: Hello and welcome to this NeurologyLive® Peer Exchange titled, “Management of Cardiac Amyloidosis.” 

I am Dr John Berk from Boston University School of Medicine.  

Joining me today in this virtual discussion are my colleagues:  

Dr Akshay Desai, director of the Cardiomyopathy and Heart Failure Program at Brigham and Women’s Hospital in Boston; Dr Mazen Hanna, codirector of the Amyloidosis Center at Cleveland Clinic in Cleveland, Ohio; and Dr Ronald Witteles, codirector, and actually founder of the Amyloid Center at Stanford University in Palo Alto, California. 

Today, we’re going to discuss a number of topics pertaining to the diagnosis and treatment of cardiac amyloidosis. Let’s get started on our first topic, which appropriately is: What’s amyloid? Amyloid is a family of diseases resulting from the misassembly and misfolding of particular proteins. There are over 30 proteins that can misfold to form amyloid. Identifying the subunit protein is critical to the management of disease. It not only determines what organs are involved, but ultimately defines what therapies are considerations. 

To begin, Ron, can you give us some insights into how you address a referral for a patient with cardiac amyloid with no idea whether we’re talking about AL [light-chain amyloidosis] or a TTR [transthyretin] amyloid? 

: Sure, thank you. When a referral comes in, most with a suspicion of cardiac amyloidosis, it tends to be for 1 of 2 reasons: either somebody has had cardiac imaging and has the suspicion based on that, that’s been raised as cardiac amyloidosis, or they have a known diagnosis of systemic amyloidosis and there’s a question of cardiac involvement. If we’re talking about the former and it’s really a question of do they have amyloidosis at all, there can be some clues to imaging—I think we’re going to get to that a little bit later, so I won’t address them right now&mdash;but often, clues that come off of echocardiography more than anything of being increased wall thickness. That’s what’s often referred to as hypertrophy, although it’s not actually hypertrophy of the muscle but rather deposition of amyloid deposits. 

There can be some other clues, things like elevations in cardiac biomarkers, troponin, BNP [brain natriuretic peptide], and more than anything, if you’re talking about systemic amyloidosis, it can be a constellation of abnormalities in other organs or organ systems. Neuropathy, for example, can certainly occur with either of the 2 main types of cardiac amyloidosis, AL, or transthyretin as we’re going to get into. But particularly with AL amyloidosis, other organ dysfunction—renal, hepatic, really just about any organ dysfunction&mdash;can occur often, and when people see clustering, it will make them think that. 

So, when I’m seeing a new patient with suspected amyloidosis, there’s a couple of things. One is there are basic laboratory screenings that we do for pretty much any patient, which will include, of course, standard labs, including standard biomarkers, but also very importantly ruling out a monoclonal protein—as I think we’ll get to in a little bit&mdash;to help guide us whether they could have AL amyloidosis or not. We’ll review basic imaging at least with an echocardiogram and an EKG, and we will go from there. Finally, we’ll look for typical findings on echo that might point us one way or another and typical findings and demographics that point us one way or the other. For example, a particularly extremely thick-looking echo would push us more toward actually thinking about transthyretin than AL, although that’s certainly not an exact science, and demographics. An older male without other signs of organ dysfunction would make me think he has transthyretin. A younger patient, a woman, would push me more toward a diagnosis of AL amyloidosis. 

: That’s great. Thanks a lot, Ron. Dr Hanna, you’ve considered the extra cardiac manifestations of disease and actually have conducted a study looking at carpal tunnel involvement. Can you tell us with much the same scenario, meeting a patient for the first time, what are the particular historical features or, more importantly, the physical manifestations that clue you in to TTR versus AL disease? 

: Yeah, it’s a great question. I will first start with AL. There is 1 physical exam finding that’s essentially pathognomonic for AL, and that’s macroglossia, or an enlarged tongue, from the deposition, although there’s 1 mutation with hereditary TTR that’s been described to have that. I would say 99% of the time, if you see an echo that looks like cardiac amyloid and you see a big thick tongue or macroglossia, that’s essentially pathognomonic for AL. Other physical exam findings which are generally found in patients with heart failure, such as elevated jugular venous pressure and edema, that’s not going to be specific to either one. Typically, if you have significant orthostatic hypotension on exam, then it could either be AL or various mutations that cause hereditary autonomic neuropathy, but wild  type doesn’t tend to have that significant of autonomic neuropathy. 

As far as historical clues, you brought up carpal tunnel syndrome. Bilateral carpal tunnel syndrome is actually pretty common in patients with ATTR, particularly wild-type ATTR cardiac amyloidosis. Upwards of 40% of patients with this diagnosis will have a preceding history of bilateral carpal tunnel surgery. This can also occur in patients with AL amyloidosis. So, the fact that you have a history of bilateral carpal tunnel syndrome, doesn’t mean you don’t have AL, but it’s more suspicious for ATTR, particularly wild type. Oftentimes, the carpal tunnel manifestations can precede the cardiac manifestations by 5, 10, and even 15 years. So it’s always very important to ask anyone who is presenting with a thickened ventricle or HFpEF [heart failure with preserved ejection fraction] if have they had carpal tunnel surgery. 

Another very important historical clue is spinal stenosis, and actually that’s much more commonly seen in patients with ATTR than AL, and in fact, again, almost exclusively in wild type. And finally, biceps tendon rupture. There’s a nice publication, about a third of patients with wild-type ATTR cardiac amyloidosis have a history of biceps tendon rupture. So, these orthopedic or entrapment neuropathy type of manifestations will really heighten the suspicion that a patient can have actual cardiac amyloidosis and more so ATTR than AL in a lot of those manifestations. 

Cardiac Amyloidosis Diagnostic Workup

: So, the patient comes into your office and they’ve been diagnosed with hypertrophic cardiomyopathy, they’re on standard medications, and they’re doing really poorly. Is that at all helpful in history, or is that just the way hypertrophic cardiomyopathies go? 

: I think it’s an important phenotype to discuss. A lot of patients who come to cardiac attention are those with an established diagnosis of heart failure, often in the setting of preserved ejection fraction, who have increased wall thickness, as Dr Witteles outlined, in the absence of a typical stimulus for left ventricular hypertrophy. So, big thick walls in the absence of things that are associated with thick walls, like hypertension, I think should raise suspicion for a possible contributor. 

In the case you described, where there’s a patient with a known or a presumed diagnosis of hypertrophic cardiomyopathy, who is responding poorly to therapies like β-blockers, I think the intolerance of standard therapy in the setting of hypertrophy or apparent hypertrophy should lead us to question the diagnosis, particularly if some of these auxiliary clues are present—orthostasis, peripheral neuropathy, biceps tendon rupture, bilateral carpal tunnel syndrome. So, I think the whole context of the patient in the historical features, in the setting of increased wall thickness, are things that should lead one to suspect that amyloidosis might be present. So those are some of the things that I think. 

Another feature that I think is often useful, although not diagnostic and sometimes absent, is really to look at the ECG in the patient who has thick walls seen on echocardiography. If there is a discrepancy between the voltage on the ECG and the wall thickness on the echo, that might be a clue, although in many patients with defined or definite amyloid heart disease, that voltage discrepancy is not apparent. 

So, I think there are a lot of clues, both from history—do you have the typical epidemiology, do you have the typical risk factors for development of hypertrophy? On physical exam, do you have some of these auxiliary signs or auxiliary diagnoses? On EKG, is there a discrepant voltage-to-mass ratio? Then, I think we can talk about other imaging features that may come up a little later in the program. 

: But I just want to add something. As Dr Desai was speaking, I thought of a couple of other things. One of the pieces of the clinical history that is often seen in AL [amyloid light-chain amyloidosis], if you really ask for it, and maybe not often seen, but more specific to AL, is jaw claudication. Another physical exam finding that you can see in patients with AL is brittle nails. So, those 2 things I didn’t mention. And finally, in any patient who presents with HFpEF [heart failure with preserved ejection fraction] or thickened walls who has nephrotic range proteinuria, you’ve got to think about AL amyloidosis. 

: And the basis of the claudication, and then we’ll get to Ron? 

: I believe the basis of the jaw claudication is related to small-vessel ischemia. As we know, the amyloid deposits can deposit in the small vessels, and I believe it’s due to small-vessel ischemia when somebody is chewing, although we can see what Ron says. 

: Ron, you had a comment about macroglossia? 

: In terms of macroglossia, I think as cardiologists we aren’t used to looking at tongues very much. Anybody who treats amyloid does get used to looking at tongues. If you start looking at them, you’ll see there are people with true, honest-to-goodness, extreme macroglossia, sometimes to the point that they can’t even handle secretions, etc. That, as Maz was saying before, is really pathognomonic for AL amyloidosis. Transthyretin will not cause that. On the other hand, when you start looking for more subtle signs, and we often talk about scalloping of the tongue, which are the indentations from the upper teeth on the tongue, at least from my standpoint, I actually see that a fair bit in people with transthyretin amyloid. So when you read in the textbook, it does say AL amyloid, scalloping of the tongue is pathognomonic, and I think that’s only true for the more severe forms, not the less severe. I’m curious if others have found the same. 

The other comment that I just wanted to make, in terms of wall thickness that was pointed out, indeed that if you see increased wall thickness without a clear cause, that’s 1 of the clear things you should be thinking about along with, for example, hypertrophic cardiomyopathy. But what I’d emphasize is that when you start getting into older populations, everybody has a history of hypertension. Just because somebody has a history of hypertension, that does not particularly explain massive wall thickening. For example, a very nice study just screening everybody with aortic stenosis found 16% of the individuals  (just all-comers being screened) had concomitant transthyretin amyloidosis, 22% of them. So the main message I would say is if you see somebody with significant increased wall thickness, regardless of whether they have reasons why they should have increased wall thickness, amyloidosis—particularly transthyretin amyloidosis&mdash;actually should be 1 of the high considerations for the cause. 

: Thank you. Dr Desai, you had a comment? 

: I was just going to build on what Ron said, and that is I think we’re starting to appreciate more and more that this very enigmatic problem of heart failure with preserved ejection fraction, where we’ve really had very little success in defining specific medical therapy, may be contaminated by a large proportion of particularly wild-type TTR [transthyretin] amyloid. So I think that deliberately looking, as has been suggested by the others, for amyloid in patients who have a little bit more wall thickening than you might expect for the degree of hypertension or the degree of aortic valve disease, suspecting and at least deliberately looking for those historical and physical exam clues in a patient who presents with HFpEF or low-gradient aortic stenosis, I think these are really important things. I think the data are suggesting to us that a large proportion of those patients may have undiagnosed amyloid. And it may be 1 of the reasons that some of our trials have really failed to hit because we’ve basically taken a population that has HFpEF that might respond to therapies, and then added in a substantial subset of people who have amyloid, that may need a very different approach. 

: I don’t want to belabor the point, but there’s 1 thing that Ron brought up in the beginning, that I just wanted to dovetail a little bit on—and that’s the epidemiology of the patient, the demographics of the patient. If a 53-year-old male walks into my office, is it possible that they have TTR cardiac amyloidosis? It is, but it’s probably going to be more likely it’s AL. So, in this era of increased imaging techniques and pyrophosphate scans, where people are not effectively ruling out AL, you have to think to yourself, does this 50-some-year-old patient actually have TTR? If you have an elderly patient, it’s going to be more likely ATTR than AL, not that it can’t be either. But in terms of demographic, if it’s an African American in their late 60s, you start to think of this hereditary form of ATTR. So, I think knowing the age and the sex of the patient, the demographic is important when you’re trying to think about these patients. 

Hypertrophic Cardiomyopathy Historical Prognosis

: Let’s talk about diagnostics a little bit. Dr Desai, can you inform us about the echo features of cardiac amyloid, per se, and then perhaps some of the subtleties that might sway you into a diagnosis of AL [light chain amyloidosis] versus TTR [transthyretin]? 

: Ultimately, cardiac amyloid is often associated with increased wall thickening. We’ve called that left ventricular hypertrophy, but in many cases, it’s not truly hypertrophy because there’s more infiltration of the myocardium that’s leading to that perception of wall thickness. So, that would be the characteristic finding. I think there are a range of more subtle findings. If one looks at Doppler tissue imaging, looking at myocardial relaxation velocity of the septal or lateral mitral annulus, there is substantial slowing of myocardial relaxation in patients with infiltrative heart disease and amyloid, in particular. So, very low myocardial relaxation velocities may suggest the diagnosis, in particular, the absence of some of those other triggers for hypertrophy or diminished relaxation that we mentioned. 

Beyond that, there are novel imaging approaches that can be applied, including longitudinal strain imaging, and there are typical patterns that have been described in patients with amyloid. Classic is this cherry on top, which is preserved apical strain and diminished longitudinal strain at the base—the bull’s-eye plot pattern of strain like a large red spot in the middle. That is a classic pattern that’s been identified in patients with amyloid. 

Then, I think there are auxiliary features. In patients who have severe hypertrophy and diastolic filling abnormalities, we often see atrial enlargement, often biatrial enlargement in these cases, that would be suggestive. So, I think those are some of the features I look for. Is the wall thickness abnormal? Is diastolic function abnormal? Is the strain pattern typical of cardiac amyloid? Is there biatrial enlargement with relatively preserved ventricular size? I think those are some of the features we should start with. 

: That’s great. Dr Hanna, when is a noncardiac biopsy sufficient in your mind to make the diagnosis of AL or TTR amyloid cardiomyopathy? 

: If you have a patient who has a monoclonal protein, significant lichen abnormalities, and they have a noncardiac biopsy, which would include a bone marrow biopsy if amyloid was found in the bone marrow and typed by MASS SPECT [mass spectrometry] as AL, or the fat pad or salivary gland biopsy, showing that there’s AL amyloid deposits elsewhere, if you have cardiac imaging features that suggest cardiac involvement, such as a wall thickness greater than 12 millimeters or diffuse LGE [late gadolinium enhancement imaging], late gadolinium enhancement on an MRI, and elevated biomarkers consistent with that systemic involvement, I think you don’t need a cardiac biopsy to say, “Hey, this person also has AL cardiac amyloidosis”. 

With TTR, if you have a patient, for example, who had a soft tissue biopsy, let’s say the carpal tunnel area or spinal stenosis area, and they have ATTR [transthyretin amyloidosis] amyloid deposits there, and you do a technetium pyrophosphate scan in addition to an echocardiogram, and there is significant uptake—grade 2 or grade 3 uptake confirmed by SPECT imaging&mdash;then without doing a cardiac biopsy, I do believe that’s enough to say that there’s cardiac involvement of the ATTR amyloidosis. 

So, I think those are the general ideas. I would think if there’s any question that we need to do a cardiac biopsy, an endomyocardial biopsy, because I think that 1 thing that hopefully we’ll discuss later is the concern and pendulum of trying to make a noninvasive diagnosis when we really need tissue. 

AL and ATTR Diagnosis: Echo and Noncardiac Biopsy

: Ron, when in your practice are heart biopsies warranted, and are there undue risks? 

: Building on what Maz was saying, first, I want to emphasize that for AL [light chain] amyloidosis, it is a diagnosis that can only be made by biopsy. Now it doesn’t have to be a cardiac biopsy as Maz was saying. If you have proven AL amyloidosis, usually proven by MASS SPECT [mass spectrometry], your biopsy sample, and you have clear indications that there’s cardiac involvement by imaging, there’s certainly no need to biopsy the heart any more than there’s the need to biopsy the kidneys in somebody where you’ve proven cardiac amyloidosis, to prove that they have it there. 

Remember that once you’ve made a diagnosis of systemic AL amyloidosis, there’s almost always a treatment indication with chemotherapy or other therapies as we’ll discuss later. So, in terms of changing what you’re going to do, yes it’s nice to know for sure if they have cardiac involvement, but the real question up front is, do we need to get them started on therapy or not? Now that gets somewhat into the choice of where you’re going to biopsy. While you can definitely find AL amyloid deposits in other places like a fat pad biopsy or sometimes in the bone marrow for somebody who has underlying AL amyloid of this, you can often miss it. You’ll find it more with AL than transthyretin in other places, but you can still miss it there. I would urge everybody who is viewing this to think of AL amyloidosis, particularly cardiac AL amyloidosis, as a near emergency to get people started on treatment. The disease can progress very quickly, and as we’ll talk about later, there are very effective therapies that we have available with it. But you have to get them started on people before they’ve had particularly too much cardiac damage. 

So, in our practice at Stanford, we generally biopsy the clinically involved organ, which is most commonly the heart, to get a diagnosis quickly. Unlike many other infiltrative diseases, you approach a sensitivity and specificity of 100% if you biopsy the clinically involved organ. It’s very different in something like sarcoid, where you could biopsy the heart and more commonly than not, you’ll miss it. So that’s where we generally go. It’s reasonable to first go, say, for a fat pad biopsy, but only if you can do so very quickly and only if you’re going to follow it up very quickly with the biopsy of the clinically involved organ. 

In terms of how risky a biopsy is, in good hands, the risks are really exceptionally low. These are very thick hearts almost by definition, so the main risk of perforation is really quite low. If these patients are being seen at a referral center, and I would say for AL amyloidosis, I would strongly urge getting patients to a referral center if at all possible. There are going to be good people with the technical skills, and you’re talking about a risk of complications that should really be far less than 1%. 

When Are Heart Biopsies Warranted?

: Doctor Desai, I’d like to move along to get your views of technetium pyrophosphate scans, what the benefit is, and also what are the vagaries we’re learning now. 

: I think technetium pyrophosphate scanning, bone scintigraphy, if you will, has really been a wonderful addition to the diagnostic armamentarium, particularly for patients with TTR [transthyretin] amyloidosis. We learned that in many patients getting bone scans for other indications, the heart would “light up” occasionally. It’s become clear that a large proportion of patients who have positive cardiac uptake of technetium pyrophosphate in particular are patients in whom there is important involvement with cardiac amyloid. I think that the early reports suggested that this testing was fairly specific for the diagnosis of TTR amyloid, and we’re learning that a proportion of the cases with AL [immunoglobulin light-chain amyloidosis] may also light up on that scan. So I think it’s important that just having a positive scan result doesn’t in and of itself confirm the diagnosis of TTR amyloid, and we need to do the appropriate investigations for serum light chains in order to exclude a monoclonal protein that might also be present in patients with a positive scan result. 

I think the presence of a negative serologic workup for amyloid with light chains and immunofixation, and a positive technetium pyrophosphate scan, really does amount to pretty compelling evidence for a diagnosis of TTR amyloid and has been enough in some of the pivotal trials in order to initiate therapy with drugs like tafamidis. 

: Doctor Hanna, with those words on technetium pyrophosphate scanning and comments you made earlier, what is the prevalence of TTR? What are we missing in particular cohorts that have become a clearer—whether they are heart failure clinic or TAVR [transcatheter aortic valve replacement] experience? 

: As far as prevalence is concerned, the most important point I’ll make is we don’t know the true prevalence. We don’t know the true denominator of how many people out there have TTR amyloid cardiomyopathy. However, there are certain cohorts that we’ve learned from. There was a study in Spain that looked at patients with heart failure with preserved ejection fraction, who were hospitalized with acute heart failure as an inpatient and those who had a wall thickness greater than 13 millimeters. I believe it was 13 or 14 millimeters. They decided to consecutively scan over 100 patients with this increased wall thickness and acute and chronic HFpEF [heart failure with preserved ejection fraction] and found that 13% actually came back positive. Some of them were confirmed with endomyocardial biopsy, but not all, suggesting that at least 10% of these hospitalized patients with HFpEF who have some increased wall thickness, are actually walking around with a diagnosis of cardiac amyloidosis. 

The TAVR study from Columbia that Ron mentioned took consecutive older patients, over the age of 65, who were coming for a TAVR evaluation, and they routinely did technetium pyrophosphate scans on these patients, along with lab work to exclude AL. They found that 16% of these patients (again, not all biopsy proven) had diagnostic criteria for a positive scan, suggesting that they have cardiac amyloidosis, and they were wild type. I should say that in the previous study I mentioned, they were wild type. 

So, between the TAVR population coming in for evaluation, between the hospitalized patients with acute and chronic HFpEF, you already see 13% to 16%. What we don’t know is in outpatients with chronic heart failure with preserved ejection fraction, what the percentage is. But a lot of the reason these trials, as Dr Desai said, may have been unsuccessful in patients with heart failure with preserved ejection fraction, is because up to 10% of these people could have this diagnosis. 

Technetium Pyrophosphate Scan Benefits

: Doctor Witteles, please give us your view of the proper laboratory testing that should occur to interpret a technetium pyrophosphate scan, and the second thing I’d like you to comment on is whether it’s important to identify these unrecognized wild-type TTR [transthyretin] cases if they’re undergoing a TAVR [transcatheter aortic valve replacement] or some other procedure. 

: On the first point, testing for monoclonal protein can’t be emphasized enough. In 2020 at least, it is the most important issue for people to understand who are doing diagnostic workups of these patients. Technetium pyrophosphate scanning is both the best and the worst thing to ever happen for patients with TTR amyloid, or for patients with amyloid, I should say. It’s the best because it has allowed most patients with TTR amyloidosis [ATTR] to get a correct diagnosis noninvasively and be able to start on treatments that can make a real difference in their disease course. But it’s the worst thing because it has, unfortunately, led to many people either getting misdiagnosed as having a TTR diagnosis when they don’t have amyloidosis at all, or really far more tragically, getting misdiagnosed as having ATTR when they actually have AL [immunoglobulin light chain amyloidosis] amyloidosis. 

So it’s important to emphasize, as doctor Desai was getting at before, that positive bone scintigraphy in this country—typically technetium pyrophosphate&mdash;is not specific for only ATTR. So, it tends to have the most uptake with ATTR, but you can absolutely get uptake with other forms, including AL. In the landmark study that really led to its widespread use, 22% of the patients who had AL amyloidosis had positive scan results. So, you can absolutely have a positive scan result in a patient with AL amyloidosis, and whereas it’s nice and can make a significant difference for a patient with ATTR to get them on treatment, it is catastrophic to miss a diagnosis of AL amyloidosis and miss the window to be able to get them started on effective light-chain therapy. 

So, with that as a preamble, nobody should have a technetium pyrophosphate scan without either concomitantly or beforehand having a monoclonal protein ruled out, and that is with 3 tests. The most important one is the serum-free light-chain assay, which is simply measuring the concentration of serum-free kappa light chains and free lambda light chains. The ratio is typically approximately 1. If it is well off in one direction or the other, it implies there is clonal production of whichever one is off, and that person cannot have a technetium pyrophosphate test to make a diagnosis of ATTR. 

The other tests are a serum and a urine protein electrophoresis with immunofixation. It is important to note that it should always be done with immunofixation, which raises the accuracy of the test. There’s no reason to do it without at this point. On the serum test, you’re mainly looking for whole immunoglobulins, and on the urine test, you’re mainly looking for light chains. Why do you need to do that in addition to the free light chain test? Well, for one, regarding those 2 tests, if they show a monoclonal spike, those have proven clonality, whereas with the free light chain test, you have implied clonality by the ratio being off—and if the ratio is off by 10:1 or 100:1, that’s proven clonality. But if the ratio is off by 2:1 or 3:1, it’s tough to say whether you have a true clonal process or not. So, you really want to have all 3 tests, and only when all 3 test results are normal, can you then use a technetium pyrophosphate scan to make a diagnosis of ATTR. 

: The second question was about the significance of finding wild-type TTR in certain populations. Is that really important to pursue? 

: Right, that’s an important question. To some extent, we don’t know the answer to it. We do know that treatment, certainly tafamidis, makes a significant difference in the treatment population who was studied in the phase 3 trial of tafamidis. Now, that was not in a population who was getting screening. So, if you start just screening everybody who is undergoing a TAVR, for example, and make a diagnosis—technically they weren’t included in the ATTR-ACT clinical trial&mdash;the phase 3 trial of tafamidis. That being said, the results of ATTR-ACT were quite compelling … in terms of making a significant difference in mortality, making a significant difference in cardiovascular hospitalization, and in progression of the disease based on quality of life and 6-minute walk distance. 

 So I think probably all of us, if we have a patient who has heart failure and a diagnosis of ATTR, will believe that we’re going to be able to make a significant difference by getting them on tafamidis, and I think screening an appropriate population does make sense. 

Monoclonal Protein Testing and Wild-Type ATTR

: Doctor Desai, I’m coming to you for some advice. I’m about to undergo a TAVR [transcatheter aortic valve replacement]. Do I need to have a technetium pyrophosphate scan? Does it matter whether I have wild-type TTR [transthyretin] if you’re going to do the procedure on me? 

: I think it’s an important consideration for the treating cardiologist to ask the question. I don’t believe that every patient coming for transcatheter aortic valve replacement needs routine evaluation for cardiac amyloid. I think the circumstances in which that should be considered—I think the populations that are not typical are probably populations where we should think about the diagnosis a little more carefully. We have a large proportion of patients who have severe aortic stenosis and a pattern of progression of that disease over time that is really quite typical, and I would be interested in the opinions of Dr Witteles and Dr Hanna. But from my perspective, it wouldn’t make sense or be economically appropriate to sort of test all those people. 

The people I would test are the ones we’ve talked about. They’re the patients where the amount of hypertrophy is disproportionate or there are other echocardiographic features that would suggest involvement by an infiltrative disorder like amyloid. I am also particularly interested in these patients with low-gradient aortic stenosis because I think those who have stenosis are a population that might be enriched a bit more for infiltrative heart disorders. But I don’t know. Dr Hanna, any other thoughts there, or Ron? 

: I agree with Dr Desai. I think that patients with low-flow, low-gradient aortic stenosis have a greater likelihood of having it. The disproportionate degree of hypertrophy—what you’d expect to the degree of the aortic stenosis&mdash;I think is a big one. Then the Columbia experience, they looked at the diastolic, the tissue Doppler velocities, which were exceedingly low in the patients who had both aortic stenosis and the cardiac amyloidosis, and I don’t remember what the cut point was. But those are the main things I would look at. Again, I don’t think we can promulgate testing every single person who is coming in for evaluation, but perhaps coming up with some kind of criteria and studying this prospectively would be a good idea. 

: Yeah. If we think about why the percentage was so high—16% of all-comers in this study&mdash;I think none of us believes it’s because TTR amyloid deposits are causing aortic stenosis. It’s because you were picking out an older, predominantly male population with thick hearts and heart failure, and if you do that, you are going to pick up quite a bit of TTR amyloid. I think the points made by doctors Desai and Hanna about the particular clues, like the low-flow, low-gradient aortic stenosis, are very good ones. And I agree, I don’t think we’re quite at the point yet that we can justify universal screening on every patient when referred for TAVR. But I would say it should probably be universally thought of and looking for other signs to make you suspicious for it. 

Technetium Pyrophosphate Scan Prior to TAVR

: I’d like to hear from doctor Hanna how you prognosticate, what survival metrics you use and share with your patients for both AL [immunoglobulin light chain amyloidosis] and TTR [transthyretin]. 

: Let me start with TTR. There are 2 staging systems out there for ATTR [transthyretin amyloidosis] cardiomyopathy. One is the Mayo Clinic stage—from a publication by Martha Grogan at the Mayo Clinic&mdash;where they looked at patients with wild-type disease. They had saved blood from these patients and retrospectively looked at 2 biomarkers: NT-proBNP [N-terminal pro-brain natriuretic peptide] and troponin T and looked at the subsequent survival in these patients. They came up with 3 stages. Stage I was if you had an NT-proBNP level less than 3000 pg/mL, and if you had a troponin T level less than 0.05 nanograms per milliliter, that would make you stage I. If you had both of them above that&mdash;so an NT-pro level greater than 3000 pg/mL and a troponin T level greater than 0.05 nanograms per milliliter&mdash;that was stage III. Then, one or the other was stage II. So the patients at stage III had the worst prognosis (under 2 years), and the patients who were stage I&mdash;who were below both those biomarkers&mdash;they had the best prognosis, close to 6 years, 5 and a half to 6 years. And then you have the patients in between (about 3 1/2 years); those patients are at stage II. So, in addition to the patient’s echocardiogram results and how much diuretics they’re on and your other gestalt type of markers of how someone is going to do, using that staging system is another way we will speak to patients. 

The other staging system that’s used in patients with ATTR cardiomyopathy is the Gillmore staging system. Julian Gillmore, at the National Amyloid Center in London, studied a large cohort of patients, and instead of looking at NT-proBNP and troponin levels, he looked at NT-proBNP and estimated GFR [glomerular filtration rate] (in this case, less than 45 mL per minute per meter squared). And the same thing, if you had an NT-proBNP level that was less than 3000 pg/mL and a GFR that was greater than 45 mL/min/1.73 m2, you were in stage I; if you had an NT-pro level greater than 3000 pg/mL and a GFR less than 45 mL/min/1.73 m2, you were in the worst stage, stage III. The survival rates pretty much paralleled more or less what the Mayo staging found.  

So, those are the 2 staging systems that I will use in patients with ATTR cardiomyopathy to enhance the discussion that I’m having with a patient. Now, remember, these staging systems were derived without treatment. Right now, if I’m going to put somebody on tafamidis or another medication with those numbers, I can’t really give them the accurate numbers because you would assume that survival is going to be better. But that’s the best we have. 

As far as AL amyloidosis, there is a Mayo Clinic staging system, I, II, III, and IV, which was revised from 2004 to a 2012 revised staging system, and again they look at 3 variables. They look at the NT-proBNP level, a troponin T level and in some cases, a troponin I level and then the difference in the involved and uninvolved free light chains. In this case, stage IV, which is the worst, would be an NT-pro level greater than 1800 pg/mL, a troponin T level greater than 0.03 ng/mL, and a difference in the involved free light chains to the uninvolved of 180 milligrams per liter, or what would be 18 milligrams per deciliter. So, again, the concept is that patients with stage IV have a very poor survival, 6 months mortality at 50%, whereas patients in stage I will have a much better prognosis, and obviously the ones in between. 

Again, this is derived before daratumumab, before some of the better chemotherapy agents we have. I know doctor Witteles will hopefully talk to us about his most recent publication regarding the survival in these patients in the newer area of having daratumumab and other medications. 

AL and ATTR Survival Metrics

: I’d like to have a few controversial words about some other topics for cardiomyopathy. For standard and starting point, someone is referred to you, they’re thought to have a nonamyloidogenic cardiomyopathy. They’re on ACE [angiotensin-converting enzyme] inhibitors after load reduction, they’re on β-blockers, they’re doing really poorly. They’re on diuretics, naturally. Is there a modification that you always consider and are they effective, Dr Witteles? 

: And we’re talking about in a patient where now a diagnosis of amyloidosis has been made, correct? 

: I would say it is actually probably quite different between AL [light-chain amyloidosis] and transthyretin amyloidosis [ATTR]. Patients with AL amyloidosis do particularly poorly with standard neurohormonal therapy, and this is likely for a number of reasons. Number 1 is that they tend to have quite profound postural symptoms, quite profound orthostasis. This happens a lot from autonomic dysfunction, plus patients with amyloidosis, in general, will often have small cavities because of the increased wall thickness. They can often have chronotropic incompetence or frank heart block. So β-blockers and RAAS [renin-angiotensin-aldosterone system] inhibitors tend to be very poorly tolerated, and I would say it would be the very rare exception that we would want a patient with AL on any of those agents, with the exception of occasionally needing something like a β-blocker for rate control of somebody with rapid atrial fibrillation that we can’t otherwise control. But, in general, the neurohormonal antagonists should not be used for patients with AL. 

For patients with transthyretin, it’s a little trickier I’d say, particularly for those with wild-type transthyretin. This is generally an older patient population with often quite significant baseline hypertension just because of their demographics—being an older male population. Certainly, we don’t like to leave them frankly hypertensive. So if somebody is tolerating their neurohormonal antagonists, in that case I won’t tend to take them off. But there is definitely a low threshold if you’re flirting with low blood pressures to pull them off. We certainly have no reason to believe that neurohormonal antagonism helps with amyloid cardiomyopathies as it does for most other forms of at least systolic heart failure. 

: Digoxin is traditionally thought of as contraindicated in patients with amyloid cardiomyopathies because of concerns it aligns amyloid fibrils and leads to local toxicities, even with normal therapeutic serum levels. I think most of us have found that particularly true for transthyretin amyloidosis, that overt Dig toxicity with using a low-level Dig when needed for rate control is generally OK. I would not personally use it otherwise, that would be the only indication I would use it for. And in patients with AL, I think I would be even more cautious. But I’m curious, Akshay and Maz, what your views are on them. 

: We’ve run into the same problem. We’ve had patients with AL cardiac amyloidosis who have had rapid AFib [atrial fibrillation] along with severe heart failure. You read the older article that Martha Skinner wrote, where they ground up fibrils that were AL and AA, in this case not ATTR, and found that Dig avidly bound those fibrils, and then imputing that: “Hey, there must be a higher local concentration,” and in conjunction with some cases of sudden cardiac death, it was dogma: Digoxin shouldn’t be given. I remember they used to give a lot higher doses then. 

Martha Grogan and her Mayo Clinic colleagues published an article—Muchtar is the first author&mdash;in the Amyloid Journal, looking at their experience with Digoxin in patients with AL, specifically AL amyloidosis, and found a rate of adverse events, I think it was 10% to 12%. But their conclusion was with careful dosing and monitoring of serum levels and monitoring, that if you really are in a corner where you need rate control, and you can’t use β-blockers or diltiazem, that you have to evaluate the risks versus the benefits.  

And with TTR [transthyretin], I agree with Ron, same thing. We have just submitted a manuscript of about 69 patients who were on Digoxin—over half had TTR&mdash;and came up with similar adverse event rates, but we didn’t see any deaths attributed to Digoxin. So, for me, the take-home message is I would be cautious. I wouldn’t use it unless you really needed it, and I would use it with lower doses with clear monitoring. But to say it’s absolutely contraindicated, I think that’s dogma. 

: I agree. I think I brought it up mainly for that reason. I think that it is important, though, that we think about aggressive management of atrial fibrillation in these patients. It’s very poorly tolerated, particularly at high rates. Some of the traditional therapies, for the same reasons that Ron mentioned, are poorly tolerated for heart failure. Aggressive rate control of atrial fibrillation with AV [atrioventricular] nodal agents is often not well tolerated in patients with amyloid heart disease. I think we often do reach for older agents like Digoxin in extreme circumstances, but then I think we also need to think more aggressively about strategies for restoration of sinus rhythm, where that’s possible. We could talk a little bit about whether there’s a role for more aggressive strategies like pulmonary vein isolation. I think most of us have concerns in patients with advanced amyloid about the likelihood of success of those strategies. 

But I think we even run to strategies like AV junction ablation a little bit earlier in this population, where we’re really struggling with adequate rate control, understanding that that leaves patients dependent on pacing systems. So, I think that management of AF is a real problem in this population—certainly thromboembolism and those risks are amplified and underscore the need for anticoagulation. 

Poor Toleration: AL and ATTR Treatment Modification

: Dr Hanna, what’s your feeling about cardioversion and nodal ablation? 

: In cardioversion, I think that if you have somebody with paroxysmal atrial fibrillation, everybody gets a chance at trying to achieve sinus rhythm. I think that some patients with cardiac amyloidosis, no matter what you do, you can’t just keep them in rhythm. You’re getting cardioverted every couple of weeks. 

The 1 thing I would say about cardioversion, is that there was a publication showing increased risk of thromboembolism. And the fact is that even in sinus rhythm, patients who have a lot of amyloid penetration in their atria can have such poor atrial function that, for example, on mitral inflow, you barely see it in an a-wave.  

It’s been documented that you can have atrial thrombus and normal sinus rhythm. Or, for example, when they’re in AFib [atrial fibrillation] and you haven’t adequately anticoagulated for a period of months, well above what you would consider needed, that you wouldn’t need a “T” any more. We’re now recommending that patients get TE, even if they’re adequately anticoagulated because there’s a percentage they’ll have persistent atrial thrombus. It’s just that the CHADSVASC score does not account for the very high risk of atrial thromboembolism that you see in patients with cardiac amyloidosis. As far as, did you say ablation? 

: We actually looked at atrial fibrillation at our institution. The consensus before we started doing was that the likelihood of this being successful is very low. There’s a lot of amyloid, there’s a lot of scarring, and so we’re going to be putting people through a procedure that’s likely not going to work.  

And 1 of our EP [electrophysiology] fellows actually looked at our patients who underwent atrial fibrillation and the propensity matches 3-to-1 to those with AFib, who did not have atrial fibrillation and actually showed that they had significant reduction atrial fibrillation burden, and [there was] actually a mortality benefit. Now that’s a very hypothesis-generating publication study. But I think in my typical elderly patients who have long-standing AFib, and they have very advanced disease, I don’t feel that in general I wouldn’t pursue an atrial fibrillation ablation. I think if somebody who has paroxysmal AFib or, and really doesn’t tolerate AFib well, I think it’s not completely unreasonable to consider an atrial fibrillation or pulmonary vein isolation, ablation.  

Cardioversion and Atrial Fibrillation Ablation 

: Pacemaker or defibrillator, Dr Witteles? 

: If somebody needs a pacemaker, that part is fairly straightforward. If they have symptomatic bradycardia like anyone, they should get a pacemaker. A heart block as I mentioned before is common, particularly in intracranial retina amyloidosis; it’s common, and patients will often not need a pacemaker. 

The fibrillator issue is a much tougher question. So traditionally, the feeling in a patient with cardiac amyloidosis was not to place defibrillators. I think that was for a couple of reasons. One was that in an era before effective therapies for both AL [amyloid light-chain amyloidosis] and transthyretin amyloidosis, the prognosis was quite poor, particularly in patients with AL amyloidosis. And the idea was, why would you want to convert what might be a peaceful sudden death into a more gruesome heart failure death with getting a bunch of shocks at the end of one’s life. Also it was found that it wasn’t that infrequent that patients would get shocked appropriately for ventricular arrhythmia, and it wouldn’t resuscitate them. 

But, again, that was when you would dive into the data. That was largely putting defibrillators in patients who met the traditional primary prevention indications for defibrillators, namely EFs [ejection fractions] under 35%, and it was mainly in AL populations. And by the time you get to a patient with a very low EF with AL amyloidosis, you really have a quite terrible prognosis, not just from arrhythmia and sudden death but from progressive heart failure. 

So, I think we and others have then looked at putting the defibrillators in and not waiting till meeting EFs below 35%. But take a population who has a reasonable life expectancy—at the very least, a minimum of a year but hopefully more than that. And, B, try to do it based on screening with ambulatory telemetry with something like a Zio Patch. And if they do have a significant burden of ventricular tachycardia on that, we will typically offer treatment with a defibrillator. We’ve clearly seen higher rates of need for appropriate shocks in patients with AL those with than transthyretin, so we’re much more likely to recommend for patients in the former group, and then you want to time it with their chemotherapy. But I do think it’s a big mistake to have a blanket policy of not putting defibrillators in patients, or we’re not putting primary prevention defibrillators in patients, because certainly I can say from our own experience, clearly, it has saved a number of patients’ lives who have in some cases, lived for many years thereafter. 

: John, before we move on, if there is a need for AV [atrioventricular] junction ablation in these patients, have you moved to single-chamber pacing, or do you think biventricular pacing is a better option for these patients?  

: We really try to avoid RV [right ventricular] pacing in general, and so either AV ablation or for complete heart block. And, again, they won’t necessarily meet the classic indications for CRT [cardiac resynchronization therapy]. But you’re talking about people with impaired ventricles, brachial and diastolic dysfunction, that add in the synchrony of RV pacing, I think is a mistake. 

: Yeah. So we had some experience with putting in ventricular-assist devices in patients with cardiac amyloidosis. We put in 6 continuous flow the newer-generation ventricular-assist devices—and probably in the last 10 years; 2 patients had AL cardiac amyloidosis, who were not transplant candidates. There was a lady in her 50s who was basically balloon-pump dependent. There’s a cohort of these patients with AL that can go into cardiogenic shock from diffuse intramural coronary deposition. Actually, their ventricles tend to not be small, they can be even normal to mildly dilated. This particular patient was bailed out with a left ventricular-assist device. She lived for 4 years, was receiving chemotherapy and the first 3 years were quite good. During the last year, she had recurrent infections and complications. 

Another patient with AL cardiac amyloidosis was 75. Again, the patient presented the same way. He was balloon-pump dependent, had cardiogenic shock, very toxic light-chain levels, and we put in … a continuous-flow VAD [ventricular-assist device], and he’s had it now for 4 1/2 years. He’s had some complications, but he went on to get chemotherapy and he’s survived 4 1/2 years. 

So those are the 2 longest survivals that we know of. And as far as TTR, we put them in 2 wild-types and in 2 patients with the V122I mutation. And 2 of those patients were successfully bridged to transplant, and the other 2 died at varying intervals. The 12-month survival was 100%. So I think it’s feasible.  

And 2 of the biggest issues are, what is the size of the LV [left ventricular] cavity? As you know, patients with cardiac amyloidosis sometimes have smaller ventricles. They certainly aren’t dilated most of the time. So will the cannula in the left ventricle or apex fit without impinging on the trabecular or the walls? Are you going to get a lot of suction events and arrhythmias? The RV is often dysfunctional and stiff. Will these patients have severe problems with right ventricular failure?  

Luckily, we have not had those issues. However, our typical rule is we will not implant a left ventricular-assist device in a patient with cardiac amyloidosis with an LV and diastolic dimension of less than 4.4 mm. That’s kind of where we’ve gone, 4.4, 4.5 mm. So, I’m not sure what we’re doing at Brigham and Women’s Hospital. 

: Right. I would just make the argument that I think those are wonderful examples. I think in general, when we’ve looked at these patients, the number that meet those criteria is a relatively small fraction of the general whole. So, I think on the whole, it’s not a great strategy.  

I will say that the 1 thing that’s helped these patients has been a transition in our listing system for transplant. And I think, particularly for the patients with TTR, those with isolated cardiac amyloidosis with wild-type TTR, or those patients now are advantaged by a listening system that moves them up in the status priority listing for transplantation.  

And I think obviates in some cases, the need for a VAD as a bridge to transplant. I think our direct-to-transplant strategy in patients with amyloidosis who are eligible for a transplant is now increasingly possible, and hopefully limits the need for the out-of-the-box thinking that Dr Hanna’s outlined. But it’s wonderful to know the examples exist, or the predicate exists, to do that when it’s possible. 

: I need to make sure I emphasize that they are out-of-the box examples. I completely agree that this is not a strategy we should be routinely employing, and this is at very specialized centers and a very specialized small percentage of cases. 

Cardiac Amyloidosis: Pacemakers and Defibrillators

: Dr Witteles, your hematology colleague comes to you needing some advice. A patient has cardiac AL [light-chain&#8239;amyloidosis], is going to undergo chemotherapy, and there are a variety of options. There are alkylating agents, there are immune-modulating agents, there are proteasome inhibitors. How do you help guide the selection of therapy? Which ones actually aggravate the congestive heart failure? 

: Thanks. So, first I’d make the point that I’d briefly mentioned before, the importance of patients with AL cardiac amyloidosis being seen at a big referral center, if at all possible. I believe that for transthyretin amyloidosis, we really need to democratize the diagnosis and treatment, which is quite straightforward and it’s a common disease. AL amyloidosis is much less common and much more complex in terms of the treatment. And it’s really important that these patients be seen by people who are experienced with treating in the disease and not just the cardiologists, but perhaps even more importantly, a hematologist who has a great deal of experience with AL amyloidosis.  

Myeloma, which is of course, is related to AL amyloidosis, also arises from a malignant plasma cell and is something that is really “bread and butter” for hematologists. But the treatment targets are very different in patients with myeloma than AL amyloidosis, particularly cardiac AL amyloidosis where you really don’t want to accept any residual pathologic light chain, if at all possible. Whereas in myeloma if you get pretty good control, you’ll often back off the therapy and say that that is pretty good. It’s very important for patients, if at all possible, to be seen at a big referral center. 

In terms of agents of choice, the standard of care most of the time is for people to get started on a regimen called CyBorD, with the alkylator cyclophosphamide, the proteasome inhibitor bortezomib, and then the steroid dexamethasone—although that I suspect may change in the coming months to a small  number of years. 

CyBorD is overall associated with quite good response rates. It doesn’t tend to be magical in everybody, or many people at all where they get started on it and within a cycle or 2 they normalize. But most people do have a response and some people have excellent responses, and a smaller number, but still not insignificant, have what we call complete hematologic response where their light chains and their electrophoreses completely normalize. 

The key though, is being ready, willing, and able to deftly move to other therapies if the treatment that was chosen is either inadequate—you’re not having a good enough response, or intolerable from a adverse event standpoint. And so, particularly for patients with significant cardiac involvement, if they’re in a cycle or 2 and their light chains haven’t come down very much, this is not somebody that you want to give another 6 months and see what happens. It’s time to make a change. And the beauty with AL amyloidosis is that we now have so many different options.  

We have multiple classes of chemoimmunotherapy, and we have multiple agents within each class. So, somebody might not respond, for example, to lenalidomide but might respond to pomalidomide. They might not respond to bortezomib, but they might respond to carfilzomib. And then, an agent that has, I would say, really revolutionized the treatment for many, which is the monoclonal antibody daratumumab, which is actually currently being studied in a clinical trial called ANDROMEDA where people with cardiac amyloidosis are randomized upfront to therapy with either the CyBorD chemotherapy I was just mentioning, or, a combination of CyBorD plus daratumumab. The results haven’t come out yet. I would be utterly shocked if daratumumab does not add significant extra control for light chains, because we’ve so obviously seen it in patients who have gotten to daratumumab after failing other treatment. 

Now, for the question of the cardiac adverse events of these agents. So fortunately, most of them are actually well tolerated from a specific cardiovascular standpoint. Steroids, of course, can cause salt and water retention as I’m sure all cardiologists are dealing with. 

The agent that has the most evidence for causing true cardiac toxicity is carfilzomib, one of the proteasome inhibitors. The toxicity of carfilzomib does not tend to cause systolic heart failure. The clearest toxicities are hypertension, increased rates with thrombosis, and diastolic heart failure, the last being the most challenging because obviously with these patients, that’s what they tend to have is diastolic heart failure. 

I certainly would not go so far as to say you cannot use carfilzomib in patients with cardiac amyloidosis. And we certainly found this to be helpful in patients who have failed treatment with bortezomib and have had good responses on carfilzomib. But you’ve got to be very careful with it and know that cardiotoxicity can be a real issue with that drug. In terms of the so-called IMiD things like lenalidomide, pomalidomide, thrombosis is the biggest risk. It’s important to know that and in some cases to prophylax. 

So when you read about hematologic therapy for patients with amyloidosis, a lot of the algorithms will point to upfront saying, is the patient a stem-cell transplant candidate, and will having that be a divergent point? I could not disagree with this strategy more. That stem cell transplant—we’re talking about an auto stem cell transplant, not an allotransplant. So we’re not getting any graph versus tumor affect. 

All an auto [autologous] stem cell transplant is in this disease is a way to give a higher dose than you could otherwise give of single class of chemotherapy, namely an alkylator agent. And then you rescue by giving the patient their own marrow back. This arose because the initial treatments of AL amyloidosis, the options for therapy were very limited—namely melphalan and prednisone, later melphalan and dexamethasone. 

And so the idea was, well if we give a higher dosage to patients, that should be better. And there was a number of retrospective studies that said, “Yes, patients who got stem cell transplant did seem to do better than the patients who didn’t.” But of course, they were hopelessly confounded because there’s a reason why those patients had gone on and gotten stem cell transplants and the others hadn’t. 

There’s only a single randomized trial that ever compared the 2, and importantly, that’s how it was done in an era when standard chemotherapy was nothing like it is today. It was melphalan and dexamethasone. And yet, in that clinical trial there were actually better outcomes, including better survival, in the patients who received the standard chemotherapy then the auto stem cell transplant. 

When you think about in today’s world where we have so many better options, I would say stem cell transplant in my mind should be a potential option for patients, particularly if they fail others, but should not be what the goal is that you’re trying to get to. 

: We have a lot to talk about in terms of TTR [transthyretin]&#8239;therapies and there have been some really monumental publications that have occurred. 

Therapy Selection for Congestive Heart Failure

: So, Dr Hanna, TTR [transthyretin] tetramer stabilizers. The idea is to keep the 4 proteins together and prevent the monomer from being released and misfolded.  

There are a couple of agents, tafamidis and diflunisal. Can you take us through the important results of the international trial? We’ll focus on cardiomyopathy with tafamidis. 

: The ATTR-ACT trial, which is testing tafamidis versus placebo in patients with transthyretin cardiac amyloidosis—and that’s both wild-type and hereditary&mdash;basically took 441 patients, and patients were randomized to 3 arms, either in a 2-to-1 ratio. So, either tafamidis 80 mg, tafamidis 20 mg, or placebo.  

The trial lasted 30 months. They took the pooled tafamidis group, both those that were in 80 mg and 20 mg, and compared them to the placebo group. And ultimately, the primary end point was a very hard end point. It was all-cause mortality, plus frequency of cardiovascular hospitalizations. And there were secondary end points looking at the Kansas City cardiomyopathy questionnaire, which is a quality-of-life metric, and also at the 6-minute walk distance. Again, it’s 0 and 30 months. 

The results were quite striking in that as far as all-cause mortality in and of itself, there was a very significant of 13-1/2 absolute risk reduction and mortality. About 71% of patients at the end of 30 months were alive in those who took the tafamidis and about 57% of patients were alive in those patients who took placebo. So, that was very striking; it was ultimately a 30% relative risk reduction in a mortality. 

The same went for hospitalizations; there was a very significant reduction in frequency of hospitalizations. As far as the 6-minute walk, the secondary end point, and the patients, the decline in the 6-minute walk was much less over the 30 months in the tafamidis group than it was in the placebo group. I think there was about a 70-, 80-meter difference by the end of those 30 months. 

The same thing goes for the Kansas City cardiomyopathy questionnaire. There was a very substantial difference in that the quality of life declines at a much slower pace in the patients who took tafamidis versus placebo.  

So, this was a very positive trial. The number needed to treat to save 1 life was about 1 in 8, which is as good as we have in cardiology. That is, to treat more than 31 patients over 30 months. That’s translated to tafamidis FDA approval in May of 2019 as the only FDA-approved stabilizer or treatment right now for ATTR [transthyretin amyloidosis] cardiomyopathy. 

The good news about this trial was the safety was excellent. There were more adverse effects in the placebo group than in the tafamidis arm. There was no signal of a safety issue. So, here we have a very effective drug that’s taken orally once a day, that not only has a mortality benefit, a decrease in hospitalization, a quality-of-life benefit, but it’s also safe. 

: Dr Desai, is the placebo the ultimate goal of therapy? Do people truly stabilize or is this just a slowing of their disease? 

: Well, I think that we have the sort of 30-month follow-up in the ATTR-ACT trial that tells us that over that time interval at least we’ve seen improvements in survival as mentioned and also stabilization of the disease. I don’t think we have longer-term data to really tell us whether the disease is truly stalled or the progression is actually simply slowed over time.  

My impression is that this is not an indefinite cure for the problem. It’s rather an approach to stabilization of the protein and stalling disease progression. But that’s quite meaningful in a disease with very limited overall survival. I think the other point to make about ATTR-ACT is, to add to Dr Hanna’s point, it’s really the bulk of the benefit was in those patients in the earlier stages of the disease, the class 2 patients. The 3 and 4 patients got a little bit less benefit over the course of the trial, and it may speak to the fact that some patients may be a bit beyond the reach of rescue with tafamidis. I think it’s probably worthwhile considering in the context of the overwhelming cost of the agent to patient, when the drug was released. I think the annualized cost was almost a quarter of a million dollars for patients. Fortunately, with subsidies, many patients can access the drug at far less of a cost. But I think it’s another reason to build on what Dr Witteles said earlier, that these patients really ought to be seen at specialized centers that have the experience of securing the drug for the patients. 

: And Dr Hanna, at the end of 30 months, the echocardiographic features of disease were improved or unchanged? 

: Well, this is something we’re looking at. There’s no published data discussing what’s happened to the echocardiographic features of baseline of 30 months. Ron, I don’t know if you can speak to that. 

: I’d empathize that patients with transthyretin amyloidosis, their echoes tend not to change that quickly. But far more important than what the echoes show is what happens clinically to the patient. And we know from ATTR-ACT that the average patient worsened on tafamidis, very clearly. You can look at the quality-of-life curves, and you can look at the 6-minute walk time. And clearly, these patients’ disease progresses over the 30 months. It just does so at a markedly slower rate than those on placebo. 

So, I’m always very careful when I’m starting a patient on tafamidis to make sure that the patient and their family understands: do not take this thinking you’re going to feel better. In fact, take this with the expectation that you’ll probably feel worse a year from now than you do today. But, that you’re going to be hopefully feeling significantly better a year from now, or 2 years or 3 years than you would have otherwise felt if you were not taking it. 

: OK, a very quick question. This is going to be quite controversial. My understanding is the VA [Veterans Affairs] system nationally recommends initiating tafamidis at 20 mg. Your very brief comment about whether this is appropriate or this should be reconsidered, Dr Witteles.  

: I think yes and yes. It should definitely be reconsidered; 20 mg is not an FDA- approved dose. It is incredible to me that the VA, a federal institution, would prescribe a non-FDA approved dose for patients. Why they’re doing it is because in ATTR-ACT, the 20- and 80-mg groups looked very similar to one another. And so, the idea was given the cost that Dr Desai noted before, if you could give them one-fourth of the dose, maybe you’d save a lot of money.  

That’s why not that it’s unreasonable, but they are using a non-FDA approved dose. And I think the jury is still out, particularly with longer-term follow-up as well as with patients with hereditary mutation, if 20 milligrams will be as good. 

: I agree with everything Dr Witteles stated, and there will be analyses looking at 80 mg versus 20 mg, but nothing really that we can discuss at this time. 

Available ATTR Selective Stabilizers

: Let me ask for your individual experience with diflunisal, a drug that was taken through an international randomized trial for neuropathy and actually performed quite well. Do you ever use it for cardiomyopathy, Dr Desai? 

: Yes. So, I think you know 1 of the challenges. Diflunisal is a nonsteroidal anti-inflammatory drug that at higher doses is used for treatment of inflammatory disorders and at lower doses seems to have efficacy, certainly in amyloid polyneuropathy and then perhaps, based on single-center sort of uncontrolled trials in TTR [transthyretin] amyloidosis. I think that the challenge, as with all NSAIDs [nonsteroidal anti-inflammatory drugs] in patients with heart failure is the fluid retention that is possible, particularly in patients with more advanced renal dysfunction.  

I think that there is a role for diflunisal in some patients with early TTR amyloid cardiomyopathy where it could be used safely and at low cost because it is far cheaper than the alternative. But we tend to reserve it for patients who don’t have very symptomatic heart failure, who have reasonable renal function, and who have adequate platelet counts so that they’re not at high risk for thrombocytopenia or bleeding. 

: Yeah, I completely agree. The same thing with us. We actually published a paper looking at a couple dozen patients’ experience with cardiomyopathy. And in that experience, we looked for worsening renal dysfunction, GI [gastrointestinal] bleeding, worsening heart failure. And with careful monitoring of these patients, a couple of patients had some full retention that we could deal with. Everybody got a PPI [proton pump inhibitor], so we’re being very careful, and I think patients can tolerate it. But I would say again, to echo Dr Desai’s comments, that it wouldn’t be more than an NY222 patient. We would avoid people on high-dose diuretics. We’d like to see the GFR [glomerular filtration rate] above 50 mL/min. Very elderly patients on anticoagulation, we would avoid. So … you’re looking at the risk-benefit ratio and we have the same experience, so we reserve it for someone whose renal function and heart failure is still reasonably intact. 

Cardiomyopathy Management: NSAID Options

: Dr Witteles, there were 2 New England Journal of Medicine articles in 2018 regarding the success of TTR [transthyretin]&#8239;gene silencers—inotersen and patisiran, both of which effectively stopped the generation of TTR mRNA by targeting a sequence in the 3’ prime untranslated region, which results in reductions in TTR, regardless of whether it’s a variant or wild-type.  

So, the cardiac findings in these trials are quite limited. But is there something we can glean from the inotersen experience or the patisiran that might suggest that these TTR gene silencers have potential for promise of better therapeutic outcomes in cardiomyopathy than the TTR gene, than the TTR tetramer stabilizers? 

: Yes, I would say there’s tremendous excitement about the silencers for TTR cardiomyopathy. They are, of course, not approved for that indication yet because both of the trials you are referring to were specifically for the hereditary or variant TTR or polyneuropathy indications. Now as everybody on this panel knows very well, the idea that there’s a clear distinction between patients with variant TTR and those with polyneuropathy and cardiomyopathy is not true. It’s a spectrum, and particularly when you get into a lot of the mutations that lead to a predominantly polyneuropathy phenotype, many, if not most, will have some degree of overt cardiac involvement as assessed by imaging and/or biomarkers.  

So, specifically for patisiran, there was a follow-up study where there were good data that were released from a cardiac subgroup that had been predefined from the APOLLO Trial, which pretty clearly showed a benefit in terms of echocardiographic parameters as well as from NT-proBNP, for the group who’s on patisiran versus placebo. 

Now, it’s worth saying that the results of these studies, even more so with patisiran, but to a real extent with both of them, were absolutely unbelievable good results from a polyneuropathy standpoint. I mean, a P value in 1 of the trials, I believe in the 10-23 level with a couple hundred patients enrolled. That’s how big the treatment difference was and how consistent the difference was.  

So, it would be utterly shocking knowing how, what the pathophysiology of the disease is if you could see that sort of result in neuropathy and not end up seeing that sort of result in cardiomyopathy.  

There were some safety concerns, more so with inotersen. There’s a little bit about the patisiran arm that was brought up because there seemed to be more cardiovascular deaths potentially in the patisiran arm. But overall, there was actually fewer in the patisiran arm, and we’re talking about small numbers, so it probably wasn’t real. With inotersen, there was a trend toward a little more deaths in the inotersen arm. And there were issues with renal dysfunction and thrombocytopenia that give people some pause with it that hopefully will be different with next-generation forums. 

In the big picture, there is tremendous excitement for the silencers and both companies have agents that are now either starting or about to start clinical trials for cardiomyopathy. 

TTR Gene Silencers as Cardiomyopathy Treatment

: Let’s talk about the future. There are 5 cardiomyopathy trials that are either underway or about to be underway: APOLLO-B looking at patisiran and applying it to a cardiomyopathy population; HELIOS-B is looking at a second-generation patisiran-like agent, vutrisiran; like a polyneuropathy, applying a second-generation inotersen agent for neuropathy; And then another one looking at cardiomyopathy population and finally AG10 Eidos. 

By stabilizing the TTR [transthyretin]&#8239;gene silencers and by adding a GalNac atenilation, so basically better targeting a delivery to the liver. The agents—patisiran and inotersen&mdash;now are potentially transformed into ones that can be given less frequently and at a much lower dose because the milligram potency is heightened. I’d like to hear from the 3 of you which of these agents you’re most excited about or whether you think that the technology is moving ahead so well that there will be multiple agents to choose from. Dr Desai. 

: Well, I think in general, I’m quite optimistic about the range of options that we’re likely to have in the near term for management of patients. I think that the silencers are very far ahead in development programs, and I think we’re likely to see broadened application of the silencers in some of the newer formulations that you’ve talked about soon. And so I’m quite optimistic based on the data that Ron’s excited about of the effects in the cardiomyopathy subpopulation of APOLLO—that those will be very useful agents moving forward, particularly if the formulations are such that we can administer them less frequently and more conveniently for patients. 

I must confess that some of the very new agents, the next-generation agents, the AG10 Eidos and others, are trials that I’m not personally involved with. So, I’ll look to the others in the group to make comments about those specific agents, although I think we’ll soon have a range of options to consider for these patients. 

: Yeah, I’m very excited about the next-generation silencers. You know the vutrisiran that you mentioned in the HELIOS-B study was given subcutaneously every 3 months, so we’re talking about only 4 shots a year. That will be a game changer as far as patient convenience and, again, the dose is significantly less than patisiran. And the inotersen modified version which has a GalNAc and change in the backbone, that was also given monthly. So, it’s still much better than weekly. And at a much dramatically lower dose, so those thrombocytopenia and renal issues were felt to be dose related. And now that you can use a lower dose specifically targeted to the liver with the new inotersen agent, I’m hoping there won’t be toxicity. 

Both trials are going to be big. HELIOS-B is going to be 600 patients, but the newer CARDIO-TTRansform trial involves a second-generation kind of inotersen-like compound. It’s going to be 750 patients. And I’d be remiss in not mentioning the ATTRibute cardiomyopathy trial, which we are also participating in with AG10, which is a stabilizer that works a little bit differently than tafamidis, but it is quite potent with excellent phase 2 and phase 2 extension data. That’s ongoing, and the goal is to get to 500 patients. So, for a quote-unquote “rare disease,” our trials are starting to ramp up as far as numbers. I’m looking forward to seeing, as Dr Desai said, the options will drive the price down in some of these drugs, which I think is a huge issue. If you have all these therapies and no one could afford them, it doesn’t do us any good. I like to see the competition.  

: I agree with Dr Witteles. The characterization of tafamidis as being sort of an end-goal therapy, I think it’s a major step forward. But it’s clear that the data show that people progress on therapy at high doses—and that the echocardiographic data&mdash;if you look at them, show no remodeling apart at the end of 2 1/2 years. In contrast, the subgroup from the patisiran trial that had features of cardiomyopathy, at the end of 18 months, as Dr Witteles said, had evidence of not only functional improvement&mdash;if you believe NT-proBNP improvement by more than 30%&mdash;but also remodeling that was slow. But there was a real signal there. So essentially, half the time, we’re potentially seeing some remodeling with the TTR gene silencer, but I do not think it is in the capacity of TTR tetramer stabilization. 

I’d like to give each of you a chance to make some final comments. Dr Hanna, you already started yours. 

: Well, I just wanted to say in addition to the patisiran substudy, the prespecified substudy looking at cardiac patients, Dr Merrill Benson at Indiana University  published data on a single-center study looking at patients with ATTR [transthyretin amyloid] cardiomyopathy who received inotersen. And he had some patients up to 2 years and up to 10 patients with up to 3 years of follow-up. They did MRI studies showing an almost 10% reduction in LV [left ventricular] mass with inotersen in this small single-center study. So, again, I’m kind of dovetailing on the point that these silencers, by knocking out the offending protein, can give the chance for the body to resorb the amyloid. I just wanted to make sure to mention that inotersen cardiac study. 

: You meant to say the TTR gene silencers. 

: No, just to build on what was said, I think 1 of the great opportunities in having approaches that target different steps in the progression of disease is the opportunity to then potentially combine therapies, which is something that might become possible. And so if we can stabilize and reduce production of the aberrant protein with silencing approaches, it’s conceivable we could get much further toward that end game that you’re talking about of stalling or even reversing disease progression in the heart. And so I think there’s a lot of opportunity here, a lot to come and to learn from the next series of randomized trials. I really am hopeful that the availability of a broader range of agents will help to drive down the cost and make them more uniformly accessible.   

But, in the gap, I think the challenge to clinicians who are watching this program is really to have a high index of suspicion for cardiac amyloid in patients that they’re seeing with heart failure, particularly those with HFpEF, [heart failure with preserved ejection fraction] those with low-gradient aortic stenosis, and those with some of the physical exam features and historical features that we mentioned at the outset of this program. Because I think only by making the diagnosis are we going to find the populations that stand to benefit from these therapies. 

: So, it’s nothing less than incredible to think about where the field of cardiac amyloidosis is today versus say, a dozen years ago. A dozen years ago, transthyretin amyloidosis was almost an afterthought. There was certainly no effective treatments available for it, and it was thought to be very rare. AL [light-chain] amyloidosis was largely a death sentence. There were poor chemotherapy options and the majority of patients would quickly succumb to the illness. Where are we a dozen years later?  

Well, for AL amyloidosis, we have far more effective therapies such that now it’s really the rare patients who can’t get pretty good or great control of their light chains. We can most of the time, and the survival—we talked earlier about prognosis and the disease. The biggest difference in what prognosis model you use is when it was published. Because in the more recent models, patients do way better, not because of any difference of the model, it’s just that the therapies have gotten so much better.  

And as for transthyretin amyloidosis, it’s just a different world. Now most patients can get diagnosed noninvasively. Now we know that it’s actually a downright common condition (particularly the wild-type form in an older population), and we just talked about all of the exceedingly promising treatments. We now have 3 FDA-approved treatments for transthyretin amyloidosis, 1 for cardiomyopathy, 2 for polyneuropathy, and many reasons to be hopeful that it’s only going to be getting better with more options in the coming year. So it’s a very exciting time for the field. 

: Dr Witteles, Dr Hanna, Dr Desai, I want to thank you very much. This has been a really enjoyable session. I think all viewers will recognize your true expertise, and it was a pleasure speaking with you all. Thank you very much. 

Management of Cardiac Amyloidosis