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Randomized Controlled Trial
. 2023 Nov 1;8(11):1083-1088.
doi: 10.1001/jamacardio.2023.2808.

Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial

Christoffer Rasmus Vissing  1   2 , Anna Axelsson Raja  1 , Sharlene M Day  3 , Mark W Russell  4 , Kenneth Zahka  5 , Harry M Lever  5 , Alexandre C Pereira  6 , Steven D Colan  7 , Renee Margossian  7 , Anne M Murphy  8 , Charles Canter  9 , Richard G Bach  9 , Matthew T Wheeler  10 , Joseph W Rossano  11 , Anjali T Owens  3 , Lee Benson  12 , Luisa Mestroni  13 , Matthew R G Taylor  13 , Amit R Patel  14 , Ivan Wilmot  15 , Philip Thrush  16 , Jonathan H Soslow  17 , Jason R Becker  18 , Christine E Seidman  2   19 , Neal K Lakdawala  2 , Allison L Cirino  2 , John J V McMurray  20 , Calum A MacRae  2 , Scott D Solomon  2 , Henning Bundgaard  1 , E John Orav  2 , Carolyn Y Ho  2 ; Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial

Christoffer Rasmus Vissing et al. JAMA Cardiol. .

Abstract

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.

Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.

Design, setting, and participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.

Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years).

Main outcomes and measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).

Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM.

Conclusions and relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.

Trial registration: ClinicalTrials.gov Identifier: NCT01912534.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Day reported receiving grants from Lexicon Pharmaceuticals, personal fees from Lexicon Pharmaceuticals and Cytokinetics, and consulting fees from Bristol Myers Squibb (BMS) outside the submitted work. Dr Colan reported receiving consulting fees from Autus Valve Technologies Inc, Clementia Pharmaceuticals, and Rocket Pharmaceuticals Inc outside the submitted work. Dr Bach reported receiving grants from BMS/MyoKardia and Cytokinetics (paid to Washington University School of Medicine) outside the submitted work. Dr Wheeler reported receiving research funding from BMS, Pfizer, Cytokinetics, and SalubrisBio during the conduct of the study and consulting fees from Leal Therapeutics outside the submitted work. Dr Rossano reported receiving consulting fees from BMS, Merck, Bayer, American Regent Inc, CRI Biotech, and BioMarin outside the submitted work. Dr Owens reported receiving grants from BMS and consulting fees from BMS, Cytokinetics, Tenaya, Pfizer, Renovacor, Lexicon, Edgewise, Stealth, and BioMarin outside the submitted work. Dr Mestroni reported receiving grants from the US National Institutes of Health (NIH) outside the submitted work. Dr Patel reported receiving payment from the NIH for VANISH subject recruitment during the conduct of the study. Dr Soslow reported receiving consulting fees from Sarepta and PepGen outside the submitted work. Dr Seidman reported receiving a salary from Howard Hughes Medical Institute and grants from the NIH during the conduct of the study as well as personal fees from Merck and MyoKardia outside the submitted work. Dr Lakdawala reported receiving research funding from Pfizer and consulting fees from BMS, Tenaya, Cytokinetics, Sarepta, and Pfizer outside the submitted work. Dr McMurray reported receiving funding (through University of Glasgow) for work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline (GSK), KBP Biosciences, and Novartis. Dr McMurray also reported receiving consulting fees from Alnylam Pharmaceuticals, Bayer, BMS, George Clinical Pty Ltd, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corporation outside the submitted work. Dr McMurray also reported receiving lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of Continued Medical Education, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy outside the submitted work. Dr McMurray reported serving as a director of Global Clinical Trial Partners Ltd. Dr MacRae reported receiving grants from the NIH during the conduct of the study. Dr Solomon reported receiving grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi-Pasteur, Theracos, and US2.AI. Dr Solomon also reported receiving grants (paid to Brigham and Women’s Hospital) and consulting fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Dr Bundgaard reported receiving lecture fees from MSD, Pfizer, BMS, and Sanofi. Dr Ho reported receiving research funding and consulting fees from BMS, Pfizer, Cytokinetics, Tenaya, and BioMarin outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
CMR indicates cardiovascular magnetic resonance.
Figure 2.
Figure 2.. Primary and Secondary Trial Outcomes
Between-group difference in primary and secondary trial outcomes between the placebo- and valsartan-treated participants in the exploratory cohort. Results are from multivariable modeling. Squares denote the point estimate of the effect, and error bars denote the 95% CIs. Adjusted mean changes (Δ) for the 2 treatment groups are provided with upper and lower 95% confidence limits. Positive values indicate improvement. LAVI indicates left atrial volume index; LV, left ventricular; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; and TnT, troponin T.
See this image and copyright information in PMC

References

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