TY - JOUR
T1 - Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75)
T2 - A Randomized, Controlled Trial
AU - Ouchi, Yasuyoshi
AU - Sasaki, Jun
AU - Arai, Hidenori
AU - Yokote, Koutaro
AU - Harada, Kazumasa
AU - Katayama, Yasuo
AU - Urabe, Takao
AU - Uchida, Yasufumi
AU - Hayashi, Masaru
AU - Yokota, Naoto
AU - Nishida, Hirokazu
AU - Otonari, Takatoshi
AU - Arai, Tadashi
AU - Sakuma, Ichiro
AU - Sakabe, Kazuo
AU - Yamamoto, Masayasu
AU - Kobayashi, Takashi
AU - Oikawa, Shinichi
AU - Yamashita, Shizuya
AU - Rakugi, Hiromi
AU - Imai, Takumi
AU - Tanaka, Shiro
AU - Ohashi, Yasuo
AU - Kuwabara, Masanari
AU - Ito, Hideki
N1 - Funding Information:
Dr Ouchi received other research support from Public Health Research Foundation. Dr Sasaki received research grant from Daiichi Sankyo Company, Limited and other research support from Public Health Research Foundation. Dr Arai received other research support from Public Health Research Foundation and honoraria from Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co, Ltd, Pfizer Japan Inc, AstraZeneca KK, Kowa Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Sanofi KK, Daiichi Sankyo Company, Limited, Astellas Pharma Inc, MSD KK, and Amgen Astellas BioPharma KK. Dr Harada received research grant from Public Health Research Foundation and other research support from Public Health Research Foundation and honoraria from Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd. Dr Urabe received research grant from Astellas Pharma, Otsuka Pharmaceutical Co, Ltd, Eisai Co, Ltd, Bayer Yakuhin, Ltd, Takeda Pharmaceutical, Daiichi Sankyo Company, Limited, Teijin Pharma Limited, MSD KK, Mitsubishi Tanabe Pharma Corporation, and Sumitomo Dainippon Pharma Co, Ltd, other research support from Public Health Research Foundation, and honoraria from Otsuka Pharmaceutical Co, Ltd, Public Health Research Foundation, Kowa Pharmaceutical Co, Ltd, Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd, Daiichi Sankyo Company, Limited, Mochida Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co, Ltd, AstraZen-eca KK, Amgen Astellas BioPharma KK, Eisai Co, Ltd, and Pfizer Japan Inc. Dr Hayashi received honoraria from Kowa Pharmaceutical Co, Ltd, Sanwa Kagaku Kenkyusho Co, Ltd, MSD KK, and Daiichi Sankyo Company, Limited. Dr Yo-kota received honoraria from Kowa Pharmaceutical Co, Ltd, Daiichi Sankyo Company, Limited, Bayer Yakuhin, Ltd, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited, Takeda Pharmaceutical Company Limited, and MSD KK. Dr Sakuma received research grant and other research support from Public Health Research Foundation. Dr Sakabe received research grant from Public Health Research Foundation. Dr Yamashita received research grant from Takeda Pharmaceutical Company Limited, MSD KK, Bayer Yakuhin, Ltd, Boehringer In-gelheim, Ono Pharmaceutical Co, Ltd, Astellas Pharma Inc, Mitsubishi Tanabe Pharma Corporation, Kyowa Medex Co, and Rohto Pharmaceutical Co, Ltd and honoraria from Kowa Pharmaceutical Co, Ltd, MSD KK, Bayer Yakuhin, Ltd, Amgen Astellas BioPharma KK, and Sanofi KK. Dr Rakugi received research grant from Takeda Pharmaceutical Company Limited, Daiichi Sankyo Company, Limited, Astellas Pharma Inc., MSD KK, Mitsubishi Tanabe Pharma Corporation, Bayer Yakuhin, Ltd, Sanofi KK, Shionogi & Co, Ltd, Teijin Pharma Limited, Mochida Pharmaceutical Co, Ltd, Sumitomo Dainippon Pharma Co, Ltd, Otsuka Pharmaceutical Co, Ltd, and Pfizer Japan Inc honoraria from Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company Limited, Bayer Yakuhin, Ltd, Sanofi KK, Shionogi & Co, Ltd, Teijin Pharma Limited, Astellas Pharma Inc., Mochida Pharmaceutical Co, Ltd, MSD KK, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co, Ltd, and Pfizer Japan Inc, and expert witness from Takeda Pharmaceutical Company Limited. Dr Imai received other research support and expert witness from Public Health Research Foundation.
Funding Information:
Public Health Research Foundation, Japan Heart Foundation, Japan Geriatrics Society, and Japan Atherosclerosis Society provided financial support for the trial. The company manufacturing and distributing the trial drug (MSD K.K.) and the company distributing the trial drug (Bayer Yakuhin, Ltd.) financed support for Public Health Research Foundation projects. None of these entities had a role in trial design, data analysis, data interpretation, or the writing of the article. Dr Ouchi had full access to all the data and final responsibility for the decision to submit for publication.
Funding Information:
Dr Ohashi received research grant from Medical Member System, honoraria from Daiichi Sankyo Company, Limited, Sanofi KK, Astellas Pharma Inc, Public Health Research Foundation, and Chugai Pharmaceutical Co, Ltd, and expert witness from Public Health Research Foundation. Dr Kuwabara received other research support from Public Health Research Foundation. Dr Ito received other research support from Public Health Research Foundation. The other authors report no conflicts.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/9/17
Y1 - 2019/9/17
N2 - 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.
AB - 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.
KW - LDL cholesterol
KW - cardiovascular disease
KW - elderly
KW - ezetimibe
KW - primary prevention
UR - http://www.scopus.com/inward/record.url?scp=85072266841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072266841&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.118.039415
DO - 10.1161/CIRCULATIONAHA.118.039415
M3 - Article
C2 - 31434507
AN - SCOPUS:85072266841
VL - 140
SP - 992
EP - 1003
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 12
ER -