Elsevier

The Lancet

Volume 356, Issue 9241, 4 November 2000, Pages 1551-1553
The Lancet

Clinical Picture
Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(00)03125-1Get rights and content

Summary

Background

Warfarin-associated coagulopathy is a frequent clinical complication. We aimed to assess whether treatment with vitamin K is safe and more effective than placebo in rapidly lowering the international normalised ratio (INR) into the therapeutic range in over anticoagulated patients receiving warfarin.

Methods

We did a multicentre, double-blind, placebo-controlled, randomised trial in five tertiary care hospitals. In this study, patients receiving warfarin who had an INR value between 4·5 and 10·0, and who did not have an indication for the immediate normalisation of their INR, had their warfarin withheld, and were randomly allocated to receive either 1 mg of vitamin K or placebo orally. The primary outcome measure was the INR value on the day after treatment. Secondary outcome measures included INR values on subsequent days, and the risk of haemorrhage and recurrent thrombosis over a 3 month follow-up period.

Findings

Patients given vitamin K had a more rapid decrease in the INR than those given placebo (25 of 45 [56%] vs nine of 44 [20%] patients with INR values of 1·8–3·2 on the day after treatment, respectively, p=0·001; odds ratio [OR] 0·21, 95% CI 0·07–0·57). Fewer patients given vitamin K had bleeding episodes during the follow-up period than those given placebo (two [4%] vs eight [17%] patients, respectively, p=0·050; OR 0·87, 95% CI 0·019–0·999).

Interpretation

Low dose oral vitamin K is more effective than placebo for the rapid lowering of raised INR values in patients taking warfarin.

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.

Section snippets

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

References (8)

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