Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke

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.