Efficacy of Oral Vitamin K to reverse chronic Warfarin Anticoagulation at 24 hours: A Phase 2 pharmacological Modelling Study.

The peri-operative management of patients on long-term warfarin therapy is a common clinical problem which poses particular problems and uncertainties given the absence of clinical trials. Approximately 400,000 patients are assessed annually in North America for temporary interruption of warfarin therapy for elective surgical or invasive procedures. In Australia, this amounts to approximately 23,000 patients per year, and it is estimated that 700 such patients undergo surgical intervention annually at Southern Health. It is also likely that warfarin will remain the predominant form of anticoagulation for a long time despite the arrival of the novel anticoagulants. For many procedures, patients need to stop their warfarin to avoid bleeding at surgery and resume this postoperatively to prevent thrombosis. The literature does not define a standard of care so that there is considerable variability in how this is achieved with strategies ranging from cessation of warfarin 5 days prior, to “bridging” with heparin therapy when the INR falls below 2. The former approach is simpler but can expose high-risk patients to a significant risk of thrombosis whereas the latter requires timely coordination, and is resource intensive as well as costly. On the other hand, if warfarin is inadequately reversed many elective procedures might be cancelled at short notice inconveniencing patients and wasting valuable surgical operating times. Therefore, there is a need to identify a safe, simple, effective and readily available strategy to reverse warfarin across a broad spectrum of perioperative scenarios. Recently, Burbury et al (BJH 2011) demonstrated that 3 mg of intravenous (IV) Vitamin K (VK1) administered on the eve of surgery is effective and safe at reversing the anticoagulant effect warfarin in most patients. Furthermore, neither warfarin “resistance” nor thrombo-embolism was observed when warfarin was resumed postoperatively (0%, 95%CI: 0% to 2.6%). However, this approach requires the inconvenience of attending an outpatient clinic for insertion of an intravenous cannula for IV VK1 administration. Moreover, there is a small risk (3 in 10, 000) of allergic/anaphylactic reaction with the IV route. Although slower in its onset of action, a few studies have shown that given sufficient time, oral VK1 is as effective and safe in reversing warfarin as IV VK1. The oral dose represents a convenient and cheaper way of administration with minimal adverse reaction when compared to the IV formulation. Moreover, oral VK1 is a convenient way of administration with minimal adverse reaction compared to the IV route. This oral approach, if proven, would simplify pre-operative management of warfarin therapy, and has the potential to improve the care of thousands of patients in the perioperative setting. However, the optimal dose of VK1 that is required to reverse the INR of the majority (95%) of patients without causing warfarin resistance is uncertain. Firstly, we propose a prospective phase 2 dose finding study using pharmacological modeling and simulation to predict the effective dose for oral VK1 capable of reversing warfarin induced anticoagulation in a group of patients who are going to complete a defined period of anticoagulation therapy and therefore at minimal risk. Once an effective oral VK1 dose is identified, we plan to validate this dose in a prospective phase 3 clinical trial involving elective surgical patients.