Incidence and Outcomes of Atrial Fibrillation and Systolic Dysfunction in Patients Receiving Mavacamten for Obstructive Hypertrophic Cardiomyopathy: A Multicenter Study

Importance Mavacamten is highly effective in treating symptomatic obstructive hypertrophic cardiomyopathy (oHCM) and was approved for commercial use with a risk mitigation program (REMS) to monitor the impact on left ventricular systolic function (LVSD). The impact of mavacamten on atrial fibrillation (AF) occurrence is not well characterized.

Determine the real-world incidence of new-onset and recurrent AF among patients with HCM treated with commercial mavacamten. Secondary objectives included assessing the incidences of LVSD, heart failure (HF), and cardiogenic shock. Design A multicenter cohort study. Center-level data were aggregated for patients who received mavacamten from May 2022 through December 2024. Setting Twenty-one outpatient HCM centers in the United States. Participants Consecutive patients ≥18 years of age with oHCM were included; those with permanent AF were excluded. Exposures At least one dose of commercial mavacamten. Main Outcomes and Measures Incidence of new-onset and recurrent AF, LVSD, HF, and cardiogenic shock.

Among 1,538 patients (median age, 66 years [95% CI, 65.9–66.1]; 57% female [95% CI, 54–59%]), 25% [95% CI, 22-27%] had prior AF. Median mavacamten exposure was 13.4 months [95% CI, 11.8–15.0]. Overall AF incidence was 13% [95% CI, 10–17%], including 5% [95% CI, 4–7%] new-onset and 39% [95% CI, 27–51%] recurrent AF in those with history of AF prior to mavacamten initiation. LVEF <50% occurred in 8% [95% CI, 6–9%], of whom 70% had AF. Symptomatic HF occurred in 1.5% [95% CI, 0.8–2.2%], cardiogenic shock in 0.6% [95% CI, 0.1–1.0%], and an overall permanent discontinuation of mavacamten in 7% [95% CI, 4–10%].

and Relevance In this multicenter cohort receiving commercial mavacamten, we identified an annual incidence of 5% new-onset AF and 39% recurrent AF, while 70% of patients who developed LVEF<50% had concurrent AF. Given this association and the morbidity that can be associated with AF, protocols for LVEF assessment and aggressive rhythm management following AF detection may be warranted to improve patient care. Further studies are needed to improve understanding of the impact of mavacamten on AF and patient outcomes. Question What are the real-world burden and consequences of atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy treated with commercial mavacamten? Findings In a multicenter cohort of more than 1,500 patients, 5% experienced new-onset AF, while 39% of those with pre-existing AF experienced recurrence after mavacamten initiation. Left ventricular ejection fraction (LVEF) fell below 50% in 8% of patients, 70% of whom had concurrent AF. Meaning Real-world experience with mavacamten emphasizes that regular surveillance for AF is an important aspect of managing patients with HCM. Additionally, the identification of AF should prompt LVEF assessment and aggressive rhythm management, given the potential association between AF and decrease in LVEF. The observed incidence of AF on mavacamten highlights the need for further studies on potential mechanisms and for proactive surveillance and management strategies. Competing Interest Statement Ahmad Masri reports research grants from Pfizer, Ionis, Attralus, Cytokinetics and Janssen and personal consulting fees from Cytokinetics, Bristol Myers Squibb, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, AstraZeneca, Avidity, Neurimmune, and Tenaya. Daniele Massera reports consulting fees from Chiesi Pharmaceuticals, Cytokinetics, Rocket Pharmaceuticals and Sanofi. Jeffrey Geske serves as a site principal investigator for industry-funded clinical trials from Bristol Myers Squibb, Cytokinetics Inc, and Lexicon Pharmaceuticals. Said Alsidawi reports research grants from Bristol Myers Squib and serves on the advisory board. Nosheen Reza reports consulting/speaking honoraria from Zoll, Inc., Roche Diagnostics, American Regent, Bristol Myers Squibb, AstraZeneca, Idorsia, Novo Nordisk and research grants to the institution from Bristol Myers Squibb. Shepard Weiner reports consulting fees and is on the Advisory Board for Cytokinetics and Bristol Myers Squibb. Anjali Owens reports consulting fees from Alexion, Avidity, Bayer, Bristol Myers Squibb, Cytokinetics, Edgewise, Imbria, Lexeo, Stealth, Tenaya, Biomarin and research grants to the institution from Bristol Myers Squibb. Neal Lakdawala reports consulting fees from Alexion, Bayer, Bristol Myers Squibb, Edgewise, Lexeo, Tenaya, Kardigan, Gemma and research grants from Pfizer. Carolyn Ho reports research support and/or consulting fees from Alexion, Astra Zeneca, Bristol Myers Squibb, Cytokinetics, Lexicon, Novo Nordisk, and Sanofi. Funding Statement Olives Nguyen is supported by the National Institutes of Health under Award Number 5T32HL166128-02. Richard T. Carrick and Jose Madrazo are supported by the Talles Family HCM Research Fund. Nosheen Reza is supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number K23HL166961. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study utilized aggregated, de-identified site-level data and did not require institutional review board approval. Any local approvals obtained at participating sites were independent of the present analysis. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Disclosures: Ahmad Masri reports research grants from Pfizer, Ionis, Attralus, Cytokinetics and Janssen and personal consulting fees from Cytokinetics, Bristol Myers Squibb, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, AstraZeneca, Avidity, Neurimmune, and Tenaya. Daniele Massera reports consulting fees from Chiesi Pharmaceuticals, Cytokinetics, Rocket Pharmaceuticals and Sanofi. Jeffrey Geske serves as a site principal investigator for industry-funded clinical trials from Bristol Myers Squibb, Cytokinetics Inc, and Lexicon Pharmaceuticals. Said Alsidawi reports research grants from Bristol Myers Squib and serves on the advisory board. Nosheen Reza reports consulting/speaking honoraria from Zoll, Inc., Roche Diagnostics, American Regent, Bristol Myers Squibb, AstraZeneca, Idorsia, Novo Nordisk and research grants to the institution from Bristol Myers Squibb. Shepard Weiner reports consulting fees and is on the Advisory Board for Cytokinetics and Bristol Myers Squibb. Anjali Owens reports consulting fees from Alexion, Avidity, Bayer, Bristol Myers Squibb, Cytokinetics, Edgewise, Imbria, Lexeo, Stealth, Tenaya, Biomarin and research grants to the institution from Bristol Myers Squibb. Neal Lakdawala reports consulting fees from Alexion, Bayer, Bristol Myers Squibb, Edgewise, Lexeo, Tenaya, Kardigan, Gemma and research grants from Pfizer. Carolyn Ho reports research support and/or consulting fees from Alexion, Astra Zeneca, Bristol Myers Squibb, Cytokinetics, Lexicon, Novo Nordisk, and Sanofi. Olives Nguyen is supported by the National Institutes of Health under Award Number 5T32HL166128-02. Richard T. Carrick and Jose Madrazo are supported by the Talles Family HCM Research Fund. Nosheen Reza is supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number K23HL166961. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data Availability All data produced in the present study are available upon reasonable request to the authors. Abbreviations - AF - atrial fibrillation - CI - confidence interval - HCM - hypertrophic cardiomyopathy - HF - heart failure - LVEF - left ventricular ejection fraction - LVOT - left ventricular outflow tract - LVSD - left ventricular systolic dysfunction - oHCM - obstructive HCM - RCTs - randomized clinical trials - SCD - sudden cardiac death - SD - standard deviation