Aprocitentan shows worth in patients with resistant hypertension, CKD

Aprocitentan appears beneficial in the treatment of patients with both resistant hypertension and chronic kidney disease (CKD), having been shown to improve blood pressure control and reduce urine albumin-to-creatinine ratio (UACR) when added to standardized background antihypertensive therapy.

In a post hoc analysis of the phase III PRECISION study, office systolic BP (SBP) from baseline to week 4 decreased by 13.5 mm Hg with aprocitentan 12.5 mg, 16.6 mm Hg with aprocitentan 25 mg, and 4.4 mm Hg with placebo. This effect persisted through week 36 with aprocitentan 25 mg, with a reduction of 16.4 mm Hg from baseline. [Hypertension 2025;doi:10.1161/HYPERTENSIONAHA.125.25563]

Aprocitentan also yielded reductions in ambulatory SBP. From baseline to week 4, daytime ambulatory SBP decreased by 8.5 mm Hg with the 12.5 mg dose and by 7.9 mm Hg with the 25 mg dose but increased by 2.7 mm Hg with placebo. For nighttime ambulatory SBP, the changes were more pronounced: −9.6 mm Hg with aprocitentan 12.5 mg, −13.8 mm Hg with aprocitentan 25 mg, and −2.5 mm Hg with placebo.

Similar changes were observed when assessing office diastolic BP (DBP) and daytime and nighttime ambulatory DBP.

UACR at week 4 dropped by 47.1 percent with aprocitentan 12.5 mg, 59.6 percent with aprocitentan 25 mg, and 2.4 percent with placebo. UACR dropped further with aprocitentan 25 mg at week 36, with a percentage change of −61.6 percent from baseline. 

As for safety, aprocitentan was generally well tolerated, with no additional safety signals, according to the authors. The most common adverse event with aprocitentan was peripheral oedema. Heart failure events occurred in 11 patients, none of which were deemed related to treatment and led to study discontinuation.

Potassium and sodium levels were stable throughout the study. There were no excess headaches, no orthostatic hypotension, and no tachycardia. None of the patients experienced acute kidney injuries.

“This is the first report on aprocitentan, a drug targeting the endothelin pathway, in patients with CKD and resistant hypertension, a group of difficult-to-treat patients with a high risk of morbidity and mortality and limited treatment options,” the investigators said.

They emphasized that the present analysis focused on patients who were categorized as high risk or very high risk based on the KDIGO criteria (eGFR ≥15 to <45 mL/min per 1.73 m², eGFR ≥45 to <60 mL/min per 1.73 m² and UACR ≥30 mg/g, and eGFR ≥60 mL/min per 1.73 m² and UACR >300 mg/g).

Subsequent analyses in patients with CKD stages 3/4 and those with microalbuminuria or macroalbuminuria confirmed the findings, with aprocitentan having similar or greater efficacy in these subgroups than in the overall phase III population, according to the investigators.

Overall, the findings indicate that “aprocitentan may confer a considerable, clinically meaningful cardiovascular and kidney-protective benefit in these difficult-to-treat patients. [The drug] may represent the preferred choice in patients with uncontrolled hypertension and advanced CKD to improve BP control and reduce proteinuria if present,” the investigators said.

“Ultimately, long-term data from real-world clinical practice will assess the net benefit-risk of aprocitentan in these patients and provide insights on optimizing fluid management strategies,” they added.

PRECISION involved 730 patients with resistant hypertension, of whom 147 (20.1 percent) had CKD categorized as KDIGO high risk or very high risk. Compared with those in the non–high-risk KDIGO group (n=583), patients with KDIGO ≥high risk were older (66.1 vs 60.6 years), more likely to be male (70.7 percent vs 56.6 percent), Black (17 percent vs 9.8 percent), on ≥4 antihypertensive medications (71.4 percent vs 60.9 percent).

More patients in the KDIGO ≥high risk than the non–high-risk KDIGO group had diabetes (79.6 percent vs 47.7 percent) and sleep apnoea syndrome (20.4 percent vs 12.5 percent). Mean baseline BP levels were similar in both KDIGO groups.

PRECISION was conducted in three parts. Part 1 was a 4-week, double-blind treatment phase (aprocitentan 12.5, aprocitentan 25 mg, or placebo). Part 2 was a 32-week, single-blind treatment phase (aprocitentan 25 mg). Part 3 was a 12-week, double-blind withdrawal phase (aprocitentan 25 mg or placebo). The study concluded following a 30-day safety follow-up period.