Andrew Morrow, Robin Young, George R Abraham, Stephen Hoole, John P Greenwood, Jayanth Ranjit Arnold, Mohamed El Shibly, Mayooran Shanmuganathan, Vanessa Ferreira, Roby Rakhit, Gavin Galasko, Aish Sinha, Divaka Perera, Rasha Al-Lamee, Ioakim Spyridopoulos, Ashish Kotecha, Gerald Clesham, Thomas J Ford, Anthony Davenport, Sandosh Padmanabhan, Lisa Jolly, Peter Kellman, Juan Carlos Kaski, Robin A Weir, Naveed Sattar, Julie Kennedy, Peter W Macfarlane, Paul Welsh, Alex McConnachie, Colin Berry
{"title":"齐博坦治疗微血管性心绞痛：一项随机、安慰剂对照、交叉试验","authors":"Andrew Morrow, Robin Young, George R Abraham, Stephen Hoole, John P Greenwood, Jayanth Ranjit Arnold, Mohamed El Shibly, Mayooran Shanmuganathan, Vanessa Ferreira, Roby Rakhit, Gavin Galasko, Aish Sinha, Divaka Perera, Rasha Al-Lamee, Ioakim Spyridopoulos, Ashish Kotecha, Gerald Clesham, Thomas J Ford, Anthony Davenport, Sandosh Padmanabhan, Lisa Jolly, Peter Kellman, Juan Carlos Kaski, Robin A Weir, Naveed Sattar, Julie Kennedy, Peter W Macfarlane, Paul Welsh, Alex McConnachie, Colin Berry","doi":"10.1161/CIRCULATIONAHA.124.069901","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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 <i>RS9349379</i> enhances expression of the endothelin-1 gene (<i>EDN1</i>) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral <i>ET-A</i> receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown.</p><p><strong>Methods: </strong>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 <i>RS9349379</i> 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.</p><p><strong>Results: </strong>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] <i>P</i>=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%; <i>P</i><0.001).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1671-1683"},"PeriodicalIF":35.5000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573082/pdf/","citationCount":"0","resultStr":"{\"title\":\"Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.\",\"authors\":\"Andrew Morrow, Robin Young, George R Abraham, Stephen Hoole, John P Greenwood, Jayanth Ranjit Arnold, Mohamed El Shibly, Mayooran Shanmuganathan, Vanessa Ferreira, Roby Rakhit, Gavin Galasko, Aish Sinha, Divaka Perera, Rasha Al-Lamee, Ioakim Spyridopoulos, Ashish Kotecha, Gerald Clesham, Thomas J Ford, Anthony Davenport, Sandosh Padmanabhan, Lisa Jolly, Peter Kellman, Juan Carlos Kaski, Robin A Weir, Naveed Sattar, Julie Kennedy, Peter W Macfarlane, Paul Welsh, Alex McConnachie, Colin Berry\",\"doi\":\"10.1161/CIRCULATIONAHA.124.069901\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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 <i>RS9349379</i> enhances expression of the endothelin-1 gene (<i>EDN1</i>) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral <i>ET-A</i> receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown.</p><p><strong>Methods: </strong>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 <i>RS9349379</i> 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.</p><p><strong>Results: </strong>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] <i>P</i>=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%; <i>P</i><0.001).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314.</p>\",\"PeriodicalId\":10331,\"journal\":{\"name\":\"Circulation\",\"volume\":\" \",\"pages\":\"1671-1683\"},\"PeriodicalIF\":35.5000,\"publicationDate\":\"2024-11-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573082/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCULATIONAHA.124.069901\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/1 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.124.069901","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.
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.
期刊介绍：
Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.
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