Aprocitentan: An Oral, Once-daily Antihypertensive Therapy for Resistant Hypertension in Adult Patients

Resistant hypertension (rHTN), defined as uncontrolled blood pressure despite adherence to three antihypertensive agents, presents a major clinical and economic burden that disproportionately affects certain minority populations. Current therapeutic options do not target the endothelin-1 pathway, a potent mediator of vasoconstriction, inflammation and sodium retention, which has been increasingly recognized as a key contributor to the pathophysiology of rHTN. However, aprocitentan, a novel dual endothelin receptor antagonist, directly targets this mechanism. In the Parallel-group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension (PRECISION) trial (Multi-center, Blinded, Randomized, Parallel-group, Phase 3 Study With Aprocitentan in Subjects With Resistant Hypertension [RHT]; ClinicalTrials.gov identifier: NCT03541174), aprocitentan demonstrated durable blood pressure-lowering effects in patients with rHTN. This study reported significant and sustained reductions in both office and ambulatory systolic and diastolic blood pressure among patients with rHTN, along with a favourable safety profile at the subsequently approved 12.5 mg dose. Pharmacokinetic studies support once-daily oral administration with low potential for drug-drug interactions. This article will discuss the significant potential benefits in the evolving landscape of hypertension management, how aprocitentan is a promising fourth-line agent for rHTN and recommendations for its use in the 2025 American Heart Association/American College of Cardiology (AHA/ACC) High Blood Pressure Guideline.