Warfarin reversal: schism between clinical practice and published guidelines

V itamin K antagonists (VKAs), such as warfarin, are used by more than three million people in the United States for prevention of thromboembolism. Warfarin treatment has a narrow therapeutic window that balances anticoagulation with the risk of bleeding. This requires frequent monitoring to maintain an international normalized ratio (INR) between 2 and 3 for venous thromboembolism and 2.5 and 3.5 for prosthetic heart valves. Maintenance of the narrow therapeutic window is made more difficult by multiple genetic, food, and drug interactions combined with temporal intraindividual variation. Consequently, patients can spend 30% or more time outside the therapeutic window. Patients with supratherapeutic INRs (ST-INR) can present along a spectrum from asymptomatic elevation to major bleeding, which is estimated to be 3% annually. Different medical societies around the world such as the American College of Chest Physicians (ACCP) and British Committee for Standards in Haematology have developed guidelines for the management of VKA over anticoagulation. These begin with conservative measures for asymptomatic INR elevation such as omission of the next VKA dose and recommend more aggressive measures that include vitamin K therapy and vitamin K–dependent factor replacement (prothrombin complex concentrate [PCC] or plasma) for significant bleeding or urgent procedure. The ACCP guidelines clearly favor the intravenous (IV) vitamin K over the oral route for urgent reversal and do not recommend the subcutaneous route. In clinical practice, however, this may not be followed. In this issue of TRANSFUSION, Meehan and colleagues retrospectively compare the time frame of INR correction by IV versus oral vitamin K in patients on VKA who presented with ST-INRs. Furthermore, they address many of the clinical misconceptions and practices that lead to delayed or inappropriate treatment. The study examined pharmacy records for vitamin K administration over a 14-month period at a tertiary care hospital and demonstrated more rapid correction of ST-INR with IV administration. Overall, 135 patients (81 receiving oral and 54 IV) who had reliable data available on vitamin K dosage and administration time along with preand postadministration INR were included. Demographic data and presenting INRs were not statistically different between patients given oral or IV vitamin K. There was a wide range (1-10 mg) of vitamin K doses administered with the median dose for oral slightly higher than IV (2.5 mg vs. 2 mg). The IV group showed a lower median INR (2.0 vs. 2.5) after vitamin K therapy despite earlier collection of post-INR sample (6.5 hr vs. 13.25 hr). Patients in the IV group achieved an INR of 2.0 within 12 hours at 3.5 times the rate of the oral group (44% vs. 12%). At 24 hours, the difference in INR correction between the two groups subsided, and approximately three of four patients corrected to an INR less than 1.5. Figures of the entire group and a subset of 10 patients clearly demonstrate a greater slope of INR correction with the IV route. In the subset analysis of 10 patients over a wide range of pre-INRs, those given IV achieved a post-INR of less than 4 within 6 hours versus 15 hours for the oral group. In the study, the reason behind vitamin K administration was split somewhat equally between bleeding, urgent procedure, and ST-INR. A higher portion of the bleeding group received IV vitamin K while a higher portion of the ST-INR group received oral; patients needing correction for an urgent procedure showed no difference in route administered. The preference for IV in bleeding patients is in line with guidelines, but almost one-third of bleeding patients received oral vitamin K despite needing emergent reversal. Additionally, patients presenting with gastrointestinal bleeding may not adequately absorb oral vitamin K, so these patients especially could benefit from IV administration. The number of red blood cell units transfused in bleeding patients on IV versus oral was not statistically different. The time between baseline ST-INR results and administration of vitamin K therapy (lag time) was surprisingly long at medians of 5.5 and 22 hours at the upper limit. The study also showed that the dosage of vitamin K used did not affect posttreatment INR. Posttreatment INR was only affected by pretreatment INR and total duration of vitamin K therapy before testing. This study concurs with previous studies that show more rapid INR correction with IV vitamin K. Watson and colleagues (64 patients) showed that 4 hours after vitamin K administration, the IV form corrected INR to less than 4 in 67% of patients versus only 0% to 25% for different oral formulations. The INR correction resulted from modest elevations in vitamin K–dependent factors, particularly Factor (F)VII. After 24 hours, almost all patients in both the IV group and better performing oral formulations achieved an INR of less than 4. These differences were achieved at lower doses of IV vitamin K and were independent of the pretreatment INR, unlike the TRANSFUSION 2013;53:476-479.