Aggressive lipid-lowering therapy in coronary artery disease

Abstract

We provide aggressive lipid-lowering therapy for coronary artery disease. [Solution] This invention provides a method to further reduce the cardiovascular risk of subjects with coronary artery disease using moderate-intensity statins.

Description

Technical Field

[0001] The present invention relates to a method for further reducing the cardiovascular risk in patients with coronary artery lesions using a moderate-intensity statin.

Background Art

[0002] Cardiovascular (CV) death is an important medical and social problem and is increasing annually, including in Japan. Although the outcomes of patients with coronary artery disease (CAD) have improved due to the widespread use of new and effective drug therapies and percutaneous coronary intervention (PCI), the recurrence rate in secondary prevention patients is still high compared to primary prevention patients (1-3).

[0003] Many epidemiological studies have demonstrated that coronary artery death and CV events are associated with an increase in low-density lipoprotein cholesterol (LDL-C) levels. Furthermore, large-scale clinical trials have shown that lipid-lowering therapy using statins reduces CV events (4-11). In the J-LIT trial and MUSASHI-AMI trial in Japan, when the LDL-C value was reduced to less than 100 mg / dL (2.6 mmol / L) by statin treatment, the recurrence risk of CV events was significantly reduced (1,12). From these facts, the guidelines of the Japanese Atherosclerosis Society state that it is desirable to lower the LDL-C value to 100 mg / dL or less for secondary prevention (13). This target is higher than the targets defined in European and previous US guidelines (14,15).

[0004] In secondary prevention trials such as the A to Z, TNT, IDEAL, and PROVE-IT studies, the proportion of CV events has been compared between high-intensity lipid-lowering treatment and moderate-intensity lipid-lowering treatment (16-19). In the meta-analysis of these trials, high-intensity lipid-lowering treatment is compared with moderate-intensity lipid-lowering therapy This significantly reduced the CV event rate by 16% (20). CV events correlated with a decrease in LDL-C in both acute coronary syndrome (ACS) patients and chronic CAD patients (21). Therefore, for secondary prevention, European guidelines recommend an LDL-C target of less than 70 mg / dL, and the American College of Cardiology (ACC) / American Heart Association (AHA) guidelines recommend high-intensity statin therapy (14,22). 4 mg of pitavastatin is administered. It has been reported that this can reduce LDL-C by 42.9% from baseline (29).

[0005] Since the CV event rate in the Asian population is much lower than in the European and American populations (23,24), it is important to confirm the benefits of statin therapy in the Asian population. In Japan, no large-scale outcome studies have been conducted on the use of statins for secondary prevention. However, several studies have shown, using intravascular ultrasound, that intensive LDL-C reduction with statins leads to plaque regression. The ESTABLISH, JAPAN-ACS, and COSMOS trials demonstrated that aggressive lipid-lowering therapy with moderate-to-high dose statins, which reduces LDL-C to 70-80 mg / dL, significantly reduces coronary artery plaque volume (25-27). Furthermore, the expanded ESTABLISH The H trial suggested that plaque regression during the randomization period correlated with a reduction in long-term cardiovascular events (28). However, no prospective clinical trials comparing high-dose statin therapy with low-dose statin therapy have been conducted in Asia, so it remains unclear whether high-dose statin therapy can safely improve clinical outcomes in the Asian population.

[0006] The objective of this invention is to further reduce the risk of cardiovascular disease (CV) than that achieved by moderate-intensity statin therapy. Another object of the present invention is to identify subject populations for whom such risk reduction strategies are effective. That is the case. Another object of the present invention is to reduce the risk of cardiovascular disease in subjects with established coronary artery disease and / or moderately elevated LDL-C levels. Another object of the present invention is to identify the unique efficacy of high-intensity statin therapy and to implement such therapy to provide such efficacy. A further objective is to modulate cardiovascular risk biomarkers using high-intensity statin therapy in high-risk patients. [Overview of the Initiative]

[0007] Accordingly, in the first main embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject under a dosage of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof, wherein the subject has an LDL-C concentration of less than 120 mg / dL, and the dosage is increased to 4 mg / day for a therapeutically effective period. The subject preferably has coronary artery disease.

[0008] In a second primary embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject with stable coronary artery disease, the method comprising the step of administering 4 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof to the subject for a therapeutically effective period. Prior to the administration of 4 mg / day, the subject is preferably administered a dose of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof and has an LDL-C concentration of less than 120 mg / dL.

[0009] In a third primary embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject under a dosage of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof, wherein the subject has stable coronary artery disease and an LDL-C concentration of less than 120 mg / dL, and the dosage is increased to 4 mg / day for a therapeutically effective period.

[0010] In a fourth primary embodiment, the present invention provides a method for modulating a biomarker of cardiovascular risk in a subject with stable coronary artery disease, the method comprising administering 4 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof to the subject for a therapeutically effective period, wherein the modification is selected from (a) lowering the subject's LDL-C level; (b) raising the subject's HDL-C level; (c) lowering the subject's TG level; (d) lowering the subject's hs-CRP level; or (e) all or a combination thereof. Prior to the administration of 4 mg / day, the subject is preferably on an LDL-C concentration of less than 120 mg / dL, with an LDL-C concentration of less than 120 mg / dL.

[0011] Further advantages of the present invention are partially described below, partially evident from said description, or can be learned through the practice of the present invention. The effects of the present invention will be realized and achieved by means and combinations of the components particularly pointed out in the appended claims. It should be understood that the above general description and the following detailed description are merely illustrative and explanatory and do not limit the invention as described in the claims. [Brief explanation of the drawing]

[0012] The accompanying drawings incorporated herein and constituting part thereof illustrate several embodiments of the present invention and serve to illustrate the principles of the present invention together with the description. [Figure 1] Figure 1 is a logical flowchart illustrating the rationale and design of the human clinical trial described in Example 1. [Figure 2] Figure 2 shows baseline-start LDL-C levels in two separate subject groups, each initially maintained with pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study period, while the second group increased their dose to pitavastatin 4 mg / day throughout the study period (as described in Example 1). [Figure 3]Figure 3 shows baseline HDL-C levels in two separate groups of subjects, initially maintained with pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study, while the second group increased their dose to pitavastatin 4 mg / day throughout the study. [Figure 4] Figure 4 shows baseline TG levels in two separate groups of subjects, initially maintained at pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study period, while the second group increased their dose to pitavastatin 4 mg / day throughout the study period (as described in Example 1). [Figure 5] Figure 5 shows baseline hs-CRP levels in two separate groups of subjects, initially maintained at pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study period, while the second group increased their dose to pitavastatin 4 mg / day throughout the study period (as described in Example 1). [Figure 6] Figure 6 shows the cumulative incidence over time of cardiovascular events (CV death, myocardial infarction (MI), ischemic stroke, and unstable angina (UA) requiring emergency hospitalization) in two separate groups of subjects. Initially, each group maintained pitavastatin at 1 mg / day. The first group remained at 1 mg / day throughout the study period, while the second group increased to 4 mg / day during the study period (as described in Example 1). [Figure 7] Figure 7 shows the cumulative incidence over time of cardiovascular events (CV death, MI, ischemic stroke, UA requiring emergency hospitalization, and coronary revascularization) in two separate groups. Initially, each group maintained pitavastatin at 1 mg / day. The first group remained at 1 mg / day throughout the study period, while the second group increased to 4 mg / day during the study period (as described in Example 1). [Figure 8] Figure 8 shows individual cardiovascular events in two separate groups, each initially maintained at pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study period, while the second group increased to pitavastatin 4 mg / day during the study period (as described in Example 1). [Figure 9]Figure 9 shows subgroup analyses of the primary endpoints (CV death, myocardial infarction, ischemic stroke, and UA requiring emergency hospitalization) in two separate groups. The initial dose was maintained at pitavastatin 1 mg / day. The first group remained at pitavastatin 1 mg / day throughout the study period, while the second group increased to pitavastatin 4 mg / day during the study period, as described in Example 1. Detailed description of the invention

[0013] Definitions and Use of Terms As used herein and in the following claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. As used herein and in the claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. For example, the term “pharmaceutical excipient” refers to one or more pharmaceutical excipients for use in the formulations and methods disclosed herein.

[0014] As used herein, and in the following claims, the terms and variations of the terms “constitutes” and “includes means” are not intended to exclude, for example, other additives, components, integers or processes, and it will be understood that if an element consists of multiple components, processes or conditions, that element also consists of such combinations, or “consists of multiple components” or “essentially consists of multiple components, processes or conditions.”

[0015] In this application, numerical values ​​may be preceded by the word "approximately." Furthermore, the disclosure of ranges includes all values ​​between the listed minimum and maximum values, as well as any values ​​formed by such values. It is intended as a continuous range that includes any and all ranges that can be made. Also, in this specification, any and all ratios (and ranges of any such ratios) that can be formed by dividing the disclosed numerical values by any other disclosed numerical value are disclosed. Thus, one of ordinary skill in the art will understand that many such ratios, ranges, and ranges of ratios can be clearly derived from the numerical values presented herein, and in all instances, such ratios, ranges, and ranges of ratios represent various embodiments of the invention.

[0016] As used herein, "cardiovascular event" or "CV event" includes any adverse CV event including CV death; non-fatal myocardial infarction ("MI"); non-fatal ischemic stroke; unstable angina (UA) (e.g., UA determined to be caused by myocardial ischemia by invasive or non-invasive testing and requiring hospitalization); cardiac arrest; peripheral CV disease requiring intervention, angioplasty, bypass surgery, or aneurysm repair; and the onset of new congestive heart failure.

[0017] As used herein, "preventing the occurrence of a CV event" includes reducing the risk of a CV event, delaying the occurrence or onset of a CV event, and minimizing the severity of a CV event. This also refers to (a) the time interval from the first administration of a therapeutically effective amount of pitavastatin or a pharmaceutically acceptable salt thereof disclosed herein to a cardiovascular event in a subject being (a') longer or substantially longer than the time interval from the first administration of a placebo to a cardiovascular event in a control subject.

[0018] As used herein, "therapeutically effective amount" refers to an amount sufficient to induce a desired biological response in a subject. A therapeutically effective amount or dose depends on the age, sex and mass of the subject, as well as the current medical condition of the subject. One of ordinary skill in the art can determine an appropriate amount or dose based on their knowledge and the teachings contained herein, taking into account the above factors.

[0019] Where the dosage of pitavastatin or a pharmaceutically acceptable salt thereof is described in this document, it will be understood that the dosage is based on the mass of the free base of pitavastatin. Therefore, a 1 mg dosage of pitavastatin or a pharmaceutically acceptable salt thereof contains 1 mg of pitavastatin as free base, regardless of whether pitavastatin is present as a free base or as a salt. 1 mg of this product contains 1 mg of free base of pitavastatin calcium and 1.045 mg of pitavastatin calcium. The preferred form of pitavastatin in all embodiments of the present invention is pitavastatin calcium.

[0020] "Pharmacologically acceptable" generally means safe, non-toxic, not biologically or otherwise undesirable, useful in preparing pharmaceutical compositions, and acceptable for veterinary and human medicinal use. "Pharmacologically acceptable salt" means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity, as defined above.

[0021] The terms “to treat” and “treatment,” as used herein, refer to the medical management of a subject intended to treat, improve, stabilize or prevent a disease, pathological condition, or disorder (collectively, “Disorder”). These terms include active treatment, i.e., treatment specifically aimed at improving the disorder; causal treatment, i.e., treatment aimed at eliminating the cause of the associated disorder; further, palliative treatment, i.e., treatment aimed at alleviating symptoms rather than curing the disorder; preventive treatment, i.e., treatment aimed at minimizing, partially or completely suppressing, or delaying the onset of the disorder; and supportive treatment, i.e., treatment used to complement other specific treatments aimed at improving the disorder. Where a method is said to “reduce” the risk of cardiovascular disease, that method also means “treating cardiovascular disease.” It can also be understood as "to place".

[0022] When used to define the subjects described herein, all analyte measurements listed herein are measured at the start of the therapy according to the claim, i.e., when the pitavastatin dose is increased.

[0023] In this specification, unless otherwise stated, all analyte measurements are performed in a fasted state and are based on the concentration of the analyte in plasma or serum. Fasting means that the subject has not eaten anything other than water for 8 to 12 hours. The standard method for measuring analytes is the Lab Protocols for NHANES published by the U.S. Centers for Disease Control and Prevention. This can be found in the 2003-2004 data.

[0024] As used herein, the term “significantly” means the level of statistical significance. The level of statistical significance may be, for example, at least p<0.05, at least p<0.01, at least p<0.005, or at least p<0.001. Whenever a numerical value or evaluation item is specified herein, in a preferred embodiment it is understood to have a statistical significance of at least p<0.05.

[0025] Description of the main embodiment The present invention is described herein in relation to primary and secondary embodiments. Each of the secondary embodiments is understood to modify any of the primary embodiments unless it is logically contradictory or expressly refuted herein. Furthermore, the primary embodiments can be combined in any way, and the secondary embodiments can be combined in any way to further modify any of the primary embodiments, unless such combination is logically contradictory or expressly refuted herein.

[0026] In a first primary embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject under a dose of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof, comprising increasing the dose to 4 mg / day for a therapeutically effective period, provided the subject has an LDL-C concentration of less than 120 mg / dL. The subject preferably has coronary artery disease.

[0027] In a second primary embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject with stable coronary artery disease, the method comprising administering the subject 4 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof for a therapeutically effective period. Prior to the administration of 4 mg / day, the subject is preferably administered a dose of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof and has an LDL-C concentration of less than 120 mg / dL.

[0028] In a third primary embodiment, the present invention provides a method for preventing adverse cardiovascular events in a subject with a dose of pitavastatin or a pharmaceutically acceptable salt thereof of 1 mg / day, wherein the subject has stable coronary artery disease and an LDL-C concentration of less than 120 mg / dL, and the dose is increased to 4 mg / day for a therapeutically effective period.

[0029] In a fourth main embodiment, the present invention provides a method for modulating a biomarker of cardiovascular risk in a subject with stable coronary artery disease, the method comprising administering 4 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof to the subject for a therapeutically effective period, wherein the modification is selected from (a) lowering LDL-C levels in the subject; (b) raising HDL-C levels in the subject; (c) lowering TG levels in the subject; (d) lowering hs-CRP levels in the subject; or (e) all or a combination thereof. Prior to the administration of 4 mg / day, the subject is preferably administered a dose of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof. Furthermore, it has an LDL-C concentration of less than 120 mg / dL.

[0030] Discussion of alternative embodiments Each of the following sub-embodiments may be applied to limit each and all of the aforementioned primary embodiments, but it will be understood that a sub-embodiment is not applicable if it is already fully encompassed by the primary embodiment. Furthermore, the sub-embodiments may be combined with each other in any way that is logically and mathematically possible, and it will be understood that further sub-embodiments may be defined by adopting the more restrictive value when two values ​​are expressed for the same restriction.

[0031] In either the main or sub-embodiment of the present invention, the subject preferably has stable coronary artery disease characterized by (a) a history of ACS such as acute myocardial infarction or unstable angina; (b) a history of coronary artery reconstructive surgery (PCI or coronary artery bypass grafting (CABG)); or (c) atherosclerosis CAD detected by coronary angiography with at least 75% stenosis in the major epicardial coronary arteries.

[0032] In one sub-embodiment, the method of the present invention prevents cardiovascular death. In another sub-embodiment, the method of the present invention prevents myocardial infarction. In another sub-embodiment, the method of the present invention prevents unstable angina (UA) requiring emergency hospitalization. In another sub-embodiment, the method of the present invention prevents any of cardiovascular death, myocardial infarction, or unstable angina (UA) requiring emergency hospitalization. In another sub-embodiment, the method of the present invention prevents any of cardiovascular death, myocardial infarction, unstable angina requiring emergency hospitalization, or coronary revascularization. In another sub-embodiment, the method of the present invention prevents death from any cause. In another sub-embodiment, the method of the present invention prevents all coronary revascularization. In another sub-embodiment, the method of the present invention prevents non-TLR coronary revascularization. In another sub-embodiment, the method of the present invention prevents coronary revascularization (TLR).

[0033] This method can also be performed in humans depending on age. Therefore, in one sub-embodiment, the method is performed on subjects under the age of 65 years. In another sub-embodiment, the method is performed on subjects 65 years of age or older.

[0034] This method can also be performed in humans depending on their type II diabetes status. Therefore, in one sub-embodied embodiment, this method is performed in subjects with type II diabetes. In another sub-embodied embodiment, this method is performed in subjects without type II diabetes.

[0035] This method can also be performed in humans based on LDL-C concentration. Therefore, in one sub-embodiment, the method is performed in subjects with an LDL-C concentration of less than 95 mg / dL. In another sub-embodiment, the method is performed in subjects with an LDL-C concentration of 95 mg / dL or greater.

[0036] This method can also be performed in humans based on hs-CRP concentration. Therefore, in one sub-embodiment, this method is performed in subjects with an hs-CRP concentration of less than 1 mg / L. In another sub-embodiment, this method is performed in subjects with an LDL-C concentration of 1 mg / L or greater.

[0037] This method can also be performed in humans based on HDL-C concentration. Therefore, in one sub-embodiment, the method is performed in subjects with HDL-C concentrations of 40 mg / dL or less. In another sub-embodiment, the method is performed in subjects with HDL-C concentrations greater than 40 mg / dL.

[0038] This method can also be performed in humans based on TG concentration. Therefore, in one sub-embodiment, this method is performed in subjects with TG concentrations less than 150 mg / dL. In another sub-embodiment, this method is performed in subjects with TG concentrations of 150 mg / dL or greater.

[0039] This method can also be implemented in humans based on their body mass index (BMI). Therefore, in one sub-embodiment, the method may be 25 kg / m². 2 BMI less than This is performed on subjects. In another sub-embodiment, the method is 25 kg / m 2 The above B This is performed on subjects with MI. 2 It has a body mass index of less than .

[0040] In another sub-embodiment, the subject has hypertension. In another sub-embodiment, the subject does not have hypertension. In another sub-embodiment, the subject has a history of acute coronary syndrome (ACS). In another sub-embodiment, the subject does not have a history of acute coronary syndrome (ACS). In another sub-embodiment, the subject has undergone coronary revascularization. In another sub-embodiment, the subject has not undergone coronary revascularization. In another sub-embodiment, the subject has ischemic stroke. In another sub-embodiment, the subject does not have ischemic stroke. In another sub-embodiment, the subject has peripheral vascular disease. In another sub-embodiment, the subject does not have peripheral vascular disease. In another sub-embodiment, the subject has chronic kidney disease (CKD) (eGFR < 60 mL / min / 1.73 m 2 )in Yes. In another sub-embodiment, the subject does not have chronic kidney disease (CKD) (eGFR < 60 mL / min / 1.73 m). 2 In another sub-embodiment, the subject is receiving aspirin treatment. In another sub-embodiment, the subjects were not receiving aspirin treatment. In another sub-embodiment, the subjects were receiving dual antiplatelet therapy (DAPT). In yet another sub-embodiment, the subjects were not receiving dual antiplatelet therapy (DAPT).

[0041] In other sub- embodiments, the method is performed to modulate biomarker levels in affected subjects. Therefore, in one sub-embodiment, the method further includes (a) lowering LDL-C levels in the subject; (b) raising HDL-C levels in the subject; (c) lowering TG levels in the subject; (d) lowering hs-CRP levels in the subject; or (e) all or a combination thereof. It is desirable that the subject's LDL-C, HDL-C, TG, and hs-CRP values ​​prior to 4 mg of pitavastatin be described elsewhere in this document (i.e., LDL-C < 95 mg / dL or ≥ 95 mg / dL; hs-CRP < 1 mg / L or ≥ 1 mg / L; HDL-C ≤ 40 mg / dL or > 40 mg / dL; and / or TG < 150 mg / dL or ≥ 150 mg / dL).

[0042] In other sub-embodiments, the method is implemented on individuals based on their ethnic background. Examples

[0043] In the following examples, efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., quantity, temperature, etc.), but some degree of error and deviation should be taken into consideration. The following examples are provided to give a full disclosure and description of how the claimed methods herein are prepared and evaluated, and are intended to be purely illustrative of the invention and not intended to limit the scope of what the inventors consider to be the invention. [Example 1]

[0044] Evaluation of aggressive lipid-lowering therapy in Japanese patients with coronary artery disease Study design and objectives: This study was a prospective, multicenter, randomized, open-label, blinded, endpoint-blinded, investigator-initiated phase IV trial designed to investigate whether high-dose statin therapy could reduce cardiovascular events in stable CAD patients compared to low-dose statin therapy. The authors hypothesized that aggressive lipid-lowering treatment with pitavastatin 4 mg / day would reduce the incidence of a composite endpoint consisting of cardiovascular death requiring emergency hospitalization, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and unstable angina. The control group received pitavastatin 1 mg / day.

[0045] Ethical approval was obtained from the Public Health Research Foundation's Ethics Review Board and the relevant ethics boards at all participating sites. All patients submitted written informed consent. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The overall design of the study is shown in Figure 1.

[0046] Selection of study population and patients: Men and women aged 20 to 80 years with clinically clear and stable elevated CAD and LDL-C were eligible for this study. CAD was defined as 1) a history of ACS such as acute myocardial infarction or unstable angina, 2) a history of coronary artery reconstructive surgery (PCI or coronary artery bypass grafting (CABG)), or 3) atherosclerotic CAD (American Heart Association classification) detected by coronary angiography with 75% or more stenosis of the major epicardial coronary arteries (30). Patients with elevated LDL-C at enrollment were defined as (1) patients with LDL-C of 140 mg / dL or higher who were not receiving chronic lipid-lowering therapy, (2) patients with LDL-C of 100 mg / dL or higher whose attending physician determined that lipid-lowering therapy was necessary, or (3) patients receiving lipid-lowering therapy.

[0047] Exclusion criteria included: (1) any planned coronary revascularization, (2) effective malignancy, (3) contraindications to pitavastatin (hypersensitivity to pitavastatin, severe liver disease or impaired liver function, concomitant use of cyclosporine, or pregnancy, current lactation, or suspected lactation), (4) severe congestive heart failure (ejection fraction less than 30% or NYHA class 3 or higher), (5) current hemodialysis, (6) familial hypercholesterolemia, (7) current participation in another clinical trial, (8) current use of any prohibited drug (lipid-lowering drug other than pitavastatin) that cannot be discontinued during the study, and (9) any other findings that the principal investigator deemed unsuitable for the study.

[0048] Randomization and treatment protocols: The study included 733 hospitals nationwide. Informed consent and baseline medical history were obtained at screening visits, and the clinical trial was conducted. Blood samples were collected to measure fasting lipid levels and the patient's standard clinical profile. After discontinuing all previous lipid-lowering therapies, all eligible patients started treatment with pitavastatin 1 mg / day for at least one month in an open-label manner (induction phase). At the end of the observation period (week 0), patients with an LDL-C level of less than 120 mg / dL, as measured by a central laboratory using Friedwald's formula, were eligible for randomization. Patients with a history of ACS or coronary revascularization could be randomized more than three months after the indicator event. Patients with poor adhesion of the investigational drug (less than 50%) during the observation period, or those who experienced the primary endpoint event during the observation period, were not eligible for randomization.

[0049] Patients were randomly assigned in a 1:1 ratio to receive either pitavastatin 4 mg or pitavastatin 1 mg. Randomized treatment assignment was stratified by five factors: 1) institution, 2) statin use history, 3) age (under 65 years or 65 years or older), 4) diabetes, and 5) sex. Patients were followed for 3 years, with the first visit scheduled at 6 months, followed by annual follow-up visits. At each visit, information on vital signs, clinical outcomes, adverse events, and concomitant medications was collected. In addition, physical examinations and electrocardiograms were performed, and blood samples were collected at 6 months and every 12 months thereafter for lipid and other clinical tests.

[0050] Evaluation criteria: The primary endpoint of the study was a composite of CV death, non-fatal MI, non-fatal ischemic stroke, or unstable angina requiring emergency hospitalization. Secondary endpoints were: (1) composite CV event (CV death, non-fatal MI, non-fatal ischemic stroke requiring emergency hospitalization, and coronary revascularization for non-target lesions in previous coronary revascularization), (2) composite coronary event (coronary death, non-fatal angina requiring emergency hospitalization, and coronary revascularization), (3) composite cerebrovascular event (fatal or non-fatal stroke and transient ischemic attack requiring hospitalization), (4) death (all-cause death, CV death, death due to coronary heart disease (CHD)), and (5) individual cardiac events (fatal). (1) Fatal and non-fatal myocardial infarction, unstable angina requiring emergency hospitalization, hospitalization for primary diagnosis of congestive heart failure, coronary revascularization. (2) Resuscitated cardiac arrest, (3) Individual cerebrovascular events (fatal and non-fatal stroke, fatal and non-fatal hemorrhagic stroke, transient ischemic attack requiring hospitalization), (4) Other events (operation or rupture of aortic aneurysm, aortic dissection, revascularization for peripheral artery disease, carotid endarterectomy or stent placement, venous thromboembolism, new onset of malignant tumor, operation for aortic valve stenosis).

[0051] Baseline data: The study population consisted of patients from 768 centers. The first patients were recruited in January 2010. Randomization took place from April 2010 to July 2013. Of the 14,774 patients who progressed to the open-label induction phase, 13,054 were randomized to either the pitavastatin 1 mg group or the 4 mg group. Randomized patients who withdrew their consent early or violated the enrollment criteria were excluded. The baseline characteristics of these 12,413 patients are shown in Table 1. BMI is body mass index; UA is unstable angina; PCI is percutaneous coronary intervention; CABG is coronary artery bypass grafting; CAD is coronary artery disease; LDL-C is low-density lipoprotein cholesterol; HDL-C is high-density lipoprotein cholesterol; Apo is apolipoprotein; hsCRP is high-sensitivity C-reactive protein; IQR is interquartile range; and HbA1C is hemoglobin A1C.

[0052] [Table 1]

[0053] result: The test results are reported in Figures 2-9. The following can be observed: When the dosage of pitavastatin was changed from 1 mg to 4 mg in patients, LDL-C levels decreased statistically significantly (Figure 2). When the pitavastatin dosage was changed from 1 mg to 4 mg in patients, HDL-C levels increased significantly (Figure 3). Changing the pitavastatin dosage from 1 mg to 4 mg in patients resulted in a statistically significant decrease in triglycerides (TG) (Figure 4). Changing the pitavastatin dosage from 1 mg to 4 mg in patients resulted in a statistically significant decrease in hs-CGP (Figure 5). Changing the pitavastatin dosage from 1 mg to 4 mg in patients resulted in a statistically significant reduction in the primary clinical endpoint (composite of cardiovascular death, myocardial infarction, ischemic stroke, and ulcerative arrest) (Figure 6). Changing the pitavastatin dosage from 1 mg to 4 mg in patients resulted in a statistically significant decrease in secondary clinical endpoints (primary endpoint + coronary revascularization) (Figure 7). The incidence rates of individual cardiovascular events in the 1 mg and 4 mg pitavastatin groups, with particular emphasis on clear death of any cause, myocardial infarction, and outcomes of coronary revascularization (Figure 8); and The incidence rates of the primary endpoint, classified based on various patient characteristics with a particular focus on the LDL-C subgroup, showed that LDL-C status (whether ≥95 mg / dL or <95 mg / dL) did not affect the outcome (Figure 9).

[0054] References 1.Mabuchi H, Kita T, Matsuzaki M, et al. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia and coronary heart disease: secondary prevention cohort study of the Japan Lipid Intervention Trial (J-LIT). Circ J 2002; 66: 1096-100. 2.Japanese Coronary Artery Disease (JCAD) Study Investigators. Current status of the background of patients with coronary artery disease in Japan. Circ J 2006; 70: 1256-62. 3.Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369: 1090-8. 4.Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9. 5.Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial inves tigators. N Engl J Med 1996; 335: 1001-9. 6.West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998; 97: 1440-5. 7.The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349-57. 8.Heart Protection Study (HPS) Collaborative Group. MRC / BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 : 7-22. 9.Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149-58. 10.Colhoun HM, Betteridge DJ, Durrington PN, et al. Primar y prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685-96. 11.Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368: 1155-63. 12.Sakamoto T, Kojima S, Ogawa H, et al. Effects of early statin treatment on symptomatic heart failure and ischemic events after a cute myocardial infarction in Japanese. Am J Cardiol 2006; 97: 1165-71. 13.Teramoto T, Sasaki J, Ishibashi S, et al. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerosis cardiovascular diseases in Japan2012 version. J Atheroscler Thromb 2012; 20: 517-23. 14.Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37: 23 15-81. 15.Grundy SM, Cleeman JI, Merz CN, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-39. 16.de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307-16. 17.LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N E ngl J Med 2005; 352: 1425-35. 18.Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. J AMA 2005; 294: 2437-45. 19.Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-504. 20.Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48: 438-45. 21.Josan K, Majumdar SR, McAlister FA. The efficacy and safety of in tensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008;178: 576-84. 22.Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC / A HA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2889-934. 23.Kaneko H, Yajima J, Oikawa Y, et al. Recent characteristics and outcomes of Japanese stable angina pectoris after percutaneouscoronary intervention. An observational cohort study using the Shinken Database. Int Heart J 2013; 54: 335-40. 24.Natsuaki M, Furukawa Y, Morimoto T, et al. Intensity of statin therapy, achieved low-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after coronary revascularization. Perspectives from the CREDO-Kyoto registry cohort-2. Circ J 2012 ; 76: 1369-79. 25.Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascularultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation 2004; 110: 1061-8. 26.Hiro T, Kimura T, Morimoto T, et al. Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome. J Am Coll Cardiol 2009; 54: 293-302. 27.Takayama T, Hiro T, Yamagishi M, et al. Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Circ J 2009; 73: 2110-7. 28.Dohi T, Miyauchi K, Okazaki S, et al. Plaque regression determined by intravascular ultrasound predicts long-term outcomes of patients with acute coronary syndrome. J Atheroscler Thromb 2011; 18: 231-9. 29.Ose L, Budinski D, Hounslow N, Arneson V. Long-term treatment with pitavastatin is effective and well tolerated by patients with primary hypercholesterolemia or combined dyslipidemia. Atherosclerosis 2010; 210: 202-8. 30.Austen WG, Edwards JE, Frye RL, et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975; 51 (4 Supp l): 5-40.

[0055] Throughout this application, various publications are referenced. The disclosures of these publications are incorporated herein by reference to more fully describe the state of the art to which the invention relates. It will be apparent to those skilled in the art that various modifications and variations can be made in the invention without departing from the scope or spirit of the invention. Other forms of the invention can be derived by those skilled in the art from this specification and the practices of the invention disclosed herein. This specification and each embodiment are intended to be illustrative only, and the true scope and spirit of the invention are set out in the following claims.

Claims

1. A method for preventing adverse cardiovascular events in a subject under a pharmaceutically acceptable dose of pitavastatin or a pharmaceutically acceptable salt thereof, comprising increasing the dose to 4 mg / day for a therapeutically effective period, provided the subject has an LDL-C concentration of less than 120 mg / dL.

2. The method according to claim 1, wherein the subject has coronary artery disease.

3. A method for preventing adverse cardiovascular events and modulating cardiovascular risk biomarkers in subjects with stable coronary artery disease, comprising administering 4 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof to the subject for a therapeutically effective period, wherein the modification a. To reduce LDL-C levels in the subject; b. To increase HDL-C levels in the subject; c. To reduce TG levels in the subject; d. To reduce the hs-CRP level in the subject, or e. All or any combination thereof A method to be selected from.

4. The method according to claim 3, wherein, prior to administering 4 mg / day, the subject is administered a dose of 1 mg / day of pitavastatin or a pharmaceutically acceptable salt thereof, and has an LDL-C concentration of less than 120 mg / dL.

5. The subjects, f. A history of acute myocardial infarction or unstable angina pectoris (ACS); g. History of coronary artery reconstruction (PCI or coronary artery bypass grafting (CABG)); or h. Coronary angiography with at least 75% stenosis in the major epicardial coronary arteries Therefore, atherosclerotic CAD was detected. The method according to any one of claims 1 to 4, characterized by having stable coronary artery disease.

6. The method according to any one of claims 1 to 4, wherein the subject has stable coronary artery disease characterized by a history of ACS such as acute myocardial infarction or unstable angina.

7. The method according to any one of claims 1 to 4, wherein the subject has stable coronary artery disease characterized by a history of coronary artery reconstruction (PCI or coronary artery bypass grafting (CABG)).

8. The method according to any one of claims 1 to 4, wherein the subject has stable coronary artery disease characterized by atherosclerotic CAD detected by coronary angiography with at least 75% stenosis in the major epicardial coronary arteries.

Images