Primary Prevention of Major Adverse Cardiac Events (MACE) With Standard and Intensive Statin Treatment in Patients With Diabetes: Survival and Cardiovascular Event Assessments

Study Overview
=================
Brief Summary
-----------------
The study is being conducted to compare the effect of standard treatment (target LDL-C level: <120 mg/dL (JASGL 2007 target level)) and intensive treatment (target LDL-C level: <70 mg/dL) in the prevention of major adverse cardiac events (MACE) in hypercholesterolemia patients with concomitant type 2 diabetes and hypertension.

Official Title
-----------------
Primary Prevention of MACE With Standard and Intensive Statin Treatment in Hypercholesterolemia Patients With Concomitant Diabetes and Hypertension

Conditions
-----------------
Hypercholesterolemia, Type 2 Diabetes, Hypertension

Intervention / Treatment
-----------------
* Drug: Pravastatin
* Drug: Rosuvastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients meeting the following inclusion criteria will be included in the study: Patients giving voluntary written consent to participate in the study Male or female patients 50 years of age or older (at informed consent) Hypercholesterolemia patients (Untreated patients: LDL-C level ≥140 mg/dL; treated patients: LDL-C level ≥120 mg/dL) Type 2 diabetes patients (HbA1c level ≥6.1% (JDS criteria), with or without history of drug therapy) Hypertension patients (SBP ≥130 mmHg or DBP ≥80 mmHg, with or without history of drug therapy) Patients with two or more of the following risk factors Male 65 years of age or older Smoker L/H ratio: ≥3.0 •HbA1c level: ≥8.0% Left ventricular hypertrophy First- or second-degree family history of MACE Microalbuminuria (quantitative testing: ≥30 mg/dL), proteinuria (qualitative testing: + or higher) or eGFR (<60 mL/min/1.73 m2) Exclusion Criteria: Patients meeting the following criteria will be excluded from the study: Patients receiving rosuvastatin, pitavastatin, or atorvastatin therapy within one month prior to informed consent Patients judged to have familial hypercholesterolemia Patients with a serum triglyceride level of ≥400 mg/dL Patients with a history of myocardial infarction Patients with a history of coronary revascularization (PCI or CABG) Patients with a history of treatment of unstable angina Patients with a history of cerebrovascular accident (excluding asymptomatic lacunar infarction) Heart failure patients Patients with a history of hypersensitivity to statins Patients with a history of drug-induced myopathy Patients with poorly controlled arrhythmia Patients with severe liver or kidney disease Patients with serious concurrent disease, such as malignancy, or patients with severely limited lifespan Patients who are or may be pregnant Patients judged by the investigators to be ineligible for participation in the study for any other reason

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active comparator: Standard Pravastatin Group<br> | Drug: Pravastatin<br>* 5 mg/day or 10 mg/day of pravastatin will be administered orally for 36 months, with a follow-up period of one month. If the target LDL-C level is not attained after one month of treatment, the steps will be taken to reduce the LDL-C to the target level of <120 mg/dL (JASGL 2007 target level) as quickly as possible. (Maximum dose increase of pravastatin: 20 mg/day)<br>|
| Active Comparator: Intensive Rosuvastatin Group<br> | Drug: Rosuvastatin<br>* 5 mg/day or 10 mg/day of rosuvastatin will be administered orally for 36 months based on the LDL-C level of the subject, with a follow-up period of one month. If the target LDL-C level is not attained after one month of treatment, the steps will be taken to reduce the LDL-C to the target level of <70 mg/dL as quickly as possible. (Maximum dose increase to rosuvastatin: 20 mg/day)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | At baseline | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | 1 month after treatment initiation | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | 3 month after treatment initiation | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | 6 month after treatment initiation | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | 12 month after treatment initiation | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | 36 month after treatment initiation | 
| MACE (time to event): MACE (time to event): myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/nonfatal cerebrovascular accident, peripheral arteriopathy, aortic event |  | At the end of the study or discontinuation up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of individual MACE |  | At baseline | 
| Prevention of MACE(combination of each category) |  | At baseline | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | At baseline | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | At baseline | 
| Frequency and distribution of type of deaths during the study period |  | At baseline | 
| Frequency and distribution of type of hospitalizations during the study period |  | At baseline | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | At baseline | 
| Frequency and type of adverse events |  | At baseline | 
| Prevention of individual MACE |  | 1 month after treatment initiation | 
| Prevention of individual MACE |  | 3 month after treatment initiation | 
| Prevention of individual MACE |  | 6 month after treatment initiation | 
| Prevention of individual MACE |  | 12 month after treatment initiation | 
| Prevention of individual MACE |  | 36 month after treatment initiation | 
| Prevention of individual MACE |  | At the end of the study (or discontinuation) | 
| Prevention of MACE(combination of each category) |  | 1 month after treatment initiation | 
| Prevention of MACE(combination of each category) |  | 3 month after treatment initiation | 
| Prevention of MACE(combination of each category) |  | 6 month after treatment initiation | 
| Prevention of MACE(combination of each category) |  | 12 month after treatment initiation | 
| Prevention of MACE(combination of each category) |  | 36 month after treatment initiation | 
| Prevention of MACE(combination of each category) |  | At the end of the study (or discontinuation) | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | 1 month after treatment initiation | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | 3 month after treatment initiation | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | 6 month after treatment initiation | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | 12 month after treatment initiation | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | 36 month after treatment initiation | 
| Prevention, frequency and distribution of type of the following non-MACE cardiac and cerebrovascular events during the study period: heart failure requiring hospitalization, transient ischemic attack (TIA), abnormal ankle-brachial index (abnormal ABI) |  | At study completion up to 4 years | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | 1 month after treatment initiation | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | 3 month after treatment initiation | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | 6 month after treatment initiation | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | 12 month after treatment initiation | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | 36 month after treatment initiation | 
| Frequency and distribution of type of MACE during the study period Including correlation with LDL-C, HDL-C and LDL-C/HDL-C ratio (hereafter referred to as L/H ratio) |  | At the end of the study or discontinuation up to 4 years | 
| Frequency and distribution of type of deaths during the study period |  | 1 month after treatment initiation | 
| Frequency and distribution of type of deaths during the study period |  | 3 month after treatment initiation | 
| Frequency and distribution of type of deaths during the study period |  | 6 month after treatment initiation | 
| Frequency and distribution of type of deaths during the study period |  | 12 month after treatment initiation | 
| Frequency and distribution of type of deaths during the study period |  | 36 month after treatment initiation | 
| Frequency and distribution of type of deaths during the study period |  | At the end of the study or discontinuation up to 4 years | 
| Frequency and distribution of type of hospitalizations during the study period |  | 1 month after treatment initiation | 
| Frequency and distribution of type of hospitalizations during the study period |  | 3 month after treatment initiation | 
| Frequency and distribution of type of hospitalizations during the study period |  | 6 month after treatment initiation | 
| Frequency and distribution of type of hospitalizations during the study period |  | 12 month after treatment initiation | 
| Frequency and distribution of type of hospitalizations during the study period |  | 36 month after treatment initiation | 
| Frequency and distribution of type of hospitalizations during the study period |  | At the end of the study or discontinuation up to 4 years | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | 1 month after treatment initiation | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | 3 month after treatment initiation | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | 6 month after treatment initiation | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | 12 month after treatment initiation | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | 36 month after treatment initiation | 
| Frequency of other events (malignancy, dementia, need of nursing care) |  | At the end of the study or discontinuation up to 4 years | 
| Frequency and type of adverse events |  | 1 month after treatment initiation | 
| Frequency and type of adverse events |  | 3 month after treatment initiation | 
| Frequency and type of adverse events |  | 6 month after treatment initiation | 
| Frequency and type of adverse events |  | 12 month after treatment initiation | 
| Frequency and type of adverse events |  | 36 month after treatment initiation | 
| Frequency and type of adverse events |  | At the end of the study or discontinuation up to 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypercholesterolemia with concomitant type 2 diabetes and hypertension