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What is the role of vitamin K in nonbleeding patients with a supratherapeutic INR?

Background

Warfarin, a vitamin K antagonist, is commonly used for primary and secondary prevention of arterial and venous thrombosis.¹ It exerts its anticoagulant effect by inhibiting the activation of vitamin K dependent clotting factors (factors II, VII, IX, X). While warfarin is an effective drug, there is considerable inter- and intra-patient variability in its anticoagulant effect due to the influence of genetic and environmental factors.² Consequently, warfarin requires frequent monitoring of the international normalized ratio (INR) to ensure optimal therapy with minimal bleeding complications.

The INR reflects the ability of coagulation factors to aggregate and synthesize a clot.^2,3 The therapeutic range for the INR depends on the indication for anticoagulation; however a goal of 2.0 to 3.0 is typically targeted. An INR less than 2.0 has been associated with thromboembolism, whereas values greater than 4.0 are associated with an increased risk of bleeding. Furthermore, the incidence of intracranial bleeding increases significantly as the INR exceeds 4.5 for prolonged periods of time. The annual incidence of major bleeding events with warfarin has ranged from 1% to 10%, while the incidence of minor bleeding may be greater than 15%.^3,4 The majority of studies have defined major bleeding as an event requiring hospitalization, transfusion of 2 or more units of packed red blood cells, or a drop in hemoglobin greater than 2 g/dL. Examples of major bleeding include intracranial hemorrhage and severe gastrointestinal bleeding.

The management of excessive anticoagulation in patients without a bleeding event remains controversial. The American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy has published recommendations for the management of patients with a supratherapeutic INR (Table 1).² Similar guidelines are also available from the British Committee for Standards in Haematology (BCSH) and the Australasian Society of Thrombosis and Haemostasis (ASTH).^5-6 All 3 sets of guidelines recommend managing an elevated INR by withholding warfarin treatment and allowing the INR to decline to a therapeutic level. In addition, there is an option to administer a single low-dose of vitamin K to achieve a greater reduction in the INR within 24 hours. The vitamin K dose ranges from 1.25 mg to 5 mg, depending on the extent of INR elevation. Oral vitamin K administration has a more predictable dose-response relationship with a more rapid onset of action compared to subcutaneous administration. As a result, the administration of subcutaneous vitamin K is not recommended for INR reversal. While several trials have demonstrated the ability of oral vitamin K to provide a more rapid INR normalization compared to no treatment, its effects on clinical outcomes remain uncertain. Consequently, the utility of vitamin K in nonbleeding patients with excessive anticoagulation remains controversial.

Table 1. Chest guidelines recommendation for supratherapeutic INR with no significant bleeding.²

Literature Review

Crowther and colleagues recently published the results of a multicenter, randomized, placebo-controlled trial which evaluated the impact of oral vitamin K administration on clinical outcomes in patients with a warfarin-induced coagulopathy.⁷ The trial was conducted at 14 anticoagulation clinics in Canada, the United States, and Italy from 2004 to 2006. The trial included 724 adult, nonbleeding patients taking warfarin with an elevated INR ranging from 4.5 to 10.0. Subjects were excluded from the trial if they had an indication for acute INR reversal, carried specific risk factors for bleeding, or were unable to take oral vitamin K. Patients were randomized to receive either 1.25 mg of oral vitamin K (n= 355) or placebo (n= 369) and followed for 90 days.

The primary endpoint was any bleeding event (major, minor, trivial).⁷ A major bleeding event was defined as fatal bleeding, requiring more than 2 units of packed red blood cells, receiving a therapeutic intervention, or objectively confirmed bleeding into a closed space. Minor bleeds were non-major bleeding requiring medical assessment, whereas trivial bleeds were patient reported events. The secondary endpoints included the frequency of any major bleeding episode, thromboembolism, and death during the 90-day post-randomization period. All patients were assessed via telephone or in person on days 1, 3, 7, 14, 28, and 90 post-randomization. Additional contact and INR monitoring was individualized to the patient’s needs at the physician’s discretion. A post-hoc analysis was performed to determine the number of bleeding events within the first 7 days post-randomization and number of events in subjects of age 70 years and older.

The study population had an average age of 69.5 years in the vitamin K group and 68.5 years in the placebo group. 7 There was an even distribution of males and females in both study groups with an average INR of approximately 6.0 at enrollment. The majority of subjects had a target INR ranging from 2.0 to 3.0 with about 20% of the study population aiming for an INR range of 2.5 to 3.5. There were no significant differences between the groups at baseline. In the 90 days post-randomization, a bleeding event occurred in 56 of the 355 patients receiving vitamin K (15.6%) and 60 of the 369 patients in the placebo group (16.3%). There was an overall 0.5% reduced risk of bleeding in the vitamin K group, which was not statistically significant (P= 0.86). The overall bleeding risk frequency reported was consistent with previous cohort studies in similar patients who were managed without active INR reversal by using vitamin K in community practice. ^3,4 Additionally, no significant difference was found between the 2 study groups regarding major bleeding events, thromboembolism, and death; however, the secondary endpoints were analyzed per protocol and were underpowered to detect a significant difference (P= 0.22, 0.72, 0.94, respectively).⁷ These findings indicate that the administration of vitamin K is safe; however, it does not impact the frequency of bleeding events in stable patients with a supratherapeutic INR.

Regarding the influence of vitamin K on the INR, the INR decrease was significantly greater in the vitamin K group compared to the placebo group 1 day after study drug administration.⁷ An INR decrease of 2.8 was observed in the vitamin K group compared to a 1.4 decrease in the placebo group (P< 0.001). In the post-hoc analysis, the number of bleeding events, thromboembolism, or death did not significantly differ between the vitamin K and placebo groups for patients age 70 years and older. Therefore, the administration of vitamin K does not appear to influence the frequency of bleeding in the elderly population.

Given the above results, the authors concluded that supratherapeutic INRs in non-bleeding patients should be managed with withdrawal of warfarin therapy and resuming an appropriately adjusted warfarin regimen once the INR reaches the therapeutic range. While administration of vitamin K may result in a more rapid normalization of the INR, it does not appear to have any impact on frequency of bleeding events.

Conclusion

While warfarin is an effective anticoagulant, its use is associated with an increased risk of bleeding. Current data have shown that vitamin K administration in nonbleeding patients with warfarin-induced coagulopathy has minimal impact on clinical outcomes compared to withdrawal of warfarin therapy alone. As a result, the role of vitamin K in this patient population appears to be limited to a more rapid reversal of INR, rather than minimizing the risk of bleeding events or mortality. The study by Crowther and colleagues supports the management of supratherapeutic INRs by holding warfarin therapy until the INR is within a therapeutic range, then resuming an appropriately adjusted warfarin regimen. However, it is important to note this management strategy does not apply to patients with active bleeding requiring rapid INR reversal, who are peri-procedural or those patients with an INR greater than 10.

References

1. Coumadin. [package insert] Princeton, NJ: Bristol-Myers Squibb; 2009.
2. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Gualtiero P. Pharmacology and management of the vitamin K antagonist. Chest. 2008;133(6 Suppl):160S-198S.
3. Haines ST, Witt DM, Nutescu EA, “Chapter 21. Venous Thromboembolism” (Chapter). DiPiro JT, Talbert RL, Yee GC, Matzke GR, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7^th Edition: http://www.accesspharmacy.com/content.aspx?aID=3198972 .
4. DeZee KJ, Shimeall WT, Douglas KM, Shumway NM, O’Malley PG. Treatment of excessive anticoagulation with phytonadione (vitamin K). Ann Intern Med. 2006;166(4):391-397.
5. Haemostasis and Thrombosis Task Force for the British Committee for Standards in Haematology. Guidelines on oral anticoagulation: third edition. Br J Haematol. 1998;101(2):374-387.
6. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492-497.
7. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin. Ann Intern Med. 2009;150(5):293-300.

By Lynley Heinrich, PharmD