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Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

SUBMITTER: Ho CY

PROVIDER: S-EPMC8666141 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Ho Carolyn Y CY Day Sharlene M SM Axelsson Anna A Russell Mark W MW Zahka Kenneth K Lever Harry M HM Pereira Alexandre C AC Colan Steven D SD Margossian Renee R Murphy Anne M AM Canter Charles C Bach Richard G RG Wheeler Matthew T MT Rossano Joseph W JW Owens Anjali T AT Bundgaard Henning H Benson Lee L Mestroni Luisa L Taylor Matthew R G MRG Patel Amit R AR Wilmot Ivan I Thrush Philip P Vargas Jose D JD Soslow Jonathan H JH Becker Jason R JR Seidman Christine E CE Lakdawala Neal K NK Cirino Allison L AL Burns Kristin M KM McMurray John J V JJV MacRae Calum A CA Solomon Scott D SD Orav E John EJ Braunwald Eugene E

Nature medicine 20210923 10

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution ...[more]

PMID: 34556856

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Project description:ImportanceValsartan 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.ObjectiveTo explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.Design, setting, and participantsThe 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.InterventionsTreatment 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 measuresThe 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).ResultsThis 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT01912534.

Project description:AimsEnd-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM.Methods and resultsA total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF) < 50% were defined as having ES-HCM, and a control group (LVEF ≥ 50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF ≥ 50%. The mean age of the patients at enrolment was 62.5 ± 10.3 years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF ≥ 50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P < 0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR] = 0.95, 95% CI [0.90, 1.00], P = 0.042), New York Heart Association (NYHA) class (OR = 7.73, 95% CI [2.93, 20.41], P < 0.001), heart rate (OR = 1.07, 95% CI [1.02, 1.12], P = 0.003), QRS duration (OR = 1.03, 95% CI [1.00, 1.05], P = 0.020), left ventricular end-diastolic diameter (LVEDD) (OR = 1.15, 95% CI [1.04, 1.28], P = 0.006), left atrial anteroposterior diameter (LAD) (OR = 1.13, 95% CI [1.03, 1.24], P = 0.012), and maximum left ventricular wall thickness (MLVWT) (OR = 0.80, 95% CI [0.68, 0.93], P = 0.005). Among the 50 patients with ES-HCM, NYHA class (P < 0.001) and heart rate (P = 0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses.ConclusionsThe influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM.

Dataset Information

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Publications

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

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