Anjali Owens, MD: So Jim, let me ask you in the last few minutes that we have, what's your approach in the real world to really implementing these agents? What kind of infrastructure is there? How do you select the patient? How do you go about doing this in the real world?

James Januzzi, MD: Yeah, great question. This illustrates the importance of a team sport here. You really do need an infrastructure because when you use cardiac myosin inhibitors, it's done under what's called a Risk Evaluation and Mitigation Strategies, or REMS approach, which includes following patients with echocardiogram to evaluate the ejection fraction [EF] in particular. Dr Owens, you made that point very, very clearly. Often our patients don't feel that their EF is low of course. So understanding where their ejection fraction is settled is critically important because temporary cessation and dose reduction in the case of mavacamten may be necessary. So it's important to coordinate this with your team. We use natriuretic peptides as well—you mentioned that right in the very beginning. One of the things that we're examining both clinically at the Massachusetts General Heart Center but also in the DISCOVER-HCM study is trying to understand if trajectories of NT-proBNP [pro-brain natriuretic peptide] helped to inform what the echocardiogram is going to show you, right? So you'll see a reduction in NT-proBNP from the reduction in the LV [left ventricular] outflow tract gradient. But then if you have excessive left ventricular ejection fraction lowering, who knows? It's possible you might see a rise in NT-proBNP overtime, so close follow up is critically important it's necessary to educate patients about the fact that, for example, mavacamten is metabolized by cytochrome P450 enzymes, so they need to know that can accommodate use of inhibitors or inducers of the P450 system could be associated with risk for progressive systolic dysfunction or loss of effectiveness of the drug. These are just important aspects that we engage with our patients on to make sure they understand—it's not a free lunch—but they really do find a substantial improvement in their symptoms and association with its use.

Andrew Wang, MD: If I could add one thing also to what Jim was saying, I think we've all noted that patients who develop atrial fibrillation are much more likely to have a reduction in their ejection fraction. So in addition to counseling them, regarding if you start any new medicines, please let us check for drug-drug interactions. In mavacamten at least. I think for cardiac myosin inhibitors in general, the occurrence of atrial fibrillation [Afib], which is common in patients with hypertrophic cardiomyopathy, can be the provocation for reduced ejection fraction. I tell my patients, if we're starting you on this and you have recurrence or develop atrial fibrillation, I would like to see you sooner than the scheduled echocardiogram to be sure we're not missing something.

Anjali Owens, MD: Yeah, it's such an important point. We've seen that in the trials and also in the long-term extension that any kind of intercurrent illness that could be non-cardiac in nature, severe pneumonia, urinary tract infection—which makes sense that it may be a time where you need more contractility, that you may have a drop in ejection fraction if you're on a myosin inhibitor, and of course the paroxysms of A-fib particularly rapid A-fib. Jim, did you have something to add to that?

James Januzzi, MD: The other thing that I think is going to be really interesting is the long-term consequences of use of the drug in terms of potential effects on reverse cardiac remodeling. We just simply don't know, but it's being examined now, cardiac myosin inhibitors in other forms of heart failure for this exact reason.

Milind Desai, MD, MBA: An important thing, brief comment. I'm going to make is as follows. This is why taking the conversation of therapy a little bit more upstream would be important because we know the biggest risk factor for Afib is a big left atrium. So can we reduce the protoplasm that results in these downstream arrhythmias, etcetera, to a point where, you know, we are breaking the cycle here. So we have to start thinking in a broader, more upstream manner.

Transcript is AI-generated and edited for clarity and readability.