Myosin inhibitors represent a novel therapeutic class for hypertrophic cardiomyopathy (HCM). While both mavacamten and aficamten have been evaluated in randomized trials, comparative evidence across the 2 agents remains limited. We performed a systematic review and meta-analysis of 8 randomized controlled trials of myosin inhibitors in HCM. Outcomes included improvement in the New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), postexercise and resting left ventricular outflow tract (LVOT) gradients, mean rest LVOT peak gradient, mean Valsalva LVOT peak gradient, change in left ventricular ejection fraction (LVEF), peak oxygen uptake, N-terminal pro-B-type natriuretic peptide (NT-proBNP), treatment-emergent adverse events, and serious adverse events. Pooled effects were estimated twice using random-effects models, once stratified by drug and once pooled altogether. Results showed that myosin inhibitors improved clinical and hemodynamic outcomes versus placebo. Both mavacamten and aficamten yielded improvements in New York Heart Association functional class and KCCQ-CSS, while reducing LVOT gradients and proBNP levels. Effect magnitudes were generally larger with mavacamten; aficamten demonstrated concordant but smaller effects and was the only agent to increase peak oxygen uptake. Safety was favorable for both agents, with pooled estimates indicating a marginally more favorable safety profile for aficamten. In conclusion, myosin inhibitors improve functional status, quality of life, and hemodynamics in HCM with an acceptable safety profile. Mavacamten generally demonstrates more robust benefits, while aficamten appears to have a more favorable safety profile. Additional trials directly comparing these agents are warranted to better clarify relative efficacy and safety.
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy and myocyte disarray, affecting approximately 1 in 500 to 600 individuals. ,, Patients experience symptoms such as exertional dyspnea, chest pain, and syncope, which can be attributed to left ventricular outflow tract (LVOT) obstruction. Despite current therapeutic options, patients remain at increased risk of heart failure, atrial fibrillation, and sudden cardiac death. ,, Historically, symptomatic management of HCM has focused on reducing myocardial contractility and improving diastolic function. Beta-blockers are first-line agents followed by nondihydropyridine calcium channel blockers. ,, Disopyramide may be added when symptoms persist despite first-line therapies. If medical management fails, septal reduction therapy, including alcohol septal ablation or surgical myectomy, becomes the preferred next step.
Cardiac myosin inhibitors represent a novel class of targeted therapies for HCM, designed to directly inhibit myosin activity and reduce hypercontractility. Our meta-analysis focused on 2 such agents: mavacamten and aficamten. Mavacamten is a small-molecule allosteric inhibitor of cardiac myosin ATPase that decreases myocardial contractility and enhances diastolic function. , Immediately downstream, its reduction of excessive actin-myosin cross-bridge formation alleviates hypercontractility and LV outflow tract obstruction. The lowered filling pressures and improved ventricular compliance leads to measurable gains in symptoms and functional capacity in patients with HCM. The drug’s clinical efficacy in improving symptoms and functional capacity has been demonstrated in multiple randomized trials, leading to the 2022 FDA approval of mavacamten for class II-III obstructive HCM. ,,,,, Aficamten, a newer myosin inhibitor, binds to a distinct site on the myosin S1 catalytic domain. , It exhibits faster pharmacokinetics and causes less reduction in left ventricular ejection fraction (LVEF), potentially offering improved safety and greater dosing flexibility. In particular, aficamten’s shorter half-life (2–3 days vs mavacamten’s 7–9 days) and faster offset of action allow more precise control of drug levels. At the time of this writing, aficamten remains under investigation, with ongoing phase II trials and no current FDA approval. ,,
Given their unique mechanisms and potential disease-modifying effects, myosin inhibitors represent a promising advancement in HCM therapy. While both agents show encouraging results in clinical trials, direct comparisons are lacking. To address this gap and guide clinical decision-making, we conducted a systematic review and meta-analysis synthesizing available randomized trial data on mavacamten and aficamten in patients with HCM.
Methods
We conducted a systematic review and meta-analysis following the guidelines provided by the Cochrane Handbook for Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This meta-analysis is registered with PROSPERO (CRD420251160383).
Inclusion criteria and search strategy
Our inclusion criteria consisted of all randomized controlled trials which study the use of myosin inhibitors in HCM. Results were not filtered by language or study size, and trials comparing patients without HCM were excluded.
We performed a systematic search in PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus from database inception to September 15, 2025. We used the search terms “HCM,” “myosin inhibitor,” “mavacamten,” and “aficamten.” Boolean operators “AND” and “OR” were used to broaden search criteria. Two reviewers independently screened titles and abstracts to exclude irrelevant records, such as case reports, reviews, or studies not involving myosin inhibitors. Only studies that included both myosin inhibitors in a diagnosis of HCM were included for quantitative analysis. Disagreements were resolved by discussion and consensus. The remaining articles were retrieved and assessed for eligibility based on prespecified inclusion and exclusion criteria. A PRISMA 2020 flow diagram ( Supplementary Figure S1 ) documented records that were identified, screened, sought for retrieval, assessed for eligibility, as well as reasons for exclusion and studies included.
Data extraction and quality assessment
Using a standardized form, 2 reviewers independently extracted study metadata, cohort characteristics (sample size, age, sex), diagnostic criteria for HCM, intervention and comparator definition (myosin inhibitor vs placebo or beta-blocker), follow-up duration, and event counts and totals in each arm. All randomized trials were appraised with the Cochrane Risk of Bias tool.
Outcomes definition
Our primary outcomes were improved New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), mean LVOT gradients (resting, postexercise, and Valsalva), treatment-emergent adverse events, and serious adverse events. Secondary outcomes included change in LVEF, peak oxygen uptake, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Pooled effects were estimated twice using random-effects models, once stratified by individual drug (mavacamten or aficamten) and once pooled altogether.
Statistical analysis
All processing, statistics, and figure generation were performed in Python 3.13.7 using standard open-source libraries (pandas, numpy, scipy, statsmodels, matplotlib). The Cochran Q test of heterogeneity and the I 2 of inconsistency were used to assess heterogeneity between studies. Statistically significant heterogeneity was defined as a Chi-square p-value less than 0.05 or an I 2 greater than 75%. We did not perform statistical testing for publication bias due to the small number of studies included (fewer than ten).
Results
Study selection and characteristics
We identified 512 reports, of which 40 were evaluated for eligibility ( Supplementary Figure S1 ). Of these studies, 23 were excluded because they did not include myosin inhibitors, 5 were excluded because they did not include patients with HCM, and 4 were excluded because they were not randomized controlled trials. Eight primary studies, all of which are randomized controlled studies, were analyzed in the final meta-analysis ( Supplementary Table S1 ). The analysis pooled all studies twice, one by individual drug (mavacamten or aficamten) and once pooled altogether. A protocol for this review was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) prior to analysis, and the review was conducted in accordance with PRISMA 2020 guidelines.
Study quality
A total of 1,594 patients were included in our analysis. The baseline characteristics of the study participants are outlined in Supplementary Table S1 . We appraised the 8 randomized controlled trials with the Cochrane Risk of Bias (RoB) tool. The overall quality of the studies was very good to excellent. All randomized trials were judged low risk of bias across all RoB 2.0 domains (randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting), with overall low risk ( Supplementary Table S2 ).
Primary outcomes
Across the 8 randomized controlled trials, myosin inhibitors doubled the likelihood of ≥1 NYHA class improvement (RR 2.00 [1.47, 2.72]) ( Figure 1 ) and increased KCCQ-CSS by 7.26 points (Mean Difference 7.26 [4.74, 9.77]) ( Figure 2 ), with effects consistent between mavacamten and aficamten. Furthermore, myosin inhibitors significantly reduced LVOT gradients. postexercise gradient (assessed in only 2 mavacamten studies) decreased by 40.02 mmHg [−48.75 to −31.28] ( Figure 3 ). Resting LVOT peak gradient decreased by 32.72 mmHg [−47.37, −18.08], and Valsalva LVOT peak gradient by 46.03 mmHg [−57.64 to −34.42] with myosin inhibitors ( Figure 3 ). Safety outcomes were comparable to placebo, with no significant differences in treatment-emergent adverse effects (RR 1.05 [1.00, 1.11]) or serious adverse events (RR 0.89 [0.57, 1.39]) ( Figure 4 ).
Random effects model of the likelihood of improved NYHA functional class. Risk ratios are expressed as myosin inhibitor to placebo, such that values greater than 1 favor myosin inhibitor.
Random effects model of the change in KCCQ-CSS. Mean difference is expressed as the difference between myosin inhibitor and placebo, such that values greater than 0 favor myosin inhibitor.
Random effects model of the change in LVOT gradient. Mean difference is expressed as the difference between myosin inhibitor and placebo, such that values less than 0 favor myosin inhibitor. A: Postexercise LVOT gradient. B: Mean rest LVOT peak gradient. C: Mean Valsalva LVOT peak gradient.
Random effects model of the likelihood of adverse effects. Risk ratios are expressed as myosin inhibitor to placebo, such that values less than 1 favor myosin inhibitor. A: Treatment-emergent adverse events. B: Serious adverse events.
Secondary outcomes
For secondary outcomes, change in LVEF was measured in 3 studies, which showed a modest decrease in ejection fraction (Mean Difference −3.77% [−5.42, −2.11]) ( Supplementary Figure S2 ). Two studies showed increased peak oxygen uptake in aficamten, but when pooled with a study with mavacamten, there was no significant overall change in peak oxygen uptake (Mean Difference 1.36 mL/kg/min [−0.43, 3.15]) ( Supplementary Figure S3 ). There was also a 70% pooled reduction in NT-proBNP levels from baseline, which was measured as a geometric ratio of myosin inhibitor compared to baseline (Mean Difference 0.30 [0.08, 0.52]) ( Supplementary Figure S4 ).
Heterogeneity and publication bias
There was no statistically significant heterogeneity in any of our primary outcomes. However, 2 secondary outcomes saw high heterogeneity: change in peak oxygen uptake (I 2 = 86.2%) and change in NT-proBNP level (I 2 = 94.3%) ( Supplementary Table S3 ). Further stratification by drug demonstrated distinct patterns: aficamten produced consistent and homogeneous improvements in NYHA functional class and KCCQ-CSS (I 2 = 0%), along with clear reductions in NT-proBNP levels and measurable increases in peak oxygen uptake; mavacamten showed similar effect sizes for the same outcomes, but with greater heterogeneity ( Supplementary Table S3 ). Regardless, neither drug met statistically significant heterogeneity across primary endpoints when analyzed individually or pooled. Mavacamten achieved larger absolute reductions in LVOT gradients, but with greater between-study variability. Overall, both agents exert clinically meaningful effects, with aficamten showing greater consistency across trials and mavacamten demonstrating larger hemodynamic effects.
We assessed small study effects and publication bias in the randomized controlled trials using Egger’s regression, Begg-Mazumdar rank correlation, and funnel plot visualization. The Egger’s intercept was −0.584 (SE 0.803, t = −0.727, p = 0.494) and the Begg’s τ was 0.071 (p = 0.905), indicating no evidence of small study effects. However, as there were only 8 studies in the analysis ( k < 10), testing of small-study effects was underpowered and cannot be entirely ruled out. Nonetheless, visual inspection of the funnel plot reveals a reasonably symmetric distribution around the pooled effect estimate and no clear absence of studies on either side of the plot, consistent with no evidence of small study effects ( Supplementary Figure S5 ).
