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Reversing the Effects of Warfarin with Phytonadione



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Am Fam Physician. 2000 Jun 1;61(11):3450-3452.

Excessive anticoagulation with marked prolongation of the prothrombin time (PT) and an International Normalized Ratio (INR) above the target range increases the risk of hemorrhagic complications. Although infusion of fresh frozen plasma rapidly corrects the coagulopathy associated with excessive anticoagulation, this therapy is reserved for use in patients who actually exhibit bleeding because of the cost and the risk of infectious complications. In asymptomatic patients with a high INR, correction can be accomplished by omitting a few dosages of warfarin, decreasing the maintenance dosage or administering oral or parenteral phytonadione. Intravenous phytonadione has been associated with anaphylaxis and death. Raj and colleagues studied the effect of subcutaneous and intravenous phytonadione on asymptomatic patients with a prolonged PT while taking warfarin.

Twenty-two patients receiving stable dosages of warfarin for at least six weeks were randomized to receive 1 mg of phytonadione intravenously or subcutaneously. Patients were enrolled if they had a supratherapeutic PT—specifically, an INR greater than 6.0. Following intravenous or subcutaneous administration of phytonadione, patients were observed for 30 minutes for any drug reaction. The PT was measured at eight hours and again at 24 hours. Warfarin was withheld for at least 24 hours after administration of phytonadione and longer if the INR at 24 hours was still greater than 6.0.

At eight and 24 hours, the two routes of administration of phytonadione had yielded significantly different INR levels. In the intravenous group, the mean decrease in INR was 3.4 and 4.9 at eight and 24 hours from baseline, respectively. In the subcutaneous group, the mean INR values at baseline and eight hours were not significantly different, but the mean INR at 24 hours was significantly lower than at the other two times. Between baseline and eight hours, the mean change in INR was 0.4. Between baseline and 24 hours, the reduction in INR was 3.4. There was a more rapid decrease in the INR by the intravenous route than by the subcutaneous route, although it was not statistically significant.

No adverse drug effects were observed after administration of phytonadione by either route. No patient experienced bleeding during the study period.

Results of this study revealed no difference in the mean decrease in INR from baseline at 24 hours between the two groups but did show a significant difference between the groups at eight hours, with the intravenous group achieving a greater correction of INR. In addition, there was a significant difference in the mean INR between the two groups at eight hours and at 24 hours. Intravenous administration of phytonadione resulted in a lower INR. Although subcutaneous administration of 1 mg of phytonadione is effective in correcting excessive anticoagulation from warfarin therapy, the effect is not as quick or as complete as that of intravenous administration. If the goal of therapy is to rapidly reduce the INR, then subcutaneous administration may not be effective. Even at 24 hours, four of 11 patients in the subcutaneous group had an INR greater than 5.0.

The authors conclude that subcutaneous administration of very small dosages of phytonadione may not correct the INR as rapidly and effectively as intravenous administration in patients with excessive anticoagulation with warfarin. Since this study's completion, the Consensus Conference on Anti-thrombotic Therapy has revised its guidelines and recommends treating patients with a high INR without bleeding with oral phytonadione (1 to 2.5 mg if the INR is above 5.0 but below 9.0 and a higher dosage, of 3 to 5 mg, if the INR is above 9.0).

Raj G, et al. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. December 13/27, 1999;159:2721–4.


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