Baxdrostat Reduces 24-Hour Blood Pressure in Resistant Hypertension

The Persistent Challenge of Resistant Hypertension

Resistant hypertension remains a major driver of cardiovascular and renal morbidity, characterized by persistently elevated blood pressure despite adherence to at least three antihypertensive medications, including a diuretic [1]. A key pathophysiological contributor to this hard-to-control phenotype is inappropriate aldosterone production, which promotes fluid retention, vascular dysfunction, and target organ damage [2]. To address this, researchers have developed highly selective aldosterone synthase inhibitors, medications designed to suppress aldosterone production without interfering with cortisol synthesis [3]. While earlier phase 2 trials and meta-analyses have demonstrated the blood pressure-lowering potential of agents like baxdrostat, questions have remained regarding their definitive efficacy and safety profiles in larger, late-stage clinical trials [4, 5]. A newly published phase 3 trial now provides rigorous ambulatory blood pressure data to clarify the clinical utility of targeting aldosterone synthesis in this high-risk patient population.

Bax24 Trial Design and Patient Selection

To assess the definitive clinical effect of baxdrostat, researchers launched the Bax24 trial (ClinicalTrials.gov registry NCT06168409). This international, phase 3, randomised, double-blind, placebo-controlled study recruited adults aged 18 years or older across 79 clinical sites in 22 countries, encompassing primary, secondary, and tertiary care facilities alongside dedicated research centers. To meet the rigorous inclusion criteria, participants had to demonstrate a seated systolic blood pressure between 140 mm Hg and 169 mm Hg despite receiving three or more antihypertensive medications, including a diuretic. The study protocol began with a two-week placebo run-in period to establish baseline stability and filter out patients with transient pressure spikes. Following this run-in, patients who maintained a 24-hour ambulatory systolic blood pressure of 130 mm Hg or higher were randomly assigned in a 1:1 ratio to receive either 2 mg baxdrostat or placebo orally once daily for 12 weeks, administered in addition to their background therapy. Randomization was stratified by baseline ambulatory systolic blood pressure (less than 140 mm Hg versus 140 mm Hg and higher) to ensure balanced treatment arms. The primary endpoint was the change in 24-hour ambulatory systolic blood pressure from baseline to week 12. By utilizing 24-hour ambulatory monitoring, a technique that captures continuous readings to provide a more accurate reflection of daily cardiovascular risk than isolated clinic measurements, the investigators ensured robust efficacy data. This endpoint was evaluated using an analysis of covariance, a statistical method that compares treatment effects while adjusting for baseline variations among patients.

Significant Reductions in Ambulatory Blood Pressure

Between March 1, 2024, and April 16, 2025, investigators screened 854 patients for the trial. The strict inclusion criteria resulted in a high exclusion rate, with 437 patients excluded before the placebo run-in and 199 excluded during the run-in phase. Ultimately, 217 patients were randomly assigned to and received either baxdrostat (n=108) or placebo (n=109). The demographic profile of the participants reflected a typical resistant hypertension population, with a median age of 60.0 years (IQR 51.0 to 68.0). The cohort included 140 male patients (65%) and 77 female patients (35%), and 170 participants (78%) were White. The primary efficacy analysis demonstrated that baxdrostat profoundly reduced blood pressure in this difficult-to-treat cohort. At 12 weeks, the change from baseline in the least-squares mean 24-hour ambulatory systolic blood pressure was -16.6 mm Hg (95% CI -18.8 to -14.3) in the baxdrostat group (n=89). In contrast, the change was only -2.6 mm Hg (95% CI -4.7 to -0.4) in the placebo group (n=95). This resulted in a highly significant placebo-corrected difference in 24-hour ambulatory systolic blood pressure of -14.0 mm Hg (95% CI -17.2 to -10.8; p<0.0001). For clinicians managing patients who remain above target blood pressure despite triple therapy, a 14-point reduction in continuous ambulatory pressure is highly clinically relevant, as drops of this magnitude are strongly associated with decreased risks of stroke, myocardial infarction, and progressive renal decline.

Safety Profile and Hyperkalemia Monitoring

In the safety analysis, investigators monitored all participants who received at least one dose of the study medication. Overall, adverse events occurred in 56 (52%) of 108 patients in the baxdrostat group, compared with 40 (37%) of 109 patients in the placebo group. Because modulating the aldosterone pathway inherently reduces renal potassium excretion, researchers closely tracked electrolyte levels throughout the 12-week period. Severe hyperkalemia, defined as a confirmed potassium level of more than 6 mmol/L, occurred in three (3%) of the 108 baxdrostat recipients. In contrast, this degree of potassium elevation occurred in none of the placebo recipients. For practicing physicians, these data underscore the necessity of routine electrolyte monitoring when prescribing agents that target this hormonal axis, particularly in patients with underlying chronic kidney disease who may be more susceptible to potassium retention. Ultimately, aldosterone dysregulation is a well-established driver in the pathogenesis of hard-to-control hypertension. By demonstrating substantial blood pressure reductions alongside a manageable safety profile, the Bax24 findings provide compelling evidence that selective aldosterone synthase inhibition could become a vital therapeutic option for patients who have exhausted standard antihypertensive regimens.

References

1. Nardoianni G, Pala B, Scoccia A, Volpe M, Barbato E, Tocci G. Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.. High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2024. doi:10.1007/s40292-024-00634-4

2. Flack JM, Azizi M, Brown JM, et al. Baxdrostat for uncontrolled and resistant hypertension: rationale and design of the Phase 3 clinical trials BaxHTN, BaxAsia, and Bax24.. Hypertension research : official journal of the Japanese Society of Hypertension. 2025. doi:10.1038/s41440-025-02297-7

3. Freeman MW, Halvorsen Y, Marshall W, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.. The New England journal of medicine. 2023. doi:10.1056/NEJMoa2213169

4. Elbahloul MA, Ali A, Al-Shammari ALIS, et al. Aldosterone synthase inhibitors for resistant or uncontrolled hypertension: a network meta-analysis of randomized clinical trials. Journal of Hypertension. 2026. doi:10.1097/hjh.0000000000004264

5. Zhang Y, Huang C, Liu L, et al. Efficacy and Safety of Aldosterone Synthase Inhibitors for Resistant Hypertension: A Systematic Review and Meta-Analysis. Reviews in Cardiovascular Medicine. 2025. doi:10.31083/rcm39555