This study will assess the effect of lowering low-density lipoprotein cholesterol (LDL-C) with evolocumab on major cardiovascular events in adults without a prior myocardial infarction (MI) or stroke who are at high risk of a cardiovascular event.

Inclusion criteria:

• Age: Adult participants ≥ 50 (men) or ≥ 55 (women) to ˂ 80 years of age (either sex) and meeting lipid criteria.

• Lipid Criteria: Low-density lipoprotein cholesterol (LDL-C) ≥ 90 mg/dL (≥ 2.3 mmol/L) or non high-density lipoprotein cholesterol (non-HDL)-C ≥ 120 mg/dL (≥ 3.1 mmol/L), or apolipoprotein B ≥ 80 mg/dL (≥ 1.56 µmol/L).

  3.Diagnostic evidence of at least one of the following (A-D) at screening:

A.Significant coronary artery disease (CAD) meeting at least 1 of the following criteria:

• History of coronary revascularization with multi-vessel coronary disease as evidenced by any of the following:

  1. percutaneous coronary intervention (PCI) of 2 or more vessels, including branch arteries,
  2. PCI or coronary artery bypass grafting (CABG) with residual 50% stenosis in a separate, unrevascularized vessel, or
  3. multi-vessel CABG 5 years or more prior to screening.

• Significant coronary disease without prior revascularization as evidenced by either a ≥70% stenosis of at least 1 coronary artery, ≥50% stenosis of 2 or more coronary arteries, or ≥50% stenosis of the left main coronary artery.

• known coronary artery calcium score ≥100 in participants without a coronary artery revascularization prior to randomization.

B. Significant atherosclerotic cerebrovascular disease meeting at least 1 of the following criteria:

• prior transient ischemic attack with ≥50% carotid stenosis.
• internal or external carotid artery stenosis of ≥70% or 2 or more ≥50% stenoses.
• prior internal or external carotid artery revascularization.

C. Significant peripheral arterial disease meeting at least 1 of the following criteria:

• ≥50% stenosis in a limb artery.
• history of abdominal aorta treatment (percutaneous and surgical) due to atherosclerotic disease.
• ankle brachial index (ABI) <0.85.

D. Diabetes mellitus with at least 1 of the following:

• known microvascular disease, defined by diabetic nephropathy or treated retinopathy. Diabetic nephropathy defined as persistent microalbuminuria (urinary albumin to creatinine ratio ≥30mg/g) and/or persistent estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2 that is not reversible due to an acute illness.

• chronic daily treatment with an intermediate or long-acting insulin.

• diabetes diagnosis ≥10 years ago.

  •At least 1 of the following 1 high-risk criteria (most recent lab values within 6 months prior to screening, as applicable):

• Polyvascular disease, defined as coronary, carotid, or peripheral artery stenosis ≥50% in a second distinct vascular location in a participant with coronary, cerebral or peripheral arterial disease (A, B, or C above).

• Presence of either diabetes mellitus or metabolic syndrome in a participant with coronary, cerebral, or peripheral artery disease (A, B, or C above).

• At least 1 coronary, carotid, or peripheral artery residual stenosis of ≥50% in a participant with diabetes meeting inclusion criterion (D above).

• LDL-C ≥130 mg/dL (≥3.36 mmol/L), OR non-HDL-C ≥160 mg/dL (≥4.14 mmol/L), OR apolipoprotein B ≥120 mg/dL (2.3 µmol/L) if available.

• Lipoprotein (a) >125 nmol/L (50 mg/dL).

• Known familial hypercholesterolemia.

• Family history of premature coronary artery disease defined as an MI or CABG in the participant's father or brother at age <55 years or an MI or CABG in the participant's mother or sister at age <60 years.

• High sensitive c-reactive protein (hsCRP) ≥3.0 mg/L in the absence of an acute illness.

• Current tobacco use.

  -≥65 years of age.

• Menopause before 40 years of age.

• eGFR 15 to <45 mL/min/1.73 m^2.

• Coronary artery calcification score ≥300 in a participant without a coronary revascularization prior to randomization.

Exclusion criteria

• MI or stroke prior to randomization.
• CABG ˂ 3 months prior to screening.
• eGFR ˂ 15 mL/min/1.73 m^2.
• Uncontrolled or recurrent ventricular tachycardia in the absence of an implantable-cardioverter defibrillator.
• Atrial fibrillation or atrial flutter not on anticoagulation therapy (vitamin K antagonist, heparin, low molecular weight heparin, fondaparinux,or non-Vitamin K antagonist oral anticoagulant).
• Triglycerides ≥ 500 mg/dL (5.7 mmol/L) measured up to 3 months prior to screening. The most recent results must be used.
• Last measured left-ventricular ejection fraction ˂ 30% or New York Heart Association (NYHA) Functional Class III/IV.
• Planned arterial revascularization.

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) The product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.