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Rationale, design features, and baseline characteristics: The Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER)

Open ArchivePublished:June 24, 2016DOI:https://doi.org/10.1016/j.jjcc.2016.05.002

      Abstract

      Background

      In contrast to current guidelines in Western countries, moderate reduction of low-density lipoprotein cholesterol (LDL-C) is recommended for Japanese patients with atherosclerotic cardiovascular disease and dyslipidemia even in secondary prevention. HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) is a prospective, randomized, open-label, blinded endpoint multicenter trial designed to assess whether closely controlled LDL-C lowering with a standard statin dose plus ezetimibe, targeting LDL-C of <70 mg/dL, would reduce cardiovascular events more than standard statin monotherapy targeting LDL-C of <100 mg/dL as per the Japan Atherosclerotic Society guideline in patients with acute coronary syndrome (ACS) and dyslipidemia.

      Methods

      We recruited patients with ACS and dyslipidemia who had undergone coronary angiography. Participants are randomly allocated to either intensive LDL-C lowering treatment (target LDL-C of <70 mg/dL; pitavastatin plus ezetimibe) or standard LDL-C lowering treatment (target LDL-C of 90–100 mg/dL; pitavastatin monotherapy). The primary endpoint is a composite of total death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, and any ischemia-driven revascularization. Patients will be followed for a minimum of 3 years.

      Results

      Between January 2010 and April 2013, 1734 patients were enrolled from 19 hospitals in Japan with a mean age of 65.6 years; 75.5% were men and 83.3% were statin-naïve. The qualifying ACS was an acute MI in 61.5%. This study is expected to report its findings in August 2016.

      Conclusion

      HIJ-PROPER will determine whether targeting LDL-C of <70 mg/dL with pitavastatin plus ezetimibe can improve cardiovascular outcomes in Japanese patients with ACS and dyslipidemia in comparison to targeting LDL-C of 90–100 mg/dL with standard pitavastatin monotherapy.

      Trial registration

      UMIN000002742.

      Keywords

      Introduction

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      Although statin therapy is highly effective in significantly reducing LDL-C, the LDL-C level decreases approximately 5–6% with each subsequent doubling of the statin dose. (The magnitude of LDL-C reduction does not fully parallel that of cholesterol absorption because, in response to statin-induced reduction in serum cholesterol, cholesterol uptake from the gastrointestinal tract is accelerated.) If the dose of a statin is doubled, there is an approximate 6% increase in LDL-lowering (termed the “rule of six”) [
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      Even in the current era of intensive statin therapy, it is hard to obtain satisfactory results in both achieved LDL-C levels and improved clinical outcomes in ACS patients with dyslipidemia. These challenges are being considered in a number of clinical trials [
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      The Heart Institute of Japan, Department of Cardiology (HIJC) Investigators’ project is an ongoing collaborative effort designed to develop a contemporary epidemiologic database and to improve the quality of care for patients with cardiovascular disease in Japan [
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      ]. As one of our projects, the Heart Institute of Japan PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER) trial was designed to clarify the effects of intensive LDL-C lowering in patients with ACS, comparing intensive lowering with a standard dose of statin plus ezetimibe to less intensive lowering with a standard dose of statin alone.

      Methods

      Study aim

      The primary objective of HIJ-PROPER is to investigate whether co-administration of ezetimibe with a standard dose of statin, targeting greater reduction of LDL-C than is ordinarily achieved with standard statin monotherapy to LDL-C levels as per the JAS guideline, will have a positive effect on secondary prevention in ACS patients with dyslipidemia.

      Study overview

      The HIJ-PROPER study is an ongoing multicenter, prospective, randomized, open-label, blinded-endpoint trial with an active-control design comparing two lipid-lowering treatment strategies involving 19 medical centers in Japan. The trial is conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board or relevant ethics committee of each participating medical center approved the protocol, and all patients provided written informed consent for trial enrollment. A Steering Committee is responsible for the scientific conduct and publication of the results of the trial, and a Working Group is responsible for its daily administration. This trial is funded by the Japan Research Promotion Society for Cardiovascular Diseases, which had no role in conducting the study, and is registered as International Standard Randomized Controlled Trial No. UMIN000002742.

      Study population

      Patient eligibility criteria are shown in Table 1. HIJ-PROPER included specifically targeted hospitalized patients with ACS and dyslipidemia. All participants had been hospitalized for ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA) within the previous 72 h before randomization. Participants with STEMI were required to have electrocardiographic changes (persistent ST-segment elevation ≥0.1 mV, new Q waves, or new left bundle-branch block), elevated troponin or creatine kinase (CK)-MB, and to be at least 20 years of age. Participants presenting with UA/NSTEMI were required to have ischemic discomfort at rest lasting at least 10 min, be at least 20 years of age, and have at least one of the following: new ST-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 grafting (CABG) at least 3 years previously, or known multivessel coronary artery disease including at least 2 major coronary arteries with stenosis of >50%.
      Table 1HIJ-PROPER inclusion and exclusion criteria.
      Inclusion criteria
       1. Patients with ACS (either AMI or UA) who underwent CAG
        ACS that developed within 10 days before admission and met at least one of the following criteria:
        (1) Ischemic electrocardiogram changes
        (2) CK ≥2-fold the institutional ULN; CK-MB or troponin (T or I) exceeding the institutional ULN; or a positive troponin T result on a simple qualitative test
        (3) Medical history or physical findings that suggest ACS and evidence of coronary vasospasm or significant coronary stenosis
       2. Age ≥20 years (male or female)
       3. LDL-C ≥100 mg/dL
        To be calculated using the Friedewald formula (LDL-C = total cholesterol − HDL-C − triglycerides/5)
      Exclusion criteria
       1. Patients with a history of hypersensitivity or allergic reaction to any statin, to ezetimibe, or to their excipients
       2. Triglyceride level ≥400 mg/dL
       3. Concurrent serious liver disease* or renal disease**
        *: Apparent hepatic disorder with AST or ALT >3-fold the institutional ULN
        **: Treatment with dialysis or serum creatinine level >3.0 mg/dL
       4. Status of hemodymamic instabilities
        (1) Hemodynamic instabilities such as hypotension, pulmonary edema, congestive heart failure, acute mitral regurgitation, and ventricular rupture
        (2) Ischemic events (stroke, recurrent symptoms of cardiac ischemia, acute occlusion of target vessel)
        (3) Arrhythmic events (ventricular fibrillation, sustained ventricular tachycardia, advanced heart block)
       5. Planned-CABG
       6. Diagnosis of malignant tumor
       7. Pregnant or lactating women or women who may be pregnant
       8. Familial hypercholesterolemia
       9. PCI within 6 months, or CABG within 2 months prior to the current ACS event
       10. Under treatment or recently treated with cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids
       11. Otherwise ineligible for the study, as determined by the investigator or subinvestigator, including considerations such as substantially reduced life expectancy or limited ability to comply with the protocol
      ACS, acute coronary syndrome; ALT, alanine aminotransferase; AMI, acute myocardial infarction; AST, aspartate aminotransferase; CABG, coronary artery bypass graft; CAG, coronary angiography; CK, creatine kinase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCI, percutaneous coronary intervention; UA, unstable angina; ULN, the upper limit of normal.
      LDL-C, measured within 24 h of hospitalization for the ACS event, was required to be ≥100 mg/dL for patients not receiving chronic lipid-lowering therapy. Subjects were required to have a fasting plasma triglyceride level ≤400 mg/dL as calculated by the Friedewald equation [
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      ].
      Major exclusion criteria are shown in Table 1. They include the occurrence within 24 h before enrollment of (1) hemodynamic instabilities such as hypotension, pulmonary edema, congestive heart failure, acute mitral regurgitation, and ventricular rupture; (2) ischemic events (stroke, recurrent symptoms of cardiac ischemia, and acute occlusion of target vessel); and (3) arrhythmic events (ventricular fibrillation, sustained ventricular tachycardia, and advanced heart block). Patients in whom CABG is planned for the treatment of an ACS event were excluded. Other exclusion criteria included pregnancy; active liver disease or persistent unexplained serum transaminase elevations [≥3 × the upper limit of normal (ULN)]; current treatment with immunosuppressants such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids; any other condition that would substantially reduce life expectancy or limit compliance with the protocol; history of alcohol or drug abuse; allergy/sensitivity to any statin, ezetimibe, or their excipients.

      Statistical considerations

      The expected occurrence of a primary endpoint in the statin-monotherapy group is 10%, based on data from contemporary studies of unstable angina pectoris and AMI with comparable follow-up time [
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      • Skene A.M.
      Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      ,
      • Nagashima M.
      • Koyanagi R.
      • Kasanuki H.
      • Hagiwara N.
      • Yamaguchi J.
      • Atsuchi N.
      • Honda T.
      • Haze K.
      • Sumiyoshi T.
      • Urashima M.
      • Ogawa H.
      Heart Institute of Japan, Department of Cardiology (HIJC) Investigators
      Effect of early statin treatment at standard doses on long-term clinical outcomes in patients with acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology statin evaluation program).
      ,
      • Sakamoto T.
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      Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in Patients With Acute Myocardial Infarction Investigators
      Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese.
      ]. An initial sample size of 3000 patients was selected to afford 80% power to detect relative risk reduction in the 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). The present study was designed to detect a 20% risk reduction rate between the two treatment arms. The primary endpoint event rate of approximately 100 events/1000 person-years in the control group was estimated from previous domestic data [
      • Nagashima M.
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      • Ogawa H.
      Heart Institute of Japan, Department of Cardiology (HIJC) Investigators
      Effect of early statin treatment at standard doses on long-term clinical outcomes in patients with acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology statin evaluation program).
      ,
      • Sakamoto T.
      • Kojima S.
      • Ogawa H.
      • Shimomura H.
      • Kimura K.
      • Ogata Y.
      • Sakaino N.
      • Kitagawa A.
      Multicenter Study for Aggressive Lipid-Lowering Strategy by HMG-CoA Reductase Inhibitors in Patients With Acute Myocardial Infarction Investigators
      Effects of early statin treatment on symptomatic heart failure and ischemic events after acute myocardial infarction in Japanese.
      ]. To detect this difference in effects at the two-tailed 5% level of significance with 80% power, 814 patients per group, or 1628 in total, are required during an enrollment period of 2 years and a follow-up period of at least 3 years. Patient enrollment began in January 2010 on the assumption that 1500 patients for each group would be enrolled by the end of 2012. The enrollment period was extended to the end of April 2013, by which point we had recruited a total of 1748 patients. The Data and Safety Monitoring Board then suggested stopping recruitment, since a recruitment period long enough to complete the enrollment might contribute to critical differences in follow-up periods between patients. Annual assessment of interim analyses was conducted by an independent Data and Safety Monitoring Board to review the safety and efficacy of the present study.

      Randomization and treatment protocol

      The study design and follow-up schedule are shown in Fig. 1. After eligibility was confirmed, patients were randomized by the minimization method with five factors (age, LDL-C level on randomization, history of statin treatment, history of diabetes mellitus, and clinical site), either to the pitavastatin plus ezetimibe group or to the pitavastatin monotherapy group. In the pitavastatin plus ezetimibe group, 2 mg of pitavastatin and 10 mg of ezetimibe were prescribed as a starting dose, targeting LDL-C of 70 mg/dL. Participants already receiving statins other than pitavastatin discontinued the previous agents and started receiving pitavastatin at 2 mg/day under the Japanese regulations related to pharmacotherapies. In the pitavastatin monotherapy arm, patients already receiving statin discontinued the previous agent, and 2 mg of pitavastatin was prescribed as a starting dose, targeting LDL-C of between 90 mg/dL and 100 mg/dL. During the entire study period, the pitavastatin dose (1–4 mg/day) is adjusted to provide the LDL-C level targeted for each specific group. During the study period, combined lipid-lowering medications other than statins and ezetimibe are also allowed in order to achieve the target level of LDL-C in each group.
      Figure thumbnail gr1
      Fig. 1Study design. ACS, acute coronary syndrome; LDL-C, low-density-lipoprotein cholesterol.
      The prespecified number of events was estimated for an α level of 5%, 80% power, and a dropout rate of 2% during a follow-up period of 3 years to provide meaningful data.
      Participants were followed by hospital doctors or other general practitioners. The incidence of endpoint events in addition to drug safety information was determined during the scheduled visits at 3, 6, 12, 24, and 36 months, through contact with each patient, or via access to certificates issued by administrative authorities if necessary. All patients were followed for at least 36 months. Pre-specified measurements, prescribed medications, and clinical events were reported to the Data Management Center every 6 months. Trained clinical research coordinators (CRC) visited the study centers regularly to collect and reconfirm the reported data. Even when patients had stopped coming to their institution, CRC personnel checked their health status by letter or telephone call.

      Study endpoints

      The study endpoints are listed in Table 2. The primary endpoint will be a composite of the first occurrence of a component of the primary endpoint: all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, or revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting. The secondary end points include (1) cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, unstable angina, ischemia-driven revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting), (2) all-cause death, (3) heart failure, (4) inflammatory markers, (5) adverse events (including new occurrence of malignant tumor).
      Table 2Study endpoints.
      Primary outcome measures
      A composit of the first occurrence of a component of:
       All-cause death
       Non-fatal myocardial infarction
       Non-fatal stroke
       Unstable angina
       Ischemia-driven revascularization with either PCI or CABG
      Secondary outcome measures
       Time to first occurrence of any of the following composite endpoints adjudicated and validated by the events adjudication committee: non-fatal myocardial infarction, non-fatal stroke, unstable angina, ischemia-driven revascularization with either PCI or CABG
       All-cause death
       Heart failure hospitalization
       Inflammatory markers
       Adverse events including new occurrence of malignant tumor
      Additional end points
       Cardiometabolic markers: glycated hemoglobin, high-sensitivity C-reactive protein, BNP
       Lipid profile
       Body weight
       Electrocardiographic findings including Holter ECG
       Echocardiographic parameters
       Patient reported outcomes
      BNP, B-type natriuretic peptide; CABG, coronary artery bypass graft; ECG, electrocardiogram; PCI, percutaneous coronary intervention.
      To evaluate the impact of co-morbidities and inflammatory and other cardiac biomarkers on clinical outcomes, mechanistic analyses done within the protocol will include blood samples obtained at baseline and during follow-up. A proteomics evaluation, evaluations of temporal change in cardiac structure, and a genetic substudy will be planned.

      Results

      Between January 2010 and April 2013, 1766 candidates were screened and 1734 patients from 19 clinical centers in Japan were randomized to either pitavastatin plus ezetimibe or pitavastatin monotherapy (see Appendix A). Baseline clinical characteristics of the randomized population are shown in Table 3. The mean ± S.D. age was 65.6 ± 11.8 years; 75.5% were male. The mean ± S.D. body mass index was 24.3 ± 0.2 kg/m2. The index ACS events were STEMI (51.0%), non-STEMI (10.5%), and UA (38.5%). The index revascularization for ACS was percutaneous coronary intervention (PCI) in 94.5% of individuals. Statin therapy was used by 16.7% of participants; 29.5%, 10.3%, 7.8% were treated with renin–angiotensin system inhibitors, beta-blockers, and acetyl salicylic acid (ASA, aspirin), respectively.
      Table 3Baseline characteristics of randomized population (n = 1734).
      Age, y, mean ± S.D.65.6 ± 11.8
      Male (%)1309 (75.5%)
      BMI, kg/m2, mean ± S.D.24.3 ± 0.2
      Qualifying ACS event
       STEMI884 (51.0%)
       Non-STEMI182 (10.5%)
       UA668 (38.5%)
      ACS intervention
       Percutaneous coronary intervention1639 (94.5%)
      Left ventricular ejection fraction
       ≥35%1679 (96.8%)
      Narrowed vessels
      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 narrowing of more than 50% was considered clinically significant.
       Right coronary artery841 (48.5%)
       Left main trunk75 (4.3%)
       Left anterior descending artery1286 (74.2%)
       Circumflex artery785 (45.3%)
       Bypass graft16 (0.9%)
      Cholesterol, mg/dL, mean ± S.D.
       Total210.5 ± 35.3
       Triglycerides130.7 ± 71.0
       High-density lipoprotein cholesterol48.7 ± 12.4
       Low-density lipoprotein cholesterol135.3 ± 29.6
      Fasting plasma glucose, mg/dL, mean ± S.D.141.6 ± 59.7
      HbA1c, %, mean ± S.D.6.1 ± 1.3
      Heart rate, beats/min, mean ± S.D.75.8 ± 16.7
      Systolic blood pressure, mmHg, mean ± S.D.137.9 ± 26.1
      Diastolic blood pressure, mmHg, mean ± S.D.79.9 ± 17.6
      CV history
       Stable angina pectoris202 (11.6%)
       Previous MI131 (7.6%)
       Percutaneous coronary intervention147 (8.5%)
       Coronary artery bypass graft18 (1.0%)
       Chronic HF36 (2.1%)
       Cerebrovascular disease105 (6.1%)
       Peripheral artery disease32 (1.8%)
      Hypertension1184 (68.3%)
      Diabetes mellitus507 (29.2%)
      Smoking
       Current596 (34.4%)
       Former476 (27.5%)
      Estimated glomerular filtration rate (mL/min/1.73 m2)
       <3015 (0.9%)
       ≥30 < 60414 (23.9%)
       ≥60 < 901031 (59.5%)
       ≥90274 (15.8%)
      CV medications
       ACEI71 (4.1%)
       ARB441 (25.4%)
       β-Blocker178 (10.3%)
       Calcium-channel blocker523 (30.2%)
       Nitrates147 (8.5%)
       Aspirin135 (7.8%)
      Statin290 (16.7%)
      Ezetimibe19 (1.1%)
      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; CRP, C-reactive protein; CV, cardiovascular; HF, heart failure; 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 narrowing of more than 50% was considered clinically significant.

      Discussion

      HIJ-PROPER is designed to determine whether the lower LDL-C level that can be obtained with standard doses of statin plus ezetimibe will improve cardiovascular outcomes in ACS patients with dyslipidemia in comparison to the level that can be obtained with standard statin monotherapy. HIJ-PROPER also may demonstrate a beneficial impact of statin plus ezetimibe on cardiovascular outcomes beyond LDL-C reduction in high-risk populations.
      LDL-C lowering is especially valuable for patients with CAD, and the guidelines of the American National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III have strongly emphasized the utility of lipid-lowering therapy in reducing LDL-cholesterol to less than 70 mg/dL in patients with CAD [
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • Brewer Jr., H.B.
      • Clark L.T.
      • Hunninghake D.B.
      • Pasternak R.C.
      • Smith Jr., S.C.
      • Stone N.J.
      Coordinating committee of the National Cholesterol Education Program
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
      ]. Japanese guidelines for the prevention of arteriosclerotic diseases specify a target value of LDL-C of less than 100 mg/dL for control of CHD patients in secondary prevention, but there is no clinical evidence for this figure in Japanese practice [
      • Teramoto T.
      • Sasaki J.
      • Ueshima H.
      • Egusa G.
      • Kinoshita M.
      • Shimamoto K.
      • Daida H.
      • Biro S.
      • Hirobe K.
      • Funahashi T.
      • Yokote K.
      • Yokode M.
      Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese.
      ,
      • Teramoto T.
      • Sasaki J.
      • Ishibashi S.
      • Birou S.
      • Daida H.
      • Dohi S.
      • Egusa G.
      • Hiro T.
      • Hirobe K.
      • Iida M.
      • Kihara S.
      • Kinoshita M.
      • Maruyama C.
      • Ohta T.
      • Okamura T.
      • et al.
      Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan – 2012 version.
      ]. The present study is designed to provide further data in this area.
      Although statin therapy is highly effective in significantly reducing LDL-C at the initial dose, a doubling of that dose provides further LDL-C reduction of only about 5–6% (termed the “rule of six”). The magnitude of LDL-C reduction does not fully parallel cholesterol absorption because, in response to statin-induced reduction in serum cholesterol, cholesterol uptake from the gastrointestinal tract is accelerated. If the statin dose is doubled, LDL-lowering efficiency increases by about 6% [
      • Leitersdorf E.
      Cholesterol absorption inhibition: filling an unmet need in lipid-lowering management.
      ].
      The ACC/AHA guideline recommends regularly scheduled follow-up visits after initiating statin therapy to monitor drug-taking compliance, to provide lifestyle advice, and to assess adverse events. Regular measurement of lipids is also required to assess therapeutic response.
      Some patients experience serious adverse effects under high-intensity statin therapy, so many clinicians have emphasized the importance of balancing benefit and potential harm. This includes the fact that statin-related adverse effects are dose-dependent and occur more commonly at the highest doses [
      • Graham D.J.
      • Staffa J.A.
      • Shatin D.
      • Andrade S.E.
      • Schech S.D.
      • La Grenade L.
      • Gurwitz J.H.
      • Chan K.A.
      • Goodman M.J.
      • Platt R.
      Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.
      ,
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study.
      ,
      • Preiss D.
      • Seshasai S.R.
      • Welsh P.
      • Murphy S.A.
      • Ho J.E.
      • Waters D.D.
      • DeMicco D.A.
      • Barter P.
      • Cannon C.P.
      • Sabatine M.S.
      • Braunwald E.
      • Kastelein J.J.
      • de Lemos J.A.
      • Blazing M.A.
      • Pedersen T.R.
      • et al.
      Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
      ]. After statin therapy has been initiated, the patient should be assessed every 3–12 months as clinically indicated, since adherence to both medication and lifestyle regimens are required for cardiovascular risk reduction. Statin characteristics may affect the incidence of muscle injury, and the incidence of rhabdomyolysis is known to increase dose-dependently with statin use [
      • Graham D.J.
      • Staffa J.A.
      • Shatin D.
      • Andrade S.E.
      • Schech S.D.
      • La Grenade L.
      • Gurwitz J.H.
      • Chan K.A.
      • Goodman M.J.
      • Platt R.
      Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.
      ,
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Begaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study.
      ]. Statins may also impact glucose metabolism and influence the development of diabetes. Previous studies have demonstrated increased risk of new-onset diabetes with intensive statin therapy in comparison to standard statin therapy [
      • Preiss D.
      • Seshasai S.R.
      • Welsh P.
      • Murphy S.A.
      • Ho J.E.
      • Waters D.D.
      • DeMicco D.A.
      • Barter P.
      • Cannon C.P.
      • Sabatine M.S.
      • Braunwald E.
      • Kastelein J.J.
      • de Lemos J.A.
      • Blazing M.A.
      • Pedersen T.R.
      • et al.
      Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
      ,
      • Carter A.A.
      • Gomes T.
      • Camacho X.
      • Juurlink D.N.
      • Shah B.R.
      • Mamdani M.M.
      Risk of incident diabetes among patients treated with statins: population based study.
      ]. All these factors suggest that a combined drug regimen, which would allow the targeting of lower LDL-C levels without the risk of high-dose statin therapy, might be beneficial particularly in improving cardiovascular outcomes in high-risk patients.

      Conclusion

      HIJ-PROPER will determine whether targeting an LDL-C level of less than 70 mg/dL with pitavastatin plus ezetimibe can improve cardiovascular outcomes in Japanese patients with ACS and dyslipidemia in comparison to targeting an LDL-C level of 90–100 mg/dL with pitavastatin monotherapy.

      Funding

      This trial is funded by the Japan Research Promotion Society for Cardiovascular Diseases, which played no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

      Disclosures

      The authors have the following disclosures: All members of the HIJ-PROPER study group report having received research support to perform clinical trials through the Japan Research Promotion Society for Cardiovascular Diseases, which is sponsored by 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., Sanofi K.K., Takeda Pharmaceutical Company Limited, Eli Lilly Japan K.K., Edwards Lifesciences Corporation, Medtronic, Inc., Boston Scientific Corporation, and Abbott Vascular Japan Co., Ltd.
      J. Yamaguchi reports that he has received honoraria from Abbott Vascular Japan Co., Ltd. and grants from Daiichi Sankyo Company, Limited. N. Hagiwara reports that he has received 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., Eizai Co., Ltd., and Otsuka Pharmaceutical Co., Ltd.
      The HIJ-PROPER Steering Committee had full access to all data in the study and had final responsibility for the decision to submit for publication.

      Appendix A. Study organization

      Executive Committee: Nobuhisa Hagiwara (Chair), Hiroshi Ogawa.
      Steering Committee: Saichi Hosoda, Hiroshi Kasanuki, Takashi Honda.
      Working Group: Tetsuya Sumiyoshi, Koichi Nakao, Tatsuro Ueda, Jun-ichi Yamaguchi, Ryo Koyanagi, Hiroyuki Arashi, Erisa Kawada-Watanabe.
      Data and Safety Monitoring Committee: Mitsuyoshi Urashima (Jikei University School of Medicine).
      Endpoint Committee: Michihiro Yoshimura (Jikei University School of Medicine), Teruo Inoue (Dokkyo Medical University), Yasuhiro Hasegawa (St. Marianna University Toyoko Hospital).
      Voting Members: Hisao Ogawa (Kumamoto University), Masakazu Yamagishi (Kanazawa University).
      Clinical Centers: Tokyo Women's Medical University, Sakakibara Heart Institute, Saisei-Kai Kumamoto Hospital, Cardiovascular Center of Sendai, Seirei Hamamatsu General Hospital, Saisei-Kai Kurihashi Hospital, National Yokohama Medical Center, Tokyo Metropolitan Tama Medical Center, Kosei General Hospital, NTT-East Kanto Medical Hospital, Tokyo Metropolitan Tama-Hokubu Medical Center, Shin-Matsudo Central General Hospital, JCHO Sagamino Hospital, Nishiarai Heart Center, Ogikubo Hospital, Shiseikai-Daini Hospital, Tokyo Metropolitan Ebara Hospital, Tokyo Women's Medical University Medical Center East, Tokyo Women's Medical University Yachiyo Medical Center.

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