Dual endothelin receptor blockade produces sustained blood pressure reduction in resistant hypertension

November 15, 2022

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Source/information

Source:

MP Schlaich, et al. LBS.09. Withstands HTN: pressure cooker. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).

Disclosures:
The PRECISION study was funded by Idorsia Pharmaceuticals and Janssen Biotech. Schlaich reports receiving institutional grants/contracts and consulting fees from Abbott Laboratories, Medtronic, and ReCor Medical; personal payments or honoraria from Abbott Laboratories, Medtronic, Merck, and Servier; support from Abbott Laboratories and Medtronic; and is President of the Hypertension Research Council of Australia and is on the Scientific Committee of the International Society of Hypertension.


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CHICAGO – Aprocitentan, a dual endothelin blocker, was superior to placebo in lowering blood pressure and was well tolerated in patients with resistant hypertension, according to results of the PRECISION trial.

“Dual endothelin antagonists with aprocitentan may represent a new alternative pharmacological approach for the treatment of resistant hypertension,” Markus P. Schlaich, doctor, professor at the University of Western Australia, said during a presentation at the American Heart Association Scientific Sessions.

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Aprocitentan, a dual endothelin blocker, was superior to placebo for blood pressure reduction and was well tolerated in patients with resistant hypertension.
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Targeting the endothelin pathway

Aprocitentan (Idorsia Pharmaceuticals/Janssen Biotech) is a once-daily, orally active dual endothelin A and B receptor agonist. It has 44 hours. half-life and low potential for drug interactions.

“The failure to control BP with currently available drugs suggests that the pathophysiological pathways involved are unopposed,” Schlaich said. The current preferred fourth-line treatment for resistant hypertension is spironolactone, which targets the renin-angiotensin-aldosterone system, according to Schlaich. “I would argue that one very important mechanism remains unchallenged and that is the endothelin pathway.” Indeed, endothelin has been clearly implicated in the pathogenesis of hypertension. Therapeutically targeting the endothelin system therefore appears to be a very attractive target, and that is exactly what we have done in the PRECISION phase 3 trial.”

results

Accuracy was performed at centers in Asia, Australia, Europe and North America. The researchers enrolled patients with resistant hypertension, defined as a sitting systolic blood pressure of 140 mm Hg or higher despite background therapy with three antihypertensive drugs, including diuretics.

The study consisted of three consecutive parts. In a 4-week double-blind, randomized, placebo-controlled portion (Part 1), 730 patients were randomly assigned to aprocitentan 12.5 mg or 25 mg or placebo. In a 32-week single-blind phase (phase 2), all received aprocitentan 12.5 mg. In a 12-week double-blind, randomized, placebo-controlled withdrawal phase (Part 3), patients were re-randomized to aprocitentan 12.5 mg or placebo.

After 4 weeks, the mean change in office systolic blood pressure was –15.3 mm Hg with aproxitentan 12.5 mg, –15.2 mm Hg with the 25 mg dose, and –11.5 mm Hg with placebo, a difference of . placebo of –3.8 mm Hg (P = .0042) and –3.7 mm Hg (P = .0046), respectively.

The mean difference in 24-h ambulatory systolic blood pressure was –4.2 mm Hg and –5.9 mm Hg, respectively.

After the 4-week withdrawal period, the researchers reported an increase in office systolic blood pressure with placebo compared with aprocitentan (5.8 mm Hg; P < .0001), according to the results.

“Aprocitentan reduced both standardized autonomic office and 24-hour ambulatory blood pressure compared with placebo at 4 weeks,” Schlaich said at the presentation. “Importantly, this effect was sustained for 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 portion of the study. Seven patients who received aprocitentan discontinued treatment.

“Oedema/fluid retention, as expected, was the most common side effect, usually occurring within the first 4 weeks and [it] was easily managed clinically with adjunctive diuretic therapy,” Schlaich said.

Eleven treatment-related deaths occurred, but the investigators did not consider any events to be related to aprocitentan.

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