Clinical Pearls & Morning Reports
Published February 1, 2023
Freeman et al. conducted a phase 2, placebo-controlled trial that assessed the efficacy and safety of baxdrostat in patients with treatment-resistant hypertension who continued to receive stable doses of at least three antihypertensive medications, including a diuretic. Read the NEJM Original Article here.
Q: How is treatment-resistant hypertension currently defined and managed?
A: Treatment-resistant hypertension is defined as elevated blood pressure despite concurrent use of at least three antihypertensive drugs of different classes, including a diuretic. Current guidelines recommend the addition of spironolactone, a mineralocorticoid receptor antagonist, as a fourth-line agent despite common, dose-limiting adverse effects. A total of 40 to 50% of patients with hypertension remain inadequately treated, and yet no new class of antihypertensive medication has been approved since 2007.
Q: Describe a key feature of the aldosterone synthase inhibitor baxdrostat.
A: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.
A: Enrolled patients received baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. After the prespecified interim analysis, the trial was stopped early because the independent data monitoring committee concluded that the trial had met the criteria for overwhelming efficacy. At week 12, baxdrostat was associated with dose-dependent changes in the least-squares mean (±SE) systolic blood pressure of -20.3±2.1 mm Hg, -17.5±2.0 mm Hg, and -12.1±1.9 mm Hg at the 2-mg, 1-mg, and 0.5-mg doses, respectively. As compared with the change in systolic blood pressure of -9.4 mm Hg in the placebo group, there were significantly greater decreases in systolic blood pressure in the 2-mg baxdrostat group (difference between the 2-mg group and the placebo group, -11.0 mm Hg; 95% confidence interval [CI], -16.4 to -5.5; P<0.001) and in the 1-mg baxdrostat group (difference between the 1-mg group and the placebo group, -8.1 mm Hg; 95% CI, -13.5 to -2.8; P = 0.003), but these decreases were not significantly greater with the 0.5-mg dose.
A: The limitations of the present phase 2 dose-ranging trial include the fact that it was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks, nor to compare aldosterone synthase inhibition with alternative antihypertensive agents. The selection of patients with an estimated glomerular filtration rate greater than 45 ml per minute reduced the likelihood of hyperkalemia, and planned longer-term studies may determine whether the incidences of hyperkalemia and other adverse events differ from those reported for currently licensed drugs. The inclusion of patients with at least 70% adherence (assessed on the basis of pill counts) was based on the PATHWAY-2 trial, in which high adherence was confirmed in a subgroup of patients by means of urinary drug analysis. Excluded patients might have had a lower response to baxdrostat.