ARB in early-stage hypertrophic cardiomyopathy improves primary outcome

31/10/2021

Treatment with valsartan reduced the primary outcome, a composite z-score of 9 individual metrics of cardiac structure/function and remodeling, compared to placebo in individuals with early-stage HCM.

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial
Literature - Ho CY, Day SM, Axelsson A et al., - Nat Med 2021, 27:1818-1824, doi: 10.1038/s41591-021-01505-4

Introduction and methods

Aim of the study

Hypertrophic cardiomyopathy (HCM), a primary heart muscle disorder, is often caused by pathogenic variants in genes encoding the sarcomere [1]. It is characterized by left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of heart failure, arrhythmias and sudden cardiac death [2]. There is an unmet need of therapies for HCM to slow progression or preventing this disease. Mouse and human studies have not showed substantial benefit using an ARB in well-established HCM, but this drug has not been tested in early HCM.

Study design

The Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial, a multi-center, double-blind, placebo-controlled phase 2 trial, examined the efficacy and safety of the ARB valsartan in patients with early-stage HCM (young age and absence of severe LVH or limiting symptoms) [3,4]. A total of 178 participants were randomized to valsartan or placebo. Mean age was 23.3 (10.1) years.

Primary outcome

Nine individual metrics were standardized and integrated into a composite z-score that assessed the change from baseline to year 2: body surface area (BSA)-indexed LV mass and BSA-indexed left atrial (LA) volume, BSA-indexed LV end diastolic and end systolic volumes determined by cardiac magnetic resonance imaging core laboratory, BSA-adjusted maximal LV wall thickness, age-adjusted Doppler diastolic (E’) and systolic (S’) velocities determined by the echocardiographic core laboratory and log-transformed serum high-sensitivity cardiac troponin T (TnT) and NTproBNP levels. An increase in the composite z-score indicates a greater than average improvement.

Main results

  • The change in the composite z-score from baseline to year 2 with valsartan was 0.136 (95%CI:0.049 to 0.223) compared to -0.095 (95%CI:-0.192 to 0.002) with placebo (between-group difference was 0.231 (9%CI:0.098 to 0.364, P=0.001).
  • The largest contributors to the improvement in the composite outcome by valsartan were E’ velocity, LV end diastolic volume and NTproBNP level.
  • Benefit of valsartan was most striking in patients with less hypertrophic remodeling. In those with baseline maximal LV wall thickness lower than or equal to the median of the cohort the between-group difference in the z-score was 0.368 (95%CI:0.169 to 0.567) vs. 0.069 (95%CI: -0.115 to 0.249) in those with baseline LV wall thickness greater than the median.
  • Maximal LV wall thickness, E’ velocity and NTproBNP remained stable or improved in the valsartan group but worsened in the placebo group. LV end diastolic volume improved in the valsartan group and was stable in the placebo group.
  • Safety and tolerability of valsartan were similar to placebo. Incidence and severity of adverse events were similar in the treatment arms.

Conclusion

The VANISH trial showed that treatment of valsartan early in the course of HCM improved the composite outcome, an integration of nine measures of cardiac structure, function and remodeling, compared to placebo. Valsartan treatment in patients with early-stage sarcomeric HCM was safe and well-tolerated with no increase in adverse events.

References

1. Seidman, C. E. & Seidman, J. G. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ. Res. 108, 743–750 (2011).

2. Writing Committee M. et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 142, e558–e631 (2020).

3. Ho, C. Y. et al. The design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial. Am. Heart J. 187, 145–155 (2017).

4. Axelsson Raja, A. et al. Baseline characteristics of the VANISH cohort. Circ. Heart Fail. 12, e006231 (2019).

Find this article online at Nat Med

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