The Off-Label Use of Four-Factor Prothrombin Complex Concentrate: A Single Institution Retrospective Study

Abstract

Background/Introduction: 4-factor prothrombin complex concentrate (PCC) is currently approved in the United States for the urgent reversal of warfarin-induced coagulopathy in adults with acute major bleeding. However, the way in which 4-factor PCC is used in a real-world setting and the outcomes associated with off-label use is less clear. The objective of this study is to identify the indications that lead to 4-factor PCC use and the associated outcomes at a single university hospital.Methods: This was a single center retrospective cohort study of patients who received 4-factor PCC for any indication between July 2015 and April 2017 at Oregon Health & Science University. Patients were followed from index date until hospital discharge or in-hospital death. A given dose was considered “on-label” if it was given specifically for major bleeding secondary to warfarin-induced coagulopathy, whereas doses given for any other reason were considered “off-label”. Patients were also categorized based on the specific indication for receiving 4-factor PCC, which included intracranial hemorrhage, trauma-related bleeding, non-trauma-related bleeding, reversal of coagulopathy prior to an urgent procedure in non-bleeding patients, and intra- or post-operative bleeding. Also documented were baseline INR/PT/PTT and which form of anticoagulation, if any, a patient was on at baseline. Outcomes included duration of time between dose and INR normalization (defined as INR <1.5), duration of time between dose and ordering of follow-up coagulation parameters, duration of time between dose and hemostasis (determined based on vital signs, hemoglobin measurements, and/or imaging assessments), incidence of thromboembolic complications, and survival to hospital discharge.Results: In total,154 patients received 4-factor PCC during the study period accounting for 165 total doses. Ninety doses (54.5%) were considered on-label, while 75 doses (45.5%) were considered off-label. Of these off-label doses, 61 doses (81.3%) were considered off-label as they were given to patients not on warfarin therapy at baseline, while 14 doses (18.7%) were considered off-label due to lack of major bleeding. Intracranial hemorrhage was the most common indication (91 doses, 55.2%), followed by non-trauma-related bleeding (26 doses, 15.8%), pre-procedural reversal of coagulopathy without bleeding (21 doses, 12.7%), intra- and post-operative bleeding (13 doses, 7.9%), trauma-related bleeding (12 doses, 7.2%), and reversal of coagulopathy without bleeding in those not undergoing a procedure (2 doses, 1.2%). One-hundred patients (64.9%) were on warfarin at baseline, while the remainder were on direct oral anticoagulants (24 patients, 15.6%), heparin (3 patients, 1.9%), or no anticoagulation (25 patients, 16.2%), as depicted in Figure 1.Comparing on-label versus off-label use of PCC, there was no difference in time to INR normalization (p=0.24) or time to hemostasis (p=0.25). There was significantly shorter duration of time to ordering follow-up coagulation parameters in on-label versus off-label use (2.52 hours vs 3.97 hours, p=0.04). Comparing on-label versus off-label use, there was no difference in incidence of thromboembolic complications (8.9% vs 5.9%, p=0.76) or survival to hospital discharge (81.4% vs 67.6%, p=0.06).Conclusion: Despite being approved only for major bleeding related to vitamin K-antagonist use, 4-factor PCC is often administered in a wide variety of other settings in patients without major bleeding and those not on warfarin therapies. With the exception of duration of time to ordering follow-up coagulation parameters, outcomes in this single-center analysis comparing on-label versus off-label use were generally equivalent. Given the frequent use of 4-factor PCC outside of its currently approved indication, larger scale prospective trials studying specific indications are needed to validate its use in these settings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.