Late-breaking data at AHA from pivotal phase III PRECISION study demonstrates significant and sustained effect of aprocitentan on lowering blood pressure for patients with difficult-to-control hypertension

These data were presented as a Late-Breaking Science presentation during the American Heart Association (AHA) Scientific Sessions 2022 (Session: LBS.09) and simultaneously published in The Lancet.

Hypertension (HTN), or high BP (usually defined as 140/90 mmHg or above), is one of the leading causes of cardiovascular disease worldwide, impacting an estimated 1.3 billion people globally. Approximately 10% of these people have difficult-to-control HTN, despite receiving at least three antihypertensive medications. Research has suggested difficult-to-control HTN may be due to a lack of treatment targeting all the underlying mechanisms of the condition, in particular the endothelin (ET) pathway, which plays an important role in the development of HTN. Compared with adults whose HTN is well controlled, adults with difficult-to-control HTN have greater risk of heart attack, stroke, end-stage renal disease (ESRD) and heart failure.

“The challenge to achieve better BP control in patients with resistant hypertension is at least in part due to the fact that currently available treatment options leave relevant pathophysiologic mechanisms unopposed,” said Prof. Markus Schlaich, M.D., FAHA, FESC, ISHF, The University of Western Australia / Royal Perth Hospital, an investigator in the PRECISION study. “The results of PRECISION demonstrate aprocitentan is a novel and generally well-tolerated potential treatment strategy for resistant hypertension with clinically meaningful and sustained blood pressure lowering effect.”

PRECISION evaluated the short-term and sustained effects of aprocitentan on BP lowering when added to standardized combination background antihypertensive therapy in patients with difficult-to-control HTN. A total of 730 hypertensive patients with difficult-to-control HTN were enrolled in the three-part study: i. From baseline through week 4 (part 1), the double-blind period, patients were randomized to receive aprocitentan 12.5 mg (n=243), aprocitentan 25 mg (n=243), or placebo (n=244) in a 1:1:1 ratio. ii. From weeks 4-36 (part 2), the single-blind period, patients who continued to part 2 (n=704) received 25 mg aprocitentan. iii. From weeks 36-48 (part 3), the double-blind withdrawal period, patients were re-randomized to receive either aprocitentan 25 mg (n=307) or placebo (n=307) in a 1:1 ratio. At baseline, 69.2% of patients were obese or severely obese, 54.1% had diabetes, 22.2% had stage 3-4 chronic kidney disease and 19.6% had congestive heart failure.

Key PRECISION Findings: The PRECISION study met its primary efficacy endpoint, which was the change in sitting systolic blood pressure (SBP), as measured by unattended automated office BP, from baseline to week 4. Specifically, after 4 weeks, aprocitentan significantly reduced SBP compared with placebo (mean change of -15.3 mmHg for aprocitentan 12.5 mg dose, -15.2 mmHg for 25 mg dose and -11.5 mmHg for placebo, for a difference versus placebo of -3.8 mmHg in the 12.5 mg group [97.5% confidence interval [CI]: -6.8, -0.8; p = 0.0042] and -3.7 mmHg in the 25 mg group [97.5% CI: -6.7, -0.8; p=0.0046]).

In addition to meeting its primary endpoint, the study also met its key secondary efficacy endpoint, showing sustained SBP lowering in patients receiving aprocitentan compared to placebo between week 36 and week 40. Specifically, at week 40, SBP increased with placebo compared to aprocitentan 25 mg, for a significant difference of +5.8 mmHg (95% CI: +3.7, +7.9; p<0.0001). this difference was sustained for the final part of the study (the entire 12-week double-blind withdrawal period), up to 48 weeks.

Other key findings included: i. Similar BP lowering effects for aprocitentan were observed with ambulatory BP monitoring, which measured BP in regular intervals over a 24-hour period, at both week 4 and week 40. Specifically, the ambulatory SBP results at week 4 showed greater BP lowering effects with aprocitentan compared with placebo (12.5 mg dose: -4.2 mmHg, 95% CI: -6.2, -2.1; 25 mg dose: -5.9 mmHg, 95% CI: -7.9, -3.8). At week 40, 24-hour ambulatory SBP increased with placebo compared with aprocitentan (+6.5 mmHg; 95% CI: +4.6, +8.5). ii. Treatment effect of aprocitentan was consistent across various prespecified subgroups, including sex, age, body mass index, race and geographic area.

Treatment-emergent adverse events (TEAEs) during the 4-week double-blind study period (Part 1) were reported in 28% and 37% of the patients treated with 12.5 and 25 mg aprocitentan, respectively, versus 19% in the placebo group. The most frequent adverse event with aprocitentan was mild-to-moderate fluid retention leading to discontinuation in seven patients during the study. Fluid retention was reported more frequently with aprocitentan than with placebo in a dose-dependent fashion (9.1%, 18.4%, and 2.1% for patients receiving aprocitentan 12.5 mg, 25 mg and placebo, during Part 1, respectively; 18.2% for patients receiving aprocitentan 25 mg during Part 2; and 2.6% and 1.3% for patients on aprocitentan 25 mg and placebo, during Part 3, respectively).

See;"Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase III trial." Prof Markus P Schlaich, MD ,Marc Bellet, MD, Prof Michael A Weber, MD,Prof George L Bakris, MD,et al. Published:November 07, 2022DOI:https://doi.org/10.1016/S0140-6736(22)02034-7.