Effects of ivabradine on vascular function in individuals at increased risk of developing cardiovascular disease and with impaired endothelial function;An international, multicentre, randomised, double-blind, placebo-controlled study over 12 weeks.

There is a clear association between endothelial dysfunction and both the
presence of ,and the development of atherosclerosis which may in part be
explained by the reduced release of NO by the endothelium. Whilst at the same
time there appears to be an association between HR, HR reduction, and the
development of atherosclerotic cardiovascular disease both in animals and in
humans with established CAD. By studying the effect of ivabradine on
endothelial function as measured by FMD and on biomarkers of endothelial
function and cardiovascular risk it is expected to explain, at least in part,
the mechanism by which this drug has a positive effect on atherosclerotic CVD.
By performing the study in patients who have not yet developed clinical CVD,
but who are at high risk due to both recognized risk factors (hypertension,
type II diabetes mellitus, hyperlipidaemia or cigarette smoking) and an
impaired FMD at baseline, we explore the hypothesis that HR reduction with
ivabradine at an early stage in the atherosclerotic disease process might
improve vascular health.

The purpose of this study is to demonstrate the beneficial effect of ivabradine
on endothelial function in individuals with risk factors for cardiovascular
disease and a resting HR * 75 bpm.

Multicenter, international, randomised, double blind, placebo-controlled in 2
parallel and balanced groups.
Following a selection visit (ASSE) , a pre-treatment period of 2 weeks and an
inclusion visit (W000); the patients will be centrally randomly assigned to one
of the 2 treatment arms.
Starting 7.5 mg, the dose will be adapted after 2 weeks and after 4 weeks
according to the tolerability and the heart rate value. The treatment period
will last 12 weeks. FMD will be performed before treatment and at the end of
treatment period. Moreover, intra-patient variability will be assessed in a
random subgroup of 20% of patients from all participating centres at baseline
and at W012

-12 lead ECG (2 ECG with 5 min interval)after at least 5 minutes rest at each
visit except the last one. -- ---FMD measurement at ASSE and W012 . To assess
the intra-patient variability, in a subset of patients FMD will be repeated
before the first medication intake and after 12 weeks of treatment.
-blood sampling for routine lab tests at ASSE and W012. Blood sampling for
biomarkers at W000 and W012.

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