Clinical trial NCT03169985: Usual Dose Rosuvastatin Plus Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque
Official title: The Effect of Usual Dose Rosuvastatin Plue Ezetimibe Versus High-dose Rosuvastatin on Coronary Atherosclerotic Plaque: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Coronary Artery Disease
Keywords: Rosuvastatin
Ezetimibe
Atherosclerotic plaque
Intravascular ultrasound
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
Collaborators: name: Hanmi Pharmaceutical co., ltd.
First posted: 2017-05-30
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, open label, two-arm, randomized controlled trial
Primary purpose: TREATMENT

Brief summary: The aim of this prospective, open-label, randomized, single center study is to compare the effect of usual dose rosuvastatin plus ezetimibe and high-dose rosuvastatin on modifying atherosclerotic plaque.

Detailed description: High-intensity statin therapy have shown improved clinical outcomes compared to placebo or moderate-intensity statin therapy. Based on these results, 2013 American College of Cardiology/American Heart Association(ACC/AHA) guideline on treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults recommended high-intensity statin therapy to patient with coronary artery disease for secondary prevention. However, high-intensity statin therapy was known to increase risk of diabetes mellitus and complication such as hepatotoxicity and myalgia. An alternative to high-intensity statin therapy is reducing the dose of statin and using drug that can improve blood cholesterol level by a different mechanism than statin. Ezetimibe acts on Niemann-Pick C1-like protein then inhibits cholesterol absorption in the intestine, which can reduce low-density lipoprotein(LDL) cholesterol more effectively when administered with statin. In IMPROVE-IT study, simvastatin plus ezetimibe decreased ischemic events more than simvastatin alone in patients with acute coronary syndrome. Although this study could confirm the additional effect of ezetimibe by using the same amount of simvastatin in both groups, it could not compare the effect of statin plus ezetimibe and high dose statin monotherapy. Moreover, there were few data on the efficacy of ezetimibe added to rosuvastatin which is one of the effective statin recommended by various guidelines. One study reported that rosuvastatin 2.5 mg plus ezetimibe 10 mg was superior to rosuvastatin 5 mg monotherapy in reducing LDL cholesterol. Another study reported that adding rosuvastatin 5 mg to ezetimibe 10 mg was more effective than rosuvastatin 5 mg alone in reducing coronary atherosclerotic lesions as measured by intravascular ultrasound. However, the previous studies did not compare the efficacy of combination therapy of usual dose rosuvastatin and ezetimibe to high-dose statin monotherapy. Therefore, investigators aimed to compare the effect of rosuvastatin 10 mg plus ezetimibe 10 mg to rosuvastatin 20 mg alone on the reduction of coronary atherosclerosis in patient with coronary artery disease. If this study shows that the combination of usual dose rosuvastatin and ezetimibe is not inferior to high dose rosuvastatin monotherapy in anti-atherosclerotic effect and safety, it would provide a basis for effective and safe cholesterol treatment.

Eligibility criteria: Inclusion Criteria:

* Among patients who undergo CAG for suspected ischemic heart disease and meet all of the followings:

  * Moderate stenosis (30-70%) in coronary artery
  * Deferred to medical treatment based on physiologic (FFR, CFR, IMR) or radiologic (IVUS with or without OCT) evaluation.
* Agreement obtained by participant

Exclusion Criteria:

* Severe renal failure(glomerular filtration rate \< 30 ml/min/1.73m2, hemodialysis or peritoneal dialysis)
* Active liver disease
* Patient taking Niacin or fibrate(if possible, patient can be enrolled to the study after stopping those medication)
* Medical or family history of myositis, unexplained CK elevation \> 3 times ULN at first visit
* Life expectancy \< 2 years (judged by investigator)
* Coadministration of cyclosporine
* Untreated hypothyroidism
* Patient with poor compliance including alcohol abuse
* History of hypersensitivity including myotoxicity for either statin or ezetimibe
* Pregnant or breast-feeding woman
* Other conditions inappropriate for enrollment by investigator

  * \* Eligible patients will be randomly assigned to treatment arms, stratified by diagnosis on admission(acute coronary syndrome or stable ischemic heart disease) and presence of chronic statin use (more than one month)

Primary outcomes:
measure: Change in percent atheroma volume(PAV) in non-culprit lesions
timeFrame: 12 months after index coronary angiography(CAG)
Secondary outcomes:
measure: Change in normalized TAV in non-culprit lesions
timeFrame: 12 months after index CAG
measure: Change in indexed TAV
timeFrame: 12 months after index CAG
measure: Change in fibrous cap thickness by OCT(optical coherence tomography)
timeFrame: 12 months after index CAG
measure: Change in fractional flow reserve(FFR)
timeFrame: 12 months after index CAG
measure: Change in coronary flow reserve(CFR)
timeFrame: 12 months after index CAG
measure: Change in index of microcirculatory resistance(IMR)
timeFrame: 12 months after index CAG
measure: Change in TAV in coronary computed tomography(CT) angiography
timeFrame: 24 months after index CAG
measure: Major adverse cardiovascular events(MACE)
timeFrame: 12, 24 and 36 months after index CAG
measure: Change in homeostatic model assessment(HOMA) index
timeFrame: 6 months after index CAG
measure: Change in fasting glucose
timeFrame: 6 and 12 months after index CAG
measure: Change in hemoglobin A1c
timeFrame: 6 and 12 months after index CAG
measure: Change in lipid profile
timeFrame: 1, 6 and 12 months after index CAG
measure: Change in high-sensitivity C-reactive protein(hs-CRP)
timeFrame: 1 and 12 months after index CAG
measure: Safety endpoint: Number of participants with abnormal laboratory values and adverse events
timeFrame: 1 and 12 months after index CAG
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Samsung Medical Center
name: Joo-Yong Hahn, MD, PhD
role: STUDY_CHAIR
References: