Warfarin Institute of America
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INR too high? Vitamin K or Fresh Frozen Plasma?
Wiyanto Winatal, Pharm. D. Candidate
University of Colorado Health Sciences Center
School of Pharmacy
Anticoagulation with warfarin is very effective for preventing blood clots. Unfortunately, sometimes a person taking warfarin has a level that is too high. Questions persist about the risks and management of an INR that is too high. The management of bleeding in the over-anticoagulated patient is complex and is based on balancing the risks and benefits of each treatment.
For life-threatening bleeding, the use of clotting factor concentrates is essential for immediate anticoagulation reversal, whereas for less severe bleeding vitamin K is the treatment of choice. Vitamin K (by the intravenous or oral route) should also be used in over-anticoagulated patients who are not actively bleeding but who are at high risk of doing so if their anticoagulation is not, at least partially, corrected.
The use of vitamin K in patients with warfarin over-anticoagulation lowers an elevated INR faster than withholding warfarin alone; however, it has not been clearly demonstrated that vitamin K treatment does, in fact, lower the risk of major hemorrhage. As vitamin K administration via the intravenous route may be complicated by anaphylactic reactions so oral administration is preferred.
Reversal can be achieved by stopping warfarin or administration of vitamin K, fresh frozen plasma or coagulation factor concentrates such as prothrombin complex concentrate (PCC). Complete reversal of anticoagulation may be life-saving. Fresh frozen plasma (FFP) and vitamin K are most frequently administered. However, there are surprisingly few studies defining the optimum dose of these products and there are no randomized studies comparing the relative benefit and risk of coagulation factor concentrates versus fresh frozen plasma.
No studies comparing PCC and FFP have shown an advantage in terms of outcome. A recent Swedish retrospective study of warfarin associated intracranial bleeding showed no difference in outcome (30 day mortality) between patients who received FFP compared with those who received a PCC. A randomized prospective study comparing PCCs with FFP would be required to answer this question and provide a conclusive answer. Reasons that PCCs are not widely used include concerns that they may lead to clot formation, transmit viruses and cost.
The role of Vitamin K and FFP in warfarin reversal varies. There are quite a number of articles that has been published with regards to warfarin reversal due to over anticoagulation. Yiu et al. compared the efficacy and safety profiles of IV Vit K and FFP. The investigators found out that there was no significant difference in INR between the groups. 58% of FFP group had INRs within target range and 51% of Vit K group has INR within range. There were no adverse reactions or outcomes in either group. In another study, Goldstein et al. found out that FFP can rapidly lower the INR and appears to be safe for patients with warfarin related ICH (Intracranial Hemorrhage).
Options for warfarin reversal:
|
Type of reversal |
Approach |
|
Rapid (complete; within 10-15 minutes) |
PCC (immediate replacement of vitamin K dependent coagulation factors) plus IV vitamin K (switch on hepatic synthesis within a few hours) |
|
Fast (partial) |
FFP (immediate replacement of vitamin K dependent coagulation factors- but the correction of the coagulopathy is partial) |
|
Prompt (within 4-6 hours) |
IV vitamin K |
|
Slow (within 24 hours) |
Oral vitamin K |
|
Ultraslow (over days) |
Omit warfarin dose (no vitamin K) |
US guideline for warfarin reversal:
|
INR |
Clinical Situation |
Action |
|
Above therapeutic but <5 |
No bleeding |
Lower dose or omit warfarin |
|
>5 but < 9 |
No bleeding |
Omit warfarin, monitor more frequently |
|
|
High risk of bleeding |
Vitamin K (1-2.5 mg orally; 2-4 mg orally if more urgent reduction needed) |
|
>9 |
No bleeding |
Omit warfarin, Vitamin K (3-5 mg orally) |
|
>20 |
Serious bleeding |
Vitamin K (10 mg IV), FFP or PCC |
|
Any INR |
Life threatening bleeding |
Vitamin K (10 mg IV), FFP, PCC |
Major bleeding in a patient on warfarin is most appropriately managed by rapid and complete reversal with a PCC and IV vitamin K, regardless of the reason for anticoagulation. This approach ensures that the acute effect of bleeding is minimized. Minor bleeding or high INR without bleeding can be safely treated by dose omission or oral vitamin K (or IV vitamin K in selected cases), which result in partial reversal, with the aim of restoring the INR to the target value of the individual.
As for which reversal medication to use, several studies found that the time to treatment is the most important determinant of anticoagulation reversal. Although additional study is required to determine the clinical benefit, minimizing delay in FFP administration is a prudent step in emergency management of over anticoagulation. When reversal over several hours is acceptable, such as for elective surgeries, the use of vitamin K would be sufficient to lower the INR to goal range. Vitamin K is available in several formulations that can be administered by a variety of routes but oral or IV is preferred. The administration of IV vitamin K leads to INR reversal fairly quickly, within four to six hours, except for those patients who are massively over anticoagulated, whereas oral vitamin K works more slowly.
The final factor to consider in making this choice is the duration of action of the agents. FFP lasts a relatively short time with the effect not being seen after a few days. Vitamin K, particularly in higher IV doses gets deposited in the fatty tissue of the body and its effect can last for two weeks or more depending on the dose.
FOR A MORE GENERAL DISCUSSION OF VITAMIN K, CLICK HERE
References:
Makris M. Management of excessive anticoagulation or bleeding. Semin Vasc Med. 2003 Aug; 3(3): 279-84
Hanslik T, Prinseau J. The use of vitamin K in patients on anticoagulant therapy: a practical guide. Am J Cardiovasc Drugs. 2004; 4(1): 43-55
Baglin T. Management of warfarin (coumarin) overdose. Blood Rev. 1998 Jun; 12(2): 91-8.
Makris M, Greaves M, Phillips WS et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost. 1997 Mar; 77(3): 477-80.
British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. The British Society for Haematology, 126, 11-28.
JP Hanley. Warfarin reversal. J. Clin. Pathol. 2004;57;1132-1139.
Joshua N. Goldstein, Stephen H. Thomas, Virginia Frontiero et al. Timing of Fresh Frozen Plasma Administration and Rapid Correction of Coagulopathy in Warfarin-Related Intracerebral Hemorrhage. Stroke 2006;37;151-155.
Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):204S-33S.
Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005; 115(6):455-9.
Taberner DA, Thomson JM, Poller L. Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal. Br Med J. 1976; 2(6027):83-5.
© 2006 Wiyanto Winatal - Used by permission
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Last updated August 31, 2006
