Effects of sacubitril/valsartan on hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial

Abstract

Diffuse interstitial fibrosis is associated with adverse outcomes in hypertensive heart disease and may be reversible. Sacubitril/valsartan could offer greater anti-fibrotic effects than valsartan alone. In the REVERSE-LVH phase 2 open-labelled trial (clinicaltrials.gov NCT: 03553810; funded by the National Medical Research Council of Singapore), 78 patients with essential hypertension and left ventricular hypertrophy (LVH) were randomized 1:1 to sacubitril/valsartan or valsartan for 52 weeks. Primary endpoint was a change in interstitial volume, assessed using cardiovascular magnetic resonance. Despite similar 24-hour systolic blood pressure at 52 weeks (125 ± 11 vs. 126 ± 11 mmHg; P = 0.762), sacubitril/valsartan resulted in a greater absolute reduction in interstitial volume compared to valsartan (-5.2 ± 5.4 vs. -2.5 ± 3.1 mL; P = 0.006). Secondary endpoints showed significant differences favoring sacubitril/valsartan in LV mass, left atrial volume, estimated LV filling pressure, and improved cardiac circulating biomarkers (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T). Other markers of cardiac volumes, function and mechanics were similar between the two treatment arms. Here we show the potential myocardial benefits of sacubitril/valsartan beyond blood pressure control, though larger studies are needed to confirm their clinical relevance.

Fig. 1. Participant recruitment, randomization and treatment.

A total of 78 participants were randomized in the trial. One patient in the sacubitril/valsartan group withdrew at week 4 due to concerns of medication side effects. One patient in the valsartan group withdrew at week 26 due to difficulties with trial commitment. This participant had final visit investigations (including cardiovascular magnetic resonance) performed at time of withdrawal, according to study protocol. Primary and secondary endpoints were analyzed as intention-to-treat.

Fig. 2. Effects of sacubitril/valsartan compared to valsartan on primary endpoint.

The primary endpoint in 78 participants. The effect estimates were presented in mean and 95% confidence intervals, with corresponding P values from one-way ANCOVA testing before and after adjustment for baseline covariates. ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker.

Fig. 3. Blood pressure control between sacubitril/valsartan and valsartan.

The mean blood pressure assessed at all timepoints during the trial were similar between the two treatment groups (n = 78). Data were presented in mean and 95% confidence interval; and P values from Student’s t test (two-sided) comparison.