All right, so I'm going to talk about treatment, but we have the quiz game coming up as well. So get out your phones. All right. I think Dr. Witalis has requested Taylor Swift music for the question, so hopefully that'll play. So case one, a 65-year-old with newly diagnosed AL, cardiac amyloidosis, returns to your office for follow-up. He's euvolemic. He's on a low dose of a loop diuretic, SGLT2 inhibitor, and an MRA. Has class 2 symptoms, normal potassium, normal creatinine, and an NT-proBNP of 1,100. So what is the most appropriate next step for the management of this patient's AL amyloidosis? Are you going to add a GLP-1 agonist as a treatment for HFPEF, refer to hematology oncology, start a TTR stabilizer, such as tefamidus or aciramidus, or start a TTR silencer, such as vitusiran or eplantericin? So, whoops, if we can go to the, there we go. I don't know if this is Taylor Swift, but we'll go with it, so. These GLP-1 agonists are all the rage. Multiple positive studies in everything, but what about AL amyloid? I don't know. All right, so good. I think the majority got the correct answer, which is refer to hematology oncology. All right, if we go back to the cases. All right, so similar stem, 66-year-old with wild-type ATTR cardiomyopathy returns to your office. He's euvolemic on a low dose of a loop diuretic, SGLT2 inhibitor, and MRA. Class 2 symptoms, normal labs, NT-proBNP of 1,100. So what is the most appropriate next step in the management of this patient's wild-type ATTR cardiomyopathy? Add a GLP-1 agonist, refer to HemOnc, consider the patient for cardiac transplant, or start the patient on an approved trans-thyroid and amyloid disease-specific treatment to prevent progression. Let's see what the answers are. ♪♪♪ got the correct answer, picked the longest answer there, so and let's see the final leaderboard update here until I think we have the last question coming up here. All right, it's a little bit longer question. You have a 60 year old who actually came to your clinic a month ago for a second opinion after four heart failure hospitalizations. He is healthy otherwise, takes all of his medications, compliant with the diet, no past medical history, ECHO shows an EF of 45 percent, wall thickness of 1.3 centimeters, and grade 3 diastolic dysfunction. Medications include Torsamide 80 milligrams twice a day, Spironolactone 50 milligrams daily, and DAPA 10 milligrams daily. Since you've watched every single available ACC educational offering, you made the diagnosis astutely a month ago and started the patient on tefamidus. Now today he comes back after being on tefamidus for a month. He has evidence of volume overload. His PCP has referred him to nephrology for elevated creatinine and he can only walk 20 feet. So what would you do next? Add a TTR silencer for combination of stabilizer and silencer therapy, add aciramidus to the tefamidus for combination stabilizer therapy, refer to an advanced heart failure center for consideration of cardiac transplant, or defer management to nephrology since when nephrology stops the diuretics, patients with heart failure always get better. So we'll see what the final answers are. Are there any nephrologists in the audience? Hopefully not. All right, so 45% said refer to cardiac transplant, which is the right answer, but there's kind of a spattering on kind of combination therapy. So all right, so I think we will kind of go through the the answers to those questions here. So the focus of the next 10 minutes or so is to really talk about disease modifying treatments. So it kind of sounds silly, but you have to have the right disease. So AL cardiac amyloidosis is not the same as ATTR cardiac amyloidosis. There's something to be said about repetition and that you've had three speakers say that is that all of us have seen patients on tefamidus when they have AL amyloidosis, and tefamidus does not work for AL amyloidosis. Patients with AL amyloidosis were excluded from all of the ATTR amyloid trials, and so if you have a patient with AL amyloidosis, you are going to phone a friend in hematology oncology. There's a lot of new developments. It's not the focus of this session, but you have to make sure you have the right diagnosis. So let's turn to ATTR amyloidosis. This is the 75th anniversary of the American College of Cardiology, so I'm going to provide a 10-minute, 75-year comprehensive history of the treatment of ATTR amyloidosis. Thankfully, there's actually not a lot to talk about up until 2018. So people have seen the path of physiology of TTR amyloid. So before 2018, the treatments we had is TTR suppression, so to speak, and that we could do a liver transplant for patients with hereditary or variant or mutant TTR, and that would remove the source of the mutant TTR protein. We could do resorptive therapy, which was a heart transplant, so if you did a heart transplant, obviously you remove any deposited amyloid in the heart, and then the combination therapy we talked about before 2018 was really combined liver and heart transplant in some highly select patients with variant ATTR cardiomyopathy. So thankfully, things have gotten better. In 2018, there were two TTR silencers that were approved for the treatment of hereditary ATTR polyneuropathy. In 2019, there was a TTR stabilizer that was approved for the treatment of ATTR cardiomyopathy, that was tefamidus. And then in 2024, we had our second TTR stabilizer, aciramidus, that was approved for the treatment of ATTR cardiomyopathy. And then finally, just about 10 days ago or so, there was a TTR silencer, vitusiran, that was approved for the treatment of ATTR cardiomyopathy. So we have a number of options that have developed just kind of recently in the last few years. It's also worth pointing out that there's been other developments in the diagnosis and management of ATTR cardiomyopathy over the last 12 years, and the reason I point these out is that when we look at the clinical trials and try to interpret the data, it's worth kind of keeping these in the back of your mind. So as Dr. Vitalis pointed out, 2016 was the paper about non-biopsy-based diagnosis with ATTR cardiomyopathy. There's been a number of educational initiatives. You saw the AHA statement up on the screen earlier. There's an European Society of Cardiology. There's an ACC, ECDP statement. There's campaigns such as this, educational offerings, that have resulted in earlier diagnosis, more diagnosis in the community, and probably as a result, that's influenced some of the trial data that I will show you. It's also worth noting there's been improvements in heart failure management, things like SGLT2 inhibitors and implantable PA pressure monitoring devices, MRAs, GLP-1 agonists. There's been improvements in our electrophysiology care as well. Think about DOACs, left atrial appendage occluder devices, catheter-based deblation, things like that have all have improved. So when we look at the three trials that have led to the approval of ATTR therapies over the 10 years, it's kind of worth keeping those in mind. So the original study was the ATTR ACT study, which compared tofamidus versus placebo. Enrolled patients over 10 years ago now, all these patients actually had to have biopsy diagnosis to get in. Most of the patients were wild-type patients, and about a third were class 3. And if you look at the NT pro BNP, about 3,000 to get into that trial. The next trial that came out was the ATTRIBUTE-CM that compared aciramidus versus placebo. Enrolled patients from 2019 to 2020. Most of the patients, again, are wild-type, but slightly higher proportion of wild-type, 90% versus about three-quarters in the ATTRACT study. And there's less class 3 patients, and a slight drop in the NT pro BNP. Tofamidus was approved about a year into this study, and so patients could start tofamidus, actually, when they were a year into the study, as it became approved. And then the most contemporary study is the HELIOS-B, that was vitusiran versus placebo, 2019 to 2021. So tofamidus had been approved, and so that's why you'll see 40% of the patients were on concomitant tofamidus, and a less sick population, again. Class 2, 77%, the NT pro BNP was significantly lower. This is on top of all of the other improvements we've seen with things like SGLT2 inhibitors, arrhythmia care, or heart failure management otherwise. So when you look at the outcomes, you see that there are differences. So in the original ATTRACT study, tofamidus versus placebo had a significant mortality benefit at 30 months, even larger benefit when you go out to the 58 months, kind of five-year open label extended follow-up. But look at the mortality and the placebo control. 43% mortality at 30 months, so pretty high, just a higher sick patient population. When you look at the more recent studies, you'll see that there is lower mortality in the placebo control group. So the 24-month attribute more placebo mortality, 24%, 21% of the HELIOS-B, so these are less sick patients that were enrolled in the more contemporary studies. So what you'll find is that big mortality benefit for tofamidus in a sick patient population. There was mortality benefit when you look out to the open label extension, kind of longer follow-up in the attribute study with acroamidus. And then similar to the HELIOS-B, you have to kind of go further out in time to see a mortality benefit. It looks like it's a smaller benefit, but again a different patient population. I think there's some additional takeaways from all these trials. One of the takeaways is that despite tofamidus and all the improvements that we've seen in heart failure care, EP care, there are patients with ATTR cardiomyopathy that continue to have a risk of worsening heart failure, worsening hospitalizations, and mortality. And a lot of this is probably related to heart failure getting worse from their underlying amyloid cardiomyopathy. It's also worth reflecting that the average age of the population is about 77, so there's comorbidities that are potentially getting worse as well. But there's certainly a suggestion that disease progresses over time. Other takeaways are that all three agents, tofamidus, acroamidus, vituceran, lower risk of heart failure hospitalizations, lower mortality, and they're all actually well tolerated with minimal side effects. And that's why we have three approved therapies now for ATTR cardiomyopathy. Another important point to come up is, and in particular as it relates to that third question, is that none of our current treatments actually result in disease-specific improvements in functional status or quality of life. So when you look at things like the six-minute walk scores, quality of life scores, whatever people are at at baseline, they don't get better a year, two years, three years down the road. They just get worse less, which is kind of weird grammar. And it's completely different than a lot of other things that we do in cardiology. So when you think about things like Arnie's or mitral valve transcatheter, esdorage repair, heart transplant, LVADs, people actually start at a certain six-minute walk and get better. Our current ATTR cardiomyopathy treatments prevent people from getting worse. And so there's a lot to be let to be done that Dr. Grodin will probably cover in his talk. So this comes up in that that question of that third patient that had multiple heart heart failure hospitalizations, high doses of diuretics. So when do you think about heart transplant in someone with ATTR cardiomyopathy? If the heart is sick enough is the first question to ask. And if the answer is yes, it's probably worth thinking about it. So there's a number of disease-specific staging systems in the amyloid world that you can look at. There's actually a lot of similarities with those disease-specific, between amyloid patients and just heart failure patients in a broader sense. And so if you have a patient that has repeated heart failure hospitalizations, if they're on IV therapies, if they have persistent class 3 or 4 symptoms, they have significantly reduced functional capacity, if they're on high doses of diuretics, or if they have that dreaded referral to nephrology for cardiorenal syndrome, those are patients that are probably sick enough that if they're otherwise candidates for cardiac transplant, they should be referred to an advanced heart failure center for consideration. I think there's a number of questions that are out there that need answers, ideally before the 100th ACC meeting. Which ATTR cardiomyopathy treatment should be started first? That is an unanswered question. There's a lot of debate, there's a lot of pontification about that, but we don't honestly know the right answer. Should patients receive single therapy versus combination therapy at the time of diagnosis? That is an unanswered question. How is ATTR cardiomyopathy progression assessed? We don't really know that right now. If a patient has progression, should the treatments be replaced or do you add treatments? How do you manage that with three therapies? That is unknown. Are there certain subtypes of ATTR cardiomyopathy patients that respond better to one therapy versus another? The hereditary ATTR cardiomyopathy patients that have polyneuropathy already, even before the approval of VITUSORAN, there was often a discussion with the neurologist. If somebody had significant polyneuropathy with hereditary ATTR cardiomyopathy, oftentimes they were getting silencers to start with, as the data for silencers in hereditary ATTR polyneuropathy is probably better than the stabilizers. In the era that we have a silencer approved for both cardiomyopathy and polyneuropathy, I think that's sort of a question. I think other things to think about are how will TIFAMATIS, ACROAMATIS, and VITUSORAN compare to newer treatments that are in trials and in development? And then the elephant in the room is the cost of these therapies. So the annual list price of TIFAMATIS, $268,000 per year. ACROAMATIS, $225,000 per year. VITUSORAN, $447,000 per year. These are lifelong therapies. This is different than even adding something like a plurinone to your patient's medical regimen at $20 a month for a plurinone. This is totally a different ballgame in terms of the cost and how is that going to be managed. Having said that, in conclusion, I would say we have a new era of ATTR cardiomyopathy treatment. Solid organ transplant should really become a historical treatment. It's really reserved for those patients with advanced disease and kind of end-stage disease. And with timely diagnosis and early diagnosis, you really should not need to think about transplant moving forward. TIFAMATIS, ACROAMATIS, VITUSORAN have been shown to improve outcomes and they're safe. We have no direct comparisons between these agents and the comparison of the clinical trials is certainly limited by different populations. But I think overall it is nice to have different options out there.

cardiac amyloidosis

ATTR cardiomyopathy

VITUSORAN

treatment advances

disease management