BackgroundPoor 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 K1 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 K1 in preparation of a large study with clinical endpoints. Design and MethodsFour 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 K1 together with their treatment with vitamin K antagonists. The treatment was administered for 6 to12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups. ResultsAfter 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 K1 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 K1 group, in favor of the vitamin K1 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. ConclusionsIn patients starting vitamin K antagonists, supplementation with low dose vitamin K1 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 . Haematologica 2011;96(4):583-589. doi:10.3324/haematol.2010 Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study
To cite this article: van Rein N , Gebuis EPA, Lijfering WM, Groeneveld JJE, van der Horst FAL, le Cessie S, Rosendaal FR, van der Meer FJM.Vitamin K1 in oral solution or tablets: a crossover trial and two randomized controlled trials to compare effects. J Thromb Haemost 2014; 12: 2017-23.Summary. Background: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects. Objectives: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials. Methods and results: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 lg L À1 h, 95% confidence interval [CI] 230-501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0-11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3-5.1) than in the tablet group (4.2, 95% CI 3.8-4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7-15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 lg L À1 ; solution, 3.4 lg L À1; P = 0.99) after 24 h. Conclusions:VK1 tablets are at least as clinically effective as the solution in countering VKAs.
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