Two hot line trials – BaxHTN and KARDIA-3 – presented at ESC Congress 2025 explore treatment options for patients with uncontrolled hypertension.

In BaxHTN, the addition of baxdrostat (1 mg or 2 mg once daily) to background antihypertensive therapy resulted in statistically significant reductions in systolic blood pressure (SBP) at 12 weeks as compared with placebo among patients with uncontrolled or resistant hypertension.

The four-part trial, simultaneously published in NEJM, involved 796 patients at 2014 sites across multiple countries. All participants were adults with a mean seated blood pressure of 149 mmhg/85 mmhg despite treatment with maximally tolerated doses of two antihypertensives or at least three antihypertensives, including a diuretic, for ≥4 weeks before screening. The median age of participants was 62 years, 39% were women, 27% had uncontrolled hypertension and 73% had resistant hypertension.

In part 1 of the trial, participants were randomized to receive either baxdrostat (1 mg), baxdrostat (2 mg) or placebo once daily for 12 weeks. At the end of the 12-week period, placebo-adjusted reductions in seated SBP from baseline (the primary endpoint) were −8.7 mmHg for the 1 mg dose and −9.8 mmHg for the 2 mg dose.

Study investigators noted that changes associated with baxdrostat were consistent across prespecified subgroups, including uncontrolled and resistant hypertension. In addition, an exploratory analysis found substantial reductions in mean ambulatory 24-hour and night-time average SBP among patients receiving baxdrostat (2 mg). After 12 weeks, the proportion of patients with controlled SBP was 39.4% in the baxdrostat (1 mg) group, 40% in the baxdrostat (2 mg) group and 18.7% in the placebo group.

In part 2, the trial involved a 12-week open-label period where patients were randomized to receive 2 mg of baxdrostat (n=483) or standard care (n=245). At the end of this period, seated SBP was 133 mmHg, according to researchers.

During part 3, which consisted of an 8-week randomized withdrawal period among 257 patients assigned to either baxdrostat (2 mg) or placebo, patients in the placebo group had a mean SBP increase (+1.4 mmHg), while those continuing baxdrostat (2 mg) saw a further mean reduction of −3.7 mmHg; p=0.0016).

Part 4 of the trial, looking at longer-term safety analysis from week 32 to week 52, is ongoing. However, in the first 12 weeks, serious adverse events were reported in 1.9% of patients in the baxdrostat (1 mg) group, 3.4% in the baxdrostat (2 mg) group and 2.7% in the placebo group. Hyperkalemia led to discontinuation in 0.8% of patients taking baxdrostat (1 mg) and 1.5% taking baxdrostat (2 mg).

"These BaxHTN trial findings are an important advance in treatment and in our understanding of the cause of hard-to-control BP," said Principal Investigator Bryan Williams, MD. "[They offer] hope for more effective treatment in the future."

In a related editorial comment, Tomasz J. Guzik, MD, PhD, and Maciej Tomaszewski, MD, write: "The next steps will include defining which patients are likely to have the best response for precision therapy, clarifying the use of these drugs as compared with MRAs, standardizing early monitoring, and providing long-term data on durability and event reduction. Success would shift aldosterone synthase inhibition from a promising adjunct to a central pillar of therapy for difficult-to-control hypertension, thereby reinforcing a broader renaissance of natriuretic strategies in blood-pressure control."

Meanwhile, in KARDIA-3, researchers investigated the efficacy and safety of the angiotensinogen RNA-interfering therapeutic, zilebesiran, in patients with cardiovascular disease or at high cardiovascular risk and uncontrolled hypertension.

Overall results found, a single subcutaneous dose of zilebesiran (300 mg) led to a 5-mmHg reduction in SBP at three months compared with placebo. However, this difference did not reach statistical significance.

In presenting the findings, Neha J. Pagidipati, MD, FACC, notes that while the results didn't meet statistical significance, the trial itself met its objective of informing the design of future trials. "The totality of the evidence from the phase II program supports the conduct of a phase III outcomes trial to further assess the potential of zilebesiran for improving cardiovascular outcomes in patients with uncontrolled hypertension," she said.