Special Feature
Reversal of Anticoagulant Effects of Warfarin by Vitamin K1
By Richard J. Hamilton, MD, FAAEM, ABMT
Consider the following scenario: an elevated internationalized normalized ratio (INR) is called to a physician’s office as a panic value from the laboratory. The patient is at home, usually asymptomatic. The INR is 9.0 and the private physician instructs the patient to go to the emergency department (ED) for a repeat INR and evaluation for bleeding complications. At the hospital, the patient encounter is preceded by a phone call to the ED physician by the referring physician explaining the referral.
It is surprising how few physicians understand the role a simple oral dose of vitamin K can play in this situation. Emergency physicians can educate each other and their referring primary care physicians about this antidote.
Background
Indeed, vitamin K is an antidote. It is used to reverse the coagulopathy of warfarin and superwarfarin rodenticides. Vitamin K is a cofactor for the activation of vitamin K-dependent coagulant proteins (prothrombin, factor VII, factor IX, and factor X) and the regulatory anticoagulant proteins (protein C and protein S). Vitamin K is recycled to its active form (vitamin K1 or phytonadione) by a series of enzymes—vitamin K epoxide reductase and vitamin K reductase. Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase and, to a lesser extent, vitamin K reductase.
Warfarin is used to induce a therapeutic coagulopathy for a variety of conditions. However, precise control of the coagulopathy is frustrated by alterations in metabolism, drug-drug interactions, and dietary sources of vitamin K1. Management is difficult, and appropriate warfarin doses frequently are achieved after a period of trial and error. Frequent monitoring of the INR allows adjustments of the dose of warfarin to maintain therapeutic values and prevent bleeding complications. When the patient is excessively anticoagulated, the traditional approach is to eliminate or reduce doses of warfarin until re-testing demonstrates a therapeutic INR. This method is unsatisfactory, as it takes as long as four days to normalize the INR from a ratio as low as the 2.0-3.0 range.1 In addition, the goal of correction is to reverse the coagulopathy into the therapeutic range for the patient—not to normalize it to 1.0. This protects the patient from an exacerbation of whatever medical problem led them to warfarin therapy (e.g., atrial fibrillation, pulmonary embolus, deep venous thromboembolism, etc.).
As an antidote, vitamin K1 is prescribed in large doses to confidently reverse the coagulopathy completely. When warfarin is used therapeutically, the correct dose of vitamin K1 would be the one that restores the patient to a safe INR. Since the risk of bleeding rises sharply when the INR exceeds 5.0, vitamin K1 should be dosed to lower the INR to at least below 5.0. If the patient has non-life threatening bleeding or requires elective or urgent surgery, then the INR should be reduced to 1.0 to 1.5. An INR of 1.0 is the goal when bleeding is serious or surgery is emergent.
A number of studies have endeavored to determine the correct dose and route of vitamin K1. The goal is to reverse the coagulopathy without unnecessary risk of thrombosis, avoid warfarin resistance, and avoid anaphylactoid reactions (a common side effect of rapid infusion of intravenous vitamin K1).
Evidenced-based Dosing of Oral Vitamin K1
The effectiveness of low-dose oral vitamin K1 was demonstrated in a randomized trial comparing 2.5 mg oral vitamin K1 to withholding warfarin for correction of the INR to 5.0 at 24 hours. In this study, simply withholding the warfarin was inadequate, whereas oral vitamin K1 was effective.2 In a prospective cohort study of 62 patients on warfarin, without bleeding but with INR values between 4.5 and 10.0, a combined strategy of low-dose vitamin K1 (1.0 mg) and omitting the next dose of warfarin was examined. Sixteen hours later, the mean INR was 2.86. None of the patients showed resistance to warfarin when it was restarted. However, three patients had an increase in INR on day two despite the vitamin K1 therapy.3
In a retrospective case series study, investigators examined the efficacy of 2.5 mg of oral vitamin K1 to reverse an INR from the 5.0-16.0 range in patients without major bleeding. Warfarin was withheld for either one or two doses, depending upon patient availability for repeat testing in 24 or 48 hours, respectively. This dose successfully reduced the INR to below 5.0 in 90% of the patients within 24-48 hours, and overcorrected the INR (i.e., < 2.0) in 14 patients (17%); yet none of these values was lower than 1.5 (only one-third of the overcorrected values were < 1.8), and no patient had thromboembolic complications. However, when the initial INR was 10.0 or more, a dose of 2.5 mg of oral vitamin K1 was effective in only five of 10 patients.4
A more precise method to calculate the oral dose of vitamin K1 is to use a regression formula based on the initial and desired INR. This formula is: Vitamin K1 dose in mg = 16 - (17 x [INR desired/INR initial]).
For example, a patient with an INR of 10.0 whose therapeutic INR is 2.5 would get 11.75 mg of vitamin K1 by mouth. This approach also has the advantage of permitting continued use of warfarin. It was studied in 65 patients who were either excessively anticoagulated or required reversal of coagulopathy for elective or urgent surgery. The formula was successful in reducing the INR to therapeutic levels for all patients but one within 48 hours. There was one bleeding complication and no thrombotic complications.5
Management of Supratherapeutic INR
Based on the above data and using a combined approach that withholds warfarin doses, the American College of Chest Physicians (ACCP) developed a consensus guideline. These guidelines were published in 1998 and have been reviewed and reinforced as an appropriate standard of care.6 (See Table.) All therapy should be monitored with daily INR levels until therapeutic levels are achieved.
| Table: Management of Supratherapeutic INR6 | ||||
| INR | Serious Bleeding |
Warfarin | Vitamin K1 Dose |
Other |
| < 5 but above therapeutic | No | Lower next dose or omit one dose | None | |
| > 5.0 but < 9.0 | No | Omit one or two doses | 1-2.5 mg PO once |
Use 2-4 mg if surgical procedure and INR must be reduced in 24 hrs. |
| > 9.0 | No | Omit until
INR corrected |
3-5 mg PO | Expect INR to reduce to therapeutic within 24-48 hrs. |
| > 20 | Yes | Omit | 10 mg slow IV | Use fresh frozen plasma or prothrombin complex concentrate. |
| Any INR | Life-threatening | Omit | 10 mg slow IV | Use prothrombin complex concentrate. |
The route of administration is important in vitamin K1 therapy. The efficacy of oral vitamin K1 is equivalent to that of intravenous vitamin K1, and dosages are the same. Intravenous vitamin K1 has the disadvantage of producing anaphylactoid reactions that generally are related to the rate of administration. Subcutaneous administration is both common and less effective. Physicians unfortunately choose this route under the mistaken assumption that it is faster or more effective. Intramuscular administration is obviously contraindicated in coagulopathy.
Despite the fact that these guidelines have been in place since 1998, compliance is low and practice patterns still are highly variable. A recent survey of internists in Ontario, Canada, showed that compliance with dose and route of vitamin K1 recommended by ACCP varied from 1% to 10%.7 One particularly disturbing trend was the tendency to use a subcutaneous injection when an oral dose was a more effective and reliable route. Obviously, there still is much work to be done on informing practitioners. Therefore, when a referring physician calls you about a patient with an INR that is above therapeutic, let him or her know that you are going to use the ACCP guidelines to reverse the patient’s anticoagulation into the therapeutic range; use the opportunity to employ a well-conceived approach for the patient while you educate other providers.
References
1. White RH, et al. Home prothrombin time monitoring after initiation of warfarin therapy. A randomized, prospective study. Ann Intern Med 1989;111:730-737.
2. Pengo V, et al. Reversal of excessive effect of regular anticoagulation: Low oral dose of phytonadion (vitamin K1) compared with warfarin discontinuation. Blood Coagul Fibrinolysis 1993;4:739-741.
3. Crowther MA, et al. Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 1998;79:1116-1118.
4. Weibert RT, et al. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997;126:959-962.
5. Wentzien TH, et al. Prospective evaluation of anticoagulant reversal with oral vitamin K1 while continuing warfarin therapy unchanged. Chest 1998;114: 1546-1550.
6. Ansell J, et al. Managing oral anticoagulant therapy. Chest 2001;119:22S-38S.
7. Wilson SE, et al. Treatment of warfarin-associated coagulopathy: A physician survey. Chest 2001;120: 1972-1976.
Dr. Hamilton, Associate Professor of Emergency Medicine, Program Director, Emergency Medicine, MCP Hahnemann University Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.
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