Endothelin Receptor Antagonists for the Treatment of Hypertension: Recent Data from Clinical Trials and Implementation Approach

Abstract

Purpose of review: The endothelin system is a highly relevant component of the pathophysiology of hypertension, which is currently unopposed by existing treatment approaches. We examined the role of dual endothelin receptor antagonists in the treatment of resistant hypertension.

Recent findings: The recent PRECISION trial demonstrated significant blood pressure lowering effect with the use of the dual endothelin receptor antagonist aprocitentan in the treatment of resistant hypertension. Aprocitentan was shown to be particularly effective in patients over 75 years of age, African-American patients, and patients with diabetes and advanced CKD. There was also a decrease in proteinuria. Aprocitentan was well tolerated and the risk of fluid retention can be mitigated by close clinical monitoring and titration of diuretic therapy. Aprocitentan presents a novel treatment option for resistant hypertension, with particular efficacy noted in patient cohorts who have historically been challenging to achieve blood pressure targets in.

Keywords: Aprocitentan; Blood pressure; Endothelin receptor antagonist; Endothelin-1; Hypertension; Pharmacotherapy.

Fig. 1

Effects on 24-h ambulatory BP. Changes in ambulatory BP in response to placebo (blue), aprocitentan 12.5 mg (yellow), and aprocitentan 25 mg (red lines and bars) after the 4-week double blind phase (Part 1) and after double-blind withdrawal (Part 3). 24-h profiles (upper panels) demonstrate BP reduction with both doses of aprocitentan compared to placebo across the 24-h period. Absolute BP changes depicted in the lower panels demonstrate a significant dose dependent effect, most pronounced during night-time (lower left panel). After re-randomization to placebo or continued aprocitentan 25 mg BP rose significantly in those receiving placebo, whereas BP was unchanged in those maintained on aprocitentan 25 mg (lower right panel). (Reprinted from: Schlaich MP, et al. Lancet 2022;400:1927–37, with permission from Elsevier) [48]

Fig. 2

Subgroup analysis and effects on urinary albumin excretion (UACR). Subgroup analysis revealed that aprocitentan at each dose seems particularly effective in patients above the age of 75 years, those with UACR > 300 mg/g, and in patients with an eGFR of < 60 ml/min/1.73 m.² (Forrest plot left panel). The impact on UACR is summarized in the right panel demonstrating significant and clinically meaningful reduction in UACR with both doses after the double-blind phase. In the single-blind phase the 30% reduction in UACR was maintained. After re-randomization UACR rose in those on placebo, but remined unchanged in those on continued aprocitentan 25 mg. (Reprinted from: Schlaich MP, et al. Lancet 2022;400:1927–37, with permission from Elsevier) [48]