Understanding EXPLORER-HCM and VALOR-HCM AFib Signals

Beyond the pivotal cardiac myosin inhibitor (CMI) trials, a growing set of real-world registries has begun characterizing atrial fibrillation (AFib) incidence in obstructive hypertrophic cardiomyopathy (oHCM) patients treated with mavacamten in everyday practice. In this segment, Mariko Harper, MD, MS, FACC, director of the Hypertrophic Cardiomyopathy Center of Excellence at Virginia Mason Franciscan Health, and James MacNamara, MD, a non-invasive cardiologist and hypertrophic cardiomyopathy (HCM) specialist at UVA Health, compare findings across several of these registries. Harper turns to MacNamara, noting his involvement with COLE-HCM, and asks what that registry revealed. MacNamara explains that COLE-HCM is a multicenter, real-world cohort spanning sites in the United States, United Kingdom, Canada, and Israel, pooling data to characterize mavacamten's real-world effects across a diverse, generalizable population. The cohort's background AFib prevalence was about 27%, notably higher than pivotal trial populations, though new incidence of AFib was about 3% over roughly 18 months, since the registry did not separately track AFib recurrence, a category MacNamara notes has driven higher numbers at other centers. Harper connects this to her own site's participation in MARBLE, a real-world mavacamten cohort spanning 465 patients across 8 high-volume HCM centers in the United States. MARBLE similarly found a background AFib prevalence of about 27%, again higher than previously published pooled trial figures, with new-incident AFib of 2.7% over about 17 months in data presented at the American College of Cardiology (ACC) meeting, a rate she calls reassuring. MacNamara notes that cross-study comparison is complicated by inconsistent definitions of new vs recurrent AFib and varying follow-up windows. He points to an 18-center multicenter registry published earlier in the year as among the higher-quality available data, reporting roughly 5% new AFib incidence over 10 to 12 months alongside a notably higher 30% rate of recurrent AFib. Across studies, he estimates new AFib incidence generally falls between 2% and 5%, depending on the center, definition, and follow-up period. Harper, whose site also participated in that larger registry, notes substantial site-to-site variation in both new and recurrent AFib rates, raising questions about how generalizable any single registry can be. MacNamara adds that recurrent AFib is especially hard to interpret, since patients who already had AFib are inherently more likely to recur, and detection bias plays a role: the intensive echocardiographic and EKG monitoring required under the CMI risk evaluation and mitigation strategy (REMS) creates far more opportunities to catch AFib than the annual visits typical of the pre-CMI era. Harper agrees, noting that current REMS requirements call for a minimum of 4 echocardiograms during initiation and 2 every 6 months during maintenance, substantially more surveillance than historical practice.