AHA 2022: Trials of New Agents for Resistant Hypertension

Among the wealth of new data presented at the American Heart Association 2022 Scientific Session in Chicago this month were 3 trials looking at new drug treatments for resistant hypertension.

Spoiler: two of the novel agents worked and one did not. 

In the PRECISION trial, investigators tested aprocitentan, a dual endothelin receptor antagonist (ERA). The endothelin pathway has been implicated in the pathogenesis of systemic hypertension, but it is currently not targeted therapeutically. 

PRECISION enrolled 730 patients who had sitting systolic blood pressures of at least 140 mm Hg despite taking standardized background therapy consisting of three antihypertensive drugs, including a diuretic.

During a 4-week double-blind, randomized treatment period, the least square mean change in office systolic blood pressure was –15.3 mm Hg for aprocitentan 12.5 mg, –15.2 mm Hg for aprocitentan 25 mg, and –11.5 mm Hg for placebo (difference versus placebo –3.8 mm Hg (p=0.0042) and –3.7 mm Hg (p=0.0046), respectively). The respective differences in 24-hour ambulatory systolic blood pressure were –4.2 mm Hg and –5.9 mm Hg, respectively.

Markus Schlaich, MD, the trial’s presenter, and the scheduled discussant for the session, Suzanne Oparil, MD, both agreed aprocitentan may represent a new alternative pharmacological approach to treating resistant hypertension.

In the BrigHTN trial, baxdrostat, an investigational selective inhibitor of aldosterone synthase, the enzyme that makes aldosterone, “significantly and substantially” reduced systolic and diastolic blood pressure in patients with treatment-resistant hypertension, reported Mason W. Freeman, MD, a professor of medicine at Harvard Medical School and the executive VP of clinical development at CinCor Pharma, the company developing baxdrostat. 

Baxdrostat also reduced serum aldosterone levels and increased plasma renin activity and demonstrated a favorable safety profile.

In the 248 patients who 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 1-mg and the 2-mg groups and the placebo group was -8.1 mm Hg (p=0.003) and −11.0 mm Hg (p<0.001), respectively.

PRECISION and BrigHTN were both published simultaneously to their AHA presentation. 

In a third trial, this one called FRESH, George Bakris, MD (a K2P faculty member) presented data on firibastat, a first-in-class inhibitor of aminopeptidase-A that prevents conversion of angiotensin II into angiotensin III at the brain level. 

In the phase 3 FRESH study, which included 515 patients with difficult-to-treat and resistant hypertension, firibastat failed to demonstrate efficacy for its primary endpoint of change from baseline in unattended systolic blood pressure at 12 weeks. Results were consistent across all the sub-groups and secondary endpoints, and the drug was generally well tolerated but caused skin reaction in 5.1% of treatment patients. 

“So, we’ve got two winners and unfortunately one agent that seems not to have panned out, but clearly these agents are exciting because not only do they lower blood pressure, but they act by novel mechanisms of action and may be better tolerated in many patients,” Dr. Oparil said in summary. 

Recent Hypertension Content in CurrentMD Cardiology

CurrentMD Cardiology provides content ranging from core cardiology basics to advanced subspecialty training. This includes a wealth of hypertension content providing tools for success to all providers who treat patients with hypertension. 

Here’s a list of hypertension-focused micro-learning activities added to CurrentMD Cardiology (since February 2022):

Prevention: Cardiovascular Risk

• “Prevention Across the Lifespan” by Ty Gluckman, MD, and Martha Gulati, MD, MS (38 min)
• “Cardiovascular Risk Assessment: Clinical Cases” by Ty Gluckman, MD (20 min)
• “Clinical Guidance on Cardiovascular Sequelae with COVID-19” by Nicole Bhave, MD, and Ty Gluckman, MD (31 min)

Prevention: Chronic Kidney Disease

• “CKD Part 1 – Epidemiology and Risk Mechanisms” by George Bakris, MD (16 min)
• “CKD Part 2 – Implications for Management” by George Bakris, MD (20 min)

Prevention: Hypertension

• “Hypertension in Pregnancy” by Odayme Quesada, MD (19 min)
• “Expert Perspective: The Art of Hypertensive Therapies” by George Bakris, MD (21 min)
• “Secondary Hypertension” by George Bakris, MD (8 min)
• “Resistant Hypertension” by George Bakris, MD (15 min)
• “Blood Pressure Management” by Karol Watson, MD, PhD (17 min)
• “Hypertension Therapies” by Karol Watson, MD, PhD (24 min)

For a full list of CME/MOC-accredited micro-learning activities recently added to CurrentMD Cardiology, click here. To learn more about CurrentMD, click here.