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Baxdrostat for Treatment-Resistant Hypertension

In the BrigHTN trial, patients with treatment-resistant hypertension had dose-related reductions in blood pressure when taking the aldosterone synthase inhibitor baxdrostat. “The reduction in blood pressure was associated with a decrease in the plasma aldosterone level and a compensatory increase in plasma renin activity, without a reduction in the cortisol level,” the authors write. “Baxdrostat generally had an acceptable side-effect profile, and none of the patients discontinued the trial because of hyperkalemia.”

Participants in the phase 2, placebo-controlled trial had baseline blood pressures of 130/80 mm Hg or higher while taking at least 3 antihypertensive agents, including a diuretic. They were randomized to baxdrostat 0.5 mg, 1 mg, or 2 mg once daily for 12 weeks or placebo.

Based on a primary end point of change in systolic blood pressure from baseline to week 12, the investigators found: “A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of −20.3 mm Hg, −17.5 mm Hg, −12.1 mm Hg, and −9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was −11.0 mm Hg (95% confidence interval [CI], −16.4 to −5.5; P <0.001), and the difference in this change between the 1-mg group and the placebo group was −8.1 mm Hg (95% CI, −13.5 to −2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.”

Editorial: “These trial results open new perspectives for treating patients with resistant hypertension, as well as for treating those with primary aldosteronism, which includes massive aldosterone excess,” writes an editorialist. “However, larger and longer trials that include 24-hour ambulatory blood-pressure monitoring as well as complete steroid profiling are warranted, including an active control group treated with a mineralocorticoid receptor antagonist.”

Editorial: “Among the new therapeutic agents that target the renin–angiotensin–aldosterone system in patients with treatment-resistant hypertension are nonsteroidal mineralocorticoid receptor antagonists and antisense oligonucleotide or small interfering RNA therapies,” editorialists write. “Nonsteroidal mineralocorticoid receptor antagonists such as finerenone and esaxerenone have a longer plasma half-life than spironolactone and are specific for the mineralocorticoid receptor, with no evident hormonal side effects. Antisense oligonucleotides and RNA-interference oligonucleotides that are designed to target the synthesis of angiotensinogen in the liver are under investigation in patients with treatment-resistant hypertension.”

Source: New England Journal of Medicine