Real-World Study Reveals Higher Than Expected Atrial Fibrillation Risk with Mavacamten in Hypertrophic Cardiomyopathy Patients
核心洞察
A large real-world study of 2,440 US patients found that 5.1% developed new atrial fibrillation (搜索) or flutter within 8 months of starting mavacamten, representing an annual incidence of 7.6% - more than triple the typical 2% rate.
Nearly half of patients required dose adjustments during treatment, with 17% discontinuing mavacamten for 90 days or more after acute care episodes, suggesting potential tolerability or safety challenges.
Despite safety concerns, long-term VALOR-HCM trial data shows mavacamten provides sustained benefits equally to both men and women, with favorable cardiac remodeling persisting through 2.5 years of treatment.
A comprehensive real-world analysis of mavacamten use in obstructive hypertrophic cardiomyopathy (搜索) (oHCM) has revealed concerning rates of new atrial fibrillation (搜索) and treatment discontinuation, while concurrent long-term trial data demonstrates sustained cardiac benefits across both sexes.
Real-World Safety Profile Raises Questions
The largest real-world evaluation to date, published in the Journal of the American Heart Association, analyzed national claims data from 2,440 US patients receiving mavacamten over more than 18,000 dispenses. The study revealed several unexpected findings that warrant clinical attention.
During a median follow-up of 8 months, 5.1% of patients developed new atrial fibrillation (搜索) or flutter, translating to an annual incidence of 7.6% - more than triple the typical 2% annual rate observed in HCM patients. Additionally, 4.1% developed new heart failure (搜索), and 12.5% required at least one acute care episode, most commonly for heart failure or atrial arrhythmias.
"It remains unclear if there is an association between mavacamten, or cardiac myosin (搜索) inhibition, and AF/AFL," the researchers noted. "However, there are some clues that the incidence of new-onset AF/AFL might be higher than expected, especially with how effective mavacamten is in lowering left ventricular outflow tract gradients and improving left atrial volume."
The study cohort was 63% female with a median age of 66 years, and patients were followed for a median of 240 days after starting treatment. The median time to atrial fibrillation (搜索) was approximately 3 months, while heart failure (搜索) events occurred at a median of 3.5 months.
Treatment Modifications and Discontinuations
Nearly half of all patients required dose adjustments during the study period, with the majority being downtitrations, reflecting the need for ongoing monitoring and individualized dosing. The most common dosage was 5 mg, with patients receiving a median of 6 prescription fills during follow-up.
Notably, about 17% of patients stopped mavacamten for 90 days or more after their first acute care episode, suggesting potential tolerability, safety, or REMS-related monitoring challenges. An additional 3.5% took treatment breaks exceeding 90 days but eventually resumed therapy.
"These longer-term discontinuations likely signal permanent discontinuation of mavacamten," the authors explained. "Although temporary hold of mavacamten typically lasts 4 to 6 weeks for LVEF <50%, we felt that it is difficult to discern these short-term temporary holds."
Patients frequently required new medications, including loop diuretics (6%), oral anticoagulants (4%), and antiarrhythmics such as amiodarone (3%), sotalol (0.7%), and dofetilide (0.2%).
Long-Term Efficacy Remains Strong Across Sexes
Despite real-world safety concerns, final 128-week results from the VALOR-HCM trial demonstrate sustained benefits of mavacamten across both sexes. The analysis, published in JACC: Heart Failure (搜索), included 108 patients (54 women, 54 men) who completed the full study period.
"Compared with men, women derived similar and sustained long-term benefit from mavacamten, including reduced need for septal reduction therapy, improvements in symptoms and quality of life, and favorable cardiac remodeling," said lead investigator Milind Desai, MD, MBA, Medical Director of Cleveland Clinic's Hypertrophic Cardiomyopathy Center.
At baseline, women were older (mean age 63 vs. 58 years) with shorter duration since HCM diagnosis (6 vs. 9 years) and lower rates of atrial fibrillation (搜索) history (5.5% vs. 26.3%) compared with men. However, both groups showed similar symptom severity and beta-blocker use.
Comparable Outcomes Across Sexes
At 128 weeks, women and men demonstrated similar improvements across multiple parameters. Reductions in septal reduction therapy eligibility were comparable (14.8% of women remained eligible vs. 16.7% of men). Functional improvement by at least one NYHA class occurred in 87.8% of women versus 93.6% of men, while improvement by at least two classes was achieved in 53.1% versus 55.3%, respectively.
Both groups experienced identical 14.2-point increases in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores. Safety parameters showed no significant sex-based differences, including rates of treatment interruption due to reduced LVEF (11.1% in women vs. 16.7% in men) and serious treatment-emergent adverse events (18.5% vs. 20.4%).
Sustained Cardiac Remodeling Demonstrates Disease Modification
A separate analysis published in JACC: Cardiovascular Imaging revealed significant structural and functional improvements persisting through 2.5 years of treatment. The study demonstrated sustained reductions in LVOT gradients, including 61% at rest, 72% post-Valsalva, and 53% post-exercise.
Reverse hypertrophy was evidenced by an 11% decrease in LV mass index, while diastolic function improved with an 18% improvement in septal E/e' ratio. Advanced strain measurements showed particularly impressive results: LV global longitudinal strain improved by 4.5%, LA volume index decreased by 6%, and all LA strain components significantly improved.
"The significant improvements in LV-GLS and LA strain are particularly relevant because abnormal strain values are linked to histopathological changes in HCM," Dr. Desai observed.
Patients experiencing meaningful clinical improvement (≥5 points in KCCQ-23 CSS) demonstrated significant improvements in LV and LA strain, supporting the connection between symptomatic relief and favorable physiologic change.
Clinical Implications for Risk Stratification
The analysis identified potential predictors of LVEF decline. Among 15 patients requiring temporary mavacamten interruption due to LVEF dropping below 50%, baseline LV and LA strain values were significantly worse compared to other patients.
"This hypothesis-generating result suggests that a lower baseline strain value, even with preserved LVEF, may help identify patients at higher risk for systolic dysfunction while receiving cardiac myosin (搜索) inhibitor therapy," Dr. Desai noted.
The findings underscore the importance of careful patient selection and monitoring, particularly given the real-world evidence of increased atrial fibrillation (搜索) risk and frequent treatment modifications. While mavacamten demonstrates clear disease-modifying effects with sustained cardiac remodeling, the elevated rates of arrhythmias and acute care utilization warrant continued vigilance in clinical practice.