In this month's WMSHP Newsletter, Heather Draper, Pharm.D. writes about strategies for managing elevated INR in patients on warfarin.

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Management of INR above the therapeutic range in patients treated with warfarin

Heather Draper, Pharm.D.

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Anticoagulation with warfarin is effective for the primary and secondary prevention of thromboembolic events. However, this therapy exposes the patient to a higher risk of bleeding. Patient factors may precipitate the risk of bleeding—including advanced age, malignancy, decreased oral intake, or the use of new medications known to potentiate warfarin.

Warfarin has a narrow therapeutic index, with the therapeutic INR typically targeted at 2-3. The risk of bleeding in patients on warfarin increases significantly when the INR exceeds 4-6, although the absolute risk of bleeding remains fairly low, at less than 5.5 per 1000 per day.¹ Therefore, patients with an INR less than 9 and no significant bleeding can be managed by omitting subsequent doses of warfarin, more frequent monitoring of the INR, and resumption of therapy at a lower dose when the INR is therapeutic.²

When rapid reversal of the INR is needed, fresh frozen plasma, prothrombin complex, or recombinant factor VIIa can be administered. Administration of coagulation factors provides only a temporary solution due to the short half-life of the provided clotting factors (3-4 hours for Factor VII), compared with a duration of action of 2 to 5 days for warfarin, as well as relative instability of clotting factors upon administration. Administration of either fresh frozen plasma or factor concentrates will decrease the PT/INR for 4 to 6 hours.³ Complete return to a therapeutic INR will require supplementation with vitamin K₁.²

Treatment of an INR above the therapeutic range requires a balance between reducing the risk for hemorrhage while minimizing the risk of thrombembolism. Treatment approaches are based on the current INR, presence of bleeding, and the time frame in which reversal is required.² Vitamin K₁ may be administered to reverse the anticoagulation effect of warfarin. The most appropriate dose of vitamin K₁ will lower the INR to a safe level without resulting in a subtherapeutic INR. High doses of vitamin K₁, although effective, may lead to warfarin resistance for a week or more, resulting in an increased risk for thromboembolism.^1,2 In this situation, heparin can be given until the effects of the vitamin K₁ are complete.

Vitamin K₁ is available for intravenous (IV), subcutaneous, and oral administration. Table 1 provides a brief summary of the advantages and disadvantages for each route of Vitamin K₁. The subcutaneous route has a delayed onset and is less predictable.¹ If rapid reversal is desired, the IV route should be utilized, as this route is associated with the fastest onset of action. Historically, intravenous vitamin K₁ has been associated with an increased risk of anaphylaxis. A retrospective review of anaphylactic reactions associated with IV vitamin K₁ from the Mayo Clinic revealed that the risk of anaphylaxis with vitamin K₁ was 3 per 10,000 doses—a rate comparable to all forms of penicillin and less than that of IV iron dextran.⁴ If is administered by the IV route, lower doses and slower infusion rates are recommended. Unless rapid reversal of the INR is critical, oral vitamin K₁ is the preferred route of administration. In the United States, oral vitamin K₁ is only available as a 5 mg tablet (Mephyton^®). Therefore, oral doses prescribed should reflect even divisions of 5 mg (e.g., 2.5 mg).

Table 1. Summary of the Use of Vitamin K¹

Route	Advantages	Disadvantages
IV	Fastest Onset of Action	Must be given by slow IV infusion Warfarin resistance
Subcutaneous	Lower risk of anaphylaxis	Delayed onset Unpredictable response Least desired route
Oral	Safest route Low risk of anaphylaxis No IV site needed	Slower onset of action Warfarin resistance

The following table provides a summary of recommendations for managing elevated INRs and bleeding patients treated with vitamin K antagonists.

Table 2. Management of Elevated INR in Patients Receiving Vitamin K Antagonists²

INR	Bleeding Present	Rapid Reduction Required	Management*
< 5	No	No	Lower dose or omit dose; resume at lower dose when INR is therapeutic
5-9	No	No	Omit one or two doses, resume at lower dose.
No	Yes — high risk	May give vitamin K1 1-2.5 mg orally if at increased risk for bleeding.
No	Yes—surgery	2-4 mg oral vitamin K1 for reduction of INR in 24 hours; if INR still high, can repeat with 1-2 mg orally.
≥9	No	No	Hold dose and give vitamin K1 5—10 mg orally to reduce INR in 24 to 48 hours; may use additional vitamin K1 as necessary. Resume at lower dose when therapeutic.
Any	Yes—Serious Bleeding	Yes	Hold dose, give vitamin K1 10 mg by slow IV infusion, supplemented with fresh frozen plasma, prothrombin complex, or recombinant factor VIIa; vitamin K1 may be repeated every 12 hours.
Any	Yes—Life Threatening	Yes	Hold dose, give prothrombin complex supplemented with vitamin K1 10 mg by slow IV infusion; repeat if necessary depending on INR.

*Note: Oral vitamin K₁ is only available in the United States as a 5 mg tablet (Mephyton^®). Therefore, oral doses prescribed should reflect even divisions of 5 mg (e.g., 2.5 mg).

 

References
1. Hanslik T, Prinseau J. The use of vitamin K in patients on anticoagulant therapy. Am J Cardiovasc Drugs 2004; 4: 43-55.

2. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonist: the seventh ACCP conference on antithrombotic and thrombolytic therapy [published correction appears in Chest 2005; 127: 415-416].Chest 2004; 126 (3 suppl): 204S-233S.

3. Wittkowsky AK. Thrombosis. In: Young LY, Koda-Kimble MA, eds. Applied Therapeutics: the Clinical Use of Drugs. 6th ed. Vancouver, WA: Applied Therapeutics, Inc; 1995: 12-16.

4. Reigert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K₁): a 5-year retrospective review. Ann Allergy Asthma Immunol 2002; 89: 400-406.