[PHNUTR-L] Anticoagulation, Warfarin and Vitamin K
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Tue Mar 20 15:07:21 PDT 2007
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Anticoagulation, Warfarin and Vitamin K
Dr. Farhad Kamali
Wolfson Unit of Clinical Pharmacology
Claremont Place, University of Newcastle upon Tyne
Newcastle upon Tyne, NE2 4HH, UK
+ 44 19 1222 8043 / + 44 19 1222 5827 (FAX)
farhad.kamali at ncl.ac.uk
"Vitamin K Supplementation Can Improve Stability of Anticoagulation for
Patients with Unexplained Variability in Response to Warfarin,"
Blood, 2006 Nov 16; [Epub ahead of print]. 44902 (3/2007)
Kirk Hamilton: Can you please share with us your educational
background and current position?
Farhad Kamali: I graduated from Nottingham University, UK. I have
worked in the area of clinical pharmacology for over 20 years. I am
currently Professor of Human and Experimental Pharmacology and lead the
Thrombosis & Anticoagulation Research Group at Newcastle University, UK.
KH: What got you interested in studying the role of vitamin K and
anticoagulation control with warfarin use?
FK: I have a keen research interest in thromboembolic diseases and
their treatment. Warfarin is indicated for several thromboembolic
disorders and is widely prescribed. The clinical effectiveness of
warfarin is critically dependent upon maintaining the target
anticoagulation, expressed as the international normalized ratio (INR)
of the prothrombin time. However, many patients fail to achieve a stable
control of anticoagulation and they are subsequently exposed to
increased risk of bleeding or thromboembolism if they become over- or
under-anticoagulated respectively. My research for several years now has
centered on identifying factors that contribute to the instability of
anticoagulation control. Warfarin causes anticoagulation by inhibiting
the action of vitamin K. It is now well established that dietary changes
in vitamin K intake influence anticoagulation response to warfarin; even
a brief period of reduced intake of vitamin K causes warfarin
sensitivity, while increased intake of vitamin K containing foods can
reduce anticoagulation which can last for several days thereafter. In
man, vitamin K is obtained primarily from the diet in the form of
phylloquinones which are found in greatest concentration in green leafy
vegetables. Earlier we demonstrated that patients with unstable control
of anticoagulation have a consistently and significantly lower intake of
vitamin K than their matched stable counterparts.
KH: What is the biochemical function of vitamin K in coagulation?
FK: Vitamin K is essential for the production of active clotting
factors II, VII, IX and X in the clotting cascade.
KH: Where did you come up with the dose of 150 mcg/d of vitamin K?
What form of vitamin K was used and why? Was the vitamin K given in a
single dose or divided dose? With meals or away from meals? Was it given
away from the warfarin or with the warfarin?
FK: This dose of vitamin K was chosen as it was deemed to override
any variability in dietary vitamin K intake without causing a
statistically significant lowering of patient anticoagulation. For our
study the vitamin K was formulated as a solution by our hospital
pharmacy. This is because currently 150 mcg tablets are not commercially
available. The vitamin K dose was given as a single daily dose. Patients
were advised to take the vitamin K with their warfarin dose (usually in
the evening after a meal) to maximize patient compliance. Taking the
vitamin K dose with a meal also maximizes its absorption.
KH: Were vitamin K levels taken in this study at all? If so was there
a correlation with stable anti-coagulation?
FK: The study was designed to see if vitamin K administration
improves stability of anticoagulation control in unstable patients. It
was not designed to look for a correlation between vitamin K levels and
stability of anticoagulation. However we did measure plasma vitamin K
levels at the beginning and the end of the study which showed that
patients who were given vitamin K had significantly higher levels than
those given matching placebo.
KH: Can you tell us about your study and the basic results?
FK: Based on our earlier findings that patients with unstable
control of anticoagulation have a consistently and significantly lower
intake of vitamin K than stable patients we hypothesized that
supplementation with oral vitamin K, by increasing and stabilizing the
body stores of the vitamin and reducing the relative variability in the
daily dietary intake, could increase stability of anticoagulation
control. Seventy patients were randomly allocated to two groups in a
double-blinded fashion. One group received a once daily supplement of
150 micrograms vitamin K in 5 ml solution (approximately twice the
recommended daily allowance, RDA), and the other 5ml placebo, with their
warfarin daily dose. All patients routinely attended their designated
anticoagulation monitoring service for the following six months, where
their INR was checked and warfarin dosage adjusted if necessary.
Measures of stability of anticoagulation control in the 6 month study
period were compared to those in the 6 months immediately prior to it.
Anticoagulation control improved in 33/35 patients receiving vitamin K
supplementation and, of these, 19 fulfilled our criteria for having
stable control of anticoagulation (defined as warfarin dose remaining
constant for at least three clinic visits over a minimum period of three
months). However, only 24/33 patients receiving placebo demonstrated
some degree of improvement with only 7 of these fulfilling the criteria
for having stable control.
KH: Were there any adverse effects to the vitamin K?
KH: What is the harm of administering the traditional low vitamin K
diet by reducing vegetable intake, especially green vegetable intake,
and anti-coagulation control with warfarin therapy?
FK: The current "dietary reference value" for vitamin K of 1mcg/kg
(~65-80 of phylloquinone/day in an average sized individual) is based on
coagulation factor function; substantially higher recommended daily
doses are being suggested as a result of findings that requirement for
vitamin K is greater for the extra-hepatic vitamin K-dependent proteins,
including those necessary for bone mineralization and vascular health.
It is not clear if chronic intakes below the current recommendations,
and further antagonized by warfarin, have long term implications for
optimal bone mineralization and vascular integrity
KH: Now the reverse question. If foods rich in vitamin K (such as green
leafy vegetables) are important for cardiovascular health due to their
richness in phytochemicals that are cardioprotective, including vitamin
K, why don’t we encourage a very high plant-based diet in patients on
anti-coagulation therapy with Warfarin, keep the vegetable intake
consistently high, and adjust the Warfarin dose accordingly? Low vitamin
K levels have been associated with increased cardiovascular disease and
bone loss. Would you just recommend the vitamin K supplement and still
the traditionally recommended “low vegetable, vitamin K diet,” that I
have heard repeatedly recommended by cardiovascular specialists? It
makes no sense to me? I also wonder if cardiovascular specialists, by
recommending low vegetable- vitamin K rich diets may have been
preventing thrombosis with Warfarin but increasing the risk to other
cardiovascular events and bone loss with increased morbidity and
mortality at the same time? Can you comment on the above and on why not
have a consistently high vegetable intake diet while on Warfarin therapy
for optimal anti-coagulation and cardiovascular/bone health?
FK: It is prudent to advocate a consistent phylloquinone intake that
at least meets the current dietary reference value of 65-80 μg/day. With
food composition data for vitamin K now available, it would be possible
to identify those foods that have the potential for interfering with the
efficacy of warfarin as an anticoagulant. This information could also be
used to design menus that will provide a constant dietary intake of
vitamin K while on warfarin therapy. This approach has the potential,
however, to be inconvenient for anticoagulated patients and the people
with whom they eat. Dietary intake changes not only with the desire for
variety, but with the seasons and with eating out or being away from
home. Recommendations to consume a constant dietary intake of vitamin K
while taking warfarin are difficult for patients and those who care for
them to follow. Advising patients to restrict their intake of vitamin K
is neither practical (in terms of patient adhering to a strict regimen)
nor realistic (in terms of its long term consequences on patient
health). I do not share the view of advising patients to restrict
vitamin K intake (because of the aforementioned reasons) and instead
giving them a vitamin K supplement. What is important is to have an
approach that is both safe and practical for the patient. Daily
supplementation of vitamin K without the need for a dietary restriction
will aim to provide a stable source of the vitamin which in turn will
translate into stable control of anticoagulation.
KH: What type of coagulation patients are candidates for vitamin K
therapy? Or, should all warfarin patients receive modest amounts of
FK: In our study, we chose patients with unstable control of
anticoagulation in order to test the hypothesis that daily vitamin K
supplementation leads to a more stable control. However, it would be
justifiable to routinely give vitamin K to all patients on warfarin as
very few patients achieve absolute stability of control over an extended
period of time. Supplementation with vitamin K will also have the added
benefit of maintaining bone density and vascular integrity.
KH: Do you have any further comments you would like to make on this
FK: In this study we have established the potential benefit of
vitamin K supplementation for patients with unstable anticoagulant
response. Investigation of the effect of vitamin K supplementation upon
anticoagulation control in a larger unselected warfarin treated patient
population is therefore warranted to demonstrate whether vitamin K
supplementation leads to improved stability of anticoagulation control
and subsequent reduction in the frequency of adverse events associated
with warfarin therapy.
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
"Ask the Parkinson Dietitian" http://www.parkinson.org/
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