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

Markus 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, Christopher Reid, Markus Schlaich, Ivor Katz, Andrew Ajani, Sinjini Biswas, Murray Esler, Grahame Elder, Simon Roger, David ColquhounJohn Mooney, Tine De Backer, Alexandre Persu, Martin Chaumont, Jean-Marie Krzesinski, Thomas Vanabsche, Ginette Girard, Lew Pliamm, Ernesto Schiffrin, Fatima Merali, George Dresser, Michel Vallee, Shivinder Jolly, Stephen Chow, Jiguang Wang, Jianjun Mu, Jing Yu, Hong Yuan, Yingqing Feng, Xin Zhang, Jianhong Xie, Ling Lin, Miroslav Soucek, Jiri Widimsky, Renata Cifkova, Jan Vaclavik, Martin Ullrych, Mary MacLeod, James McLay, David Calhoun, PRECISION investigators

Research output: Contribution to journalArticlepeer-review

Abstract

Summary 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
Original languageEnglish
Pages (from-to)1927-1937
Number of pages11
JournalThe Lancet
Volume400
Issue number10367
Early online date1 Dec 2022
DOIs
Publication statusPublished - 9 Dec 2022

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