Aprocitentan for Treatment-Resistant Hypertension: Pharmacology Concepts and Clinical Insights

Treatment resistant hypertension (TRH) occurs in nearly 20% of patients with a diagnosis of hypertension despite receiving three or more antihypertensives and places individuals at an increased risk of morbidity and mortality compared to essential hypertension. Numerous pathophysiological factors underlie TRH, including endothelin-1, which until recently no approved treatments targeted. Endothelin-1 exhibits multiple actions through binding to ETA and ETB receptors. Vasoconstriction of the vascular smooth muscle occurs when endothelin-1 binds ETA and ETB, however; vasodilation of endothelial cells also occurs through activation of ETB. Currently available endothelin receptor antagonists (ERA) were only approved for pulmonary hypertension until 2024 when the Food and Drug Administration approved aprocitentan as the first ERA for hypertension treatment in combination with other antihypertensives. The approval of aprocitentan occurred following the publication of the phase 3 PRECISION trial that compared aprocitentan versus placebo for patients with "true" TRH. Aprocitentan 12.5 mg exhibited a placebo-adjusted reduction in sitting systolic and diastolic blood pressure of 3.8/3.9 mmHg at 4 weeks of treatment. A dose-dependent increase in peripheral edema and a small reduction in hemoglobin due to hemodilution were greater in the aprocitentan-treated patients. Animal study data from past endothelin receptor antagonists showed this class of agents may lead to birth defects and was the basis for aprocitentan's black-box warning. Overall, clinical trial data supports aprocitentan's use as an effective agent for the TRH, but clinicians will need to individualize patient treatment selection and consider the safest and most efficacious options currently available.