon: Correct. Certainly some intermediate lesions you can stent at low risk, but the more stents you put in, the greater the chance of a complication and what FAME really taught us is that FFR guidance allows you to more judiciously and accurately place stents and in that manner maximize the benefit and minimize the risks of stenting.

Q: At Stanford, do you use FFR on all of your mutivessel cases at this point?
Dr. Fearon: Yes. There are certainly instances where you don't need FFR, like you mentioned, in single vessel disease. If you have a patient who has typical symptoms and has an abnormal stress test and you find single vessel disease -- you have all the information you need there and you can just go ahead and treat with stenting. But that's certainly that's the minority. In most cases there’s multivessel disease, where you have one high grade lesion and that is clearly the culprit and you go ahead and shoot that, but then there's another vessel or two that has maybe a 50% or 70% narrowing and using the pressure wire there can be quite helpful.
    Stanford Medical Center
Stanford Medical Center

Q: FAME II is just getting started. What are we going to find out from this trial that's new?
Dr. Fearon: What FAME II is really going to address again is the importance of ischemia and its impact on adverse outcomes. COURAGE compared Optimal Medical Therapy (OMT) for patients with stable coronary disease to Optimal Medical Therapy PLUS Percutaneous Intervention (PCI).
What FAME II is going to do is build on that. In COURAGE, the percutaneous intervention was not guided by FFR, it was an angio-guided study, so presumably there were instances where lesions that were not causing ischemia received stents, and perhaps vice-versa, lesions that were causing ischemia didn't get stented. What we're hoping in FAME II is that, by using FFR-guidance, we'll be able to identify truly ischemia-producing lesions and then take that group and compare medical therapy to stenting. The goal is to look at stable patients with coronary disease who have real myocardial ischemia and compare the role of stenting in that setting vs. Optimal Medical Therapy.

Q: So some patients who have ischemic lesions will be treated by Optimal Medical Therapy only?
Dr. Fearon: Correct. The way the trial is set up in fact is that in order to get into the study and be randomized, FFR is first measured. And only if you have an ischemia-producing lesion can you be included in the study. We're taking an enriched population, just those with ischemia, and we're then going to compare medical therapy plus or minus PCI in that setting to try to really get to the bottom of the benefit of reversing ischemia and the benefit of PCI.

Q: Fascinating. When can we expect the results?
Dr. Fearon: The follow-up is going to be two years and we started enrollment just now. We probably won't complete enrollment for another year or year-and-a-half, so we're looking at three years off from now, something like that.

Q: In the very beginnings of balloon angioplasty, intracoronary pressures were extremely important. Gruentzig used to do pressure gradients on every single patient and really didn't stop the procedure until the pressure gradient was pretty much eliminated from distal and proximal. Is FFR harking back to that concept?
Dr. Fearon: Yes. I think the concept of FFR certainly builds on the early seminal work by Gruentzig and others. One of the big breakthroughs that Nico Pijls and Bernard De Bruyne made was in identifying the importance of making these measurements during maximal vasodilation or maximal hyperemia. The resting measurements of pressure tend not to be as useful, just because changes in heart rate and blood pressure and things like that have an impact on the resting flow, as well as the fact that the heart and the body are so good at compensating at rest. But during maximal vasodilation, that's really when the measurements become so useful. The other key breakthrough was the miniaturization of the pressure transducer so that these measurements could be made without a large balloon catheter which could cause obstruction in the vessel. So those two things were really the key additional things that built on what was already observed by the early pioneers.

Q: The vasodilation is induced by pharmacological means during the procedure?
Dr. Fearon: Yes. The most common way is by giving intravenous adenosine.

Q: Do you foresee a big growth in FFR over the next year or two? Or do you think people are doing a wait-and-see to see what comes out of the newer studies?
Dr. Fearon: I do think that there's going to continue to be growth. Again, it takes time for data to get disseminated and become adopted and for education and for people to learn the technique, although it's not a very complex technique. So I'm guessing that as that happens there'll be more use. And then there's ongoing studies besides FAME II, there are smaller studies comparing IVUS guidance to FFR guidance. So, as more and more data come out, that will also generate more interest. And then finally, there are all these advances being made as far as the wires that are used, and the technique that make it simpler and easier, and that should help people adopt it more. Who knows, if maybe there will some changes in reimbursement too which could always improve its use.

Q: Because of the controversy about the problems in Maryland and Texas, with doctors now who have been accused of over-stenting and stenting lesions that didn't need to be stented, do you think that something like FFR could help give some evidence which would then help justify the procedure. You could say, "Look. This was necessary. Here's the number."
Dr. Fearon: Right. I think that certainly we're moving in that direction where whether it's FFR or non-invasive testing or other methods of assessing for ischemia, but something beyond just the angiogram needs to be present to justify intervention.

Q: Are you using Fractional Flow Reserve in other areas that we haven’t discussed?
Dr. Fearon: I think the other area that doesn't get as much attention is the small vessels, the microvasculature. We focus on the epicardial vessels, the large vessels, because those are the ones that you can stent. But there are more and more data emerging showing that, if we can accurately assess the status of the coronary microvasculature, that we can have a better idea of the patient's prognosis and also diagnose the ideology of chest pain more accurately.

The reason I mention this is that with the pressure wire we can also estimate flow: the pressure sensor can act as a thermistor and we can measure the transit time of room temperature saline and get the estimate of flow. And we can use that estimate of flow in our pressure measurement and then calculate the microvascular resistance. We've been working on something called the Index of Microcirculatory Resistance (IMR) -- and we've studied, using this index, patients who have had acute myocardial infarction, as well as in patients with stable chest pain syndromes, or patients before and after percutaneous intervention, and have found that the resistance in the microvesssels can predict which patients are going to do well and which patients are going to have big heart attacks and small heart attacks. As we get more understanding, one could envision, for example, deciding whether or not to deliver stem cell therapy based on the status of the microvascular resistance in someone with an acute MI -- or monitoring the effects of stem cell therapy. So I think that's another kind of growth area for coronary physiology and our understanding of the coronary circulation.

Q: Would this be something that's more prevalent in women than men?
Dr. Fearon: That's exactly right. At Stanford, one of my colleagues, Jennifer Tremmel, is working on measuring not only FFR but IMR in women who have normal appearing coronary arteries based on the angiogram. And we're finding very interesting things. Some patients have mild diffuse disease that doesn't show up on the angiogram, yet the FFR is very abnormal. Others have a totally normal FFR but have a very high IMR, suggesting that they have microvascular dysfunction or so-called syndrome X. And others have normal FFR and normal IMR and then you can reassure them that their coronary circulation is doing fine and likely the chest pain is coming from another source. So it can be quite helpful and a very thorough way to evaluate our patients.

Q: How exactly is the IMR measured?
Dr. Fearon: Basically you use the same pressure wire and you again administer intravenous adenosine and you measure the distal coronary pressure during maximal flow, maximal vasodilation -- and at the same time you inject small aliquots (like 3cc) of room temperature saline. And a kind of thermodilation curve is generated by the thermistor on the pressure wire and based on that the analyzer can automatically calculate the transit time. You take the pressure and divide it by flow and you get a resistance. And that number is a reflection of the status of the microvasculature.

We found that an IMR of less than 20 is normal and people coming in with acute MI, usually it's in the 30-40 range -- and the higher it is, the larger the MI will be. It correlates with the CPK. It also correlates with the degree of LV dysfunction and also with the recovery of LV function over time. So that people who have a high IMR, when you look three months later, their LVs don't improve as much as those who have low IMR. Hopefully it will become a powerful tool.

This interview was conducted in September 2010 by Burt Cohen of Angioplasty.Org.