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

January 8, 2018 updated by: Hiromasa Otake, Kobe University
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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
50

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Lipid index change between baseline and 12 month follow-up
Time Frame: 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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Macrophage grade change between baseline and 12 month follow-up
Time Frame: 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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Kobe University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Hiromasa Otake, ph.D, Kobe University Graduate School of Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 26, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 2, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 2, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 15, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 17, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 20, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 9, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 8, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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