Cardiovascular Disease Clinical Trial
Official title:
Effect of Vitamin K2 (MK7) on Cardiovascular and Bone Disease in Dialysis Patients: A Prospective, Randomized Placebo-controlled Double Blind Trial
Cardiovascular disease (CVD) is the most frequent cause of death in patients (ptt.) with
chronic kidney disease (CKD). Compared to the general population death due to CVD is 10-20
times higher in CKD ptt. being treated with hemodialysis. Vascular calcification and hence
arterial stiffness is of great importance for the high incidence of CVD.
CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures. Both
vertebral and other fractures of low energy are associated with a high mortality.
Matrix Gla Protein (MGP) is an important inhibitor of vascular calcification and Osteocalcin
(OC) is an important regulator of bone metabolism. The function of both MGP and OC depend on
vitamin K.
Vitamin K is supplied with food. The content is low in food recommended to CKD ptt. which is
reflected in very low concentrations of vitamin K in their blood samples. A correlation
between vitamin K level, incidence of vascular calcification and bone density has been
proven; yet there are no trials elucidating the clinical effect of vitamin K on vascular
calcification or bone strength.
The investigators will conduct a randomized placebo controlled trial examining the clinical
effects of vitamin K2 on vascular calcification and bone mineralization in order to prevent
and treat CVD and bone disease in CKD ptt.
Primary study endpoints:
1. Changes in arterial stiffness assessed by pulse wave examination
2. Changes in bone mineral density (BMD) in distal radius assessed by DXA-scans.
Secondary study endpoints:
Changes in coronary artery and valvular calcification assessed by heart-CT-scans, blood
pressure, body composition, total and regional BMD, lateral column/aortic calcification score
as well as a panel of correlating blood tests.
BACKGROUND
Vascular calcification is a significant problem among patients (ptt.) with chronic kidney
disease (CKD) and the prevalence of aortic calcification is twice as high as the general
population e.g. Cardiovascular disease (CVD) is the most frequent cause of death in ptt. with
CKD. Death due to CVD is 10-20 times higher in CKD ptt. being treated with hemodialysis
compared to the background population. Whereas atherosclerosis is a dominating cause of CVD
in the general population CKD ptt. tend to develop medial calcification and hence arterial
stiffness which is thought to be of great importance in the high incidence of CVD.
CKD ptt. in dialysis treatment also have a 3 times higher risk of bone fractures compared to
the general population. Both vertebral and other fractures of low energy are associated with
a high mortality in CKD ptt.
The genesis of the arteriosclerosis is still unresolved but seems to be multifactorial. The
impaired kidney function itself and the treatment so far both seem to be of importance. The
vitamin K-dependent Gla proteins; Matrix Gla Protein (MGP) and Osteocalcin (OC) are described
as the most potent inhibitors of vascular calcification and osteoporosis. Until recently CKD
ptt. have been treated with vitamin K antagonists which just adds to the focus on vitamin K
in this progressive, vascular calcification- and bone demineralization process.
Vitamin K is supplied with food. It consists of several subtypes, e.g. vitamin K1 which is
transformed into K2 during digestion. The recommended diet for CKD ptt. is low on vitamin K
which is reflected in very low concentrations of vitamin K in blood samples from CKD ptt. in
hemodialysis. A supplement of vitamin K1 or K2 will make activation possible for MGP and OC
by increasing the concentration of vitamin K2.
A correlation between vitamin K level and incidence of vascular calcification in dialysis
ptt. has been proven; yet there are no trials elucidating the clinical effect of vitamin K on
vascular calcification in CKD ptt. There are not any trials elucidating the effect of vitamin
K on bone strength or number of fractures in dialysis ptt, although a relation between
vitamin K and bone mineral density in dialysis ptt. has been shown and a significant increase
in age related bone strength was found in a study by introducing a daily supplement of
vitamin K.
OBJECTIVE AND HYPOYHESIS
To examine the clinical effect of vitamin K2(MK7) on arterial stiffness assessed by pulse
wave examination and bone mineral density assessed by DXA-scans in a group of dialysis ptt.
in order to be able to prevent and treat cardiovascular and bone disease in CKD ptt. in the
future.
The hypothesis is that a daily supplement of vitamin K2 (MK7) will reduce the calcification
process in larger arteries, coronary arteries and -valves and hence reduce the risk of CVD as
well as increase the bone mineral density and hence the frequency of bone fractures.
DESIGN
RenaKvit is an investigator initiated, prospective, randomized, double-blinded, placebo
controlled intervention trial performed as a nationally, multicenter trial that will run for
2 years. Data will be compiled after 1 and 2 years.
The trial is divided into two sub-studies; RenaKvit-kar (vessel) (n= 48) and RenaKvit-knogle
(bone) (n=123), in which the effect of vitamin K2(MK7) on larger arteries, coronary arteries-
and valves and the effect on bone with regards to bone mineral density and frequency of
fractures are respectively examined.
PATIENTS AND RECRUITMENT
Ptt. will be equally divided by randomization and hence daily be given a tablet of either
vitamin K2(MK7) or placebo. According to the criteria of inclusion ptt. will either join the
RenaKvit-vessel or the bone group. If criteria are fulfilled ptt. are to join both vessel and
bone groups.
Determined by calculation of statistical power, incl. a level of significance of 5%, a
standard deviation of 0,95 and strength of 80%, a minimum of 40 ptt (RenaKvit-vessel) and 140
ptt. (RenaKvit-bone) will be included, thus taking potentially drop-outs in account. Both
ptt. in hemo- and peritoneal dialysis treatment will be included.
Ptt. will be recruited by the dialysis departments at Zealand University Hospital Roskilde,
Holbaek Hospitals, Aarhus University Hospital and Aalborg University Hospital.
There will be no fee for participating ptt.
MEDICINE
Patients are given a daily tablet of either vitamin K 360 micrograms or placebo during a
period of 2 x 12 months. Both types of tablets will be of similar look and content, besides
vitamin K2.
METHODS
- Pulse Wave examination: Includes both pulse wave analysis and pulse wave velocity
measurements. Done by using SphygmoCor©-pulse wave apparatus. Pulse wave examination is
used as a measure of the arterial stiffness and is performed after standardized method.
- 24-hour blood pressure and blood pressure measurements: Done by current Danish
guidelines (17).
- Coronary artery and -valve calcification: Assessed by CT-scans of the heart using the
Agatston Score.
- Bone Mineral Density: Assessed by DEXA-scans.
- Lateral lumbal x- ray and aortic calcification score: A semi-quantitative scoring system
used to describe the plaques on the front and the back of the aorta level with each
level of the lumbar vertebrae. The method has been found to be predictive of vascular
morbidity and mortality.
- Measuring predictors/establishing a biobank: Partly as "routine tests" during dialysis
and partly as special kits developed at Vejle Hospital.
STATISTICS
Both groups will have descriptive statistics performed for as well as the presentation of the
total population, stratified for gender, age and weight.
Normal-distributed data will be expressed as mean value +/- standard deviation (SD), while
other distributed data also will be expressed as median values (interquartile range;
interquartile range, IQR). Categorical values will be expressed in numbers and percentages.
Normal-distributed variables will be compared with Student's t-test. Where found appropriate,
logarithmic transformation shall be performed. Non-normally distributed variables will be
compared with the Mann Whitney U test. Categorical values are to be compared with the Chi
Square test.
Changes within the treatment groups over time will be analyzed by paired analysis, and
between the treatment groups compared with the non-paired analysis. Forward stepwise
multivariate logistic regression analysis is carried out to correct significant confounders
of the primary and secondary endpoints.
Analysis of Cox proportional hazards will be performed from time to first clinical event.
P≤0.05 will be considered statistically significant. All results - negative and positive -
are expected to be published in peer-review magazines.
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