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

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.

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

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

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

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

< 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

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.