VANISHing the progression of cardiac abnormalities in hypertrophic cardiomyopathy with early use of valsartan?

Key Points The VANISH trial1 was a multi-centre (17 sites in four countries), double-blind, placebo-controlled phase-2 trial that analysed the effects of the angiotensin II receptor blocker (ARB), valsartan, in subjects with early-stage hypertrophic cardiomyopathy (HCM). From April 2014 to May 2017, 178 patients affected by HCM were randomized to receive valsartan titrated to 320 mg (after an active run-in period) or placebo for 2 years. They were required to have a pathogenic (or likely pathogenic) sarcomeric variant and non-obstructive physiology. The mean age was 23.3 ± 10.1 years, and 39% of participants were female. Over 90% were in New York Heart Association (NYHA) functional Class I and the remaining in NYHA II. A small proportion of participants were taking beta-blockers or calcium channel blockers; none received mineralocorticoid receptor antagonists. The groups were balanced with respect to baseline characteristics, with the valsartan group having slightly greater maximal left ventricular (LV) wall thickness and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels. The primary end point of the study was a composite z-score of nine variables (some of which were body surface area or age adjusted): LV mass and left atrial (LA) volume (decrease considered improvement); LV end diastolic and end systolic volumes (increase considered improvement); maximal LV wall thickness (decrease considered improvement); tissue Doppler diastolic (E′) and systolic (S′) velocities (increase considered improvement); and serum levels of high-sensitivity troponin T and NTproBNP levels (decrease considered improvement). For each patient, the nine individual z-scores for change in each metric from baseline to end of study at Year 2 were averaged to produce the composite z-score. An increase (positive change) in the composite z-score from baseline to the end of Year 2 indicated improvement. One hundred fifty-two participants completed the study on target dose with an average adherence of ∼86% in both arms. The adjusted mean change at 2 years was 0.136 in the valsartan group vs −0.095 with placebo [between-group difference, 0.231; 95% confidence interval (CI), 0.098–0.364; P = 0.001]. Of the individual components of the z-score, maximal LV wall thickness, E′ velocity and NTproBNP levels remained stable or improved in the valsartan group but worsened progressively in the placebo group; LV end diastolic volume improved in the valsartan group while remaining stable in the placebo group. The results were not influenced by age, gender, or gene mutation. However, the benefit of valsartan appeared greater in participants with less hypertrophic remodelling. Safety and tolerability of valsartan were comparable to placebo. Comment on ‘Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial’ published in the Nature Medicine (https://doi.org/10.1038/s41591-021-01505-4). The prognosis of HCM is much improved in the last two decades as a consequence of the remarkable improvements in the knowledge of the disease mechanisms and of the progress in the contemporary management.2 For HCM patients at risk for or with disease-related complications several non-pharmacological management options have been developed over the last years, with a significant impact on natural history and disease course.3 These strategies include implantable cardiac defibrillators for the prevention of sudden death; myectomy/alcohol septal ablation for relief of LV outflow tract (LVOT) outflow tract obstruction; transplant for the HCM end-stage phase; and anticoagulant and atrial fibrillation ablation for the prevention of stroke.3 However, these treatment options target only HCM cardiac structural abnormalities and not abnormal cellular processes such as inefficient utilization of adenosine triphosphate, sarcomere hypercontractility, microvascular ischaemia, and fibrosis. Among the available pharmacological studies in HCM (often non-randomized and with insufficient follow-up),4 the most recent EXPLORER HCM and VANISH trials have finally provided interesting results. The former was the first study to investigate an HCM-specific treatment with the demonstration that mavacamten, a first-in-class, selective allosteric inhibitor of cardiac myosin ATPase, reduces myocardial contractility and ameliorates myocardial energetics, improved symptoms, exercise capacity, and LVOT obstruction in patients with obstructive HCM.5,6 The VANISH trial, instead, had the ambitious goal of addressing fibrosis and disease progression in HCM, on the basis of previous studies supporting beneficial effects of ARBs on an increase in LV hypertrophy and entity of fibrosis.7–9 In particular, studies in mouse models of HCM indicated that activation of transforming growth factor-beta (TGF-β) is centrally involved in triggering the development of myocardial hypertrophy and fibrosis. ARBs can inhibit TGF-β activation, and administration of the ARB losartan to HCM mice prevented the development of LVH and fibrosis if administered early in life, when cardiac morphology was still normal.1 The results of the VANISH study are interesting since they show that among asymptomatic young individuals with pathogenic sarcomeric gene mutations, participants randomized to valsartan showed more favourable overall cardiac structure adaptations at 2 years compared with those treated with placebo. The authors adopted a study design based on the effects of valsartan on a multi-parametric index represented by nine markers of cardiac structure and function. This choice was dictated by the characteristics of the study population composed of asymptomatic patients with a baseline low-risk profile. Despite not being powered to assess the effects on morbidity/mortality endpoints, this study raises the possibility of slowing down disease progression in sarcomeric HCM with a widely available, inexpensive, and well-tolerated medication. Moreover, participants with a baseline LV wall thickness below the median were those who experienced the largest benefit, supporting the hypothesis that valsartan may act as a disease-modifying therapy, especially if given when LV hypertrophy is less pronounced. As noted by the authors, baseline groups characteristics were not entirely balanced at baseline (maximal LV wall thickness and NTproBNP levels were lower in the placebo group). Therefore, it cannot be excluded that the favourable effect of valsartan on these measures might have been partly driven by regression to the mean in the placebo group. Moreover, the relationship between the composite z-score and long-term clinical outcomes has not yet been established.1 Since valsartan targets TGF-β and fibrosis is one of the main alterations in HCM, it would have been interesting to provide data about serum biomarker levels reflecting myocardial remodelling and microfibrosis, and information about late gadolinium enhancement (LGE) modifications after two years, though this time-span might not be sufficient to explore LGE changes. Another aspect that deserves further investigation is a proper characterization of the dose-response for the observed benefit and the optimal timing of valsartan administration. In conclusion, the VANISH trial provides preliminary evidence for the efficacy and safety of a novel therapeutic approach to HCM and may open a field of investigation for therapeutic preventive strategies in early stages of sarcomeric HCM. However, the favourable effects of valsartan on the progression of cardiac adaptations in HCM seen in this study would be reinforced by longer studies providing more informative imaging approaches (e.g. cardiac magnetic resonance) and clinical data (e.g. symptoms, exercise capacity and arrhythmias). Conflict of interest: M.V. reports personal fees for speaker bureau and/or consulting in Advisory Board from Amgen, Astra Zeneca, Daiichi-Sankyo, Menarini Int, MSD, Novartis Pharma, and Novo Nordisk, outside the submitted work. G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network.