The Use of 4F-PCC to Correct Direct Oral Anticoagulant (DOAC)-Induced Coagulopathy: An Observational Analysis

Introduction

With the approval of four-factor prothrombin complex concentrate (4F-PCC, Kcentra) for the reversal of vitamin K antagonist-associated bleeding in the US, it has become a relatively common practice for 4F-PCC to be used in an 'off-label' fashion to correct coagulopathy caused by direct oral anticoagulants (DOACs) such as anti-Xa inhibitors. However, the efficacy and safety of 4F-PCC have not been well-studied in this scenario.

Methods

We performed a retrospective observational study on the off-label use of 4F-PCC for reversing DOAC-associated bleeding in a level one trauma center between November 2014 and February 2017; this time frame reflects the earliest time of using 4F-PCC as part of a DOAC reversal protocol at our facility. Data collected from the electronic medical record included: age, gender, and weight of patients, indications and dosage of 4F-PCC, INR as well as hemoglobin (Hgb) prior to and post 4F-PCC administration, clinical outcomes, and acute and chronic thromboembolic events occurring within 24 hours and 45 days of 4F-PCC administration respectively. In addition, thromboembolic events (if documented by primary teams) post 4F-PCC infusions were subsequently evaluated by both authors to determine the potential contributions of 4F-PCC.

Results

We identified 25 patients on DOACs who received 4F-PCC in our center during the study time frame. The patients included 14 females and 11 males with an average age of 68.27 ±17.46 years old. DOACs were essentially used in these patients for either atrial fibrillation (n=19) or prophylaxis for deep venous thrombosis /pulmonary embolism (n=6). Specifically, 13 patients were on Apixiaban, 11 on Rivaroxaban, and one on Fondaparinux. 4F-PCC was used to reverse DOAC-induced coagulopathy in the context of acute life-threatening bleeding and urgent surgeries /invasive procedures. The most common indications for 4F-PCC in our patients were intracranial hemorrhage (ICH; n=13), and gastrointestinal (GI) bleeding (n=8). Others were emergent surgeries (n=2), retroperitoneal hematoma (n=1) and vaginal bleeding (n=1). All except one patient (24/25 patients) received one dose of 4F-PCC; dosages of 4F-PCC were as follows: 50 U/Kg for 20 patients, 25 U/Kg for five patients and undocumented for one patient. Patients on DOACs did not show a significant decrease of INR after 4F-PCC administration (average pre-INR=1.13±0.21, average post-INR =1.03±0.05, p=0.06). However, clinically 4F-PCC appeared effective in stopping DOAC-associated bleeding. The bleeding of most patients (20/25 patients) improved as demonstrated by stabilized intracranial hemorrhage sizes and/or by steady Hgb concentrations (average Hgb concentration change = 0.13 ±1.94mg/dL, or average Hgb percentage change=3.22±23% of pre-Hgb concentration). Of note, some patients received RBC transfusions as well, thus the post-Hgb values were the combination results of 4F-PCC and RBC administrations. Notably, five patients died within one week of their bleeds/4F-PCC administration: four due to ICH and one due to GI bleeding. The cause of death for the four patients with ICH was attributable in all cases to irreversible brain damage associated with the initial hemorrhage (this despite the fact that bleeding was apparently controlled in all of these cases as per stabilization of hemorrhage size by imaging). The patient with massive GI bleeding died from intolerance to surgical intervention. In addition, we found 4F-PCC as associated with no thromboembolic events during the first 24 hours after 4F-PCCadministration. During 2-45 days post-4F-PCC infusion, four patients (4/25=16%) were found to have thromboembolic events: stroke, myocardial infarct, atrial thrombi and non-occlusive IJ tube thrombi.

Conclusions

Our data showed that 4F-PCC was relatively efficient in aiding the 'reversal' of DOACs for patients with severe hemorrhage. We did notice that 16% of patients experienced some form of thromboembolic events in the days-to-weeks after 4F-PCC administration, although the imputability of 4F-PCC in these processes (versus their underlying disease) is difficult to parse out. Additional, prospective studies would be warranted to further evaluate the safety of 4F-PCC for this off-label indication.