| アブストラクト | BACKGROUND: Mavacamten, a cardiac myosin inhibitor for symptomatic obstructive hypertrophic cardiomyopathy (HOCM), carries a risk of excessive negative inotropy. Because mavacamten is metabolized primarily by the cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4, concomitant CYP inhibitors may increase mavacamten exposure. We evaluated real-world heart failure-related reporting patterns associated with concomitant CYP inhibitor exposure in mavacamten-treated HOCM reports. METHODS: We conducted a retrospective pharmacovigilance study using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from the second quarter (Q2) of 2022 to the fourth quarter (Q4) of 2025. Mavacamten-treated HOCM reports were screened for concomitant exposure to ten prespecified CYP2C19 and/or CYP3A4 inhibitors. Heart failure-related signals were defined using seven Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms. Severe outcomes were extracted from FAERS outcome fields; hospitalization was defined as initial or prolonged hospitalization, and death as a reported fatal outcome. Analyses included the reporting odds ratio (ROR), additive signal amplification index (S), time-to-onset modeling, multivariable logistic regression, and 1:4 propensity score matching (PSM). RESULTS: Among 3,570 mavacamten-treated HOCM reports, 347 involved concomitant CYP inhibitor exposure. Combination therapy showed an elevated heart failure-related reporting signal (ROR = 25.08; 95% confidence interval [CI], 18.63-33.76) and potential reporting signal amplification (S = 2.71). Agent-specific reporting signals were heterogeneous across prespecified inhibitors. Weibull modeling showed an early-failure pattern (beta = 0.88; median onset, 80 days). Compared with mavacamten monotherapy, combination therapy had higher reported proportions of hospitalization (28.5% vs. 13.5%) and death (5.5% vs. 2.3%). Concomitant CYP inhibitor exposure showed higher heart failure-related reporting odds after multivariable adjustment (adjusted odds ratio [aOR], 2.52; 95% CI, 1.10-5.62) and in the PSM sensitivity cohort (aOR, 1.99; P < 0.001). CONCLUSION: Concomitant use of mavacamten with selected CYP inhibitors was associated with increased heart failure-related reporting in FAERS. Careful medication reconciliation and clinical vigilance are warranted, while recognizing that spontaneous reporting data cannot establish causality. |
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| 投稿者 | Chen, Daqiu; Wu, Yanqing; Xie, Zhanxiong; Qiu, Wenchao; Huang, Xiaomai; Xu, Shanghua; Luo, Shunxiang |
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