Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled despite the use of 3 or more antihypertensive drugs, including a diuretic.1 Patients with resistant hypertension are at a higher risk for cardiovascular events and have limited treatment options.

Endothelin (ET) is a powerful vasoconstricting peptide exerting its effects through ETA and ETB receptors, which can be blocked by selective receptor antagonists.2 ET plays an important role in development and progression of pulmonary hypertension, chronic kidney disease (CKD), and arterial hypertension, particularly when it is resistant or difficult to control.2 Until very recently, ET antagonists were only approved for the treatment of primary pulmonary hypertension and for immunoglobulin A nephropathy.

Aprocitentan, a novel dual ET antagonist,3 has recently been studied in patients with resistant hypertension. The PRECISION study4,5 was a multicenter, randomized, double-blind, placebo-controlled trial that specifically looked at the ability of aprocitentan to lower BP in this patient population.

Participants were initially subjected to a run-in period to confirm persistence of high BP despite optimized treatment. The main inclusion criteria were age 18 to 75 years, systolic BP (SBP) of 140 mm Hg or higher, and diastolic BP (DBP) of 90 mm Hg or higher despite using 3 antihypertensive drugs. Overall, 1965 individuals were screened at 193 sites in 22 countries, and 730 were randomized to receive either aprocitentan at doses of 12.5 mg or 25 mg, or a placebo, in addition to their standard treatment regimen. The primary objective was to evaluate the effect of aprocitentan on office SBP after 12 weeks of treatment. Important strengths of the study included thorough confirmation of resistant hypertension with standardized background therapy (amlodipine / valsartan / hydrochlorothiazide single-pill combination) and monitoring of treatment adherence.

The study’s findings revealed significant reductions in both SBP and DBP in the aprocitentan groups vs the placebo group. The reduction in office SBP was 3.7 mm Hg with the 12.5 mg dose and 5.9 mm Hg with the 25 mg dose, as compared with the placebo group. DBP reductions were also notable, with 4.3 mm Hg and 5.8 mm Hg in the 12.5 mg and 25 mg groups, respectively. One of the crucial aspects of the PRECISION study was assessing the sustainability of BP reduction. BP control was sustained over a 48-week treatment with either dose of aprocitentan. Upon withdrawal, a significant increase in BP was observed, indicating the efficacy of aprocitentan in maintaining lower BP levels during active treatment.

Furthermore, ambulatory BP monitoring, which provides a more accurate reflection of BP changes over a 24-hour period, supported these findings. The 24-hour SBP reduction was 4.2 mm Hg with 12.5 mg and 5.9 mm Hg with 25 mg dose, and similar trends were observed for DBP. Importantly, reduction in ambulatory BP was most pronounced during night time, which might translate into additional cardiovascular risk reduction. Finally, the study demonstrated antiproteinuric effect of aprocitentan, which tended to be greater in patients with chronic kidney disease (CKD) stage 3 or 4.

As anticipated for an ET receptor antagonist, edema or fluid retention was the most common adverse event reported with aprocitentan within the first 4 weeks of treatment. Edema or fluid retention was more frequent in patients with CKD stage 3 to 4. The incidence was dose-related, suggesting that 12.5 mg might represent a preferred dose for initiation of the therapy. With the addition or uptitration of a diuretic therapy, this event was clinically manageable.

In conclusion, the PRECISION study has demonstrated the efficacy of aprocitentan in reducing BP in this difficult-to-treat population, with a manageable safety profile. The trial supports the role of aprocitentan in addressing the unmet needs of patients with resistant hypertension. It also adds valuable data on the benefits and risks associated with ET receptor antagonists, suggesting that careful patient selection and monitoring are key to optimizing treatment outcomes. Further research and comparative studies with other therapeutic options will be crucial to fully establish the place of aprocitentan in hypertension management. Importantly, aprocitentan has been approved by the United States Food and Drug Administration on March 20, 2024, under the brand name Tryvio for treatment of hypertension in combination with other antihypertensive drugs in adult patients whose BP is not adequately controlled with standard therapy.