当前位置:科学网首页 > 小柯机器人 >详情
双内皮素拮抗剂Aprocitentan治疗顽固性高血压耐受良好、持续有效
作者:小柯机器人 发布时间:2022/11/15 20:41:47

西澳大利亚大学Markus P Schlaich团队研究了双内皮素拮抗剂aprocitentan治疗顽固性高血压的疗效与安全性。这一研究成果发表在2022年11月7日出版的《柳叶刀》杂志上。

顽固性高血压与心血管风险增加有关。内皮素途径与高血压发病机制有关,但目前还没有靶向治疗,因此这一相关的病理生理途径与目前可用的药物没有拮抗作用。该研究旨在评估双内皮素拮抗剂Aprocitentan对顽固性高血压患者的降压效果。

研究组在欧洲、北美、亚洲和澳大利亚的医院或研究中心进行了一项多中心、双盲、随机、平行组、临床3期研究,招募尽管接受了由三种降压药物(包括利尿剂)组成的标准化背景治疗,但坐姿收缩压仍为140 mm Hg或更高的患者。

该研究由三个顺序部分组成:第1部分是为期4周的双盲、随机和安慰剂对照部分,其中患者以1:1:1的比例接受aprocitentan 12.5 mg、aprocitentan 25 mg或安慰剂;第2部分是32周的单盲部分,所有患者均接受25 mg aprocitentan;第3部分是为期12周的双盲、随机、安慰剂对照的停药部分,其中患者按1:1的比例重新随机接受25 mg aprocitentan或安慰剂。主要和关键次要终点分别是从基线到第4周和从戒断基线到第40周的无人值守办公室收缩压变化。次要终点包括24小时动态血压变化。

该研究于2018年6月18日至2022年4月25日进行。共筛选了1965人,随机分配730人。在这730名患者中,704人(96%)完成了研究的第1部分;613人(87%)完成了第2部分,577人(94%)完成第3部分。4周时办公室收缩压的最小二乘平均值(SE)变化为:Aprocitentan 12.5 mg组降低15.3 mm Hg,aprocitentan 25 mg降低15.2 mm Hg,安慰剂组降低11.5 mm Hg,Aprocitentan组与安慰剂相比,差异分别为-3.8 mm Hg与-3.7 mm Hg,组间差异显著。

24小时动态收缩压的差异分别为-4.2 mm Hg和-5.9 mm Hg。停药4周后,安慰剂组的办公室收缩压显著升高(5.8 mm Hg)。最常见的不良事件是轻度至中度水肿或液体潴留,在4周的双盲部分中,接受aprocitentan 12.5 mg、25 mg和安慰剂治疗的患者分别发生9%、18%和2%。这一事件导致7名接受aprocitentan治疗的患者停药。在试验期间,共有11例患者治疗中死亡,研究人员认为这些死亡均与研究治疗无关。

研究结果表明,在顽固性高血压患者中,aprocitentan耐受性良好,在第4周降压方面优于安慰剂,在第40周持续有效。

附:英文原文

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

Author: 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, Christopher Reid, Markus Schlaich, Ivor Katz, Andrew Ajani, Sinjini Biswas, Murray Esler, Grahame Elder, Simon Roger, David Colquhoun, John 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, Martin Lukac, Ivan Rychlik, Thomas Guldager Lauridsen, Ilkka Kantola, Jyrki Taurio, Olavi Ukkola, Olivier Ormezzano, Philippe Gosse, Michel Azizi, Pierre-Yves Courand, Pascal Delsart, Jean Michel Tartiere, Felix Mahfoud, Roland Schmieder, Johannes Stegbauer, Philipp Lurz, Michael Koziolek, Christian Ott, Nicole Toursarkissian, Konstantinos Tsioufis, Konstantinos Kyfnidis, Athanasios Manolis, Sotirios Patsilinakos, Pantelis Zebekakis, Apostolos Karavidas, Pall Denes, Katalin Bezzegh, Marianna Zsom, Laszlo Kovacs, Yehonatan Sharabi, Mazen Elias, Ivetta Sukholutsky, Chaim Yosefy, Irina Kenis, Shaul Atar, Massimo Volpe, Muiesan Maria Lorenza, Stefano Taddei, Guido Grassi, Franco Veglio, Jung Woo Son, Jang-Young Kim, Joong-Il Park, Chang Hoon Lee, Hae-Young Lee, Rasa Raugaliene, Jolanta Elena Marcinkeviciene, Roma Kavaliauskiene, Jaap Deinum, Abraham Kroon, Bert-Jan van den Born, Andrzej Januszewicz, Andrzej Tykarski, Jolanta Walczewska, Zbigniew Gaciong, Andrzej Wiecek, Marzena Chrostowska, Andrzej Kleinrok, Jan Krekora, Grzegorz Kania, Anna Podrazka-Szczepaniak, Cezary Golawski, Maciej Podziewski, Barbara Kaczmarek, Grzegorz Skoczylas, Andrzej Wilkolaski, Iwona Wozniak, Marzena Janik-Palazzolo, Barbara Rewerska, Alexandra Konradi, Yuriy Shvarts, Tamara Pecherina, Konstantin Nikolaev, Gapon Liudmila, Olga Orlikova, Viktor Mordovin, Natalia Petrochenkova, Gadel Kamalov, Elena Kosmacheva, Konstantin Nikolaev, Vadim Tyrenko, Vladimir Gorbunov, Andrey Obrezan, Tatiana Supryadkina, Irina Ler, Oleg Kotenko, Anatoly Kuzin, Fernando Martinez, Josep Redon, Anna Oliveras

Issue&Volume: 2022-11-07

Abstract:

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.

DOI: 10.1016/S0140-6736(22)02034-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02034-7/fulltext

期刊信息

LANCET:《柳叶刀》,创刊于1823年。隶属于爱思唯尔出版社,最新IF:59.102
官方网址:http://www.thelancet.com/
投稿链接:http://ees.elsevier.com/thelancet