Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial

Abstract

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.

Keywords: angina with no obstructive coronary arteries; endothelin receptor antagonist; exercise test; genetics; microvascular angina; pharmacotherapy.

Figure 1.

Study design to assess the effects of 10 mg of zibotentan or matched placebo. A prospective, registry-based, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of 10 mg of zibotentan or matched placebo, once daily for 12 weeks. B indicates blood; C, clinical check; ETT, exercise tolerance test (ie, Bruce protocol); GB, genomic blood test; OD, once daily; PD, pharmacodynamic; PK, pharmacokinetic; Q, quality of life questionnaire; RNA, ribonucleic acid sampling; and spCMR, stress perfusion cardiac magnetic resonance.

Figure 2.

Flow diagram of the registry-based randomized trial. Clinical information, patient-reported outcome measures, and a blood test were acquired at enrollment (visit 1), at the end of the medical optimization period (visit 2), after a 3-week placebo run-in (visit 3, baseline), and at the end of treatment period 1 (visit 4) and treatment period 2 (visit 5, end of trial). A genomic blood test was obtained at visit 1. An exercise tolerance test was obtained on 4 occasions, including visits 1, 3, 4, and 5. An optional imaging study involved cardiovascular magnetic resonance imaging at visits 3, 4, and 5. The registry population included individuals with microvascular angina who provided written informed consent at visit 1. The trial population included participants who fulfilled eligibility and genotype criteria and who were randomized at visit 3.

Figure 3.

Effect of zibotentan on mean myocardial blood flow. Blood flow is represented by milliliters per minute per gallon. A, Global (N=14). B, Subendocardium (N=14). In the magnetic resonance imaging study, baseline was defined by visit 3 (end of placebo-run-in phase, prerandomization). MBF indicates myocardial blood flow.