John A. Spertus, MD, MPH: The EXPLORER-HCM trial systematically collected the KCCQ [Kansas City Cardiomyopathy Questionnaire] before randomization and out to 30 weeks. Most interestingly, they repeated it again at 38 weeks after the drug was withdrawn. What was discovered is that there’s a substantial greater improvement in the KCCQ across all the domains, but they focused on the clinical summary score, which is the closest that the KCCQ gets to the New York Heart Association classification. It’s the combination of symptoms and physical limitation, and doesn’t include quality of life or social limitation domains. At the end of 30 weeks, there was a 9-point mean difference. As Javed has done a lot of seminal work in SGLT2s and other HFrEF [heart failure with reduced ejection fraction] treatments, that’s a very large mean effect.

What’s more informative to interpret the KCCQ is the distribution. How many patients got a whole lot better, an improvement of 20 points or greater? The absolute difference was 20%, so in about every 5 patients treated with active drug vs placebo, 1 would feel a whole lot better. This is the magnitude of impact that Marty would say, “This worked really well for this patient. They’re doing great.”

I’ve seen this magnitude of benefit in terms of patients’ symptoms, function, and quality of life in structural interventions, TAVR [transcatheter aortic valve replacement] and mitral clip, but you can never pull out the TAVR. You can never unclip the mitral valve. When they withdrew the drug in EXPLORER-HCM and repeated the study 8 weeks later, the health status went right back to baseline. All the benefit that was attained dropped. This is 1 of the underemphasized features of the EXPLORER-HCM study, is that it fulfills Koch’s postulates. You put them on the drug, they get better. You take them off the drug, they go right back to where they were.

It’s going to be very interesting to monitor these patients. The drug isn’t available, but as it becomes available—I’ll be very interested in what my clinical expert colleagues think about this—we spend a lot of time worrying about EF [ejection fraction], and when you introduce this drug, are we going to have to monitor EF very carefully? EF is ultimately a surrogate marker. Nobody here knows what their EF is, but you do know what your symptoms, function, and quality of life are. It’s going to be very interesting. Do you accept an EF that has gone from 60% to 45% or 48% if the patient feels a whole lot better? Or we can be too nervous because it has been so inculcated in our training that any depression in EF is a very bad thing and you don’t want to do it. It’s going to be interesting as we gain more experience. I don’t know what you guys think, I might be stepping on the third rail here, but I’m curious about that.

Martin S. Maron, MD: The issue of the importance to be placed on systolic dysfunction and decreases in ejection fraction with this drug is really important. I’d like to make a couple of points on that. We’re talking about pretty big swings in ejection fraction, differences of up to 15%, 20%, or 25% from baseline. It’s true that when you stop the drug, those are reversible in the short term. This is what we have information on. It isn’t exactly clear what the implications of that difference in decreased systolic function means. Does it increase risk of adverse events in the short term or long term? We don’t know. The answer is, we don’t know what the implications are from a safety standpoint in this disease with these decreases in systolic function.

That said, there are examples of the EF dropping in hypertrophic cardiomyopathy not related to the drug but with other mechanisms. With what we call the end-stage phase of HCM, where ejection fractions drop below 50%, we do know that a lot of adverse issues occur, arrhythmic and heart failure. That’s where this 50% line in the sand comes from in a way. But of course, different mechanisms, so we’re going to need more time to understand that.

John A. Spertus, MD, MPH: I agree. Burned-out hypertrophy is going be a completely different ball game.

Martin S. Maron, MD: It could be.

Transcript Edited for Clarity