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Aprocitentan superior to placebo in resistant hypertension

Aprocitentan has been found to provide significant reductions in systolic blood pressure in patients with resistant hypertension

Use of aprocitentan in patients with treatment-resistant hypertension provides a superior reduction in systolic blood pressure compared to placebo with a sustained action four weeks after discontinuation according to the results of a randomised, double-blind trial by Australian and US researchers.

The incidence of hypertension, which is a major factor for cardiovascular disease, appears to be on the increase. In a 2021 study, the number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 million women and 317 million men in 1990 to 626 and 652 million respectively in 2019. Resistant hypertension has been defined as above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a diuretic. In fact, the prevalence of resistant hypertension has been found present in 10.3% of the general population. One potential pharmacological target for patients with resistant hypertension is blockage of endothelin, which is a powerful vasoconstrictor peptide derived from the endothelium. Initial studies with a selective endothelin type A antagonist, darusentan, in patients with resistant hypertension, showed that the drug provided additional reduction in blood pressure in patients who had not attained their treatment goals with three or more antihypertensive drugs. Early studies with aprocitentan, which is an orally active, dual endothelin receptor antagonist, found that it was well tolerated and that there were no clinically significant findings for any safety variable. Moreover, in a dose ranging study in patients with essential hypertension, compared to lisinopril 20 mg, aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office blood pressure. This led the authors to conclude that their findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension

In the current study, researchers undertook the PRECISION trial, that recruited patients with a sitting systolic blood pressure of 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts. The first was a 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. In part 2, all patients received aprocitentan 25 mg and in the final part, which was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary endpoint was the change in unattended office systolic blood pressure from baseline to week 4 and the secondary endpoint, the blood pressure changes from withdrawal baseline to week 40.

Aprocitentan and treatment outcomes

A total of 730 participants with a mean age of 61.7 years (59.3% male) were included in part 1 and of whom, 577 (94%) completed part 3 of the study. At screening, between 62 and 65% of participants were receiving > 4 antihypertensive agents.

The change in systolic blood pressure at 4 weeks was -15·3 mm Hg for aprocitentan 12·5 mg, -15·2 mm Hg for aprocitentan 25 mg, and -11·5 mm Hg for placebo. In both cases, the difference compared to placebo was statistically significant (p = 0.0042 and 0.0046) for the 12.5 and 25 mg doses respectively. There was also a significant reduction in diastolic blood pressure (-3.9 mmHg and – 4.5 mmHg) for the 12.5 and 25 mg doses.

After 4 weeks of withdrawal, the office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 – 7·9, p < 0·0001). 

In terms of adverse effects, the most frequent were mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the initial 4-week double-blind phase, leading to treatment discontinuation in seven aprocitentan patients.

The authors concluded that for patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.

Schlaich MP et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 2022