Atherosclerosis, Cardiovascular Diseases, Dyslipidemia, Hypercholesterolemia, Renal Insufficiency
Conditions
Brief summary
The ULTRA-CKD trial is a prospective, randomized, open-label, multicenter trial designed to compare the efficacy and safety of moderate-intensity statin plus ezetimibe combination therapy versus high-intensity statin monotherapy in patients with chronic kidney disease (CKD) and concomitant atherosclerotic cardiovascular disease (ASCVD). Patients with CKD are at very high risk for ASCVD. In this population, it is important to establish a lipid-lowering strategy that optimizes cardiovascular outcomes while ensuring long-term safety. While high-intensity statins are generally considered as initial treatment option for secondary prevention, the optimal strategy for CKD patients remains to be clinicaly defined. This study aims to evaluate whether the combination of moderate-intensity statin and ezetimibe is non-inferior to high-intensity statin monotherapy in terms of 3-year composite of major adverse cardiovascular events.
Detailed description
All eligible patients with chronic kidney disease (CKD) and concomitant atherosclerotic cardiovascular disease (ASCVD) will be enrolled according to inclusion/exclusion criteria after voluntary agreement with informed consent. At the time of enrollment, we will stratify the patients according to diabetes mellitus and dialysis status, and randomly assign them in two groups according to lipid-lowering regimen with a 1:1 ratio: "Moderate-intensity statin plus ezetimibe group" vs. "High-intensity statin monotherapy group". In this study, the combination therapy strategy will utilize Pitavastatin 1-4 mg plus Ezetimibe 10 mg once daily or Atorvastatin 10-20 mg plus Ezetimibe 10 mg once daily. The monotherapy strategy will utilize Atorvastatin 40 mg once daily. Study visits are scheduled at 4 weeks and at 6, 12, 18, 24, 30, and 36 months. The primary outcome is the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary outcome is CKD progression defined as a ≥40% decline in eGFR confirmed on at least two consecutive measurements
Interventions
DRUGModerate-intensity statin and ezetimibe combination therapy
Participants will receive moderate-intensity statin plus ezetimibe (pitavastatin 1-4 mg + ezetimibe 10 mg once daily or atorvastatin 10-20 mg + ezetimibe 10 mg once daily), with 36-month follow-up.
DRUGHigh-intensity statin monotherapy
Participants will receive high-intensity statin monotherapy (atorvastatin 40 mg once daily), with 36-month follow-up.
Sponsors
Yonsei University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age 19-85 years. 2. Chronic kidney disease stage III, IV, or V (CKD-EPI eGFR \<60 / \<30 / \<15 mL/min/1.73 m² or on dialysis). 3. Established ASCVD, meeting at least one of the following: * Prior acute coronary syndrome (myocardial infarction or unstable angina). * Stable angina confirmed by imaging studies. * History of coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). * Peripheral artery disease. * Ischemic stroke or transient ischemic attack.
Exclusion criteria
1. Baseline LDL cholesterol \<55 mg/dL in the absence of statin therapy. 2. Acute liver disease or persistently unexplained serum AST/ALT ≥2 × the upper limit of normal. 3. Allergy or hypersensitivity to statins. 4. Life expectancy \<1 year. 5. Expected inability to complete at least 1 year of follow-up. 6. Inability to read or understand the informed consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major adverse cardiovascular events | 3 years | Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CKD progression | 3 years | CKD progression: ≥40% decline in eGFR from baseline, confirmed on at least two consecutive measurements during follow-up. |
| Cardiovascular death. | 3 years | Death due to cardiovascular causes during follow-up. |
| Myocardial infarction. | 3 years | Occurrence of myocardial infarction during follow-up. |
| Stroke. | 3 years | Occurrence of stroke during follow-up |
| Hospitalization for unstable angina. | 3 years | Hospitalization due to unstable angina during follow-up. |
| Coronary revascularization. | 3 years | Any coronary revascularization procedure, including percutaneous coronary intervention or coronary artery bypass graft surgery, during follow-up. |
| Composite of cardiovascular death, myocardial infarction, and stroke. | 3 years | First occurrence of cardiovascular death, myocardial infarction, or stroke during follow-up. |
| Composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina | 3 years | First occurrence of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina during follow-up |
| Composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization. | 3 years | First occurrence of cardiovascular death, myocardial infarction, stroke, or coronary revascularization during follow-up. |
| Composite of all-cause death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization. | 3 years | First occurrence of all-cause death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization during follow-up. |
| Proportion of participants achieving the LDL-C <70 mg/dL in each group. | 3 years | Proportion of participants achieving a low-density lipoprotein cholesterol (LDL-C) level below 70 mg/dL in each treatment group during follow-up. |
| Proportion of participants achieving LDL-C <55 mg/dL in each group. | 3 years | Proportion of participants achieving a low-density lipoprotein cholesterol (LDL-C) level below 55 mg/dL in each treatment group during follow-up. |
| Proportion of participants crossing over to the non-assigned treatment group in each group. | 3 years | Proportion of participants who crossed over from the assigned treatment group to the non-assigned treatment group during follow-up. |
| New-onset diabetes mellitus. | 3 years | Occurrence of new-onset diabetes mellitus during follow-up. |
| New-onset diabetes mellitus requiring initiation of antidiabetic medication. | 3 years | Occurrence of new-onset diabetes mellitus requiring initiation of antidiabetic medication during follow-up. |
| Worsening glycemic control. | 3 years | Occurrence of worsening glycemic control during follow-up |
| Marked decline in kidney function | 3 years | eGFR \<10 mL/min/1.73 m², confirmed on at least two consecutive measurements during follow-up. |
| Initiation of dialysis or kidney transplantation. | 3 years | Initiation of maintenance dialysis or receipt of kidney transplantation during follow-up. |
| Statin-associated muscle symptoms requiring a change in regimen or dose. | 3 years | Occurrence of statin-associated muscle symptoms requiring a change in statin regimen or dose during follow-up. |
| Rhabdomyolysis. | 3 years | Occurrence of rhabdomyolysis during follow-up. |
| Elevated creatine phosphokinase (CK >4 × the upper limit of normal) | 3 years | Elevation of creatine phosphokinase greater than 4 times the upper limit of normal during follow-up. |
| Elevated liver enzymes (AST and/or ALT ≥3 × the upper limit of normal) | 3 years | Elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) equal to or more than 3 times the upper limit of normal during follow-up. |
| Cancer diagnosis | 3 years | New diagnosis of cancer during follow-up. |
| Cataract surgery. | 3 years | Occurrence of cataract surgery during follow-up. |
| Hemorrhagic stroke. | 3 years | Occurrence of hemorrhagic stroke during follow-up. |
| Major bleeding (BARC type 2, 3, or 5 bleeding), assessed among participants who underwent percutaneous coronary intervention with new stent implantation at study enrollment. | 3 years | Major bleeding defined as BARC type 2, 3, or 5 bleeding, assessed among participants who underwent percutaneous coronary intervention with new stent implantation at study enrollment. |
Countries
South Korea
Contacts
CONTACTJung-Sun Kim, Professor
Outcome results
None listed