Aldosterone pathway blockade therapies for resistant hypertension: An update

Abstract

Dear Editor, Resistant hypertension (RH) is defined as the persistent blood pressure (BP) elevation above the target values utilizing three antihypertensive medications (a diuretic should be part of therapy) at the highest doses, and this BP elevation is not attributable to the whitecoat effect. If a patient with RH achieves BP control using ≥4 antihypertensive agents, the term describing this situation is “controlled RH.”[1] The advent of new therapies to manage RH is evolving, and some of the antihypertensive therapies that have shown significant benefits in randomized controlled trials are the mineralocorticoid receptor antagonists (MRA) such as spironolactone, eplerenone, and a new selective aldosterone inhibitor (AI), baxdrostat. The PATHWAY-2 and the BrigHTN studies are two of the most important randomized controlled trials demonstrating outstanding outcomes from the MRA and AI treatment in RH. In the PATHWAY-2 trial, patients with RH were randomized to receive spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin (4–8 mg), or placebo for 12 weeks. Then, the dosage with each intervention was doubled after 6 weeks. Spironolactone showed the best reduction in home systolic BP compared to bisoprolol (−4.48 [−5.50 to −3.46]; P < 0.0001), doxazosin (−4.03 [−5.04 to −3.02]; P < 0.0001), and placebo (−8.70 mmHg [95% confidence interval (CI) −9.72 to −7.69]; P < 0.0001). However, serum potassium above 6·0 mmol/L was noted in 6 of the 285 patients that received spironolactone.[2] One of the most ambitious therapies for RH is baxdrostat, which acts by inhibiting aldosterone synthase selectively without altering cortisol levels.[3] The BrigHTN study, a phase 2 multicenter trial, compared the values of systolic BP at 12 weeks in patients with RH receiving either baxdrostat (0.5 mg, 1 mg, or 2 mg) or placebo. The median systolic BP decrease with baxdrostat was −20.3 mmHg (2 mg group), −17.5 mm Hg (1 mg group) and −12.1 mmHg (0.5 mg group). The reduction in systolic BP observed with the placebo group was −9.4 mmHg. The change in systolic BP showed a significant difference between the 2-mg group and the placebo group, with a decrease of 11.0 mmHg (95% CI, −16.4 to −5.5; P < 0.001). Similarly, the 1-mg group also exhibited a significant difference compared to the placebo group, with a decrease of 8.1 mmHg (95% CI, −13.5 to −2.8; P = 0.003). Even though the baxdrostat groups were associated with an increment in the potassium level above 6.0 mmol/L in two patients of the 248 individuals, there was no need for baxdrostat withdrawal or reinitiation. No deaths or serious adverse events (including adrenocortical insufficiency) were linked to baxdrostat.[4] In conclusion, patients with RH can achieve better BP control from MRA and baxdrostat therapies, particularly because of significant systolic BP reduction. However, potassium levels must be monitored in patients receiving these therapies since a few individuals might experience hyperkalemia. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.