Everything you wanted to know about cardiac PET and more (this is the more!)

You asked and the experts answered. During the webinar Q&A, we ran out of time to answer all the questions so we reconvened the expert panel with Drs. Dilsizian, Bateman, Thompson and Bering and they answered them ALL! Check out the great insight for programs wanting to know more about cardiac PET, strategies on reimbursement and patient selection, ways to build physician awareness, timing for new agents on the horizon, the challenge of PET/MR and cardiac PET’s role in retasking the cath lab and even serving as gatekeeper. Just click on the question and take a look!

 

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Our biggest barrier to performing PET studies is insurance prior authorization. Do you have any advice to get past this hurdle?

Tim Bateman: That's a common question. It plagues all of us in cardiology today, not just with PET, but with SPECT and echo, as well as cath and some of the EP procedures. I think Randy will also have some comments here because he has rich experience with this as well. From my standpoint, I think the most important thing is to avoid a denial. We'll talk about how to handle a denial in a second, but most importantly is to set things up so you avoid the denial.

How do you do that? Well, the first thing is to be sure that the patient actually warrants a PET scan, and in that regard you should be very familiar with the position statement that was published by ASNC and SNMMI last year, as well as with guidelines. The SNMMI is actually developing appropriate use criteria specific for PET, and that will also be helpful. What you really need to be careful about is that the paperwork that gets submitted electronically to the RBM or to the insurance company has all of the important details that would warrant the patient's undergoing a PET study. So, that requires you to educate your admin folks, and also your referring doctors to be sure that what's in their document can be easily identified and lifted by the admin people to go in with the paperwork. So, things like chest pain, shortness of breath, the patient is complicated, the patient cannot exercise, the patient has chronic kidney disease, advanced diabetes, prior myocardial infarction, cardiomyopathy, arrhythmias, and certainly the BMI all have to be readily available, and your people have to be sure to get those key descriptors in with the original paperwork.

If it does come to a denial, I would suggest that you don't call unless you're convinced the case actually warrants that PET, otherwise you're wasting your time and you're wasting the medical director's time on the other end of the line. Look carefully for whether the patient has had a prior imaging procedure, a prior stress echo, a prior SPECT. If these studies have been challenging, or interpreted as uncertain, or were plagued by artifact, or did not correlate with subsequent tests such as a coronary angiogram, that is very convincing data to get approval for a PET scan.

And finally, if you are in a denial situation, and you are going to talk with one of the medical directors from the RBM or the insurance company, you should always request to discuss the case with a cardiologist. Many of the general medical panelists don't know the distinction between SPECT and PET, but every company has got cardiologists available on its panel. They may not be able to talk to you at that particular minute, but they will set up a time when they can call you back and discuss the case.

Randy Thompson: That is a comprehensive review of what to do and not do. I would add and emphasize a couple things. In terms of submitting the baseline information on the patient on why they need a test, usually most practices like ours will send a copy of the letter that was, or the report that was generated, at the time of the office visit, and we've already needed to coach some of our colleagues not to say certain things and to say other things. So, for example, we had one colleague that would use words like "screening" or "baseline" PET study, which obviously would be a red flag to any radiology benefits manager. I don't know why he used such sort of terms, but people do. Then, as Tim said, it's very helpful to end that document justifying with a few more words why the study needs to be done. The patient cannot exercise because of this reason. The patient needs a pharmacologic study or needs a PET study because of things like complexity or whatever.

And in that letter or in the denial situation, it's sometimes helpful to bring up the previous discordant SPECT and cath lab results, for example, or the previous inadequate SPECT studies. So, even if it was an old study that will sometimes be enough for even a stingy radiology benefits manager to acquiesce. They don't want to do another SPECT study if it's going to be a waste of time, just like the one before. Those are the main points there when you do to get on the telephone with the radiology benefits managers, and of course some of them are just recalcitrant, despite the ASNC and other medical society position papers. They have their own algorithm and they're just very rigid on those, but when you get to talking to them about things like what we just said, especially the BMI, especially why the patient can't exercise and why you expect, based on their body habitus, to have a challenging SPECT study, they'll often come around and be reasonable.

Sometimes, they have a BMI cutoff in their protocols. That's not what we think ought to be the way you make a decision between PET and SPECT, but sometimes the radiology benefits managers have that as one of their written criteria, but when you're on the phone with one of their medical directors you can sometimes make the case that, "Well, although the BMI isn't at your cutoff, it's not 40, but the patient has very challenging body habitus." Such as a very top heavy woman or man with a great big belly, and that'll sometimes allow them to use a reason to override a rigid, specific criteria.
 

Has there been any evidence to show that FFR correlates with PET CFR? Would it be camera system dependent?

Randy Thompson: That's an important and interesting question, but not a quick answer. I'll ask you to think about what you're measuring with FFR and think about what you're measuring with CFR. Honestly, both are estimates of the functional schematic of coronary stenosis and so you would expect them to be comparable, but for FFR we're measuring by putting a pressure catheter down the coronary artery across the lesion, and measuring the pressure drop across that specific lesion both at rest and then with maximal hyperemic blood flow. That measurement is relatively insensitive to heart rate and blood pressure.

Now, with CFR we're measuring something different. We're measuring the coronary flow to the myocardium or to the territory of the myocardium, for example, at rest and with hyperemic blood flow, so measuring something different there. If you look at studies that have been done, if there's single vessel disease then myocardial perfusion imaging corresponds well with FFR. Myocardial perfusion imaging corresponds well with CFR or CPF for that matter. When you get into multivessel disease, that's when the correlation is only modest, and the question is, is it technique, or is the question to ask, is it related to the type of system? It's probably mostly related to the physiology and the differences in what you're measuring.

So if you think about it, if you have increased resistance, the coronary artery should have no resistance, even with extreme hyperemia, you don't get a drop in blood flow normally or a drop in pressure normally. But if you have resistance because of either diffused disease or microvascular disease, then you're not going to get that sort of pressure drop across a coronary lesion because you won't get maximal coronary hyperemia.

And so in a sense, FFR might be insensitive. The cutoff that we give of 0.75 or 0.80 might be insensitive for determining the degree of coronary obstruction. And you can take the most extreme case, say, severe three vessel coronary artery disease, and SPECT or PET studies are sometimes normal in that setting. And the answer we'd always give as well, you have exactly balanced ischemia in all three coronary beds and the better answer might be that you've got decrease, even increase resistance and you're not able to achieve coronary hyperemia because of the combination of obstructive epicardial disease, diffused epicardial disease, and microvascular disease.

And so the MPI might be normal, the catheter based FFR might be normal, or not abnormal beyond the cutoffs, but a CFR would be distinctly abnormal because you would not get an augmentation of coronary flow at rest until you measure it.

You know, is one abnormal, is one or two positive, the other a false positive? Well, not exactly because what they're measuring ... perhaps you can think of the FFR as measuring the pressure drop (a lot) across the lesion, not the ischemia as much as the amount of the ischemia that can be treated with a stent. And so in a sense that's a helpful thing to know. The CFR is also very helpful to know because you quantitate either the ischemia or the inability to achieve maximal coronary hyperemia. That in itself is prognostic information.

So kind of a round about answer but, to say that you're measuring different things. There's correlation in the simple cases, much better than in the complex cases, and both offer understanding of what's going on with the complex patient.

Tim Bateman: I found it helpful to think of CFR in four categories. So if you think of it in four categories, suddenly it makes a lot of sense about when it will and when it won't correlate with FFR. The four categories would be that the epicardial coronaries are normal and the microvasculature is normal. Obviously in that situation, if there's a stenosis in an epicardial coronary artery, it would have a high FFR and would not need an intervention.

Another category would be that you have a normal microvasculature but abnormal epicardial coronary arteries. So in that situation, the CFR will be low and the FFR will almost always correlate very directly with it.

Then you have the more difficult cases where the microvasculature is horribly abnormal and the epicardials are horribly abnormal. You're obviously not going to expect a correlation there between FFR and CFR. Both of them will be abnormal. The CFR will be much lower than the FFR would suggest. Probably an intervention is not going to do much good in a patient with stable coronary disease because the microvasculature is so diseased.

And then rarely, you'll have a situation where the epicardial coronary arteries are normal but the patient has very severe microvasculature disease. And of course, in that situation, FFR and CFR will be discordant.

Randy Thompson: I'd like to say, in that later category, the FFR might actually be normal because if there's a lot of resistance, the pressure won't drop because you won't be able to achieve maximum coronary hyperemia. If there's no flow or no augment of flow, then there's not a drop or there's a very gradual drop, so the measurement would be, although there's severe obstructive and microvascular disease, you won't be able to see a positive FFR drop.
 

You all have good experience with coronary flow reserve measured CFR with PET absolute flow quantification. Do you have experience with relative flow reserve measurement and if their experience with it correlates with FFR?

Vasken Dilsizian: So, the whole idea of moving away from relative uptake to flow reserve is that in conventional SPECT imaging, or with PET you can look at radiotracer uptake in an abnormal region and use the normal reference region as the normal uptake and get a ratio. What we get is a percent uptake relative to the normal reference region.

That's what we've been doing all these years with SPECT imaging. The advantage of PET imaging is that instead of looking at radiotracer uptake, in relative terms, we can actually measure blood flow in CC's per minute, per gram, and therefore you are closer to true flow measurement rather than radio tracer uptake.

With flow reserve, instead of looking at relative uptake in terms of radiotracer content in a region, now they take the ratio of the hyperemic myocardial blood flow in the stenotic area, the abnormal area, and divide it by the hyperemic myocardial blood flow in the normal area.

So again, it's a ratio of abnormal to a normal reference region rather than using hyperemic blood flow and resting flow in the same region, vascular territory.

So the bottom line is that when the investigators did this, it really did not significantly improve the accuracy for detecting disease. It did re-change the area under the curve to hyperemic blood flow alone or coronary flow reserve. And therefore, it's an idea, it's another index of measurement, but certainly it's not worthy of introducing it beyond to what we currently do with hyperemic blood flow or coronary flow reserve.

In 2014, it was published in the European Heart Journal a consensus report, where we can say that the strengths of the PET perfusion tracers are image quality and ability to quantify perfusion, whereas their weaknesses are availability and cost. In other words, advances in gamma cameras such as solid-state detectors and more accurate reconstruction techniques (resolution recovery) have increased diagnostic accuracy and have the potential to reduce imaging duration, radiation exposure and cost. In your opinion, what are the actual educational needs in nuclear cardiac imaging?

Tim Bateman: The educational needs in modern day nuclear cardiac imaging are substantial. Most of us were exposed in our training to large field of view Anger cameras with filtered back projection. The field had moved ahead tremendously in the last ten years, both SPECT and PET.

From the SPECT standpoint, the cameras are now smaller field of view cameras, solid-state cameras, newer processing routines, newer protocols, newer acquisition routines, so keeping up with the times does require a significant investment. Most people practicing nuclear cardiology today, in their training, had no exposure at all to things like stress only imaging, to attenuation correction, to list mode acquisition. Even fewer have exposure to cardiac PET.

So, the educational needs are big. I think there was an allusion here also to availability and cost. Quite frankly, I think in terms of instrumentation today, state-of- the-art SPECT and state-of-the-art PET can be priced at a very similar price point. You don't have to have a PET 128 slice camera in order to do high-quality cardiac PET CT imaging. If you want to do really good high-quality state-of-the-art SPECT imaging, however, you probably are going to be looking at one of the new solid-state cameras with or without CT, and that's going to cost a fair penny as well.

This webinar is about PET, so how can somebody get educated about PET who wasn't initially trained in it in their fellowship. First, I would say there are about 200 sites that are doing cardiac PET on a day in day out basis across the U.S. Pick one and see if you can't go there and spend some amount of time. Depending on your background, I would say a minimum of two to five days will give you a pretty good working understanding of the differences between SPECT and PET and will give you a foundation that you need.

ASNC is proceeding through its PET task force to develop an educational curriculum for cardiac PET. This is directed to cardiologists and others who are already in practice. Also, to technologists, many of whom also have not had exposure to PET. So this has modules throughout it covering the fundamentals all the way up to the more complicated aspects of it and hopefully this will be available within the next year.

Randy Thompson: I'd like to say one more thing regarding the educational needs. I would identify this educational need to the referring doctor community about PET and advanced SPECT. Certainly from talking to radiology benefit managers on these reviews, it's pretty clear, sometimes they don't understand why there is an advantage for PET or why we think it would be a better way to go. And that's probably true for a lot of cardiologists and certainly the primary care doctors that refer to testing. Why it is an advantage to have a PET over a SPECT, which patient should have which test, the patient centered imaging approach is the one that we like to take.


 

What are some of the ways you build awareness with physicians?

Randy Thompson: We do call physicians who refer the patient if the patient is hospitalized. We'll call them and give them the results. We'll go over the levels of certainty that we have, the confidence that we have in the test and we explain why a different test might be better if that's the case.

That's one way. And of course we do the things that doctors do on a regular basis. We speak at grand rounds, speak at medical meetings, we communicate with our referring doctors in various ways, but perhaps others want to talk.

Vasken Dilsizian: For us, there have been three basic points, both referring physicians and patients say how come nobody's told us about this regarding PET.

One, with Rubidium, the study is done in 30 minutes. They love that. They don't want to spend half a day, a whole day, come back the next day. Those days are gone and patients just say, "why is it that my referring physician didn't tell me that," and the referring physician sometimes doesn't know that.

Second, it is the really low radiation exposure to patients and high-quality images. And that's also very important that referring physicians don't seem to know. And the third, is the added value of the quantification of blood flow. So the fact that it's fast, provides higher resolution, high quality images, low radiation exposure, with the addition of quantification, a lot of the referring physicians are really puzzled at how come they're not more aware about this. I don't know how the ASNC or SNMMI can educate the referring physicians, but that's what's needed here.

Tim Bateman: I agree with all of that. A big challenge, I think, for us is there's a whole generation of doctors who refer for myocardial profusion imaging who really think of it as black and white. It's normal or abnormal based upon the presence of the perfusion defect.

I guess they are interested in the size of the defect and its severity and its location, but fundamentally, their reaction relates to normal or abnormal. PET confuses people a lot because there are so many relatively independent variables beyond the appearance of the profusion defect itself. So, for example, with Rubidium, there's the change in ejection fraction between rest and the peak of hyperemia because, as Vasken said, the patient doesn't even get off the table for this test. It's a true rest with a true peak hyperemia, regional wall motion, wall thickening, and ejection fraction measurement that you get to compare with the rest value.

You most often will be using a PET/CT hybrid device so you have some information about both coronary calcium and perhaps other important information, and then you've got the flow information. So there's a lot more data here, and explaining how all this fits together to determine an optimal next step really is almost as much word of mouth, at this point in time, than anything that you can easily impart in a review article, for example.

Vasken Dilsizian: That's why it's part of the level 3 training in the fellowship and I think that we as nuclear cardiologists have to interpret it, convey the impression that it's safe, that it reflects the indication, the clinical history. I think we should take the responsibility as the authors of those referred tests, to make sure that we are succinct in our interpretation, and not just describe, why the calcium score's this, the flow reserve is this, but there's no ischemia, and the EF goes up. If we just give facts but do not interpret it for them, then it becomes confusing.

So I think what we're saying is both the nuclear cardiologist who is currently practicing who wants to get into PET needs to continue their education through the professional societies it is not enough just through webinars. I really think that active participation either in experienced laboratory or at the scientific meetings be required so that the field actually grows and reflects the true value of the advancement of PET or SPECT.


 

What imaging test is the best for cardio viability and can you speak to the pros and cons of the available tests?

Vasken Dilsizian: So, viability is something that I've worked extensively on over the past 3 to 4 decades. It goes back to thallium imaging with rest redistribution or thallium reinjection. And during that time, dobutamine, or biphasic response, low and high dose dobutamine came about and most of the literature was comparing echo vs thallium. Then subsequently, PET imaging with FDG was introduced which was the only viability study that actually went through the FDA process for approval.

And then with MRIs, we were also able to identify what's scarred myocardium, transmural vs non-transmural, by applying the delayed enhancement technique.

So, I think regarding the current state of viability systems, I would really lean on the two big techniques. FDG PET with resting blood flow, or delayed enhanced MRI. Now, the advantages of PET over delayed enhanced MRI is that PET not only provides the information on myocardial blood flow and areas of hypo perfusion, but it also tells you whether there is scarring, non transmural scarring, hibernation or stunned myocardium. In the case of delayed enhanced MRI, the advantage is that you can actually look at the whole transmural wall and be able to look at the enhanced regions, whether it's involving only 25 percent of the scarred myocardium, 50 percent or more, or transmural.

So, MRI is great for as long as you just want to know how much of the myocardium is scarred, transmural versus non transmural.

In the case of PET imaging, however, the value is that you are able to look at the metabolism- perfusion mismatched pattern, which has been shown to correlate both with symptomatic improvement of heart failure and functional recovery after revascularization. Two very important indices; symptomatic and functional improvement, which translate to improved survival.

And so, at Maryland, even though the referring physicians may order both PET and MRI, the majority of the viability studies are ordered for PET imaging. I tend to read one to two viability studies per day for PET and there would be undoubtedly also some requests for MRI. Also, the other advantage of PET imaging, obviously, is if you have any mechanical or prosthetic instrumentation, AICD, pacemakers, or any metallic objects, those are contraindications for MRI, where nukes have no contraindications. Randy?

Randy Thompson: Vasken's a world expert in the topic so I don't have a whole lot to add to that. Indeed, the ability to do robust viability imaging, viability testing is another one of the reasons to have a PET program. MRI is comparable if both are available and an MRI is not as widely available as PET is. With the addition of wall motion and gadolinium enhancement, the accuracy of MRI for predicting viability has approached that of FDG PET but as Vasken said, the advantages of PET are extensive including the ability to be able to do it in all patients.
 

Tim Bateman: What do you think is most valuable, Vasken, recognition that there is ischemia, as in a stress test, or the FDG uptake?

Vasken Dilsizian: That's a great question. I always assume that before someone comes for a viability study, that they have already had a stress-rest study to assess the presence and extent of myocardial ischemia and fixed defects in the dysfunctional region. The clinical question is whether the fixed defect in a dysfunctional region represents scarred versus viable, hibernating myocardium. This is where FDG PET metabolism differentiates between viable, hibernating myocardium (metabolism-perfusion mismatch pattern) and scarred myocardium (metabolism-perfusion match pattern). That would be the thought process.

But what's happening, and I'm glad you brought this up, Tim, because what's happening now is that patients with myocardial infarction,transmural or non-transmural, who present with progressive and worsening heart failure, are taken directly to the cath lab. In the cath lab, they determine whether the patient has multivessel disease or not and determine whether there is extensive LV dysfunction and regional wall motion abnormalities that would warrant viability testing.

At that point, the surgeon will decide, before surgery, to order a myocardial viability study and in our institution, most commonly that would be PET imaging. In those cases, they tend to simply order resting myocardial blood flow and FDG PET because they say, "I already know the anatomy. I don't want to know ischemia."

In my report, I always state, because as you know they can be coexisting, dilated cardiomyopathy, from alcohol or other causes of valvular disease with ischemic coronary artery disease. In those patients, it's really tough to know what's remodeled myocardium from what is truly viable but stunned myocardium. So, in my reports I always state that in the absence of paired stress images, the presence of underlying myocardial ischemia cannot be assessed.

I keep saying that I don't think anybody orders stress myocardial perfusion study, because in the surgeon’s mind, they are simply trying to determine whether the patient is a candidate for CABG, wherethere is enough dysfunctional myocardium that would recover function after revascularization versus placing an LVAD or enlisting the patient on the cardiac transplant list.

Randy Thompson: Very good point.


 

Tim Bateman: So even if a patient has been in the cath lab and the anatomy is known but the question remains about viability, and sometimes this happens where the patient has not really had a stress test yet, would you recommend a stress test first?

Vasken Dilsizian: Yeah. I do. I always like ischemia information always. Because with the thallium reinjection, that was the concept. I was one of those advocates standing up with some of the more senior attendants always with rest redistribution. My question always was, don't you want to know ischemia? Because you really don't know if that's myopathic heart versus coronary disease. In case someone is worried that if you induce ischemia before you do FDG, does that change the FDG signals? And my answer is, it may, but if anything it will boost up the FDG signals. Because we have shown, and others have shown, as with ischemic memory, when you develop ischemia, there will be a broad switch from fatty acid to glucose, even with stress exercise. And so when you induce ischemia with pharmacologic stress, that area of myocardium, which may have had very subtle FDG uptake will actually boost up FDG confirming that it's ischemic but viable myocardium. So, there's really no problem. It's just that the pattern will look very differently from a resting study because the ischemic character will have much higher FDG uptake and normal regions may have very little uptake because glucose utilization has increased in those territories.

What does it take to establish a cardiac PET program? We are currently referring outside our facility, mainly for sarcoid evaluation.

Tim Bateman: Well, first of all, myocardial profusion imaging is the backbone of any cardiac PET program. There are other things such as mentioned here, cardiac sarcoid, device infections. There are other applications for a cardiac PET program but, when thinking about how to establish a PET program the focus predominately is going to be on myocardial perfusion.

So, what does it take? First of all, you have to think about instrumentation. There are really two choices. There's a dedicated PET scanner or there is a hybrid PET type device. So, years ago, most people used dedicated PET scanners where the attenuation correction was done with a built in radionuclide source. Today, most folks are wanting the CT for attenuation correction, recognizing that they can also use the CT for other things.

Even a low-end CT scanner, such as four slice or an eight slice, is good enough to recognize the presence of coronary calcium and to visually estimate its extent and severity. Obviously, when you're thinking about what kind of instrumentation you might want, you have to also think about what you might use the CT for. So, if for example you're going to want to quantify coronary calcium as part of a coronary calcium scoring program, well then you probably want at least a 16-slice scanner.

Patients can hold their breath for the 10 or 12 seconds, they need to hold it with a 16-slice scanner obviously. You'll get better image quality with more CT slices and patients will hold their breath for a shorter time interval.

If you want to do large vessel imaging, such as lead thoracic or abdominal aorta, the peripheral vessels, the renals, or carotids, you will need higher CT slices in order to do that well. With respect to the radionuclide, by far most users are using Rubidium. Already coming on board this year are additional sources for Rubidium. The current number of sites using Rubidium is about 200 and there is now enough availability of Strontium and Rubidium for about 400 sites in America. So, the shortage that was present several years ago is no longer an issue.

Historically, the delivery system for the Rubidium has been available only through one vendor, which was Bracco. Now there's a second vendor that has a delivery system that is FDA approved. That's Jubilant DraxImage, or JDI, and it is actively being marketed and sold in the U.S. at this point in time. Shielding will obviously be different, depending on if you're going to use just Rubidium with a dedicated camera, or whether you're going to also want to use FDG, which has a much longer half life, and a CT scanner. So that's another issue that will have to be thought about.

And finally, if you want to do things like sarcoid imaging and device infections. In labs like ours, and I'm sure Vasken could talk about his lab as well, these are now becoming common place studies, day in day out type studies. You clearly will need a PET/CT in order to do those types of evaluations.

Vasken Dilsizian: I agree. I just want to emphasize that even though I agree with you that perfusion imaging is a driver for PET, undoubtedly, the growth is going to be viability, sarcoidosis, device infections, and so I think that with the F18 labeled perfusion tracers coming along, I think this is going to be a really growing field. So while one might invest in a less expensive PET system early on, I think, with the volume increasing, you may replace it with a higher end PET/CT system.

Do you think that PET/MR will become an important imaging tool over the next few years not only regarding inflammatory cardiomyopathies but also for the assessment of CAD?

Patrick Bering: I certainly think that it will. I think the integrated imaging has added benefit as well as prognostic information for the patient. For certain disease conditions, including those for inflammatory cardiomyopathy, whether it's acute myocarditis, lymphocytic myocarditis, myocarditis, or cardiac sarcoidosis with acute inflammation.

The integration of PET and MR have a lot of benefits, but again, that's a very specialized test, but it does have great diagnostic advantage as far as getting the right diagnosis to guide your therapies and treatments for your patients.

Obviously, the integration of those can take a little bit more time, and would typically be done at specialized centers or academic centers that have a high volume in looking for these kinds of cases. And a PET/CT integration has some benefit of a little bit quicker turnaround and speed for patients.

Both PET/CT and PET/MR have combined low radiation exposure. I'm recalling a recent article in JACC Cardiovascular Imaging quoting about 7.2 milliseverts for PET/MR combined imaging when looking for coronary atherosclerosis, and indeed it is also being used in cases of cardiac sarcoidosis, not only for risk stratification but also to figure out in what phase of the disease does the patient find themselves? Are they in an active, inflammatory phase of the disease, or do they find themselves in a scarred and more burned out or placid phase?

The utilization or integration of those two modalities together, I think, provide additive information. But again, PET is very useful in identifying areas of acute inflammation with FDG uptake in the myocardium and cases like acute inflammatory sarcoidosis, whereas parametric measures like T2 mapping and cardiac MRI really just measure water in the myocardial interstitium is sensitive, but not necessarily specific for cardiac sarcoidosis. And so the integration of the two have added value for those kinds of disease conditions.


 

How difficult is the preapproval process for PET?

Tim Bateman: It needn't be a scary proposition for people. Just kind of looking at it from the 10,000 foot level.

Patients in the hospital and patients in the emergency room do not need preapproval for PET. Secondly, the over 65 year olds in America, the Medicare population, the vast majority do not need any preapproval for PET. So fundamentally we're talking about younger people who have commercial insurance, some of those are administered through a radiology benefits manager (RBM). That's really what we were talking about at the start of this session, is how to get pre authorization through an RBM or directly through an insurance company.

When we look at our operation, about 80 percent of the patients who have a PET scan at our center did not require pre authorization at all. They're Medicare patients, emergency room, inpatients and so forth. The RBMs since last year, since the position statement has come out, many of the RBM's have lightened up their criteria for PET quite substantially.

The RBM's don't control the whole process. They make recommendations to the insurance companies about what the standards ought to be, but I know for a fact that at least one of America's major RBMs adopted almost word for word last year's position statement.

Randy Thompson: I would just reiterate what Tim just said. I was taught to give it a phone call. Most patients can have a PET without a lot of discussion with the insurance companies. They're getting less troublesome than it used to be and by following a few rules you can get most patients who need a PET past the radiology benefits managers even if they're a tough one.

We spend so much time and aggravation on those few cases. We sometimes lose track of the fact that they're really the minority of cases and most patients can get a PET without too much trouble.
 

Does performing PET prior to a cardiac authorization free up the cath lab to retask it from less diagnostics to more interventions?

Randy Thompson: We certainly hope so. But when you have better myocardial perfusion imaging, better imaging results, more reliable results, results that the doctors trust and believe in, fewer patients get sent for diagnostic cardiac catheterization or the half artery cardiac catheterization. That's what we found certainly in our experience, for many years, the number of patients in our cath lab who get coronary angiograms and have no intervention done are a lot lower than the national average, and the percentage of patients who have a coronary intervention done in the same setting are higher than the national average.

It makes sense if you have better quality diagnostic tests, it ought to let the cath lab to do more focused work on interventions.
 

What do you consider to be the ideal PET perfusion tracer available?

Vasken Dilsizian: This is actually a very, very good question. So, as an academician, if I put my hat on, I would have said, well, the best perfusion tracer would be the one that tracks blood flow linearly and that would be O15 water. O15 water is not approved in the United States but it's being used in Europe.

The problem with O15 water is that you really have to rely on the quantitative value that you get from the computer software and cannot verify the quantitative blood flow value visually, since there's no trapping of O15 in the myocardium, and therefore, there are no delayed images to assess visually. What I'm saying is that those absolute blood flow measurements that you get with O15 water better be as reliable as chem-7 blood work, such as serum potassium, sodium BUN or creatinine levels. I am afraid that the quantitative data of O15 water and the reproducibility of the measurement is not there yet.

And so what's the advantage to trapping agents that are FDA approved like Rubidium and ammonia? The advantage is that you get both absolute myocardial blood flow assessment plus visual assessment of delayed images of the myocardium, where the radiotracer is trapped in the myocyte, permitting time for imaging. Accordingly, in our recent uptake PET guidelines, we specifically stated that there are a certain subgroup of patients where absolute hyperemic myocardial blood flow, and flow reserve, may not add diagnostic value to the visual interpretation or can even be ambiguous or misleading. This would apply to patients who are post CABG, with a defuse reduction in myocardial blood flow despite the surgical grafts being patent. You have competitive flow from the native vessels and the grafted vessels, so the quantitative numbers sometimes may be misleading.

Among patients with transmural infarction, a small increase in hyperemic blood flow during stress, divided by a low resting blood flow value, will give a normal or near normal myocardial flow reserve value, which would be erroneous. Same applies to patients with severe chronic left ventricular dysfunction in the absence of coronary artery disease. So, in my opinion, while quantitative O15 water values may be great for patients with no prior history of coronary artery disease, such as infarction, CABG or left ventricular dysfunction, who present with new onset chest pain, unfortunately it is not practical or generalizable to have all patients referred to our clinic, such as those with prior CABG or chronic renal insufficiency.

Now regarding practical differences of imaging Rubidium versus ammonia, with N13 ammonia, because of its 10-minute half-life, serial rest and stress PET imaging requires approximately 1 hour delay between the 2 studies, since one has to wait five half-lives between rest and stress studies in order for the prior injected dose of N-13 ammonia decays, and that's a significant problem, for it can tie up your cyclotron for a single myocardial perfusion PET study. Even if it's a tabletop cyclotron, the 1 hour delay between rest and stress studies is often unacceptable for the use of PET camera time.

Once you get used to the idea of the 72-second half-life of Rubidium, despite the expense of the rubidium-82 generator, the fact that one can complete an entire rest and stress sequential myocardial perfusion PET study in 30 minutes, without the patient having to come off the PET table, is a tremendous advantage for running a nuclear laboratory and for patient throughput. Sequential rubidium PET imaging, along with quantitative myocardial blood flow data within 30 minutes, is priceless for the emergency room physicians and for hospital administrators. In a world where rapid throughput of patients in the emergency room or in hospital beds is at a premium, Rubidium has all the advantages as the “ideal” PET flow tracer.

Tim Bateman: You summarized it very well. We're going to talk in a few minutes about a new F18 agent that is making its way through the FDA approval process. But, at least in my opinion, Rubidium is here to stay. Certainly labs that do a high volume will not be very intrigued with either ammonia or an F18 perfusion tracer for the reasons that you just mentioned.

When it comes to justifying purchase of a PET/CT, for example to a hospital system, these secondary advantages to PET compared to SPECT are prominent in the minds of the folks in the hospitals. The opportunity to have the radionuclide onsite, ready to go at any time, a 30-minute turnaround time so that patients can be imaged quickly and decisions can be made within in an hour, about whether the patient can go home or needs to be moved on to another test such as a cath procedure on that same day.
 

Does the set threshold between normal and abnormal CFR now exist? Literature shows variability on this. Which threshold do we use?

Tim Bateman: So, first of all, CFR is a physiologic measurement so it's a continuous measurement. There are physiologic changes in people as they age so the concept of a set threshold is a little bit wishful thinking in my mind.

What we do know is, the higher the CFR the better. It establishes, as we talked about earlier, that the epicardial coronaries, as well as the microvasculature, is healthy. The lower the CFR the worse the outcomes, and thresholding can be used, as I mentioned earlier, to determine or to assess and evaluate as to whether this is most likely epicardial coronary disease or microvascular disease, or both.

Much of the literature says that prognosis substantially worsens when CFR becomes below 2 or 2.2 type threshold. The different software programs that are FDA approved at this point in time do provide directional values that are very similar but the absolute values do differ plus or minus about 20 percent.

So, I think in terms of feeling comfortable that everything is normal, you have to know the software that you are using. It's all be validated in order to get FDA approval, and some of those software programs have a threshold of 2. Some of them have a threshold of 2.2, some 2.3. You have to know your software, I guess, is the way I would answer this question.


 

Do you have experience in using RFR (relative flow reserve) to differentiate between epicardial CAD and microvascular disease?

Vasken Dilsizian: I don't have experience. I do know the literature and as I said earlier, I don't think this is going to be an index that we're going to be using because it really hasn't shown any incremental value over hyperemic blood flow or noncoronary flow reserve. Plus, I think the advantage again isn't to go back to what we had been doing with SPECT imaging, comparing an abnormal region to a referenced normal region, but it's much better to look at abnormal flow during hyperemia in the same vascular territory because that has physiological implications just like FFR and revascularization. So, I just don't think that FFR is going to be in any way adopted as an index in the clinical setting but, we'll see what the rest of the literature says. But so far it hasn't shown itself to be a unique index for either microvascular disease or epicardial disease.

What is the cost and reimbursement for cardiac PET/CT?

Tim Bateman: Randy will weigh in there too because he is heavily involved with that ACC and ASNC over these issues.

So, first of all, in America, as I think everybody knows, there is a physician fee schedule for testing that is performed in physician’s private offices and there is a hospital outpatient schedule or HOPPS, paid under APC classifications for patients who are imaged in hospitals or hospital outpatient settings. The physician fee schedule varies across the country by Medicare region because there is not a national coverage determination for PET at this point in time.

For hospitals and hospital outpatients, there is a technical fee for PET. In 2017, the fee was $1321. That compares to rest-stress SPECT, which was $1138. On top of that, there is a stress test. The technical fee for the stress test under the HOPPS schedule is $232 and then of course there's a professional fee to be added onto that perspective. For rest-stress SPECT it's about $80 and for rest-stress PET it's about $90. Randy will also bring us up to date with what's going on with coding and billing for CFR.

Randy Thompson: In terms of the cost of PET, of course it's a relatively high fixed cost, the cost of the scanner, the cost of the Rubidium generators, there's a monthly fee. So how well one does in the cost versus reimbursement in large part depends on the number of cases that are put through the system. If you have a very busy laboratory, then the cost of the camera and the cost of the generator are spread over more patients and obviously the economics work very powerfully in that setting.

What Tim was referring to in terms of billing codes is just to bring you up to date on where we are with billing for the coronary flow reserve and the absolute quantitation of myocardial blood flow. We approached the CPT editorial panel this year and starting in January there'll be a category 3 code for absolute quantification of myocardial blood flow with PET. It's an add-on code.

Now, a category 3 code is a temporary code, a technical code. It can be tracked. It doesn't necessarily mean you're going to get reimbursed for it. In fact, oftentimes you're not. It does give individuals the opportunity to go to their carriers, the private commercial payers and the Medicare advisory council and ask them to reimburse for this code.

And oftentimes they do and they may in this setting because the literature with flow is so robust. We hope within the next year to again go to the CPT editorial panel and ask for a permanent category 1 code. That would then trigger evaluation of the RUC and then a similar successful process to get in the books in 2020. And so we don't really have a standard normal reimbursement for PET as for quantitation of myocardial blood flow until over two years from now assuming things go well.


 

Under the context of recent government initiatives with quality. Also using the assumption that some labs reduce unnecessary normal cath after implementing PET. Do you feel one day that PET with coronary flow reserve should serve as a gate keeper before cath or revascularization?

Randy Thompson: I think that's a very interesting question. As the question alludes to we’re in a transition from volume to value, that value-based practices should be the norm in the future. And I believe in that setting, PET ought to do very well and it's a test where you've got much more confidence of all the ancillary benefits that we've been talking about here.

I would think that for moderately complicated patients or complicated patients, it will be the right test, the right patient at the right time and you'll do fewer other tests and if the question was asked, you should do fewer normal cardio catheterizations and so forth.

Now the other part of the question is will we one day have requirement that someone have a PET with coronary flow reserve before a cardiac cath. That seems sort of far off to me. I just mentioned the timeframe of when we will get even reasonable reimbursement for flow measurements. Many patients are not all that complicated. Many patients can be diagnosed without a PET scan of course. Some people ought to go to the cardiac catheterization laboratory for symptoms without a test, or have a simpler stress test that shows substantial ischemia causing the chest pain.

In that case, I don't believe a PET scan would be necessary, but I do think PET will do very well in that paradigm.
 

Dr. Gould has published about coronary flow capacity providing more information over coronary flow reserve alone. Do any of you have experience in measuring coronary flow capacity and if so, how has it impacted your practice?

Vasken Dilsizian: So, Dr. Gould has been a leader in this field and he has used PET and clinical decision making in Houston and he has written some seminal papers where he's used the mapping of both hyperemic blood flow and flow reserve combination because they can be variable in certain patients.

For example, we can have a high resting blood flow so that even the hyperemic blood flow is normal. The flow reserve will appear abnormal. This is much more common in patients with hypertropic cardiomyopathy and hypertensive heart disease. And so you can have some disparate numbers.

Most of us would be able to simply look at the resting flow and explain the LVH and therefore not really dwell too much on the flow reserve because the ratio will appear as if it's abnormal. We tend to look at the hyperemic blood flow as the truth in those cases as saying whether those epicardia there or not.

But Dr. Gould has come up with this term called chronic flow capacity where he takes into consideration both the flow reserve and hyperemic blood flow and he has gradations of when they're both the same corner, high and normal, or they’re both abnormal or where they are disparate, and comes up with these metrics of prognosis.

It's interesting. I think that again he uses it correctly. I know that some of the fellows that have used his software. Again, this is a software that's personal based in use, and it's not commercially available though he's willing to give it to those who are interested in using it. So I will just say that it's a unique software for a particular laboratory that's not generalizable to those with different vendors and different machines. Therefore, I would say interesting physiological description but most of us seem to be doing quite well except in looking at the two parameters rather than coming up with one coronary flow capacity index. We just look at both and we obviously visually and intellectually dissect out what the underlying disease is.

So the answer is, I don't use it, most of us don't use it. Only Dr. Gould and some of the fellows in his lab use it.
 

F18-Flurpiridaz (phase III radiopharmaceutical for PET cardiac imaging) seems very promising given high cardiac extraction (higher than ammonia). Also, once FDA approved clinical PET without cyclotrons or generators will be able to perform cardiac PET with quantification. So it could be a game changer for cardiac PET nationwide. Most recently GE has invested in the production of Flurpiridaz. Should we expect this radiopharmaceutical to be in the market in the next couple of years? How realistic is this?

Vasken Dilsizian: Well, the whole idea of an F18 labeled perfusion tracer, because of the longer half life of F18, you are able to exercise patients on a treadmill, and inject just like you'd inject thallium or technetium perfusion tracers and have time to move the patients from the treadmill subsequently to the PET camera and acquire images that reflect the trapping of Flurpiridaz just like the trapping of thallium and technetium sestamibi or ammonia in the myocardium. The advantage therefore is that currently, because of the short half-lives of the current FDA approved tracers, we are limited to pharmacologic stress only and therefore, if you're a private practice or you're in a hospital setting, you have to have both a treadmill laboratory which is SPECT based, and then pharmacologic lab which would be PET based.

And that's dual system. You have to have either technology, with some nurses running both or simultaneously. It will be wonderful if you could have purely PET based myocardial perfusion imaging where you could do both a treadmill and pharmacologic stress for patients in the same camera.

That would be the advantage of F18. Clearly with F18, also, because of the longer half-life rather than Rubidium which has a shorter half-life and a normal positive range, the images are much sharper than Rubidium, even though Rubidium is fantastic compared to SPECT agents. It can be improved further with F18 labeled perfusion tracers.

So, the answer to your question is that visually, and from the four characteristics, I think F18 Flurpiridaz seems to be a very promising agent and clearly with interest in the repeat phase 3 clinical trial, I have no doubt that someday this agent and others similar to Flurpiridaz will be approved by the FDA for clinical use.

One would love to have one agent and have both exercise and vasodilated stress done all in PET. We'd rather have a dual system, two cameras, SPECT with exercise process with PET. And that would be the advantage of moving with F18 perfusion tracers.

The disadvantage would be that you lose the rapid throughput that we've come to love with Rubidium. Thirty-minute rest and stress studies, absolute blood flow measurements and rather high accuracy even though the image quality with Rubidium may not be as pretty, and sharp as F18 labeled perfusion tracers might be.

I have no doubt that F18 labeled perfusion tracers will be approved at some point. Perhaps more than one. The question that's going to come us is will people still use Rubidium for pharmacologic stress and F18 Flurpiridaz for exercise stress treadmill? Only given the rapid throughput and the advantage that has in patients with 30-minute turnaround time with Rubidium.

Now that would be costly. Because again, Rubidium generators are expensive. The advantage of F18 labeled perfusion tracers is that you don't have to have a cyclotron or a generator investment. You can simply order unit doses just like private offices do now. You order unit doses on a daily basis as needed and therefore it will tremendously bring down the cost of all the procedure.

Tim Bateman: Sure. Well, there's been a lot of due diligence on the agent Vasken has been talking about. It's called F18 Flurpiridaz. The due diligence has been on the clinical side and it has also been on the business side. And I agree with Vasken, there is close to certainty that this agent is going to be able to come to market. The images are very, very good. The flow quantification is robust. It will not have the throughput capability that Rubidium has. The liver also likes this agent kind of like the liver likes sestamibi and there needs to be a waiting period to clear out the liver before starting to take image, which really means the protocol is going to be sort of like, the sestamibi type protocol.

The first of two obligatory phase 3 studies has been completed. The hope is the second will be launched in early 2018. The big study will require enrollment that's close to 1,000 patients and there will need to be a gold standard which would be coronary angiography and there will also be a comparator which would be sestamibi. So you can kind of do the math about how long it's going to take to complete that phase 3 study. Probably a couple of years. Probably another year, or year and a half for data analysis, and all the things the FDA would like so what is a realistic timeline? The question was in the next couple of years? Well no, that's not realistic. Within five years, I would say, yes, that's a very realistic assumption.
 

Are you considering PET/MR for evaluation of cardiac sarcoid instead of PET/CT? Since these patients often required both PET and MR studies, a single stop shop for a PET/MR study seems logical at least in theory.

Patrick Bering: That's a very good question and a tough one because there are advantages to both modalities. I think when you combine PET with CT imaging you can get the added advantage of having a low dose CT that looks at extra-cardiac tissues because sarcoidosis is a systemic disorder than can affect many different organs, you may also want to look and see if you can find evidence of PET activity that you correlate with the low dose CT throughout other regions of the body outside of the mediastinum.

So, PET/CT has great advantages there. One of the things that I think is useful about PET/MR images is that the presence of delayed gadolinium enhancement is associated with an increased risk of death or significant ventricular tachycardia in patients who have cardiac sarcoidosiseven in those with preserved left ventricular ejection fraction. So it's very useful in the risk stratification of these patients outside of what you get just from PET/CT itself.

So, using the PET, plus the cardiac MRI, can give you risk stratification as the strength of the PET, which is to identify disease state and also to track disease progression with treatment. One of the nice things about PET, as we mentioned earlier, is it can identify this active or inflammatory phase of cardiac sarcoidosis and then you can get longitudinal studies at an interval after you've started immunomodulating therapy to look at how well you're doing with your therapy and to see are you able to suppress PET avid activity in the heart and in so doing, you can be very confident that your treatment is very successful.

And again, I think PET has a very strong advantage there. It's not only diagnosing inactive inflammatory phase and cardiac sarcoidosis, but also when tracking disease progression as well as the efficacy of your therapy. So the use of PET plus MR does have some benefit by looking at whether or not there are small areas of myocardial damage with delayed gadolinium enhancement and whether that adds additional risk stratification for patients who might have sudden cardiac arrest.

Vasken Dilsizian: I agree with you, Patrick except that the question was a single stop shop for hybrid PET/MR. As you know, the equipment is out there. It costs more than $5 million. It's really looking for a real true unique clinical application that would require hybrid system rather than sequential imaging.

So everything you said, Patrick, I agree with you, but it came down sequentially. There's no reason to invest a $5 million hybrid system. It can simply do PET and MR, right, two different days or two different machines and get the same information.

Patrick Bering: I think that statement is definitely true. I think you can get accurate co-localization of the two signals from PET and CMR. It doesn't necessarily need to be a hybrid system and I think for general purposes as well as cost considerations for many centers, the use of PET/CT hybrid I think makes a lot more financial sense and overall practice sense. As Dr. Dilsizian was very right to point out, you can still get additive information even if you don't get PET and MR information at the same time or with an integrated hybrid system.