Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke (VESALIUS-CV)

Amgen

Status and phase: Completed; Phase 3

Conditions: Coronary Heart Disease (CHD)

Treatments: Drug: Evolocumab; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT03872401

20170625

2018-004565-14 (EudraCT Number)

2023-503673-38-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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.

Enrollment: 12,301 patients

Sex: All

Ages: 50 to 79 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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12,301 participants in 2 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Participants will receive placebo subcutaneous injection once every 2 weeks (Q2W).

Treatment:

Drug: Placebo

Evolocumab 140 mg Q2W

Experimental group

Description:

Participants will receive 140 mg evolocumab by subcutaneous injection Q2W.

Treatment:

Drug: Evolocumab