Effect of Rosuvastatin and Eicosapentaenoic Acid on Neoatherosclerosis: The LINK-IT Trial
Condition: Coronary Artery Disease Progression
MeSH terms: Coronary Artery Disease; Disease Progression
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): EPA and high dose rosuvastatin; Standard dose rosuvastatin
Intervention type(s): Drug; Drug
Intervention description(s): After randomization, patients with intensive lipid lowering therapy start EPA (1800mg/day) and high dose rosuvastatin (10mg/day) for 12 months.; After randomization, patients with standard lipid lowering therapy start only rosuvastatin (2.5mg/day) for 12 months.
Other intervention name(s): Rosuvastatin; Eicosapentaenoic acid; rosuvastatin
Intervention MeSH terms: Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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 (Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: neoatherosclerosis