European Heart Journal (2017) 38, 2264–2275 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehx162 Coronary artery disease

Low-density lipoprotein cholesterol targeting

with pitavastatin 1 ezetimibe for patients with
acute coronary syndrome and dyslipidaemia:
the HIJ-PROPER study, a prospective,
open-label, randomized trial
Nobuhisa Hagiwara1, Erisa Kawada-Watanabe1, Ryo Koyanagi1, Hiroyuki Arashi1,
Junichi Yamaguchi1, Koichi Nakao2, Tetsuya Tobaru3, Hiroyuki Tanaka4,
Toshiaki Oka5, Yasuhiro Endoh6, Katsumi Saito7, Tatsuro Uchida8, Kunihiko Matsui9,
and Hiroshi Ogawa1*
1
Department of Cardiology, The Heart Institute of Japan, Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan; 2Division of Cardiology,
Cardiovascular Center, Saisei-Kai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto-shi, Kumamoto 861-4193, Japan; 3Department of Cardiology, Sakakibara Heart
Institute, 3-16-1 Asahi-cho, Fuchu-shi, Tokyo 183-0003, Japan; 4Division of Cardiology, Tokyo Metropolitan Tama Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo 183-8524,
Japan; 5Department of Cardiology, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-ku, Hamamatsu-shi, Shizuoka 430-8558, Japan; 6Department of Cardiology,
Saisei-Kai Kurihashi Hospital, 714-6 Kouemon, Kuki-shi, Saitama 349-1105, Japan; 7Department of Cardiology, Nishiarai Heart Center, 1-12-8, Nishiarai-honcho, Adachi-Ku,
Tokyo 123-0845, Japan; 8Department of Cardiology, Cardiovascular Center of Sendai, 1-6-12 Izumichuo, Izumi-ku, Sendai-shi, Miyagi 981-3133, Japan; and 9Department of
General and Community Medicine, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

Received 4 November 2016; revised 10 January 2017; editorial decision 13 March 2017; accepted 16 March 2017; online publish-ahead-of-print 18 April 2017

See page 2276 for the editorial comment on this article (doi: 10.1093/eurheartj/ehx275)

Aims To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in pa-
tients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), com-
pared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L).
...................................................................................................................................................................................................
Methods The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering
and results with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering
with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were
randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard
lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3–2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint
was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-
driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan.
Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was
65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy.
LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard
statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76–1.04, P = 0.152). In, ACS patients
with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with signifi-
cantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56–0.91).
...................................................................................................................................................................................................
Conclusion Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit
than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more

* Corresponding author. Tel: þ81 3 3353 8111, Fax: þ81 3 3356 0441, Email: [email protected].
C The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.
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LDL-C targeting with statin þ ezetimibe for ACS 2265

effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is
needed.
...................................................................................................................................................................................................
Trial No UMIN000002742, registered as an International Standard Randomized Controlled Trial.
! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Keywords Clinical trial • Ezetimibe • Pitavastatin • Combination therapy • Lipid-lowering • Acute coronary syndrome

..
Pitavastatin is a new member of the statin family that shows con-
Introduction ...
.. siderable promise. Its unique chemical structure provides potent effi-
Today the development of atherosclerotic cardiovascular disease has .. cacy against dyslipidaemia, high systemic bioavailability, and
..
been clearly linked to elevated concentrations of low-density lipo- .. favourable oral absorption.9 It offers potent anti-inflammatory ef-
protein cholesterol (LDL-C), and research on LDL-C lowering ther- .. fects,10 and provides equivalent regression of plaque volume at lower
..
apy has built a widely accepted consensus that lowering cholesterol .. doses than conventional statins in ACS patients.11
levels can reduce cardiovascular events to some extent.1,2 Some find- .. Initial statin therapy tends to significantly reduce LDL-C, but fur-
..
ings have even suggested ‘the lower, the better’ for the management .. ther reductions can be challenging. Generally, after the initial reduc-
of dyslipidaemia, at least in patients at high risk; the American
.. tion, a doubling of the statin dose is required for each additional
..
National Cholesterol Education Program Adult Treatment Panel .. reduction of 5–6% in LDL-C treatment.12 (This occurs because chol-
..
(NCEP ATP III) recommends target LDL-C of less than 70 mg/dL .. esterol uptake from the gastrointestinal tract is accelerated, in re-
(1.8 mmol/L) in patients with diabetes mellitus, chronic kidney dis- .. sponse to statin-induced reduction in serum cholesterol.) Since
..
ease, or recent acute coronary syndrome (ACS).3 This position has .. statin-related adverse effects are dose-dependent and occur more
been substantiated by cholesterol treatment trialists’ (CTT) collabor- .. commonly at higher doses,13 massive doses of statin monotherapy
..
ators, who have reported a strong association between lower LDL-C .. are clearly not the answer for lipid management. High-dose statin
(reduced by 38.7 mg/dL, 1.0 mmol/L) and lower 5-year risk of major .. therapy increases proprotein convertase subtilisin kexin type
..
events (reduced by 23%),2 and supported by recommendations from .. 9 (PCSK9) levels, which impairs LDL-C clearance from the plasma.
the American Diabetes Association and the American College of
.. This limits the effectiveness of statin therapy.14 In addition, most
..
Cardiology Foundation (LDL-C below 70 mg/dL [1.8 mmol/L]) in any .. hyperlipidaemic patients will remain under treatment for years, and
patient with known coronary artery disease (CAD).4 However, these
..
.. although lipids should be measured regularly to assess therapeutic re-
recommendations have not yet been supported with data-driven evi- .. sponse, such assessment is not always continued over the long term.
..
dence for the benefits of such reduction. .. This is unfortunate, since patients with atherosclerotic disease need
One roadblock has been the difficulty of achieving these very low .. ongoing lipid assessment to ensure that their treatment regimen is ac-
..
levels of LDL-C with conventional pharmacotherapy in real-world .. tually providing the desired results.
clinical practice. This may be due in part to the mechanism of action .. As noted previously, even in the current era of intensive statin
..
of the statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase in- .. therapy, ACS patients with dyslipidaemia may not reach their tar-
hibitors), which target cholesterol synthesis in the liver. Although the
.. geted LDL-C or obtain improved clinical outcomes. These challenges
..
statins are clearly effective in reducing the risk of coronary events in .. are now being considered in a number of clinical trials. Although no
high-risk populations,5 it is difficult to reach the recommended ag-
.. data are yet available on cardiovascular outcomes, it seems feasible
..
gressive targets with the use of statin alone. Even in the Lipid .. that statins in combination with non-statin drugs might provide
..
Treatment Assessment Project 2,6 for example, only 30% of the very .. greater lipid lowering and thus prove more effective in the preven-
high-risk patients reached the optional goal of LDL-C less than .. tion of cardiovascular events than statins alone, particularly in high-
..
70 mg/dL (1.8 mmol/L). And in a real-world setting among high-risk .. risk populations. However, to the best of our knowledge, no pro-
patients treated with statin monotherapy for >90 days, 67–77% .. spective clinical trials have yet evaluated the effects of LDL-C target-
..
achieved LDL-C <100 mg/dL (2.6 mmol/L), but only 20–26% reached .. ing therapy on subsequent cardiovascular outcomes in ACS patients.
the optional goal of LDL-C < 70 mg/dL (1.8 mmol/L). .. To explore this question, we needed a drug regimen that would
..
Recently a new paradigm has emerged for the treatment of hyperlip- .. reliably reduce LDL-C to the aggressive target level of < 70 mg/dL
idaemic patients who are at risk for cardiovascular events: high-
.. (1.8 mmol/L). We decided to combine a statin with ezetimibe, an in-
..
intensity statin therapy for high-risk patients in the absence of safety .. testinal cholesterol transporter inhibitor that selectively inhibits chol-
concerns, and moderate-intensity statin therapy for lower-risk primary
..
.. esterol absorption by blocking the Niemann-Pick C1-like 1
prevention and for high-risk patients if safety concerns are present .. receptor.15 Two recent studies that demonstrated the benefits of a
..
(introduced in the 2013 American College of Cardiology [ACC]/ .. combination of statin plus ezetimibe in patients with CAD support
American Heart Association [AHA] Guideline on the Treatment of .. our choice of ezetimibe.16,17
..
Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in .. We hypothesized that we could achieve intensive LDL-C lowering
Adults).7 The European Society of Cardiology (ESC) and the European .. by administering ezetimibe in conjunction with a standard dose of statin,
..
Atherosclerosis Society (EAS) also updated their therapeutic guidelines .. and that this treatment would be more beneficial for secondary preven-
for health professionals, based on accumulating evidence.8
.. tion than statin monotherapy in ACS patients with dyslipidaemia.
2266 N. Hagiwara et al.

..
The Heart Institute of Japan, Department of Cardiology (HIJC) .. included pregnancy; active liver disease or persistent unexplained serum
Investigators’ project is an ongoing collaborative effort designed to .. transaminase elevations (>_3 " the upper limit of normal), current treat-
.. ment with immunosuppressants such as cyclosporine, tacrolimus, aza-
develop a contemporary epidemiologic database and to improve the ..
quality of care for patients with cardiovascular disease in Japan.18–20 .. thioprine, or long-term oral glucocorticoids; any other condition that
.. would substantially reduce life expectancy or limit compliance with the
One project of HIJC is the Heart Institute of Japan PRoper level of ..
.. protocol; history of alcohol or drug abuse; or allergy or sensitivity to any
lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syn- .. statin, ezetimibe, or their excipients.
drome (HIJ-PROPER) trial, which was designed to investigate ..
whether such combined treatment would positively affect secondary ..
.. Randomization and masking
prevention in ACS patients with dyslipidaemia. The study investigated .. After patient eligibility was confirmed, patients were randomized either
the effect in patients with ACS of intensive LDL-C lowering treat-
..
ment with a standard dose of statin and ezetimibe, targeting less than
... to the pitavastatin plus ezetimibe group or to the pitavastatin monother-
.. apy group. Randomization was by the minimization method, based on the
70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering .. five factors of age, LDL-C level on randomization, history of statin treat-
lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L).
..
.. ment, history of diabetes mellitus, and clinical site. Although treatment
.. was not masked for patients and physicians, these events and pertinent
.. patient documents were reviewed by an Endpoint Committee masked to
..
Methods ..
..
treatment assignment (Appendix).
..
Study design .. Procedures
The HIJ-PROPER study21 is a multicentre, prospective, randomized, .. The starting dose for pitavastatin plus ezetimibe was 2 mg of pitavastatin
..
open-label, blinded-endpoint trial with an active-control design compar- .. and 10 mg of ezetimibe, targeting LDL-C of 70 mg/dL (1.8 mmol/L).
ing two lipid-lowering treatment strategies. The study involved 19 hos- .. Participants already receiving statins other than pitavastatin discontinued
pitals in Japan and was conducted in accordance with the principles of the
.. the previous agents and started receiving pitavastatin 2 mg/day under the
..
Declaration of Helsinki. The institutional review board or relevant ethics .. Japanese regulations related to pharmacotherapies. In the pitavastatin
committee of each participating medical centre approved the protocol, .. monotherapy arm, patients discontinued their previous statin, if any, and
..
and all patients provided written informed consent for trial enrolment. A .. began taking 2 mg of pitavastatin, targeting LDL-C of between 90 mg/dL
Steering Committee was responsible for scientific conduct and publica- .. (2.3 mmol/L) and 100 mg/dL (2.6 mmol/L). During the entire study period,
tion of the results of the trial, and a working group was responsible for
.. the pitavastatin dose (1–4 mg/day) was adjusted to provide the LDL-C
..
daily administration. .. level targeted for each specific group. During the study period, combined
.. lipid-lowering medications other than statins and ezetimibe were also
..
Inclusion criteria .. allowed in order to achieve the target level of LDL-C in each group.
Heart Institute of Japan PRoper level of lipid lOwering with Pitavastatin
.. Participants were followed by hospital doctors or other general practi-
..
and Ezetimibe in acute coRonary syndrome enroled specifically targeted .. tioners. The incidence of endpoint events in addition to drug safety infor-
hospitalized patients with ACS and dyslipidaemia. All participants had been .. mation was determined during the scheduled visits at 3, 6, 12, 24, and
.. 36 months, through contact with each patient, or via access to certificates
hospitalized for ST-segment elevation myocardial infarction (STEMI) or ..
for non-ST-segment elevation myocardial infarction (NSTEMI) or unstable .. issued by administrative authorities if necessary. All patients were fol-
angina (UA) within 72 h before randomization. All participants were at
.. lowed for at least 36 months. Pre-specified measurements, prescribed
..
least 20 years of age. Participants with STEMI had electrocardiographic .. medications, and clinical events were reported to the Data Management
changes (persistent ST-segment elevation >_ 0.1 mV, new Q waves, or new .. Center every 6 months. Trained clinical research coordinators (CRC) vis-
.. ited the study centres regularly to collect and reconfirm the reported
left bundle-branch block), and elevated troponin or creatine kinase (CK)– ..
MB. Participants presenting with UA/NSTEMI had ischaemic discomfort at .. data. If a patient stopped coming to their institution, CRC personnel con-
rest, lasting at least 10 min, and at least one of the following: new ST-
.. firmed the patient’s health status by letter or phone call.
..
segment deviation of at least 1 mV, elevated troponin or CK-MB, a history ..
of prior MI, peripheral arterial disease, a history of coronary artery bypass .. Outcomes
..
grafting (CABG) at least 3 years previously, or known multivessel CAD .. The primary endpoint was a composite of the first occurrence of a
including at least two major coronary arteries with stenosis of >50%. .. component of the primary endpoint: all-cause death, non-fatal myocardial
.. infarction, non-fatal stroke, UA, or revascularization with either percutan-
Low-density lipoprotein cholesterol, measured within 24 h of hospital- ..
ization for the ACS event, was at least 100 mg/dL (2.6 mmol/L). Fasting .. eous coronary intervention (PCI) or CABG. The secondary endpoints
plasma triglyceride level was at least 400 mg/dL (4.5 mmol/L) (Friedewald
.. included (i) cardiovascular event (non-fatal myocardial infarction, non-
..
equation). Levels of the cholesterol absorption markers sitosterol and .. fatal stroke, UA, ischaemia-driven revascularization with either PCI or
campesterol and the cholesterol synthesis intermediate lathosterol were .. CABG), (ii) all-cause death, (iii) heart failure, (iv) inflammatory markers,
.. and (v) adverse events (including new occurrence of malignant tumour).
also measured at enrolment and 12 weeks after randomization. All la- ..
boratory analyses were performed at SRL Inc. (Tokyo, Japan). ..
.. Statistical analysis
Major exclusion criteria were the occurrence within 24 hours before ..
enrolment of (i) hemodynamic instabilities such as hypotension, pulmon- .. The prespecified number of events required to provide meaningful data
ary oedema, congestive heart failure, acute mitral regurgitation, or ven-
.. was estimated for an a level of 5%, 80% power, and a dropout rate of 2%
..
tricular rupture; (ii) ischaemic events (stroke, recurrent symptoms of .. during a follow-up period of three years. The expected occurrence of a
cardiac ischaemia, acute occlusion of target vessel); and (iii) arrhythmic .. primary endpoint in the statin-monotherapy group was 10%, based on
..
events (ventricular fibrillation, sustained ventricular tachycardia, .. data from contemporary studies of UA pectoris and AMI with compar-
advanced heart block). Patients in whom CABG was planned for the .. able follow-up time.5,20,22 An initial sample size of 3000 patients was se-
treatment of an ACS event were excluded. Other exclusion criteria
.. lected to afford 80% power to detect relative risk reduction of 20% in the
LDL-C targeting with statin þ ezetimibe for ACS 2267

primary endpoint by a two-sample t-test at a significance level of 0.05.

The sample size was based on anticipated event rates at one year
(100 events/1000 patients/year).
Patient enrolment began in January 2010 on the assumption that 1500
patients for each group would be enroled by the end of 2012. The enrol-
ment period was extended to the end of April 2013, by which point we
had recruited a total of 1734 patients. The Data and Safety Monitoring
Board then suggested stopping recruitment, since a recruitment period
long enough to complete the enroled might contribute to critical differ-
ences in follow-up periods between patients.
Accordingly, we re-calculated the sample size on the basis of previous
domestic data.20,22 We estimated relative risk reduction as 25%, the pri-
mary endpoint event rate of approximately 100 events/1000 person-
years in the control group, and then concluded that 814 patients per
group, or 1628 in total, were required during a two-year enrolment
period and at least three years of follow-up to detect this difference in ef-
Figure 1 Study flow chart.
fects at the two-tailed 5% level of significance with 80% power.
The intention-to-treat approach was used for efficacy and safety ana-
lyses, and all randomized patients were included in all analyses, regardless
of protocol violations. Time-to-first-occurrence of events was analysed ..
134.8 ± 29.3 mg/dL (3.49 ± 0.76 mmol/L) in the intensive treatment
using the Kaplan–Meier method with log-rank test and conventional Cox ...
proportional hazards model. Treatment effects on the primary endpoints
.. group at baseline and 84.6 mg/dL (2.19 mmol/L) in the standard
.. treatment group and 65.1 mg/dL (1.68 mmol/L) in the intensive treat-
in subgroups, were analysed by the Cox regression model, using tests for ..
interaction to examine consistency of the results. The subgroups were .. ment group at follow-up. Reduction from baseline was 37.6% for
.. standard treatment and 51.7% for intensive treatment. LDL-C dif-
gender, age (<65 years vs. >_65 years), type of index ACS event, number
... fered significantly between the two groups throughout the trial
of diseased vessels, history of hypertension, history of diabetes mellitus, ..
smoking habit, body mass index, history of statin treatment, baseline lipid .. (DLDL-C = 19.5 mg/dL, (0.50 mmol/L) P < 0.001).
profile including cholesterol absorption and synthesis markers, and base-
..
.. During a median observation period of 3.86 years, a total of 2004
line renal function (30>, 30 <_ <60, 60<_ mL/min./1.73 m2). To assess renal .. events were reported. Incidence of the primary endpoint was 36.9%
function, creatinine clearance was calculated using the Cockcroft-Gault ..
.. for standard treatment (128.1/1000 patient-years) and 32.8% for in-
formula. Categorical data are expressed as frequencies. For continuous .. tensive treatment (111.6/1000 patient-years). The reduction in the
variables with a normal distribution, means ± standard deviation (SD) are ..
reported. For LDL-C during the treatment period, the geometric means
.. incidence of major adverse cardiac events did not achieve statistical
.. significance [Hazard ratio (HR) 0.89; 95% confidence interval (CI),
and interquartile ranges are reported. An independent statistical data ..
centre (Data Research Section, Kondo P.P. Inc., Osaka, Japan) analysed ... 0.76–1.04; P = 0.152; Figure 2A]. No significant differences were noted
data using SAS ver. 9.1 software (SAS Institute, Cary, NC, USA). .. between standard and intensive treatment in terms of all cause
..
.. of death (7.0% vs. 4.9%; HR, 0.70; 95% CI, 0.47–1.04; P = 0.075);
Role of the funding source .. non-fatal myocardial infarction (1.2% vs. 1.3%; HR, 1.10; 95% CI,
..
This trial was funded by the Japan Research Promotion Society for .. 0.47–2.58; P = 0.834); non-fatal stroke (2.1% vs. 2.0%; HR, 0.94; 95%
Cardiovascular Diseases, which had no role in conducting the study. The .. CI, 0.49–1.83; P = 0.866); or UA (3.9% vs. 4.3%, HR, 1.13; 95% CI,
HIJ-PROPER Steering Committee had full access to all data in the study
..
.. 0.70–1.80; P = 0.623) (Table 3). A composite of hard endpoints of any
and had final responsibility for the decision to submit for publication. .. cause of death, non-fatal MI, and non-fatal-stroke showed no signifi-
..
.. cant difference between the two groups (Figure 2B). Ischaemia-driven
... coronary revascularization, a soft endpoint, also showed no signifi-
Results ..
cant difference between two treatment groups (Figure 2C).
..
Between January 2010 and April 2013, 1734 patients were enroled
.. For secondary endpoints, ischaemia-driven coronary revasculari-
..
and randomized to either pitavastatin plus ezetimibe or pitavastatin .. zation was performed in 257 patients (30.0%) in the standard treat-
monotherapy (Figure 1). Final follow-up assessment was performed
.. ment group and in 225 patients (26.0%) in the intensive treatment
..
in March 2016 and the trial database was locked on 31 March 2016. .. group (HR, 0.87; 95% CI, 0.72–1.04; P = 0.115). Heart failure hospital-
.. ization occurred in 40 patients (4.7%) in the standard treatment
Baseline clinical characteristics of the randomized population are ..
shown in Table 1. The two treatment groups were well balanced with .. group and in 19 patients (2.2%) in the intensive treatment group (HR,
.. 0.47; 95% CI, 0.27–0.81, P = 0.006). (Table 3)
respect to baseline characteristics. Mean age (±SD) was 65.6 ± 11.8 ..
years. PCI for acute revascularization had been performed success- .. Table 4 shows relative risk and 95% CI for the primary endpoint
..
fully in 94.6% of patients. Before randomization, 83.0% of the patients .. by selected demographics and background treatment. Most point
were statin-naı̈ve. Prior to enrolment, ACEIs had been prescribed for .. estimates demonstrated similar HRs, and no statistical heterogen-
..
27.4% of patients, calcium channel blockers for 23.2%, b-blockers for .. eity was identified among subgroups. Hypertension significantly
66.4%, aspirin for 97.4%, and ARBs for 49.7%. .. modified the effect of intensive lipid lowering treatment (P-value
..
Table 2 shows mean LDL-C for the two groups: 135.6 ± 30.0 mg/ .. for interaction = 0.017). Specifically, in non-hypertensive patients,
dL (3.51 ± 0.78 mmol/L) in the standard treatment group and
.. intensive therapy significantly reduced the risk of the primary
2268 N. Hagiwara et al.

Table 1 Baseline characteristics of randomized population

Variable Pitavastatin monotherapy Pitavastatin 1 ezetimibe

(n 5 857) (n 5 864)
....................................................................................................................................................................................................................
Age, y, mean ± SD 65.5 ± 11.9 65.7 ± 11.7
Male (%) 661 (77.1%) 639 (74.0%)
BMI, kg/m2, mean ± SD 24.3 ± 3.6 24.3 ± 3.5
Qualifying ACS event
STEMI 448 (52.3%) 432 (50.0%)
Non-STEMI 88 (10.3%) 92 (10.6%)
UA 321 (37.5%) 340 (39.4%)
ACS intervention
Percutaneous coronary intervention 817 (95.3%) 821 (95.0%)
Left ventricular ejection fraction
>_35% 829 (96.7%) 837 (96.9%)
Narrowed vesselsa
Right coronary artery 420 (49.0%) 414 (47.9%)
Left main trunk 42 (4.9%) 33 (3.8%)
Left anterior descending artery 642 (74.9%) 634 (73.4%)
Circumflex artery 396 (46.2%) 382 (44.2%)
Bypass graft 7 (0.8%) 6 (0.7%)
Cholesterol, mg/dL (mmol/L), mean ± SD
Total 210.8 ± 36.1 210.0 ± 34.4
(5.45 ± 0.93) (5.43 ± 0.89)
Triglycerides 132.5 ± 72.8 129.1 ± 69.3
(1.50 ± 0.82) (1.46 ± 0.78)
High-density lipoprotein cholesterol 48.3 ± 12.3 49.0 ± 12.5
(1.25 ± 0.32) (1.27 ± 0.32)
Low-density lipoprotein cholesterol 135.6 ± 30.0 134.8 ± 29.3
(3.51 ± 0.78) (3.49 ± 0.76)
Fasting plasma glucose, mg/dL, mean ± SD 142.5 ± 60.6 140.8 ± 58.8
HbA1c, %, mean ± SD 6.07 ± 1.36 6.06 ± 1.31
Sitosterol, lg/mL, mean ± SD 2.51 ± 1.47 2.49 ± 1.63
Campesterol, lg/mL, mean ± SD 4.76 ± 2.38 4.66 ± 2.40
Lathosterol, lg/mL, mean ± SD 1.89 ± 1.32 1.84 ± 1.24
Eicosapentaenoic acid/arachidonic acid ratio, mean ± SD 0.40 ± 0.26 0.38 ± 0.22
hs-CRP, ng/mL, mean ± SD 20960 ± 30510 21212 ± 30731
Heart rate, beats/min. 76.8 ± 17.5 74.9 ± 15.8
Systolic blood pressure, mmHg 138.3 ± 26.5 137.4 ± 25.6
Diastolic blood pressure, mmHg 80.2 ± 17.3 79.7 ± 17.9
CV history
Stable angina pectoris 100 (11.7%) 98 (11.3%)
Previous MI 68 (7.9%) 62 (7.2%)
Percutaneous coronary intervention 75 (8.8%) 71 (8.2%)
Coronary artery bypass graft 8 (0.9%) 10 (1.2%)
Chronic HF 15 (1.8%) 21 (2.4%)
Cerebrovascular disease 49 (5.7%) 56 (6.5%)
Peripheral artery disease 17 (2.0%) 15 (1.7%)
Hypertension 576 (67.2%) 599 (69.3%)
Diabetes mellitus 260 (30.3%) 260 (30.1%)
Smoker
Current 300 (35.0%) 294 (34.0%)
Former 248 (28.9%) 219 (25.3%)
Continued
LDL-C targeting with statin þ ezetimibe for ACS 2269

Table 1 Continued

Variable Pitavastatin monotherapy Pitavastatin 1 ezetimibe

(n 5 857) (n 5 864)
....................................................................................................................................................................................................................
Estimated glomerular filtration rate, mL/min/1.73 m2
30> 5 (0.6%) 8 (0.9%)
30<_, <60 213 (24.9%) 198 (22.9%)
60<_, <90 503 (58.7%) 522 (60.4%)
90<_ 136 (15.9%) 136 (15.7%)
CV medications at randomization
ACEI 230 (26.8%) 241 (27.9%)
ARB 417 (48.7%) 438 (50.7%)
b-Blocker 585 (68.3%) 558 (64.6%)
Calcium-channel blocker 211 (24.6%) 189 (21.9%)
Nitrates 176 (20.5%) 157 (18.2%)
Aspirin 841 (98.1%) 835 (96.6%)
Thienopyridines 790 (92.2%) 797 (92.2%)
Statin use on admission 149 (17.4%) 143 (16.6%)
Ezetimibe use on admission 7 (0.8%) 12 (1.4%)

Data presented are number (percentages) unless otherwise indicated. Percentages are calculated based on the number of patients with available data.
ACEI, Angiotensin-converting enzyme inhibitor; ACS, Acute coronary syndrome; ARB, angiotensin receptor blocker; BMI, Body mass index; CV, Cardiovascular; HF, Heart fail-
ure; hs-CRP, high-sensitivity C-reactive protein; MI, Myocardial infarction; STEMI, ST-elevation myocardial infarction; UA, Unstable angina.
a
A narrowing of the lumen by more than 75% of the prestenotic diameter was considered to indicate clinically significant stenosis, except for the left main artery, in which a nar-
rowing of more than 50% was considered clinically significant.

Table 2 Changes in low-density lipoprotein cholesterol (mean 6 SD)

Months after randomization Pitavastatin Pitavastatin 1 P-value

monotherapy ezetimibe
(Number) (Number)
....................................................................................................................................................................................................................
0 (mg/dL) 135.6 ± 30.0 (857) 134.8 ± 29.3 (864) 1.00
(mmol/L) 3.51 ± 0.78 3.49 ± 0.76
3 (mg/dL) 85.7 ± 23.0 (794) 66.1 ± 22.2 (799) <0.001
(mmol/L) 2.22 ± 0.59 1.71 ± 0.57
6 (mg/dL) 87.6 ± 22.5 (788) 66.7 ± 22.9 (775) <0.001
(mmol/L) 2.27 ± 0.58 1.72 ± 0.59
12 (mg/dL) 87.2 ± 21.7 (763) 67.5 ± 20.8 (754) <0.001
(mmol/L) 2.25 ± 0.56 1.75 ± 0.54
24 (mg/dL) 87.7 ± 22.9 (696) 68.8 ± 22.3 (693) <0.001
(mmol/L) 2.27 ± 0.59 1.78 ± 0.58
36 (mg/dL) 88.5 ± 21.6 (642) 71.3 ± 24.8 (647) <0.001
(mmol/L) 2.29 ± 0.56 1.84 ± 0.64
During treatment perioda (mg/dL) 84.6 [83.3–86.0] 65.1 [64.0–66.1] <0.001
(mmol/L) 2.19 [2.15–2.22] 1.68 [1.66–1.71]
Mean dose of study drug during
follow-up period
Pitavastatin, mg/day (mean ± SD) 2.02 ± 0.91 (817) 2.36 ± 0.90 (813)
Ezetimibe, mg/day (mean ± SD) – 10.0 ± 0.61 (787)

a
Expressed as geometric mean [95% CI] because of its non-normal distribution.

..
endpoint (HR, 0.65; 95% CI, 0.48–0.88), but there was no signifi- .. for the predetermined variable of baseline sitosterol, significantly
cant reduction in the hypertensive group when compared with pa- .. modified the effect of intensive lipid lowering treatment (P-value
..
tients on monotherapy (HR, 1.01; 95% CI, 0.83–1.22). Increased .. for interaction = 0.010). In patients with elevated sitosterol, inten-
cholesterol absorption, represented by comparatively high values
.. sive therapy significantly reduced the risk of the primary endpoint
2270 N. Hagiwara et al.

Figure 2 Kaplan–Meier curves for the primary efficacy endpoint and composite of several hard endpoints. (A) Primary endpoint, (B) All-cause
death, non-fatal MI, or non-fatal stroke (C) Ischaemia-driven coronary revascularization. MI, myocardial infarction.

..
(HR, 0.71; 95% CI, 0.56–0.91), there was no significant reduction .. and optimal medical therapy, LDL-C lowering to a target of <70 mg/
in patients without enhanced cholesterol absorption when .. dL (1.8 mmol/L) with a standard dose of pitavastatin plus ezetimibe
..
compared with patients on monotherapy (HR, 1.11; 95% CI, .. provided no greater reduction of subsequent cardiovascular events
0.88–1.39) (Table 5 ).
.. than standard pitavastatin monotherapy. In ACS patients who
..
Table 6 shows the occurrence of pre-specified adverse events. No .. showed elevated cholesterol absorption at baseline, however, statin
..
significant between-group differences were seen in the percentage of .. plus ezetimibe treatment reduced such cardiovascular events more
patients whose alanine aminotransferase levels exceeded three times .. than standard statin monotherapy.
..
the upper limit of the normal range or in the rates of gallbladder- .. Dyslipidaemia is a risk factor for patients with CAD, which means
related adverse events, muscle-related adverse events, or incidence
.. that lipid management, and especially LDL-C lowering, can be espe-
..
of cancer. The attending physician decided to discontinue the study .. cially valuable in these patients. But how low is ‘low enough’?
.. Previous guidelines from NCEP ATP III recommend lipid-lowering
drug because of an adverse event in 8.52% of pitavastatin monother- ..
apy patients and in 6.37% of pitavastatin þ ezetimibe patients. .. therapy to bring LDL-cholesterol below 70 mg/dL (1.8 mmol/L) in pa-
..
.. tients with coronary artery disease.23 Similarly, a recent European
.. guideline24 encourages lowering LDL-C to less than 70 mg/dL
..
Discussion .. (1.8 mmol/L) or by at least 50% for baseline between 70 mg/dL
.. (1.8 mmol/L) and 135 mg/dL (3.5 mmol/L) in very high-risk patients,
..
The present study demonstrates that, in ACS patients with dyslipi- .. and lowering to less than 100 mg/dL (2.6 mmol/L) or by at least 50%
daemia under contemporary aggressive coronary revascularization
.. for baseline between 100 mg/dL (2.6 mmol/L) and 200 mg/dL
LDL-C targeting with statin þ ezetimibe for ACS 2271

Table 3 Primary, secondary, and individual endpoints

Outcome Pitavastatin Pitavastatin 1 Hazard Ratio P-value

monotherapy ezetimibe (95% CI)
(n 5 857) (n 5 864)
Number of Rate per 1000 Number of Rate per 1000
events (%) patient-year events (%) patient-year
....................................................................................................................................................................................................................
Primary endpoint: any 316 (36.9%) 128.1 283 (32.8%) 111.6 0.89 (0.76–1.04) 0.152
cause of death, major
coronary event, or
non-fatal stroke
Secondary endpoints
Non-fatal myocardial 10 (1.2%) 3.0 11 (1.3%) 3.3 1.10 (0.47–2.58) 0.834
infarction
Non-fatal stroke 18 (2.1%) 5.5 17 (2.0%) 5.2 0.94 (0.49–1.83) 0.866
Unstable angina 33 (3.9%) 10.2 37 (4.3%) 11.5 1.13 (0.70–1.80) 0.623
Ischaemia-driven 257 (30.0%) 102.8 225 (26.0%) 86.7 0.87 (0.72–1.04) 0.115
coronary revascularization
All-cause death 60 (7.0%) 18.1 42 (4.9%) 12.6 0.70 (0.47–1.04) 0.075
Heart failure 40 (4.7%) 12.5 19 (2.2%) 5.8 0.47 (0.27–0.81) 0.006
hospitalization

..
(5.2 mmol/L) in high-risk patients. However, the medical community .. differed substantially (70% in IMPROVE-IT vs. 95% in HIJ-PROPER).
has not yet reached consensus on the appropriate statin dose, or on .. Previous studies30,31 demonstrated that primary coronary interven-
..
whether LDL-C should be a factor in determining that dose.7,25,26 .. tion improved both short-term and long-term clinical outcomes in
The initial statin dose is generally quite effective in reducing LDL- .. ACS patients. With the introduction of second-generation drug-elut-
..
C, but further reductions require disproportionately large dose in- .. ing coronary stents (DES) into clinical practice in this decade, PCI
creases,12 as statin-induced reductions in serum cholesterol trigger .. now shows long-term beneficial effects comparable to coronary ar-
..
increased cholesterol uptake from the gastrointestinal tract. This is of .. tery bypass surgery in high-risk CAD patients.32 Indeed, we found a
particular importance because statin-related adverse effects are
.. very low incidence of hard endpoints in HIJ-PROPER (6% for total
..
dose-dependent and occur more commonly at the highest doses.13 ... death, 3% for cardiac death, and 1% for non-fatal MI in the entire HIJ-
After statin therapy has been initiated, the patient should be as- .. PROPER cohort). The respective findings in the IMPROVE-IT study
..
sessed every 3–12 months as clinically indicated, since adherence to .. were 15.3% for any cause of death, 6.8% for cardiovascular death,
both medication and lifestyle regimens are required for cardiovascu- .. and 11.2% for non-fatal MI. The low incidence of hard endpoints in
..
lar risk reduction. Statins may affect the incidence of muscle injury, ... our study could have resulted in insufficient power to detect signifi-
and the incidence of rhabdomyolysis increases dose-dependently .. cant differences in primary composite outcomes. We postulate that
with statin use.27 Statins may also impact glucose metabolism and in- .. the effects of sample size and duration of the study period in combin-
..
fluence the development of diabetes.28 Previous studies have demon- .. ation with the low event rates may explain why the primary outcome
strated increased risk of new-onset diabetes with intensive statin
.. was not significantly reduced in the intensive lipid lowering arm of
..
therapy in comparison to standard statin therapy.29 All of these fac- .. HIJ-PROPER, as was seen in the IMPROVE-IT study.
..
tors suggest that a combined drug regimen, which would allow the .. Serum cholesterol concentration is determined both by endogen-
targeting of lower LDL-C levels without the risk of high-dose statin .. ous cholesterol from hepatic and extrahepatic synthesis and by ex-
..
therapy, might be beneficial particularly in improving cardiovascular .. ogenous cholesterol from intestinal absorption of dietary and biliary
outcomes in high-risk patients. ... cholesterol.33 Statins produce beneficial effects by inhibiting hepatic
The present study shows some inconsistencies with the results of .. cholesterol synthesis but do not directly affect intestinal absorption.
..
the IMPROVE-IT trial,16 a landmark study in this area. The investiga- .. Subgroup analysis in a Scandinavian simvastatin survival study (4S)34
tors of the IMPROVE-IT trial clearly demonstrated the usefulness of
.. suggested that patients with high baseline synthesis of cholesterol
..
intensive lipid lowering with statin þ ezetimibe compared with statin .. seemed to respond to statin treatment, while those with low choles-
..
monotherapy, but the results of our study do not support the .. terol synthesis were non-responders. In the present study, intensive
IMPROVE-IT findings of beneficial effects on the primary outcome. .. lipid lowering with ezetimibe was associated with a significant reduc-
..
To interpret the differences between these two trials, it is useful to .. tion of primary endpoint events in patients with increased cholesterol
compare the characteristics of participants and the resulting individ- .. absorption as expressed through higher baseline sitosterol. Further
ual event rates. ... investigation is needed to elucidate the mechanisms underlying the
..
Although participants in both trials received contemporary opti- .. beneficial effects of statin plus ezetimibe in ACS patients with high
mal medical therapy at baseline, the rates of acute revascularization
.. baseline cholesterol absorption.
2272 N. Hagiwara et al.

Table 4 Subgroup analyses for primary endpoint

Subgroup Pitavastatin Pitavastatin 1 Hazard ratio P-value for

monotherapy ezetimibe (95% CI) interaction
Number of Number of Number of Number
patients events patients of events
....................................................................................................................................................................................................................
Gender 0.473
Women 196 64 225 71 1.00 (0.71–1.40)
Men 661 252 639 212 0.86 (0.72–1.04)
Age (years) 0.992
<65 381 118 379 104 0.89 (0.69–1.16)
>_65 476 198 485 179 0.89 (0.72–1.08)
Type of Index ACS event 0.162
STEMI 448 178 432 138 0.77 (0.62–0.97)
Non-STEMI 88 26 92 34 1.36 (0.82–2.27)
Unstable angina 321 112 340 111 0.97 (0.75–1.26)
Number of Diseased vessels 0.118
1 402 121 430 95 0.72 (0.55–0.94)
2 247 96 246 98 1.07 (0.81–1.41)
3 156 78 146 72 0.98 (0.71–1.35)
Hypertension 0.017
No 281 107 265 70 0.65 (0.48–0.88)
Yes 576 209 599 213 1.01 (0.83–1.22)
Diabetes 0.482
No 597 203 604 176 0.85 (0.70–1.04)
Yes 260 113 260 107 0.96 (0.74–1.26)
Smoker 0.529
No 557 201 570 187 0.92 (0.76–1.13)
Yes 300 115 294 96 0.83 (0.63–1.09)
Body Mass Index, kg/m2 0.965
<25 551 209 541 184 0.91 (0.74–1.10)
25<_, <30 250 88 248 74 0.83 (0.61–1.13)
30<_ 49 16 55 19 1.02 (0.52–2.01)
Statin use before randomization 0.911
No 708 259 721 234 0.89 (0.74–1.06)
Yes 149 57 143 49 0.90 (0.61–1.32)
Estimated GFR, mL/min/1.73 m2 0.586
30> 5 3 8 4 1.12 (0.24–5.28)
30<_, <60 213 89 198 69 0.82 (0.60–1.12)
60<_ 639 224 658 210 0.92 (0.76–1.11)

ACS, acute coronary syndrome; GFR, glomerular filtration rate; STEMI, ST-elevation myocardial infarction.

..
A recently published analysis and meta-analysis of data from the .. emphasized. PCSK9 inhibitors induce a marked lowering of LDL-C,37
Minnesota Coronary Experiment indicate that drastic changes in eat- .. but no data are yet available on their effects on cardiovascular mor-
..
ing habits led to significant lowering of serum cholesterol. However, .. bidity and mortality. Data from an ongoing trial38 to evaluate the ef-
these cholesterol-lowering interventions were not associated with .. fects of PCSK9 inhibitors on cardiovascular outcomes may provide a
..
benefits in mortality from coronary heart disease or in all-cause mor- .. breakthrough in the therapeutic limits for high-risk patients with ath-
tality.35 A recent cohort study also demonstrated that statin-taking .. erosclerotic disease.
..
coronary heart disease patients with LDL-C 70 mg/dL (1.8 mmol/L)– .. At this point, the impact of statin therapy remains controversial in
100 mg/dL (2.6 mmol/L) had a lower risk of adverse cardiac out- .. reducing hospitalization for heart failure.39–41 Findings from the pre-
..
comes than those with LDL-C between 100 mg/dL (2.6 mmol/L) and .. sent study suggest that heart failure hospitalization decreased in the
130 mg/dL (3.4 mmol/L), but no additional benefit was gained by .. intensive lipid lowering arm in comparison with standard statin
achieving LDL-C of 70 mg/dL (1.8 mmol/L) or less.36 Although the re- ... monotherapy. However, further investigation is needed to determine
..
sults of the present study are consistent with these two studies, ex- .. the precise mechanisms for potential prevention of heart failure with
pectations based on CTT analysis2 continue to be widely
.. statin plus ezetimibe as suggested in the present study.
LDL-C targeting with statin þ ezetimibe for ACS 2273

Table 5 Baseline lipid profiles and subgroup analyses for primary endpoint

Subgroup Pitavastatin Pitavastatin 1 Hazard Ratio P-value for

monotherapy ezetimibe (95% CI) interaction
(n 5 857) (n 5 864)
Number of Number of Number of Number of
patients events patients events
....................................................................................................................................................................................................................
Low density lipoprotein cholesterol, 0.140
mg/dL (mmol/L)
<129 (3.3)a 414 141 415 140 1.01 (0.80–1.28)
>_129 (3.3) 443 175 449 143 0.79 (0.64–0.99)
High density lipoprotein cholesterol, 0.179
mg/dL (mmol/L)
<47 (1.2)a 418 170 401 136 0.80 (0.64–1.00)
>_47 (1.2) 439 146 463 147 0.99 (0.79–1.25)
Triglycerides, mg/dL (mmol/L) 0.542
<114 (1.3)a 423 161 434 139 0.84 (0.67–1.06)
>_114 (1.3) 434 155 430 144 0.94 (0.75–1.17)
Eicosapentaenoic acid/Arachidonic 0.161
acid ratio
<0.34a 271 99 299 82 0.70 (0.52–0.94)
>_0.34 299 109 285 95 0.93 (0.71–1.23)
Sitosterol (lg/mL) 0.010
<2.2a 398 142 411 157 1.11 (0.88–1.39)
>_2.2 416 156 399 111 0.71 (0.56–0.91)
Campesterol (lg/mL) 0.094
<4.2a 395 143 404 147 1.03 (0.82–1.30)
>_4.2 419 155 408 121 0.78 (0.61–0.99)
Lathosterol (lg/mL) 0.299
<1.6a 384 143 391 123 0.82 (0.64–1.04)
>_1.6 429 155 420 145 0.98 (0.78–1.23)

a
median.

This study had some limitations. First, the prospective, random- .. was underpowered for demonstrating that intensive lipid lowering
..
ized, open-label, controlled trial with blinded end-point assessment .. with pitavastatin þ ezetimibe had a significant effect on reducing total
(PROBE) design is potentially less reliable than a double-blind
.. adverse cardiovascular events. The small difference between the two
..
randomized trial. Although endpoint classification was conducted by .. groups (65.1 mg/dL vs. 84.6 mg/dL, i.e. 1.68 mmol/L vs 2.19 mmol/L),
a blinded independent committee on validation of data and events,
.. may have led to this lack of statistical power.
..
and committee members were unaware of group assignment, partici- .. Our study consisted entirely of Japanese patients with ACS, which
pants who knew that they were assigned to standard statin mono-
.. could affect the generalizability of our findings to patients in the rest
..
therapy might work harder on life-style modification. In addition, .. of the world. Extrapolation of our results to non-Japanese patients
..
treatment strategies such as requiring hospitalization and revasculari- .. with stable CAD might lead to incorrect conclusions; results should
zation treatment were used at the discretion of the responsible phys- .. be validated in other cohorts. Among the 19 participating hospitals,
ician at each hospital, although all potential endpoints were ... 16 had a catheter laboratory and were ready on a 24-h basis to con-
..
adjudicated by an endpoint committee whose members were blinded .. duct primary PCI, which may explain the higher rate of PCI in the pre-
to treatment group assignment. Second, a total of 8538 consecutive .. sent study than in the previous report.42 Additionally, the Norwegian
..
patients with ACS were screened at 19 clinical centers in Japan be- .. Coronary Stent Trial (NORSTENT)43 has provided recent evidence
tween January 2010 and April 2013. Of those, 1734 were considered .. that the use of newer-generation DES decreases the rate of subse-
..
eligible for study participation, based on the evaluation of the attend- .. quent revascularization in comparison with contemporary bare-
ing physicians, and also agreed to participate in the study. .. metal coronary stents. The frequent use of newer-generation DES
..
Unfortunately, the individual reasons for exclusion of each non- .. would reduce the event rate, and may have caused this study to be
eligible patient were not consistently recorded, and thus could not .. underpowered.
be fully reported here. Consequently, we cannot exclude the possi- ... Another is the relatively short duration (median of 3.86 years) of
..
bility of selection bias. Third, the actual event rate was much lower .. clinical follow-up. The time required for lipid-lowering therapy to af-
than expected. Given the low event rate in HIJ-PROPER, our study
.. fect cardiovascular events is not well defined, and this could have
2274 N. Hagiwara et al.

Table 6 Adverse events and study drug discontinuation

Pitavastatin monotherapy Pitavastatin 1 ezetimibe P-value

(n 5 857) (n 5 864)
Number of events (%) Number of events (%)
....................................................................................................................................................................................................................
Incidence of cancer 42 (4.90) 33 (3.82) 0.27
Rhabdomyolysis 1 (0.12) 2 (0.23) 0.57
Myopathya 8 (0.93) 8 (0.93) 0.99
Hepatobiliary system
ALT and/or AST>_3 " ULN 15 (1.75) 28 (3.24) 0.05
c-GTP >_3 " ULN 5 (0.58) 5 (0.58) 0.99
Gallbladder-related 11 (1.28) 10 (1.16) 0.81
Creatine kinase elevation >_5 " ULN 4 (0.47) 2 (0.23) 0.41
Doubling of serum creatinine 3 (0.35) 2 (0.23) 0.65
Study drug discontinuation
Pitavastatin 73 (8.52) 19 (2.20)
Ezetimibe — 46 (5.32)
Both — 55 (6.37)

ALT, alanine amino transferase; AST, aspartate aminotransferase; GTP, glutamly transpeptidase; ULN, upper limit of the normal range.
a
Defined as new muscle pain, tenderness, or weakness without another obvious cause that was associated with an elevation of creatine kinase (CK) >_ 10 " ULN.

influenced differences in the main outcomes between the IMPROVE-

.. patients. Tatsuro Uchida: Enrolment of patients. Kunihiko Matsui:
..
IT and HIJ-PROPER trials. .. Statistical analysis. Hiroshi Ogawa: A member of the executive com-
..
Although our results provide no evidence of superiority for inten- .. mittee and the writing committee.
sive lipid lowering over standard statin therapy in all patients, analysis ..
..
of several subgroups yielded findings that are potentially hypothesis- .. Acknowledgements
generating. Caution is needed in their interpretation, but our results ..
.. This trial was funded by the Japan Research Promotion Society for
suggest the possible superiority of concomitant ezetimibe over stand- .. Cardiovascular Diseases. We thank the HIJ-PROPER participants as
ard statin monotherapy for secondary prevention in CAD patients ..
.. well as the staff and investigators of the HIJ-PROPER study for their
with dyslipidaemia due to increased cholesterol absorption. .. contributions.
In conclusion, within the modern context of aggressive coronary
..
..
revascularization and optimal medical therapy, LDL-C lowering to a .. Funding
target of <70 mg/dL (1.8 mmol/L) with a standard dose of pitavastatin ... This trial was funded by the Japan Research Promotion Society for
..
plus ezetimibe showed no more cardiovascular benefit than standard .. Cardiovascular Diseases.
pitavastatin monotherapy in ACS patients with dyslipidaemia. In ACS ..
.. Conflict of interest: The authors have the following disclosures: All
patients with increased cholesterol absorption, statin plus ezetimibe ..
treatment may be more effective than standard statin monotherapy .. members of the HIJ-PROPER study group report having received re-
.. search support to perform clinical trials through the Japan Research
for reducing subsequent cardiovascular events. We consider this sub- .. Promotion Society for Cardiovascular Diseases, which is sponsored by
analysis outcome to be of considerable interest and to warrant fur-
..
.. Abbott Vascular Japan Co., Ltd., AstraZeneca K.K., Bayer Yakuhin, Ltd.,
ther investigation. .. Boston Scientific Corporation, Bristol-Myers K.K., Daiichi Sankyo
..
.. Company, Limited, Kowa Pharmaceutical Co., Ltd., Mochida
.. Pharmaceutical Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co.,
Contributions ..
.. Ltd., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., and Takeda
.. Pharmaceutical Company Limited. N. Hagiwara reports that he has
Nobuhisa Hagiwara: Chair of the HIJ-PROPER Investigators and a ..
member of the writing committee. Erisa Kawada-Watanabe: Clinical
.. received honoraria from Bristol-Myers K.K., and Nippon Boehringer
.. Ingelheim Co., Ltd., and grants from Astellas Pharma Inc., Daiichi Sankyo
follow-up of patients. Ryo Koyanagi: A member of the executive ..
.. Company, Limited, Eisai Co., Ltd., Mitsubishi Tanabe Pharma
committee, Design of the study. Hiroyuki Arashi: Clinical follow-up .. Corporation, Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., and
of patients. Junichi Yamaguchi: A member of the executive commit- ..
.. Takeda Pharmaceutical Company Limited. J. Yamaguchi reports that he
tee, Design of the study. Koichi Nakao: Clinical follow-up of patients. .. has received honoraria from Abbott Vascular Japan Co., Ltd., and grants
Tetsuya Tobaru: Enrolment of patients. Hiroyuki Tanaka: Clinical .. from Daiichi Sankyo Company, Limited. The HIJ-PROPER Steering
..
follow-up of patients. Toshiaki Oka: Enrolment of patients. Yasuhiro .. Committee had full access to all data in the study and had final responsi-
Endoh: Clinical follow-up of patients. Katsumi Saito: Enrolment of
.. bility for the decision to submit for publication.
LDL-C targeting with statin þ ezetimibe for ACS 2275

..
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