Valsartan seems to attenuate hypertrophic cardiomyopathy progression

The phase 2 VANISH trial assessed whether valsartan could decelerate the disease course of hypertrophic cardiomyopathy (HCM). The positive results demonstrated a slower relative cardiac remodelling in those treated with the sartan.

“HCM is typically diagnosed by identifying unexplained left-ventricular (LV) hypertrophy and the prevalence in the general population is roughly 1 in 500,” Prof. Carolyn Ho (Brigham and Women’s Hospital, MA, USA) outlined. Prof. Ho stated that familial HCM is caused by known genetic variants in about 65% of cases [1]. Results of pre-clinical trials have pointed to TGF-β neutralisation antibodies or sartans as a possibility to prevent LV hypertrophy and fibrosis in HCM [2,3]. Thus, the VANISH trial (NCT01912534) investigated whether disease evolution could be reduced by valsartan treatment in early sarcomeric HCM [1,4].

The presented primary analysis cohort included 178 patients who all initially received valsartan in an active run-in period with up-titration to a dose of 320 mg in adults or 80 to 160 mg in children (depending on age and weight). Upon completion, the participants were randomised to further treatment with valsartan or placebo until the study ended after 2 years. All patients were aged between 8 and 45 years and had a (likely) sarcomeric variant with NYHA class I-II, a maximal LV wall thickness (LVWT) of 12–25 mm and no signs of obstruction. The mean age of the cohort was around 23 years with 43% of participants under the age of 18 and 39% women. Baseline maximal LVWT ranged between 8.1 and 8.2 (z-score) or 16.4 and 17.9 mm in the placebo and valsartan group, respectively.

“In developing the primary endpoint, we carefully considered the challenges we would face in demonstrating a treatment response. Mainly, we recognised that the magnitude of the impact of valsartan was unknown, our participants were healthy and asymptomatic at enrolment and, therefore, clinical events would be extremely rare,” Prof. Ho stated. She further explained that the researchers for this reason strove to interrogate disease biology rather than traditional clinical outcomes by identifying moderate effects in 9 different cardiac metrics. These consisted of markers for myocardial injury and stress, morphology, and function. The effect size was then defined as change in composite z-score at 2 years compared with baseline.

The results showed a positive trial with a between-group difference of 0.231 (P=0.001), which stood for a relative amelioration in cardiac remodelling. “In the individual components, improvement was most marked for NT-ProBNP level, LV end-diastolic volume and e’ velocity, each individually significant after adjusting for covariates,” said Prof. Ho. Within the analysis of pre-specified subgroups, valsartan led to all in all consistent effects, with the most pronounced benefit in subjects with LVWT less than the median z-score of 7.3. However, treatment with valsartan did not result in significant amelioration of left atrial volume index or LV mass index.

Prof. Ho stressed that treatment with valsartan was safe with no excess of adverse events, no instances of hypotension, hyperkalaemia, or renal insufficiency. “The VANISH trial suggested that there is an opportunity to attenuate disease progression in sarcomeric HCM with a widely available and well-tolerated medication,” she concluded.

1. 
   
   1. Ho CY. VANISH Trial Results. Late-Breaking Science in Heart Failure, ESC Congress 2021, 27–30 August.
   2. Teekakirikul P, et al. J Clin Invest. 2010;120(10):3520–9.
   3. Raja AA, et al. Circ Heart Fail. 2019;12(12):e006231.
   4. Ho CY, et al. Nat Med 2021;Sept 23. DOI:10.1038/s41591-021-01505-4.

 

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Posted on 26 October 2021