Dual endothelin receptor antagonist yields sustained BP lowering in resistant hypertension
CHICAGO — Aprocitentan, a dual endothelin antagonist, was superior to placebo for BP lowering and was well tolerated in patients with resistant hypertension, according to results of the PRECISION trial.
“Dual endothelin antagonism with aprocitentan may represent a new alternative pharmacological approach to treat resistant hypertension,” Markus P. Schlaich, MD, professor at University of Western Australia, said during a presentation at the American Heart Association Scientific Sessions.
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Targeting the endothelin pathway
Aprocitentan (Idorsia Pharmaceuticals/Janssen Biotech) is a dual endothelin A and B receptor agonist that is given once daily and is orally active. It has a half-life of 44 hours and low potential for drug-drug interactions.
“The failure to control BP with currently available drugs suggests that the relevant pathophysiologic pathways remain unopposed,” Schlaich said. The current preferred fourth-line therapy for resistant hypertension is spironolactone, which targets the renin-angiotensin-aldosterone system, according to Schlaich. “I would argue that leaves one very important system still unopposed and that is the endothelin pathway. Indeed, endothelin has clearly been implicated in the pathogenesis of hypertension. Targeting the endothelin system therapeutically, therefore, appears to be a very attractive target and that’s exactly what we’ve done in the PRECISION phase 3 study.”
Results
PRECISION was conducted at centers in Asia, Australia, Europe and North America. Researchers enrolled patients with resistant hypertension, which was defined as sitting systolic BP of 140 mm Hg or higher despite background therapy with three antihypertensive drugs including a diuretic.
The study had three sequential parts. In a 4-week double-blind, randomized, placebo-controlled part (part 1), 730 patients were randomly assigned aprocitentan 12.5 mg or 25 mg or placebo. In a 32-week single-blind part (part 2), everyone received aprocitentan 12.5 mg. In a 12-week double-blind, randomized, placebo-controlled withdrawal part (part 3), patients were re-randomly assigned to aprocitentan 12.5 mg or placebo.
At 4 weeks, the mean change in office systolic BP was –15.3 mm Hg with aprocitentan 12.5 mg, –15.2 mm Hg with the 25 mg dose and –11.5 mm Hg with placebo, for a difference vs. placebo of –3.8 mm Hg (P = .0042) and –3.7 mm Hg (P = .0046), respectively.
Mean difference in 24-hour ambulatory systolic BP was –4.2 mm Hg and –5.9 mm Hg, respectively.
After the 4-week withdrawal period, the researchers reported that office systolic BP increased with placebo compared with aprocitentan (5.8 mm Hg; P < .0001), according to the results.
“Aprocitentan lowered both standardized automated office and 24-hour ambulatory BP compared to placebo after 4 weeks,” Schlaich said during the presentation. “Importantly, these effects were maintained over 48 weeks.”
Mild to moderate edema or fluid retention occurred in 9% of the aprocitentan 12.5 mg group, 18% of the 25 mg group and 2% of the placebo group during the 4-week double-blind part of the study. Seven patients assigned aprocitentan discontinued treatment.
“Edema/fluid retention, as expected, was the most common adverse event, usually occurred in the first 4 weeks and [it] was easily clinically managed with additional diuretic therapy,” Schlaich said.
Eleven treatment-emergent deaths occurred, but the researchers deemed no event related to aprocitentan.
Reference:
Perspective
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This trial represents a promising new drug class for the treatment of resistant hypertension. It was well designed and executed. The placebo-subtracted office systolic BP lowering was somewhat underwhelming, though statistically significant (3.7 to 3.8 mm Hg), but the 24-hour ambulatory systolic BP lowering (4.2 and 5.9 mm Hg in the respective doses studied) was in the same range as seen with renal denervation studies, including the contemporary RADIANCE-HTN TRIO study.
Spironolactone, a mineralocorticoid receptor antagonist (MRA), is strongly recommended as the drug of choice in resistant hypertension. However, hyperkalemia is a clearly established side effect and aprocitentan may find a role in the treatment of patients who have a history of hyperkalemia or are at risk for it. I do worry about the high incidence of edema with the 25-mg dose — it was almost 20% of participants. The background diuretic therapy for the trial was mandated to be hydrochlorothiazide, so it is possible that use of concurrent chlorthalidone or indapamide may ameliorate this risk. There was an antiproteinuric effect of aprocitentan that was more pronounced in participants with stage III or IV chronic kidney disease compared with estimated glomerular filtration rate > 60 mL/min/1.73 m2 — which is another potential benefit of this class.
We'll see what the FDA thinks of the data, but I anticipate it will be approved for use in a resistant hypertension population, and may be particularly useful in patients that cannot take an MRA.
Cleveland Clinic
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Schlaich MP, et al. LBS.09. Resistant HTN: A Pressure Cooker. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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