Coronary Artery Disease ProgressionPhase 4NCT03192579
Effect of Rosuvastatin and Eicosapentaenoic Acid on Neoatherosclerosis: The LINK-IT Trial
A Phase 4 study testing EPA and high dose rosuvastatin and Standard dose rosuvastatin in people with Coronary Artery Disease Progression, run by Kobe University.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 20 to 85 years
- Conditions the study is for
- Coronary Artery Disease Progression
- What is being tested?
- EPA and high dose rosuvastatin and Standard dose rosuvastatin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- No sites listed yet
- Study dates
- 26 Jul 2013to 2 Jun 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
About this study
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.
Read the 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.
- Conditions
- Coronary Artery Disease Progression
- Being tested
- EPA and high dose rosuvastatin, Standard dose rosuvastatin
- Keywords
- neoatherosclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EPA and high dose rosuvastatinDrug
Also called Rosuvastatin, Eicosapentaenoic acid
After randomization, patients with intensive lipid lowering therapy start EPA (1800mg/day) and high dose rosuvastatin (10mg/day) for 12 months.
Standard dose rosuvastatinDrug
Also called rosuvastatin
After randomization, patients with standard lipid lowering therapy start only rosuvastatin (2.5mg/day) for 12 months.
| Study group | Role | What they receive |
|---|---|---|
| Standard lipid lowering therapy | Experimental | Start with only rosuvastatin 2.5mg and up to 20mg/day Receives: Drug: Standard dose rosuvastatin |
| Intensive lipid lowering therapy | Active comparator | Start EPA and rosuvastatin 10mg/day and up to 20mg/day Receives: Drug: EPA and high dose rosuvastatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and 12 month follow-up
Secondary outcomes (1)
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.
Measured: Baseline and 12 month follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2017
- Study start26 Jul 2013
- Primary completion2 Jun 2017
- Study completion2 Jun 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Coronary Artery Disease ProgressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Consecutive patients with stent implantation who were performed coronary angiography and OCT follow-up of the coronary arteries were screened. The patients with neoatherosclerosis were randomly assigned to either 2.5-5mg/day of rosuvastatin therapy or 10mg/day(up to 20mg) of rosuvastatin and 1800mg/day of eicosapentaenoic acid therapy at a 1:1 ratio for 12 months.
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kobe University
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Principal investigator, Hiromasa Otake, Kobe University
- Investigators
- Hiromasa Otake, ph.D, Study chair, Kobe University Graduate School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03192579
- Sponsor's protocol ID
- KobeU
- Status last verified
- Jan 2018
- First submitted
- 15 Jun 2017
- Last updated
- 9 Jan 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 9 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Rosuvastatin and Eicosapentaenoic Acid on Neoatherosclerosis: The LINK-IT Trial
- ClinicalTrials.gov ID
- NCT03192579
- Acronym / sponsor ID
- KobeU
- Conditions
- Coronary Artery Disease Progression
- Keywords
- neoatherosclerosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Kobe UniversityIndustry (pharma, biotech, devices)
- Study start
- 26 Jul 2013 (actual)
- Primary completion
- 2 Jun 2017 (actual)
- Study completion
- 2 Jun 2017 (actual)
- First posted
- 20 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Consecutive patients with stent implantation who were performed coronary angiography and OCT follow-up of the coronary arteries were screened. The patients with neoatherosclerosis were randomly assigned to either 2.5-5mg/day of rosuvastatin therapy or 10mg/day(up to 20mg) of rosuvastatin and 1800mg/day of eicosapentaenoic acid therapy at a 1:1 ratio for 12 months.
| Arm | Type | Receives |
|---|---|---|
| Standard lipid lowering therapy | Experimental | Drug: Standard dose rosuvastatinStart with only rosuvastatin 2.5mg and up to 20mg/day |
| Intensive lipid lowering therapy | Active comparator | Drug: EPA and high dose rosuvastatinStart EPA and rosuvastatin 10mg/day and up to 20mg/day |
Who may qualify
- Ages
- 20 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EPA and high dose rosuvastatinAlso: Rosuvastatin, Eicosapentaenoic acidAfter randomization, patients with intensive lipid lowering therapy start EPA (1800mg/day) and high dose rosuvastatin (10mg/day) for 12 months. | Drug | Intensive lipid lowering therapy |
| Standard dose rosuvastatinAlso: rosuvastatinAfter randomization, patients with standard lipid lowering therapy start only rosuvastatin (2.5mg/day) for 12 months. | Drug | Standard lipid lowering therapy |
Primary outcome
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.
1 secondary outcome
Macrophage grade change between baseline and 12 month follow-up
Time frame: Baseline and 12 month follow-up
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jan 2018.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hiromasa Otake, ph.D study chair
Kobe University Graduate School of Medicine
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing EPA and high dose rosuvastatin and Standard dose rosuvastatin in people with Coronary Artery Disease Progression, run by Kobe University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Lipid index change between baseline and 12 month follow-up (time frame: Baseline and 12 month follow-up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2018.