Niacin/Laropiprant and Endothelial Function
Condition: Coronary Heart Disease
MeSH terms: Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Primary objective:

      To evaluate the impact of 12 weeks' administration of extended release niacin/laropiprant
      (ERN/LRPT) compared to placebo added to statin therapy on endothelial dependant dilatation of
      the arterial wall assessed by brachial vasoreactivity in stable coronary heart disease (CHD)
      patients.

      Secondary objective:

      To evaluate the impact of 12 weeks' administration of extended release niacin/laropiprant
      (ERN/LRPT) compared to placebo added to statin therapy on serum lipids and the parameters of
      inflammation in stable coronary heart disease (CHD) patients.

      CHD-coronary heart disease ER-extended release
    

Detailed description: 
      Endothelial dysfunction can be regarded as a syndrome which exhibits systemic manifestations
      and is detectable prior to obvious intimal lesions which are considered to be important
      factors in the pathogenesis of atherosclerosis and its complications. Endothelial function is
      determined by the integrated index of all atherogenic and atheroprotective factors present in
      an individual, including known, as well as yet unknown variables and genetic predispositions.
      Should the hypothesis of endothelial dysfunction reflecting a vascular phenotype prone to
      atherogenesis be true, endothelial function could then serve as a marker of an inherent
      atherosclerotic risk. Dysfunction of either the coronary or peripheral vascular endothelium
      can be considered an independent predictor of cardiovascular events, offering valuable
      prognostic information additional to that derived from conventional risk factor assessment.
      Interventions, such as risk factor modification and treatment with various drugs, including
      statins and angiotensin-converting enzyme inhibitors, have shown to improve endothelial
      function.

      Endothelial dependant vasomotion has been used as a clinical endpoint for assessment of
      endothelial function. Testing involves pharmacological and/or physiological stimulation of
      endothelial release of NO and other vasoactive compounds, and often a comparison of vascular
      responses to endothelium-independent dilators such as nitroglycerine. Determination of local
      NO bioavailability not only reflects its influence on vascular tone, but also the other
      important functions of this molecule, which include thromboregulation, cell adhesion, and
      proliferation

      A non-invasive technique has been developed to evaluate endothelium-dependent, brachial
      artery FMD. Endothelium of the brachial artery is provoked to release nitric oxide (NO) by
      the pressure created by inflated sphygmomanometer cuff placed on the forearm distal to the
      brachial artery and its subsequent release 4-5 minutes later.FMD occurs predominantly as a
      result of local endothelial release of NO and it can be imaged and quantitated as an index of
      vasomotor function. The advantages of this high-frequency ultrasonographic imaging of the
      brachial artery are two-fold: it is non-invasive and it allows repeated measurements.

      Large prospective epidemiological studies have demonstrated an inverse correlation of high
      density lipoprotein cholesterol (HDL-C) and the risk of cardiovascular events. Although the
      atheroprotective effects of HDL have mainly been attributed to its function in reverse
      cholesterol transport, lately numerous beneficial effects of HDL such as the improvement of
      endothelial function, anti-inflammatory, anti-thrombotic, antioxidative effects and the
      stimulation of endothelial regeneration have been identified. Consequently, therapeutic
      elevation of HDL become more and more important goal of the treatment of patients with
      coronary artery disease (CAD). Warnholtz et al recently demonstrated that extended-release
      (ER) niacin 1000 mg daily significantly improved endothelial function in CAD patients with
      low HDL-C, but not in normal HDL-C. The biggest obstacle for niacin therapy is flushing which
      makes many patients non compliant to the prescribed medication.

      Tredaptive TM [(ERN/LRPT); Merck & Co., Inc, Whitehouse Station, NJ, USA)] is a combination
      tablet containing 1 g of extended release niacin (ERN) and 20 mg of laropiprant, highly
      selective PGD2-receptor (DP1) antagonist, which offers improved tolerability, supporting a
      simplified 1-2 g dosing paradigm and improved compliance.

      Statins and niacin have been shown to improve endothelial function in CAD patients, however,
      the question whether niacin improves endothelial function in statin treated patients still
      remains open. What would be the time needed to show an effect is also not known, but based on
      the recent publication by Warholtz it seems that 12 weeks should be sufficient.

      This study would prospectively test influence of the higher dose of ER-niacin (2000mg) than
      used in the latest publications (1000 mg) in addition to laropiprant (40mg) in the CHD
      patients with low HDL-C, the subgroup which in the recent publication by Warhnoltz seem to
      have benefited from the treatment with niacin.
    

Intervention name(s): Niacin/laropiprant; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): After two weeks patients, who have already been on a stable dose of a statin for at least 6 weeks, willer receive ER niacin/laropiprant in addition to the statin therapy. Patients will receive ER niacin/laropiprant 1000mg/20 mg tablet for 4 weeks, after that the dose will be increased to 2000mg/40mg tablet. The intention is that all patients receive 2000 mg/40mg dose for the rest of the study period, but should they be intolerant to the higher dose, the maximum tolerated dose will be used.; After two weeks patients, who have already been on a stable dose of a statin for at least 6 weeks, will receive placebo in addition to the statin therapy. Patients will receive 1 tablet for 4 weeks, after that the dose will be increased to 2 tablets for the rest of the study period.
Intervention MeSH terms: Niacin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: niacin/laropiprant; endothelial function