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Haematologica. 2011 Apr;96(4):583-9. doi: 10.3324/haematol.2010.035162. Epub 2010 Dec 29.

Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study.

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Department of Thrombosis and Haemostasis, Leiden University Medical Center, 2300 RC Leiden. The Netherlands.



Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K(1) was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K(1) in preparation of a large study with clinical endpoints.


Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 μg of vitamin K(1) together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups.


After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K(1) groups was 2.1% (95% CI: -3.2% - 7.4%) for the group taking 100 μg, 2.7% (95% CI: -2.3% -7.6%) for the group taking 150 μg and 0.9% (95% CI: -4.5% - 6.3%) for the group taking 200 μg vitamin K(1) group, in favor of the vitamin K(1) groups. The patients from both the 100 μg group and the 150 μg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups.


In patients starting vitamin K antagonists, supplementation with low dose vitamin K(1) resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at as ISRCTN37109430).

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