Omega 3 Action on Cardiovascular Risk Factors in Patients Treated With Statins
Condition: Inflammation; Blood Pressure; Platelet Function; Endothelial Function
MeSH terms: Inflammation
Study type: Interventional

Summary: 
      Recent evidences showed beneficial effects of omega-3 fatty acids on cardiovascular morbidity
      and mortality.

      Regular Omega-3 fatty acid consumption reduces cardiovascular mortality, ischemic heart
      disease and stroke mortality. There is probably no single mechanism of action that explains
      this beneficial effect; but possible mechanisms include reduce susceptibility of the heart to
      ventricular arrhythmia, antithrombogenic effect, reduce triglyceride level, promotion of
      nitric oxide-induced endothelial relaxation, and retard growth of atherosclerotic plaque.

      The combination of satins and omega3 was proved to be better the any of the drugs alone in
      several studies.

      The purpose of the study is to investigate several possible mechanisms that may explain the
      add on beneficial effect of omega-3 in hypercholesterolemic patients already treated with
      satins.
    

Detailed description: 
      Cardiovascular disease is a leading cause of death in the western world. HMG-co A Reductase
      (statins) stands in the first line of treatment of cardiovascular disease because of their
      direct effect on LDL and their pleotrophic effect (mainly anti-inflammatory).

      Recent evidences showed beneficial effects of omega-3 fatty acids on cardiovascular morbidity
      and mortality

      Regular Omega-3 fatty acid consumption reduces cardiovascular mortality , , ischemic heart
      disease and stroke mortality. There is probably no single mechanism of action that explains
      this beneficial effect; but possible mechanisms include reduce susceptibility of the heart to
      ventricular arrhythmia, antithrombogenic effect , reduce triglyceride level , promotion of
      nitric oxide-induced endothelial relaxation , , and retard growth of atherosclerotic plaque.

      Statins have a proven survival benefit in patients with hypercholesterolemia by preventing
      both primary and secondary cardiovascular events . Statins also has beneficial effect on
      lipid profile (mainly LDL and less triglycerides), they reduce plaque growth and improves
      endothelial function.

      Many studies have demonstrated the additive effect of the combination of statins and omega-3
      fatty acids on lipid profile, as well as additive effect on inflammatory markers (IL-6 and
      CRP).

      JELIS 3is a recent study that examined 19000 patients with hypercholesterolemia treated with
      statins. This study demonstrated 19% reduction in coronary events under statins and omega 3
      co-treatment.

      The purpose of the study is to investigate several possible mechanisms that may explain the
      add on beneficial effect of omega-3 in hypercholesterolemic patients already treated with
      satins.

      Methods 80 patients age 30-70 with known dyslipidemia treated with statins will be enrolled
      at the research center in Asaf-Harofeh medical center.

      All patients will pass an interview, physical examination, lipid profile, CBC; and glucose
      level at base line.

      Exclusion criteria: thrombocytopenia, bleeding disorder, uncontrolled hypertension, LDL>160,
      uncontrolled diabetes mellitus, recent (3m) cardiovascular event, or omega-3 pretreatment.

      During the first 3 weeks all the patients will receive placebo. After randomization 40
      patients will receive Omega-3 (2 pills omega-950, Solgar, every day) for the next 5 months,
      40 patients will receive placebo.

      At baseline, after 3 weeks of placebo and after 6 weeks of omega-3 treatment, and after
      another 3 months, all patients will come to the research center and have interview, physical
      examination, lipid profile, including oxidized LDL. In order to learn about inflammation we
      will measure hsCRP, we will measure Isoprostane as a marker for oxidative stress,Lp-PLA2 will
      be measures in order to learn about plaque activity, Augmentation index will be measured to
      learn about arterial stiffness and central hypertension, platelet aggregation tests in a new
      method called cone and platelet analyzer will be measured. In every meeting a blood pressure
      recorder will measure 24h blood pressure.

      Augmentation index:

      Brachial blood pressure will be measured using a validated, manual oscillometric device
      .Patients were seated and rested for 5 minutes in a quiet room, after which time blood
      pressure will be measured over the brachial artery 3 times at 5-minute intervals. The mean of
      the last 2 measurements was recorded as representative of brachial blood pressure. After the
      last measurement, radial artery pressure waveforms of the same arm will be sampled over 10
      seconds with a Millar tonometer (SPC-301, Millar Instruments) and calibrated to the average
      blood pressure. Waveforms were then processed with dedicated software (SphygmoCor version 7,
      AtCor). The integral system software will be used to calculate an averaged radial artery
      waveform and to derive a corresponding central aortic pressure waveform using a previously
      validated generalized transfer function. Aortic pressure waveforms will be subjected to
      further analysis by the SphygmoCor software to identify the time to the peak/shoulder of the
      first and second pressure wave components (T1, T2) during systole. The pressure at the
      peak/shoulder of the first component will be identified as P1 height (outgoing pressure
      wave), and the pressure difference between this point and the maximal pressure during systole
      ( P or augmentation) will be identified as the reflected pressure wave occurring during
      systole. Augmentation index (AIx), defined as the ratio of augmentation to central pulse
      pressure, is expressed as a percentage: AIx=( P/PP)x100, where P is pressure and PP is pulse
      pressure.

      Cone and platelet analyser:

      The CPA tests platelet activation in whole blood under flow conditions. 200 µL of citrated
      blood will be placed in polystyrene wells and circulated at a high shear rate (1875 s-1) for
      2 minutes with a rotating Teflon cone. Wells will be washed with water, stained
      (May-Grünwald), and analyzed with an inverted-light microscope connected to an image analysis
      system. Results are expressed as the percentage of the well surface covered by platelets.

      Isoprostane Isoprostane is a marker for oxidative stress. Isoprostane level is measured by
      EIA (Cayman Chemical Company)

      Blood Pressure monitor:

      Twenty-four-hour ABPM will be executed with Spacelabs 90207. The monitor was mounted on the
      nondominant arm between 8:00 AM and 10:00 AM and removed 24 hours later. Recordings were made
      every 20 minutes between 6:00 AM and midnight and every 30 minutes between midnight and 6:00
      AM.

      Patients will be classified as having normal awake BP if the corresponding value was <135-mm
      Hg systolic BP (SBP) and <85-mm Hg diastolic BP (DBP). Normal sleep BP was considered <120/70
      mm Hg.20,21 The overall 24-hour normality definition was <125/80 mm Hg.22 The normal dip was
      defined separately for SBP and DBP as 10% reduction in BP during sleep compared with the
      awake period.23 Nondipping was defined as a decrease <10% but 0%. Dipping beyond 20% was
      considered "extreme," and sleep-related BP "rising" denoted negative dipping.

      PLAC The PLAC Test is a blood test that measures the level of Lp-PLA2, an enzyme highly
      specific to vascular inflammation and implicated in the formation of rupture-prone plaque.

      The PLAC Test is the only blood test cleared by the FDA to aid in assessing risk of both
      coronary heart disease and ischemic stroke associated with atherosclerosis.
    

Intervention name(s): omega-3; placebo
Intervention type(s): Drug; Drug
Intervention description(s): omega-3: 2 pills of Omega"950"®, Solgar, New Jersey, USA. Each pill contained 542mg of eicosapentaenoic acid, EPA, and 405mg of docosahexanoic acid, DHA; hard gelatin capsule of Capsugel®, France, filled with 1ml of soya oil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: omega 3; inflammation; augmentation index; endothelial function