Managing Hypertrophic Cardiomyopathy: New Guidelines and Drugs

Steve R. Ommen, MD; Christopher V. DeSimone, MD, PhD


August 02, 2021

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This transcript has been edited for clarity.

Christopher V. DeSimone, MD, PhD: Hello, and welcome back to the Mayo Clinic–Medscape video series.

I'm Christopher DeSimone, a cardiologist and medical director of CV marketing at the Mayo Clinic in Rochester, Minnesota. Today I'll be discussing hypertrophic cardiomyopathy (HCM) with my colleague, Steve Ommen, a consultant, professor of medicine, and expert in this area. Welcome, Dr Ommen.

Steve R. Ommen, MD: Thanks, Chris.

SCD and New Guidelines

DeSimone: The new American Heart Association (AHA)/American College of Cardiology (ACC) guidelines on HCM are out. You played an integral role in shaping them and served as the lead author. One of the takeaways from these guidelines relates to changes in sudden cardiac death screening. How has that evolved over the years?

Ommen: That's an important question. Historically, if you go back to the prior guidelines in 2011, we basically just counted up a series of risk factors. Anyone who had two or more risk factors was eligible for an implantable cardioverter-defibrillator, there was lots of debate and controversy about what to do with patients with one risk factor, and patients who had zero risk factors were reassured.

We tried to put some weighting around the various risk factors in those previous guidelines and elevated some like massive hypertrophy, family history of sudden death, and arrhythmic syncope as being slightly more important based on the data. That served us for a while. But then people pointed out that in massive hypertrophy, your risk does not just go up as a step function when you hit 30 mm, but rather it's increasing the thicker your heart is.

Our colleagues in Europe developed the HCM sudden cardiac death risk score, which used continuous variables and generated an estimate of risk. That really was a game changer, because prior to that you would tell a patient they had a risk factor but they would want to know what their risk level was. This tool allowed us to put it in context and inform them of the magnitude of their risk.

There were some issues with the way the European guidelines were written, and I happen to know that it was one of the most arduous discussions they had in their debate. They a priori set specific risk markers as essentially being high risk and determined that a patient would get a defibrillator depending on whether they were above or below a certain percentage. We felt like that probably took the decision-making out of the patients' hands and didn't consider an individual's risk tolerance.

So, in the 2020 guidelines we really blended those two methods. We use classic risk factors to identify which patients have elevated risk; if they did not have the risk factor, their risk would not be as high. Then we used the risk tool to frame that for the patient and help them decide for themselves.

The other thing that happened with this guideline was that we noted new risk factors that have emerged in the past decade, like late gadolinium enhancement on cardiac MRI. If you have a lot of that scarring, it acts as the substrate around which ventricular arrhythmias can start. A low ejection fraction in HCM is also a bad prognostic marker. Apical aneurysm was another important risk factor that was newly added to the latest guidelines.

The last important change we made in these guidelines was addressing patients under the age of 16 for the first time. We had a series of pediatric cardiologist experts in HCM who contributed to that discussion, which was new to these guidelines.

DeSimone: I think those are excellent points. As a cardiac electrophysiologist who works with these patients, I can say it's very tough to balance what is both a life-and-death situation and a quality-of-life situation, especially with patients younger than 16 or even into their 20s, 30s, and above. So I thank you for speaking to that concern.

Specialty vs Community Care of HCM

DeSimone: What do you believe is the current role for a specialized HCM center compared with your traditional cardiac teams, not just for sudden cardiac death screening but for managing and treating these patients?

Ommen: We think that primary cardiologists can handle much of the care of an HCM patient, such as initiating the screening and starting first-line therapies. But eventually, most patients will come to a point where they have to make a major decision about their treatment, where they probably should have conversations with people who see this condition day in and day out.

Most cardiology practices see single-digit numbers of HCM patients every year, whereas at the HCM-specific centers, like here at Mayo Clinic, I see hundreds of these patients. Observing the many different nuances and patient circumstances helps me teach the patients about their disease and make those decisions.

If a patient is receiving HCM-specific therapy — for example, if we're considering septal ablation or septal myectomy — that really should be in the hands of an expert center where the outcomes are good. There is a steep learning curve you have to account for. Publications have reported that lower-volume centers have worse outcomes than the true expert centers.

Another consideration is when you look at any guideline documents, whether for HCM or other conditions, any recommendation graded as Class IIb is probably something that the writing committee spent hours agonizing over how to word. If the experts sitting around the table writing the guidelines have difficulty phrasing the wording just right, that's exactly the kind of treatment decision that needs their input.

For these guidelines, those Class IIb recommendations are for patients who haven't responded to frontline therapies and you're now considering doing something more, which might be associated with certain risks. That's probably when a referral or inclusion of an HCM expert in that patient's treatment plan is really helpful.

I think it's important to recognize that we as an HCM center want to be part of that patient team. They need to have a cardiologist who is taking care of them locally. If something happens on some random afternoon — a new episode of atrial fibrillation that's highly symptomatic or chest pain they haven't had before — they need that local team who knows what their underlying diagnosis is and what their current therapies are.

We don't want to take patients from the primary cardiologist; we want to help take care of those patients with them.

DeSimone: As you mentioned, the Class I and Class III recommendations are easy. It's the Class II recommendations that are not so clear-cut and where the nuances are. That's where the seasoned experience of you and your colleagues at the Hypertrophic Cardiomyopathy Clinic come into play and where patients get the most benefit.

Ommen: That's right.

Where Will Mavacamten Fit In?

DeSimone: There's a new drug coming to the market for HCM: mavacamten. What's your take on this drug and the EXPLORER-HCM trial, which has gained a lot of attention in the journals and news media?

Ommen: We in the HCM community are super-excited that pharmaceutical companies have taken up developing drugs specific to this condition. We haven't ever seen that before. Instead, we've taken advantage of drugs designed for other purposes whose mechanisms of action can be used to treat our patients, such as beta-blockers and non-dihydropyridine calcium channel blockers.

Mavacamten is the first of several myosin inhibitors that have been developed to specifically attack one of the main cellular functions in HCM, which is enhanced interaction between myosin and actin.

EXPLORER-HCM was a placebo-controlled trial of mavacamten over standard therapy with predefined endpoints of improvement in peak oxygen consumption and symptom status. Overall, about 37% of the patients taking mavacamten achieved the primary study endpoint, compared with about 17% of those in the non-mavacamten arm. It was not 100%, but all the trending data were in the right direction for those taking mavacamten, which is encouraging.

There are a couple of important points to note about the trial. Most of the patients started in New York Heart Association Class II symptoms. They were not necessarily the most severely impacted patients, which is something being looked at in a separate, ongoing next-phase trial of mavacamten.

Also, mavacamten is a very powerful negative inotrope. About 10% of patients in EXPLORER-HCM had a drop in their ejection fraction to < 50%. This was temporary and it returned to normal once mavacamten was discontinued. However, since the trial was only 30 weeks long, we do not know the implications of using this as a potential lifelong therapy if it is going to have that potent of a negative inotropic effect, particularly as we have data in HCM that an ejection fraction of < 50% is associated with a lot of bad outcomes. We have a lot of safety information that we need to obtain in the follow-on trials.

DeSimone: How do you think mavacamten is going to influence your practice in the near future, as well as later on down the road when more data come out?

Ommen: I think the best guess is that mavacamten will likely slot into a position of what I'd term "advanced therapies." When someone is symptomatic with HCM, you usually start them on a beta-blocker and/or diltiazem and verapamil. You might switch those around to find the right cocktail for the patient in that situation, depending on the side effects they may or may not be experiencing or the treatment benefits.

If patients do not respond adequately to those, presently we then consider disopyramide or septal reduction therapy. I think mavacamten represents a third arm of that approach. Some patients may consider going on mavacamten rather than disopyramide or going to an invasive therapy, particularly if they would be high risk from the latter.

But all of this has one other wild card in that we don't know yet what the pricing will be for mavacamten. If we look at a drug like tafamidis for cardiac amyloid, that's very expensive. A similar pricing structure will influence how many people may choose that when we have options like surgical myectomy, which might be the last therapy they need directed at their outflow tract obstruction and mean they don't have to take medications going forward.

The jury is still out. But my best guess is it will slot into that decision-making for patients who maybe are not ready or are high risk for invasive therapies and did not respond to first-line therapy.

DeSimone: One concern I had when reading the study results was that people might think they can take this drug as opposed to other things, especially the younger patients, that need a lot of septal reduction either with alcohol or surgically. When considering a negative inotropic from my electrophysiology background, a lot of that ventricular debulking is a substrate for ventricular tachycardia. Given that we started off our conversation talking about sudden cardiac death, that would be one thing I would be worried about.

Do you have any concerns about this drug coming out?

Ommen: I don't have concerns about the drug coming out. I think it will be very beneficial for some patients.

I do have concerns that perhaps it will be easier to prescribe it than offering someone a referral to one of the major centers for a procedure. Again, most myectomies are the last procedure patients will need. We've reported a good success rate from that, with 90%-95% of patients having a New York Heart Association class improvement of 2 and many no longer having to take cardioactive medications following their surgery. We do not want to deny patients the opportunity for that type of procedure just because it's easier to prescribe a medication.

Again, the safety and cost information has to come in. As you said, in a young person, we are talking about lifelong therapy. Every medication has some side effect, so we do not want to saddle patients with lifelong side effects unnecessarily. I do not have concerns about the drug coming out as long as we understand that it will be safe for our patients.

DeSimone: Thank you, Steve, for these very important insights. And thank you for joining us on | Medscape Cardiology.

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