JEFFREY GESKE: Hello, I'm Jeffrey Gorski, Professor of Medicine here at Mayo Clinic, joined by my colleagues, Dr. Steve Ommen, Chair of the Guidelines 2024 Update for Hypertrophic Cardiomyopathy. And Dr. Hartzell Schaff, cardiac surgeon with expertise in myectomy, amongst other things. And we're going to be discussing today the 2024 HCM Guidelines and management of patients with hypertrophic cardiomyopathy. Thanks for joining me.

STEVE OMMEN: Thanks, Jeff.

JEFFREY GESKE: Good to have you here.

HARTZELL SCHAFF: Thank you.

JEFFREY GESKE: Steve, I might start with you as kind of chairperson of the 2024 Guideline Update. What kind of-- if you had to pick a top three or top four take home points, changes within the 2024 Guidelines, what's the cliff notes, the high-yield things that have changed with this guideline?

STEVE OMMEN: Yeah. I mean, the number one obviously is what's prompted the rewrite of the guidelines was the introduction of cardiac myosin inhibitors, specifically mavacamten. So that would be the number one is where mavacamten fits in therapy for patients with symptomatic obstructive HCM. We also evolved the guidelines we give to patients around healthy levels of exercise that are now encouraged in patients with HCM.

Next thing is, we formally split sudden cardiac death risk assessment of children away from adults. Before they were-- in prior iterations, were kind of in one big ball. And there's enough differences in the way you approach someone under the age of 16 versus someone older than that, that we had separated those in the guidelines. And then lastly, there's some new advice around maybe screening more frequently for atrial fibrillation-- subclinical atrial fibrillation in patients who have risk factors for that. So those would be the four biggest things that I think were the changes.

JEFFREY GESKE: Knowing that the introduction of myosin inhibitors has been the trigger for this update, I'd like to get both of your thoughts as to how mavacamten, and now, another coming aficamten, how is this impacting care of patients with HCM?

STEVE OMMEN: It makes the conversation longer.

[LAUGHTER]

So it does impact care. It doesn't impact the beginning of care. I still think that patients deserve an opportunity to respond to beta blockers or the non-dihydropyridine class calcium channel blockers. Because so many patients do respond to those medications, and they're simple to use. But for patients that don't respond to those, or can't take them for some reason, we now have another option, mavacamten, to include in what I put into an advanced therapies bucket. So it includes disopyramide, mavacamten, septal myectomy, and alcohol septal ablation. So going through the pros and cons and logistics of all of those as part of the discussion.

JEFFREY GESKE: And logistics. Dive into that a little bit. What have you seen?

STEVE OMMEN: Yeah, so with mavacamten, it came with what's called a REMS program, a risk evaluation and mitigation strategy. Because there is a small percent, 5% to 10% of patients, who drop their EF when they're on this agent. And so the FDA required that we do frequent monitoring. When we initiate mavacamten, we have to do every month-- an echo every month for the first three months that they're on it, any time you do a dose change, and every three months during maintenance phase. So that's 4 to 7 echos per year that these patients need to be willing to undergo.

JEFFREY GESKE: And Hartzell, does everyone need to try mavacamten before they head to myectomy?

HARTZELL SCHAFF: I don't know that everyone has to try it, but everyone needs to be aware of it. And when you balance the option of septal reduction therapy with surgery or alcohol septal ablation versus continued medical treatment, people respond very differently to that presentation. Some patients object to taking a medicine the rest of their life, and if there is an easier, or at least a more certain solution for their symptoms, will choose surgery.

Other patients have tried mavacamten and have not had the relief that they expected. And then other patients are put off by the idea of continued close surveillance over the years.

JEFFREY GESKE: Yeah.

STEVE OMMEN: Yeah, I think that's right. I mean, we haven't really seen much of a drop off in our surgical volumes for myectomy. And all of the patients that are going to myectomy, for all intents and purposes over the past two years, have been offered mavacamten as part of their treatment plan, and still are choosing to have surgery. Either because they failed therapy or for the reasons Hartzell mentioned, that they just prefer a mechanical solution to a mechanical problem.

JEFFREY GESKE: And say you have someone who's tried mavacamten, they're on therapy, but maybe not getting the symptom relief desired. How do you manage that medication preceding operative intervention?

HARTZELL SCHAFF: Well, that's a discussion to have with the cardiologist. And it depends on which are the drugs they're taking. But as I understand it, the mavacamten should be discontinued for at least four weeks before operation. Steve, do you have any--

STEVE OMMEN: Yeah, so the concern would be in someone who's taking such a potent cellular level, negative inotrope and giving them cardioplegia. So we have recommended 3 to 4 weeks, at least, of washout in the trials of mavacamten. They actually had a longer washout period than that. But in talking to the other high-volume surgical centers, that 3 to 4 week is a minimum of time to have patients stop taking mavacamten before they go to the OR.

JEFFREY GESKE: I have to say, when this first came about, I was worried it was going to be so complex discussing which option to take. But I found a lot of times in office, people kind of have an opinion. They either want less medications and want to opt for the procedure. As you said, kind of a structural fix for a structural problem. Others say, listen, if there's a way I can try a medication that avoids a procedure, I definitely want to do that. And the number of patients that are really torn between the two is fairly small. Has that been your experience?

STEVE OMMEN: Yeah, I think that's true. I've got a few that are wringing their hands over the choice between the two. And often in those cases, we'll say, well, why don't we try the medication first and see if you get relief of your symptoms? And if you do, we know you're going to get that same relief with surgery, but you'll have more confidence going into the surgery if you want to.

JEFFREY GESKE: I've seen cases go both ways. I have a particular patient who's had an amazing response to mavacamten. I've also had several patients who have tried it and realized, I'm not sure that I feel as good as I want. And then underwent operative intervention and felt substantially better. So it's certainly a shifting landscape.

STEVE OMMEN: Yeah. Yeah, it definitely is. And patients are certainly more aware of new options. There's advertisements on national television shows, and those kind of things. So patients are coming in informed about their options. But you're right, many of them come in with a preconceived notion of which one they would prefer, if all else was equal.

HARTZELL SCHAFF: Maybe I could ask you two a question about the use of mavacamten. Because as you mentioned, it's now being widely advertised. Is it something that should be used earlier in the conversation with patients in terms of medical treatment? And then secondly, do you think it has a place for the patients who have a very hyperdynamic ventricle without much outflow tract obstruction, but with symptoms, just to treat that very hyperdynamic patient?

STEVE OMMEN: Yeah, I think that's a really good question. So I think it can be used early, but it shouldn't be used first. Again, there's simple medications that are beneficial. Now, if we ever get data to show that these agents are disease modifying apart from relieving outflow tract obstruction, then that conversation will change. And there's some hope that may be the case since it directs some specific pathophysiology in HCM that it might have long-term consequences. But I think that's going to take us a long time to get data on that. Since the event rate in HCM is so low, it's going to take many years of follow up to determine that.

For right now, it should come after failure of the other ones. But you don't have to go through this rigorous thing of making people go to some massive dose of beta blockers that makes them incapacitated otherwise, or stop their statins because they have to be on-- because calcium channel blockers interact with that. So there's a bunch of reasons why you can now introduce that sooner. What are your thoughts?

JEFFREY GESKE: Yeah, I would agree and echo that. And maybe I'll tackle the second question. I think it's certainly a hypothesis-generating question. Could these be used as a target treatment for things beyond outflow tract obstruction. And perhaps we'll learn more about that in some of the trials looking at non-obstructive HCM come in. Right now, the only FDA approved indication is for outflow tract obstruction. And even the trials that looked at obstruction actually excluded mid ventricular obstruction.

So those hyperdynamic patients that don't have outflow tract obstruction but have mid ventricular obstruction, they were taken out, but are being included in some of the non-obstructive trials. I think it's exciting. We'll see how this evolves. Right now, if you were choosing to target one of those patients off label, it'd be hard to know how to dose titrate. Because all of the REMS program and dose titration is based on outflow tract gradient. So I'm not sure how I would do that. I don't have any specific patients that I'm doing that in right now. But I think as more trial data comes in, it will be helpful.

STEVE OMMEN: Yeah, I have used it in people that had multi-level obstruction, both outflow tract and mid ventricular-- or true obstruction at the mid ventricle. But the ones where it's just complete systolic cavity obliteration, I haven't tried it or thought about it in any of those patients yet. But I do think that the data coming from these next rounds of trials may be helpful in that regard.

JEFFREY GESKE: Well, maybe I'll let you conclude with just one more question. Say that you're a practitioner. You're caring for someone with hypertrophic cardiomyopathy. You're thinking about whether to initiate a myosin inhibitor. What kind of-- are there any pearls or lessons learned that you'd want that person to as they're considering that therapy?

STEVE OMMEN: Yeah, it's a great question. I mean, I think right now, most of the prescriptions of mavacamten are coming from HCM centers because they have a large understanding of all aspects of HCM. There are some smaller areas that are prescribing mavacamten, but it ends up being complicated. And in a busy clinical practice, it's hard to fit in all these clinical assessments and evaluations.

So I would still urge someone, if you've never used a mavacamten before, to refer them to a center where they can get a discussion about all of the options. And then participate as part of the team taking care of that patient if they choose to go on mavacamten at that point. And then from there, you start to build experience, et cetera.

JEFFREY GESKE: I think that's wise, considering informed decision making between the advanced therapies is something that I think high-volume centers are going to be really expert at guiding. And then even just some of the ins and outs of frequency of monitoring, drug-drug interactions. I think it's nice to have that initial guidance with someone who's very familiar with the process.

STEVE OMMEN: And again, just to remind you, if you are thinking about prescribing mavacamten, you do have to register as a prescriber with that REMS program as well. So there's some education requirements you have to fulfill in order to be authorized to prescribe.

JEFFREY GESKE: Wonderful. Well, thank you both for joining me. I appreciate it. It's been great having you here as we explore some of the changes and shifts to the landscape in hypertrophic cardiomyopathy.