Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension

Abstract

Background: Aldosterone dysregulation plays an important pathogenic role in hard-to-control hypertension. In several studies, baxdrostat, an aldosterone synthase inhibitor, reduced the seated systolic blood pressure of patients with uncontrolled or resistant hypertension.

Methods: In this phase 3, multinational, double-blind, randomized, placebo-controlled trial, we recruited patients with a seated systolic blood pressure of between 140 mm Hg and less than 170 mm Hg despite the receipt of stable treatment with two antihypertensive medications (uncontrolled hypertension) or three or more such medications (resistant hypertension), including a diuretic. After a 2-week placebo run-in period, we randomly assigned patients with a seated systolic blood pressure of 135 mm Hg or more in a 1:1:1 ratio to receive baxdrostat at a dose of 1 mg, baxdrostat at a dose of 2 mg, or placebo once daily for 12 weeks. The primary end point was the change in seated systolic blood pressure from baseline to week 12.

Results: A total of 796 patients underwent randomization and 794 received 1-mg baxdrostat (264 patients), 2-mg baxdrostat (266 patients), or placebo (264 patients) in addition to background therapy. At 12 weeks, the change from baseline in the least-squares mean seated systolic blood pressure was -14.5 mm Hg (95% confidence interval [CI], -16.5 to -12.5) with 1-mg baxdrostat, -15.7 mm Hg (95% CI, -17.6 to -13.7) with 2-mg baxdrostat, and -5.8 mm Hg (95% CI, -7.9 to -3.8) with placebo. The estimated difference from placebo (placebo-corrected difference) was -8.7 mm Hg (95% CI, -11.5 to -5.8) with 1-mg baxdrostat and -9.8 mm Hg (95% CI, -12.6 to -7.0) with 2-mg baxdrostat (P<0.001 for both comparisons). A potassium level of more than 6.0 mmol per liter was reported in 6 patients (2.3%) with 1-mg baxdrostat, in 8 patients (3.0%) with 2-mg baxdrostat, and in 1 patient (0.4%) with placebo.

Conclusions: Among patients with uncontrolled or resistant hypertension, the addition of baxdrostat to background therapy resulted in a significantly lower seated systolic blood pressure at 12 weeks than placebo. (Funded by AstraZeneca and others; BaxHTN ClinicalTrials.gov number, NCT06034743.).

Figure 1. Blood Pressure Changes in Participants with Uncontrolled or Resistant Hypertension.

The line graphs show time courses for LSM change from baseline in seated systolic blood pressure up to week 12 (Panel A), change from randomized withdrawal period baseline (week 24) in seated systolic blood pressure up to week 32 (Panel B), change from baseline in seated systolic blood pressure up to week 12 in the resistant hypertension subpopulation (Panel C), and change from baseline in seated diastolic blood pressure up to week 12 (Panel D). I bars on the line graphs indicate the standard error. LSM denotes least-squares mean.

Figure 2. Change from Baseline in Seated Systolic Blood Pressure at Week 12 by Subgroup for Baxdrostat 2 mg versus Placebo.

Forest plot shows least-squares mean difference versus placebo for change from baseline in seated systolic blood pressure at week 12 with baxdrostat 2 mg by subgroup. The analysis was performed within each subgroup category using an ANCOVA model with treatment and baseline hypertension (uncontrolled hypertension, resistant hypertension) as factors, and baseline seated systolic blood pressure value as a covariate. For the baseline hypertension subgroup analysis, the baseline hypertension factor was removed from the ANCOVA models for uncontrolled and resistant hypertension categories. Missing data were handled via multiple imputation. Circle denotes the point estimate. The widths of confidence intervals have not been adjusted for multiplicity and cannot be used to infer treatment effects. ANCOVA denotes analysis of covariance, CI confidence interval, and eGFR estimated glomerular filtration rate.