Effect of the Dual Endothelin Receptor Antagonist Aprocitentan on Albuminuria

Objective: Upregulation of the endothelin pathway is frequently observed in patients with resistant hypertension (RHT) and those with kidney disease. Albuminuria, a biomarker for kidney disease, is associated with poor long-term outcomes and increased mortality risk. The dual endothelin ETA/ETB receptor antagonist aprocitentan is indicated in combination with other antihypertensives for the treatment of hypertension in adults not adequately controlled on other drugs. Previously, we showed that aprocitentan markedly reduced blood pressure in patients with RHT across all urine albumin-creatinine ratio (UACR) categories. This analysis of PRECISION evaluated the effect of aprocitentan (plus =/>3 antihypertensives including a diuretic) on UACR (geometric mean) and on albuminuria risk category in patients with resistant hypertension and normal albumin (UACR 300 mg/g). Design and method: In PRECISION, patients with confirmed RHT (N=730) were randomized to double-blind aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo for 4 weeks followed by single-blind aprocitentan 25 mg to Week 36. Results: In patients with microalbuminuria (N=174) and macroalbuminuria (N=90), aprocitentan (both doses) markedly reduced mean UACR from baseline to Week 4 compared with marginal changes with placebo (Table). From baseline to Week 36, aprocitentan 25 mg reduced mean UACR levels from 77.5 mg/g to 34.2 mg/g (-55.9%) and from 860.2 mg/g to 286.7 mg/g (-66.7%) in patients with baseline microalbuminuria and macroalbuminuria, respectively. At Week 4, 45.0%, 32.0%, and 27.5% of patients with baseline microalbuminuria achieved albumin levels in the normal range with aprocitentan 12.5 mg, aprocitentan 25 mg, and placebo, respectively. Similarly, of patients with baseline macroalbuminuria, 20.0%, 35.7%, and 8.0% achieved microalbuminuria, and 3.3%, 3.5% and 0% achieved normal albumin levels. At Week 36, 46.7% and 46.2% of patients with baseline microalbuminuria and macroalbuminuria, respectively, achieved UACR levels indicative of a lower albuminuria risk (normal and microalbuminuria/normal, respectively). Most patients with normal albumin levels at baseline remained within the normal range at both time points while receiving aprocitentan (>92%; Table). Conclusions: Targeting the endothelin pathway, aprocitentan lowered the albuminuria risk category for almost 50% of patients with elevated UACR levels (Week 36). Aprocitentan may confer substantial long-term health benefits in patients with RHT and albuminuria.