LAUSR

Managing dynamic left ventricular outflow tract (LVOT) obstruction remains one of the most chal lenging therapeutic aspects of hypertrophic cardio myopathy. Individuals who are affected frequently present with disabling symptoms, which can be ameliorated following reduction of LVOT obstruction. Pharmacological treat­ ment currently comprises non­disease specific therapies such as β blockers, negatively inotropic calcium channel blockers, and disopyramide, which offer a variable degree of symptomatic relief and are often limited by side­effects. Enhanced myo cardial contractility is a key factor in the patho physiology of LVOT obstruction. Mavacamten is a first­in­class, selective allosteric inhibitor of cardiac myosin ATPase, which reduces actin­myosin cross­bridge formation, thereby reducing myocardial contractility and improving myocardial energetics. Animal studies showed that mavacamten reduced myocardial contrac tion in a dose­dependent manner and relieved LVOT obstruction. These findings were replicated in a phase 2 trial (PIONEER­HCM), in which mavacamten reduced the post­exercise LVOT gradient, increased peak oxygen consumption (pVO2), and improved symptoms in patients with the condition. In The Lancet, Iacopo Olivotto and colleagues report the EXPLORER­HCM trial, a phase 3, randomised­controlled trial that randomly assigned 251 patients (mean age 58·5 years; 41% women) with obstructive hypertrophic cardiomyopathy to either mavacamten or placebo. Despite the multiple inclusion and exclusion criteria, the study population was generally representative of patients with obstructive hypertrophic cardiomyopathy who physicians are likely to encounter, making the results applicable to wider clinical practice. Impor­ tantly, the authors explored primary and secondary outcomes commonly used in clinical practice, such as shortness of breath and fatigue, functional capacity, LVOT gradient, and overall health status. After 30 weeks of treatment, mavacamten showed benefit across the spectrum, including the composite primary endpoint, its components, all secondary endpoints, patient­reported outcomes, and reductions in biomarkers of cardiac wall stress and myocardial injury. Specifically, compared with placebo, patients given mavacamten were more likely to reach the primary endpoint of pVO2 and New York Heart Association (NYHA) class improvement (19·4%, 95% CI 8·7 to 30·1; p=0·0005), and showed greater reduction in post­exercise LVOT gradient (–36 mm Hg, –43·2 to –28·1; p<0·0001), had a greater increase in pVO2 (1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and displayed improved patient­reported symptom scores (p<0·0001). Moreover, mavacamten induced a complete response, defined as NYHA class I and LVOT peak gradients less than 30 mm Hg (at rest, after Valsalva manoeuvre, or post exercise), in 27% of patients compared with only 1% in the placebo group. The effect of mavacamten on LVOT obstruction becomes more striking when we consider that the overwhelming majority (92%) of patients in the study were on background β blocker or calcium channel blocker therapy, agents which reduce the LVOT gradient. Moreover, it is well established that β blockers blunt heart rate response to exercise and therefore negatively affect pVO2, which was part of the study’s primary endpoint. Encouragingly, the side­effect and safety profile did not differ between groups. A decrease in left ventricular ejection fraction to less than 50% was observed in seven (6%) patients on mavacamten, which resolved upon temporary discon tinuation of treatment. There were no significant changes in heart rate and blood Lif in V ie w /S cie nc e Ph ot o Li br ar y Published Online August 29, 2020 https://doi.org/10.1016/ S0140­6736(20)31793­1