Vascular Effects of Ezetimibe/Simvastatin and Simvastatin on Atherosclerosis
Condition: Atherosclerosis
MeSH terms: Atherosclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Multiple clinical trials, using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase
      inhibitors (statins), have shown benefit in the primary and secondary prevention of
      atherosclerotic complications. However, till now, there is an incomplete understanding of all
      the mechanisms of the biologic effects of statins beyond LDL cholesterol (LDL-C) reduction,
      but there is accumulating evidence that the Rho-GTP/Rho-Kinase pathway (Rho/Rho-K) plays an
      important role and may be a strategic therapeutic target in cardiovascular diseases. With
      similar LDL-C reduction ability, the availability of Ezetimibe offers the potential to begin
      to address the question whether some of the benefits conferred by statins may accrue
      independently of their effects on LDL-C lowering. A better understanding of the role of the
      Rho/Rho-kinase signaling pathway in the pathogenesis of atherosclerosis in human is
      essential. Inhibition of Rho/Rho-kinase by statins may explain some of the biological
      beneficial effects of statins observed in clinical trials. This study aims to translate into
      patients important experimental discoveries regarding the initiation of inflammation in
      atherosclerosis in an attempt to improve upon the present treatment of cardiovascular
      diseases.
    

Detailed description: 
      Study Design:

      A single-blind controlled trial with two arms will be conducted at National Chen-Kung
      University Hospital (NCKUH). We will screen subjects with stable atherosclerosis to complete
      enrollment of 40 subjects in the study (see inclusion and exclusion criteria section below).
      A central pharmacist at NCKUH will randomize the patients to 40mg or Simvastatin (n=20) or
      10mg/10mg of Ezetimibe/Simvastatin (n=20) for 28 days. If the patient is already on a statin
      a two-week washout period will be 2 weeks prior to trial initiation.

      Primary Outcomes and measurement:

      The primary outcomes are the mean changes in the Rho-kinase expression and activity in
      leukocytes in response to 40mg or Simvastatin (n=20) or 10mg/10mg of Ezetimibe/Simvastatin
      (n=20) over 28 days.

      Secondary Outcomes and measurement:

      The secondary outcomes are the correlation between the mean changes in Rho-kinase expression
      and activity in leukocytes and vascular tissue with the mean changes in LDL-C, hsCRP, and
      BAFMD, as well as its relation with clinical characteristics.

      Subjects:

      Participants will be recruited from the ambulatory clinics at the NCKUH Clinic.

      Inclusion Criteria:

        1. Male or female subjects aged 40 to 80 years

        2. Documented stable atherosclerosis by angiography or vascular ultrasound (more that 20%
           luminal narrowing), peripheral arterial disease or type 2 diabetes mellitus (coronary
           heart disease (CHD) risk equivalent - Adult Treatment Program (ATP)-III guidelines)

        3. LDL-cholesterol >100mg/dL (indication to treat with statin)

        4. Written informed consent

        5. Primary care physician authorization letter to participate in the study.

      Exclusion criteria:

        1. Inability to give consent

        2. Pre-menopausal women

        3. Current use of antibiotics, anti-inflammatory or immunosuppressant drugs

        4. History of LFT >2 times the upper normal limit

        5. History of myopathy / myositis or CPK > 10 times the upper normal limit

        6. CPK above normal limits at study onset

        7. Any evidence of inflammatory, infectious or neoplastic disease

        8. History of CABG, PCI or acute ischemic syndrome in the preceding 3 months.
    

Intervention name(s): Simvastatin (Zocor); 10mg/10mg of Ezetimibe/Simvastatin (Vytorin)
Intervention type(s): Drug; Drug
Intervention description(s): 40mg of Simvastatin (n=20) orally per-day for 28 days; 10mg/10mg of Ezetimibe/Simvastatin (n=20) orally per-day for 28 days
Other intervention name(s): Zocor; Vytorin
Intervention MeSH terms: Simvastatin; Ezetimibe; Ezetimibe, Simvastatin Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science
Keywords: HMG-CoA Reductase Inhibitors; endothelial function; HMG-CoA Reductase Inhibitors on vascular protection