James Januzzi, MD

 I’d love for you to share with the viewers what strategies you have implemented based on your experiences to educate patients about their journey. Because that’s so important, as John has said, about making this a patient-centered diagnosis. What’s a day in the life of Dr Maron and Dr Ommen in how you approach these issues?

 I’ll go first. Like I’m sure Steve does, we spend a lot of time with patients when they come and do our own education with them, along with our health care team and nurse practitioners to educate patients about the disease. We spend a lot of time on education, reassurance, putting these issues that we’ve talked about in perspective, and doing a lot of shared decision-making, going through treatment options. At the end of the day, we try to deliver the message that hypertrophic cardiomyopathy [HCM] is a highly treatable disease. It’s going to probably be more so in the future, but even today it’s very treatable and a disease that’s compatible with normal life expectancy and good quality of life for the vast majority of patients. That’s the messaging that we give to patients the best that we can.

 I’d echo the same thing. Patients come to us after having done their own education attempts on the internet, freaked out with wide eyes because they’ve read all the dramatic stories that are available, and we have to remind them that people who have normal lives don’t usually blog about it.

I’d like to reiterate the same words about HCM in the modern era. We’ve gone from an era where it was 100% fatal in 1958 when Donald Teare described it to a 6% annual mortality in the 1980s to an annual mortality that’s the same as the general population. It’s a highly treatable disease for most patients. There are patients in whom there are issues. This discussion wasn’t about sudden cardiac arrest, which would be another 2 hours. Then there are quality-of-life issues that some patients have. But it’s a highly treatable disease and we’re getting more tools in our toolbox for the future, which is exciting.

 That’s super. Javed, any final thoughts you want to share?

 My final thought is that we have these therapies and we want to do anything and everything that we can for the patients to not unnecessarily suffer. The question is how do we educate the clinical community at large to refer the patients to the appropriate centers and to diagnose and screen these patients? While the specialists are very interested in and have a lot of these tools, more mass education about this disease would also be needed.

 From an administrator’s point of view, let me ask you to put that hat on for a second. When you’re looking at making recommendations for clinicians who are interested in getting involved in this, what things would you say are needed in terms of understanding things like catheter-based approaches, surgical approaches, and volume, which you talked a bit about? What do you think about setting certain expectations?

 You can modify behavior quite a lot by creating appropriate incentive structures in terms of education, screening, and quality metrics. You can also set up tools. We live in this digital age and everybody is on an electronic health record. A lot of the education and best practice advisories can be had for our patients in this era. Education and reminder systems are easier in the current day and age.

 Super. John, I’m going to turn to you last. You always keep the patient in the center. I’m curious to hear your final thoughts.

 First, I’m humbled by the expertise at this panel and not being an HCM expert. I feel a tremendous need to think about the infrastructure for elevating the quality of care throughout the nation. What does that entail? Does it entail thinking about algorithms, building shared decision-making tools, integrating routine assessments of health status with the KCCQ [Kansas City Cardiomyopathy Questionnaire], and coming up with very practical management strategies so that you don’t have to be in Boston or Rochester, Minnesota, to get high-quality care?

 Or Kansas City. That’s what I’m left with. It’s a complicated disease, but it’s an exciting disease. As more treatment options become available, there’s a greater call for thinking about the infrastructure of delivering high-quality patient-centered care. That’s what I’d like to see us move toward so that we can all benefit from the advances being made.

 Super. That’s a great way to conclude. I want to thank all of you for this rich and informative discussion. I want to thank you, our viewers, for watching this 

. If you enjoyed the content, please subscribe for our e-newsletters to receive upcoming 

 and other great content right in your inbox. I’m Jim Januzzi from the Massachusetts General Hospital. Thanks very much for joining.

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Expert cardiologists share strategies for educating patients on the treatment and management of hypertrophic cardiomyopathy. 

Patient Education of HCM

 Let me ask the 2 content experts here. Once you have a drug like a direct myosin inhibitor proven to be safe and effective, how do you feel the landscape will change in terms of treatment? It strikes me that a lot of what all 4 of us are saying is very reminiscent in some ways to when we started doing alcohol septal ablation and people were like, “They’re young patients. How do you know ablating a 30-year-old won’t cause problems when they’re 50?” They’re 50 now, and we don’t see any problems. You’ve got very effective, albeit invasive treatments. You’ve got some drug therapy options that have been traditional and may or may not help. Where do you think mavacamten [Camzyos] will ultimately fit in?

 That’s a great question. I’ll go back to something you said early on when you talked about when we go from standard therapy to more advanced therapies. Mavacamten fits in the advanced therapies category of that. Assuming the long-term data stays true the way it’s going now and that it has long-term efficacy, there will be patients—those that John identified as getting that 20-point improvement in their KCCQ [Kansas City Cardiomyopathy Questionnaire]—for whom it’s going to be destination therapy and they’re going to do well on that drug for a long time. There will be other patients in whom it might end up being bridge therapy until they can get to a center that has a high enough volume invasive specialist. They can feel better, but they know in the end that they’ve chosen to have this operation because they know they can get off drug and those types of things.

We’ll also use it as a diagnostic therapeutic trial for some patients. You’ve got the person who’s short of breath who has 3 other reasons why they’re short of breath. If we try mavacamten for 2 months and they get better, but they get worse when you take them off, then I know I can offer that next step therapy potentially if that’s the right thing for them. It’s going to be there, but it’s going to be once they’ve failed beta blockers and non-dihydropyridine class calcium channel blockers. It’s going to be as part of that shared discussion with disopyramide myosin inhibitor and septal reduction therapy, and there will be nuances around anatomy and other structural heart diseases that will go through the discussion. To me, that’s where it slots. I don’t know what you think.

 I’ll echo your comments completely, with 2 additional comments. One is that there are always going to be patients, because this is a mechanical form of obstruction, in which drug therapy can’t relieve symptoms. That’ll always be a principal point. Second is that 1 aspect of this discussion that we haven’t talked about in terms of answering that question but bears enormously on the answer is cost.

 We don’t know the cost because that doesn’t come until the drug is approved, but we have some idea that it could be expensive. Remember, this is a drug given to young patients for long periods of time. Cost is a real concern in this disease. They just went through a similar issue in other inherited heart diseases like [transthyretin] amyloid [cardiomyopathy] with tafamidis. We’re going to be in a similar but even more complicated situation because of that issue. Cost is going to be important in terms of how we talk about this therapy with patients.

 That’s very helpful. Any other points?

 I just want to ask 1 quick question. The fact that it’s advanced therapy and that based on the inclusion/exclusion criteria for these trials, we don’t have the data for what I’m about to ask, does it pathophysiologically make sense that in the future we can give it in the earlier form of the disease to prevent the progression and development of severe disease and severe gradients and start it upfront? Does that make sense?

 Certainly, that makes sense in principle. Obviously, if we have a therapy that can be given earlier in an asymptomatic or mildly symptomatic obstructive patient that’s going to alter the natural history in a beneficial way with low risk, then that’s an attractive, additional potential support for this initiative. It’s going to take a long time for that to be worked out though.

 Interesting question, though. If you think about individualizing care and trying to almost use it like a disease modifier, it’s a curious idea. We’ve talked a lot about medical therapies. We’ve talked about catheter-based or surgical myectomy. Are there any other treatments that you can think of? These are early things, device treatment, but we haven’t even talked about the old traditional RV [right ventricular] apical pacemaker that we don’t see too much anymore. Are there devices that are being examined as potential treatments for HCM [hypertrophic cardiomyopathy]?

 There are a few things. There’s always interest in different ways to do catheter-type ablation, like doing electroporation or something that’s more RV that allows the catheter team to be more precise and not just holding where the coronary arteries go. There’s work going on in those types of things. Using MitraClips to keep the mitral valve from maybe flipping up so far to the outflow tract has been tried. It can be effective in some patients, but in some patients, you get bileaflet SAM [systolic anterior motion] with it.

 You might actually worsen things. Absolutely.

 Then there’s work being done on direct gene therapies, which is beyond my expertise.

 That’s probably too far off to get too much into, but there’s also other drug therapy initiatives going forward that deal with relief of symptomatic obstructive disease that have different mechanisms of action. Some of them are myosin-based, others aren’t. There’s a lot going on.

 What other targets are there from drug therapy?

 The analogy would be how disopyramide works as a late sodium channel inhibitor, which alters intercellular calcium to decrease contractility. There are ways to decrease contractility different from addressing the sarcomere that we’ve been talking about for myosin inhibitors that are effective because disopyramide can be very effective. These are drugs being developed that have similar mechanisms of action.

 Very interesting. We’re drawing to a close. I’ve learned a lot and I’m grateful to all of you for offering useful information.

Drs Steve R. Ommen, Martin S. Maron, Javed Butler, and James Januzzi provide insight on the evolving treatment landscape for obstructive hypertrophic cardiomyopathy.

Future Directions for oHCM Treatment

 What about VALOR-HCM? I’m curious about this one.

 VALOR-HCM was the next-level study that was a direct response to the fact that in EXPLORER, most of the patients enrolled were NYHA [New York Heart Association] class II patients. For surgery and ablation, most patients are class III or higher, so we should compare those 2 groups. That’s what VALOR-HCM was designed to do. For patients who were referred for consideration of septal reduction therapy, let’s randomize them in a trial. That’s what was done in VALOR-HCM. The results of that are promising: 75% of the placebo patients went on to septal reduction therapy during the 16 weeks of the study vs only just under 20% of the patients with active drugs. It was a tremendously different outcome in a period of 16 weeks.

 I’ll expand on that by saying that in the context of time, it was a short period of time.

 Sixteen weeks is short. Especially with a here-and-gone set of symptoms.

 There’s a limited amount we can take away from that in terms of how effective these drugs are in either delaying or eliminating the need for definitive invasive septal reduction therapy. It’s too short a period of time.

 That’s very useful. Javed, let me ask you in general terms about approval of a drug. The FDA looks at it, there’s time to review, time to respond, and then there’s a date that’s given for when the drug is supposed to be approved. What do we know about mavacamten [Camzyos] at this point?

 From the perspective of the efficacy and improvement in functional capacity and quality of life, those data, I don’t think that there’s any concern or challenge there. The issue here is all the discussion that we’re having right now, which is how to monitor this therapy in the long run. Those are the considerations, figuring out the long-term monitoring, how frequently echocardiography should be done, how frequently the post-approval study be done, and what it should look like. Those are the discussions where I can see that the regulatory agencies will take some time to come up with a plan where we make sure that the patients who need this therapy and deserve this therapy get it.

At the same time, we have enough safeguards that we learn, and that learning could be to what John is saying, that we should do this for a year and learn that we don’t need to do this or that we don’t need to do this as frequently or that we should do this differently. I assume that those things will come to a conclusion in the near future, but that’s what we’re awaiting.

 We’re waiting to hear. Once regulatory approval is granted, assuming that it is, there will be follow-up.

 There’s a planned long-term registry to look at patients with HCM [hypertrophic cardiomyopathy] treated with and without mavacamten to understand a lot of the questions we’re talking about. That will be interesting to see.

A panel of experts in cardiovascular medicine review the use of mavacamten as seen in the VALOR-HCM study for patients with symptomatic oHCM who are eligible for septal reduction therapy.

VALOR-HCM Study in oHCM

 We are at the 71st Scientific Sessions for the American College of Cardiology. There have been a couple of studies presented and more data, but we have a long-term extension for patients treated with mavacamten [Camzyos]. Steve, do you want to summarize what we saw there?

 I’m going to turn to Martin and have him answer that because we were talking about that on the way over.

 You’re referring to the long-term extension data from mavacamten. These are patients who were in the phase 3 EXPLORER-HCM trial who continued on drug for a fair amount of time. It was an average of a year or more.

 When you’re treating someone with a drug that could reduce EF [ejection fraction] substantially, this opens the door to ask, is this safe to do? What are the ramifications?

 That’s a great question. We don’t know the answer to 2 things: what’s a reasonable way to longitudinally follow patients who go on this drug in terms of echocardiography and possibly serum concentrations of the drug? Because the reality is that in EXPLORER-HCM both were used to change dose of the drug up or down for safety and efficacy issues. We don’t know because these drugs aren’t approved and we don’t know what conditions will be around that approval from regulatory agencies about what will be mandated in terms of longitudinal surveillance of these drugs. We don’t know yet. But of course, it will probably include some amount of echocardiography and possibly serum concentration of the drug.

 When you think about serial echocardiography, it isn’t unreasonable to wonder whether we might get pushback from payers. If you’re doing echocardiography every few months on someone, it isn’t unusual in my heart failure clinic where we order an echocardiogram and it happens to be 11 months from the last echocardiogram and it gets denied. What solutions might be present?

 One solution would be that the pharmaceutical companies could pay for that. Or insurers could pay for it. Or it will be a problem.

 We’re talking about use of point-of-care ultrasound, for example, not billing, but essentially utilizing the echocardiography in a manner that allows us to ensure that we’re safe.

 I have a comment on that. These are difficult hearts to image. There’s a certain amount of expertise that goes into acquiring the images and interpreting them, for things as what would theme as routine as ejection fraction, and also for gradient assessment. Those are the 2 primary variables that are dictating the drug dosing issue. We have to be a little careful about how we do it.

 The calculation of EF and HCM [hypertrophic cardiomyopathy] is notoriously difficult because it’s a geometric equation.

 The denominator is small. Any change, even if a little error by a mm or 2 in your measurement of end-diastolic dimensions, is going to make a big difference in the ejection fraction. As you all know from your heart failure stuff, while we have lots of clinical stuff that’s predicated on it, EF is a broad categorization.

 I’d argue that it’s the New York Heart Association equivalent of a shaky variable. In the EXPLORER long-term extension experience, the other thing that was noteworthy was that, coming back to biomarkers, the concentrations of NT-proBNP followed the reduction in gradient pretty well. It was pretty highly correlated. There has been some interest in utilizing serial biomarker monitoring as another way to tell if you’ve overdone the ventricle, and now you’re getting into a situation where you’re remodeling into reduced ejection fraction.

 Can I go back to this whole ejection fraction and frequent echo-monitoring issue? Appropriately, whenever new classes of drugs come, there’s a lot of concern. Even drugs that we consider completely simple now, ACE [angiotensin-converting enzyme] inhibitors and beta blockers, when they were first approved, you had patients in the clinic for an RF [radiofrequency] for giving them and all that stuff. Obviously, we don’t know the answer, but do you foresee a world where because this is so new and we don’t know the natural history that over time, there’s potential that if there’s a drop in EF of 10% but the person is symptomatically doing better, it doesn’t portend any poor prognosis and we don’t have to do these things?

 That’s a great question. We don’t have the answer, as Martin said before. We know other conditions where people do pretty well. With people who are high-level athletes who don’t have cardiovascular diseases, their EF is often measured low at rest. That’s adaptation to what they’re doing. Not every low EF is a bad EF. Is it conceivable that this drug results in a low EF in 10% of patients, and that’s not really a bad thing? Sure. But we’ll need a long time to follow those patients to know that. That’s going to be one of the main things that we’ll see as we’re trying to implement these drugs when they do get approved, is how we monitor that and ensure that safety is there.

 Yes. On that point, it’s the age here. You’re talking about long periods of time. That’s the other point. We’ve never been in this space before where we’re going to be changing the contractility for potentially long periods of time.

 The academic geek in me has to ask you this. Do we need a randomized trial of patients with an EF that drops below 50% where we back off on the drug or not and follow their health status for a year? You may say, “We need years and years of follow-up.” It may also be that there are errors in measuring the EF, and maybe their EF will be transiently down and even on the same dose of drug will rebound.

 In fact, in the long-term extension, there were 7 patients who dropped below 55% who were successfully rechallenged once their EF bounced back up. It’s hard to know.

 Also on this point, you don’t need an ejection fraction below 50% to get rid of the gradient. The gradient is dependent on contractility. You’ve already reduced it so substantially that you wouldn’t want to be living at an EF of 45% because your gradient would already be gone anyway so you could tolerate higher EF. You have to remember that too.

 In EXPLORER-HCM, they completely stopped and then they rechallenged, and maybe that’s an overreaction.

 Before we get into a knee-jerk pattern in practice that when the EF drops, they can’t tolerate this drug anymore and we got to go do something else. We can’t randomize patients with left pain. It’s considered so ingrained in our practice, and before it gets ingrained that with any EF, to immediately stop the drug at the EF drop below 50% because of EXPLORER-HCM, I challenge us to think, should we gather the data now to inform what will be a generation of practice and hard to change after the fact?

That’s a good point. That’s a point well taken.

 That’s very important. For our viewers, it’s important to recognize we’re talking about a drug that isn’t even FDA approved.

Martin S. Maron, MD, examines long-term data with mavacamten for oHCM treatment that was presented at ACC 2022.

James Januzzi, MD

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