顽固性高血压与心血管风险增加有关。内皮素通路与高血压的发病机制有关，但目前还没有靶向治疗，因此目前可用的药物未对这一相关病理生理通路进行对抗。这项研究的目的是评估双重内皮素拮抗剂阿普罗伊坦对难治性高血压患者的降压效果。

PRECISION研究于2018年6月18日至2022年4月25日进行。1965人被筛选，730人被随机分配。4周时办公室收缩压的最小二乘平均值(SE)变化为:阿普罗伊坦12.5 mg组- 15.3 (SE 0.9) mm Hg，阿普罗伊坦25mg组- 15.2 (0.9)mm Hg，安慰剂组- 11.5 (0.9)mm Hg，与安慰剂组的差异为- 8 (1.3)mm Hg (97.5% CI - 6.8至- 0.8,p= 0.0042)和- 7 (1.3)mm Hg(- 6.7至- 0.8;分别p = 0·0046)。24小时动态收缩压的差异分别为- 4.2 mm Hg (95% CI为- 6.2 ~ - 2.1)和- 5.9 mm Hg(- 7.9 ~ - 3.8)。停药4周后，安慰剂组办公室收缩压明显高于阿普罗伊坦组(5.8 mm Hg, 95% CI 3.7 ~ 7.9, p＜0.0001)。

最常见的不良事件是轻度至中度水肿或液体潴留，在4周双盲部分中，接受阿普罗伊坦12·5 mg、25 mg和安慰剂的患者分别发生9%、18%和2%。这一事件导致7例接受阿普罗伊坦治疗的患者停药。在试验期间，共发生了11例因治疗引起的死亡，研究人员认为没有一例与研究治疗有关。

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.

文章连接：

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

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