The endothelin system: a new target for resistant high blood pressure

Two different doses of the dual endothelin receptor antagonist aprocitentan were superior to placebo in lowering the systolic blood pressure (SBP) in patients with resistant hypertension, results from the PRECISION trial show.

The phase 3 PRECISION trial (NCT03541174) investigated the endothelin receptor antagonist aprocitentan as a treatment option for patients with resistant hypertension [1].

The study consisted of 3 parts and included 730 participants: a 4-week double-blind part with randomisation to either placebo or aprocitentan (12.5 mg or 25 mg), a consecutive single-blinded part of 32 weeks of 25 mg aprocitentan for all participants, and a withdrawal part with re-randomisation to either placebo or 25 mg of aprocitentan for 12 weeks. The study population had a mean age of 62 years, 60% men, over 60% of participants were treated with ≥4 baseline anti-hypertensives, about 20% of participants had heart failure and more than half had diabetes.

The primary endpoint was mean office SBP after 4 weeks of treatment (part 1) and the secondary endpoint was blood pressure (BP) change after the first 4 weeks of the withdrawal phase (part 3, week 40).

“With both doses of aprocitentan there was a clinically meaningful and significant BP reduction of around 15.3 mmHg, and this is significantly more pronounced than the effect with placebo [11.5 mmHg], thereby meeting the primary endpoint,” Prof. Markus P Schlaich (University of Western Australia, Perth) revealed, referring to a P-value of 0.0042 for 12.5 mg and a P-value of 0.0046 for 25 mg aprocitentan versus placebo [2]. Over part 2 of the trial (continuous aprocitentan for all participants), the lowered BP results were maintained at both doses. At week 4 of withdrawal (part 3), office SBP was again significantly reduced (delta 5.8 mmHg; P<0.0001) in the aprocitentan compared with the placebo arm. Hence, the key secondary endpoint was met. “Importantly, very similar results were seen for diastolic BP,” Prof Schlaich added. The ambulatory BP results were also significantly in favour of both aprocitentan doses.

“As expected, oedema or fluid retention was the most common adverse event, usually occurring in the first 4 weeks, and easily clinically managed with additional diuretic therapy,” Prof. Schlaich stated. This side effect led to treatment discontinuation in 7 participants. “Dual endothelin antagonism with aprocitentan may represent a new alternative pharmacological approach to treat resistant hypertension,” Prof Schlaich concluded.

1. 
   
   1. Schlaich MP. Sustained blood pressure lowering effect with the dual endothelin receptor antagonist aprocitentan in resistant hypertension: results from a randomized, controlled study including a withdrawal phase. LBS.09, AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.
   2. Schlaich MP, et al. Lancet. 2022;400(10367):1927-1937.

 

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Posted on 11 January 202313 June 2024