Shizuya Yamashita1,2, Hidenori Arai3, Hideaki Bujo4, Daisaku Masuda1, Tohru Ohama1,5, Toshiyuki Ishibashi6, Koji Yanagi7, Yasuji Doi8, Satoshi Nakagawa9, Koichi Yamashiro9, Kenichiro Tanabe9, Toru Kita10, Masunori Matsuzaki11, Yasushi Saito12, Masanori Fukushima9, Yuji Matsuzawa13. 1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine. 2. Department of Community Medicine, Osaka University Graduate School of Medicine. 3. The National Center for Geriatrics and Gerontology. 4. Department of Clinical Laboratory and Experimental Research Medicine, Toho University, Sakura Medical Center. 5. Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry. 6. Ohara General Hospital. 7. Kenporen Osaka Central Hospital. 8. Saiseikai Senri Hospital. 9. Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe. 10. Kobe City College of Nursing. 11. St. Hill Hospital. 12. Chiba University Graduate School of Medicine. 13. Sumitomo Hospital.
Abstract
AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with an low-density lipoprotein (LDL)-cholesterol (HDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).
RCT Entities:
AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemiapatients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with an low-density lipoprotein (LDL)-cholesterol (HDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).
Entities:
Keywords:
Antioxidants; Coronary heart disease; Prevention; Probucol; Reverse cholesterol transport
Authors: Aniket Mishra; Rainer Malik; Tsuyoshi Hachiya; Tuuli Jürgenson; Shinichi Namba; Daniel C Posner; Frederick K Kamanu; Masaru Koido; Quentin Le Grand; Mingyang Shi; Yunye He; Marios K Georgakis; Ilana Caro; Kristi Krebs; Yi-Ching Liaw; Felix C Vaura; Kuang Lin; Bendik Slagsvold Winsvold; Vinodh Srinivasasainagendra; Livia Parodi; Hee-Joon Bae; Ganesh Chauhan; Michael R Chong; Liisa Tomppo; Rufus Akinyemi; Gennady V Roshchupkin; Naomi Habib; Yon Ho Jee; Jesper Qvist Thomassen; Vida Abedi; Jara Cárcel-Márquez; Marianne Nygaard; Hampton L Leonard; Chaojie Yang; Ekaterina Yonova-Doing; Maria J Knol; Adam J Lewis; Renae L Judy; Tetsuro Ago; Philippe Amouyel; Nicole D Armstrong; Mark K Bakker; Traci M Bartz; David A Bennett; Joshua C Bis; Constance Bordes; Sigrid Børte; Anael Cain; Paul M Ridker; Kelly Cho; Zhengming Chen; Carlos Cruchaga; John W Cole; Phil L de Jager; Rafael de Cid; Matthias Endres; Leslie E Ferreira; Mirjam I Geerlings; Natalie C Gasca; Vilmundur Gudnason; Jun Hata; Jing He; Alicia K Heath; Yuk-Lam Ho; Aki S Havulinna; Jemma C Hopewell; Hyacinth I Hyacinth; Michael Inouye; Mina A Jacob; Christina E Jeon; Christina Jern; Masahiro Kamouchi; Keith L Keene; Takanari Kitazono; Steven J Kittner; Takahiro Konuma; Amit Kumar; Paul Lacaze; Lenore J Launer; Keon-Joo Lee; Kaido Lepik; Jiang Li; Liming Li; Ani Manichaikul; Hugh S Markus; Nicholas A Marston; Thomas Meitinger; Braxton D Mitchell; Felipe A Montellano; Takayuki Morisaki; Thomas H Mosley; Mike A Nalls; Børge G Nordestgaard; Martin J O'Donnell; Yukinori Okada; N Charlotte Onland-Moret; Bruce Ovbiagele; Annette Peters; Bruce M Psaty; Stephen S Rich; Jonathan Rosand; Marc S Sabatine; Ralph L Sacco; Danish Saleheen; Else Charlotte Sandset; Veikko Salomaa; Muralidharan Sargurupremraj; Makoto Sasaki; Claudia L Satizabal; Carsten O Schmidt; Atsushi Shimizu; Nicholas L Smith; Kelly L Sloane; Yoichi Sutoh; Yan V Sun; Kozo Tanno; Steffen Tiedt; Turgut Tatlisumak; Nuria P Torres-Aguila; Hemant K Tiwari; David-Alexandre Trégouët; Stella Trompet; Anil Man Tuladhar; Anne Tybjærg-Hansen; Marion van Vugt; Riina Vibo; Shefali S Verma; Kerri L Wiggins; Patrik Wennberg; Daniel Woo; Peter W F Wilson; Huichun Xu; Qiong Yang; Kyungheon Yoon; Iona Y Millwood; Christian Gieger; Toshiharu Ninomiya; Hans J Grabe; J Wouter Jukema; Ina L Rissanen; Daniel Strbian; Young Jin Kim; Pei-Hsin Chen; Ernst Mayerhofer; Joanna M M Howson; Marguerite R Irvin; Hieab Adams; Sylvia Wassertheil-Smoller; Kaare Christensen; Mohammad A Ikram; Tatjana Rundek; Bradford B Worrall; G Mark Lathrop; Moeen Riaz; Eleanor M Simonsick; Janika Kõrv; Paulo H C França; Ramin Zand; Kameshwar Prasad; Ruth Frikke-Schmidt; Frank-Erik de Leeuw; Thomas Liman; Karl Georg Haeusler; Ynte M Ruigrok; Peter Ulrich Heuschmann; W T Longstreth; Keum Ji Jung; Lisa Bastarache; Guillaume Paré; Scott M Damrauer; Daniel I Chasman; Jerome I Rotter; Christopher D Anderson; John-Anker Zwart; Teemu J Niiranen; Myriam Fornage; Yung-Po Liaw; Sudha Seshadri; Israel Fernández-Cadenas; Robin G Walters; Christian T Ruff; Mayowa O Owolabi; Jennifer E Huffman; Lili Milani; Yoichiro Kamatani; Martin Dichgans; Stephanie Debette Journal: Nature Date: 2022-09-30 Impact factor: 69.504