Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

Microvascular angina, linked to endothelin system dysregulation, was the focus of this double-blind, placebo-controlled, randomized, sequential crossover trial (NCT04097314). The trial compared zibotentan, an oral endothelin A receptor selective antagonist, with placebo in 118 patients with microvascular angina. Over 12 weeks, participants received either 10 mg daily zibotentan or placebo, with the primary outcome treadmill exercise duration. The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). However, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.