Episode 6 - HCM Update, part 2 - Management and New Therapies

Join us as we continue our discussion with Dr. Milind Y. Desai, an authority on hypertrophic cardiomyopathy and lead author of the highly touted VALOR-HCM study presented at ACC.22.    In this second of two parts, we discuss patient management, including the role of new agents. Please subscribe to receive updated episodes automatically! More information at https://www.ohioacc.org/cardiohio-podcast/.  

“Upbeat Party” by scottholmesmusic.com

Please subscribe to receive updated episodes automatically! Visit https://www.ohioacc.org/cardiohio-podcast/.

“Upbeat Party” by scottholmesmusic.com

Transcript

Kanny 0:03

This is the cardio Ohio podcast, the presentation of the Ohio chapter of the American college of cardiology. This is canny gray wall president of the Ohio chapter and host for today's discussion. Further information about this podcast, including speaker biographies, as well as references are available@ohioacc.org. Where you can also provide feedback and suggestions for future topics. The podcast will also be available for download wherever you access podcasts, and we encourage you to subscribe, to receive updates on future sessions And now for today's discussion

0:44

Welcome to episode six of our cardio Ohio podcast. We're delighted to continue our interview with Dr. Desai on the clinical presentation, diagnosis and management of patients with hypertrophic cardiomyopathy. I'd also like to welcome back my co-host, imaging fellow from the Cleveland clinic, Dr. Ben Allen cherry, Ben. Welcome back. Thanks, Dr. Gro all. I'm excited. You know, we learned a lot about the diagnostics of HCM from one of my staff faculty at Cleveland clinic, Dr. Desai, and I'm, I'm interested to see his approach to the management of the disease, So without further ado we'll continue our interview with Dr. Desai.

Ben 1:26

I had a question you talked about the prevalence and, and as we're starting to pick up more and more of these patients, not everyone can go to HCM centers of excellence. but have you seen an increase in patients at least being managed in the community or in, in ancillary hospitals where they at least get one CMR or one visit at a center of excellence to help co-manage that plan with their community cardiologist?

Dr Desai 1:51

So that's a very important and interesting question, especially in the current context of new therapies, et cetera. So, yes, look. Every patient, at least in my practice, you know, vast majority of my patients, I see, come to see me from outside of a hundred mile radius, which means I cannot be their primary cardiologist. I, you know, if they call 9 1, 1, they are probably gonna end up in a hospital where I do not have admitting privileges. That means by default, we have to have a co-management plan and, and at the end of the day, it is about that given patient who is appropriately taken care of, and it is important, the way I think it is, this is still evolving with, with the realignment of hospital systems and. Payer networks and all that stuff. So the, the last word has not been written on this, but it is absolutely important that, you know, there is a. Yes. Ideally, a patient with ACM should be seen, at a, at a center of excellence, at least once have a management plan and then have more importantly, a co-management plan with periodic check backs. and open channels of communication now with, with electronic medical records to take an example, I mean, you know, Dr. Greyal can, I think if, if we share electronic health records, on the same platform that he can see my note and I can see his note, his office can push images electronically at the click of a button and why versa. So the last word has not been written, but the most important thing here, you said it is we have to recognize the need for co-management and it should be encouraged.

Kanny 3:39

Yes. I would definitely agree that the technology is improved a lot, so that, and I do have some common patients with you and your colleagues in Cleveland, and it's really the, the use of, care everywhere and, and so forth is really advance. That co-management, I'd like to spend the last 15 minutes or so talking about clinical management, but I think Ben had one, excellent question about symptoms and whether they can be masked.

Ben 4:04

maybe we can briefly touch on this part, Dr. Desai, based on some of these treatment algorithms, they say no treatment. If the patient is asymptomatic and, and we know from other, pathologies that patients learn to live with their disease. Are you finding that you, you often stress almost all of these patients, if not only to get a, an adequate Mets, or Mets equivalent for them to see truly what their functional status is, or how do you go about assessing symptoms in the

Dr Desai 4:33

patient? Yeah. So no, and you, you know, me, you work with me enough for me. No, is a starting point for negotiations. So when a person says they're asymptomatic at the very least, they're gonna prove it to me. So, you know, a few years ago we published a paper, more than 400 patients that came to the Cleveland clinic saying they are asymptomatic. With HCM diagnosis of HCM, they're asymptomatic prove it to me. So they get put on a treadmill and about 50% patients did not achieve their age, gender matched exercise capacity, so Mets, et cetera, and the folks that did less than 85% of a gender match capacity. Their long term mortality was significantly higher than those who hit their a hundred percent target. So is this a reflection of poor functional capacity is equal to bad outcomes, or like you said, people learn to live with their symptoms. So clearly for me, if you tell me you are asymptomatic, and if I suspect that your phenotype is eight cm, I'm gonna make you prove it to me. And often we are patients who surprise themselves. Pleasantly or unpleasantly. so it, the, if the impact of a good exercise stress test is, is on both ends of the bell curve.

Ben 6:01

Yeah. I think we've, we've all seen even reading echoes with you both in the stress lab and in the, in the main reading room. How patients who have come asymptomatic, their Mets are, are much lower than you would think.

Dr Desai 6:12

And, and many of them, you know, have a provocable gradient that was not picked up on resting or Valsalva maneuvers. So, this puts them, a lot of these patients then come back and say, this is exactly what I've been experiencing in my real life, but nobody's been able to pick it up.

Kanny 6:28

Well, those are excellent clinical points. really appreciate your insight. I I obviously we can't touch on every aspect of HCM management, even though there's so many fascinating areas, but, as a sports cardiologist myself, We often have to have this discussion with our patients who are sometimes young athletes about restricting activity and other lifestyle changes. It can be quite a shocking discussion sometimes, especially to a young athlete. We were just curious about your approach to shared. Decision making, obviously this is a new concept that's really being emphasized clinically. And in the guidelines that, we shouldn't be using black and white rules that we should be, sharing the discussion with our patient, their coaches, their families. So I'm just curious how you bring up the discussion about activity restriction with. Your parish patients and how you make that a shared decision.

Dr Desai 7:19

Yeah. So, you know, first and foremost, as I've alluded to just a few minutes ago, is. You need to understand the patient and the phenotype completely. As a physician, you should not be making recommendations on semi complete information or incomplete information. So if you are gonna. Tele restrict somebody's activity or, or give them a free pass. Then you better have done the full extent of the workup, including a good quality stress echo. Make sure they don't ever arrhythmias the appropriate arrhythmia monitoring access. So cannot be underscored the importance of a thorough workup after that. I basically, you need to gauge, gauge the patients and their level of activity. What they're gonna do, what they're not. We talk about data. I am very upfront about the following thing. I'm about to say a lot of these sports recommendations are based on the Bethesda guidelines. If you look at the beta guidelines closely, What are they based on what data are they based on? They're based on no data, they're based on consensus opinion of a bunch of people who sat in Bethesda making guidelines. That's the bottom line. So that's the first thing I talk to the patient that what we are doing is based on JAL consensus, not really hardcore data, having said. If you have severe case of LVH, if you have severe, if you have significant myocardial fibrosis, et cetera, obviously some high intensity, sports, like one on one basketball or football, or, singles tennis. These things, are not gonna be something that you're gonna, be endorsed to play. Having said that, you know, You still vast majority of the people that you are gonna see are not gonna be elite NFL, NBA type athletes. Most of them are gonna be warriors. So it is important to give them understanding of hydration, understanding of avoiding isometric exertion, weight restrictions, keep keeping where your heart rate needs to be kept. And, and then making sure they do not have the arrhythmic burden, et cetera. So a lot of this is nuanced conversation as you very well know, and we don't end the, the simplest thing. I always end by saying I don't have all the answers. What I'm telling you is based on. What I know. and that is based on consensus opinion, not a randomized controlled trial. And, and, this is why we are doing shared decision making. there is no black and white answer and, and, you know, there are patients who ask me, you told me I cannot lift more than 40 pounds. Does that mean I can lift 39 pounds? I mean, This is a, just all, so that's the kind of conversation you need to have. I think, and humility is, is what I resort to when, when I don't have solid footing of data.

Kanny 10:25

I think that approach makes a lot of sense and, Appreciate your insight. Ben, I think we should move on to talk more specifically about the valor HCM study. It generated a lot of excitement at ACC last month. I know you've, are very familiar with that study and, and participated.

Ben 10:39

Yeah, so I, I think, Dr. Desai, this comes on the, specifically Val. comes on the back of, you know, pioneer Explorer, Maverick, these, these use of Makaton in specific populations in HCM. And I kind of just wanted to hear from you. You know, you valor picked really sick patients who, you know, were being referred for sepal reduction therapy. Why, if you can just take us a step back in the design committee, why specifically that population and what made you really attracted to answering that specific question with Makaton in the high risk group?

Dr Desai 11:16

So thanks a lot. So, first of all, there has never been a drug specifically developed to manage hypertrophic cardiomyopathy. So the medical therapy, the way it stands, the way it stands, medical therapy related to HCM is all. serenity. So beta blockers, we used them, the only trial, there was a recent trial, a single center, almost 30 patient study, which showed, reduction in grad, but no improvement, functional capacity. That was in Jack last year, before that the only prospective trial on beta blocker was conducted in late sixties, early seventies. So everything else is again, JAL calcium channel blockers have no data. Dysopyramide has some data from the early eighties, but that was all retrospective observational. And DYS O was developed as a class one C one a, antirrhythmic with a lot of systemic side effects as you very well know. So not the easiest drugs to, to, to use a lot of side effects and, and you. Drug side effects cannot be worse than, than the disease related effects. So there was clearly an unmet need to develop precision drug therapy for ACM. So it was developed myin inhibitor, cardiac myin inhibitor reduced the, the hyper contractility by reducing the actin myin crossbridge. And we are not gonna get into the full details of that. Essentially what that showed is it also significantly reduced the left ventricular gradient by reducing, the hyper contractility reduces Sam. It also makes the patients feel better ostensibly by reducing the degree of Mr. Et cetera, that is associated with Sam. So the first step, the pioneer was the early, delving into this and then the Explorer. Moderately symptomatic patients who did not need, surgical therapy. And those were the ones that were tested and it proved that it reduced gradient and increased functional capacity. But the bigger picture is what, we are not here to just reduce gradient, you know, at the end of the day, it's about the patient. Can they feel better? And more importantly, what ends up happening, patients who don't feel good eventually because of suboptimal, current state of affairs of the medical therapy, the only therapies that worked where cardiac surgery, septal reduction therapy with surgical myectomy or alcohol sepal ablation. And when they work, they work great. but unfortunately there's not enough centers, that can do an effective surgical myectomy or alcohol ablation guidelines recommend that you need less than 1% mortality centers to be doing these. And there ain't enough such centers around. So there's a huge unmet need for people. And people with advanced symptoms to see if we can, provide a medical alternative to SEP reduction therapy. So that was the conversation. The Explorer did not address that specific question. And as we were planning and we were thinking about it is what is it that these patients want? And these patients want potentially, you know, a, can I avoid surgery together? B can I potentially defer surgery for whatever reason people have their reason. C I may not be a good candidate to have sepal reduction therapy be for whatever reason. And D a huge chunk of patients do not have access to good centers. So. All, so all these led to this glaring unmet need of wanting to develop this, test this, cardiac myin inhibitor therapy. That was the basic Genesis of, of valor HCM.

Ben 15:14

I just wanna say it's, it's, it's amazing to see science kind of evolving in front of us, cuz even med school for me was nine years ago. we only had those drugs. You named beta blocker, calcium channel blocker in Daso PIDE. And so this is, this is really exciting to have another tool in our armamentarium. and, and to see where it goes next.

Dr Desai 15:33

Yeah, I agree.

Kanny 15:36

Yeah, thanks Ben. unfortunately I wish my med school was only nine years ago as well, but that's not the case. And, for majority of the 30 years I've been in practice, we really did not have, a lot of these options. So it's very exciting. I think to, to kind of see the next, wave of therapy. So Dr. Decide just one more specific question about your study. obviously, in the 16 weeks of follow. Your main endpoint was, patients continuing to be eligible for septal reduction therapy. I know there was a discrepancy between the percent of patients who were eligible and the small percent who actually went on to S RT during the study, was that just a function of the short amount of follow up. And the fact that S RT is obviously a complex decision that most patients will not, necessarily rush.

Dr Desai 16:24

So again, a complex question and I'm gonna try and package it, slowly but surely. So first of all, At baseline each and every patient was a candidate for SEP reduction therapy and was actively considering SEP reduction therapy, meaning they were symptomatic enough that they had reached the end of their medical road and they were referred to a high volume center. That's why we only did. This study in high SRT volume type, centers. Number one, number two, because these patients were advanced symptoms. I don't think it's the wisest idea to take a highly symptomatic patient and offer them placebo for a relatively long period of time. So we did. A lot about the duration of the trial. Should we keep it, you know, do I subject a highly symptomatic patient through one year of placebo or six months of placebo? What's the right timeframe. So we know the halflife of MAVA Campton and, and the time it takes for it to have full effect. was, is about the time it takes to take full effect could be about four weeks. So we, we wanted to at, it needs to be at least four weeks. And then should we do it for 24 weeks, 48 weeks? We ultimately decided these were sick enough patients. If we are able to see a signal by 16 weeks, then that's where we were. So that's how we ended up with 16 weeks now. every time point. we saw patients every month, every time point patients were offered an option to go for S RT and patients continued to choose, to stay in the trial at 16 weeks, they were, again, offered to go for S R T and 95% patients. Chose not to go for S RT this study. So what we presented, at ACC is only part one of the story. The part two of the story is every patient that including the placebo folks got moved over to the active drug arm, and with up titration, et cetera. So between 16 and 32 weeks, we are conducting the same study, but everybody is now knows their own. We just don't know what dose they are on and, and, and still the measurements, et cetera, are done in a blinded core lab fashion. So basically one can argue patients. Have enough hope for a noninvasive option that they first chose to per persevere in the first 16 weeks. But now they're all getting the real good. So at 32 weeks, we are gonna evaluate and see how, you know, how many people. still continue to meet criteria for Sr. How many people continue to choose? S R is there a fatigue factor? That's the important, that's the question you are asking? Are the patients gonna say the, he do, you know, we are, we are not going to take. anymore pills. Let me just have a procedure. I don't know the answer to that, but time will tell as, as we are studying these patients in the long term extension,

Kanny 19:39

well, we, definitely look forward to those results. And I think that does lead to, one of our final questions, this whole field of medications, the myin inhibitors, do you think MAVA Kein is just the first. Of, several in that category. And, in addition to the future data, you just outlined, what are some of the other unanswered questions that you think we can address with randomized trials in the near future as perhaps this, class of, medication grows?

Dr Desai 20:07

I mean, you know, so. This is clearly not the only, kind of, in this class, there is a, a new drug that is being developed by another company cytokine. And that is in currently phase two and phase three trial is being started. So that is testing similar to what Explorer tested, and data will be forthcoming in the next few years. So always, you know, New therapies are, are anchored welcome and are expected. Number one. So what are some of the other unmet needs where RCTs? So if you think about obstructive HCM, these patients have a very good surgical option. especially if they come to a good center. But, but the, the bigger populations in HCM that does not have good options is the non-obstructive HCM. These folks, we have nothing, not a whole lot to give them other than unproven therapy. So that's the next unmet need. And we are in the process of, setting up a randomized controlled trial. Of Maha in the context of non-obstructive ACM and, and, you know, let's see when that gets online and we'd be curious to see what the results show the in the non-obstructive ACM group, the Maverick trial did show some important trends, but it was, we need to expand it to a much larger population. So that's one aspect, obviously. We should be expecting randomized control trials, for every clinical indication, if possible. I mean, you know, to, to sidetrack a bit. The best thing that happened to aortic stenosis was TAVR. Now, you know, when was the last time you had a randomized controlled trial, it related to surgical outcomes? Never. Now we have out ran RCTs galore. So I think we should be asking more from our, scientists and researchers. And like you said, sky's the limit. The other aspect is the, the emerging field of gene therapy and genetics. So let's see where that takes us.

Ben 22:19

Right. DRS. Those are, those are definitely avenues in the future. You know, you, you, when you were on the cardio nerds podcast, I think the FDA approved simultaneously ma Kempton. Yeah. As this is now, gonna be rolling out. Can you just talk briefly about, you know, access to the drug, how itll be, monitored and who can prescribe.

Dr Desai 22:40

So, that's a very important point now, you know, we are no longer talking about trials and this and that. Now we are talking reality. So FD approved the drug, as we were on a live journal club, you cannot make that up and it was not planned. I can assure you that, It also, but FDA put some guardrails. this is a first in class brand new therapy. We have to make sure, that EF dropped, which in, in trials was not that big of a proportion of patients. But, but if, if it is ex if a wide swath of population is, is exposed to it potentially. it could become a problem. So, FDA has put guardrails called the Rams program, risk evaluation and mitigation strategy. In order to prescribe, you will need monthly echos for the first few months, and it has to be prescribed through specialty pharmacies. So this is what this is gonna do is this is gonna force us to up our gain, at high quality echo. Again, life comes a full circle. We started our conversation with imaging. We are gonna end our conversation with precise, imaging, not, not just suboptimal imaging. So at this point of time, it is you have to be REM certified and they recommend that patients be evaluated and prescribed at the centers of excellence. But, bottom line is, as we have talked about. We have way too many patients and not enough centers of excellence. So everybody will have to, elevate their understanding and, and try to do not try. We will have to do the right thing, but bottom line is echo monitoring, specialty pharmacy, and, and prescribed by people who are experienced and trained in this.

Kanny 24:32

Yeah, I think that's an excellent point to wrap up our discussion. I think, it all comes back to the patients and the fact that we clearly know that this is an underdiagnosed condition in our population here in Ohio and everywhere else. So I think, it is gonna take a lot of collaboration between. thought leaders and centers of excellence like you have in Cleveland, as well as our clinicians on the front line to collaborate. I hope a discussion like the one we just had now is gonna help advance that by helping disseminate some of the newest, concepts out to our. Frontline practitioners. So having said that, Dr. Desai just wanna thank you so much for your insight and taking so much time, not just to, explain that to our clinicians today, but for all, all you've done to advance the overall understanding of this disease. And I certainly, hope we can welcome you back in the future to hear some of the, follow up results you alluded to, as more and more, information comes out to expand our evidence base.

Dr Desai 25:31

Thank you so much for having me here and hope this was helpful.

Kanny 25:34

Absolutely. And thank you, Ben, for your, insight into the questions and for, co-host on the podcast. Of

Ben 25:40

course it was a pleasure.

25:42

Thank you for joining today's podcast. For more information about the speakers or the topics, please go to Ohio acc.org,