Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors

The factor Xa inhibitors rivaroxaban, apixaban and edoxaban gained popularity through their predictable pharmacokinetics, minimal food and drug interactions, and minimal monitoring (Mekaj et al., 2015). In addition, DOACs have lower rates of bleeding and act as a more effective stroke prevention treatment than warfarin (Granger et al., 2011; Patel et al., 2011). However, reversal of DOACs has proven challenging, especially given the pro-thrombotic nature of the conditions often being treated. The problem with reversing factor Xa inhibitors arises from the lack of available antidotes. This study by Toa et al. explores the safety of one potential antidote – 4-factor prothrombin complex concentrate (4F-PCC).

Despite limited data, 4F-PCC has shown some promising results in patients receiving rivaroxaban, restoring thrombin time and improving thrombin generation (Eerenberg et al., 2011; Schultz et al., 2017). While the results from these smaller-scale studies provide hope for the efficacy of this treatment, there are still questions hanging over the safety of 4F-PCC in this setting and the associated thrombotic risk is yet to be fully understood.

Hoping to add to the limited data and shed some light on the associated thrombotic risk, Tao et al. conducted a retrospective pilot study of 43 patients who were administered 4F-PCC for emergent reversal of rivaroxaban or apixaban between 2013 and 2017. Patients were identified from an inpatient pharmacy database at Yale-New Haven Hospital, a tertiary care hospital and level 1 trauma centre.

Is 4F-PCC safe for reversal of factor Xa inhibitors?

In order to determine the safety of 4F-PCC for reversal of DOACs in patients undergoing chronic anticoagulation treatment, the number of thrombotic complications was assessed. Determining a time scale of complication relevance has varied in previous studies; Tao et al., decided that only events that occurred within 14 days of treatment were a potential complication of 4F-PCC treatment. This was based on the half-lives of the various coagulation factors contained in 4F-PCC, particularly factor II (approximately 60 hours) which is believed to be highly associated with thrombotic events (Xi et al., 1989; Dielis et al., 2008).

The study sought to identify patients that experienced a thrombotic complication including deep vein thrombosis (DVT), pulmonary embolism, myocardial infarction, cerebral vascular accident, arterial thrombosis of limb or mesentery. Of these complications, only one patient had a reported event (2.1%, 95% CI 0.1–12.3) – an acute upper extremity DVT.

The small number of thrombotic complications could indicate that 4F-PCC appears to have a reasonable safety profile for the reversal of rivaroxaban and apixaban. However, the dose of 4F-PCC varied between patients, with only 16 patients (37.2%) receiving 50 IU/kg, as recommended by the European Heart Rhythm Association 2017 practical guidelines (Heidbuchel et al., 2017). The varied doses could be explained by the limited data and relatively new off-label purpose; of the cases analysed 74% had occurred within the last 2 years of the review period. It is thought that lower doses of 4F-PCC pose a lower risk of thrombotic complications as low doses have been shown to provide incomplete reversal in previous studies (Marlu et al., 2012; Escolar et al., 2013). The majority of patients in this study were underdosed, and, therefore, the results may not give a true representation of the safety of this treatment. 

Another variable that may have had an effect on the safety and efficacy of 4F-PCC in this study is the timing and type of DVT prophylaxis administered after 4F-PCC. Just over half of patients (51.2%) received both a sequential compression device and subcutaneous heparin with the remaining patients receiving a sequential compression device only. The low frequency of DVT prophylaxis with heparin treatment is likely due to concerns of further bleeding.

This study demonstrates the complexity of treating this patient group and establishing the safety of 4F-PCC as these patients will have a higher risk of thrombotic complications due to their underlying medical conditions. Further research is required in large, multicentre, prospective settings to determine the true risk of this anticoagulation reversal treatment.

Since this research was published andexanet alfa has been approved by the US Food and Drug Administration (FDA) with indications for reversal of rivaroxaban and apixaban (FDA, 2018). In addition, ciraparantag, another hopeful antidote for factor Xa inhibitors, is currently in clinical trials.