Hypertrophic cardiomyopathy (HCM) is considered an autosomal dominant genetic disease caused by a sarcomere protein gene mutation, which is the most common hereditary cardiac condition featuring disorganized architecture of the myocardium and left ventricular hypertrophy [1, 2, 3]. The prevalence of HCM is 0.2% in the general population, and HCM is the primary cardiac cause of sudden cardiac death [4].

The pathogenic mechanism of HCM is highly complex, and is associated with $\beta$-cardiac myosin hypercontractility and impaired myocardial compliance [4, 5]. The hypercontractility often results in cardiac hypertrophy and diastolic dysfunction. Variable clinical symptoms of HCM may be associated with the severity of mitral regurgitation and diastolic dysfunction [4]. Dyspnea is one of the most common presenting symptoms [5]. HCM often progresses to obstruction of the left ventricular outflow tract (LVOT), patients may have increased dizziness, fainting or near fainting, syncope, angina, paroxysmal nocturnal dyspnoea, congestive heart failure, and sudden cardiac death [5].

Traditional medication treatments of HCM are not disease-specific, HCM medical therapy depends on the patient’s clinical picture and remains limited to beta adrenergic blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiarrhythmics, diuretics and oral anticoagulants [5, 6].

Mavacamten (MYK-461), a selective and reversible cardiac myosin inhibitor, is a novel $\beta$-cardiac-specific small molecule drug design-based on current knowledge of HCM disease pathology [5, 7, 8]. Mavacamten directly inhibits cardiac myosin adesonine triphosphatase (ATPase) and decreases the number of myosin heads that can enter the on-actin state, inhibiting the binding of myosin to actin and the sarcomere force and ultimately causing a reduction in the cardiac contractility and improvement in compliance [5, 8]. Up to now, results from several recent randomized clinical trials (RCTs) with mavacamten indicated that mavacamten has a favorable therapeutic potential [8].

This study aimed to perform a meta-analysis to assess the efficacy and safety of mavacamten in treating HCM from available RCTs. By synthesizing the results of all published RCTs, the efficacy and safety of mavacamten in treating HCM can be more certain. This meta-analysis will also provide guidance and direction for future research on mavacamten and its role in HCM.

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) and Cochrane Handbook [9, 10]. We registered the review prospectively in Open Science Frameworks, https://osf.io/qryds/.

6 RCTs [12, 13, 14, 15, 16, 17] allocating 732 patients diagnosed with HCM were included in this meta-analysis. Among them, 673 patients were diagnosed with obstructive HCM, and 59 patients were diagnosed with non-obstructive HCM. The results of this study provide evidence for the efficacy and safety of mavacamten for treating HCM. The main finding as follows: (1) overall, mavacamten can achieve higher rates of $\ge$1 NYHA improvement, KCCQ-CSS and primary composite endpoint compared to placebo; (2) NT-proBNP and cTnI were significantly lower in the mavacamten group than in the placebo group; (3) patients receiving mavacamten achieved a Valsalva LVOT gradient less than placebo; (4) mavacamten had little effect on $△$pVO2, as there were no significant differences in the levels of these parameters between mavacamten and placebo group among HCM patients; (5) there was no significant difference in the incidences of $\ge$1 TEAE and $\ge$1 SAE between groups; (6) the results of common symptoms of TEAEs and SAEs showed that there was no significant difference between the mavacamten group and placebo group; (7) mavacamten can significantly improve in $\ge$1 NYHA improvement and composite functional endpoint levels among obstructive HCM. There were no significant differences in $\ge$1 NYHA improvement and composite functional endpoint levels among non-obstructive HCM; (8) only two RCTs reported $△$pVO2. Notably, the two RCTs evaluated obstructive and non-obstructive HCM, respectively. The subgroup results showed that mavacamten can significantly improve $△$pVO2 levels among obstructive HCM, but there were no significant differences in $△$pVO2 levels among non-obstructive HCM. Therefore, when using mavacamten in patients to improve pVO2 levels, it is necessary to distinguish the type of HCM before deciding whether to use it.

During our search in the above-mentioned databases, we found several meta-analyses [8, 18, 19] have reported the effect and safety of mavacamten in the treatment of HCM. The results of our study are consistent with the conclusions stated in these 3 studies that mavacamten can effectively improve $\ge$1 NYHA class. However, our conclusions on the outcome indicators were different from those in the reports after we increased our sample size. Several meta-analyses [8, 18] reported that mavacamten treatment has a higher incidence of $\ge$1 TEAE than placebo. But after we increased our sample size, we found there was no significant difference between mavacamten and placebo in the incidences of $\ge$1 TEAE.

Before the emergence of mavacamten, the treatment of HCM could only be achieved through non-specific drugs and surgery to improve symptoms and prevent sudden death. But, these therapies did not show any benefits in clinical trials [20]. The emergence of mavacamten has reversed this passive situation. Mavacamten can target and affect myosin, leading to a decrease in ATPase activity [21]. While improving the symptoms and signs of HCM, it can also prevent further disease progression, reduce ventricular wall tension, improve cardiac structure, and reduce heart damage [12, 14]. Mavacamten is a major advancement in HCM precision therapy, opening a new era of HCM treatment.

Due to the limitations of conventional drug therapy for HCM patients, the emergence of a targeted drug named mavacamten is undoubtedly a ray of hope in the darkness for HCM patients. However, as a cardiac myosin inhibitor, mavacamten directly interferes with the contractile function of myocardial cells and disturbs the processes involving energy production, storage, and utilization within the myocardial cells. It also disrupts the uptake, release, and reuptake of calcium ions within the myocardial cells, thereby affecting the excitation-contraction coupling of the myocardium. This ultimately leads to a decrease in myocardial contractility and relaxation of the heart muscle. While it is effective in treating HCM, it can also result in a reduction in left ventricular ejection fraction (LVEF). It is worth noting that the specific pathological mechanism leading to a reduction in LVEF caused by mavacamten is currently not fully understood. Although the mechanism of mavacamten has been described, the specific cellular and molecular-level pathological changes have not been completely elucidated. Fortunately, several RCT [12, 14, 16, 17] findings have indicated that the LVEF reduction caused by mavacamten is reversible, and the incidence rate is low. Out of the 6 RCTs included in this study, 3 RCTs reported the effect of mavacamten on LVEF. Ho et al. [12] found that 5 cases of patients experienced a decrease in LVEF to below 45% after taking mavacamten, but the LVEF recovered to above 50% after discontinuation of the drug. Olivotto et al. [14] found that a total of 9 patients experienced a decrease in LVEF after taking mavacamten. Among them, 5 patients had their LVEF recovered to baseline levels after discontinuing mavacamten treatment, 3 patients had their LVEF restored during the drug washout period at the end of the trial, but 1 patient with concomitant atrial fibrillation opted for atrial fibrillation ablation due to severe LVEF reduction and still had incomplete LVEF recovery at the end of the trial. The research findings by Desai et al. [16] showed that the resting LVEF remained stable throughout the entire treatment process, with only 2 patients experiencing a decrease in LVEF after taking mavacamten. These 2 patients resumed treatment without further adverse effects and remain in the long-term extension study. Tian et al. [17] found that no patient had an LVEF less than 50% or developed heart failure. The above results suggest that mavacamten is generally well-tolerated, and in the few cases where there was a decrease in LVEF, most patients were able to recover to normal levels after discontinuing the medication. But the instructions for mavacamten (CAMZYOS) state two precautions: (1) Initiation of CAMZYOS in patients with LVEF 55% is not recommended; (2) Interrupt CAMZYOS if LVEF is 50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. These should draw the attention of general cardiologists/clinicians.

The Food and Drug Administration (FDA) has approved mavacamten for the treatment of HCM, which can further expand the sample size of clinical studies and obtain more reliable data based on current clinical studies. Meanwhile, different from the race and living environment limitations of foreign clinical research samples, RCTs of mavacamten should be conducted on a large scale in the Asian region. Additionally, there are several aspects that need to be further explored regarding the research of mavacamten: (1) conduct clinical trial research with the main indicator of “hard endpoint”, such as reducing death, atrial fibrillation, and heart failure; (2) conduct clinical research on the correlation between mavacamten and the occurrence of arrhythmia; (3) conduct research on contraindications of mavacamten; (4) conduct research on interactions between mavacamten and other therapeutic drugs; (5) although there is no difference in the incidence of TEAE and SAEs between the mavacamten group and the placebo group in this study, the longest follow-up time of the included RCTs was only 30 weeks, and long-term monitoring is still needed in the future, which requires real-world observation and follow-up after marketing.

Compared with other meta-analyses [8, 18, 19], we have expanded the sample size and obtained results that are more informative, but our study still has several limitations. First, only 6 RCTs met our inclusion criteria as mavacamten is a new drug in the market. As a result, these findings may underestimate the efficacy and overestimate the safety of mavacamten. More RCTs with a large number of patients are needed to obtain a definite conclusion. Second, not all included RCTs reported the outcome indicators for evaluation, which further restricted the sample size for certain outcomes. Third, the longest follow-up time of the included RCTs was only 30 weeks, hence the value in predicting clinical effects is limited, and we have to rely on post-marketing safety surveillance systems for adverse events (AEs). Long term research data is needed to confirm the safety and efficacy of mavacamten. Nonetheless, our findings still provide preliminary evidence supporting favorable outcomes of mavacamten in treating HCM.

This meta-analysis found that mavacamten could improve the NYHA function class, KCCQ-CSS scores and composite functional end point. Meanwhile, mavacamten can decrease the NT-proBNP, cTnI and Valsalva LVOT gradient. This meta-analysis did not find any increased risk of AEs or SAEs following treatment with mavacamten. Further research should focus on a long-term follow up study to evaluate the efficacy and safety of mavacamten for the treatment of HCM.

The data presented in the study were included in the article or in its supplementary material.

LZ and DPL designed the research study. LZ and DPL performed the research. XTG and YMC screened studies. LZ and XTG extracted and analyzed the data. LZ and YMC performed the quality assessment of the included studies. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2510375.