A randomised, double blind placebo controlled trial to (A) assess the optimal vitamin K dosage for supplementation, and (B) to access wether complications of anticoagulation treatment will diminish by suppletion of vitamin K.

Anticoagulationtherapy with vitamin K antagonists (VKA) is indicated to prevent
and treat venous and arterial thrombo-embolisms and are among the most frequent
prescribed medicines in the Netherlands.
There are important disadvantages of treatment with VKA: its narrow therapeutic
window and a strong variability in the sensitivity for VKA.
An important cause for the variability in sensitivity for VKA is the intake of
vitamin K (Franco et al, 2004; Cushman et al, 2001; Khan et al, 2004; Sconce et
al, 2005; Schurgers et al, 2004; Rombouts et al, 2007).
One other possible cause is thought to be polymorphisms in the enzymes CYP2C9
and VKORC1 (limdi et al, 2007).

VIKS-2A:
To determine the optimal dosage of vitamin K for supplementation to obtain a
stable anticoagulation effect.
VIKS-2B:
To determine whether supplementation with the found optimal dosage of vitamin K
from study VIKS-2A will decrease the number of complications of treatment wit
VKA.
To determine the possible influence of polymorphisms in CYP2C9 and VKORC1 on
the sensitivity for VKA and the suppletion of vitamin K.

Randomised doubleblind placebo controlled trial.

VIKS-2A:
400 patients who will start with anticoagulationtherapy with VKA will be
randomised over 4 equal groups: 3 groups that will receive vitamin K in 3
different dosages (100 microgr., 150 microgr. and 200 microgr.) and 1 group
that will receive a placebo. The estimated duration of the studies is 6 to 12
months.
VIKS-2B:
2200 patients will be randomised over 2 equal groups: 1 group that will receive
vitamin K in the found optimal dosage from VIKS-2A and 1 group that will
receive a placebo. The estimated duration of the studies is 24 to 36 months.

At the start of the studies some blood will be taken from the patients in
addition to the blood used for INR monitoring. This additional blood will be
used for genetic research into the enzymes CYP2C9 and VKORC1. These
bloodsamples will be completely anonymous.
In studies VIKS-2A patients will have an appointment with the researcher after
8 to 12 weeks after the start of the studies to assess compliance and the wish
to further participate in the studies. In studies VIKS-2B patients will have an
appointment 2 or 3 times during the studies.
In studies VIKS-2B the patients vitamin K status need to be assessed as well.
At this moment it*s not sure whether we do this by additional bloodtesting or
by questionnaire. In case of a bloodtest this sample will also be taken during
the regular sample taking. In case of a questionnaire there will be a slightly
higher burden for the patient but as little as possible.
The risks in both studies are minimal. No side-effects for vitamin K are known.
The dosage for VKA will probably be increased slightly, what, in theory, could
increase the number of side-effects from VKA. This, however, is not the case
for the most important side-effect of VKA: bleeding. In earlier studies in our
department there were no indications for an increase of side-effects from VKA
(Rombouts et al, 2007).
Since theirs is virtually no risk and little burden for our patients and a
potential great benefit from our studies it seems justified to proceed with
these studies.