Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease.1 The risk of atrial fibrillation (AF) is substantially higher in individuals with HCM than in the general population, with an estimated prevalence of 20% to 30% and an annual incidence of 2% to 7%.1 Mavacamten, the first targeted drug therapy for obstructive HCM, works by selectively inhibiting cardiac myosin. In pivotal clinical trials of mavacamten, 2% to 7% of patients had AF adverse events, some leading to rapid reduction in systolic function and discontinuation of the study drug.2,3 Data are urgently needed to inform the optimal strategies for arrhythmia monitoring and treatment. The goal of this study was to determine the incidence, prevalence, and clinical implications of AF in a real-world cohort of patients treated with mavacamten.
Included patients were started on mavacamten between April 2022 and December 2023 and followed through February 2024. Patients were ≥18 years of age, had left ventricular ejection fraction (LVEF) ≥55%, NYHA functional class II or III symptoms, and left ventricular outflow tract (LVOT) gradients ≥30 mm Hg. The study protocol was approved by the University of Pennsylvania Institutional Review Board.
All patients underwent clinical and echocardiographic assessment at baseline. The US Food and Drug Administration–mandated Risk Evaluation and Mitigation Strategy program requires additional visits and echocardiograms after mavacamten initiation at weeks 4, 8, and 12 (initiation phase), and every 12 weeks thereafter for patients on stable dosing. More frequent monitoring is indicated for patients undergoing dose titration.
Electrocardiograms were collected before mavacamten start and with every clinical visit. Ambulatory rhythm monitoring was performed at regular intervals or obtained from existing implanted devices. The primary endpoint was a composite of new or progressive AF. AF progression was defined as paroxysmal AF becoming persistent or the need for increased antiarrhythmic drug therapy or unplanned catheter ablation. Statistical analyses were performed using SPSS (version 28, IBM).
We enrolled 96 patients and followed them for median 47 (Q1-Q3: 25–68) weeks after mavacamten start. Mean age was 63 ± 14.4 years, 54% were female, and 41% had NYHA functional class III symptoms. On baseline echocardiogram, mean LVEF was 68% ± 6.1%, maximal left ventricular wall thickness 19 ± 3.1 mm, and mean resting LVOT gradient was 56 ± 39.1 mm Hg. All but 3 patients (97%) were taking at least one calcium channel blocker or beta-blocker. Echocardiographic and clinical outcomes through 36 weeks of treatment have been previously reported.4
Nearly all patients (92%) underwent ambulatory rhythm monitoring before starting mavacamten, with a mean 42 days of monitoring in the year before initiation. All patients were in sinus- or atrial-paced rhythm at the time of mavacamten start. However, 23 patients (24%) had a history of AF, which was paroxysmal in 19 (20%) and persistent in 4 (4%). Nine (9%) patients had previously undergone cardioversion, 5 (5%) had catheter ablation, and 9 (9%) were taking antiarrhythmic drugs at baseline (4 taking dofetilide, 3 disopyramide, and 2 sotalol).
Eleven patients (11%) met the primary endpoint, including 6 (6%) with new AF and 5 with AF progression (5% of the total cohort, 22% of those with a history of AF) (Table 1). AF led to temporary discontinuation of mavacamten in 1 patient who had persistent recurrences despite amiodarone and decrease in LVEF to 50%. Following successful catheter ablation, her LVEF recovered to 75% and mavacamten was restarted.
TABLE 1.
AF Onset and Management in Patients With Incident or Progressive AFa
| Case No. | AF History | AF Event | Time of AF Onset or Progression, wks | Mavacamten Dose at AF Onset or Progression, mg | Mavacamten Dose Modification After AF | AF Management | AF Outcome |
|---|---|---|---|---|---|---|---|
| 1 | None | New | 30 | 5 (stable) | Temporary stop due to AF | Amiodarone; cardioversion; cardioversion; ablation | 0% AF 7 mo after ablation. Off amiodarone |
| 2 | Paroxysmal | Progression | 32 | 5 (stable) | No change | Cardioversion; dofetilide; ablation | 0% AF 14 mo after ablation. On dofetilide |
| 3 | None | New | 36 | 5 (stable) | No change | No intervention | 1% AF through 84 weeks of treatment |
| 4 | None | New | 39 | 15 (stable) | No change | No intervention | 1% AF through 68 weeks of treatment |
| 5 | Paroxysmal | Progression | 38 | 10 (stable) | No change | Sotalol increase; cardioversion | 0% AF 6 mo after cardioversion |
| 6 | None | New | 12 | 2.5 (initiation phase) | No change. Eventually discontinued after mitral valve surgery | Maze procedure at time of cardiac surgery | 0% AF 12 mo after maze procedure |
| 7 | Paroxysmal | Progression | 0 | 5 (initiation phase) | No change | Cardioversion; amiodarone | Symptoms controlled for 12 mo after cardioversion. Burden not quantified |
| 8 | None | New | 32 | 10 (stable) | No change | Cardioversion | 1% AF 10 mo after cardioversion |
| 9 | Paroxysmal | Progression | 4 | 5 (initiation phase) | Temporary dose reduction due to LVOT gradient <20 mm Hg | Cardioversion; dofetilide (stopped due to QTc prolongation); amiodarone; ablation | 0% AF 12 mo after ablation. On amiodarone |
| 10 | Paroxysmal | Progression | 8 | 2.5 (initiation phase) | Temporary stoppage due to LVOT gradient <20 mm Hg | Two cardioversions scheduled but converted spontaneously; metoprolol increase | 3% AF at 10 wks of treatment. 1% AF at 36 wks of treatment |
| 11 | None | New | 43 | 10 (stable) | No change | None | 0% AF on 12-d Holter at 19 wks of treatment |
Burden determined with continuous rhythm monitoring unless otherwise specified.
AF = atrial fibrillation; LVOT = left ventricular outflow tract.
Mavacamten clinical trials were selective about including patients with history of AF. This resulted in baseline AF prevalence of 14% in EXPLORER-HCM (Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy) and 17% in VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy).2,3 In our registry, the baseline prevalence of AF was higher at 24%. However, mavacamten was not initiated in our patients unless AF was considered well-controlled with background atrioventricular nodal blockade, antiarrhythmic drugs, and catheter ablation when indicated.
Randomized trials showed a low AF incidence overall, and no significant difference between individuals in the mavacamten and placebo arms. In contrast, incident or progressive AF was more common (11%) in our real-world cohort, similar to that reported by the Mayo Clinic.5 This may be in part explained by the higher background rate of traditional AF risk factors and more intensive rhythm monitoring. There were several patients who, despite having no history of AF or well-controlled paroxysmal AF, developed persistent AF that did not respond to cardioversions and required antiarrhythmic drugs and/or catheter ablation to achieve control during mavacamten therapy. With aggressive monitoring and rhythm control, we were able to restore sinus rhythm in all patients. Only 1 patient had mavacamten stopped due to AF and associated mild decline in LVEF, but it was able to be resumed after catheter ablation.
Because of the low number of AF primary outcome events, we were unable to identify risk factors for incident or progressive AF; future studies should address this. The arrhythmia monitoring strategy was not uniform, which may have resulted in under recognition of AF incidence or progression. Conclusions about the impact of mavacamten on AF incidence are limited by lack of a control group not treated with the myosin inhibitor.
In a large registry of patients starting mavacamten for obstructive HCM, the prevalence of AF at baseline and incidence of progression during follow-up was higher than in pivotal clinical trials. With vigilant monitoring and aggressive rhythm control, AF could be suppressed and did not necessitate permanent discontinuation of the myosin inhibitor.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Reza is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K23HL166961; has received consulting fees/speaking honoraria from Zoll Inc, Roche Diagnostics, American Regent, and Bristol Myers Squibb; and has received research grants to the institution from Bristol Myers Squibb. Ms Marzolf has received consulting fees from Bristol-Myers Squibb and Cytokinetics. Dr Margulies has received research grant support from Bristol Myers Squibb and Amgen. Dr Owens is supported by the Winkelman Family Fund for Innovation and has received consulting fees/research support from Cytokinetics, MyoKardia/Bristol-Myers Squibb, Pfizer, Lexicon Pharmaceuticals, Tenaya Therapeutics, Stealth BioTherapeutics, Renovacor, Edgewise Therapeutics, and BioMarin Pharmaceuticals. Dr Frankel is supported by the EP Research and Education Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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