Advances in Treatment of Obstructive Hypertrophic Cardiomyopathy - Episode 12
Martin S. Maron, MD, examines long-term data with mavacamten for oHCM treatment that was presented at ACC 2022.
James Januzzi, MD: 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?
Steve R. Ommen, MD: I’m going to turn to Martin and have him answer that because we were talking about that on the way over.
Martin S. Maron, MD: 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.
James Januzzi, MD: 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?
Martin S. Maron, MD: 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.
James Januzzi, MD: 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?
Martin S. Maron, MD: One solution would be that the pharmaceutical companies could pay for that. Or insurers could pay for it. Or it will be a problem.
James Januzzi, MD: 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.
Martin S. Maron, MD: 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.
James Januzzi, MD: That’s very useful.
Steve R. Ommen, MD: The calculation of EF and HCM [hypertrophic cardiomyopathy] is notoriously difficult because it’s a geometric equation.
James Januzzi, MD: Tell us why.
Steve R. Ommen, MD: 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.
James Januzzi, MD: 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.
Javed Butler, MD, MPH, MBA: 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?
Steve R. Ommen, MD: 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.
Martin S. Maron, MD: 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.
John A. Spertus, MD, MPH: 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.
James Januzzi, MD: 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.
Martin S. Maron, MD: 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.
John A. Spertus, MD, MPH: In EXPLORER-HCM, they completely stopped and then they rechallenged, and maybe that’s an overreaction.
Steve R. Ommen, MD: Maybe it’s a dose reduction.
John A. Spertus, MD, MPH: 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?
Martin S. Maron, MD: That’s a good point. That’s a point well taken.
James Januzzi, MD: That’s very important. For our viewers, it’s important to recognize we’re talking about a drug that isn’t even FDA approved.
Transcript Edited for Clarity