Effect of Rosuvastatin and Eicosapentaenoic Acid on Neoatherosclerosis: The LINK-IT Trial

This study aim to evaluate whether intensive lipid lowering therapy may improve the clinical outcomes in coronary artery disease patients with in-stent neoatherosclerosis, in comparison with standard therapy.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease Progression
• Intervention / Treatment: Drug: Standard dose rosuvastatin; Drug: EPA and high dose rosuvastatin

Detailed Description

Eicosapentaenoic acid and statin therapy prevents cardiovascular events. However, the impact of these treatment in patients with in-stent neoatherosclerosis (NA) has not been clarified.

Drug-eluting stent (DES) use has successfully offered a significant reduction of mid-term restenosis and repeat revascularization by controlling acute-phase excessive intimal growth after stent implantation. However, several issues still exists mainly with respect to the late-phase clinical events, including late stent thrombosis and delayed restenosis after first- and second-generation DES implantation. A growing number of evidence have suggested the potential contribution of atheromatous changes within neointimal tissue, namely neoatherosclerosis (NA) on these phenomena occurring long-term after stent implantation.

Rosuvastatin is one of the most widely used statin that has an extensive evidence for reducing adverse cardiovascular event in patients with coronary artery disease. The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin ) trial demonstrated that 20mg/del of Rosuvastatin significantly reduced combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes in patients with elevated CRP level. Also, the ASTEROID Trial showed that high-intensity statin therapy with rosuvastatin of 40 mg/d reduced low-density lipoprotein cholesterol (LDL-C) level to 60.8 (20.0) mg/dL (53.2% reduction) and induced significant plaque volume reduction measured by intravascular ultrasound (IVUS) (JAMA. 2006;295:1556-1565). Although the dose of lipid-lowering therapy is one of the major contributing factors to the effect of lipid-lowering therapy, it is also well known that the effect of statin therapy has ethnic variation, being less statin dose required for Asians. Indeed in Japan, relatively less intensive statin therapy has been reported to reduce serum LDL-C level on average by 70mg/dl (change from baseline: -42%) and reduced atheroma volume measured by IVUS. Using Virtual histology IVUS, Hong et al. demonstrated that 10 mg/day Rosuvastatin therapy reduced serum low-density lipoprotein cholesterol (LDL-C) on average by 83 mg/dl (change from baseline: -32%) and decreased atheroma burden in 67% of enrolled patients.

Eicosapentaenoic acid (EPA) is another lipid-lowering therapyAccording to a recent study, the addition of highly purified EPA to statin therapy provides further benefits in preventing cardiovascular events (Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.). Also, we had reported that the concomitant use of eicosapentaenoic acid (EPA) and rosuvastatin reduced serum hs-CRP level significantly and increased fibrous cap thickness in patients who were detected thin-cap fibroatheroma by OCT.

Recently, we conducted a retrospective, nonrandomized OCT study to demonstrate that higher LDL cholesterol and CRP levels were independent determinants of NA progression. Also, Therefore, we designed a prospective, randomized OCT study in Japan to assess the effect of 10 mg/day plus eicosapentaenoic acid (EPA) versus 2.5-5.0 mg/day of rosuvastatin on the extent of NA after stent implantation.

The OCT operators randomly assigned 50 patients who were detected NA on follow-up optical coherence tomography (OCT) examination to either 2.5-5mg/day of rosuvastatin therapy (standard dose group) or 10mg/day(up to 20mg/day) of rosuvastatin and 1800mg/day of eicosapentaenoic acid therapy (intensive dose group). Serial coronary angiography and OCT were performed at 12 months after baseline OCT procedure. Sample size was calculated based on the assumption that the average difference in multiplication of lipid arc and lipid length growth between the groups receiving only rosuvastatin and EPA (1800mg/day) adding on rosuvastatin is 81.5, and the SD of multiplication of lipid arc and lipid length growth distribution for either group is 102.1. With a 2-sided alpha level of 0.05 and a power of 80%, 25 patients were required in each group.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Consecutive patients with stent implantation who were performed coronary angiography and OCT follow-up of the coronary arteries were candidate. During this period, OCT was performed for the following reasons: 1) planned follow-up coronary angiography and OCT for routine stent follow-up or due to other study protocols, regardless of symptoms; 2) evidence of myocardial ischemia such as silent myocardial ischemia, stable angina, or acute coronary syndrome; or 3) planned follow-up angiography for other stent segments. These patients were implanted bare metal stent, sirolimus-eluting stents (Cypher, Cordis, Miami Lakes, FL, USA), paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, MA, USA), or everolimus-eluting stents (XIENCE V, Abbott Vascular, Santa Clara, CA, USA). The investigators assessed their OCT examination at the follow-up OCT time and patients who were detected NA on OCT findings were eligible for the presence study.

Exclusion Criteria:

• Exclusion criteria for OCT were 1) anatomically unsuitable target artery for OCT according to previously described criteria, 10 2) apparent congestive heart failure, 3) renal insufficiency with baseline creatinine level ≥2.0 mg/dL expect for under hemodialysis, or 4) lack of written informed consent from the patient.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard lipid lowering therapy; Start with only rosuvastatin 2.5mg and up to 20mg/day	Drug: Standard dose rosuvastatin; After randomization, patients with standard lipid lowering therapy start only rosuvastatin (2.5mg/day) for 12 months.; Other Names: rosuvastatin
Active Comparator: Intensive lipid lowering therapy; Start EPA and rosuvastatin 10mg/day and up to 20mg/day	Drug: EPA and high dose rosuvastatin; After randomization, patients with intensive lipid lowering therapy start EPA (1800mg/day) and high dose rosuvastatin (10mg/day) for 12 months.; Other Names: Rosuvastatin; Eicosapentaenoic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid index change between baseline and 12 month follow-up	Lipid core arc was measured by every 0.2-mm interval throughout segments with NA on OCT findings. The mean lipid core arc was calculated for each lesion. Then, the lipid index was calculated by multiplying the mean lipid core arc by the lipid core longitudinal length.	Baseline and 12 month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophage grade change between baseline and 12 month follow-up	Macrophage arc were measured on OCT images with NA every 0.2-mm intervals and divided 4 groups as follows: grade 0, no mac¬rophage; grade 1, localized macrophage accumulation (<30°); grade 2, clus¬tered accumulation ≥30° and <90°; grade 3, clus¬tered accumulation ≥90° and <270°; and grade 4, clustered accumulation ≥270° and <360° . Macrophage grade was evaluated as summation of 0 to 4 grades across all cross section in NA.	Baseline and 12 month follow-up

Collaborators and Investigators

• Sponsor: Kobe University
• Investigators: Study Chair: Hiromasa Otake, ph.D, Kobe University Graduate School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2013
• Primary Completion (Actual): June 2, 2017
• Study Completion (Actual): June 2, 2017

Study Registration Dates

• First Submitted: June 15, 2017
• First Submitted That Met QC Criteria: June 17, 2017
• First Posted (Actual): June 20, 2017

Study Record Updates

• Last Update Posted (Actual): January 9, 2018
• Last Update Submitted That Met QC Criteria: January 8, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: neoatherosclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Disease Attributes; Coronary Disease; Coronary Artery Disease; Disease Progression; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium
• Other Study ID Numbers: KobeU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No