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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
3,048
For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 10 or 20 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.
For statin naive patients, patients would initially receive Rosuvastatin 20mg or Atorvastatin 40 or 80 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.
For statin naive patients, patients would initially receive Ezetimibe 10mg plus Rosuvastatin 5 or 10mg. 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.
For statin naive patients, patients would initially receive Rosuvastatin 10 or 20mg or Atorvastatin 20 or 40mg. 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.
Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine
Seoul, South Korea
Clinical outcomes by different lipid-lowering therapy
Composite of cardiovascular death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for unstable angina
Time frame: Within 3 years after the enrollment
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 unstable angina
Time frame: 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 unstable angina
Time frame: Within 3 years after the enrollment
Proportion of subjects achieving target LDL-cholesterol level
Time frame: Within 3 years after the enrollment
Rate of cross-over into the non-allocated therapy regimen in order to achieve target LDL-cholesterol level
Time frame: Within 3 years after the enrollment
Proportions of subjects requiring proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to achieve target LDL-cholesterol level
Time frame: Within 3 years after the enrollment
Difference in rate of primary outcome according to sex
Time frame: Within 3 years after the enrollment
Difference in rate of primary outcome according to body mass index
Time frame: Within 3 years after the enrollment
Rate of New-onset diabetes mellitus
Time frame: Within 3 years after the enrollment
Rate of worsening of glycemic control or homeostatic model assessment (HOMA)-index
Time frame: Within 3 years after the enrollment
Occurrence of statin-associated muscle symptoms (SAMS) requiring change of therapy regimen or dosage
Time frame: Within 3 years after the enrollment
Occurence of elevation of muscle enzymes (CPK > 4 x UNL)
Time frame: Within 3 years after the enrollment
Occurence of elevation of hepatic enzymes (AST, ALT, or both ≥ 3 x UNL)
Time frame: Within 3 years after the enrollment
Occurence of elevation of serum creatinine level (>50% from baseline)
Time frame: Within 3 years after the enrollment
Change of proteinuria
Time frame: Within 3 years after the enrollment
Rate of cancer diagnosis
Time frame: Within 3 years after the enrollment
Rate of operation due to cataract
Time frame: Within 3 years after the enrollment
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