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Lookup NU author(s): Professor Ioakim SpyridopoulosORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
BACKGROUND: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. METHODS: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. RESULTS: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95% CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). CONCLUSIONS: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314.
Author(s): Morrow A, Young R, Abraham GR, Hoole S, Greenwood JP, Arnold JR, El Shibly M, Shanmuganathan M, Ferreira V, Rakhit R, Galasko G, Sinha A, Perera D, Al-Lamee R, Spyridopoulos I, Kotecha A, Clesham G, Ford TJ, Davenport A, Padmanabhan S, Jolly L, Kellman P, Kaski JC, Weir RA, Sattar N, Kennedy J, Macfarlane PW, Welsh P, McConnachie A, Berry C
Publication type: Article
Publication status: Published
Journal: Circulation
Year: 2024
Volume: 150
Issue: 21
Pages: 1671-1683
Print publication date: 19/11/2024
Online publication date: 01/09/2024
Acceptance date: 10/07/2024
Date deposited: 10/12/2024
ISSN (electronic): 0009-7330
Publisher: American Heart Association
URL: https://doi.org/10.1161/CIRCULATIONAHA.124.069901
DOI: 10.1161/CIRCULATIONAHA.124.069901
PubMed id: 39217504
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