Clinical bottom line
Novel oral myosin inhibitors, such as mavacamten and aficamten, represent a promising therapeutic advance for patients with hypertrophic cardiomyopathy (HCM), particularly those with obstructive physiology. Recent randomized controlled trials demonstrate that these agents can reduce left ventricular outflow tract (LVOT) gradients, improve symptoms, and enhance exercise capacity. However, their long-term impact on hard clinical outcomes such as mortality and heart failure progression remains under investigation. Clinicians should consider these agents as adjuncts or alternatives to invasive septal reduction therapies in selected patients with symptomatic obstructive HCM, while carefully monitoring for systolic dysfunction and other adverse effects.
What the evidence shows
Hypertrophic cardiomyopathy is characterized by left ventricular hypertrophy, often with dynamic LVOT obstruction, leading to symptoms such as dyspnea, chest pain, and syncope. Traditional management includes beta-blockers, calcium channel blockers, disopyramide, and invasive septal reduction therapies (surgical myectomy or alcohol septal ablation). Novel oral myosin inhibitors target the underlying hypercontractility by modulating cardiac myosin-actin interactions, reducing excessive contractile force and LVOT obstruction.
The pivotal phase 3 EXPLORER-HCM trial (2020) evaluated mavacamten in patients with symptomatic obstructive HCM. Mavacamten significantly reduced LVOT gradients (mean resting gradient decreased by approximately 36 mmHg vs placebo), improved New York Heart Association (NYHA) functional class, and increased peak oxygen consumption (peak VO2) over 30 weeks of treatment (Olivotto et al., 2020). Importantly, a subset of patients experienced normalization of LVOT gradients and symptom resolution, suggesting potential disease-modifying effects. Safety signals included transient reductions in left ventricular ejection fraction (LVEF), necessitating regular echocardiographic monitoring.
Subsequent studies, including the VALOR-HCM trial (2022), demonstrated that mavacamten reduced the need for septal reduction therapy in patients with severe symptomatic obstruction (Heitner et al., 2022). Aficamten, a next-generation myosin inhibitor with a shorter half-life, showed similar efficacy and safety profiles in phase 2 trials, with ongoing phase 3 studies expected to provide further data (Semsarian et al., 2023).
Systematic reviews and expert consensus guidelines (2022 ACC/AHA HCM guidelines) have incorporated these agents as emerging options for patients with obstructive HCM who remain symptomatic despite first-line medical therapy (Gersh et al., 2022). However, evidence for their use in nonobstructive HCM or asymptomatic patients is limited.
Caveats and uncertainty
While the available data are encouraging, several uncertainties remain:
- **Long-term outcomes:** Current trials primarily assess surrogate endpoints (LVOT gradient, symptoms, exercise capacity) over relatively short durations (up to 1 year). The impact on mortality, sudden cardiac death, heart failure hospitalization, and disease progression is unknown.
- **Patient selection:** Most evidence pertains to patients with obstructive HCM and NYHA class II-III symptoms. The role in nonobstructive HCM or advanced heart failure is unclear.
- **Safety monitoring:** Mavacamten can cause reversible LV systolic dysfunction, requiring frequent echocardiographic surveillance and dose adjustments. Real-world adherence to monitoring protocols may affect safety.
- **Cost and accessibility:** These novel agents are likely to be costly, potentially limiting widespread use.
- **Comparative effectiveness:** Direct comparisons with invasive septal reduction therapies are limited; thus, individualized risk-benefit assessment is essential.
How this may change practice
The introduction of oral myosin inhibitors offers a noninvasive pharmacologic option targeting the pathophysiology of obstructive HCM. For patients who remain symptomatic despite beta-blockers or calcium channel blockers, these agents may reduce the need for septal reduction procedures, which carry procedural risks and require specialized centers.
Clinicians should:
- Consider myosin inhibitors for symptomatic obstructive HCM patients who are candidates for septal reduction or who prefer medical therapy.
- Implement structured echocardiographic monitoring protocols to detect LV systolic dysfunction early.
- Engage in shared decision-making discussing benefits, risks, monitoring requirements, and costs.
- Stay informed on emerging data regarding long-term outcomes and expanding indications.
Incorporation of these agents into clinical practice aligns with precision medicine approaches targeting disease mechanisms rather than solely symptom control.