Positioning Cardiac Myosin Inhibitors as First-Line Therapy: Evidence Versus Beta-blockers

In this segment, Dr Maron poses a key practical question: in newly presenting, treatment-naive patients with symptomatic obstructive HCM, should clinicians still begin with traditional beta-blockers or calcium channel blockers, or has the evidence base matured sufficiently to justify first-line use of cardiac myosin inhibitors? Dr Masri responds by highlighting the MAPLE-HCM trial, in which aficamten, used as first-line monotherapy, outperformed metoprolol in terms of LVOT gradient reduction and symptomatic improvement. Notably, metoprolol was associated with worsening exercise capacity, higher N-terminal pro–brain natriuretic peptide levels, and increased left atrial volume index.

Both faculty members emphasize that, while formal head-to-head comparisons of beta-blockers with mavacamten are lacking, the limited and largely nonrandomized evidence for beta-blockers contrasts sharply with the robust phase 3 data for myosin inhibitors. Given the magnitude and consistency of gradient reduction and symptom improvement, Masri explains that in his practice, he moves rapidly toward myosin inhibition in highly symptomatic, markedly obstructed patients rather than spending prolonged periods titrating conventional agents to maximal tolerated doses. Maron argues that, based on current data, it is reasonable to consider aficamten as initial monotherapy in suitable patients.

The clinicians also acknowledge real-world constraints, including payer requirements that may still mandate a trial of traditional negative inotropes before authorizing myosin inhibitors. Maron clarifies that this first-line positioning pertains specifically to treatment of obstruction-related symptoms and does not supersede beta-blocker use when indicated for other conditions such as atrial fibrillation or hypertension. Nonetheless, both experts concur that the totality of evidence now supports consideration of aficamten as a legitimate first-line option for symptomatic obstructive HCM, reflecting a substantial evolution in standard of care.