Aprocitentan in Patients with CKD: Subgroup Analysis of the PRECISION Trial

Background: Resistant hypertension is common and often difficult to control in patients with CKD. Hyperkalemia and decrease in eGFR are two main limitations of available antihypertensive therapies. The phase-3 PRECISION trial demonstrated that aprocitentan, a dual endothelin receptor antagonist, lowers blood pressure in patients with resistant hypertension and is safe. We now investigated the subgroup with CKD of the PRECISION trial. Methods: Of the730 patients with resistant hypertension on a standardized fixed-dose combination of amlodipine, valsartan and hydrochlorothiazide, 147 were classified as high-risk or very high-risk based on the KDIGO criteria. They were randomized to 2 doses of aprocitentan or placebo in PRECISION. Changes in office systolic blood pressure (SBP), the primary endpoint in PRECISION, urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were assessed at multiple time points: a) the end of the double-blind treatment phase at Week 4; b) the single-blind aprocitentan 25mg treatment phase at Week 36; c) the double-blind withdrawal phase at Week 40. Results: Changes in office SBP and UACR are summarized in Table 1. At Week 4, aprocitentan reduced office SBP by 13.5 mm Hg and 16.6 mm Hg in the 12.5 mg and 25 mg groups, respectively, compared with a 4.4 mm Hg reduction in the placebo group. At Week 36, the reduction in office SBP was maintained (16.4 mm Hg vs baseline). UACR was also reduced by 62% at Week 36 in the 25 mg group. Baseline eGFR of the subgroup was 50 ml/min/1.73 m2. Changes in eGFR (mL/min/1.73m2) from baseline to Week 4 were 0.5 and -2.5 in the 12.5 mg and 25 mg groups, respectively, and -0.4 in placebo. An eGFR slope of -0.9 mL/min/1.73m2/year was observed (“chronic slope”) from Week 6 to Week 36 (all patients on 25 mg aprocitentan). At Week 4, edema or fluid retention occurred in 14% and 17% of patients receiving aprocitentan 12.5mg and 25mg, respectively, vs 1% in the placebo group. Conclusion: In patients with CKD and resistant hypertension, aprocitentan substantially reduced BP and UACR vs placebo. Funding: Commercial Support - Idorsia Pharmaceuticals Ltd.Table 1: Office SBP and UACR reduction in PRECISION: high-risk and very high-risk patients

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