Understanding Risks Associated with AF in oHCM Management

Even as atrial fibrillation (AFib) incidence data with cardiac myosin inhibitors (CMIs) accumulates, one question remains central to patient counseling: does any of this translate into higher stroke risk? In this segment, James MacNamara, MD, a non-invasive cardiologist and hypertrophic cardiomyopathy (HCM) specialist at UVA Health, and Mariko Harper, MD, MS, FACC, director of the Hypertrophic Cardiomyopathy Center of Excellence at Virginia Mason Franciscan Health, address that question and turn to what early data suggests about aficamten's AFib profile relative to mavacamten.

MacNamara raises a question the conversation had not yet directly addressed: stroke risk. He notes that despite the extensive discussion of detection bias and new vs recurrent AFib, no published data he is aware of shows an increased stroke rate associated with CMI therapy, and he suspects the HCM field is now learning lessons the broader AFib community absorbed decades earlier.

Harper agrees, noting that the AFib event rate in EXPLORER-HCM was about 2%, with a similar figure in SEQUOIA-HCM for aficamten, and that neither trial signaled meaningfully increased adverse events. She points to the mavacamten risk evaluation and mitigation strategy (REMS) database, which, while not designed to specifically track AFib, includes more than 11,000 real-world patients and shows a hospitalization rate for low ejection fraction (EF) of just 0.5%. MacNamara calls that figure remarkably low and says he counsels patients that if their drug does need to be held for a low EF, they will likely be more frustrated by the interruption than by any symptoms, since the REMS data suggest patients rarely feel unwell when this occurs. Both speculate, without being able to confirm from REMS data alone, how many of those rare low-EF hospitalizations may be linked to underlying AFib.

The conversation then turns to aficamten specifically. MacNamara notes that the field is essentially retracing where it stood with mavacamten in 2022 and 2023, when AFib was not yet a prominent concern. He highlights 1 recent analysis that pooled FOREST (the aficamten long-term extension), REDWOOD-HCM (phase 2), and SEQUOIA-HCM (phase 3) data, comparing observed AFib rates against 2 predictive risk scores, HCM-AF and CHARGE-AF. The analysis found new AFib incidence just under 2%, closely matching what CHARGE-AF would have predicted and notably lower than the HCM-AF prediction. MacNamara cautions this design does not eliminate the field's core limitation, the absence of a randomized control group, and stresses there is no head-to-head data comparing AFib risk between mavacamten and aficamten. He notes that when he has applied these risk scores retrospectively to his own CMI patients who developed AFib, they consistently scored high risk, reinforcing the possibility that many of the same factors driving oHCM disease severity also predispose to AFib independent of drug exposure.