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

PRECISION investigators, Markus P Schlaich, Marc Bellet, Michael A Weber, Parisa Danaietash, George L Bakris, John M Flack, Roland F Dreier, Mouna Sassi-sayadi, Lloyd P Haskell, Krzysztof Narkiewicz, Ji-guang Wang, David Webb

Research output: Contribution to journalArticlepeer-review


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, poedema 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.
Original languageEnglish
Pages (from-to)1927-1937
JournalThe Lancet
Issue number10367
Publication statusPublished - 3 Dec 2022


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