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Oral Anticoagulation Reversal Learning Zone

Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices

Read time: 4 mins
Last updated:12th Mar 2020
Published:12th Feb 2020
Continuous flow left ventricular assist devices (CF-LVADs) are a life-saving device used in patients with severe heart failure, acting as an artificial pump while patients are waiting for a heart transplant (British Heart Foundation, 2018).

In conjunction with CF-LVADs anticoagulation therapy should be administered to prevent thrombus formation at the blood-pump interface. With this in mind, reversal of anticoagulation therapy during surgical procedures or to control bleeding can be complex and often requires partial or temporary reversal. However, some uncertainty remains over the safety and effectiveness of the use of four factor prothrombin complex concentrate (4F-PCC) for warfarin reversal in this setting. Hoping to discover how effective this approach can be and what safety implications may arise, Rimsans et al. retrospectively analysed 49 cases of 4F-PCC administration in 37 patients with CF-LVADs on warfarin therapy.

In patients with a bleed or requiring urgent surgery, warfarin reversal has been traditionally achieved though administering vitamin K and/or fresh frozen plasma (FFP) along with holding warfarin. However, reversal with vitamin K and FFP is often suboptimal. Vitamin K reversal can result in sustained, delayed or unpredictable reversal, while FFP has been reported to be time consuming and can result in transfusion associated reactions, volume overload, and allosensitisation – a particular concern for patients bridging to cardiac transplant.

Alternatively, reversal can be achieved by administering 4F-PCC, a human plasma-derived concentrate of clotting factors II, VII, IX, X, along with proteins C and S and a small amount of heparin (Beriplex® Prescribing Information, 2018). Despite 4F-PCC having an immediate effect on the international normalised ratio (INR), the effect can also be transient if vitamin K isn’t administered simultaneously. Further concerns over the safety of this approach exist due to the inherent risk of pump thrombosis, stroke, and systemic thromboembolism in patients with CF-LVADs (Sorensen et al., 2011; Kirklin et al., 2015).

Hoping to eliminate the concerns surrounding the safety of 4F-PCC by measuring thrombotic events and hoping to discover whether 4F-PCC is a feasible reversal option for this patient population, Rimsans et al. conducted a retrospective analysis of patient records between 2014–2017. The single-centre study was conducted at Brigham and Women’s Hospital, Boston, where 4F-PCC is the current clinical practice for warfarin reversal in the majority of CF-LVAD cases.

Patients with CF-LVADs undergoing elective or urgent procedures, or with major bleeding were assessed for post-procedure INR and thrombotic events within 30 days of 4F-PCC administration, including confirmed or suspected pump thrombosis. Thrombotic events included stroke, venous thromboembolism, arterial thrombosis, and myocardial infarction. The reversal approach and dosing of 4F-PCC was varied and at the discretion of the multidisciplinary team. Patients undergoing emergency procedures or major bleeding received the standard FDA approved dose for complete reversal, whereas those with mild-to-moderate bleeding or receiving an elective procedure were administered lower doses with a goal of the minimum reversal needed to allow procedures to be carried out safely.  Blood products were also used at the discretion of the operating team with 21 cases of emergency or major bleeding patients receiving packed red blood cells (PRBC), FFP, and platelets pre- and post-4F-PCC administration.

The effectiveness of 4F-PCC

In their analysis, Rimsans et al. found 37 patients received a total of 49 administrations of 4F-PCC. Of these, 47 administrations had available post-procedure INR values. However, post-infusion INR testing was decided by the operating team and therefore the timing varied between patients, ranging between 0.5–29 hours. The shortest interval for post procedure INR testing was observed in patients undergoing emergency procedures or major bleeding at 4 ± 3 hours. Patients undergoing elective procedures or minor bleeding had an average of 8 ± 9 hours for post-procedure INR testing.

Importantly, warfarin reversal was achieved following all 47 administrations with available data and a lowered INR value was observed in both the standard and in the lowered dose of 4F-PCC (figure 1).


Figure 1: Average INR values before and after 4F-PCC administration and associated average 4F-PCC doses administered (Rimsan et al., 2018).

The safety profile of 4F-PCC

The safety of 4F-PCC for warfarin reversal in patients with CF-LVAD was determined by thrombotic events within 30 days of administration, with this time point used as events after this period are unlikely to be related to 4F-PCC administration (Sarode et al., 2013).

Confirmed or suspected CF-LVAD pump thrombosis was evaluated per the standard definition:

  • a rise in lactate dehydrogenase (LDH) >2.5 times the upper limit of normal

  • plasma free haemoglobin >20 g/dL

  • haemoglobinuria or urobilinogen positive

  • power spike

  • changes in flow

  • signs of heart failure (Kirklin et al., 2015)

Overall, observed LDH values increased from 272 u/L before 4F-PCC administration to 317 u/L post administration (p=0.016). However, three patients were excluded from the analysis as they had elevated LDH values prior to 4F-PCC administration thought to be related to their critical condition. These patients subsequently died after 4F-PCC administration due to initial catastrophic events – as autopsies were not obtained, pump thrombosis could not be confirmed in these patients. After excluding these patients from the analysis, LDH increase was not reported to be significant (266 u/L before vs. 279 u/L after, p=0.138). This would indicate that pump thrombosis, the primary concern in this study, was not observed.

No further thrombotic complications were reported in this study, further supporting the safety of 4F-PCC for warfarin reversal in patients with CF-LVADs. However, this study did exclude patients with suspected acute pump thrombosis prior to 4F-PCC administration, and therefore it is advised that these patients are treated with caution.

Rimsans et al. have demonstrated how warfarin can be effectively reversed, both partially and temporarily, in patients with CF-LVADs using 4F-PCC. However, there were limitations to this study, such as a small sample size, lack of control sample, and varied time of INR measurement. A prospective phase 4 clinical trial is currently in progress which will improve upon some of the limitations within this study such as standardised INR monitoring, along with furthering our understanding of the safety of this treatment (US National Library of Medicine, 2018).