Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.

BACKGROUND

Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension.

METHODS

PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174.

FINDINGS

The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment.

INTERPRETATION

In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.

FUNDING

Idorsia Pharmaceuticals and Janssen Biotech.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests MPS has received institutional grants or contracts and personal consulting fees from Medtronic, Abbott Laboratories, and ReCor Medical; personal payment or honoraria from Medtronic, Abbott Laboratories, Merck, and Servier Laboratories; personal support for attending meetings, travel, or both from Medtronic and Abbott Laboratories; serves as the President of the High Blood Pressure Research Council of Australia; and is on the International Society of Hypertension scientific committee. MB is an employee of Idorsia Pharmaceuticals. MAW is has received consulting fees or performed research services for Janssen, Bristol Myers Squibb, CinCor, Medtronic, ReCor, and Ablative Solutions. PD and RFD are employees of Idorsia Pharmaceuticals and hold stock or stock options in Idorsia Pharmaceuticals. GLB has received consulting fees from Bayer, KBP BioSciences, Ionis Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Quantum Genomics, Novo Nordisk, Janssen, Dia Medica Therapeutics, and InREGEN. JMF has received consulting fees from Ardelyx, Janssen, Amgen, FibroGen, Teva Pharmaceuticals, and ReCor Medical; and payment for a lecture at a continuing medical education event from Janssen. MS-S is an employee of Idorsia Pharmaceuticals. LPH is an employee of Janssen and holds stock in Janssen. KN has received personal honoraria from Bausch Health, Berlin-Chemie (Menarini Group), Egis, Gedeon Richter, Krka, Medtronic, Merck, Novo Nordisk, Polpharma, Recordati, and Servier Laboratories; and has participated in an advisory board for Idorsia Pharmaceuticals. J-GW declares no competing interests.