Hypertrophic cardiomyopathy (HCM) is a prevalent heart condition primarily affecting sarcomere-related genes and is characterized by increased left ventricular (LV) wall thickness and asymmetric septal hypertrophy [1]. Imaging-based detection of the disease phenotype suggests a prevalence of 1 in 500 (0.2%) in the general population [2]. HCM is linked to an annual mortality rate of approximately 1%, with sudden cardiac arrest, heart failure, and atrial fibrillation being the key contributors to the increased risk of mortality in affected individuals [3]. LV outflow tract (LVOT) obstruction, caused by the high rate of actin-myosin interactions, holds an important prognostic value for patients with HCM and therefore is the main therapeutic target [4]. Conventional pharmacologic therapies like beta blockers, calcium channel blockers, and disopyramide relieve symptoms but do not affect the underlying pathology [5].

Recently, cardiac myosin inhibitors have been found effective in reducing myocardial contractility. Mavacamten is a first-in-class myosin inhibitor that inhibits its cross-binding with actin, thereby reducing the contractile force which is believed to be the major contributor to LVOT obstruction. Mavacamten has been shown to decrease LVOT gradients and improve functioning in HCM patients [6]. Aficamten is a newer drug that binds to a distinct allosteric site and inhibits actin-myosin cross bridges [7]. Previous studies have well demonstrated the efficacy and safety of mavacamten in reducing myocardial wall stress. This is also associated with the fact that it is well tolerated by a large percentage of the population [8]. Mavacamten has been compared with a placebo in various studies in different ethnic groups, with the results predominantly in favor of mavacamten in primary and secondary outcomes [9]. It has also shown promising effects on health status in HCM patients [10]. Aficamten, which is a newer drug and has yet to have FDA approval, has also been compared with a placebo and tested for its efficacy and safety. It has also shown a substantial amount of improvement in oxygen uptake and LVOT gradients when compared with a placebo. This underlines the potential of sarcomere-targeted therapy [11]. However, there are no trials that compare mavacamten and aficamten directly with each other and determine which one gives better results in terms of efficacy and safety.

This network meta-analysis aims to pool the evidence from pre-existing literature and compare aficamten and mavacamten indirectly via a common comparator (placebo) in order to rank the two myosin inhibitors. Clinicians can benefit from the findings this study provides in optimizing patient care.

This network meta-analysis was conducted following the guidelines recommended by the Cochrane Handbook for Systematic Reviews [12] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [13]. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42025635255.

This network meta-analysis compares the effectiveness and safety of two cardiac myosin inhibitors, mavacamten versus aficamten, utilizing six RCTs. Four of these trials (EXPLORER-HCM, MAVERICK-HCM, VALOR-HCM, EXPLORER-CN) compared mavacamten, and two (REDWOOD-HCM, SEQUOIA-HCM) compared aficamten to placebo. Through indirect comparison by a common comparator, i.e., placebo, this study shows that mavacamten is ranked higher than aficamten for HCM when change in resting LVOT gradient, NYHA class improvement, and change in LVEF are considered.

Left ventricle outflow obstruction is a strong predictor of progression to heart failure in HCM patients, with high resting LVOT gradient associated with increased risk of heart failure and death [21, 22]. The patients with severe obstruction may require invasive procedures like septal reduction surgery or myomectomy for relief [23]. Reduction in resting LVOT gradient can improve clinical outcomes and quality of life in patients with obstructive HCM [24]. Mavacamten and aficamten, while working on myosin cross-bridging and preventing force generation [25, 26], affect the hypertrophied myocardium on a molecular level [27]. They reduce cardiac contractility and provide relief of obstruction, holding a promising future in HCM management [28, 29].

With the exception of MAVERICK-HCM, which included patients with non-obstructive disease, all of the studies demonstrated improvement in resting LVOT gradient by both medications. However, mavacamten showed a stronger impact in improving the resting LVOT obstruction as shown by a higher P-score ranking of mavacamten (0.9966) as compared to that of aficamten (0.5034) achieved via indirect comparison of five of the six RCTs. There was no inconsistency between the study designs; however, the heterogeneity was high for direct comparisons, indicating differences in effect sizes that could be due to different study durations, populations, or drug dosages. The statistical significance of the decrease in LVOT gradient in HCM does not always translate into clinically significant effects; it varies according to the severity of symptoms. It holds significance in cases of mild symptoms but becomes less meaningful in cases of severe symptoms [30]. Hence, although the 14.7 mmHg greater reduction with mavacamten is statistically significant and directionally favorable, it is quite modest with respect to the major decision-making criteria that define the severity of obstruction. Even though it may contribute to gradual hemodynamic improvement, this difference may not consistently translate into a clinically noticeable benefit in every patient.

LVEF decreased in all six clinical trials that were analyzed. This is in line with findings of previous studies, which reported a transient decrease in LVEF [31]. Decrease in LVEF indicates a decline in systolic function, which can lead to serious complications of heart failure and is associated with higher mortality rates [32, 33]. It could be due to inhibition of contractile mechanics of sarcomere by these drugs [34]. In MAVERICK-HCM, five mavacamten subjects saw a reversible decrease in LVEF of less than 45%. However, VALOR-HCM revealed that changes in baseline systolic function linked to mavacamten were minimal, in contrast to the steep drop in LVOT gradients. The average decrease in LVEF was –3.9%, while the placebo caused a –0.01% decrease. In EXPLORER-HCM, seven patients on mavacamten (four patients at the end of treatment) developed an LVEF of less than 50%, indicating only slight decreases in mean global LV systolic function. Real-world data from the Risk Evaluation and Mitigation Strategy (REMS) program for mavacamten demonstrated that only 4.6% of the 5,573 patients experienced LVEF < 50% during a 22-month evaluation [35]. In the MAVA-LTE study, an EXPLORER extension cohort, 12 (5.2%) of 231 enrolled patients experienced a transient reduction in LVEF < 50% with mavacamten. However, these were reversible and treatment was resumed [36]. The LVEF of the aficamten group was marginally lower than that of the placebo group, per both aficamten trials, which could require monitoring. However, the FOREST-HCM study, a 36-week extension study of the REDWOOD cohort, demonstrated that most of the patients being treated with aficamten were able to maintain normal LVEF. Only 2 of the 34 non-obstructive HCM patients experienced LVEF < 50% for which they had to undergo dose adjustment, but the small sample size is the studyʼs limitation [37]. The reductions in LVEF were reversible with the changes in dose [38] and led to discontinuation rates ranging from 1.3% to 8% across studies [39]. Our investigation showed that mavacamten could be a better choice than aficamten since aficamten demonstrated a greater degree of reduction in LVEF, which is undesirable, as indicated by the P-score ranking of mavacamten (0.5053) and aficamten (0.0059).

Myosin inhibitors led to a considerable improvement in the NYHA class, a quality-of-life predictor in HCM patients [40]. Aficamten showed better early results at week 10 than mavacamten did at week 16, and all clinical studies revealed a reduction of at least one NYHA functional class in greater numbers when compared to placebo. Mavacamten demonstrated the greatest improvement of 37% in the EXPLORER-HCM cohort, whereas aficamten demonstrated this improvement in over 50% of the cohort in REDWOOD-HCM. However, no statistical difference was observed when they were compared to each other indirectly, yet P-score ranking showed that mavacamten was more effective. NYHA class improvement could predict the risk of hospitalizations and mortality [41, 42]. The high heterogeneity observed in the direct comparisons could be due to differences in dosage and follow-up durations. The research populations varied among trials based on HCM phenotype (obstructive vs. non-obstructive), baseline LVOT gradients, and background medical therapy, with MAVERICK-HCM enrolling only non-obstructive HCM and all other studies enrolling only obstructive illness. Drug exposure varied significantly, with mavacamten utilizing fixed or titrated low-dose regimens or target serum concentrations, and aficamten adopting broader, higher dose ranges over shorter titration intervals. The follow-up period spanned from 10 to 30 weeks, and outcome evaluation differed in terms of LVOT gradient reporting (mean vs. median; resting vs. peak), NYHA class distributions, and LVEF measurements, all of which contributed to heterogeneity. Also, these possible causes of heterogeneity were not systematically investigated via subgroup analyses or meta-regression owing to the limited number of included studies. As a result, these explanations continue to be hypothesis-generating, and the degree to which certain patient or therapy features alter treatment results remains yet to be assessed.

The distinct pharmacological profiles of mavacamten and aficamten should be taken into consideration while assessing the differences in their hemodynamic efficacy and reduction in LVEF. The extended half-life and prolonged exposure of mavacamten may result in notable and sustained decreases in LVOT gradients, but it also requires thorough dose titration and monitoring. Aficamten, on the other hand, has a shorter half-life and a quicker pharmacokinetic offset, which might allow for a wider dosage range as well as a quicker recovery of systolic function after dose modification or interruption.

These pharmacologic differences imply that future therapy choices could be tailored according to patient factors, such as comorbidities, relative sensitivity to negative inotropy, baseline LVOT obstruction, and the practicality of regular echocardiographic monitoring. Aficamten may eventually be taken into consideration in cases when quick titratability and reversibility are important, even though mavacamten may be preferred in patients needing prolonged gradient lowering. However, after regulatory approval, direct comparative trials and actual safety data would be necessary for drawing firm conclusions.

There are numerous strengths of this network meta-analysis. First, this study is the first to compare mavacamten with aficamten; no trial has yet compared these two drugs with each other. Second, the use of only RCTs enhances the strength of the evidence. Third, there was no inconsistency across the employed study designs, which adds to the credibility of the findings.

Notwithstanding its novelty, our research has a number of limitations. Inclusion of only six RCTs limits the data, excludes populations with distinct traits that could cause unpredictability, and makes it impossible to extrapolate our findings without additional proof from direct trials. These two medications are not compared directly in any of the included studies, which is a source of bias. Although the MAVERICK-HCM study differed in having patients with non-obstructive HCM compared to other studies with obstructive HCM patients, sensitivity analysis excluding this study was not performed. Compared to aficamten, mavacamten has an unfair advantage because of the increased number of clinical trials. Aficamten has a favorable profile and is promising as an alternative, but mavacamten has a greater body of clinical evidence proving its efficacy and safety, giving it a distinct edge in terms of dependability and clinical expertise; thus, it seems to have the advantage for the time being. Despite promising results, long-term safety and efficacy data are still needed, and further research is required to explore the potential of myosin inhibitors in modifying disease progression and their application in non-obstructive cardiomyopathy. Regulatory approval and additional clinical testing could make aficamten a viable choice for patients, and in the future, it may even outperform mavacamten due to its higher potency and longer half-life [43].