Interview: The Future of FFR with Jagat Narula, MD, PhD

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. A recent State-of-the-Art paper in JACC reviewed basic clinical concepts of coronary physiology—pressure and flow—as clinical tools for treating patients.1 A soon-to-be-published commentary by Jagat Narula, MD, PhD (a co-author of the JACC paper), and Pedro R. Moreno, MD, further explores the role of fractional flow reserve (FFR).2 CSWN: Interventions Executive Editor Rick McGuire spoke with Dr. Narula, from the Icahn School of Medicine at Mount Sinai, New York and the Editor-in-Chief of JACC: Cardiovascular Imaging, at the 2013 Transcatheter Cardiovascular Therapeutics Conference.

Rick McGuire: The COURAGE trial suggested that in the non-acute setting, medical or interventional therapy might actually be equally effective. Then came the other trials saying, “No, that’s not true if you are looking at fractional flow reserve.” This whole question of physiology versus anatomy is an important one. Dr. Narula, this has to be an exciting time to be in imaging.

Jagat Narula, MD, PhD: It has always been an exciting time to be an imager but it’s getting to be if you are not an imager, you will not be a doctor—that’s the future of imaging!

We have talked about the anatomy and the physiology of coronary artery stenosis for a long time, but it has really become important—especially with the COURAGE and the two-staged FAME and FAME 2 trials. COURAGE showed that in severe stenosis, as assessed by angiography, after 5 years there was not much of a difference in adverse outcomes whether you had up-front PCI or optimal medical therapy. In FAME, people with an FFR less than 0.8 did better compared to those who had an FFR more than 0.8, although the anatomic severity was severe in both cases. In FAME 2, those who had less than 0.8 FFR who were treated with up-front PCI did better compared to those assigned medical therapy. It really brings into focus whether we should be identifying FFR in all these cases.

Was there a “cost” if you went down one path versus the other?

As far as myocardial infarction and death, there was no difference in both arms whether it was the COURAGE trial or FAME 2 trial. However, there was a significant decrease in the number of urgent revascularizations needed in FAME 2 with up-front PCI. If you really analyze the COURAGE trial, you also see a decrease in the need for revascularization in the up-front PCI arm.

How did the trials differ in ways that could influence the findings?

The major difference in the two trials was a much shorter follow-up in the FAME 2 study, leaving us to question whether both arms would have become equal if we had followed them longer. The other important difference was that FAME 2 seemed to have less severely symptomatic subjects as compared to COURAGE. Study participants all had stable disease, so this was not an acute setting where you would more typically image. If you really focus on the acute coronary syndrome and concentrate on the non-culprit lesions studied in the PROSPECT study, you would find that, at 3 years of follow-up, about 12% of patients with a 35% lesion would develop an acute event of a non-culprit lesion. You would see these lesions become more stenotic over the 3-year period.

What’s the clinical message?

This puts us into a situation where we need to recognize plaques that are anatomically important versus functionally important. We really need to add a third variable: the morphology of a plaque; that is, is it a stable morphology or an unstable morphology? (This was addressed in another soon-to-be-published paper in JACC.3) Plaques that are bigger will lead to inducible ischemia; the plaques that become bigger, if they have unstable morphology, they are the ones that lead to adverse events also. So, essentially, FFR works very well when we go that route, but the difference is whether it’s a stable plaque or an unstable plaque. In the same issue of JACC, Dr. Moreno and I say we must start looking outside the lumen also; looking out of the box to identify the functional importance of a lesion.2 Would it be FFR? Or would it be coronary flow reserves? Or would it be an absolute coronary flow reserve or a relative coronary flow reserve? We’ll need another trial to answer that. To an extent, the ISCHEMIA trial, which is underway, is going to be addressing some of those questions. It’s a COURAGE 2-type trial. There’s another underway that is more like a FAME 3–type study where the SYNTAX-scored patients will be divided to receive PCI versus CABG based on their FFR.

But is that what we really need to know? Or do we need to go a step further and throw in optical coherence tomography (OCT)? With OCT, we should be able to see whether the plaque has a thin fibrous cap or a large necrotic core, either of which might lead to more acute events. PROSPECT 2 is going to be looking at plaque burden; similarly, SECRET 2 is looking at plaques that are not significantly stenotic and without a large plaque burden. That will give us some results indicating whether or not pre-emptive stenting is given. This really needs to be addressed because of the results we have recently seen with the PRAMI (Preventive Angioplasty in Myocardial Infarction) study. (Editor’s note: The PRAMI study found that in patients with STEMI and multivessel CAD undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses significantly reduced the risk of adverse cardiovascular events.) I can tell you that I’m still trying to grapple with the results to explain what we saw in the PRAMI study.

For now, clinically speaking, do you trust your eyes? Do you go with the angiographic image? Do you have to measure fractional flow reserve? How do you decide?

If it’s stable disease, the most important thing is that the patient has to be on optimal medical therapy.

Including optimal doses?

Yes, but with the FAME results, how would we exactly be going ahead? I don’t know. I think the jury is still out. We need more definitive trials before we can answer those questions one way or the other.

You mentioned your editorial in the same issue of JACC. Could you talk about that for a moment?

In that particular editorial, we discussed the relevance of looking at the plaque morphology in addition to the luminal stenosis. We tried to communicate that plaques that are large are likely to result in an acute event or inducible ischemia. If the plaques are stable, they are likely only to cause inducible ischemia and less likely to result in an acute event. On the other hand, if a plaque has an unstable morphology and it is a large plaque, it is ready to rupture—that’s the one that will lead to the acute coronary event. The question is: can we really pick up the right ones? Should we really go after those that are the right ones or is it that we have to pluck all large plaques? That needs to be answered and, as we discussed, the PROSPECT 2 and SECRET 2 studies may be getting into that direction.


1. Gould KL, Johnson NP, Bateman TM, et al. J Am Coll Cardiol. 2013;62:1639-53.
2. Moreno PR, Narula J. J Am Coll Cardiol. 2013 July 29. [Epub ahead of print]
3. Puri R, Nicholls SJ, Ellis SG, et al. J Am Coll Cardiol. 2013 August 14. [Epub before print]

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Follow-Up Studies, Coronary Stenosis, Tomography, Optical Coherence, Angioplasty, Cost of Illness, ACC Publications, CardioSource WorldNews

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