Aprocitentan, a novel, dual endothelin A and B receptor antagonist, shows safety and efficacy in lowering blood pressure (BP) in patients with resistant hypertension, concludes a randomized trial in The Lancet (1).
The Parallel-group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension (PRECISION) trial enrolled 730 patients with resistant hypertension, drawn from 193 centers in 22 countries. Eligible patients had a sitting systolic BP of 140 mm Hg or higher, despite standardized background therapy with three anti-hypertensive medications, including a diuretic.
In the first part of the study, patients were assigned to 4 weeks of double-blind treatment with placebo or aprocitentan at a dose of 12.5 mg or 25 mg. This was followed by a single-blind phase in which all patients received aprocitentan at a dose of 25 mg for 32 weeks. In a subsequent withdrawal phase, patients were re-randomized to 12 weeks of double-blind treatment with aprocitentan at a dose of 25 mg or placebo.
After the first 4 weeks, the least-squares mean change in office systolic BP (primary outcome) was -15.3 mm Hg with the lower dose of aprocitentan and -15.2 mm Hg with the higher dose compared with -11.5 mm Hg in the placebo group. Differences in sitting BP were -3.8 mm Hg and -3.7 mm Hg with aprocitentan versus placebo; differences in 24-hour ambulatory systolic BP were -4.2 mm Hg and -5.9 mm Hg, respectively. The urine albumin-to-creatinine ratio decreased by -28% with aprocitentan at a dose of 12.5 mg and -31% with a 25-mg dose compared with a 5% increase with placebo.
In the withdrawal phase, office systolic BP increased by 5.8 mm Hg in the placebo group. Mild to moderate edema or fluid retention occurred in 9% of the lower-dose and 18% of the higher-dose aprocitentan group—leading to treatment discontinuation in seven patients—compared with 2% of the placebo group. Of 11 treatment-emergent deaths during the study, none was classified as treatment related.
Patients with resistant hypertension are at increased risk of cardiovascular events. Although the endothelin pathway is believed to play a role in the pathogenesis of hypertension, it is not targeted by current therapeutic options.
The dual endothelin antagonist aprocitentan offers an effective and well-tolerated, new alternative for resistant hypertension, the PRECISION findings suggest. The researchers believe this treatment has the potential to lower the risk of cardiovascular events in patients with resistant hypertension and associated comorbidity, such as diabetes, chronic kidney disease, albuminuria, and previous cardiovascular events.
Schlaich MP, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet, published online ahead of print November 4, 2022. doi: 10.1016/S0140-6736(22)02034-7; https://doi.org/10.1016/S0140-6736(22)02034-7
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