Introduction: The Evolution of Obstructive HCM Management
Obstructive hypertrophic cardiomyopathy (oHCM) has long been characterized by a challenging therapeutic landscape. For patients who remain symptomatic despite maximally tolerated medical therapy—typically beta-blockers, calcium channel blockers, or disopyramide—the traditional gold standard has been septal reduction therapy (SRT), either through surgical myectomy or alcohol septal ablation. While effective, these procedures are invasive and carry inherent perioperative risks. The emergence of cardiac myosin inhibitors, specifically mavacamten, has shifted the focus toward a precision-medicine approach that targets the underlying pathophysiology of the disease: the excessive actin-myosin cross-bridging that drives hypercontractility and outflow tract obstruction.
The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy) was designed to determine if mavacamten could serve as an alternative to SRT. Following initial positive short-term results, two landmark publications have now released the 128-week (end-of-trial) follow-up data. These results, published in JACC: Cardiovascular Imaging and Circulation, provide a comprehensive look at both the clinical outcomes and the structural remodeling induced by long-term mavacamten therapy.
Highlights of the 128-Week Follow-Up
Through 128 weeks of treatment, several key findings have emerged that define the long-term utility of mavacamten:
1. Sustained avoidance of SRT: Nearly 85% of patients who were originally referred for septal reduction therapy remained free from the procedure and was no longer guideline-eligible for it at the end of the trial.
2. Disease modification through remodeling: Significant and sustained improvements were observed in left ventricular (LV) mass index, left atrial (LA) volumes, and markers of myocardial strain, suggesting that the drug does more than just alleviate obstruction.
3. Clinical and functional improvement: Over 80% of patients experienced an improvement of at least one NYHA functional class, which correlated strongly with enhanced quality of life scores.
4. Manageable safety profile: While a small percentage of patients experienced transient reductions in left ventricular ejection fraction (LVEF), the majority were able to continue therapy after dose adjustment or temporary interruption.
Study Design and Methodology
VALOR-HCM was a double-blind, randomized, placebo-controlled multicenter trial conducted across 19 sites in the United States. The study enrolled 112 adult patients (mean age 60.3 years) with severely symptomatic oHCM (94% NYHA Class III/IV) who met American College of Cardiology/American Heart Association (ACC/AHA) criteria for SRT. Patients were randomized 1:1 to receive mavacamten or placebo for the first 16 weeks.
Following the initial 16-week period, patients in the placebo group transitioned to mavacamten (receiving 112 weeks of exposure), while the original mavacamten group continued for a total of 128 weeks. Dose titrations were performed based on echocardiographic monitoring of the left ventricular outflow tract (LVOT) gradient and LVEF. The primary longitudinal endpoints included the proportion of patients proceeding with SRT, changes in echocardiographic indices of remodeling (using vendor-neutral software for strain analysis), and patient-reported outcomes via the Kansas City Cardiomyopathy Questionnaire (KCCQ-23).
Sustained Relief from Obstruction and SRT Avoidance
The clinical data published in Circulation highlights the remarkable durability of mavacamten’s effect on hemodynamics. At week 128, only 15.7% (17 of 108) of the total study sample met the composite endpoint of proceeding with SRT or remaining guideline-eligible. Specifically, only 7 patients underwent SRT over the two-year period. This represents a significant shift in the treatment trajectory for patients who were previously deemed to have failed medical therapy.
Hemodynamic improvements were robust. The resting LVOT gradient showed a sustained reduction of 38.2 mm Hg, while the Valsalva-provoked gradient was reduced by 59.4 mm Hg. These physiological changes translated directly into functional gains. By week 128, 80.5% of patients demonstrated at least a one-class improvement in NYHA status, and nearly half (48.1%) improved by two or more classes. The high transition rate to commercial mavacamten (88%) at the end of the trial further underscores the clinical value perceived by both patients and investigators.
Evidence of Favorable Cardiac Remodeling
The JACC: Cardiovascular Imaging paper provides the mechanistic underpinnings for these clinical gains, focusing on structural changes within the heart. Mavacamten therapy led to significant improvements across several critical echocardiographic parameters from baseline to week 128:
Left Ventricular Structure and Function
There was an 11% reduction in the LV mass index, indicating a regression of the pathological hypertrophy that defines HCM. Furthermore, LV global longitudinal strain (GLS) improved by 4.5%, suggesting better myocardial efficiency. The septal E/e’ ratio, a marker of LV filling pressure and diastolic function, improved by 18%.
Left Atrial Dynamics
Left atrial enlargement is a known predictor of adverse outcomes, including atrial fibrillation and heart failure, in HCM. Mavacamten treatment resulted in a 6% reduction in LA volume index. More importantly, LA strain indices showed dramatic improvements: conduit strain increased by 16%, contraction strain by 35%, and reservoir strain by 32%. These improvements in LA function are particularly noteworthy as they suggest a holistic improvement in cardiac hemodynamics beyond the relief of the LVOT obstruction itself.
Correlation with Quality of Life
Interestingly, the study found a strong correlation between remodeling and patient well-being. Patients who reported a significant improvement in quality of life (a gain of 5 points or more on the KCCQ-23-CSS) also showed the most significant improvements in LA and LV strain values. Conversely, the minority of patients who did not report clinical improvement also failed to show significant remodeling on imaging, suggesting that structural regression is a key driver of symptomatic relief.
Safety and Tolerability Over 128 Weeks
Safety remains a paramount concern with cardiac myosin inhibitors due to their mechanism of reducing contractility. In VALOR-HCM, 15 of 108 patients (13.8%) experienced an LVEF drop to below 50% at some point during the 128 weeks (an incidence rate of 5.41 per 100 patient-years). Two patients experienced a significant drop to 30% or less. However, the protocol-driven dose titrations and temporary interruptions were largely successful; 80% of those who experienced an LVEF drop were able to resume and continue treatment.
New-onset atrial fibrillation occurred in 11 patients (10.2%), which is consistent with the known risks in this patient population, though the rate (4.55 per 100 patient-years) warrants continued monitoring. There was one death reported during the study, but the overall safety profile was considered acceptable for a population with such high baseline disease severity.
Expert Commentary: Is This Disease Modification?
The findings from VALOR-HCM suggest that mavacamten may be more than just a “pharmacological myectomy.” The term “disease modification” is increasingly used to describe the effects observed. In oHCM, the chronic obstruction and high intracavitary pressures lead to secondary remodeling, including LA stretching and worsening diastolic function. By targeting the primary molecular defect, mavacamten appears to reverse some of these secondary structural changes.
Clinical experts note that the sustained reduction in LV mass and the improvement in LA strain are particularly encouraging. These changes are rarely seen to this degree with traditional medical therapies like beta-blockers. However, it is important to maintain a balanced perspective. Mavacamten requires lifelong administration and rigorous echocardiographic monitoring. For some patients—particularly younger individuals who may face decades of drug therapy—the one-time definitive nature of surgical myectomy remains a compelling alternative. The 128-week data provides clinicians and patients with the evidence needed to have an informed discussion about these two distinct management pathways.
Conclusion
The 128-week results from the VALOR-HCM trial solidify the role of mavacamten as a potent and durable therapeutic option for patients with symptomatic obstructive HCM who are candidates for SRT. By providing sustained relief from obstruction, facilitating favorable structural remodeling, and significantly improving quality of life, mavacamten offers a non-invasive alternative that addresses the root cause of the disease. As the cardiovascular community continues to integrate cardiac myosin inhibitors into standard practice, the VALOR-HCM data serves as a critical benchmark for long-term efficacy and safety.
Funding and Trial Registration
The VALOR-HCM trial was funded by Bristol Myers Squibb. ClinicalTrials.gov Identifier: NCT04349072.
References
1. Desai MY, Okushi Y, Wolski K, et al. Long-Term Favorable Cardiac Remodeling in Obstructive Hypertrophic Cardiomyopathy Patients Treated With Mavacamten for Up to 128 Weeks: Insights From the VALOR-HCM Trial. JACC Cardiovasc Imaging. 2025;18(12):1300-1311.
2. Desai MY, Wolski K, Owens A, et al. Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results From VALOR-HCM. Circulation. 2025;151(19):1378-1390.
