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Oral Anticoagulation Reversal Learning Zone

Evaluating fixed-dose 4F-PCC for VKA reversal

Read time: 15 mins
Last updated:11th May 2020
Published:11th May 2020
Fixed-dose four-factor prothrombin complex concentrate (4F-PCC) is a commonly used rapid first-line reversal agent for vitamin K antagonists (VKA). However, the optimal dosing strategy for 4F-PCC is unknown. In this multicentre, noninferiority, interventional, quasi-experimental cohort study a fixed-dose 4F-PCC protocol shows non-inferiority to the standard weight-based dosing protocol.

Bitonti MT, Rumbarger RL, Absher RK, Curran LM. J Emerg Med. 2019 Nov 28. DOI:

Combined with intravenous vitamin K, 4F-PCC is an important first-line agent for patients requiring VKA reversal for major bleeding complications or during invasive surgery (Tomaselli et al., 2018).

It has become the preferred treatment over fresh frozen plasma (FFP) because of its superior efficacy and similar level of safety (Goldstein et al., 2015) as well as its lower volume requirements, faster preparation times and reduced immunogenicity risk (Leissinger et al., 2008).

Despite its prevalence, the optimal dosing strategy for 4F-PCC is still unknown. FDA-approved dosing guidelines currently depend on dosage calculations using the patient’s baseline international normalised ratio (INR) and weight (Khorsand et al., 2015).

This has led to new research investigating the potential of a low, fixed-dose strategy for 4F-PCC products due to the decreased cost of administration as well as the benefits of removing the dosage calculation and allowing for bedside admixture (Hall et al., 2018). This new strategy could allow for more rapid administration as well as an accelerated INR reversal and achievement of homeostasis (Hall et al., 2018).

Is a fixed-dose protocol for warfarin reversal inferior?

Across four hospitals and one stand-alone emergency department in the United States, the authors aimed to prospectively evaluate the efficacy and safety of a low, fixed-dose 4F-PCC protocol for the rapid reversal of warfarin in cases of severe bleeding or the need for an invasive procedure.

The study compared a retrospective cohort of thirty subjects using a baseline weight-based dosing protocol of 4F-PCC described in the Kcentra package insert (Kcentra™ Prescribing Information, 2013) against a prospective cohort of twenty-four subjects receiving a low, weight dependent, fixed-dose of Kcentra 4F-PCC 1500 or 2000 units factor IX trial (FIX) (Klein et al., 2015).

The primary endpoint was the achievement of a post-infusion INR of <2. Secondary endpoints included achieving a post-infusion INR of <1.5, comparable mean INR values after 24 hours as well as comparable mortality and venous thromboembolic events (VTE) after seven days (Figure 1).


Figure 1: The percentage of patients reaching the primary and secondary endpoints. INR, international normalised ratio; VTE, venous thromboembolic events; 4F-PCC, fixed-dose four-factor prothrombin complex concentrate.

The primary endpoint of a post-infusion INR <2 was achieved in 95.8% vs 96.7% of patients, respectively (p=0.0035). This showed that a fixed dose of 1500 units for the majority of patients was not inferior to the INR and weight-based protocol and fixed doses of 2000 units were similarly effective in the subgroup of patients with a higher baseline weight or INR.

Unexpectedly, while the authors achieved similar percentages in the secondary endpoint of a post-infusion INR <1.5 for the INR and weight-based dose protocol and fixed-dose protocol (75% vs 90%, respectively), the results were not found to be statistically significant for non-inferiority (p>0.4).

Despite this, a sustained anticoagulation reversal with lower doses of 4F-PCC was observed. The secondary endpoint of comparable INR values twenty-four hours after administration were found to be almost identical between the two groups. There were also no significant differences in mortality or venous thromboembolic events during the seven days following administration of 4F-PCC.

The results of this study suggest that a fixed-dose 4F-PCC dosing strategy is not inferior to the standard weight-based protocol and that a fixed-dose 4F-PCC strategy is safe and effective for the rapid reversal of VKA-associated anticoagulation. This aligns well with previous research that has shown mostly positive results with varying dosing protocols (Khorsand et al., 2011; Varga et al., 2013) and recent retrospective trials showing the successful implementation of a fixed-dose protocol (Astrup et al., 2018; Scott et al., 2018).

There are some notable differences to this study compared with other recent fixed-dose 4F-PCC trials including using lower levels of FFP, having a higher baseline INR and having two weight dependent FIX doses (Klein et al., 2015; Astrup et al., 2018; Scott et al., 2018). But, given the quasi-experimental nature of the study, further randomised studies with haemostatic outcome measures will be required to definitively determine if a fixed-dose 4F-PCC strategy is effective and safe for the reversal of VKA-associated major bleeding.


Astrup G, Sarangarm P, Burnett A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis. 2018;45(2):300–305.

Goldstein JN, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: A phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385(9982):2077–2087.

Hall ST, Molina KC. Fixed-dose 4-factor prothrombin complex concentrate: we don’t know where we’re going if we don’t know how to get there. Journal of Thrombosis and Thrombolysis. 2018;46(1):50–57.

Kcentra Prescribing Information. CSL Behring LLC. 2013. Available at: (accessed 1 April 2020)

Khorsand N, Veeger NJGM, Muller M, Overdiek JWPM, Huisman W, van Hest RM, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2):116–123.

Khorsand N, Kooistra HAM, Van Hest RM, Veeger NJGM, Meijer K. A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy. Thrombosis Research. 2015;135(1):9–19.

Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213–1218.

Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature. Am J Hematol. 2008;83(2):137–143.

Scott R, Kersten B, Basior J, Nadler M. Evaluation of fixed-dose four-factor prothrombin complex concentrate for emergent warfarin reversal in patients with intracranial hemorrhage. J Emerg Med. 2018;54(6):861–866.

Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042–3067.

Varga C, Al-Touri S, Papadoukakis S, Caplan S, Kahn S, Blostein M. The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin (CME). Transfusion. 2013;53(7):1451–1458.