Introduction: There has been a lack of novel medication classes approved for reducing blood pressure (BP) in hypertensive patients. Endothelins, powerful vasoconstricting peptides, have been at the forefront of experimental hypertension research since they were discovered in 1988. The recent PRECISION trial demonstrated the efficacy of aprocitentan, a novel endothelin receptor antagonist, in lowering blood pressure in patients with resistant hypertension (RH). This trial was the driving force behind the approval of aprocitentan in 2024 for the treatment of resistant hypertension.
Areas covered: This clinical trial review will cover the literature leading to the approval of aprocitentan and argue for its use on top of current treatments of hypertension. We argue for the need of novel anti-hypertensive medication classes and provide a brief overview of endothelin receptor antagonists. Finally, we will describe the PRECISION trial and highlight the key benefits of aprocitentan that it elucidated.
Expert opinion: The PRECISION trial demonstrated numerous key benefits of aprocitentan, including efficacy in reducing BP and proteinuria, minimal adverse side effects, and efficacy in patients with advanced chronic kidney disease (CKD) without development of hyperkalemia. However, a lack of long-term data necessitates future investigation regarding safety. Aprocitentan may represent a novel therapeutic alternative to treat patients with RH and CKD.
Keywords: Aprocitentan; chronic kidney disease; endothelin receptor antagonists; endothelin-1; resistant hypertension.
Aprocitentan, a dual endothelin ETA/ETB receptor antagonist, was studied in a phase 3 double blind randomized clinical trial in patients with resistant hypertension (the PRECISION trial). The trial took place on background standardized therapy with maximum doses of an angiotensin receptor blocker, a dihydropyridine calcium channel antagonist and a thiazide diuretic, and demonstrated a placebo-subtracted clinically relevant blood pressure lowering similar with the 12.5 and 25 mg dose of aprocitentan daily, which returned to placebo-subtracted baseline levels during a withdrawal phase of both doses of aprocitentan. There was a significant reduction of urinary albumin/creatinine ratio during the active phase and a return to higher levels of albumin/creatine ratio after stopping the administration of the active drug. Treatment with aprocitentan on top of the standardized therapy was well tolerated with infrequent mild adverse side effects, mainly fluid overload and edema. Aprocitentan has been approved by the FDA and the European Medicines Agency for adult patients with uncontrolled hypertension at a dose of 12.5 mg daily on top of usual antihypertensive therapy. An important precaution for aprocitentan is its relative contraindication with pregnancy. Women of childbearing age should refrain from taking aprocitentan without contraception due to teratogenicity demonstrated in preclinical studies.