How to manage a patient with an elevated International Normalized Ratio (INR) greater than 9 with no evidence of bleeding?

From the Guidelines

For a patient with an INR greater than 9 without bleeding, immediately hold warfarin and consider administering oral vitamin K, but the use of oral vitamin K is conditional and depends on the patient's risk of bleeding and other factors, as the latest guidelines suggest that the net benefit of oral vitamin K administration is uncertain 1. The patient should have their INR rechecked within 24-48 hours to assess response. If the INR remains significantly elevated, an additional dose of vitamin K may be given, but higher doses should be avoided as they can cause prolonged warfarin resistance when therapy is restarted. The management of elevated INR without bleeding involves:

• Holding warfarin to allow the INR to decrease
• Considering oral vitamin K administration for patients at high risk of bleeding or with prolonged INR elevation
• Monitoring the patient closely for signs of bleeding, such as bruising, blood in urine or stool, or neurological changes
• Restarting warfarin at a reduced dose with frequent INR monitoring once the INR returns to the therapeutic range. This approach is necessary because an INR above 9 indicates excessive anticoagulation that significantly increases bleeding risk, even without current bleeding, as supported by studies showing the risk of bleeding increases with INR values above 4.5 and rises sharply above an INR of 6.0 1. Vitamin K works as an antidote to warfarin by promoting synthesis of functional clotting factors II, VII, IX, and X. Patients should also be educated about avoiding activities with high bleeding risk and instructed to seek immediate medical attention if bleeding occurs. However, the latest guidelines from 2018 suggest that the use of oral vitamin K is conditional and depends on the patient's risk of bleeding and other factors, highlighting the need for individualized management decisions 1.

From the FDA Drug Label

The recommended dose to correct excessively prolonged prothrombin times caused by oral anticoagulant therapy is, 2.5 mg to 10 mg or up to 25 mg initially. In some instances 50 mg may be required. Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition. If, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, repeat the dose Evaluate INR after 6 to 8 hours, and repeat dose if INR remains prolonged. Modify subsequent dosage (amount and frequency) based upon the INR or clinical condition.

To manage a patient with an elevated International Normalized Ratio (INR) greater than 9 with no evidence of bleeding, phytonadione (Vitamin K1) can be administered. The initial dose is typically 2.5 mg to 10 mg or up to 25 mg. In some cases, a dose of up to 50 mg may be required. The dose should be repeated if the INR remains prolonged after 6 to 8 hours. Subsequent doses should be determined based on the INR response or clinical condition 2.

From the Research

Management of Elevated INR

• The management of a patient with an elevated International Normalized Ratio (INR) greater than 9 with no evidence of bleeding is crucial to prevent potential bleeding complications 3, 4.
• According to the study by 3, patients without anticoagulant treatment with INR higher than 9 had a poor prognosis, with 67% experiencing bleeding and 74% dying.
• The study by 4 suggests that in the absence of bleeding, elevated INR values may be treated with either simple warfarin withdrawal or the administration of low doses of oral vitamin K.
• Oral vitamin K will more rapidly return the INR to the therapeutic reference interval; however, its impact on bleeding is unknown 4.
• If the INR is in excess of 10, most experts would recommend the administration of vitamin K, and in the case of active bleeding, additional administration of coagulation factors either in the form of fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC) 4.

Treatment Options

• A prospective cohort study by 5 found that a single 2.5 mg dose of oral vitamin K effectively treats INR values in excess of 10, with a low rate of observed major bleeding.
• The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) recommends the use of oral vitamin K to reverse a mildly elevated INR, and prothrombin complex concentrates or recombinant factor VIIa to immediately reverse the INR in patients with life-threatening bleeding or intracranial hemorrhage 6.
• Fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage is also effective in reversing coagulopathy and improving outcome, with time to treatment being the most important determinant of 24-hour anticoagulation reversal 7.

Key Recommendations

• Withholding warfarin or giving vitamin K treatment may be ineffective at reducing the INR within 24 hours, whereas plasma infusion may be needed to reduce INR and the risk of bleeding within 24 hours 3.
• The administration of vitamin K and coagulation factors, such as FFP or PCC, may be necessary to urgently correct the INR and prevent bleeding complications 4, 6.
• Patient self-testing or patient self-management of dosing are effective alternative treatment models that result in improved quality of anticoagulation management, with greater time in the therapeutic range and fewer adverse events 6.