Commentary

Aldosterone Synthase Inhibitors as a Therapeutic Option for Patients With Resistant Hypertension

AUTHOR:
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC

CITATION:
Bloch MJ. Aldosterone synthase inhibitors as a therapeutic option For patients with resistant hypertension. Consultant360. Published online March 20, 2023.

Disclosure: Dr Bloch serves as a Principal Investigator for studies of renal denervation and serves a paid consultant to Recor Medical and Medtronic who are developing investigational renal denervation platforms.

Despite the wide-spread availability of inexpensive, well-tolerated antihypertensive medications, approximately 20% of all patients with hypertension have apparently treatment-resistant hypertension, which is defined by the American Heart Association/American College of Cardiology (ACC/AHA) guidelines as a blood pressure (BP) above target despite the concurrent use of three antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic.1 The PATHWAYS-2 study demonstrated that the mineralocorticoid receptor antagonist (MRA) spironolactone was safe and effective in the treatment of patients with resistant hypertension.2 Based on this and other studies, the ACC/AHA Scientific Statement on Resistant Hypertension suggests that spironolactone be the preferred fourth medication in most patients with resistant hypertension.3 Yet, spironolactone remains underutilized in resistant hypertension, in part because of the real and perceived risk of intolerance.

Inhibition of aldosterone synthesis has been proposed as a potential alternative to blocking the mineralocorticoid receptor. The recently published BrightHTN study examined the use of the investigational aldosterone synthase inhibitor baxdrostat in patients with resistant hypertension.4 In this double-blind, prospective, multicenter trial, a total of 248 patients whose office BP was greater than 130/80 mmHg despite receiving stable doses of at least three hypertensive agents, including a diuretic, were randomly assigned to receive one of three doses of baxdrostat or matching placebo for 12 weeks. Key exclusion criteria included a glomerular filtration rate (GFR) of less than 45 per minute per 1.73m2, uncontrolled diabetes or use of an MRA or potassium-sparing diuretic in the four weeks before the patients were randomly assigned. The prespecified primary endpoint was change in office systolic BP from baseline to week 12 in each baxdrostat group as compared with placebo.

After 12 weeks of baxdrostat therapy, dose-dependent decreases in office systolic BP were -20.3 mmHg, -17.5 mmHg, -12.1 mHg, and -9.4 mmHg in the 2 mg, 1 mg, 0.5 mg, and placebo groups respectively. The placebo-corrected difference in systolic BP was 11.0 mmHg in the 2 mg group. Hyperkalemia was exceedingly rare, renal function remained stable, and baxdrostat was generally well tolerated. As expected, the baxdrostat groups had a decrease in plasma aldosterone levels and a compensatory increase in plasma renin activity.

Based on their mechanism of action, aldosterone synthase inhibitors block the actions of aldosterone without the off-target steroid receptor effects of gynecomastia in men and menstrual irregularities and post-menopausal bleeding in women that are sometimes seen with spironolactone and to a lesser extent eplerenone (which is a more selective MRA) but should share the same risks of azotemia and electrolyte disturbances as these established therapies. The exclusion of patients with a GFR less than 45 and inclusion of relatively few patients with GFR less than 60 is an important limitation of this study. The relative merits of this investigational strategy over established MRA inhibitors remains to be seen and will also require some degree of economic analysis since spironolactone is a widely available and inexpensive medication.

The unexpected -9.4 mmHg reduction in systolic BP from baseline in the placebo group highlights the importance of placebo or sham control in studies of resistant hypertension. Although the exact reasons for this reduction in the placebo group are unknown, we do know that variable adherence with background anti-hypertensive medications has been a problem in previous clinical trials in resistant hypertension. Of note, this change in the placebo group was seen despite a 2-week single blind placebo run in where adherence of at least 70% was confirmed prior to randomization. The use of office BP as the primary endpoint in this clinical trial mirrors the endpoint generally used in clinical practice but is more susceptible to placebo effect than 24-hour ambulatory BP monitoring that has been utilized in many other studies of resistant hypertension.

We certainly know that suboptimal adherence to daily medications is a significant contributor to apparently treatment-resistant hypertension. As a once daily oral medication, the ultimate effectiveness of baxdrobat would be impacted by adherence, especially if indicated only in patients already on three or more background medications. How this strategy would compare with less adherence-dependent strategies like renal denervation or long-term injectable therapies in patients with resistant hypertension remains to be determined.5

References:

  1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065
  2. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068. doi:10.1016/S0140-6736(15)00257-3
  3. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:e53-e90. doi:10.1161/hyp.0000000000000084
  4. Freeman MW, Halvorsen YD, Marshall W, et al. Phase 2 trial of baxdrostat for treatment-resistant hypertension. New Eng J Med. 2023;388:395-405. doi:10.1056/nejmoa2213169
  5. Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomized, multicenter, single-blind, sham-controlled trial. Lancet. 2021;397:2476-2486. doi:10.1016/S0140-6736(21)00788-1