Primary Prevention, Vascular Calcification
Conditions
Keywords
Cardiovascular Diseases, Aspirin, Statin
Brief summary
A Multicenter, randomized trial comparing the efficacy and safety of intensive lipid-lowering therapy using a statin-ezetimibe combination without aspirin versus statin monotherapy with aspirin in asymptomatic patients with coronary artery calcification
Detailed description
Coronary artery calcification is a well-established marker of subclinical atherosclerosis that effectively identifies high-risk individuals for cardiovascular events, even in asymptomatic patients. However, the optimal intensity of preventive interventions-particularly regarding the balance between efficacy and safety-remains unclear in asymptomatic patients with significant coronary calcification. While aspirin has traditionally been used for the primary prevention of cardiovascular events, recent evidence suggests that its routine use in asymptomatic individuals may carry greater bleeding risks than cardiovascular benefits. In contrast, intensive lipid-lowering therapy with statins and ezetimibe has proven effective in reducing LDL-C levels and preventing cardiovascular events by slowing atherosclerotic progression and stabilizing plaques. This study aims to evaluate whether intensive lipid-lowering therapy using a statin-ezetimibe combination (without aspirin) is non-inferior to statin monotherapy (with aspirin) in reducing cardiovascular events among patients with significant coronary artery calcification. By comparing these two strategies, we seek to establish whether more aggressive lipid management might obviate the need for aspirin in these intermediate- to high-risk yet asymptomatic patients.
Interventions
DRUGPitavastatin 4mg and ezetimibe 10mg, taken once daily
Intensive lipid-lowering therapy without aspirin
DRUGPitavastatin 2 mg with aspirin 100 mg, taken once daily.
Moderate-intensity lipid-lowering therapy with aspirin
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults aged 19 years and older 2. Asymptomatic patients with significant coronary calcification (Agatston score ≥ 100) and no physiologically significant coronary artery disease (CAD) * The coronary CT scan used to establish the CAC score must be performed within 3 years prior to randomization. * The assessment of physiological significance must be performed within 6 months prior to randomization 3. Participants will be eligible for inclusion regardless of prior statin or anti-platelet agents use.
Exclusion criteria
1. Major ASCVD events (clinically documented ASCVD) If at least one of the following criteria is present via patient history, physical examination, or medical records at the time of screening, the patient is not eligible: * Acute coronary syndrome (MI or unstable angina) * Coronary revascularization (PCI, CABG) or other arterial revascularization * Ischemic stroke (Not TIA) * Symptomatic peripheral arterial disease (history of claudication with ABI \<0.90, or previous revascularization or amputation 2. Patients with physiologically significant CAD * Moderate to severe CAD (diameter stenosis \>50%) on CCTA with positive strest test (thallium, treadmil, stress echocardiography) * Moderate to severe CAD (diameter stenosis \>50%) on CAG with positive fractional flow reserve (FFR) \< 0.8 3. Patients with familial hypercholesterolemia. 4. Patients with low-density lipoproteins cholesterol (LDL-C) ≥ 190 mg/dL regardless taking a statin or not. 5. Continuation of PCSK9 inhibitor is required during the clinical trial 6. Patients with chronic kidney disease (\<eGFR 30mL/min/1.73m2) 7. Advanced liver disease (Child-Pugh B or C) 8. Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST \> 5 times upper limit of normal). 9. History of gastrointestinal bleeding, peptic ulcer, or intracranial hemorrhage within 6 months prior screening 10. Patients with a history of organ transplantation who are on immunosuppressive therapy 11. Concurrent use of other medications that may increase bleeding risk such NOAC and warfarin 12. A history of significant allergic reaction to aspirin or statin/ezetimibe 13. A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer. 14. Life expectancy \< 1 years for any non-cardiac or cardiac causes. 15. Patient's pregnant or breast-feeding or child-bearing potential. 16. Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study. 17. Unwillingness or inability to comply with the procedures described in this protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event rate of a major adverse cardiovascular events | 48months | Death from any cause, myocardial infarction, stroke, urgent coronary revascularization, resuscitated cardiac arrest, or unstable angina related hospitalization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event rate of a urgent coronary revascularization | 48months | 1. Elective: 2. Urgent: 3. Emergency: 4. Salvage: |
| Event rate of a Resuscitated cardiac arrest | 48months | — |
| Event rate of a stroke | 48months | A. Ischemic Stroke B. Hemorrhagic Stroke C. Undetermined Stroke |
| Event rate of a all cause death | 48months | All-cause mortality was used instead of cardiac mortality to avoid potentially difficult adjudication of causes of death, especially given the relatively low expected mortality rate. In addition, the cause of death will be adjudicated as being due to cardiovascular causes, non-cardiovascular causes, or undetermined causes. |
| Event rate of a cardiovascular death | 48months | includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes |
| Event rate of a unstable angina related hospitalization | 48months | — |
| Event rate of a composite of hard outcomes (all cause death, myocardial infarction and ischemic stroke) | 48months | — |
| Event rate of a Clinically relevant bleeding (Bleeding Academic Research Consortium definition ≥ type 2) | 48months | Bleeding Academic Research Consortium definition ≥ type 2 |
| Changes of Lipid profile | 48months | — |
| Treatment-emergent Serious Adverse Events resulting in Study Drug Discontinuation | 48months | Liver function abnormalities(AST or ALT \> 5x ULN) Renal function abnormalities (serum creatinine increase ≥3-fold from baseline OR increase to ≥4.0 mg/dL OR initiation of renal replacement therapy) Muscle-related events (Statin-associated muscle symptoms OR CK \>5x ULN) (CK reference range: 50-250 IU/L) |
| Event rate of a spontaneous myocardial infarction | 48months | A spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection, resulting in intraluminal thrombus in one or more of the coronary arteries |
Countries
South Korea
Contacts
Primary ContactSeung-Whan Lee
Outcome results
None listed