Warfarin reversal: schism between clinical practice and published guidelines

Vitamin K antagonists (VKAs), such as warfarin, are used by more than three million people in the United States for prevention of thromboembolism.1 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.2 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.1 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.2, 3 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 pre- and 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.4-7 Watson and colleagues4 (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 study by Meehan and colleagues. The study by Lubetsky and colleagues7 (61 patients) reports very similar findings. A recent British study8 (178 patients) found that IV vitamin K (3 mg) can be effectively used to lower INR in VKA patients before surgical intervention as long as it was given 12 to 18 hours preoperatively. This resulted in almost all patients with INR of less than 1.5 and K-dependent factor levels of greater than 0.30 IU/mL on operative day. There were four patients with major bleeding that required blood products; this bleeding was likely procedure related and not from K-dependent factor deficiency as all of these patients had INR of less than 1.4 and K-dependent factor levels were greater than 0.30 IU/ml. Therapeutic INR was achieved postoperatively at a median of 4 days (range, 2-11 days) with no reports of thromboembolic episodes at follow-up. This demonstrates that a concern for ability to achieve a therapeutic INR after vitamin K therapy or the risk of thromboembolism while patient is temporarily unanticoagulated should not be used as barriers to IV vitamin K therapy. Comparison between the oral and subcutaneous route strongly favors oral for more rapid and predictable INR correction.9 Variation in subcutaneous vitamin K absorption can not only delay INR correction, but also can make it difficult to achieve a therapeutic INR in the following days.9 Despite earlier studies, the study by Meehan and colleagues contributes to the growing literature as it includes a large patient population (135), a variety of vitamin K doses, and analysis in a real clinical environment that includes asymptomatic to bleeding patients. Most importantly, it uncovers many of the clinical barriers to the use of vitamin K. The study finds a median lag time of 5 to 6 hours between INR results and vitamin K infusion in their bleeding cohort; the authors astutely advocate for increased laboratory and clinical coordination to communicate ST-INR results. The study also points out that VKA reversal may account for a large percentage of plasma use in the United States and the authors' effort to reduce unnecessary plasma usage should be applauded. The study also touches on the fear of using IV vitamin K among clinicians due to the risk of anaphylaxis. Anaphylaxis from vitamin K was linked to the solubilizing agent polyethoxylated castor oil.10 New formulations that use a polyoxyethylated fatty acid derivative instead, such as Konakion or Aquamephyton, should have a much lower risk for anaphylaxis, but true incidence is hard to determine given the rarity of reported cases.11 The overall incidence is estimated to be 3 per 10,000 with a wide confidence interval (0.04-11) and similar to common medications such as penicillin or contrast dye.10 These findings suggest that the perceived risk of anaphylaxis to the IV form of vitamin K is likely overexaggerated. Meehan and colleagues also point out that some of the alternatives used to vitamin K such as plasma have their own allergic and anaphylactoid risks. Moreover, the volume of plasma needed for INR correction in patients on VKA could cause transfusion-related circulatory overload, especially in an elderly population with cardiac conditions.12 Also, the cost of vitamin K therapy is miniscule compared to agents such as plasma, PCC, or rFVIIa. A retrospective review such as that by Meehan and colleagues will suffer from some shortcomings. The time between vitamin K administration and post-INR sample collections encompasses a wide range and results in very different median therapeutic times between the IV and PO group. There were no preestablished follow-up times for INR such as 4, 6, or 8 hours, which can be important to monitor in patients with severe hemorrhage. The timelier rechecking of INR in the IV group likely represents more vigilant care in sicker patients and coincides with the clinicians' preference for using IV route in bleeding patients. It would have been important to know how the time of vitamin K administration was documented since there can be a large difference between time of order placement, pharmacy dispense, and actual administration to patient. It would also be important to know how acute bleeding was graded and the type of bleeds present in this group. Since the risk of serious bleeds such as intracranial hemorrhage does not sharply increase until INRs are above 4.5,13 patients should have been stratified using this INR in addition to 1.5 and 2.0 in the study. Most importantly, the study is devoid of reporting adjunct use of plasma, PCC, or rFVIIa for VKA reversal in bleeding patients as these present serious confounders in the evaluation of INR correction by vitamin K. In our own large academic center, we have a protocolled approach for VKA reversal14 based on ACCP guidelines and support many of the conclusions drawn in the study by Meehan and colleagues. The IV form of vitamin K is favored for urgent INR reversal and often shows correction beginning within 4 to 8 hours. Oral forms correct INR in the 18- to 24-hour time frame. We totally discourage the subcutaneous route as INR corrections are sporadic and unpredictable with respect to time. Our program also has a prospective monitoring system to determine appropriate use of blood products and derivates such as plasma, PCC, and rFVIIa; the process is triggered by algorithms in the laboratory information system and the electronic health record. Through this mechanism, the transfusion medicine service is often involved in the care of patients with ST-INR and educates clinicians on appropriate reversal guidelines.15 Due to increased IV vitamin K use, there has been significant reduction in three-factor PCC use and almost complete elimination of plasma use.16 The low dose of vitamin K (1-2.5 mg) as opposed to high dose (10 mg) is not associated with difficulty in achieving a therapeutic INR when warfarin is restarted. We also promote the use of IV vitamin K in patients with elevated PT/INRs for reasons beyond VKA such as liver disease or long hospitalization because many of these patients can suffer from subclinical vitamin K deficiency17-19 and often show impaired gastrointestinal absorption of oral vitamin K.18 Thus, vitamin K should form a cornerstone for treatment of VK-associated ST-INRs with the IV form used for urgent reversal (4-8 hr). In clinical practice, the timing of vitamin K therapy and chosen route remain at odds with published guidelines. Overcoming these gaps will require greater collaboration between the laboratory and practitioners while addressing perceived risks from anaphylaxis or thromboembolic episodes after vitamin K therapy. Recently new oral anticoagulants (dabigatran etexilate and rivaroxaban) appear to be very attractive agents for thromboprophylaxis in certain clinical conditions as they do not require laboratory monitoring like VKA and are generally unaffected by diet and most drugs. However, some bleeding complications remain higher than VKA,20, 21 and there are no antidotes for both these agents compared to VKA, which can be specifically and rapidly reversed with vitamin K along with PCC or plasma. Unfortunately, vitamin K will not reverse anticoagulation with dabigatran or rivaroxaban. Since VKA administration is likely to remain a common practice for the foreseeable future, the observations of the study by Meehan and colleagues that VKA can be rapidly reversed, particularly with IV administration, should lead us to promote its more common use. None.