The following are key points to remember from a state-of-the-art review on cardiac myosin inhibitors for managing obstructive hypertrophic cardiomyopathy (HCM):

1. Up to two in three HCM patients have a pathogenic variant in genes encoding the cardiac myosin heavy chain (MYH7). Accordingly, two cardiac myosin inhibitors (CMI)—mavacamten and aficamten—have been developed that modify myosin manochemistry and reduce sarcomere force generation, myocardial hypercontractility, and left ventricular outflow tract (LVOT) obstruction in a dose-dependent fashion.
2. Compared with mavacamten, aficamten has a shorter half-life enabling more rapid dose titrations, drug washout, and hence has a wider therapeutic window. It also does not have significant drug-drug interactions unlike mavacamten.
3. In a randomized trial (EXPLORER-HCM), mavacamten has been proven to be superior to placebo for improving New York Heart Association (NYHA) functional class and peak oxygen consumption in obstructive HCM (oHCM) with reduction in obstruction and cardiac biomarkers. Benefits have been sustained out to 84 weeks.
4. In another randomized trial (VALOR-HCM) with oHCM patients with NYHA class III-IV symptoms, mavacamten reduced a proportion of patients needing myectomy compared with placebo (absolute difference, 59%) sustained to week 32.
5. Similarly, in a phase 2 trial with aficamten, there was a significant and dose-dependent reduction in resting and post-Valsalva LVOT gradient observed as soon as 2 weeks, with improvement in NYHA class and natriuretic peptide. A phase 3 trial with aficamten is currently ongoing.
6. Since all CMI trials have included high baseline rates of beta-blocker (BB) or calcium channel blocker (CCB) use, BB and non-dihydropyridine CCB remain first-line treatment for oHCM. In patients with refractory symptoms on these agents, CMI may be considered along with septal reduction therapy or disopyramide.
7. A short trial of CMI may help delineate if symptoms are secondary to oHCM or other comorbid conditions with similar symptoms, as trials show these agents demonstrate an effect within 4-6 weeks.
8. CMI also may be used in patients post-septal reduction therapy with persistent symptoms.
9. In trials, nearly 6% of participants needed mavacamten discontinuation due to reversible reduction in LV ejection fraction to <50%. Therefore, mavacamten has been approved by the Food and Drug Administration (FDA) with a black box warning on associated heart failure risk with systolic dysfunction. For drug safety monitoring, it is currently available only through an FDA-mandated surveillance program needing frequent monitoring via echocardiography. It is also available only through a registered pharmacy for a 1-month supply.
10. In trials, one in three to one in four oHCM patients were CMI nonresponders. These patients likely have a more advanced phenotype or there may be other factors playing into symptoms such as valvular or subvalvular abnormalities or noncardiac comorbidities.
11. The effect of CMI in young patients <18 years with oHCM has not been studied. A phase 2 trial of mavacamten in nonobstructive HCM showed reduction in biomarkers and a phase 3 trial is ongoing.
12. Commercial mavacamten is currently priced at $89,500/year in the United States. Accordingly, at present, septal reduction therapy is more cost-effective than CMI.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Genetic Arrhythmic Conditions, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound

Keywords: Adrenergic beta-Antagonists, Biomarkers, Calcium Channel Blockers, Cardiac Myosins, Cardiomyopathy, Hypertrophic, Disopyramide, Drug Interactions, Echocardiography, Heart Failure, Genetics, Myosin Heavy Chains, Natriuretic Peptides, Phenotype, Sarcomeres, Ventricular Outflow Obstruction

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