British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom (A.M., N.S., P.W.M., P.W., C.B.).
Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, United Kingdom (R.Y., A.M.).
Circulation. 2024 Nov 19;150(21):1671-1683. doi: 10.1161/CIRCULATIONAHA.124.069901. Epub 2024 Sep 1.
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 enhances expression of the endothelin-1 gene () in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown.
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 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.
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] =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%; <0.001).
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.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314.
微血管性心绞痛与内皮素系统失调以及心肌血流、运动能力和健康相关生活质量受损有关。非编码单核苷酸多态性的 G 等位基因增强了内皮素-1 基因（）在人类血管细胞中的表达，可能会增加循环内皮素-1（ET-1）的浓度。口服内皮素 A 受体选择性拮抗剂西他生坦治疗微血管性心绞痛是否有效和安全尚不清楚。
本研究纳入了微血管性心绞痛患者，他们参加了这项西他生坦（每日 10mg，持续 12 周）的双盲、安慰剂对照、序贯交叉试验。该试验人群经过富集，以确保单核苷酸多态性的 G 等位基因频率为 50%。参与者和研究者对基因型均不知情。主要结局指标是布鲁斯方案下的跑步机运动持续时间（秒）。主要分析估计了西他生坦治疗与安慰剂治疗后运动持续时间的患者内平均差异。
共有 118 名参与者（平均年龄 63.5 [9.2]岁；71 名[60.2%]女性；25 名[21.2%]患有糖尿病）被随机分组。在 103 名完成数据的参与者中，与安慰剂相比，西他生坦治疗的运动持续时间无差异（治疗间差异，-4.26 秒[95%CI，-19.60 至 11.06] =0.5871）。次要结局显示西他生坦无改善作用。西他生坦降低了血压并增加了血浆 ET-1 浓度。与安慰剂（14.4%；<0.001）相比，西他生坦更常见不良事件（60.2%）。
在微血管性心绞痛患者中，短期使用相对高剂量（每日 10mg）的西他生坦治疗没有益处。与治疗目标相关的不良反应很常见。
