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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
Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome
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Conflict of Interests The HIJ-PROPER study group received research support to perform clinical trials
through the Japan Research Promotion Society for Cardiovascular Diseases.
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.
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Hypothesis
HIJ-PROPER is
a prospective, randomized, open-label, blinded endpoint multicenter trial
to determine whether standard statin dose + ezetimibe, targeting LDL-C of < 70 mg/dL would reduce cardiovascular events more than statin monotherapy, targeting LDL-C of 90 to 100 mg/dL
in patients with acute coronary syndrome (ACS) and dyslipidemia
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ACS with dyslipidemia n = 1734
Minimum 3 years follow-up (mean: 3.9 years)
Primary Endpoint: All-cause death, Non-fatal myocardial infarction, Non-fatal stroke, Unstable angina, Ischemia-driven revascularization
Pitava n = 857 (loss of follow-up n = 8) Follow-up rate 99.1%
Pitava/EZ n = 864 (loss of follow-up n = 5) Follow-up rate 99.4%
1:1 Randomization Pitavastatin + Ezetimibe LDL-C < 70 mg/dL
n = 869
Pitavastatin monotherapy 90 ≤ LDL-C < 100 mg/dL
n = 865
Study Design
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1yr mean
Pitava, mg/dL
Pitava/EZ, mg/dL
Δ in mg/dL
87.2
67.5
-19.7*
LDL-C TC TG HDL-C
165.3
142.7
-22.6*
144.2
125.2
-19.0*
Pitava mean dose (mg/day)
2.02
2.36
50.3
50.9
+0.6
Pitava
Pitava/EZ
† Mean time avg
Time since randomization (months)
Me
an
LD
L-C
(m
g/d
L)
140
120
100
80
60
0 0 3 6 12 24 36
135.6 84.6† (Δ-37.6%)
134.8 65.1† (Δ-51.7%)
LDL-C and Lipid Changes
*P<0.001
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857 618 566 507 280 134 864 622 584 536 302 140
Number at risk
Primary Endpoint (composite)
Eve
nt ra
te
0 720 1080 1440 1800 0.0
0.1
0.2
0.3
0.4
Time since randomization (days)
Pitava: 36.9% (128.12 / 1000 pt-yr)
HR = 0.89, 95% CI (0.76-1.04)
Log-rank test
P = 0.152
360
Pitava/EZ: 32.8% (111.58 / 1000 pt-yr)
Pitava
Pitava/EZ
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< 2.2 μg/mL (median)
0 360 720 1080 1440 1800
0.1
0.2
0.3
0.4
Time since randomization (days)
Eve
nt ra
te
HR = 1.11 (0.88-1.39) P = 0.388
0.0
38.2% (157 / 411)
35.7% (142 / 398)
Pitava
Pitava/EZ
≥ 2.2 μg/mL (median)
0 360 720 1080 1440 1800
Time since randomization (days)
Eve
nt ra
te
HR = 0.71 (0.56-0.91) P = 0.006
0.1
0.2
0.3
0.4
0.0
37.5% (156 / 416)
27.8% (111 / 399) Pitava
Pitava/EZ
Subgroup Analysis: Sitosterol Primary Endpoint (composite)
Sitosterol (cholesterol absorption marker)
P-value for interaction = 0.010
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Conclusions
Intensive LDL-C lowering with statin (standard dose) + ezetimibe did not significantly reduce CV events more than statin alone in patients with ACS and dyslipidemia.
Statin + ezetimibe did reduce CV events more than statin alone in patients with higher baseline levels of sitosterol, a cholesterol absorption marker.
This intestinal cholesterol absorption marker may offer a potential therapeutic target for the treatment of dyslipidemia in patients with ACS.