Comparing Different Routes and Doses of Phytonadione for Reversing Excessive Anticoagulation

Background  Significant controversy exists concerning how best to reverse excessive anticoagulation (due to warfarin sodium therapy) with phytonadione (vitamin K₁) while avoiding overcorrection in patients who need to have anticoagulation therapy maintained.

Methods  A retrospective review of phytonadione use in reversing excessive anticoagulation was performed in 3 institutions. The effectiveness of low-dose (≤0.5 mg) intravenous (LDIV), high-dose (1-10 mg) intravenous (HDIV), subcutaneous (1-10 mg) (SC), and oral (2.5 or 5 mg) (PO) phytonadione was evaluated within 48 hours of administration. Anticoagulation correction (international normalized ratio [INR], ≥2.0 and ≤5.0) occurred in 5 of 8 patients in the LDIV, 5 of 9 in the HDIV, 7 of 10 in the SC, and 5 of 6 in the PO groups. Correction was inadequate (INR >5.0) in 2 of 8 patients in the LDIV, 0 of 9 in the HDIV, 3 of 10 in the SC, and 1 of 6 in the PO groups. Overcorrection (INR <2.0) occurred in 1 patient in the LDIV, 4 patients in the HDIV, 0 in the SC, and 0 in the PO groups.

Conclusions  Anticoagulation correction was achieved in most patients in all 4 groups. The HDIV method was most effective in lowering the INR to less than 5.0, but overcorrection occurred more frequently (4 patients in the HDIV vs 1 patient in the LDIV and 0 patients in the SC and PO groups). Failure to achieve an INR of less than 5.0 was a greater problem in the SC group (3 patients in the SC vs 2 patients in the LDIV and 1 patient in the PO groups). The LDIV and PO methods appear to be acceptable alternatives to the HDIV and SC methods currently recommended.

ORAL ANTICOAGULATION is used widely for treatment and prevention of thromboembolic events, and bleeding is its most significant adverse effect. Several recent studies have shown that the risk for major hemorrhage can be reduced dramatically if the prothrombin time (expressed as the international normalized ratio [INR]) is kept below 5.0.^1-3 If the patient's INR exceeds 6.0, the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy recommends that reversal using phytonadione (vitamin K₁) be considered (Table 1).⁴ The ACCP recommendations appear to favor subcutaneous (SC) administration of phytonadione, with the intravenous (IV) route being reserved for more severe cases or when poor absorption may be anticipated in patients with "peripheral circulatory failure." The recommendations further indicate that a significant reduction in the INR can be anticipated within 6 to 8 hours. Intravenous phytonadione administration is probably not encouraged because, in rare instances, it causes a severe allergic reaction. A careful literature search, however, failed to identify data on the use of SC administration of phytonadione for reversing the effects of warfarin sodium. Although the ACCP recommendations do not endorse the oral (PO) administration of phytonadione, a few reports have found this route to be effective. Pederson et al⁵ evaluated the effect of different amounts of vitamin K₁ ingested in the diet, while Pengo et al⁶ and Weibert et al⁷ examined the effectiveness of 2.5 mg of PO phytonadione. Pengo et al found that the administration of phytonadione corrected the INR to less than 5.0 at 24 hours more effectively than did simply withholding the warfarin dose.⁶ More recently, Weibert et al reported that 2.5 mg of PO phytonadione reversed excessive anticoagulation in almost all patients within 24 or 48 hours and induced only limited overcorrection in a few patients.

The IV administration of phytonadione (in doses of 0.1-2.5 mg) has been shown to be effective in reversing the effects of warfarin in 5 studies.^8-12 Shetty et al¹¹ suggested that low doses of IV phytonadione can reverse the effects of excessive anticoagulation and possibly lead to less overcorrection in the INR than that seen with larger doses. This would be beneficial in treating patients with high INRs in whom the goal is to reverse anticoagulation to a safe level and maintain it adequately. A more recent study by Brophy et al,¹² however, found that low doses of IV phytonadione (<1 mg) showed limited efficacy.

The available data, therefore, may cause some confusion for the clinician who is faced with reversing warfarin-induced excessive anticoagulation but wishes to avoid overcorrecting the INR. Oral phytonadione was not included in the most recent ACCP recommendations, SC use of phytonadione has not been well-studied, and data on the dose-response effect of IV phytonadione are unclear. The purpose of our study, therefore, was to evaluate retrospectively the effect of different doses and routes of phytonadione administration on the reversal of excessive anticoagulation. Other end points of the study included determining if any route was less likely to overcorrect the INR and whether the SC or IV doses were consistent with the 1995 ACCP recommendations.

Medical records of patients who received phytonadione at 1 of 3 institutions (Methodists' Southwest Texas Hospital, University Hospital, and South Texas Veterans Health Care System, all in San Antonio, Tex) were identified by reviews of charts and pharmacy records and personal communication with the clinical pharmacists staffing the affiliated anticoagulation clinics. Patients were included if they had received IV, SC, or PO phytonadione to reverse excessive anticoagulation. Patients were excluded from the analysis if they did not have baseline and follow-up INRs, had received blood products containing clotting factors (fresh frozen plasma or prothrombin concentrate), had significant liver disease, or had received phytonadione for reversal of warfarin therapy before surgery or other intervention. For patients included in the analysis, the recorded data included the initial and subsequent INR values, the times at which the INRs were measured, and the timing, dose, and route of phytonadione administration. Patient data were grouped according to the route and dose of phytonadione administered. Those who received an IV dose of 0.5 mg or less were designated the low-dose IV (LDIV) group, whereas those receiving an IV dose of 1 to 10 mg were designated the high-dose IV (HDIV) group. The remaining 2 groups were designated the SC and PO groups according to method of phytonadione administration. The patient's response to phytonadione administration was considered to be the difference between the initial and subsequent INRs as measured at no later than 12 hours, 13 to 24 hours, 25 to 36 hours, or 37 to 48 hours after administration. When the timing of phytonadione administration was unavailable, it was presumed to have been given at the time of the first INR measurement. For patients who received multiple doses of phytonadione during a single episode, only INRs obtained between the first and second dose were included. If a single patient had more than 1 episode of phytonadione administration, the second episode was included only if it occurred at least 1 week later.

Other information collected for each patient included age and sex, indication for warfarin therapy, and whether low- (INR, 2.0-3.0) or high-intensity anticoagulation (INR, 3.0-4.5) was indicated. The dose of warfarin taken 1 week before phytonadione administration, the reason for an increase in the INR (if documented), and the presence and severity of bleeding complications also were recorded. Bleeding events were classified according to a modified version of the Warfarin Optimized Outpatient Follow-up study.¹³Minor bleeding was defined as bleeding that had little or no clinical significance and that did not require referral; significant bleeding, that required referral or was associated with a drop in hematocrit level of greater than 0.03 (3%) or in hemoglobin level of greater than 12 g/L (1.2 g/dL). Major bleeding was defined as bleeding that required hospitalization and transfusion of at least 2 units packed red blood cells. Life-threatening bleeding was defined as bleeding that resulted in irreversible sequelae or led to cardiopulmonary arrest, surgery, angiography, or other intervention. Fatal bleeding was defined as death related to a bleeding event.

Baseline data for the patients in each group were compared using the χ² test for categorical data and analysis of variance for numerical data. The groups' responses to phytonadione administration were assessed on the basis of how many patients in each group experienced correction to an INR of less than 5.0 within 48 hours and by the absolute reduction in the INR. Secondary end points were whether any dose or route of phytonadione was less likely to lead to overcorrection in the INR (defined as the number of patients with INRs ≤2.0) and whether the doses administered were similar to those recommended by the ACCP.⁴

Ninety-seven individuals were identified who received a total of 131 doses of phytonadione. Forty-six medical charts were excluded from analysis because data were incomplete or unavailable. Of the remaining 85 episodes, 52 were excluded because multiple doses of phytonadione were given (n=23), anticoagulation reversal was performed before a procedure (n=12), blood products were given (n=10), a subsequent INR was not measured within 48 hours (n=6), and the patient had significant liver disease (n=1). Among the remaining 33 episodes that occurred in 32 patients, 8 were classified as LDIV; 9, HDIV; 10, SC; and 6, PO. Only 1 patient received phytonadione twice, and the episodes were 6 weeks apart.

The baseline characteristics (excluding bleeding events) of the patients in each group are presented in Table 2. Overall, the groups were not statistically different. Sixteen patients (50%) were age 65 years or older. Sex was distributed evenly between groups. Twenty patients (62%) required anticoagulation at low intensity. Three patients in the LDIV, 2 in the HDIV, 3 in the SC, and 0 in the PO groups had their high INRs identified while they were hospitalized for unrelated reasons. Bleeding events are identified with individual patients in Table 3. The patient in the LDIV group who had the scleral hemorrhage presented to the emergency department; the patient in the HDIV group who had a gastrointestinal tract hemorrhage was admitted to the hospital; and the patient in the SC group who had gross hematuria also was admitted to the hospital. The other 5 patients with identified bleeding episodes did not require hospitalization or emergency department visits. There was 1 significant (gross hematuria in the SC group) and 1 major bleeding event (gastrointestinal tract hemorrhage in the HDIV group). Both events required hospitalization of the patient. There were no fatal bleeding episodes in any group.

The primary end points (changes in INRs following phytonadione administration) are listed in Table 3. With LDIV administration, INRs in 5 of 6 patients undergoing evaluation within 24 hours corrected to less than 5.0, whereas 1 patient had an INR of 5.1. Of the remaining 2 patients undergoing evaluation at 25 to 36 hours, correction did not occur in 1, and overcorrection occurred in the other. For the group, a mean dose of 0.4 mg of phytonadione reduced the mean INR from 11.9 to approximately 3.0 to 4.0 during 36 hours or less.

The INRs in all 9 patients in the HDIV group corrected to less than 5.0, but 4 of 9 experienced overcorrection. Of the 5 patients undergoing evaluation within 24 hours, all INRs corrected to less than 5.0, and 1 INR overcorrected. Of the 4 patients undergoing evaluation at 25 to 48 hours, 1 patient had an INR of 2.1, and the other 3 experienced overcorrection. For this group, a mean dose of 4.2 mg reduced the mean INR from 13.9 to approximately 2.0 to 3.0 within 24 to 36 hours.

Excessive anticoagulation was corrected in 7 of 10 patients in the SC group. Specifically, correction was evident in 5 of 7 patients undergoing evaluation within 24 hours and in 2 of 3 undergoing evaluation at 25 to 48 hours. The INRs failed to correct in 3 patients (2 patients undergoing evaluation within 24 hours and 1 patient undergoing evaluation at 25 to 36 hours), and overcorrection did not occur. The mean phytonadione dose of 2.5 mg reduced the mean INR from 14.9 to an approximate range of 4.5 to 5.0 within 24 to 48 hours.

The INRs in the PO group corrected in 5 of 6 patients (2 undergoing evaluation within 24 hours; 3, within 25-48 hours). Correction failed in 1 patient (undergoing evaluation at 25-36 hours), but no overcorrection occurred. For this group, a mean phytonadione dose of 3.8 mg reduced the mean INR of 9.4 to an approximate range of 2.5 to 4.0 within 24 to 48 hours.

Comparing the doses of phytonadione administered to patients in the HDIV and SC groups with the doses recommended by the ACCP revealed that most doses did not comply with the recommendations (Table 1 and Table 3). Only 1 (11%) of the 9 patients in the HDIV group received phytonadione in accordance with the guidelines. The SC group also did not follow the guidelines in that only 2 (20%) of 10 patients received recommended doses.

Present ACCP recommendations for use of phytonadione in reversing excessive anticoagulation include only SC or large-dose (≥1 mg) IV administration. Our results suggest that phytonadione can be administered effectively and safely by several routes and in a variety of doses to patients with high INRs. For IV administration of phytonadione, lower doses than those recommended by ACCP resulted in rapid reversal of the INR in most patients and caused less overcorrection than that seen with HDIV administration. Within the HDIV group, patients receiving 1 mg of phytonadione had at least as large a decline in the INR as those receiving larger doses (Table 3). In addition, the 4 patients in the HDIV group with overcorrection received a wide range of doses (1, 2, 8, and 10 mg). It was difficult, therefore, to identify any dose-response relationship for IV doses of phytonadione in the range of 1 to 10 mg.

The effectiveness of LDIV phytonadione in our trial was similar to that reported by Shetty et al,¹¹ but different from that reported by Brophy et al.¹² Brophy et al found that IV doses of less than 1 mg usually failed to reverse the INR within 24 hours, and that doses of 1 mg did not result in overcorrection of the INR. The difference between our data and those of Brophy et al may be due to how the low doses of phytonadione were prepared and administered. In our study, doses were prepared by using 1 mg/0.5 mL or 10 mg/mL and making only 1 dilution. The dose was then given using slow IV push. Brophy et al prepared low doses of phytonadione using serial dilutions of 10 mg/mL and then administering the dose for 5 to 10 minutes as an IV infusion. Because the product is a light-sensitive colloidal preparation, some of the drug may have been destroyed by exposure to light or lost through binding of the drug to the container or tubing during the serial dilution process and the slow infusion. Obviously, such conjecture can be confirmed or refuted only by objective testing.

Another concern regarding IV phytonadione administration that deserves discussion is the safety of this route. Several case reports have documented anaphylactic reactions and even death following IV administration of phytonadione.^14-19 Initially, this reaction was attributed to the polyoxyethylated castor oil vehicle found in certain phytonadione preparations. However, there have been case reports of anaphylaxis with phytonadione preparations formulated without this vehicle (Aquamephyton). Some authors have suggested that slow rates of infusion of IV phytonadione can avoid this adverse effect, but at least 1 published case report describes anaphylaxis with infusion rates of 1 mg/min.^16,18,19 In our study, there were no cases of anaphylaxis to IV phytonadione. There are at least 2 probable explanations for this. First, relatively low doses of IV phytonadione were administered. Second, anaphylaxis to IV phytonadione is rare, and, therefore, unlikely to be observed in the small number of patients in this trial.

Subcutaneous administration of phytonadione was reasonably effective in reversing excessive anticoagulation (INRs were corrected in 7 of 10 patients), and no overcorrection occurred. We believe that ours is the first study to demonstrate effectiveness with this route of administration. It is somewhat troubling, however, that this group contained 3 of the 4 patients in whom an INR of less than 6.0 was not achieved. Many would consider this to be an inadequate response and, therefore, may choose not to rely on this method when anticoagulation reversal is of critical importance.

Most SC and IV doses of phytonadione in our report were lower than those recommended by the ACCP. This suggests that physicians may not be aware of the recommendations, or, more likely, that they believe that smaller doses of phytonadione are effective, less likely to result in overcorrection, and/or less likely to lead to complications. Our results support the efficacy of lower doses with a low risk for overcorrection or other complications.

Finally, our results with PO phytonadione are consistent with those of a larger trial recently reported by Weibert et al.⁷ In their report, 81 patients were given 2.5 mg of PO phytonadione to lower elevated INRs to a range between 2.0 to 5.0 within 24 or 48 hours. Seventy-three patients (90%) achieved an INR of less than 5.0, and only 14 (17%) had an INR of less than 2.0. None of these low INRs, however, were below 1.5. Five of the 6 patients in our PO group achieved an INR of less than 5.0, and none had an INR of less than 2.0. Weibert et al also noted that 5 of their patients who failed to achieve an INR of less than 5.0 had an initial INR of greater than 10.0. They recommended, therefore, that a larger dose of PO phytonadione might be needed for those whose initial INR was above 10.0. In our PO group, only 1 patient had an INR above 10.0, and that was the same patient who did not achieve an INR of less than 5.0.

When the available data are viewed collectively, the following tentative conclusions appear reasonable. Intravenously administered phytonadione can reverse excessive anticoagulation within 24 to 48 hours in most patients, and low doses (0.1-0.5 mg) appear to be almost as effective as larger doses (1-10 mg), but with less risk for overcorrecting the INR. The risk for anaphylaxis with LDIV phytonadione appears to be small and may be related in part to the dose, rate of infusion, and a formerly used diluent. Subcutaneous administration of phytonadione has not been well-studied, but our data suggest that it is reasonably effective with little risk for overcorrection. There is some concern, however, that reversal of excessive anticoagulation may be inadequate in some patients. Finally, PO phytonadione, at a dose of 2.5 mg, effectively reverses INRs in the range of 6.0 to 10.0 with limited risk for slight overcorrection. Those INRs above 10.0, however, may require a larger dose. Obviously, PO phytonadione offers the advantage of easier administration at lower cost than parenteral routes.

Our study has several limitations in that it was retrospective and involved a relatively small number of patients who were not randomly assigned to different therapies. In addition, we could not determine whether resistence to warfarin was less likely to develop in patients receiving phytonadione by a particular route or dose. Because of these limitations and the scarcity of clinical trials, we agree with other authors that randomized controlled trials are needed to determine the best method of using phytonadione to reverse excessive warfarin-induced anticoagulation. Since this article was accepted for publication, the ACCP guidelines for phytonadione use have been revised and will likely be substantially different than the 1995 recommendations.²⁰

Accepted for publication February 16, 1998.

Presented at the American College of Chest Physicians Consensus Conference, Tucson, Ariz, April 18, 1998.

We appreciate the helpful critique of Lisa E. Farnett, PharmD.

Reprints: Henry I. Bussey, PharmD, Division of Pharmacotherapy, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-6220 (e-mail: BUSSEY@UTHSCSA.EDU).