What are the guidelines for using Zilebesiran in a patient with a history of cardiovascular disease?

Zilebesiran in Patients with Cardiovascular Disease

Zilebesiran is not currently endorsed by any major cardiovascular guidelines for routine use in hypertension management, including in patients with cardiovascular disease, as it awaits supportive evidence from cardiovascular outcomes trials. 1

Current Guideline Status

The 2024 ESC Guidelines explicitly classify zilebesiran as a "new therapy with blood pressure-lowering properties that awaits supportive evidence from cardiovascular outcomes trials prior to guideline endorsement and routine use in hypertension." 1 While the drug shows promising blood pressure reduction, it remains investigational and should not be used outside of clinical trial settings until outcomes data are available.

Mechanism and Clinical Trial Evidence

Zilebesiran is an RNA interference therapeutic that inhibits hepatic angiotensinogen synthesis through subcutaneous administration, with a single dose reducing 24-hour blood pressure over approximately 6 months. 1

Blood Pressure Efficacy

• In the KARDIA-1 phase 2 trial, zilebesiran doses ranging from 150-600 mg administered every 3-6 months produced systolic blood pressure reductions of 14-17 mm Hg compared to placebo at 3 months (P < 0.001 for all doses). 2
• Single doses ≥200 mg achieved sustained reductions in systolic blood pressure >10 mm Hg and diastolic blood pressure >5 mm Hg by week 8, with effects persisting up to 24 weeks. 3
• The blood pressure lowering effect was consistent throughout the diurnal cycle. 3

Safety Profile in Clinical Trials

• Over 6 months in KARDIA-1,60.9% of zilebesiran-treated patients experienced adverse events versus 50.7% with placebo, while serious adverse events occurred in only 3.6% versus 6.7% with placebo. 2
• The most common adverse effects were mild injection-site reactions and mild hyperkalemia (16.9% drug-related adverse events versus 8.0% with placebo). 2
• Critically, there were no reports of hypotension, clinically significant hyperkalemia requiring medical intervention, or worsening renal function in phase 1 studies. 3

Critical Limitations for Cardiovascular Disease Patients

Lack of Outcomes Data

No cardiovascular outcomes trials have been completed with zilebesiran, meaning there is zero evidence regarding its effects on mortality, myocardial infarction, stroke, heart failure, or other cardiovascular endpoints in patients with established cardiovascular disease. 1, 4

Specific Concerns in Cardiovascular Disease

• The long duration of action (up to 6 months) raises safety concerns during acute cardiovascular events, volume depletion, sepsis, or situations requiring rapid adjustment of renin-angiotensin-aldosterone system blockade. 4
• There is no data on how zilebesiran performs in patients already taking standard cardiovascular medications (ACE inhibitors, ARBs, beta-blockers, diuretics) that are proven to reduce cardiovascular mortality. 1
• The modest blood pressure reduction (10-17 mm Hg) suggests it would likely need to be used as add-on therapy rather than monotherapy in most cardiovascular disease patients. 4

Guideline-Recommended Alternatives for Cardiovascular Disease

For patients with cardiovascular disease and hypertension, use proven therapies with established mortality and morbidity benefits:

First-Line Agents with Cardiovascular Outcomes Data

• ACE inhibitors or ARBs are indicated in all patients with prior MI, left ventricular systolic dysfunction, diabetes, or chronic kidney disease (Class I, Level A). 1
• Beta-blockers should be started and continued indefinitely in all post-MI patients and those with heart failure (Class I, Level A). 1
• Thiazide or thiazide-like diuretics have demonstrated cardiovascular event reduction in multiple trials including patients with coronary disease. 1, 5
• Calcium channel blockers can be added for additional blood pressure control or symptom management in stable angina. 1

Combination Therapy Approach

• Most cardiovascular disease patients require 2-3 antihypertensive medications for adequate blood pressure control. 1, 5
• Single-pill combinations are preferred to improve adherence. 1, 5
• The combination of beta-blocker, ACE inhibitor/ARB, and thiazide diuretic should be considered for comprehensive cardiovascular protection. 1

Clinical Bottom Line

Until zilebesiran completes cardiovascular outcomes trials demonstrating safety and efficacy in reducing cardiovascular events, mortality, and morbidity, it should not be used in patients with cardiovascular disease. 1 Continue using guideline-directed medical therapy with proven agents (ACE inhibitors/ARBs, beta-blockers, thiazide diuretics, calcium channel blockers) that have decades of evidence supporting their use in reducing cardiovascular death, myocardial infarction, stroke, and heart failure. 1, 5

The investigational nature of zilebesiran, combined with its prolonged duration of action and lack of cardiovascular outcomes data, makes it inappropriate for routine clinical use, particularly in the high-risk population of patients with established cardiovascular disease who require medications with proven mortality benefits. 1, 4