Clinical trial NCT04626973: Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease; Randomized Comparison of LDL-cholesterol Targeting <70 Versus <55mg/dL; Ez-PAVE Trial
Official title: 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 type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Atherosclerotic Cardiovascular Disease
Keywords: Dyslipidemia
ASCVD
Coronary artery disease
Lead sponsor: Yonsei University
Sponsor class: OTHER
First posted: 2020-11-13
Enrollment: 3048
Sex: ALL
Minimum age (years): 19
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention 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".
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 19-80 years
2. 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:

1. LDL-cholesterol level less than 70 mg/dL without statin therapyAllergy or hypersensitive to ezetimibe or statin
2. Active liver disease or persistent unexplained serum AST/ALT elevation more than 2 times the upper limit of normal range
3. Allergy or hypersensitivity to any statin or ezetimibe
4. Solid organ transplantation recipient
5. Pregnant women, women with potential childbearing, or lactating women
6. Life expectancy less than 3 years
7. Inability to follow the patient over the period of 1 year after enrollment, as assessed by the investigator
8. Inability to understand or read the informed content

Primary outcomes:
measure: Clinical outcomes by different lipid-lowering therapy
timeFrame: Within 3 years after the enrollment
Secondary outcomes:
measure: Each component of primary endpoint within 3 years
timeFrame: Within 3 years after the enrollment
measure: Various composite outcomes within 3 years
timeFrame: Within 3 years after the enrollment
measure: Proportion of subjects achieving target LDL-cholesterol level
timeFrame: Within 3 years after the enrollment
measure: Rate of cross-over into the non-allocated therapy regimen in order to achieve target LDL-cholesterol level
timeFrame: Within 3 years after the enrollment
measure: Proportions of subjects requiring proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to achieve target LDL-cholesterol level
timeFrame: Within 3 years after the enrollment
measure: Difference in rate of primary outcome according to sex
timeFrame: Within 3 years after the enrollment
measure: Difference in rate of primary outcome according to body mass index
timeFrame: Within 3 years after the enrollment
measure: Rate of New-onset diabetes mellitus
timeFrame: Within 3 years after the enrollment
measure: Rate of worsening of glycemic control or homeostatic model assessment (HOMA)-index
timeFrame: Within 3 years after the enrollment
measure: Occurrence of statin-associated muscle symptoms (SAMS) requiring change of therapy regimen or dosage
timeFrame: Within 3 years after the enrollment
measure: Occurence of elevation of muscle enzymes (CPK > 4 x UNL)
timeFrame: Within 3 years after the enrollment
measure: Occurence of elevation of hepatic enzymes (AST, ALT, or both ≥ 3 x UNL)
timeFrame: Within 3 years after the enrollment
measure: Occurence of elevation of serum creatinine level (>50% from baseline)
timeFrame: Within 3 years after the enrollment
measure: Change of proteinuria
timeFrame: Within 3 years after the enrollment
measure: Rate of cancer diagnosis
timeFrame: Within 3 years after the enrollment
measure: Rate of operation due to cataract
timeFrame: Within 3 years after the enrollment
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine
Study officials:
affiliation: Severance Hospital
name: Byeong-Keuk Kim, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: