Valsartan fails to slow cardiac remodeling among patients of subclinical HCM: JAMA

The VANISH trial aimed to explore the potential of valsartan to modify disease development and to characterise short-term phenotypic progression in individuals with subclinical HCM. Subclinical HCM refers to the presence of early phenotypic manifestations, such as reduced E′ velocity, electrocardiographic abnormalities, or an increased left ventricular (LV) wall thickness to cavity diameter ratio, without apparent LV hypertrophy. This multicenter, double-blind, placebo-controlled trial was conducted from April 2014 to July 2019 across 17 sites in four countries. The cohort studied included individuals with sarcomere variants associated with subclinical HCM. Participants were randomly assigned to receive either valsartan or a placebo for the duration of the study.

The primary outcome was assessed using a composite z score that incorporated changes in nine parameters of cardiac remodelling, including LV cavity volume, LV wall thickness, LV mass, left atrial volume, E′ velocity, S′ velocity, and serum troponin and N-terminal prohormone of brain natriuretic peptide levels. The findings of the study were:

• The study involved 34 participants, all of whom were of White ethnicity, with an average age of 16 years (with a standard deviation of 5 years). Among them, 18 were assigned to receive valsartan (44% female, 56% male), while 16 received a placebo (56% female, 44% male).

• The study found that valsartan had no statistically significant effects on cardiac remodelling compared to the placebo. The mean change in the composite z score was -0.01 (with a 95% confidence interval ranging from -0.29 to 0.26), with a p-value of 0.92. In other words, valsartan did not significantly alter cardiac remodelling in these individuals with subclinical HCM.

• Over the course of two years, the study observed modest phenotypic progression in the participants. There was a slight increase in left atrial (LA) volume, measuring 3.5 mL/m2 (with a 95% confidence interval of 1.4-6.0 mL/m2), and a p-value of 0.002. This indicates that, on average, LA volume increased during the study period.

• Over the course of two years, the study observed modest phenotypic progression in the participants. There was a slight increase in left atrial (LA) volume, measuring 3.5 mL/m2 (with a 95% confidence interval of 1.4-6.0 mL/m2), and a p-value of 0.002. This indicates that, on average, LA volume increased during the study period.

• 26% of participants experienced an increase in left ventricular wall thickness (LVWT), a key marker of HCM. Among these individuals, 18% developed clinically overt HCM. This suggests that even in cases of subclinical HCM, there is a risk of progression to clinically evident disease.

• Participants who went on to develop HCM had higher baseline left atrial volume index (LAVI) and an average interventricular septum thickness compared to those who did not. Specifically, the baseline LAVI was 35 mL/m2 for those who developed HCM, compared to 28 mL/m2 in those who did not (p-value: 0.01). The average interventricular septum thickness was 8.5 mm in individuals who developed HCM, as opposed to 7.0 mm in those who did not (p-value: 0.009).

The VANISH trial provides valuable insights into the management of subclinical HCM. While valsartan did not prove effective in slowing disease progression, the study emphasizes the importance of closely monitoring individuals with sarcomere variants associated with HCM and the need for further research to enhance our understanding of the factors influencing disease development and progression. These findings underscore the complex nature of hypertrophic cardiomyopathy and highlight the ongoing efforts to develop effective therapeutic strategies for this condition.

Reference:

Vissing, C. R., Axelsson Raja, A., Day, S. M., Russell, M. W., Zahka, K., Lever, H. M., Pereira, A. C., Colan, S. D., Margossian, R., Murphy, A. M., Canter, C., Bach, R. G., Wheeler, M. T., Rossano, J. W., Owens, A. T., Benson, L., Mestroni, L., Taylor, M. R. G., Patel, A. R., … Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators. (2023). Cardiac remodeling in subclinical hypertrophic cardiomyopathy: The VANISH randomized clinical trial. JAMA Cardiology. https://doi.org/10.1001/jamacardio.2023.2808