Comparing Clinical Experience to Trials in oHCM Patients

The pivotal cardiac myosin inhibitor (CMI) trials in obstructive hypertrophic cardiomyopathy (oHCM) enrolled specific patient populations that do not always map cleanly onto everyday clinical 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 their real-world patients against those trial cohorts, then turn to what new adolescent data from SCOUT-HCM adds to the AFib safety picture. Harper asks MacNamara whether the patients he sees in clinic more closely resemble the sicker VALOR-HCM population or the NYHA class II patients enrolled in EXPLORER-HCM. MacNamara says his practice sees a wide mix of both, from patients who have been on beta-blocker therapy for years and remain highly symptomatic from obstruction, to those who are functioning reasonably well but still limited by their disease. He notes that across both the clinical trial data and his own real-world experience, CMI therapy consistently makes these patients better, a point he says should not get lost in the broader AFib discussion. Harper agrees she sees both patient types as well, though she notes an encouraging trend of patients presenting earlier and with milder disease, which she attributes partly to greater awareness and earlier referral to HCM centers. The conversation then turns to SCOUT-HCM, presented at the American College of Cardiology (ACC) meeting, the first published study of mavacamten in obstructive HCM patients 12 years and older. Harper asks MacNamara for his read on the AFib signal in this adolescent population. MacNamara calls SCOUT an important trial precisely because it introduces an entirely different phenotype from EXPLORER-HCM and VALOR-HCM, younger patients with a distinct disease trajectory. He notes the reassuring headline finding, no incidence of AFib in the trial, but cautions that SCOUT was both a shorter and smaller study than the adult pivotal trials, making it premature to conclude that CMIs carry no AFib risk in adolescents or young adults. He raises the open question of whether CMIs and AFib share a causal link at all, or whether additional factors such as age-related atrial remodeling play a role. Harper offers a counterpoint: symptomatic pediatric obstructive HCM, by definition, tends to reflect a more accelerated and aggressive disease course, and most SCOUT-HCM participants were genotype positive with an early disease onset. Given that, she says she was somewhat surprised by how little arrhythmia was observed, while agreeing more data is needed. MacNamara notes that time, and continued uptake of myosin inhibitors in younger patients, will tell how this population fares longitudinally. Harper closes by noting that the second-in-class agent, aficamten, showed a similarly reassuring signal in the SEQUOIA-HCM trial, with no new AFib signal and relatively low overall AFib rates.