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Cited by 231Lipoproteins and Cardiovascular HealthBlood Pressure and Hypertension StudiesDiabetes, Cardiovascular Risks, and Lipoproteins

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Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial

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Ouchi, Yasuyoshi, Sasaki, Jun, Arai, Hidenori, Yokote, Koutaro, Harada, Kazumasa, Katayama, Yasuo, Urabe, Takao, Uchida, Yasufumi, Hayashi, Masaru, Yokota, Naoto, Nishida, Hirokazu, Otonari, Takatoshi, Arai, Tadashi, Sakuma, Ichiro, Sakabe, Kazuo, Yamamoto, Masayasu, Kobayashi, Takashi, Oikawa, Shinichi, Yamashita, Shizuya, Rakugi, Hiromi, Imai, Takumi, Tanaka, Shiro, Ohashi, Yasuo, Kuwabara, Masanari, Ito, Hideki·2019·Circulation
DOI 10.1161/circulationaha.118.039415
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Abstract

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C–lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50–0.86; P =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37–0.98; P =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18–0.79; P =0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. Conclusions: LDL-C–lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp . Unique identifier: UMIN000001988.

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Authors
Ouchi, Y., Sasaki, J., Arai, H., Yokote, K., Harada, K., Katayama, Y., Urabe, T., Uchida, Y., Hayashi, M., Yokota, N., Nishida, H., Otonari, T., Arai, T., Sakuma, I., Sakabe, K., Yamamoto, M., Kobayashi, T., Oikawa, S., Yamashita, S., Rakugi, H., Imai, T., Tanaka, S., Ohashi, Y., Kuwabara, M., & Ito, H.
Affiliations
  • Toranomon Hospital (JP)
  • International University of Health and Welfare, Fukuoka, Japan (J.S.).
  • National Center for Geriatrics and Gerontology (JP)
  • Chiba University (JP)
  • Tokyo Metropolitan Geriatric Hospital (JP)
  • Tokyo General Hospital (JP)
  • Juntendo University Urayasu Hospital (JP)
  • Saga Memorial Hospital, Saga, Japan (Y.U.).
  • Nagahama City Hospital (JP)
  • Yokota Clinic, Miyazaki, Japan (N.Y.).
  • Nishida Clinic, Neyagawa, Japan (H.N.).
  • Otonari Clinic, Chikushino, Japan (T.O.).
  • Arai Clinic, Yamagata, Japan (T.A.).
  • Hokko Memorial Hospital (JP)
  • Sakabe Clinic, Kyoto, Japan (K.S.).
  • Yamamoto Clinic, Shimoniikawa, Japan (M.Y.).
  • Jyuzen General Hospital (JP)
  • Fukujuji Hospital (JP)
  • Rinku General Medical Center (JP)
  • The University of Osaka (JP)
  • Kyoto University (JP)
  • Chuo University (JP)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-09-17
Volume
140
Issue
12
Pages
992-1003
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.118.039415
OpenAlex
W2973595439
Semantic Scholar
2721aaaae9442849ff5ff5ea663c4d8d393199db
Cited by
231
References
25
Citations by year
2026: 31 · 2025: 29 · 2024: 43 · 2023: 33 · 2022: 33 · 2021: 31 · 2020: 28 · 2019: 3
FWCI
22.88
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Sanofi
  • Chuo University
  • Daiichi-Sankyo
  • Astellas Pharma
  • National Center for Geriatrics and Gerontology
  • Chiba University
  • Chugai Pharmaceutical
  • Sanofi K.K.
  • Japan Society for the Promotion of Science (17H01558)
  • Daiichi Sankyo Company
  • Daiichi Sankyo Europe
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
oldest old, ezetimibe, LDL cholesterol lowering, primary prevention, atherosclerotic cardiovascular disease, cardiovascular events, coronary revascularization, myocardial infarction, sudden cardiac death, stroke, nutrition counseling, older adults aged 75 and over, cardiovascular risk reduction, all-cause mortality, adverse events
MeSH terms
Ezetimibe, Aged, Aged, 80 and over, Hypolipidemic Agents, Female, Follow-Up Studies, Humans, Japan, Male, Primary Prevention, Prospective Studies, Incidence, Survival Analysis, Treatment Outcome, Atherosclerosis

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