All right, so before we get to our final talk, we have a case presentation and to get the thoughts from the panel. And so I will be presenting the case and tossing the questions to our panelists. And this is based on a true story. This is a real patient. 80 year old Caucasian man who was newly diagnosed with ATTR, wild type ATTR cardiomyopathy. He had NYJ class two symptoms. He had good volume status, some mild peripheral neuropathy, which has been gradually worsening. He has a type two diabetes with the most recent A1C of 8%. Hypertension, bilateral carpal tunnel and spinal stenosis. His medications are only low dose furosemide and metformin. He has no notable family history and is of German ancestry. His labs show a negative monoclonal protein evaluation and NC pro BNP of 1200 and normal potassium with mild kidney dysfunction. Imaging shows an EF of 55%, one and a half centimeter wall thickness, minus 16% on the global longitudinal strain and a very positive PYP scan. And his EKG is essentially normal. Okay, so for the panel, and I wanna make sure we stay on time. So we'll do brief answers. Maybe we'll start by a show of hands. Does everybody recommend genetic testing? Yes, if you put your hand up. Okay, so everybody does. So low yield probably in this patient, but still generally recommended. Okay, arrhythmias screening. Should it be done? Maybe I'll just toss it to the panel. I will look at it and tell them to turn it on at age 80. I don't think they're turning it on. Why don't you keep talking while we try to figure this out. I would say I tend to use smart watches because they actually work pretty well. I kind of navigate at age 80. We have a pharmacologist here on our panel, so maybe we'll turn the next question to you. In terms of non-amyloid-specific therapies. You have to realize now, we live in a very curvy state, let's say in Colorado. But nonetheless, in terms of some nonspecifics, what are the roles that a pharmacist can add to your multidisciplinary team outside things like access and cost, is managing some of these specific therapies. One of the questions that I get asked a lot, because our patients get online and they go, oh my God, you're gonna make me blind. And the answer is no, not with Japan. With Japan, it's because you have to consider vitamin A supplementation. I call it the Vulcan drug. But it's only with that particular one that you run into. The other thing we run into are using additional supplements. And I don't know if the panel has run into this before. I've run into this with L-Arginine, because there are some data with regards to that. Can you just, with regards to this, but it's in very, very high doses. And I, and particularly in patients with Hep-Nep, they, and amidebrap, they can plummet their pressures. The neuropathies are another thing. The one question I have for you is, what is this guy's creatinine clearance? Most likely the EGFR in this patient's gonna be in the commode. So with that being said, your pharmacist is gonna be able to say, that metformin is less than 30. We're gonna get rid of that. We're gonna switch it to some other sexy drugs, number one. And then number two, we're gonna manage that neuropathy that's going on with that as well and making some recommendations. So those are some of the things that I, that at least we look at. I'm more inpatient. Perfect. And anyone else in terms of SGLT2s? How do you think about that? Maybe just pass the one that works, if you don't mind. Yeah, so, oops. So I, ooh, that's loud. I would certainly put this gentleman on a SGLT2 inhibitor. I consider them sort of standard of care for wild type ATTR. He also has poorly controlled diabetes. So he's got multiple indications here. And I would throw an MRA on there as well. Okay. I'm gonna leave the last question aside because we're gonna kind of come back to it at the end. So let's move on to chapter two of the case, an irregular development. So he started on tefamidus, impagliflozin and spironolactone. This was actually in an era where tefamidus was the only therapy. So it was an easy choice at that moment. Does well for the first six months and then develops more dyspnea and palpitations, found to be a new atrial fibrillation with normal ventricular response. He started on apixaban, undergoes to e-cardioversion, feels better for two weeks, and then has recurrent AFib with a recurrence of symptoms. You see his NC-proBNP has come up to 2100. The remainder of his labs are unremarkable. And his imaging is unchanged. He has mild to moderate left atrial enlargement. So for the panel, would you pursue rhythm control in this patient and how? If you do. Dr. Grodin. Sure, I'll try to tackle that one. So I still would. I think this is certainly somebody that I would at least consider ablation. I mean, I would certainly refer them to an electrophysiologist. They've got a recidivism of a atrial arrhythmia. This can be associated with both morbidity and obviously the stroke risk, as was mentioned already. You know, and then in terms of an antiarrhythmic, that's quite tricky. So, you know, I'll be interested to what our pharmacist says but, you know, a lot of these individuals that have kidney insufficiency then, you know, that kind of negates some of the other antiarrhythmics which we might go to, or if they might have substantial beta-blocking properties may not be poorly tolerated. So a lot of what we have from an antiarrhythmic standpoint in these individuals could be amiodarone. But yes, I mean, in somebody like this that would be symptomatic, it would be recur. I would consider all of these. Any comments on the antiarrhythmic choice? You know, again, it's typically. The mic. I'll have to do the mic thing, sorry. I completely, whoa. I completely agree with regards to the amnio. The one I would not recommend, though, is I don't know if you're using dronitorone but we find patients will tank their heart rate. Anyway, so, and then again, you have to really consider stuff. I mean, propafenone has calcium channel blocker activity, a little bit of beta blocker activity. Sotolol has to be adjusted renally. Of course, we, Dr. Omberdecker, we just added IV sotolol to our formulary so you can play with that now. Much quicker loading inpatient, a day, out. But again, you have to worry about the, in terms of the creatinine clearance. So, and so again, you're in a catch-22. Yep. Great, and then maybe for Dr. Omberdecker, do you always pursue TE before cardioversion in ATTR or cardiomyopathy patients? Would you do it two weeks after the first cardioversion? I mean, if a patient's been on a DOAC and you know for sure, or morphine with the therapeutic INR and you can know for sure if it's been at least four weeks, then I don't know that you have to do a TE, but if there's been any interruption, I do think the stroke risk is higher in amyloid patients, and so it is safer to do a TE cardioversion if they've only been on two weeks anticoagulation. Oh yeah, no, I meant for more. There's been a conventional wisdom, of course, you know, in this disease, every single time you do a cardioversion, you should do a TE because the clotting risk, as you know, is higher. I think that's been called into some question in terms of are we maybe making too much out of tiny, tiny thrombi that have been there forever. Yeah, Dr. Rhoad. Dr. Rhoad, tell us, I've got a question back at you. So what if you had a patient who was systemically anticoagulated for six weeks? Let's take that even further, let's say three months, and now they've got a several-week paroxysm of AFib, and they're in the middle of AFib, they feel bad. Would you order a TE for that individual? Yeah, no, I mean, that's why I asked it. I historically have, but I must confess that particularly for a very symptomatic patient, I do worry that we then find a tiny clot that's been there forever, that, you know, and for those who didn't see it out of the Brigham, they published a case series a few months ago that said we don't do TEs in a lot of these patients, and none of them get strokes. So to the extent that that counts as evidence. I was just gonna say that. I mean, I have found clots in patients on TE, and then you have to switch them to Warfarin and all this rest. I also have a million patients who've been cardioverted in tiny little town emergency departments without it, and none of them have strokes, so. Okay, well, let's move on to our final chapter, disease progression. So this patient underwent an AFib ablation, it was successful, and has generally maintained sinus rhythm, did not get an antiarrhythmic, and has needed a single cardioversion since. However, over the next two years, he had gradually worsening symptoms, now borderline NYHA class three, diuretic dose has increased, volume status is okay on that, antiprobian P is about 3,000. You can see his echo has worsened a bit, he Fs down a little bit, wall thickness and GLS are maybe a bit worse as well. Other medications remain unchanged, which includes ephamidus, epixaban, and pagliflozin and spironolactone. So, the big question, how do you define disease progression, and would you recommend a change in therapy for this patient by either adding or substituting acramidus or vutriceran? Who wants to take it? I'll take the first one. Okay. The first one's actually very easy, I don't know. So, I think the big, and I'll unpack that, since we only have five minutes and not five hours, you know, I think, when I think about disease progression and ATTR amyloidosis, I mean, there is, I think of two buckets, really, there is a category whereby the disease progression is largely related to increased or ongoing fibral deposition that is progressive beyond your current treatment, right? I think we would all agree that that is amyloid disease progression, but then we have to remember that a number of these individuals have a number of other contributing comorbid conditions, which also might, you know, further add to the morbidity, might also enhance the heart failure phenotype, and then a number of these patients have concomitant cardiovascular disease as well. Great, okay, so for the sake of time, maybe we'll just do it by a show of hands. Question one, would you change amyloid-specific therapy on the patients? Nobody would. Oh, no, I'm asking everybody, show of hands. Okay, you've said it, so what are you changing them to? I live in Canada, I can't change anything. Okay, imagine you lived in the US where everything, where cost doesn't matter. I mean, I think that this patient does show signs of progression. I would try and get them into a clinical trial, perhaps, of a depleter therapy, but failing that, I think it makes sense at this point to try switching them to something else. Is one of those better than the other? We have no data to support this at all, so I'll throw that out there, but, you know, I think instinctively it makes sense to switch classes. Okay, so as you can see, there's not a clear answer. Did you want to say something? I was gonna say, it's really, the honest answer is we don't know, because that's the data, we don't know. But I do think it's kind of, when you say treatment failure, it's like this patient's now 82 and not 80. Their renal function is probably worse at age 82 than it was at age 80. Their NT-proBNP's gone up, but is that related to their renal function getting worse versus actual amyloid deposition, as Dr. Groten mentioned? We don't know. We don't know how to quantify that. We don't really know how to measure that. And this is what's really hard for us in the field, is that there's a lot of stuff that happens to 80 going to 82. And how much of it is a treatment failure versus how much of it is other stuff that's not related to the amyloid? I don't think we know the answers. Terrific. Okay, I just want to, there's been some questions submitted we don't have a lot of time. I'll just hit the very top one, which was are there specific pointers to hereditary versus wild type ATTR? And I'll say the demographics. So Dr. Davis showed some of the parts of the world where people might come from. So that's one. And the other big one is neuropathy, particularly for the mutations other than V122I. Most of them do cause significant clinical neuropathy. So when you see neuropathy plus cardiomyopathy, that's a big pointer. All right, with that, or did you want to give another pointer? Please. Oh, I just wanted to add that I think one thing about hereditary ATTR is that the genotype can, the genotype can inform your workup and how you think about penetrance and how you think about the severity of the clinical manifestation. So it really is a nice example of a genotype first paradigm way of thinking about a disease. Yeah, great point.

ATTR cardiomyopathy

peripheral neuropathy

amyloid-specific therapies

clinical trials

disease progression