Bleeding is the most common complication of warfarin therapy and elevated INR is a significant risk factor. However, most intracranial bleeds occur in patients with an INR in the therapeutic ranges, occurring in 0.5% -1.0% of patients on warfarin for atrial fibrillation per year. Bleeding risk is also related to patient factors including age, a prior bleeding history, specific comorbidities, heavy alcohol consumption and certain medications.(1)
General principles for preventing high INR include careful therapeutic monitoring and consideration of warfarin-drug interactions including avoiding concomitant non-steroidal anti-inflammatory drugs, certain antibiotics and antiplatelet therapy except where clinical benefit is known eg. mechanical heart valves, acute coronary syndrome, or recent coronary stent insertion.
- Withhold warfarin with careful monitoring
- Resume therapy at a lower warfarin dose when the INR approaches therapeutic range
- If the INR is only minimally above the therapeutic range (up to 10%) dose reduction is generally not necessary
- Vitamin K1 (phytomenadione)
- Vitamin K1 is an effective antidote to warfarin
- Both oral and intravenous (IV) routes are effective in reducing a raised INR due to warfarin with a similar correction of INR by 24 hrs. IV has a more rapid response, within 6-8 hours
- Anaphylaxis to IV vitamin K1 is rare (1)
- Vitamin K1 should not be administered by subcutaneous or intramuscular routes
- Dosage of Vitamin K1 varies between 1 mg and 10 mg based on whether bleeding is present or absent as well as the risk of bleeding. See the Guidelines for the management of an elevated INR in adults for details.
- Prothrombin complex concentrate (PCC) eg Prothrombinex-VF
- Prothrombinex-VF is a coagulation factor concentrate containing factors II, IX and X and a small amount of factor VII.
- PCCs are reconstituted into a small volume for rapid infusion and have a fast onset of action.
- Prothrombinex-VF is able to completely reverse an excessive INR within 15 minutes however, vitamin K1 is also required to sustain the reversal effect as the half-lives of the infused clotting factors are similar to endogenous factors.
- The suggested dose of Prothrombinex-VF ranges from 15-50 IU/kg and is based on bleeding risk as outlined in the Guidelines for the management of an elevated INR in adults.
- Fresh frozen plasma (FFP)
- Not routinely used to reverse warfarin anticoagulation
- Where PCC is unavailable and emergency reversal is required, FFP should be used, along with Vitamin K1 to sustain the reversal effect
- FFP is also used to supplement PCC in patients with major or life-threatening bleeding or INR > 10.0 accompanied by high risk of bleeding
For life-threatening (critical organ) and clinically significant bleeds, the consensus is to use the maximum dose of Prothrombinex-VF (50 IU/kg) with vitamin K1 (5-10 mg IV) and FFP (150-300 mL) or when Prothrombinex-VF is not available, use the maximum amount of FFP (15 mL/kg). (1) Refer to the Guidelines for the management of an elevated INR in adults and/or seek specialist haematology advice.
- Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS. An update of consensus guidelines for warfarin reversal. MJA 2013;198(4):198–199.