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

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.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerotic Cardiovascular Disease
• Intervention / Treatment: Drug: Ezetimibe/Statin Combination therapy; Drug: Statin monotherapy; Drug: Ezetimibe/Statin Combination therapy; Drug: 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.

• Study Type: Interventional
• Enrollment (Anticipated): 3048
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Byeong-Keuk Kim, MD, PhD; Phone Number: 82-2-2228-8465; Email: KIMBK@yuhs.ac

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine
    • Contact: Byeong-Keuk Kim, MD, PhD; Phone Number: 82-2-2228-8465; Email: KIMBK@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intensive-targeting group	Drug: Ezetimibe/Statin Combination therapy; 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.; Drug: Statin monotherapy; 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.; Drug: Ezetimibe/Statin Combination therapy; 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.; Drug: Statin monotherapy; 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.
ACTIVE_COMPARATOR: Conventional-targeting group	Drug: Ezetimibe/Statin Combination therapy; 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.; Drug: Statin monotherapy; 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.; Drug: Ezetimibe/Statin Combination therapy; 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.; Drug: Statin monotherapy; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yonsei University
• Investigators: Principal Investigator: Byeong-Keuk Kim, MD, PhD, Severance Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 15, 2021
• Primary Completion (ANTICIPATED): September 1, 2025
• Study Completion (ANTICIPATED): September 1, 2025

Study Registration Dates

• First Submitted: October 20, 2020
• First Submitted That Met QC Criteria: November 8, 2020
• First Posted (ACTUAL): November 13, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 9, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Dyslipidemia; Coronary artery disease; ASCVD
• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Other Study ID Numbers: 4-2020-0903

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No