The purpose of this study is to evaluate whether zilebesiran versus placebo reduces the risk of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or heart failure (HF) events. This is an event-driven study that will continue until the targeted number of positively adjudicated primary endpoint clinical outcome events (COEs) have been reached.

Inclusion Criteria:

• Is 18 years or older for patients with established cardiovascular disease (CVD)
• Is 55 years or older for patients with high risk for CVD
• Has established CVD (defined as coronary, cerebrovascular, or peripheral artery disease) or high risk for CVD
• Has treated hypertension on stable therapy with at least 2 standard of care antihypertensive medications, one of which must be a thiazide, thiazide-like, or loop diuretic

Exclusion Criteria:

• Has known history of secondary hypertension
• Has symptomatic orthostatic hypotension
• Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×upper limit of normal (ULN)
• Has total serum bilirubin >1.5×ULN
• Has international normalized ratio (INR) >1.5
• Has serum potassium >4.8 mEq/L
• Has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2

Phase 2-4 trials:

Access to anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Access to data may be declined where there is likelihood a patient could be identified or other feasibility issue, where there is a potential conflict of interest, a planned business activities or an actual or potential competitive risk. Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Timeframes for data access may vary and can take up to 6 months or more.

Requests for access to data can be submitted via the website www.vivli.org. Questions can also be directed to datasharing@alnylam.com.