Among individuals with cardiovascular disease or high cardiovascular risk and uncontrolled hypertension on multiple anti-hypertensive agents, a single subcutaneous dose of zilebesiran 300 mg led to a 5-mmHg reduction in systolic blood pressure at Month 3 compared with placebo, a difference that did not reach statistical significance. These results were presented as a late-breaking trial in a Hot Line session today at ESC Congress 2025.
High blood pressure (BP) is one of the largest modifiable contributors to global death and disability. Despite the wide availability of oral antihypertensives, many patients do not achieve or maintain adequate BP control, with poor adherence thought to be a contributing factor.
New therapeutic approaches are clearly needed to help address the global burden of hypertension. Zilebesiran is an investigational RNA interference therapeutic with a prolonged duration of action that reduces the production of angiotensinogen - the most upstream precursor in the renin-angiotensin-aldosterone system (RAAS) and a key player in BP regulation. In the phase II KARDIA-2 trial, a single subcutaneous dose of zilebesiran significantly reduced BP at 6 months when added to a single antihypertensive medication in patients with uncontrolled hypertension. We conducted the phase II KARDIA-3 trial to evaluate zilebesiran added on to multiple antihypertensives in patients with uncontrolled hypertension with cardiovascular disease (CVD) or at high cardiovascular risk."
Doctor Neha Pagidipati, trial presenter from the Duke Clinical Research Institute, Durham, USA
The double-blind, placebo-controlled, randomized trial was conducted in five countries. The trial included adult patients with established CVD or high cardiovascular risk (10-year atherosclerotic CVD risk score >15% or an estimated glomerular filtration rate [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 two to four antihypertensives (including either a calcium channel blocker or a diuretic). Results were analysed from participants with eGFR ≥45 mL/min/1.73 m2; results from participants with eGFR 30 to <45 mL/min/1.73 m2 will be reported separately. Participants in this analysis were randomized 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. The primary outcome was change from baseline in mean office SBP at 3 months.
The 270 patients analysed had a median age of 67 years and 45% were female. Approximately 23% had prior CVD and 77% were at high cardiovascular risk. At baseline, mean office SBP and diastolic BP (DBP) were 144 mmHg and 80 mmHg, respectively, while mean 24-hour ambulatory SBP and DBP were 142 mmHg and 79 mmHg, respectively. Participants were on two (53%), three (36%) or four (11%) antihypertensives at baseline.
For the primary endpoint, the placebo-adjusted mean change in office SBP at Month 3 was − 5.0 mmHg (95% confidence interval [CI] −9.9 to −0.2) with zilebesiran 300 mg and −3.3 mmHg (95% CI −8.2 to 1.6) with zilebesiran 600 mg. Neither were statistically significant after adjusting for multiplicity.
Placebo-adjusted mean changes in office SBP at Month 6 were −3.9 (95% CI −8.5 to 0.7) and −3.6 (95% CI −8.2 to 1.0) for zilebesiran 300 mg and 600 mg, respectively. Placebo-adjusted mean changes in 24-hour ambulatory SBP at Month 6 were −5.5 mmHg (95% CI −9.4 to −1.5) and −7.4 mmHg (95% CI −11.3 to −3.4) for zilebesiran 300 mg and 600 mg, respectively. Placebo-adjusted change in nighttime SBP at Month 6 was −6.6 mmHg (95% CI −11.0 to −2.2) with 300 mg and −8.2 mmHg (95% CI −12.6 to −3.8) with 600 mg. Because the primary endpoint was not statistically significant, significance for secondary outcomes could not be claimed.
In a post-hoc analysis of patients receiving a diuretic with SBP ≥140 mmHg at baseline, zilebesiran 300 mg resulted in placebo-adjusted mean office SBP lowering of −9.2 mmHg (95% CI −17.3 to −1.2) at Month 3.
For the double-blind period, most adverse events, including hyperkalaemia, kidney dysfunction and hypotension, were mild or moderate, non-serious and transient, with few requiring intervention. Across study arms, serious adverse events were observed in 3.8% and 4.5% in zilebesiran and placebo-treated patients, respectively.
Summarizing, Doctor Pagidipati said: "In KARDIA-3, a single dose of zilebesiran 300 mg led to a 5-mmHg reduction in SBP at 3 months compared with placebo, a difference which did not reach statistical significance. However, the trial met its objective of informing the design of future trials. The totality of the 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."
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