The Design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Trial

Abstract

Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease.

Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype.

Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained.

Figure 1

Proposed model of how sarcomere mutations may lead to hypertrophic cardiomyopathy and the potential impact of angiotensin receptor blockade. Studies using mouse models of hypertrophic cardiomyopathy (HCM) have suggested that sarcomere mutations increase force generation and calcium sensitivity, and activate profibrotic pathways early in disease pathogenesis, before cardiac hypertrophy develops. These abnormalities activate numerous cellular pathways, including transforming growth factor-beta (TGF-β) signaling pathways, culminating in the development of myocardial fibrosis and hypertrophy. In mouse models of HCM, inhibiting TGF-β activation, using either neutralizing antibody or losartan, attenuated the development of left ventricular hypertrophy and fibrosis if given early in the prehypertrophic phase of disease (modified from Teekakirikul P, et al. JCI; 2010 (12)).

Figure 2

VANISH trial schema. This schematic illustrates the overall structure of the trial from patient selection to completion of 2 years of blinded therapy, followed by primary and secondary analyses.

Figure 3

Summary of the flow from enrollment to randomization in the VANISH Trial. Participants will undergo baseline studies and await rapid echocardiographic core laboratory evaluation to confirm eligibility and to determine whether they will be stratified to the primary or exploratory cohort (based on measurement of maximal left ventricular wall thickness, LV thickness to dimension ratio, and E′ velocity). Eligible participants will then enter into active run-in and undergo up titration of valsartan to target dose over the course of 2 to 6 weeks. Those who tolerate active run-in will undergo stratified randomization and begin 24-months of blinded treatment with study medication. Ineligible subjects will be followed in a registry.