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.

Extended Data Fig. 1 |. Longitudinal changes in blood pressure.

Measures at baseline, Year 1, and Year 2 (end of study) for systolic (a) and diastolic (b) blood pressure are shown for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue). Values are presented as mean and standard deviation.

Extended Data Fig. 2 |. Longitudinal changes in serum creatinine and potassium levels.

Mean values and standard deviation are shown for serum creatinine (a) and potassium (b) levels for participants treated with valsartan (n = 88; red) and placebo (n = 90; blue).

Fig. 1 |

Participant enrollment, allocation and follow-up.

Fig. 2 |. Forest plots of pre-specified subgroups and secondary outcomes.

a, Mean difference in primary composite z-score between placebo- and valsartan-treated participants, along with 95% confidence interval, for pre-specified subgroups. b–e, Mean differences in z-score for the following key endpoint components: BSA-adjusted LV maximal wall thickness (b), age-adjusted tissue Doppler diastolic velocity (e′) (c), BSA-adjusted LV end diastolic volume (d) and log-transformed NTproBNP levels (e). CI, confidence interval.

Fig. 3 |. Longitudinal changes in key components of the primary composite outcome.

Values at baseline, year 1 and year 2 (end of study) for the valsartan (n = 88; red) and placebo (n = 90; blue) groups are presented as mean and standard error of the mean. a–d, Shown are data for BSA-adjusted z-score for maximal LV wall thickness (a), age-adjusted tissue Doppler diastolic velocity (E′) (b), BSA-indexed LV end diastolic volume, measured by CMR imaging performed only at baseline and year 2 (echo measures substituted for both time points if participants could not undergo either baseline or year 2 CMR imaging) (c) and log-transformed NTproBNP serum levels (d).