Aprocitentan lowers BP in resistant hypertension patients with assured safety and results: LANCET

Australia: A recent investigation on “PRECISION STUDY” published in the Lancet has interpreted that Aprocitentan lower blood pressure in patients with resistant hypertension. The results indicate its tolerability and superiority over a placebo.

Resistant hypertension is tied to increased cardiovascular risk and kidney disease progression. The pathogenesis is related to the endothelin pathway, which is therapeutically non-targeted. This relevant pathophysiological pathway remains unopposed with currently available drugs.

Endothelin-1 acts through 2 receptors, ETA and ETB. ETA receptor activation causes vasoconstriction, while ETB receptor activation causes vasoconstriction (vascular smooth muscle cells) and vasodilation (endothelial cells). Aprocitentan is a dual endothelin-receptor antagonist, and previous studies have reported its role in significantly reducing BP. Additional research is required to confirm its suitability for the management of treatment-resistant hypertension.

Considering this, a study was conducted by a team of researchers led by Dr Schlaich, MD, from the Dobney Hypertension Centre at the Royal Perth Hospital Research Foundation to assess whether dual endothelin receptor antagonist “aprocitentan” is efficacious in lowering BP in patients with resistant hypertension or not.

The structured study points are as follows:

• PRECISION was a multicentre, randomised, parallel-group, phase 3 study. It was conducted in hospitals/research centres in Europe, North America, Asia, and Australia. (June 18, 2018, to April 25, 2022)

• The study included patients with a systolic blood pressure of 140 mm Hg or even higher, even after taking therapy (three antihypertensive drugs, including a diuretic also).

• There were three sequential parts to the study.

• Parts 1, 2 and 3 were 4-week double-blind, 32-week single-blind and 12-week double-blind.

• In part 1, the patients received aprocitentan 12·5 mg and 25 mg, or placebo, in a ratio of 1:1:1.

• In part 2, the patients received aprocitentan 25 mg.

• In part 3 (double-blind and placebo-controlled withdrawal), patients were re-randomised to aprocitentan 25 mg or placebo in a ratio of 1:1.

• The changes in systolic blood pressure (unattended office) from baseline to week four and from withdrawal baseline to week 40 were the primary and key secondary endpoints measured.

• 24-h ambulatory blood pressure changes were included in the secondary endpoints.

The key points of the study interpretation are:

• One thousand nine hundred sixty-five individuals were screened.

• Seven hundred thirty patients were assigned randomly.

• Part 1 of the study was completed by 704 participants constituting 96%

• Six hundred thirteen participants constituting 87%, completed part 2 of the study.

• Five hundred seventy-seven participants constituting 94%, completed part 3 of the study.

• At four weeks, the least square mean (SE) change in office systolic blood pressure for aprocitentan 12.5 mg, aprocitentan 25 mg and placebo was recorded as –15·3 (SE 0·9) mm Hg, –15·2 (0·9) mm Hg mg, and –11·5 (0·9) mm Hg respectively.

• For the readings recorded above, the difference versus placebo was –3·8 mm Hg (p=0·0042) and –3·7 mm Hg (p=0·0046), respectively.

• For 24 h ambulatory, the respective difference in systolic blood pressure was –4·2 mm Hg and –5·9 mm.

• The office systolic blood pressure significantly increased with placebo versus aprocitentan after four weeks of withdrawal (5·8 mm Hg, p<0·0001).

• In patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, the most frequent adverse event was mild-to-moderate oedema or fluid retention, which occurred in 9%, 18%, and 2%, respectively (during the 4-week double-blind part).

• Seven patients treated with aprocitentan were discontinued.

• A total of 11 treatment-emergent deaths occurred and were unrelated to the treatment.

They concluded that aprocitentan is well tolerated and superior compared to a placebo in patients with resistant hypertension. It lowers blood pressure at week 4 with a sustained effect at week 40.

The study was funded by Idorsia Pharmaceuticals and Janssen Biotech, as acknowledged.

Further reading:

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial. Schlaich et al. The Lancet.

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