Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial

Study Overview
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Brief Summary
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Although the clinical efficacy of LDL-cholesterol lowering therapy has been proven with strong evidences and emphasized, there are also growing concerns that intensive lipid-lowering therapy would be related to increased risk of adverse effects. In addition, statin potency from recent guidelines was set from the studies composed of mainly Caucasian population, although there is an inconsistency of statin effect according to ethnicity. Asian population showed more profound LDL reduction not only from high potent statin but also from moderate to low potent statin. Conventional strategies for lowering LDL-cholesterol focused on statins, therefore doubling of previously described dose of statin would be common way in patients with inadequate LDL-cholesterol levels. Adding ezetimibe will be an alternative strategy not only to lower LDL-cholesterol level and also to reduce the need of dosage of high-intensity statin to achieve sufficient LDL-cholesterol lowering effect. However, studies regarding the effect of intensive-targeting of lipid-lowering therapy and therapy regimens are lacking. Thus, on these basis, we sought to evaluate whether intensive-targeting of lipid-lowering therapy will have more prominent beneficial effect compared to conventional-targeting in patients with documented ASCVD with either an ezetimibe/statin combination therapy or a statin monotherapy.

Detailed Description
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All eligible patients who have documented ASCVD will be enrolled according to inclusion/exclusion criteria after voluntary agreement with informed consent. At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: Intensive-targeting group vs. Conventional-targeting group. In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: Ezetimibe/Statin combination therapy vs. Statin monotherapy. Patients allocated to each treatment group will receive lipid-lowering therapy with following protocols.

Official Title
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Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: Ezetimibe/Statin Combination therapy
* Drug: Statin monotherapy
* Drug: Ezetimibe/Statin Combination therapy
* Drug: Statin monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 19-80 years Documented atherosclerotic cardiovascular disease (ASCVD) Previous acute coronary syndrome (myocardial infarction [MI] or unstable angina), Or stable angina with imaging or functional studies Or coronary revascularization (percutaneous coronary intervention [PCI], coronary artery bypass graft [CABG], and other arterial revascularization procedures) Or stroke and transient ischemic attack (TIA) Or peripheral artery disease Exclusion Criteria: LDL-cholesterol level less than 70 mg/dL without statin therapyAllergy or hypersensitive to ezetimibe or statin Active liver disease or persistent unexplained serum AST/ALT elevation more than 2 times the upper limit of normal range Allergy or hypersensitivity to any statin or ezetimibe Solid organ transplantation recipient Pregnant women, women with potential childbearing, or lactating women Life expectancy less than 3 years Inability to follow the patient over the period of 1 year after enrollment, as assessed by the investigator Inability to understand or read the informed content

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: At the time of enrollment, we will stratify all patients according to LDL-cholesterol <100mg/dL, DM, and acute coronary syndrome, and randomly assign them in two groups according to LDL-cholesterol targeting level with a 1:1 ratio: Intensive-targeting group vs. Conventional-targeting group. In addition, patients in each group will be randomly assigned to receive two lipid-lowering therapy regimen with a 1:1 ratio: Ezetimibe/Statin combination therapy vs. Statin monotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive-targeting group<br> | Drug: Ezetimibe/Statin Combination therapy<br>* For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.<br>Drug: Statin monotherapy<br>* For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<55 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.<br>|
| Active Comparator: Conventional-targeting group<br> | Drug: Ezetimibe/Statin Combination therapy<br>* For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin naive patients, regimens are to be changed to the equivalent dose of ezetimibe+rosuvastatin combination in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.<br>Drug: Statin monotherapy<br>* For statin naive patients, patients would initially receive Ezetimibe 10 mg plus Rosuvastatin 10 mg , For non-statin native patients, regimens are to be change to equivalent dose of atorvastatin or rosuvastatin in case of already achieved LDL-cholesterol target (<70 mg/dL) and to be dosed up than the equivalent dose of study drugs in case of not yet achieved LDL-cholesterol target.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcomes by different lipid-lowering therapy | Composite of cardiovascular death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for angina | Within 3 years after the enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Each component of primary endpoint within 3 years | A. Rate of Cardiovascular death B. Rate of non-fatal MI C. Rate of non-fatal stroke D. Rate of any revascularization E. Rate of hospitalization for angina | Within 3 years after the enrollment | 
| Various composite outcomes within 3 years | A. Rate of composite of cardiovascular death, non-fatal MI, and non-fatal stroke B. Rate of composite of cardiovascular death, non-fatal MI, non-fatal stroke, and any revascularization C. Rate pf composite of cardiovascular death, non-fatal MI, and any revascularization D. Rate of composite of all-cause death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for angina | Within 3 years after the enrollment | 
| Proportion of subjects achieving target LDL-cholesterol level |  | Within 3 years after the enrollment | 
| Rate of cross-over into the non-allocated therapy regimen in order to achieve target LDL-cholesterol level |  | Within 3 years after the enrollment | 
| Proportions of subjects requiring proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to achieve target LDL-cholesterol level |  | Within 3 years after the enrollment | 
| Difference in rate of primary outcome according to sex |  | Within 3 years after the enrollment | 
| Difference in rate of primary outcome according to body mass index |  | Within 3 years after the enrollment | 
| Rate of New-onset diabetes mellitus |  | Within 3 years after the enrollment | 
| Rate of worsening of glycemic control or homeostatic model assessment (HOMA)-index |  | Within 3 years after the enrollment | 
| Occurrence of statin-associated muscle symptoms (SAMS) requiring change of therapy regimen or dosage |  | Within 3 years after the enrollment | 
| Occurence of elevation of muscle enzymes (CPK > 4 x UNL) |  | Within 3 years after the enrollment | 
| Occurence of elevation of hepatic enzymes (AST, ALT, or both ≥ 3 x UNL) |  | Within 3 years after the enrollment | 
| Occurence of elevation of serum creatinine level (>50% from baseline) |  | Within 3 years after the enrollment | 
| Change of proteinuria |  | Within 3 years after the enrollment | 
| Rate of cancer diagnosis |  | Within 3 years after the enrollment | 
| Rate of operation due to cataract |  | Within 3 years after the enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dyslipidemia, ASCVD, Coronary artery disease