I'm a cardiologist at the Smitt Heart Institute at Cedars-Sinai in Los Angeles, and I'm delighted to be here today to discuss reviewing treatment options for cardiac amyloidosis with the CV Care team. I'm joined by two experts, Janelle Grazzini-France, who is a nurse practitioner in the Division of Cardiology with specific affiliation and expertise in heart failure and amyloidosis at the Mayo Clinic in Rochester, Minnesota, and Dan Landup, cardiovascular clinical pharmacist in Advocate Health in Chicago. So before we dive into the hugely important CV Care team roles, I'll give you a quick overview of cardiac amyloidosis. So as you know, it's a condition where there's a protein that the body produces naturally that for reasons we don't understand, decides to deposit into the heart muscle, resulting in a heart that is thicker and stiffer than normal, restrictive cardiomyopathy, heart failure symptoms. The two most common sources of this protein will be immunoglobulin light chains, AL amyloidosis, a form of a plasma cell dyscrasia along the spectrum from NGUS to multiple myeloma. And the second is the TTR protein, transthyratin, a binding protein in the body, which in turn can have one of two sources of variant form from a mutation in the gene or the wild type form. It is very important to think about cardiac amyloidosis on your differential of a patient who presents with a dyspnea, edema, preserved or mildly reduced ejection fraction, and increased LV wall thickness because this is an under-recognized condition for which there are disease-directed therapies. There are three major challenges when we think about management. Number one is thinking about the diagnosis. If you don't think about it, you won't order the right tests. It's not going to pop up on routine clinical testing. So a high index of suspicion in that clinical scenario with other clinical clues from other places the amyloid protein infiltrates, like the nerves or the musculoskeletal orthopedic system. So sensory peripheral neuropathy, autonomic dysfunction, carpal tunnel syndrome, spinal stenosis. Think about amyloidosis. Second is the challenge is diagnosis. It's important to order the right tests and interpret them in the right way. So the monoclonal protein screen is a hugely important starting point to exclude AL amyloidosis before moving further. The serum immunofixation electrophoresis, the urine immunofixation electrophoresis, and the serum-free light chains. If abnormal, do not pass go. Do not collect 200. Tissue is the issue. Talk to your hematologist and biopsy something, remembering organ is the gold standard, heart or kidney. The fat pad and bone marrow have less sensitivity. If the monoclonal protein screen is negative, you can breathe a deep sigh of relief and then focus your attention on TTR amyloidosis, where a bone scintigraphy, most commonly technetium pyrophosphate scan, affords the ability for non-invasive diagnosis. Because a positive technetium scan in the context of a negative monoclonal protein screen is diagnostic for TTR amyloidosis, but it must be interpreted in the context of a negative monoclonal protein screen because AL can cause false positives to the scan. And finally, if you've settled on the diagnosis of TTR cardiac amyloidosis, then you should do genetic testing to look for a variant form, which will be important for therapeutic options as well as cascade screening of first-degree relatives. The third challenge is treatment, and the therapeutic landscape is exploding. So we know for AL amyloidosis, we trust our friendly hematologist to guide plasma cell-directed therapies to eradicate the toxic light chains and hopefully lead to organ recovery and response nine months later. But if there is TTR amyloidosis, then it is the cardiologist's job to guide therapy. We have stabilizers that stabilize the TTR protein in its happy, tetramer form so it doesn't dissolve into fibrils that deposit into tissues. We have tefamidase 2019, aciramidase 2024. And emerging onto the landscape now will be vutricerin, a silencer which halts production. This is not yet FDA-approved, but the Helios B trial, which came out in late 2024, indicated that patients had improvement in the endpoints we care about, heart death and heart failure hospitalization. So two stabilizers on the market, potentially a silencer in the future, lots of unanswered questions on how we will give therapy, how the care team can care for these patients with this multidisciplinary roles because of the multiple organ involvement. So with that background, I want to give our first question to Janelle. Janelle, tell me, how is your amyloidosis clinic structured? What is the role of the nurse practitioner in the amyloidosis clinic? All right. So it takes, first of all, a vision or leadership to say, we're going to need a team, a multidisciplinary team to help give the best care we can and reduce morbidity and mortality. So hats off to Dr. Martha Brogan, who is our director of the amyloid clinic at Mayo Clinic. So she asked me about 10 years ago to join the crew and then gave me time actually to learn how and get more in-depth knowledge because even with heart failure expertise, which I have and many of us have, you can make mistakes because there are specific issues that maybe aren't handled the same with amyloidosis patients. So hats off to her to give me the time and to get to be expertise on this. So the way we set it up, every new consult at Mayo meets with a cardiologist first, unless it's urgent, urgent, urgent, then they'll reach out to me. Can you get them in faster? Because it's like, hey, I'll need to move quickly. But then I meet with them a few days, a few weeks later because they're usually super overwhelmed by the diagnosis, have never heard the word, there's no point of reference. And sometimes they're like, I don't know why I'm here, why are we having this visit? And I'm like, well, just what questions do you have? Forty-five minutes later, they're like, oh, this is so helpful because there's so many things that are a little unanswered, a little, well, do I have AL, do I have TTR, is it hereditary? So they're pretty overwhelmed with that. We go over final testing, what are we waiting on, the biopsy, the overnight oximetry, let them know if this is TTR, it's going to take a few weeks to get your DNA testing, we'll get back to you, and then any questions on the therapies that we're going to be using. That's so helpful. And I love that model where oftentimes patients don't recognize the fact that they haven't heard of this before, they don't know what it is, it's an under-recognized, potentially rare condition. And then to have that backup visit where additional expertise is offered is hugely important. And then what's the vision for a long-term follow-up? What's the role of the nurse practitioner when it comes to the serial assessment of patients as they move through their amyloid journey? Great. I'm glad you asked that because that is, I think, even more important because sometimes that's where we stumble. We're not following them closely enough, say an AL that's getting new chemo, having a lot of cardiac toxicity. We need to step in. And luckily, we have a very cohesive, hand-in-glove relationship with our hematology team, and they can just call me, hey, Janelle, can you see this patient? I'm like, when? Today? And I'm like, yes, I'll add them on as an extra, get them down here, we'll get them sorted out. But also like with the TTRs, they don't always just, they're done when they're on their stabilizer. If they're late enough in the game or they've had it long enough, several years, it is still progressive at this point. And they're going to develop atrial fib, they're going to develop heart block, they're going to develop heart failure, and to be able to step in and go, hey, I think you're having more trouble with heart failure, we might need a belly tap, we might need a thoracentesis, let's maybe get you off that beta blocker, because your cardiac index is pretty low, let's maybe make you feel well. And that can be episodic and urgent, like I said, with the AL, and then the TTRs, because our cardiologists are not always in clinic. I'm in clinic all the time. So I'm there, I have urgent slots held, so that's important for other clinics that are thinking about this. You can't just jam the schedule and then expect people to always be able to take on extra, because at least in my practice, 70% of it is amyloid. There's a ton of phone calls coming in, people are scared, they're worried. I'm in a hospital, are they doing the right thing? And I'm like, well, I don't want to step on my other colleague's thing. But just to reassure them, hey, I've looked at the record, everything looks appropriate, or have them call me if there's any questions. So we even do that kind of thing. You know, I think you brought up so many important points that people can apply to their centers. Number one, you touched on the fact that we treat heart failure differently in patients with cardiac amyloidosis. Because it's a restrictive cardiomyopathy with a fixed stroke volume, patients are often very dependent on heart rate to maintain their cardiac output. So backing off on beta blockers, it's hugely important to improve quality of life. The phasodilators are often poorly tolerated because afterload reduction in the context of a fixed stroke volume and orthostasis, so low threshold to back off if there's any symptomatic orthostasis. And as you said, that link of availability and education that is so essential when we care for patients with a chronic condition and managing the expectations of none of the medications we have to date will reverse disease. You're not going to feel better. We're trying to prevent you from feeling worse with a two-pronged approach of giving you amyloid-directed therapies and appropriately managing this unusual animal of heart failure in the context of restrictive physiology. That was so helpful. And I want to thank you for that. And now, speaking of medications, I'm going to turn to Dan, our cardiovascular clinical pharmacist. So we've got defamidus and now acaramidus approved for treatment, potentially butrecerin on the horizon. Tell us what clinicians should be aware of regarding drug interactions, side effects, and tips for a smooth prescription process. Thank you. So like you mentioned before, and one of the most exciting updates in cardiac amyloidosis is the rapidly evolving treatment landscape that continues to evolve with new agents like you mentioned. Defamidus and acaramidus are both oral options, oral TTR stabilizers. Defamidus comes as a 61-milligram oral capsule, given once daily under the brain name Endomax, or as a 20-milligram capsule that's given four capsules daily under the brain name Vindickel. Acaramidus, also an oral tablet, doses two 356-milligram tablets twice a day under the brain name Atruvi. Butrecerin, if it does become approved for ATTR cardiac amyloidosis, will be an injection that's given simultaneously every three months by a healthcare provider. Now, in addition to being very effective, they're also very well-tolerated. There's essentially no significant adverse reactions that are seen in clinical trials other than some mild GI upset or diarrhea that patients may report with the TTR stabilizers and some local injection site reactions with the Atrecerin injection. There is, in the acaramidus trial, they did notice that there was a small, non-significant increase in serine creatinine, about 0.2 milligrams per deciliter, that can happen with therapy, but that's harmless and reversible upon stopping the medication. Now, drug interaction-wise, there are some interactions to be noteworthy with these agents. So, tefamidus is a breast cancer resistance protein inhibitor. So, it can increase levels of medications that are substrates for this transporter. One being methotrexate, but a common one in the cardiovascular space is versuvastatin. So, if you are using versuvastatin with tefamidus, the dose should start at 5 milligrams a day up to a max of 20 milligrams daily, or alternatively, just choose a different statin that does not have the interaction. For acaramidus, acaramidus is metabolized by UGT enzyme-mediated glucuronidation. So, any medication that can induce these enzymes should be avoided with acaramidus. Now, the big culprit here is strong CYP3A4 inducers can induce these enzymes. So, the recommendation is to avoid strong CYP3A4 inducers if you're using acaramidus. Now, as far as the tips for our prescription process, this can often be the most challenging aspect after trying to identify and diagnose the patient. So, my tips are have a dedicated team that is familiar with the process, and then plan ahead. So, when we have the patient in the first visit in the office, we'll make sure all our patient and information insurance is up to date. And we'll also have the patient submit or fill out the manufacturer's system program forms at that first visit should we need to enroll the patient later on. And then we'll send a prescription to the pharmacy and do a PA authorization at the same time as all these medications will require a PA. Now, when sending the PA, it's important to make sure all the clinical notes are there and all the criteria are met for the insurance to approve the agent for the first time. And then once we have the patient's co-pay, if it's unaffordable, that's where we do some investigative work. So, for commercially insured patients, we have co-pay assistance programs. And then for Medicare patients, we can refer them to Extra Help, either one of those three foundational grants or the manufacturer assistance program to give them help for affording their co-pays. Now, it is important to let the patient know that this process can sometimes take a few weeks depending on what services they need. And then lastly, don't be afraid to use some of the resources that the manufacturers provide. There are different support programs. Tefamatis has something called Vendolink. And Acramatis has something called Forging Bridges that can help with this process as well. Incredible. Having that kind of expertise and wisdom to guide clinicians, to guide centers, is hugely important. And then just to amplify on what you said, we worry about resubastatin at doses above 20 milligrams. With tefamatis, it can cause rhabdomyolysis. And that is something we want to avoid at all costs, especially in these patients who are often older and frail. They don't need another problem. When you mentioned the CYP3-4 inducers, the ones I remember off the top of my head from medical school 25 years ago were rifampin and phenytoin. Are there any other big ones, which aren't very commonly prescribed, but there are other big ones that clinicians should know about when they're giving Acramatis? Right. Those are two big ones. Also, carbamazepine often. So if you have someone with seizures or try gemmoneuralgia, they may be on carbamazepine or phenobarbital. Amazing. These medications are not often used, so you may not encounter them. However, if you do, with a medication like Acramatis, you really should not be using them together. Amazing. Another important point, I think, is that the tefamatis comes in the two formulations. There's a 61 milligram tablet, and then there's the 420 milligram tablets. Some insurers prefer one versus the other. And medically, they're equivalent. So I tell patients, don't stress out if your insurance has decided they want you to switch. It might be more annoying to take 420 milligram capsules. But honestly, medically, you're getting the same stuff. Do you think that's a reasonable recommendation? Yes. And it's really insurance-driven. So we prefer the 61 because it's one capsule. But whatever they can get, we'll use. Yeah. And I think a huge unanswered question, which we're not going to figure out on this podcast right now, is which one should patients get? And I think my take on that is that the current clinical evidence does not sway us for one versus the other. There are no direct head-to-head comparisons. We know that every medication tested against placebo is beneficial. This is good news for our patients. Tefamatis, Acramatis, Lutricerin all work against placebo. It's impossible to compare the trials head-to-head because in successive eras, more contemporary eras, the patients are less sick. So really, we can't compare point estimates for outcomes of the trials. But ultimately, the future is bright. And if you find the process overwhelming, we'll put Dan's cell phone in the chat. Just kidding. You should always be free to reach out to your local tertiary, quaternary center where there is an amyloid program where there is additional support for those patients. Well, I think we've covered everything so beautifully. I've learned a lot. So thank you so much to Janelle, to Dan. Thank you so much for listening to this Reviewing Treatment Options for Cardiac Amyloidosis with the CV Care Team.

cardiac amyloidosis

restrictive cardiomyopathy

immunoglobulin light chains

transthyretin protein

heart failure symptoms

protein deposits

diagnosis

treatment

therapeutic landscape