Hot Line 4: KARDIA-3
31 Aug 2025
Hot Line ESC Congress 2025 Zilebesiran in patients with uncontrolled hypertension and high CV risk: KARDIA-3
Doctor Neha Pagidipati (Duke Clinical Research Institute - Durham, USA) presented the key findings from the KARDIA-3 trial evaluating zilebesiran, an RNA interference therapeutic agent that inhibits hepatic angiotensinogen synthesis.
The double-blind phase II trial included patients with established cardiovascular disease (CVD) or high cardiovascular risk (10-year risk >15% or eGFR 30–59 ml/min/1.73 m2) with uncontrolled hypertension (mean screening office systolic BP [SBP] 140–170 mmHg and 24-hour mean ambulatory SBP 130–170 mmHg) on 2–4 antihypertensives (including either a calcium channel blocker or a diuretic). Results were presented from participants with eGFR ≥45 ml/min/1.73 m2. Participants were randomised 1:1:1 to a single subcutaneous dose of zilebesiran 300 mg or 600 mg or placebo. In the first 3 months, investigators were encouraged not to change the background antihypertensive therapy unless SBP was >160 mmHg or unless clinically indicated. After 3 months, investigators could intensify antihypertensive therapy for patients with persistent SBP >140 mmHg.
For the primary endpoint at 3 months, the placebo-adjusted mean change in office SBP was –5.0 mmHg with zilebesiran 300 mg and –3.3 mmHg with zilebesiran 600 mg.
Neither were statistically significant after adjusting for multiplicity.
Placebo-adjusted change in nighttime SBP at 6 months was –6.6 mmHg with 300 mg and –8.2 mmHg with 600 mg. In a post-hoc analysis of patients receiving a diuretic and with SBP ≥140 mmHg at baseline, zilebesiran 300 mg resulted in placebo-adjusted mean office SBP lowering of –9.2 mmHg at 3 months.
Most adverse events, including hyperkalaemia, kidney dysfunction and hypotension, were mild or moderate, non-serious and transient, with few patients requiring intervention. Across study arms, serious adverse events were observed in 3.8% and 4.5% in zilebesiran- and placebo-treated patients, respectively.
Summarising, Dr. Pagidipati said: “In KARDIA-3, a single dose of zilebesiran 300 mg led to a 5-mmHg SBP reduction at 3 months vs. placebo, a difference which did not reach statistical significance. The totality of evidence from the phase II programme supports the conduct of a phase III outcomes trial to further assess the potential of zilebesiran for improving cardiovascular outcomes in patients with uncontrolled hypertension.”
