Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial
- Type de publi. : Article dans une revue
- Date de publi. : 07/11/2022
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Auteurs :
Markus SchlaichMarc BelletBarthelemy von HallerParisa DanaietashGeorge BakrisJohn FlackRoland DreierMouna Sassi-SayadiLloyd HaskellKrzysztof NarkiewiczJi-Guang WangChristopher ReidMarkus SchlaichIvor KatzAndrew AjaniSinjini BiswasMurray EslerGrahame ElderSimon RogerDavid ColquhounJohn MooneyTine de BackerAlexandre PersuMartin ChaumontJean-Marie KrzesinskiThomas VanabscheGinette GirardLew PliammErnesto SchiffrinFatima MeraliGeorge DresserMichel ValleeShivinder JollyStephen ChowJiguang WangJianjun MuJing YuHong YuanYingqing FengXin ZhangJianhong XieLing LinMiroslav SoucekJiri WidimskyRenata CifkovaJan VaclavikMartin UllrychMartin LukacIvan RychlikThomas Guldager LauridsenIlkka KantolaJyrki TaurioOlavi UkkolaOlivier OrmezzanoPhilippe GosseMichel AziziPierre-Yves CourandPascal DelsartJean Michel TartiereFelix MahfoudRoland SchmiederJohannes StegbauerPhilipp LurzMichael KoziolekChristian OttNicole ToursarkissianKonstantinos TsioufisKonstantinos KyfnidisAthanasios ManolisSotirios PatsilinakosPantelis ZebekakisApostolos KaravidasPall DenesKatalin BezzeghMarianna ZsomLaszlo KovacsYehonatan SharabiMazen EliasIvetta SukholutskyChaim YosefyIrina KenisShaul AtarMassimo VolpeMuiesan Maria LorenzaStefano TaddeiGuido GrassiFranco VeglioJung Woo SonJang-Young KimJoong-Il ParkChang Hoon LeeHae-Young LeeRasa RaugalieneJolanta Elena MarcinkevicieneRoma KavaliauskieneJaap DeinumAbraham KroonBert-Jan van den BornAndrzej JanuszewiczAndrzej TykarskiJolanta WalczewskaZbigniew GaciongAndrzej WiecekMarzena ChrostowskaAndrzej KleinrokJan KrekoraGrzegorz KaniaAnna Podrazka-SzczepaniakCezary GolawskiMaciej PodziewskiBarbara KaczmarekGrzegorz SkoczylasAndrzej WilkolaskiIwona WozniakMarzena Janik-PalazzoloBarbara RewerskaAlexandra KonradiYuriy ShvartsTamara PecherinaKonstantin NikolaevGapon LiudmilaOlga OrlikovaViktor MordovinNatalia PetrochenkovaGadel KamalovElena KosmachevaKonstantin NikolaevVadim TyrenkoVladimir GorbunovAndrey ObrezanTatiana SupryadkinaIrina LerOleg KotenkoAnatoly KuzinFernando MartinezJosep RedonAnna OliverasLuis Beltran RomeroValerii ShatyloLeonid RudenkoAndriiy BazylevychYurii RudykOleksandr KarpenkoMykola StanislavchukVira TseluykoMykola KushnirErvin AsanovYuriy SirenkoAndriy YagenskyDavid CollierPankaj GuptaDavid WebbMary MacleodJames MclayAaron PeaceSamir AroraPatricia BuchananRobert HarrisRonald DegarmoMario GuillenAdam KarnsJoel NeutelYogesh PaliwalKarlton PettisPhillip TothJeffrey WayneBain ButcherPhillip DillerSuzanne OparilDavid CalhounDonald BrautigamJohn FlackJesse GoldmanArash RashidiNabeel AslamWilliam HaleyNabil AndrawisBrian LangRandy MillerJames PowellRobert DewhurstJames PritchardDinesh KhannaDennis TangNashwa GabraJean ParkConigliaro JonesCranford ScottBlanca LunaMurtaza MussajiRavi BhagwatMichael BauerJohn McgintyRajesh NambiarRenee SangrigoliWilliam Ross DavisWilliam EavesFrank McgrewAhmed AwadEric BolsterDavid ScottParamjit KaliraoPascal DabelWesley CalhounSteven GougeMark WarrenMary Katherine LawrenceAamir JamalMohamed El-ShahawyCarlos MercadoJayant KumarPedro Velasquez-MieyerRobert BuschTodd LewisLisa Rich
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Organismes :
The University of Western Australia
Baker Heart and Diabetes Institute
State University of New York
University of Chicago
Biozentrum [Basel, Suisse]
Medical University of Gdańsk
Ruijin Hospital [Shanghai, Chine]
University of Melbourne
The University of Western Australia
Baker Heart and Diabetes Institute
Human Neurotransmitter Laboratory
Imagerie Ultrasonore
- Publié dans The Lancet le 02/11/2020
Résumé : 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.
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