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

Abstract

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

Evidence-Based Management of Anticoagulant Therapy

“…41 Three randomized, placebo-controlled trials using pharmaceutically prepared vitamin K have addressed this issue. [42][43][44] There are important differences among these RCTs, including the daily dose of vitamin K studied (100 m g, 42,44 150 m g, 43,44 or 200 m g 44 ), the study participants (general anticoagulation clinic patients 42,44 or patients with unstable INR control 43 ), the width of targeted INR range (1.5 42,44 or 1.0), and type of VKA (phenprocoumon or warfarin). Table 5 (and Table S5) shows the quality of evidence and main fi ndings of our meta-analysis of the three RCTs.…”

The use of vitamin K supplementation to achieve INR stability: A systematic review and meta-analysis

“…Table summarizes the findings of the individual studies. Of the three RCTs, only the Sconce et al () study demonstrated a significant clinical benefit with TTR increasing, on average, by 28% for those receiving vitamin K. Both Rombouts et al () and Gebuis et al () saw an increase in TTR for subjects receiving vitamin K compared to placebo in all dosing groups, but these findings did not achieve statistical significance. Differences between groups regarding other outcome measures were identified.…”

“…The majority of included studies used a randomized controlled design (Gebuis et al, ; Rombouts et al, ; Sconce et al, ). Sconce et al () randomized 70 patients with unstable INRs unrelated to poor adherence on warfarin treatment for atrial fibrillation to either 150 μg of vitamin K or placebo.…”

“…Gebuis et al () conducted the largest RCT with 400 patients initiating phenprocoumon or acenocoumarol. Unstable INR was not an inclusion criterion.…”

Approaches to Optimal Dosing of Vitamin K Antagonists

“…30 Ingesting a consistently high amount of vitamin K-containing food is challenging for many patients, thus supplementing the diet with pharmaceutically prepared vitamin K has been explored as a means to improve INR control in three RCTs. [31][32][33] When results of these trials were pooled, the absolute improvement in TTR was 3.54% (95% CI, 1.13-5.96%). Unfortunately, these trials mostly enrolled patients with already stable INR control and therefore failed to address the more relevant issue of whether daily vitamin K supplementation would improve INR control in patients with unstable INRs not due to other correctable factors.…”