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

Yasuyoshi Ouchi, Jun Sasaki, Hidenori Arai, Koutaro Yokote, Kazumasa Harada, Yasuo Katayama, Takao Urabe, Yasufumi Uchida, Masaru Hayashi, Naoto Yokota, Hirokazu Nishida, Takatoshi Otonari, Tadashi Arai, Ichiro Sakuma, Kazuo Sakabe, Masayasu Yamamoto, Takashi Kobayashi, Shinichi Oikawa, Shizuya Yamashita, Hiromi RakugiTakumi Imai, Shiro Tanaka, Yasuo Ohashi, Masanari Kuwabara, Hideki Ito

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112 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)992-1003
Number of pages12
Issue number12
Publication statusPublished - 2019 Sept 17


  • LDL cholesterol
  • cardiovascular disease
  • elderly
  • ezetimibe
  • primary prevention


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