McErlean, Ellen

Introduction: The performance of automated left ventricular ejection fraction (LVEF) assessment in patients with altered cardiac chamber geometry, such as those with obstructive hypertrophic cardiomyopathy (HCM), is not well described. Aims: Accurate assessment of LVEF is required for dose titration and continuation of myosin inhibitors in obstructive HCM. From the VALOR-HCM trial (NCT04349072), the agreement of two commercially available software packages was compared with blinded core lab assessment of LVEF. Methods: From baseline and week 16, among 112 patients randomized to either mavacamten or placebo, 178 echocardiograms were analyzed. Representative clips were manually selected, and automated LVEFs were calculated. Comparisons of LVEFs were made using Pearson’s correlation coefficients and Bland-Altman analysis. Results: With core lab assessment, the overall median LVEF was 68% (Q1 66%, Q3 70%). The correlation with vendor 1 was moderate (r = 0.47, 95% CI 0.35-0.58, p <0.001) and weak with vendor 2 (r =0.21, 95% CI 0.07-0.35, p =0.004). Correlation was also weak between vendor 1 and 2 (r = 0.14, 95% CI 0.00-0.28, p = 0.06). Vendors 1 and 2 had an underestimation bias of LVEF of 8% (95% CI 6-9%) and 8% (95% CI 7-9%), respectively, compared to core lab LVEF (Figure 1). Conclusions: In VALOR-HCM, the concordance of LVEF between different commercially available software packages with each other and with a core lab assessment was limited. Further study is needed to evaluate and improve the performance of automated LVEF tools in obstructive HCM patients who have altered cardiac chamber geometry.

Importance There is an unmet need for novel medical therapies before recommending invasive therapies for patients with severely symptomatic obstructive hypertrophic cardiomyopathy (HCM). Mavacamten has been shown to improve left ventricular outflow tract (LVOT) gradient and symptoms and may thus reduce the short-term need for septal reduction therapy (SRT). Objective To examine the cumulative longer-term effect of mavacamten on the need for SRT through week 56. Design, Setting, and Participants This was a double-blind, placebo-controlled, multicenter, randomized clinical trial with placebo crossover at 16 weeks, conducted from July 2020 to November 2022. Participants were recruited from 19 US HCM centers. Included in the trial were patients with obstructive HCM (New York Heart Association class III/IV) referred for SRT. Study data were analyzed April to August 2023. Interventions Patients initially assigned to mavacamten at baseline continued the drug for 56 weeks, and patients taking placebo crossed over to mavacamten from week 16 to week 56 (40-week exposure). Dose titrations were performed using echocardiographic LVOT gradient and LV ejection fraction (LVEF) measurements. Main Outcome and Measure Proportion of patients undergoing SRT, remaining guideline eligible or unevaluable SRT status at week 56. Results Of 112 patients with highly symptomatic obstructive HCM, 108 (mean [SD] age, 60.3 [12.5] years; 54 male [50.0%]) qualified for the week 56 evaluation. At week 56, 5 of 56 patients (8.9%) in the original mavacamten group (3 underwent SRT, 1 was SRT eligible, and 1 was not SRT evaluable) and 10 of 52 patients (19.2%) in the placebo crossover group (3 underwent SRT, 4 were SRT eligible, and 3 were not SRT evaluable) met the composite end point. A total of 96 of 108 patients (89%) continued mavacamten long term. Between the mavacamten and placebo-to-mavacamten groups, respectively, after 56 weeks, there was a sustained reduction in resting (mean difference, −34.0 mm Hg; 95% CI, −43.5 to −24.5 mm Hg and −33.2 mm Hg; 95% CI, −41.9 to −24.5 mm Hg) and Valsalva (mean difference, −45.6 mm Hg; 95% CI, −56.5 to −34.6 mm Hg and −54.6 mm Hg; 95% CI, −66.0 to −43.3 mm Hg) LVOT gradients. Similarly, there was an improvement in NYHA class of 1 or higher in 51 of 55 patients (93%) in the original mavacamten group and in 37 of 51 patients (73%) in the placebo crossover group. Overall, 12 of 108 patients (11.1%; 95% CI, 5.87%-18.60%), which represents 7 of 56 patients (12.5%) in the original mavacamten group and 5 of 52 patients (9.6%) in the placebo crossover group, had an LVEF less than 50% (2 with LVEF ≤30%, one of whom died), and 9 of 12 patients (75%) continued treatment. Conclusions and Relevance Results of this randomized clinical trial showed that in patients with symptomatic obstructive HCM, mavacamten reduced the need for SRT at week 56, with sustained improvements in LVOT gradients and symptoms. Although this represents a useful therapeutic option, given the potential risk of LV systolic dysfunction, there is a continued need for close monitoring. Trial Registration ClinicalTrials.gov Identifier: NCT04349072

Background: Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) examined the effect of mavacamten on the need for SRT through week 32 in oHCM. Methods: A double-blind randomized placebo-controlled multicenter trial at 19 US sites included patients with oHCM on maximal tolerated medical therapy referred for SRT with left ventricular outflow tract gradient ≥50 mm Hg at rest or provocation (enrollment, July 2020–October 2021). The group initially randomized to mavacamten continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded mavacamten from week 16 to week 32. Dose titrations were based on investigator-blinded echocardiographic assessment of left ventricular outflow tract gradient and left ventricular ejection fraction. The principal end point was the proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups. Results: From the 112 randomized patients with oHCM, 108 (mean age, 60.3 years; 50% men; 94% in New York Heart Association class III/IV) qualified for week 32 evaluation (56 in the original mavacamten group and 52 in the placebo cross-over group). After 32 weeks, 6 of 56 patients (10.7%) in the original mavacamten group and 7 of 52 patients (13.5%) in the placebo cross-over group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting left ventricular outflow tract gradient (−33.0 mm Hg [95% CI, −41.1 to −24.9]) and Valsalva left ventricular outflow tract gradient (−43.0 mm Hg [95% CI, −52.1 to −33.9]) was observed in the original mavacamten group. A similar reduction in resting (−33.7 mm Hg [95% CI, −42.2 to −25.2]) and Valsalva (−52.9 mm Hg [95% CI, −63.2 to −42.6]) gradients was quantified in the cross-over group after 16 weeks of mavacamten. After 32 weeks, improvement by ≥1 New York Heart Association class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) after 16 weeks in the cross-over group. Conclusions: In severely symptomatic patients with oHCM, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.