Aprocitentan, a dual endothelin receptor A and B antagonist, shows modest efficacy in treating resistant hypertension, but is associated with increased risks for edema and fluid retention, according to new study findings.
In part 1 of the PRECISION study, investigators randomly assigned 730 patients to receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo for 4 weeks. In part 2, all patients received aprocitentan 25 mg for 32 weeks. In part 3, the withdrawal phase, investigators randomly assigned patients to receive aprocitentan 25 mg or placebo for 12 weeks. All patients had resistant hypertension at baseline with a sitting systolic blood pressure of 140 mm Hg or higher despite use of 3 antihypertensive drugs, including a diuretic. Two-thirds of patients were taking 4 or more antihypertensive drugs.
At 4 weeks, the least square mean change in office systolic blood pressure, the study’s primary endpoint, was significantly greater with aprocitentan vs placebo: -15.3 mm Hg for aprocitentan 12.5 mg and -15.2 mm Hg for aprocitentan 25 mg, compared with -11·5 mm Hg for placebo, Markus P. Schlaich, MD, of Dobney Hypertension Centre, Royal Perth Hospital Research Foundation at The University of Western Australia in Perth, and colleagues reported in The Lancet. Similarly, 24-hour ambulatory systolic blood pressure declined 4.2 mm Hg and 5.9 mm Hg more with aprocitentan vs placebo at the low and high dose, respectively.
At 4 weeks into the withdrawal phase, investigators found that office systolic blood pressure significantly increased 5.8 mm Hg more with placebo compared with aprocitentan, confirming a blood pressure-lowering effect with the endothelin receptor antagonist. Diastolic blood pressure followed these same patterns.
Up to a quarter of patients had stage 3-4 chronic kidney disease (CKD) at baseline (estimated glomerular filtration rate of at least 15 but less than 60 mL/min/1.73 m2). A third of patients had albuminuria with a urinary albumin to creatinine ratio (UACR) of more than 30 mg/g. Investigators observed a greater decrease in systolic blood pressure at week 4 for patients with stage 3-4 CKD, albuminuria, and age 75 years or older. They also observed an antiproteinuric effect with aprocitentan at 4 weeks: UACR decreased 28% and 31% in the 12.5 mg and 25 mg aprocitentan groups, respectively. Other common comorbidities of the cohort included diabetes, ischemic heart disease, and congestive heart failure.
The most frequent adverse event was mild-to-moderate edema or fluid retention, occurring in 9.1% and 18.4% of patients receiving aprocitentan 12.5 mg and 25 mg, respectively, compared with 2.1% of those receiving placebo, at 4 weeks (part 1). It was treated with additional diuretic as needed. Seven patients taking aprocitentan discontinued treatment for this reason. Anemia or hemodilution occurred in 3.7% and 1.2% of the low and high dose aprocitentan groups. Eleven patients overall had a heart failure hospitalization. Eleven patients died, but none due to treatment.
“Aprocitentan represents a novel, effective, and well tolerated treatment for resistant hypertension,” Dr Schlaich’s team concluded.
Among the strengths of the study, patients received a single-pill combination of amlodipine, hydrochlorothiazide, and valsartan during the screening and study periods, which eliminated pseudo resistant hypertension. The 3-part study design was single- or double-blind and involved participants from Europe, North America, Asia, and Australia. The large placebo effect may represent a study limitation. The study also lacked placebo control in part 2.
“We would like to congratulate the authors on the sophisticated design of their study,” Ralf Dechend, MD, PhD, of the University and Max Delbrück Center for Molecular Medicine in Berlin, Germany, and Christian Delles, MD, of the University of Glasgow in the UK, commented in an accompanying editorial.
Drs Dechend and Delles pointed out that the observed blood pressure effect of aprocitentan “was moderate but statistically significant; whether it is clinically relevant remains to be seen.”
Disclosure: This research was supported by Idorsia Pharmaceuticals and Janssen Biotech. Please see the original reference for a full list of disclosures.
Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. 2022 Dec 3;400(10367):1927-1937. doi:10.1016/S0140-6736(22)02034-7
Dechend R, Delles C. Endothelin antagonists and the quest for a new therapeutic option in resistant hypertension. Lancet. 2022 Dec 3;400(10367):1900-1901. doi:10.1016/S0140-6736(22)02181-X