Oral Vitamin K for Excessive Anticoagulation
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study. This article originally appeared in the April 2009 issue of Clinical Oncology Alert. It was edited by William B. Ershler, MD, and peer reviewed by V.R. Veerapalli, MD. Dr. Ershler is works for INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, and Dr. Veerapalli is Staff Clinician, INOVA Fairfax Cancer Center, Falls Church, VA. Dr. Ershler is on the speaker's bureau for Wyeth, and does research for Ortho Biotech, and Dr. Veerapalli reports no financial relationships relevant to this field of study.
Synopsis: Whether oral vitamin K reduces the risk of bleeding related to excessive anticoagulation from warfarin remains unclear. Across 14 anticoagulation clinics, 724 patients with an asymptomatic elevated INR between 4.5 and 10.0 were randomized to 1.25 mg of oral vitamin K or placebo. Within the first 90 days, 15.8% in the vitamin K group and 16.3% in the placebo group had at least one bleeding episode (p = 0.86). There were no differences in major bleeding, thromboembolism, or death. The INR fell more quickly in the vitamin K group. Oral vitamin K does not substantially reduce the bleeding in warfarin-treated patients with an INR from 4.5 to 10.0.
Source: Crowther M, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin. Ann Intern Med. 2009;150:293-300.
Warfarin is a frequently prescribed oral anticoagulant. The highly variable, dose-response characteristics mandate monitoring, and this is usually accomplished by targeting an international normalized ratio (INR) value between 2.0 to 3.0. Non-therapeutic values are common, and values above 4.5 predispose to serious bleeding.1 Low-dose oral vitamin K can effectively reduce the INR within 24 hours in patients excessively anticoagulated from warfarin.2 In this study, Crowther et al evaluated whether low-dose vitamin K would reduce bleeding relative to withholding warfarin alone in non-bleeding patients with a high INR from warfarin.
Adult patients from anticoagulation clinics were eligible if an outpatient INR was found to be 4.5-10.0 within the past 24 hours; the target INR was 2.0-3.5, with no bleeding. Patients with other risk factors for bleeding, or a need for acute normalization of the INR, were excluded. Patients were randomized to receive a formulated capsule of 1.25 mg of oral vitamin K or placebo. Patients were followed in person or over the telephone for 90 days to assess the primary endpoint of bleeding within 90 days of randomization. The INR was managed as per local practice. The mean age of enrolled patients was 69 years, and the mean INR at enrollment was 5.8 to 6.0 among the 724 enrolled patients. In the vitamin K group, 56 of 355 (15.8%) experienced a bleeding event compared to 60 of 369 (16.3%) in the placebo group. Major bleeding occurred in 2.5% and 1.1% in the vitamin K and placebo groups, respectively. There were no significant differences for the bleeding event (p = 0.86), major bleeding events (p = 0.22), thromboembolism (p = 0.72), or death (p = 0.94) by day 90. The average decrease in the INR the following day was 2.8 units for the vitamin K-treated patients but only 1.4 units for the placebo patients (p < 0.001).
Commentary
Warfarin has found widespread use as an anticoagulant to prevent venous and arterial thrombosis. Despite a host of new anticoagulants, the low cost and familiarity with warfarin promote its continued use, as well as alternative management models such as telephone monitoring.3 Supratherapeutic INR values are not uncommon, predispose to bleeding, and represent a management challenge. Multiple studies have shown that for high INR values, low doses of oral vitamin K can hasten correction, compared to holding warfarin alone.2 It is unknown whether an asymptomatic patient with an incidentally elevated INR benefits from low-dose vitamin K.
In this study, Crowther et al randomized patients with an asymptomatic, newly elevated INR from 4.5 to 10.0 to receive 1.25 mg of oral vitamin K or placebo. They found no difference in any of the study endpoints of bleeding at 30, 60 or 90 days. The primary outcome of bleeding at 90 days was around 16% in both groups. No differences were found in major bleeding, new thromboembolism, or death. The data support a strategy of withholding warfarin without giving oral vitamin K for asymptomatic elevations of the INR.
Interestingly, only three serious bleeding events occurred among all subjects in the first seven days, two from placebo-treated patients and one case in a vitamin K-treated patient. Thus, these data suggest outpatient management appears safe, at least for those meeting the protocol criteria.
As noted by Crowther et al, the study was not powered to detect small differences in bleeding between each arm. The largest limitation rests with the restrictive criteria of a randomized study that limits generalizability. These patients were being followed closely at an anticoagulation clinic. In addition, patients at higher risk of bleeding were not included, such as those who already had bleeding, INR levels above 10.0, low platelets, or liver disease. Although data are lacking, it may be reasonable for such higher-risk patients to receive oral vitamin K. The data in this study were at least reassuring that thromboembolism was no more frequent in the vitamin K-treated patients. For patients having overt or serious bleeding, more immediate corrective actions will be needed. A practical problem related to the 1.25 mg dose of vitamin K is not readily available. However, the 2.5 mg dose could be broken in half, or an alternative is to use a 1 mg tablet.
In conclusion, low-dose oral vitamin K correction does not reduce bleeding risk for asymptomatic supratherapeutic elevations of the INR from warfarin.
References
1. Palareti G, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996;348:423-428.
2. Dezee KJ, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. 2006;166:391-397.
3. Wittkowsky AK, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest. 2006;130: 1385-1389.
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