A Randomized, Double-Blind, Dose-Ranging Study of Zilebesiran in Patients With Mild-to-Moderate Hypertension - KARDIA-1

Contribution To Literature:

Highlighted text has been updated as of February 27, 2024.

The KARDIA-1 trial showed that subcutaneous zilebesiran is associated with sustained reduction in systolic blood pressure.

Description:

The goal of the trial was to evaluate zilebesiran compared with placebo among patients with hypertension. Zilebesiran is a subcutaneous injectable that targets hepatic angiotensinogen (AGT) synthesis by RNA interference.

Study Design

  • Randomized
  • Parallel
  • Blinded
  • Placebo

Patients with hypertension were randomized to zilebesiran 150 mg every 6 months (n = 78) vs. zilebesiran 300 mg every 6 months (n = 73) vs. zilebesiran 300 mg every 3 months (n = 75) vs. zilebesiran 600 mg every 6 months (n = 76) vs. placebo (n = 76).

  • Total number of enrollees: 378
  • Duration of follow-up: 6 months
  • Mean patient age: 57 years
  • Percentage female: 44%

Inclusion criteria:

  • 18-75 years of age
  • Daytime mean systolic blood pressure ≥135 mm Hg and ≤160 mm Hg

Principal Findings:

The primary outcome, 24-hour mean ambulatory systolic blood pressure change vs. placebo at 3 months, was: –14.1 mm Hg for zilebesiran 150 mg every 6 months, –16.7 mm Hg for zilebesiran 300 mg once every 6 months or every 6 months, and  –15.7 mm Hg for zilebesiran 600 mg every 6 months (p < 0.001 for each group).

Secondary outcomes:

Change in office systolic blood pressure vs. placebo at 6 months: –7.5 mm Hg for zilebesiran 150 mg every 6 months, –10.5 mm Hg for zilebesiran 300 mg every 6 months, –12.1 mm Hg for zilebesiran 300 mg every 3 months, –10.2 mm Hg for zilebesiran 600 mg every 6 months (p < 0.003 for each group).

At least one adverse event: 58% for zilebesiran 150 mg every 6 months, 60% for zilebesiran 300 mg every 6 months, 61% for zilebesiran 300 mg every 3 months, 64% for zilebesiran 600 mg every 6 months.

Serum AGT level was reduced 88% with zilebesiran 150 mg every 6 months vs. 93% for zilebesiran 300 mg every 6 months vs. 98% for zilebesiran 300 mg every 3 months vs. 96% zilebesiran 600 mg every 6 months.

Interpretation:

Among patients with hypertension, the novel subcutaneous injectable zilebesiran improves ambulatory and office systolic blood pressure compared with placebo. This reduction in systolic blood pressure was achieved at 3 months and sustained to 6 months. Adverse events were minimal. Zilebesiran is an RNA interference agent that subsequently lowers AGT synthesis. This was a dose ranging study with zilebesiran being evaluated further in the KARDIA-2 trial.

References:

Bakris GL, Saxena M, Gupta A, et al. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial. JAMA 2024;Feb 16:[Epub ahead of print].

Editorial: Schiffrin EL. RNA Injection Every 6 Months to Improve Adherence and Lower Blood Pressure in Patients With Hypertension. JAMA 2024;Feb 16:[Epub ahead of print].

Presented by Dr. George Bakris at the American Heart Association Scientific Sessions, Philadelphia, PA, November 11, 2023.

Clinical Topics: Prevention, Hypertension, Vascular Medicine

Keywords: AHA23, Blood Pressure, Hypertension, RNA Interference


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