Abstract Body (Do not enter title and authors here): Background and objectives: Micro- and macroalbuminuria measured by urinary albumin-to-creatinine ratio (UACR) (30-300 mg/g and > 300 mg/g, respectively), and high normal UACR (10-30 mg/g) are associated with higher risk of mortality, CV disease and CKD progression in patients with hypertension, diabetes, decreased renal function, or even the general population and reduction can lower these risks. The endothelin ETA/ETB receptor antagonist aprocitentan reduced albuminuria in patients with confirmed resistant hypertension (RHT). In the PRECISION trial, in addition to standard background therapy including valsartan, aprocitentan 12.5 mg reduced UACR by 30% compared to placebo (LS Geom Mean [95 CL] 0.70 [0.61, 0.80], p< 0.0001) and 25 mg by 34% (0.66 [0.58,0.75] p< 0.0001) at the end of double-blind part 1 (4 weeks) in the overall population. In this analysis, we evaluated the effect of aprocitentan on UACR at both doses according to the baseline (BL) albuminuria (30-300 mg/g and >300mg/g).

Methods: 730 patients with RHT on a standardized fixed-dose combination of amlodipine/ valsartan/hydrochlorothiazide were randomized to aprocitentan (12.5 mg or 25 mg) or placebo. Of these, 174 and 90 had BL microalbuminuria or macroalbuminuria, respectively. Changes from BL in UACR and office systolic blood pressure measured at trough (SBP, the primary endpoint in PRECISION) after 4 weeks of double-blind treatment.

Results: In subjects with microalbuminuria, aprocitentan reduced UACR by 43% in the 12.5 mg group (0.57 [0.42, 0.78], p= 0.0005) and by 45% in the 25mg group (0.55 [0.40,0.77] p=0.0004) compared to placebo. In subjects with macroalbuminuria, aprocitentan reduced UACR by 48% with 12.5 mg (0.52 [0.37, 0.75], p= 0.0006) and by 61% with 25mg (0.39[0.27,0.57] p<0.0001) compared to placebo. Placebo did not have any noticeable effect on albuminuria in any group. The effect of aprocitentan in lowering blood pressure, measured at trough, was independent of the level of albuminuria at baseline.
After 4 weeks of treatment, 53.3% and 60% of patients achieved a decrease of ≥10 mmHg from baseline with 12.5 mg aprocitentan, respectively in the microalbuminuria and macroalbuminuria groups, compared to 64% with aprocitentan 25mg (both cohorts) and 48% and 29% in the placebo group.

Conclusion: Aprocitentan produced a major decrease of albuminuria regardless baseline level in patients with RHT. These finding support further research for aprocitentan in CKD patients