Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients

Direct oral anticoagulants (DOACs), including direct factor Xa inhibitors, are often an appealing treatment choice for long-term anticoagulation and the prevention of thromboembolic complications compared to warfarin. In contrast to warfarin, DOACs offer a more rapid onset of action, shorter half-lives, have fewer food and drug interactions, and more predictable pharmacokinetics removing the need for routine monitoring (Eliquis^® Summary of Product Characteristics, 2018; Lixiana^® Summary of Product Characteristics, 2018; Pradaxa^® Summary of Product Characteristics, 2018; Warfarin Summary of Product Characteristics, 2018; Xarelto^® Summary of Product Characteristics, 2018). However, treating DOAC-associated bleeding remains a concern as until recently there were no specific reversal agents; idarucizumab was approved for the reversal of dabigatran in 2015, and andexanet alfa was approved for the reversal of apixaban and rivaroxaban in 2018 (Praxbind^® Summary of Product Characteristics, 2018; Andexxa^® Prescribing Information, 2018). An alternative reversal treatment, which has been used off-label, is four-factor prothrombin complex concentrate (4F-PCC). It is believed that the combination of vitamin-K dependent coagulation factors II, VII, IX, X, and proteins C and S in 4F-PCC may overcome factor Xa inhibitors. Despite this theory, current data supporting the use of 4F-PCC for DOAC-associated bleeding reversal is limited, and the optimum dose remains unclear with some studies finding 50 U/kg to be successful (Eerenberg et al., 2011). But could low-dose 4F-PCC be an effective reversal treatment and prevent bleeding progression?

This retrospective, observational study, included 33 adult patients admitted to Memorial Hermann-Texas Medical Center with a major bleed between 2013–2015. All patients had received a direct factor Xa inhibitor prior to the bleed and their admission, of which rivaroxaban was the most common (81.8%). A single dose of 35 U/kg 4F-PCC was administered to all patients, at a median of 2.5 (IQR 1.2–4.2) hours after initial computed tomography (CT) scan; however, four patients required a second dose due to elevated clotting time on thromboelastography (TEG) (n = 2), worsening contusions on CT scan (n = 1), or continued bleeding in the operating room (n = 1). Blood products were also administered in some patients with 33.3% (n = 11) receiving 1–2 U of fresh frozen plasma (FFP), 27.2% (n = 9) of patients receiving a platelet transfusion, and 21.2% (n = 7) of patients receiving 1–2 U of packed red blood cells (PRBCs) while one patient received 4 U of PRBCs.

Monitoring bleeding progression

The primary outcome of this study was the measure of successful haemostasis; to evaluate the progression of bleeding repeat CT scans were performed in 27 patients, with the remaining patients being followed up clinically (n = 2), undergoing oesophagogastroenteroscopy (n = 1), or going into the emergency room immediately after receiving the dose (n = 1). Two patients were not included in the primary outcome assessment due to withdrawal of care and the inability to determine drug efficacy. Repeat CT scans revealed bleeding progression in 4 patients, and 1 patient was reported to have continued intra-abdominal wound bleeding in the operating room. Interestingly, of these patients with bleeding progression, only 2 received a further dose of 4F-PCC. Despite this, the overall effect of 4F-PCC appeared to be positive, with haemostasis being achieved in 83.8% (n = 26) of patients.

Secondary outcomes of low-dose 4F-PCC

Secondary outcomes of all 33 patients revealed a median length of hospital stay of 7.1 (IQR 3.2–12.2) days, and a median length of intensive care unit stay of 2 (IQR 1.2–5) days, with the majority of patients being discharged to either home (36%), or another facility (36%), while the remaining patients were discharged to a hospice (12%).

Mortality rates appeared to be low, with death occurring in 5 patients. Cause of death was reported to be due to withdrawn care (n = 3) or pneumonia and multi-organ failure (n = 2). Perhaps unsurprisingly, of the patients who died, bleeding progression had been seen in 2 patients during repeat CT scans.

Thromboembolic events had been reported to be extremely low in a previous study (1.4%) investigating 4F-PCC in patients taking warfarin (Siegal, 2015). In Allison et al., no thromboembolic events due to 4F-PCC were reported, however, routine imaging studies weren’t carried out unless clinically indicated, and therefore the study was not designed to detect the incidence of these complications.

Summary

This study offers new insights and is the first of its kind to investigate the effectiveness of 4F-PCC for reversal of DOAC-associated bleeding and haemostasis at a dose of 35 U/kg. This study suggests that DOAC-associated bleeding can be overcome with 4F-PCC with active haemostasis being achieved in the majority of patients with a major bleed after receiving 35 U/kg of 4F-PCC. However, further larger studies are needed to assess the safety of this treatment.