Ask the Investigator: Q&A With Iacopo Olivotto, MD

Is it time to admit that β-blockers do not work in most patients with obstructive hypertrophic cardiomyopathy? Do you believe that improvement in diastolic function played a part in the positive findings?

Iacopo Olivotto, MD: In this trial, β-blockers seem to have created more problems than they solved. Patients on β-blockers had worse oxygen consumption findings, and that was expected. The long-term extension trial to gather more safety information is ongoing, and we are considering [whether] to allow physicians to withdraw β-blockers from patients [who] are doing well on mavacamten.

With regard to [the second part of the question], we definitely have very good animal data [in dogs] showing that mavacamten had an effect on diastolic parameters. And we do have the MAVERICK-HCM [NCT03442764] data showing promise in patients with nonobstructive HCM [hypertrophic cardiomyopathy], showing a very promising fall in troponin and NT-proBNP [N-terminal pro b-type natriuretic peptide].

[Regarding EXPLORER-HCM,] we are now looking very actively at the diastolic parameters in this particular subset of patients with obstructive HCM. When patients have obstructive HCM and you relieve the gradient, you have a number of benefits on diastolic function, which are directly mediated from gradient reduction. Distinguishing the direct effects of mavacamten on the myocardium from those that are mediated by gradient reduction is not easy at this stage. We are hopeful and confident that we can show [benefit] in the very near future.

Just to clarify, regarding the issue of maintenance of medications like β-blockers and verapamil—in this trial, these medications may have been maintained for safety reasons. Do you think that mavacamten has a future as a single therapy?

Olivotto: Yes, I think so. I think that it is quite possible. Of course, in patients with HCM, it is also nice to have control of heart rate, because faster heart rates are not beneficial for these patients. So we know now that to some extent, wisely used β-blockers can be useful in patients, particularly when young and active. So I think that these are to some extent complementary. But if you are interested in treating obstruction per se, then a single [drug] approach with mavacamten is probably a very reasonable approach.

One of the major risks in hypertrophic cardiomyopathy is sudden death. The EXPLORER-HCM trial was 30 weeks, so that’s a little short to see any effect on sudden death. But what are your expectations regarding any effect on sudden death?

Olivotto: It’s an excellent question. Well, first of all, we know that obstruction is associated with doubling of risk of sudden death, so though we are talking about small absolute numbers, if you look at relative numbers, if you have obstructive HCM, you have double the chances of having sudden death compared with nonobstructive disease. So although it’s never been proven that if you relieve obstruction you reduce the risk of sudden death, we have a long follow-up after myectomy in many patients showing very small rates of sudden death. So I would expect that just by reducing the gradient, you are somehow providing benefit.

We know that with sarcomere gene mutations, we have electrophysiological remodeling of cardiomyocytes. I would be hopeful, and again this has to be proven, that by acting on the remodeling caused by the downstream effects of these mutations, there may be favorable electrophysiological effects to be identified in these patients. If we just look at the small numbers [from EXPLORER-HCM], we don’t have the power to see this. In terms of looking at ventricular arrhythmias, the rate of nonsustained VT [ventricular tachycardia] was the same in the 2 treatment arms.

Do you believe mavacamten will reduce symptoms in patients with HCM with left ventricular outflow tract obstruction in the long term, or should mavacamten be seen more as a bridge to myectomy?

Olivotto: Actually, I think that the aim is the opposite. There is an ongoing study called VALOR-HCM [NCT04349072], which will hopefully demonstrate that if you use mavacamten, you may postpone or reduce the need for surgery. So, of course, the big question here is: What is the long-term safety [profile] of mavacamten, and [for] how long can we give it? Can we give it for decades, as many of these patients would require, in a safe manner? We know that the effects of mavacamten are very reversible in the short to mid-term. But hopefully this drug will allow much earlier and broader treatment. For patients with obstructive HCM, who are in [New York Heart Association] class II, for example, they are still not doing well, but they would not be referred to a surgeon. So they are basically left to live with their symptoms. Also, surgical expertise and interventional expertise for this disease are limited, and we know from real-world trials and registries that aside from a very few experienced centers, patients with HCM [don’t have access to surgical] interventions. So having a drug that can [relieve symptoms] makes it sort of more democratic to treat obstruction worldwide.

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