Ezetimibe in Prevention of Cerebro- and Cardiovascular Events in Middle- to High-Risk, Elderly (75 Years Old or Over) Patients With Elevated LDL-Cholesterol - EWTOPIA 75

Contribution To Literature:

The EWTOPIA 75 trial showed that, compared with dietary counseling alone, the use of additional ezetimibe for primary prevention among elderly Japanese patients with LDL ≥140 mg/dl and ≥1 high-risk feature reduced CV events, primarily cardiac events, with no difference in all-cause mortality.

Description:

The goal of the trial was to assess the safety and benefit of using ezetimibe for primary prevention of cardiovascular (CV) events among Japanese patients ≥75 years and with low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dl.

Study Design

Eligible patients were randomized in a 1:1 fashion to either ezetimibe 10 mg daily plus dietary counseling (n = 1,716) or dietary counseling (n = 1,695). A placebo pill was not administered in the control arm.  

  • Total screened: 5,333
  • Total number of enrollees: 3,796
  • Duration of follow-up: Median 4.1 years
  • Mean patient age: 80.6 years (14% were ≥85 years)
  • Percentage female: 74%

Inclusion criteria:

  • ≥75 years old at the time of enrollment
  • Outpatients
  • Serum LDL-C level ≥140 mg/dl
  • ≥1 of the following high-risk features:
  1. Diabetes mellitus
  2. Hypertension
  3. Low high-density lipoprotein (HDL)-cholesterolemia
  4. Hypertriglyceridemia
  5. Smoking
  6. Previous history of cerebral infarction documented by apparent clinical symptoms and computed tomography/magnetic resonance imaging scanning
  7. Peripheral artery disease

Other salient features/characteristics:

  • Body mass index: 23.6 kg/m2
  • HDL: 56 mg/dl, triglycerides: 132 mg/dl, LDL: 161 mg/dl
  • Systolic blood pressure: 136 mm Hg, diastolic blood pressure: 74 mm Hg
  • Never smoked: 85%
  • Diabetes: 25.3%

Principal Findings:

The primary CV outcome of sudden cardiac death, myocardial infarction (MI), percutaneous coronary intervention or coronary artery bypass grafting, and/or stroke, for ezetimibe vs. control, was 5.2% vs. 7.8%; hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.50-0.86 (p = 0.002).

Secondary outcomes, for ezetimibe vs. control:

  • Cardiac events: 1.5% vs. 2.5% (p = 0.04)
  • All MI: 0.6% vs. 1.2% (p = 0.10)
  • All stroke: 3.2% vs. 4.1% (p = 0.17)
  • Coronary revascularization: 0.6% vs. 1.5% (p = 0.007)
  • All-cause mortality: 11.0% vs. 10.2%, HR 1.09, 95% CI 0.89-1.34 (p = 0.43)

Interpretation:

The results of this trial indicate that, compared with dietary counseling alone, the use of additional ezetimibe for primary prevention among elderly Japanese patients with LDL ≥140 mg/dl and ≥1 high-risk feature reduced CV events, primarily cardiac events, with no difference in all-cause mortality. None of these patients were on statin therapy.

This is an interesting study and is one of the first to show a benefit with a nonstatin agent as monotherapy for primary prevention among patients with high LDL-C. This is also one of the few trials exclusively conducted among patients aged ≥75 years. One limitation is that this was an open-label study since the control arm did not receive a placebo pill.

References:

Ouchi Y, Sasaki J, Arai H, et al. Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized Controlled Trial. Circulation 2019;Aug 22:[Epub ahead of print].

Presented by Dr. Yasuyoshi Ouchi at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Interventions and Imaging, Interventions and Vascular Medicine, Magnetic Resonance Imaging, Hypertension, Smoking

Keywords: AHA Annual Scientific Sessions, AHA18, Coronary Artery Bypass, Cerebral Infarction, Cholesterol, LDL, Counseling, Death, Sudden, Cardiac, Diabetes Mellitus, Dyslipidemias, Geriatrics, Hypertension, Hypertriglyceridemia, Lipoproteins, HDL, Magnetic Resonance Imaging, Myocardial Infarction, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Primary Prevention, Risk Factors, Smoking, Stroke, Tomography


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