By Michael H. Crawford, MD, Editor
SYNOPSIS: A study of the echocardiographic characteristics of symptomatic patients with obstructive hypertrophic cardiomyopathy treated with mavacamten showed a persistent 30-week improvement in several key pathophysiologic characteristics.
SOURCE: Hegde SM, Lester SJ, Solomon SD, et al. Effect of mavacamten on echocardiographic features in symptomatic patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2021;78:2518-2532.
The Clinical Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM) showed mavacamten (MC), a cardiac myosin inhibitor, alleviated symptoms, expanded exercise capacity, and reduced left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (OHCM).1 In a secondary analysis of EXPLORER-HCM, Hegde et al evaluated the effect of MC on the transthoracic echocardiographic characteristics of OHCM in relation to exercise capacity and cardiac biomarkers.
EXPLORER-HCM was a multicenter, double-blind, placebo-controlled, randomized, Phase III study of MC for OHCM. Entry criteria included New York Heart Association class II-III symptoms; peak LVOT gradients of ≥ 50 mmHg at rest, with a Valsalva maneuver or post-exercise; and a LV ejection fraction (EF) ≥ 55%. Patients could be taking beta-blockers or non-dihydropyridine calcium blockers, but not disopyramide. Serial echocardiograms, serum troponins, and N-terminal pro-brain natriuretic peptides (NT pro-BNP) were performed throughout the 30-week study period. There were 251 patients randomized (mean age = 59 years; 41% were women, and 92% were on the allowed baseline OHCM therapy). During the study, nine patients (seven on MC) experienced a decrease in EF and temporarily stopped MC, then resumed at a lower dose, which allowed them to finish the study. The baseline echoes exhibited more LV wall thickness, mildly enlarged left atrial volume index (LAVI), and diastolic dysfunction.
More than 80% had systolic anterior motion of the mitral valve (SAM) and almost all experienced mitral valve regurgitation (MR). MC completely abrogated SAM in 81% vs. 34% on placebo (P < 0.0001) and MR in 9% vs. 0% (P < 0.001) in those with these features. EF at baseline was 74% in both groups, and MC changed EF by -4% vs. 0.01% in those on placebo (P < 0.001).
MC changed the LAVI by -7.5 mL/m2 compared to 0.1 mL/m2 for placebo patients (P < 0.0001), changed septal e’ by 0.7 cm/s vs. -0.02 cm/s on placebo, and septal E/e’ by -3.5 compared to 0.3 on placebo (P < 0.0001). These changes in diastolic function were observed by 18 weeks and persisted until the end of the study. Inferolateral wall thickness (apical long axis or three-chamber view) changed by -0.6 mm vs. 0.3 mm and septal thickness by 0.1 mm vs. 1.4 mm (P < 0.0001 for both).
The strongest relationship between the reductions in NT pro-BNP was with the decrease observed in LVOT gradient (P < 0.0001). There also was a relationship between improvements in LAVI and measures of diastolic function and reductions in NT pro-BNP (both P < 0.03). The authors concluded MC improves several key pathophysiologic features of OHCM, demonstrating almost complete abrogation of SAM and significant improvements in echo measures of diastolic function, with only mild reductions in EF. In addition, improvements in LVOT gradients, diastolic function, and LAVI were associated with reductions in NT pro-BNP.
COMMENTARY
The EXPLORER-HCM trial is noteworthy because there are few randomized, controlled trials (RCTs) of any therapy in OHCM. LAVI, E/e’, LVOT gradients, and NT pro-BNP are predictors of mortality. In this substudy, these parameters all were changed in a beneficial direction, providing encouragement that MC could positively affect long-term outcomes. Most patients probably would prefer a pill to invasive septal reduction therapies. In fact, in the patient population of EXPLORER-HCM, < 10% had undergone septal reduction therapies (16 alcohol, three surgical), but 92% were on pharmacologic therapy at baseline.
There were several limitations to this study. The patient population is somewhat unique in that those with no symptoms, those on disopyramide, and those with reduced EF were excluded. In those on other standard pharmacologic therapies, there was no dosage information provided. Also, there were few ethnic minorities and patients younger than age 50 years.
In addition, fewer than one-third of subjects presented with a family history of HCM or genetic markers known to be associated with HCM (more than 40% had been diagnosed with hypertension). Atrial fibrillation was reported in 14% of the population; this and septal reduction therapy could affect echo measures of diastolic dysfunction. Finally, the study duration was relatively short at 30 weeks. Despite these limitations the authors are to be congratulated on conducting a randomized, controlled trial on this promising new therapy that addresses the basic pathophysiology of OHCM.
REFERENCE
- Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-769.
A study of the echocardiographic characteristics of symptomatic patients with obstructive hypertrophic cardiomyopathy treated with mavacamten showed a persistent 30-week improvement in several key pathophysiologic characteristics.
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