Heart Institute of Japan apan-PR PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute co coRonary syndrome LDL cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidemia: the HIJ-PROPER, a randomized trial Nobuhisa Hagiwara, Erisa Kawada-Watanabe, Ryo Koyanagi, Hiroyuki Arashi, Jun-ichi Yamaguchi, Koichi Nakao, Tetsuya Tobaru, Hiroyuki Tanaka, Kunihiko Matsui, Hiroshi Ogawa The HIJ-PROPER Investigators
Conflict of Interests The HIJ-PROPER study group received research support to perform clinical trials through the he Jap apan an Res esea earch h Prom omot otion on Soc ociet ety for or Car ardi diov ovas ascul ular ar Disea eases es . Sponsored by Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., AstraZeneca K.K., Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Bristol-Myers K.K., Kowa Pharmaceutical Co.Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Sanofi K.K., Takeda Pharmaceutical Company Limited, Boston Scientific Corporation, and Abbott Vascular Japan Co., Ltd. N. Hagiwara: honoraria from Nippon Boehringer Ingelheim Co., Ltd., and Bristol-Myers K.K., and grants from Daiichi Sankyo Company, Limited, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd., Eisai Co., Ltd., and Otsuka Pharmaceutical Co., Ltd.
Hypothesis HI HIJ-PR PROP OPER ER is a prospective, spective, randomized, domized, open-label, label, blinded nded endpoint dpoint multi ticent center er tr trial to to dete termine rmine whether ther st standard ndard st statin tin dose se + + ezetimibe, etimibe, ta targeting geting LDL-C C of f < 7 < 70 mg/dL dL would ld reduce duce cardiovascular diovascular events nts more th than st statin tin monothera otherapy, py, ta targeting geting LDL-C C of f 90 to to 100 0 mg/dL dL in pati tients ents with th acute te coronary onary syndrome rome (ACS) ) and d dys yslipi lipidemia emia
Study Design ACS S with dysli lipide pidemia ia n = 1 1734 Pitava tavasta statin tin monot nothera rapy py Pitava tavasta statin tin + Ezetimibe timibe 1:1 Randomi omizat zation on 90 ≤ LDL-C < 100 0 mg/dL /dL LDL DL-C < 7 70 mg/dL /dL n = 865 865 n = 8 869 Min inimum imum 3 years ars follow low-up up (me mean: an: 3.9 years) ars) Pitava tava n = 8 857 Pitava tava/EZ /EZ n n = 8 864 64 (loss loss of f fo follow low-up n = 8 8) (loss loss of f fo follow low-up n = 5 5) Follow llow-up rate te 99.1 .1% Follow llow-up rate te 99.4 .4% Primar imary y Endpoint point: : All-cau cause se death th, , Non-fatal fatal myocardial ocardial infa farc rction, tion, Non-fatal Non fatal stroke, oke, Unstable table angina, ina, Ischemia hemia-driven driven revas ascula cularization rization
LDL-C and Lipid Changes 140 Pitava va dL) g/dL 120 Pitava va/EZ /EZ C (mg/ † Mean time avg 84. 84.6 † (Δ -37.6 .6%) %) 100 135.6 .6 an LDL-C 80 Mean 60 134.8 .8 65.1 † (Δ -51.7 .7%) %) 0 0 3 6 12 24 36 Time e since ce rando domiza mization ion (mont onths) hs) 1yr mean LDL-C TC TG HDL-C Pitava mean dose (mg/day) Pitava, mg/dL 87.2 165.3 144.2 50.3 2.02 Pitava/EZ, mg/dL 67.5 142.7 125.2 50.9 2.36 Δ in mg/dL -19.7* -22.6* -19.0* +0.6 *P<0.001
Primary Endpoint (composite) 0.4 Pitava va: : 36.9% % (128. 28.12 12 / 1 1000 0 pt-yr) yr) 0.3 Pitava va/EZ: /EZ: 32.8% % (111.58 11.58 / 1000 0 pt-yr) yr) nt rate Event 0.2 Pitava va HR HR = 0.89, 9, 95% CI CI (0.76-1.04) 1.04) Pitava va/EZ /EZ 0.1 Log-ran Log rank k test P = 0.152 0.0 0 360 720 1080 1440 1800 Time since randomi mizatio zation (days) Number at risk 857 618 566 507 280 134 864 622 584 536 302 140
Subgroup Analysis: Sitosterol Primary Endpoint (composite) Sitoster sterol (choleste holesterol ol absorpt orption on mark rker) er) < 2.2 μg/mL (median) ≥ 2.2 μg/mL (median) HR = 1.11 (0.88-1.3 1.39) 9) P = 0.388 HR = 0.71 (0.56-0.9 0.91) 1) P = 0.006 38.2% % (157 / 411) 0.4 0.4 37.5% % (156 / 416) ent rate 0.3 ent rate 0.3 35.7% % (142 / 398) 0.2 0.2 27.8% % (111 / 399) Event Event Pitava ava Pitava ava 0.1 0.1 Pitava ava/EZ /EZ Pitava ava/EZ /EZ 0.0 0.0 0 360 720 1080 1440 1800 0 360 720 1080 1440 1800 Time e since randomiza mizati tion on (days) Time e since randomiza mizati tion on (days) P-va value lue for intera raction ction = 0 0.010 10
Conclusions Int ntensi ensive ve LD LDL-C C low ower ering ng wi with h stat atin n (standard andard do dose) e) + ez ezetimibe imibe did not signifi ficantly cantly reduce ce CV CV ev events ts mo more e than statin n alone in pa patients nts wi with ACS CS an and dysl slip ipidemia idemia. Statin in + ez ezetimibe mibe did reduce ce CV CV ev events ts mo more than stati tin n alone in pa patients ts wi with hi higher r baseli line ne levels s of sitosterol osterol, , a c a cho holes esterol terol ab absorpt orption ion ma marker. er. Th This intesti tinal nal cholesterol esterol absorptio rption n ma marker er ma may offer er a p potentia tial l therapeuti peutic c target et for the treatment ment of dysl slip ipidemia idemia in patients ts wi with ACS CS.
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