Current guidelines and routine practice often involves the administration of vitamin K to reverse supra-therapeutic International Normalized Ratio (INR) values in warfarin-treated patients. The effect of this practice to reduce bleeding events and/or thrombosis was assessed in a recent study by Crowther and colleagues.1 Their data indicated that vitamin K administration was not warranted. Details of the study, however, raise questions about the applicability of this conclusion.
Low dose vitamin K or matching placebo was administered to warfarin-treated patients with an INR between 4.5 and 10.0. Any bleeding (major, minor, and trivial), major bleeding, and thromboembolic events were not different at 90 days or at 7 days (see Table 1).
So, should clinicians do as the authors suggest and not feel compelled to administer vitamin K to patients with an INR between 4.5 and 10? There are a few factors that make us reluctant to adopt this conclusion:
- Size of the study: Although this multi-center trial was relatively large, it was under-powered to identify a difference in the risk of major bleeding and, in fact, apparently no major bleeds occurred during the first 7 days.
- Extent of INR elevation: The majority of patients included in the 7 day analysis had only modest elevations in their INRs. Specifically, 226 of 355 or 63.7% of the vitamin K group and 261 of 369 or 71% of the placebo group had INRs between 4.5 and 6.0, a level at which many clinicians might not ordinarily administer vitamin K. INRs were above 8 in only 26 patients (7%) in each group and apparently patients with an INR greater than 10 were excluded from the study. This may be a critically important point since evidence indicates that the risk of major bleeding—and especially intracranial bleeding—increases exponentially as the INR rises above a value of 6.
- Reliability of the INR: As far as could be determined, there was no evidence that the high INR readings were confirmed. Therefore, one must question the degree to which lab error may have contributed to the enrollment of these patients.
- Dosage formulation: The vitamin K was administered as a capsule reformulation compounded from the traditional 5 mg vitamin K tablet, but the dose was only 1.25 mg. Several previous studies have reported effective lowering of moderately elevated INRs with 1 mg to 2 mg of vitamin K but each of those studies used the injectable liquid formulation given orally. The effectiveness of a low dose formulation as used in this study has not been established. The authors chose not to use one-half of the tablet formulation based on their anecdotal experience that such a dose would over-correct the INR in too many patients. Such over-correction was not a problem in the reports by Whitling, et al. and Weibert, et al. in two earlier studies.2,3 In those trials, however, the extent of INR elevation was considerably higher than the mean INRs of 6.0 and 5.8 in this study. For example, in the paper by ...