High-Density Lipoprotein (HDL) Modulation and Endothelial Function
Condition: Atherosclerosis
MeSH terms: Atherosclerosis
Study type: Interventional
Phase: Phase 3

Summary: 
      It is well known that lowering low-density lipoprotein (LDL) (bad cholesterol) is beneficial
      for decreasing heart attacks and death. More recently, focus has been on trying to raise HDL
      (good) cholesterol. The purpose of the present study is to determine if the addition of a
      sustained release preparation of niacin (Niaspan - a medicine to raise HDL cholesterol) to
      LDL lowering with a statin type medication results in improved vascular health. The study of
      the well being of one's vessel wall (endothelial function) will serve as a marker of
      treatment effect in the study.

      Hypotheses: Extended-release (ER) niacin will improve endothelial function measured as
      brachial flow-mediated dilation (FMD - 10 end-point) and as pulse volume amplitude by pulse
      arterial tonometry (PAT) (20 end-point) in subjects with established atherosclerosis whose
      LDL cholesterol is optimally treated with statin therapy.
    

Detailed description: 
      Purpose: To determine the incremental value of extended-release (ER) niacin in combination
      with high dose statin therapy on brachial endothelial function in subjects with coronary
      atherosclerosis.

      Hypotheses:

        1. ER niacin will improve endothelial function measured as brachial flow-mediated dilation
           (FMD - primary end-point), hyperemic velocity and as pulse volume amplitude by PAT (20
           end-point) in subjects with established atherosclerosis whose LDL cholesterol is
           optimally treated with statin therapy.

        2. Hyperemic pulse volume amplitude in the finger assessed by pulse arterial tonometry
           (PAT) will correlate with brachial FMD as assessed by high resolution ultrasound of the
           brachial artery.

      Background: In patients with established coronary atherosclerosis, secondary prevention
      strategies with lipid lowering agents have resulted in event reductions of 25-30%. Despite
      aggressive cholesterol lowering with statins event rates remain 2-3% per year for subjects at
      high risk. While many new therapeutic targets have been suggested, recently there has been
      much interest in modulation of HDL cholesterol. Low HDL is a powerful risk factor for
      coronary events. HDL functions in the reverse cholesterol transport system to remove excess
      cholesterol from tissues including the vessel wall. In addition, HDL has other vascular
      benefits including anti-oxidant and direct endothelial effects. The most effective available
      way to modulate HDL is with niacin. An ER formulation of niacin (Niaspan - Kos) will be
      available in Canada in 2005 and has been shown to be efficacious and safe.

      The endothelium plays a key role in vascular homeostasis through the release of paracrine
      factors such as nitric oxide. Dysfunction of the endothelium occurs in response to risk
      factors and atherosclerosis. Endothelial function can be readily measured non-invasively in
      humans and pharmacotherapy that has been shown to reduce cardiovascular events improves
      endothelium-dependent vasodilation. In addition, recent studies have suggested that measures
      of endothelial function have prognostic implications for subjects at risk for vascular
      events. As such the measurement of endothelial function has become well established as a
      surrogate marker of disease activity and will be utilized in the current study. The effect of
      niacin on endothelial function has not been studied.

      Design: The study is a single center, randomized, placebo controlled cross-over design. An
      open label one month run in phase of atorvastatin therapy will be utilized to establish
      baseline endothelial function and ensure tolerability of the atorvastatin. Brachial
      ultrasound determination of FMD and pulse arterial tonometry (PAT) will be utilized. Open
      label atorvastatin will be continued throughout the study in all subjects. Following baseline
      measurements of endothelial function, patients will be randomized to placebo or escalating
      doses of ER niacin for a treatment phase of 3 months. At this point, repeat measurements will
      be undertaken and subjects will cross-over to the alternate therapy for an additional 3
      months followed by final measurements. The use of different methods of endothelial function
      measurement will allow a comparison of the two.

      Subjects will have established coronary atherosclerosis and an HDL < 1.1 mmol/L, and be at
      least one month post percutaneous coronary intervention (PCI) or 3 months post coronary
      artery bypass graft (CABG). Exclusion criteria include active gout, gallbladder or peptic
      ulcer disease, change of endothelial modulating drugs within one month of study initiation or
      use of niacin.

      The primary end-point of the study is brachial artery flow-mediated vasodilation. The primary
      efficacy analysis will be a comparison of the change in FMD during active ER niacin treatment
      compared with baseline. The sample size is based on an expected 2% difference in FMD (SD 5%),
      p <0.05 and power of 80%.

      Significance: Despite the reduction of mortality with current LDL lowering approaches,
      morbidity and mortality remain unacceptably high. HDL has recently gained favor as a
      therapeutic target to lower cardiovascular event rates. The current study will evaluate the
      effect of HDL raising on endothelial health, a surrogate marker of atherosclerosis activity.
    

Intervention name(s): atorvastatin (or other tolerated statin + Niaspan/placebo)
Intervention type(s): Drug
Intervention description(s): atorvastatin 80 mg for all, randomized to 1500 mg niacin/placebo and then crossed over
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: atherosclerosis; endothelial function; HDL; Niacin; statins; Stable Atherosclerotic Vascular Disease