The online version of this article, along with access to discussion threads on NATF’s eForum, is available at: www.NATFonline.org/ethrombosis.php (February, 2010)

Combining Vitamin K Administration and Vitamin K Antagonist Therapy: Antagonizing the Antagonist Authored by, Henry I. Bussey, Pharm.D., Professor, The University of Texas at Austin College of Pharmacy and President and Senior Editor, ClotCare.org

The purpose of this discussion is to examine new trends in how vitamin K may be used to modulate the control of the International Normalized Ratio (INR) in warfarin-treated patients. Specifically, the following areas will be addressed; the use of vitamin K to: 1. Reverse an excessively elevated INR. 2. Increase the rate of decline in the INR and thereby minimize the need for pre-procedure “bridging” with low molecular weight heparin. 3. Help stabilize the INR (as measured by the percent of time in the therapeutic range – or “TTR”) during chronic warfarin therapy. Note: One over-riding issue that may be relevant to the first two issues above is that many of the conclusions in the literature, and the subsequent recommendations in published guidelines, do not differentiate whether the dosage form of oral vitamin K used was the traditional tablet formulation or the injectable liquid given orally. With one exception, 3 the published studies that used doses of less than 2.5 mg of oral vitamin K to lower the INR used the injectable formulation of vitamin K given orally. The one study that used a tablet formulation dose of less than 2.5 mg to reverse

high INRs did not find benefit.3 Because the injectable and tablet formulations given orally may produce different results, it may be important to take note of the dose and dosage formulation used in various studies. 1.

Vitamin K to reverse an excessively elevated INR.

General considerations: Whether an excessively elevated INR requires vitamin K reversal depends on the degree of INR elevation, the projected rate of fall in the INR, the bleeding risk of the patient, whether there is active bleeding, and whether there is some other factor that warrants rapid reversal of the INR. What constitutes an emergent vs a non-emergent situation, therefore, must be based on the clinician’s assessment of the risks of the high INR to the particular patient in question. Furthermore, in two studies, each using two different laboratories, we found that approximately 10 to 15% of INR results were erroneous.1 Therefore, it is always appropriate to question whether a high INR may be due to lab error and consider repeating the test before intervening. Reversal of excessive anticoagulation in a non-emergent situation: A study by Hylek and associates found that 45% of 114 patients with an INR greater than 6 had INRs above 4 at 48 hrs after warfarin was discontinued. 2 Further, 27% had INRs greater than 4 at 72 hours, 10 (8.8%) had significant to major bleeding; two of which were fatal and three others that resulted in hospitalization. The substantial duration of excessive anticoagulation and the bleeding complication rates would suggest that reversal with vitamin K may be beneficial. A more recent and larger randomized, placebo-controlled trial, found that there was no clear benefit of vitamin K administration. 3 As discussed in more detail on ClotCare.org (www.clotcare.com/clotcare/vitaminkforhighinr.aspx), there are several issues of study design that raise questions about the authors’ conclusions. For example, this is the one study that used a tablet formulation of less than 2.5 mg rather than using the injectable formulation given orally. Also, approximately two-thirds of patients in this study had INRs of 6 or less (a group in

whom many – if not most – clinicians would question the need to administer vitamin K). Lastly, patients with an INR greater than 10 were excluded from this trial. Consequently, this study did not address adequately the benefit of vitamin K use in more severe INR elevations or the benefit of vitamin K in a dose and dosage formulation used previously. Therefore, whether vitamin K reversal is indicated and, if so, what dose and dosage form to use remains controversial. If the clinician chooses to administer vitamin K [in addition to omitting warfarin dose(s)] the current recommendations from the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines (8th Edition) – the “Chest guidelines” - call for oral vitamin K at 1 to 2.5 mg if the INR is greater than 5 but less than 9; and a higher dose (2.5 to 5 mg) if the INR is greater than 9.4 As mentioned above, the studies that support an oral vitamin K dose of less than 2.5 mg for reversing high INRs in either range used the injectable formulation given orally. Unfortunately, the Chest guidelines do not make this differentiation in dosage formulation. Two studies that used the tablet formulation for oral vitamin K, however, found that 2.5 mg was usually adequate for reversing INRs between 5 and 9 within a 24 to 48 hour window.5,6 The same 2.5 mg dose, however, often was inadequate for INRs greater than 9; leading the authors to suggest that the 5 mg tablet be considered for INRs above 9.5,6 Therefore, in our own practice, we typically use one-half of the 5 mg tablet if the INR is less than 9 and the full 5 mg tablet if the INR is above 9. Although there are no published data to support the practice, we also have used doses of approximately 500 mcg to partially reverse moderately high INRs (such as INRs of 4.5 to 6) in patients who are already taking daily vitamin K supplementation (as will be discussed later). Reversal of excessive anticoagulation in an emergent situation: Obviously, if significant bleeding is an active problem with an excessive INR, other measures

(such as the administration of fresh frozen plasma or other clotting factor products) are warranted in addition to vitamin K administration. 4 If clinical circumstances warrant reversal of the INR within less than the 24 to 48 hours required for oral vitamin K to have its effect, then the injectable vitamin K formulation should be used. Once it was thought that subcutaneous (SC) administration of vitamin K would produce a more rapid fall in the INR than oral administration; and SC administration was recommended in the Chest guidelines prior to 1998. In 1997, however, one of our doctor of pharmacy residents observed instances in which witnessed SC administered vitamin K had no effect on an elevated INR. 5 Upon further review of the literature, Dr. Whitling was unable to find any data to support the use of SC administered vitamin K for INR reversal and this recommendation was subsequently abandoned in the Chest guidelines. Intramuscular (IM) administration of vitamin K is contraindicated for reversing excessively elevated INRs because of the risk of inducing a hematoma. Also, large IM doses may have a “repository” effect which may complicate achieving adequate anticoagulation in the days to weeks following the administration of large vitamin K doses IM. Intravenous (IV) administration is the remaining option since IM is contraindicated and SC too unreliable. In the past, anaphylaxis was a significant consideration with IV vitamin K. Anaphylaxis, however, appears to be much less likely with the currently available preparation if the administration rate is limited to no more than 1 mg per min.; as reviewed by Whitling, et al.5 Further, it appears that a dose of greater than 1 mg is rarely necessary if the dose is administered in 50 to 150 ml of fluid.5 The fact that others have administered larger doses without a prompt response in the INR probably relates to very slow administration in a large volume of fluid and the fact that the product is light sensitive and may bind to the plastic of the IV fluid bag and/or the IV tubing. Therefore, it is

postulated that administering vitamin K very slowly in a large volume of IV fluid may result in very little of the dose actually reaching the patient. Further, doses of 1 mg or less are less likely to over-correct an excessively elevated INR.5 IV administered vitamin K may lower the INR within a matter of a few hours. 2.

Vitamin K to accelerate the rate of decline in the INR prior to an invasive procedure.

Two relatively similar approaches have been employed to use vitamin K to correct the INR right before an invasive procedure. In the data reported by Woods and colleagues, 7 warfarin was stopped five days before a procedure and 1 mg of the injectable formulation of vitamin K was administered the day before the procedure if the INR was 1.4 to 1.9. If the INR was 2 or higher the day before surgery, then the patient received either a larger oral dose of vitamin K or IV vitamin K. In their study, 39 of 43 patients who received the 1 mg dose of vitamin K achieved an INR of 1.4 or less the following day; the day of the surgery. The vitamin K administration apparently did not have an effect on achieving a therapeutic INR following the procedure since there was no difference in this measurement between those who did or did not receive vitamin K. How well 1 mg of the tablet formulation might work in this practice remains in question. In our own clinic we have used a somewhat similar approach but typically discontinue the warfarin closer to the day of the procedure; usually day 3 prior to the procedure. Continuing the warfarin for approximately 2 days longer may reduce the number of pre-procedure doses of low molecular weight heparin that are needed The INR is usually checked close to the date that the warfarin is discontinued and again the day before the procedure. Oral vitamin K (tablet formulation) may be administered the day before the procedure based on the rate of decline in the INR and the target INR value for the day of the procedure. In an analysis of this approach in 237 instances of warfarin interruption, the administration of vitamin K was not predictive of achieving the target INR.8 The

fact that vitamin K administration was not predictive of achieving the target preprocedure INR might suggest that such an approach is not beneficial. However, the administration of vitamin K was considered necessary in only 37% of patients and the doses of vitamin K ranged from 100 mcg to 5 mg. It would appear that stopping warfarin for three days prior to the procedure is adequate for the majority of patients. For the remainder, pre-procedure vitamin K may still be appropriate, but further research is needed to determine the correct dose. Early in our use of this approach there were numerous instances in which very small doses of vitamin K (100 to 500 mcg) appeared to be effective in lowering the INR for the procedure the following day. In gaining more experience, it was observed that doses as high as 2.5 mg appeared to have no effect to lower the INR by the next day in 1 or 2 patients. In view of the lack of evidence that 2.5 mg of warfarin induces warfarin resistance post procedure, it may be wise to abandon lower doses and use either 2.5 or 5 mg. of the tablet formulation. An additional consideration is that the smaller doses required use of the 100 mcg tablets which are available only as a vitamin supplement rather than a prescription-quality product. 3.

Daily vitamin K to help stabilize the INR and increase the percent of time spent with the INR in the therapeutic range (TTR).

Because warfarin exerts its effect by blocking the hepatic utilization of vitamin K in the synthesis of functional forms of clotting factors II, VII, IX, and X; many clinicians in the past advised their patients to avoid vitamin K containing foods and supplements. More recently, however, studies demonstrated that those patients with more stable INR values had a substantially higher intake of dietary vitamin K.9 That observation led our group to suggest daily vitamin K supplementation to our patients with the greatest difficulty in keeping their INR within the target range.

In a small case series of 8 patients, administration of 100 or 200 mcg of vitamin K more than doubled the TTR from 18% to 42%.10 Expanding the target range by +/- 0.2 INR units revealed that the TTR improved from 32% before the daily vitamin K supplementation to 57% TTR with vitamin K supplementation. Subsequently, two randomized, placebo-controlled trials demonstrated improved INR control with the daily administration of either 100 mcg or 150 mcg of vitamin K.11,12 The current Chest guidelines advocate “a trial” of low dose vitamin K for patients with unexplained variability in their INRs. Restriction of this recommendation to those with unexplained variability in their INRs presumably was advocated because studies prior to the development of the Chest guidelines had used daily low dose vitamin K only in patients who had difficulty achieving good INR control.4 The study by Rombouts, et al.,12 however, did not base enrollment on poor INR control. In fact, the patients in that study had TTR values of approximately 80% at entry into the study. The TTR improved to 89.5% with vitamin K vs. 85% without vitamin K. This difference failed to achieve statistical significance but is still consistent with an absolute improvement in TTR. Furthermore, the percent of patients who had 100% of their INRs in range during the six-month study was 43% in the vitamin K group vs. 24% in the placebo placebo. This overall improvement in INR control in a group of patients who entered the study with excellent INR control raises the question of whether daily vitamin K administration should be used routinely in chronic warfarin therapy. Presently we are nearing completion of a “triple intervention” trial that is evaluating the impact of combining daily low dose vitamin K supplementation, frequent INR self-testing, and online automated management. An interim analysis revealed an increase in TTR from approximately 55% before study entry to almost 80% during the study.13 Further, when the target range was expanded by +/- 0.3 INR units, the TTR increased to 94%. Clearly, the impact of daily vitamin K supplementation in this trial can not be isolated from the impact of the other two interventions.

For those choosing to add daily vitamin K supplementation to a patient’s warfarin regimen, it is important to monitor the patient closely because the dose of warfarin may have to be increased. The need to increase the dose of warfarin, however, appears to be somewhat unpredictable. A post-hoc analysis in a small group of patients by Sconce and colleagues found that patients with the “AA” VKORC1 genotype (“sensitive” warfarin receptor) did not require a warfarin dosage change when vitamin K was added to their regimen. Patients with the “resistant” “GG” VKORC1 genotype, however, required approximately a 25% increase in the warfarin dose while the “moderate” “AG” VKORC1 genotype patients required about an 8% increase in warfarin dose.14 One last consideration regarding the daily low dose supplementation of vitamin K, at least in the U.S., is that there is no “prescription grade” or USP approved solid formulation other than the 5 mg tablet. Therefore, use of the 100 mcg vitamin supplement available in health food stores must be used to achieve these low daily doses. Conclusion: Although further research is needed in all three areas of vitamin K use, various formulations of vitamin K may be used in different doses to transiently alter the INR or to improve INR stability with chronic therapy. For oral vitamin K doses of less than 2.5 mg, a formulation other than the injectable liquid and the 100 mcg vitamin supplement product would be of value. References: 1. Bussey HI, Chiquette E, Bianco TM, et al. A statistical and clinical evaluation of fingerstick and routine laboratory prothrombin time measurements. Pharmacotherapy 1997; 17:861-66. 2. Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Archives of Internal Medicine 2000; 160:1612-7. 3. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin; A randomized trial. Annals of Internal Medicine 2009; 150:293-300. 4. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. Chest 2008; 133:160s-98s.

5. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Archives of Internal Medicine 1998; 158:2136-2140. 6. Weibert RE, Le DT, Kayser SR, et al. Correction of excessive anticoagulation with low dose oral vitamin K1. Annals of Internal Medicine 1997; 125:959-962. 7. Woods K, Douketis JD, Kathirgamanathan K, Yi Q, Crowther MA. Low-dose vitamin K to normalize the international normalized ration prior to surgery in patients who require temporary interruption of warfarin. Journal of Thrombosis and Thrombolysis 2007; 24:93-97. 8. Martin C, Farnett LE, Lyons RM, Bussey HI. A retrospective analysis of vitamin K dosing and INR decline during interruption of warfarin therapy for invasive procedures. (abstract #413). American College of Clinical Pharmacy meeting abstracts, Pharmacotherapy 2004. 9. Sconce E, Khan T, Mason J, Noble F, Wynne H, Kamali F. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thrombosis and Haemostasis 2005; 93:872-875. 10. Reese AM, Farnett LE, Lyons RM, Patel B, Morgan L, Bussey HI. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25:1746-1751. 11. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109:2419-2423. 12. Rombouts EK, Rosendaal FR, van der Meer FJM. Daily vitamin K supplementation improves anticoagulant stability. Journal of Thrombosis and Haemostasis 2007; 5:2043-2048. 13. Bussey HI, Walker MB, Bussey-Smith KL, Frei C. Abstract PP-MO-469. XXII Congress, International Society of Thrombosis and Haemostasis, Boston, July, 2009. 14. Sconce SA, Avery PJ, Wynne HA, Kamali F. Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study. Journal of Thrombosis and Haemostasis 2008; 6:1226-1228.