Dave is an associate professor at Duquesne University School of Pharmacy and emergency medicine pharmacist at UPMC Mercy Hospital. He completed residency training at The Johns Hopkins Hospital and Maimonides Medical Center in Brooklyn, NY. His practice interests include medication dosing in patients that are obese and pain management in the ED.
The Pre-brief
There is a lot of great discussion on warfarin reversal and dosing of 4-factor prothrombin concentrate concentration (PCC), package label vs. flat-dose, but what sometimes gets overlooked is dosing of phytonadione (technically vitamin K1). I know my immediate reflex is to recommend 10mg intravenous (IV) but is that the optimal dose to always use? The answer may not be so simple…
Please note I use the terms phytonadione and vitamin K terms interchangeably in this post as vitamin K is the most commonly used (and easier to say) formulation and term.
What we already know about Vitamin K for warfarin reversal
Administration of vitamin K can bypass or overcome the effect of warfarin on vitamin-K-epoxide reductase, leading to the production of vitamin K dependent clotting factors (II, VII, IX, X). The reduction in INR is dose-dependent which we will discuss in a little bit. Route of administration is also important as this impacts the onset and timing of reversal. Administration via the IV route has the shortest onset of action as factors will start to be produced 2-4 hours after administration and full effect seen ~12 hours after administration.1 Oral vitamin K has a longer onset of action and can take up to 24-36 hours for the full effect to be seen. Intramuscular and subcutaneous administration should be avoided when reversing warfarin due to erratic absorption. And yes, as I get this question a lot, IV administration has a connotation with anaphylaxis but this is not a concern when we dilute and administer over 15-30 mins. Anaphylaxis, with a reported rate of 3 per 10,000 doses, is thought to be associated with older IV formulations that contain polyethoxylated castor oil compared to the more modern micelle formulations.
What dose of vitamin K do the guidelines recommend?
A full review of all the various organizational guidelines is beyond the scope of this post (see a great recent review here). Typical dosing for emergent reversal of warfarin with Vitamin K is 5-10 mg IV but lower doses for non-emergent situations can be utilized as well.
Tsu and colleagues conducted a retrospective analysis of 400 patients who received vitamin K for reversal of warfarin between February 2008 and November 2010 to evaluate the effect of the dose and route on the reduction of the INR. Higher doses (5-10mg) were more likely to fully reverse the INR (<1.5) compared to lower doses (< 5mg) but lower doses more likely reached a partial reversal (INR 1.5-2) at 48 hours. One of the potential concerns with using higher doses of vitamin K is difficulty in obtaining a therapeutic goal upon reinitiating warfarin. But in this study, patients receiving larger doses (5-10mg) compared to doses of 0.25-1.25mg had a non-statistically significant increase in the duration of bridging of 9.7 days vs. 7.2 days. There are several limitations to note including a retrospective study design, small study population, and co-administration of fresh frozen plasma (FFP). Of note, patients were included if they received FFP but not if they received PCC or activated VIIa.
Most recently, Culig et al compared low dose (1-2mg) to ultra-low dose (0.25-0.5mg) IV vitamin K for warfarin reversal. A total of 88 patients were included in this observational, retrospective cohort study. The median INR in the low dose group decreased from 4.5 to 1.8 at 12 hours and then to 1.5 at 36 hours vs. the ultra-low dose group with an initial INR decrease of 5.1 to 2.3 at 12 hours and then to 1.7 at 36 hours. The decrease in INR was not statistically different at 12 or 36 hours between the two groups.
As you can imagine there are a lot of confounders when studying warfarin reversal but in this study, patients were excluded if they received PCC or FFP. This makes it easier to evaluate the effect of vitamin K by itself, but limits application as the use of PCC/FFP is standard for emergent reversal. We must conclude that this study population did not have life-threatening bleeds requiring emergent reversal and caution should be made when applying to this population. Additional limitations include the small, retrospective design, and missing INR values.
Interested in reading additional articles on the use of vitamin K and the effect that dose and route have on warfarin reversal? Check out this review.
What are the issues if I overcorrect the INR?
- Thrombotic complications depending on the indication for anticoagulation
- Difficulty or potential delay in obtaining therapeutic INR when warfarin is restarted
Things to consider in general when reversing warfarin:
- The severity and/or urgency for reversal
- What is their initial INR as we know low doses of vitamin K are less likely to meet INR targets when the initial INR >10
- Patient indication for warfarin and risk of thrombosis if and/or when sub-therapeutic (i.e., remote DVT vs. atrial fibrillation vs. mechanical mitral valve are vastly different risks)
- Planned procedures and timing that have a target INR
The Debrief
- IV vitamin K, in addition to 4-PCC, should be given for emergent reversal of warfarin
- Most guidelines recommend vitamin K 5-10mg IV for emergent reversal
- Lower doses of vitamin K may be appropriate in non-life-threatening bleeds and/or in patients where lowering the INR below goal could be more detrimental
- Baseline INR prior to reversal is also important as low doses of vitamin K may not reverse significantly elevated INRs. Likewise large doses of vitamin K may not be needed if INR is slightly above goal range
References
- Makris M, van Veen JJ, Maclean R. Warfarin anticoagulation reversal: management of the asymptomatic and bleeding patient. J Throm Thrombolysis. 2010; 29(2):171-81. https://pubmed.ncbi.nlm.nih.gov/19882303/
- Milling TJ, Pollack CV. A review of guidelines on anticoagulation reversal across different clinical scenarios- is there a general consensus? Am J Emerg Med. 2020;38(9):1890-1903. doi: 10.1016/j.ajem.2020.05.086. https://pubmed.ncbi.nlm.nih.gov/32750627/
- Tomasselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American college of cardiology solution set oversight committee. J Am Coll Cardiol. 2020;76(5):594-622. https://pubmed.ncbi.nlm.nih.gov/32680646/
- Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: executive summary. Crit Care Med. 2016;44(12):2251-57. https://pubmed.ncbi.nlm.nih.gov/27858808/
- Tsu LV et al. Vitamin K dosing to reverse warfarin based on INR, route of administration, and home warfarin dose in the acute/critical care setting. Ann Pharmacother. 2012;46(12):1617-26. doi: 10.1345/aph.1R497 https://pubmed.ncbi.nlm.nih.gov/23249867/
- Culig CE et al. INR response to low-dose Vitamin K in warfarin patients. Ann Pharmacother. Feb 5, 2021. doi: 10.1177/1060028021993239 https://pubmed.ncbi.nlm.nih.gov/33543639/
- Brophy MT, Fiore LD, Deykin D. Low-dose vitamin K therapy in excessively anticoagulated patients: a dose finding study. J Thromb Thrombolysis. 1997;4:289.92. https://pubmed.ncbi.nlm.nih.gov/10639272/
- Lubetsky A, Shasha Y, Olchovsky D, Loebstein R, Halkin H, Exra D. Impact of pre-treatment INR level on the effect of intravenous low dose vitamin K in patients with excessive anticoagulation. Thromb Hamost. 2003;90(1):71-6. https://pubmed.ncbi.nlm.nih.gov/12876628/
