Randomised trial to investigate possible differences in biological availability and effectiveness between vitamin K solution in oil and vitamin K tablets.

Anticoagulation therapy with vitamin K antagonists is an effective way to
counteract the formation of clots in diseases like atrial fibrillation.
However, in several situations the anticoagulation effect must be reduced or
even normalised. In case of the shortacting acenocoumarol this can be achieved
by suspending treatment for one of two days. With the longacting phenprocoumon
(of, internationally, warfarin) this does not work because of the long half
life of both drugs. In these case treatment with vitamin K is necessary.
In the Netherlands there is sufficient experience in dosing vitamin K solution
in oil. Recently vitamin K tablets were presented which should have the same
effect in theory. However, since these tablets are marketed as medication but
as dietary supplement these tablets have not been subjected to the same
rigorous testing as they would have been had these tablets been marketed as
medication.
Vitamin K as tablets do have a practical advantage for both the pharmacy and
the patient when dealing with transport, storage, production and intake. Also
dosing vitamin K tablets could be more accurate than dosing the vitamin K
solution.

1. Determining whether or not the vitamin K tablets have the same biological
availability in humans as the vitamin K solution has.
2. Determining whether or not the vitamin K tablets are as effective as the
vitamin K solution is.

Step 1:
25 healthy volunteers will receive 5 mg vitamin K in either tablet or solution.
5 will receive 5 mg vitamin K in solution and 5 will receive tablets.
Participants are asked to postpone their breakfast untill ingestion of the
vitamin K. Before intake and 7 times after (after 2, 4, 5, 6, 8, 10 and 24
hours) blood will be drawn to determine the ammount of vitamin K in the blood.
Additionally, participants are asked to follow a low-vitamin K diet during 24
hours. In a crossover model with a wash out period of 2 weeks this will be
repeated with the ones who first received tablets now receiving the vitamin K
solution and vice versa.

Step 2:
72 patients who need to undergo (small) surgery or an invasive diagnostic
procedure according to which they need to be treated with 5 mg vitamin K
according to the protocols from the Leiden anticoagulation clinic will be
randomised over two groups. One group will receiver 5 mg vitamin K as tablets
and one group will receive the vitamin K solution. Before intake and after 24
and 48 hours the INR will be determined. The effectiveness of the vitamin K
will be expressed as the difference in the number of INR values below 2.0
between the two groups.

Step 3:
72 patients who have an INR between 7.0 and 10.0 will be randomised over two
groups: one receiving 5 mg vitamin K as tablets while the other group receives
the vitamin K solution. Before intake and after 24 and 48 hours the INR will be
measured. Also, before intake and 24 hours after intake some extra blood will
be taken to determine the ammount of vitamin K in the blood. The endpoints
consist of the difference in the INR reduction between both groups and the
difference in the increase of the ammount of vitamin K in the blood.

De healthy volunteers will receive both 5 mg vitamin K tablets and 5 mg vitamin
K solution with a wash out period of 2 weeks in between.

The patients will receive either 5 mg vitamin K tablets or 5 mg vitamin K
solution depending on the randomisation.

There is no risk involved for the healthy volunteers since no adverse effects
of vitamin K intake are known.
The burden excist in the need of a multiple blood sampling over a period of two
times 24 hours.

The risk for the patients undergoing either (small) elective surgery or
invasive diagnostic procedures lies in the fact the planned procedures need to
be cancelled should the INR respond inadequately to the vitamin K tablets.
Also, there is a theoretical risk the vitamine K tablets have a higher
biological availability or effectiveness than the solution, causing an
increased thrombo-embolic risk,
In these patients either one or two additional INR measurements need to be done.

The risk in the patientgroup that has a high INR excist in the extended
duration of the bleeding risk should the biological availability or the
effectiveness be less for the vitamin K tablets. Also in this groups of
patients there is a theoretical risk of thrombo-embolic complications should
the biological availibility or the effectiveness of the vitamin K tablets be
superior to the vitamin K solution.
These patients will need to ondergo another blood sampling the day of the
initial INR monitoring in order to determine the ammount of vitamin K in the
blood. Furthermore this group will also have two additional INR measurements
and, 24 hours after vitamin K intake, an additional ammount of blood for
vitamin K measurement in the blood.