Is Aprocitentan's Effect on Albuminuria Merely Due to Lowered BP? Subgroup Analysis of the PRECISION Trial

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Background: Hypertension is a known risk factor for CKD. Aprocitentan (APRO), a dual endothelin receptor antagonist, effectively reduced BP on top of ≥3 antihypertensives and was well tolerated in patients with resistant hypertension (RHT) in the PRECISION trial. Previously, we showed that APRO markedly reduced office systolic blood pressure (SiSBP) and urinary albumin-to-creatinine ratio (UACR) in a subgroup of patients with renal impairment. Here we investigated if reductions in SiSBP and UACR were a) consistent in differently defined subgroups of patients with renal impairment and b) if reductions in SiSBP and UACR were correlated. Methods: The study design of PRECISION (NCT03541174) has been previously described. Subgroups with renal impairment were defined as patients categorized as high-risk or very high-risk based on KDIGO criteria (termed ‘KDIGO ≥high-risk’); patients with CKD stage 3–4 (eGFR 15–<60 mL/min/1.73 m2); and patients with microalbuminuria (UACR 30–300 mg/g) or macroalbuminuria (UACR >300 mg/g). Placebo-corrected changes in SiSBP at trough and percentage change in UACR from baseline to Week 4 with APRO 12.5 mg or 25 mg were assessed. The correlation between changes in SiSBP and changes in UACR was assessed at Week 4 (APRO 12.5 mg or 25 mg, or placebo) and Week 36 (APRO 25 mg) in patients with KDIGO ≥high-risk. Results: The placebo-corrected effect of APRO 12.5 mg and 25 mg on SiSBP and UACR at Week 4 was substantial and consistent across the three subgroups of patients with renal impairment and RHT, with pronounced effects in patients with KDIGO ≥high-risk, CKD stage 3–4, and albuminuria (Table). In patients with KDIGO ≥high-risk, the correlation between changes in SiSBP and UACR at Week 4 and Week 36 was low (R range: 0.12–0.32). Conclusion: APRO in addition to ≥3 antihypertensives substantially reduced SiSBP and UACR vs placebo across all subgroups with renal impairment and RHT. The low correlation between change in SiSBP and change in UACR suggests that APRO’s effect on UACR is at least partly independent of its effect on blood pressure. Funding: Commercial Support - Idorsia Pharmaceuticals Ltd.Table: Placebo-corrected changes in SiSBP and UACR (baseline to Week 4) with aprocitentan 12.5 mg and 25 mg in subgroups with renal impairment

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