Clinical PictureTreatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial
Introduction
Large increases of the international normalised ratio (INR), without symptoms, are frequently encountered in patients receiving warfarin. Although patients with raised INR values have an increased risk of haemorrhage,1, 2, 3, 4 the approach to management of these patients varies. Some doctors favour a passive approach, simply withholding warfarin and allowing the INR to return to the therapeutic range over several days. Others use an active approach to hasten the fall in INR values by giving vitamin K. Although there is evidence that vitamin K produces a more rapid decrease in excessively raised INR values, vitamin K is not the treatment of choice for symptomless patients with moderate increases in the INR.5 Most clinicians favour a passive approach based on the following perceptions: in patients without symptoms, moderate increases in the INR are rarely associated with serious bleeding; the risks and inconvenience of vitamin K treatment outweigh any benefits; and the data supporting the benefits of vitamin K are not convincing. When patients with INR values of 6·0 or more were managed by stopping warfarin treatment and restarting it when the INR declined into the therapeutic range; over a 2 week period, five of 114 patients had major bleeding, including two fatal bleeds.1 Several studies have shown that low dose vitamin K is safe and does not seem to cause warfarin resistance.6, 7, 8 Most of the clinical studies assessing low dose vitamin K have been non-randomised,6, 7, 8 and the only randomised trial was small and did not use a clinically applicable protocol.7 Since symptomless moderate increases of the INR are frequently associated with serious bleeding,1 a compelling case can be made for the use of low dose oral vitamin K in such patients, provided that this treatment will lower the INR rapidly, without increasing the risk of thrombosis or producing warfarin resistance.
We did a double-blind randomised controlled trial in symptomless patients receiving warfarin who presented with an INR of 4·5–10·0. The experimental intervention, temporary discontinuation of warfarin and administration of 1 mg of oral vitamin K, is one that could be easily applied in everyday clinical practice.
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Methods
The INR range for inclusion (4·5–10·0) was chosen by surveying physicians and nurses who regularly prescribe warfarin. The risk of haemorrhage in patients with an INR of less than 4·5 is sufficiently low that such patients can likely be safely managed by withholding warfarin alone, whereas placebo likely should not be given to a patient with an INR greater than 10·0. Patients were identified by five thromboembolism services at teaching hospitals in Hamilton and London, Canada. The study was
Results
Patient enrolment began in September, 1997, and finished in September, 1999. 184 patients were screened for the study, of whom 119 were eligible and 92 consented to participate (figure). Table 1 shows the clinical characteristics of the study participants. Three patients (two allocated to placebo) did not return for INR testing on the day after the study drug was given, and were excluded from the primary analysis. 25 of 45 patients (56%) who received vitamin K, and 9 of 44 (20%) patients who
Discussion
We have shown that the administration of 1 mg of oral vitamin K to patients without symptoms, who are taking warfarin and have INR values of 4·5–10·0, not only brings the INR into the treatment range more quickly than simply withholding warfarin, but does so without causing warfarin resistance. Thus patients who received vitamin K did not have persistently lower INR values than those who received placebo.
We chose inclusion criteria that would capture a representative population of patients with
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