Fixed-Dose 4F-PCC for Reversal of Anticoagulation: Safety, Efficiency, and Cost Savings

Abstract

Objectives

The primary aim of this

study was to evaluate cost savings associated with fixed‑dose four-factor prothrombin complex concentrate (4F‑PCC) compared with historical weight‑based dosing. Secondary outcomes included INR reduction in patients taking warfarin, need for repeat dosing, 30‑day thromboembolic, hemorrhagic, and mortality events, and time to pharmacist verification and administration.

Study Design

This was a retrospective, single-center, institutional review board–approved chart review evaluating patients who received 4F-PCC for reversal of warfarin or a direct factor Xa inhibitor for clinically significant bleeding from May 2, 2024, to May 2, 2025.

Methods

Patients aged ≥18 years were included. Patients who were pregnant, had a diagnosis of disseminated intravascular coagulation or heparin-induced thrombocytopenia, were cardiothoracic surgery patients, or had a known allergic reaction to study components were excluded. Descriptive statistics were used to analyze and present study results. Cost savings were calculated by comparison with historical weight-based dosing strategies.

Results

Among the 130 patients analyzed, intracranial hemorrhage was the most frequent reason for reversal (33%). Approximately $369,472.30 was saved through fixed dosing. The mean time from order to administration was 46.19 minutes. Within 30 days, thromboembolic events occurred in 0.8% of patients, hemorrhagic events in 4.6%, and mortality was 16.9%. Repeat dosing was required in 11.54% of patients. Among warfarin users, 83.3% achieved an INR <2 following dosing.

Conclusions

Fixed dosing of 4F-PCC is a financially viable and safe option for reversal of clinically significant bleeding. Use of fixed-dose 4F-PCC can lead to substantial cost savings.

Introduction

Vitamin K antagonists (VKAs) and factor Xa inhibitors are widely prescribed for the prevention and treatment of thromboembolic events, yet both agents can carry substantial risk for clinically significant bleeding that requires rapid reversal. Four-factor prothrombin complex concentrate (4F-PCC) is routinely used for reversal but has several dosing strategies available. Although manufacturer guidelines recommend variable dosing based on patient weight or baseline INR, fixed‑dose regimens have emerged as an alternative to simplify administration and reduce preparation time in emergency settings.¹

Available literature suggests that many institutions have shifted from weight- and INR-based 4F‑PCC dosing strategies toward fixed-dose regimens, with these protocols now implemented across numerous hospitals and health care systems because of practical advantages.¹ This policy change was supported by an abundance of evidence that fixed-dose strategies can achieve comparable clinical outcomes while substantially reducing medication preparation and administration times.¹

Despite growing adoption of fixed-dose protocols for both VKA and factor Xa inhibitor reversal, real-world data evaluating the financial and clinical impact of transitioning from weight-based to fixed-dose policies at the institutional level within our health system remain limited. The purpose of this study was to evaluate the impact of our institution's transition from variable, weight-based 4F‑PCC dosing to a fixed-dose protocol for both VKA and factor Xa inhibitor reversal. Specifically, we aimed to quantify cost savings associated with the policy change while assessing safety and efficiency outcomes as seen in routine clinical practice.

Methods

This was a retrospective, single-center, institutional review board–approved chart review that examined patients from May 2, 2024, to May 2, 2025, who received 4F-PCC for reversal of warfarin or a direct factor Xa inhibitor for clinically significant bleeding. Patients were identified for review using a data report that captured individuals who received 4F-PCC during inpatient hospitalization at Novant Health New Hanover Regional Medical Center. Patients were included if they were 18 years or older, experienced clinically significant bleeding requiring reversal of either warfarin or a direct factor Xa inhibitor, received fixed-dose 4F-PCC, and had available documentation of pre- and post–4F-PCC administration laboratory values and imaging. Individuals were excluded if they had incomplete medical records, were pregnant, had a current or prior diagnosis of disseminated intravascular coagulation or known heparin-induced thrombocytopenia, were a patient who received a cardiothoracic surgery, or had a known allergic reaction to components of 4F-PCC.

Descriptive statistics were used to assess and present baseline characteristics and study findings. This included baseline and repeat INR for patients on warfarin, requirements for repeat dosing, the prevalence of 30-day outcomes (including hemorrhagic events, thrombotic events, and mortality), and time to key medication administration steps. Cost savings were determined by assessing the number of units not administered through the use of fixed-dose 4F-PCC compared to historical weight-based dosing. Units saved were multiplied by our current acquisition cost to determine overall annual cost savings.

Results

After the initial data extraction and exclusion of patients, a total of 130 patients were included in the analysis. Baseline characteristics are summarized in Table 1.

Among the analyzed cohort, the mean age was 76.2 years, and the mean weight was 80.1 kg. Male patients comprised 51.5% of the total population included. Most patients were White and received 4F-PCC in the emergency department (ED), with smaller proportions of patients receiving 4F-PCC in intensive care unit settings.

Regarding anticoagulation therapy, apixaban was the most common agent (70%), followed by warfarin (18.5%) and rivaroxaban (14.6%). The primary indication for anticoagulation was atrial fibrillation (73.8%), with other indications including history of deep vein thrombosis (DVT) or pulmonary embolism (PE) (7.7%), active DVT/PE (3.9%), mechanical valve replacement (5.4%), and other conditions (9.2%). For anticoagulation reversal, the most common indication was intracranial hemorrhage (ICH), either traumatic or nontraumatic (56.2%).

The primary outcome of cost savings was approximately $369,472.32. This estimate was calculated using an acquisition cost of $1.65 per unit (IU). Among the patients included in the analysis, approximately 223,500 units were avoided through the use of fixed-dose 4F-PCC compared to historical weight-based dosing. This is equivalent to around 447 of the 500-unit vials. The most frequently administered dose was 2000 units.

In the population included (N = 130), secondary outcomes and redosing requirements can be seen in Table 2. Hemorrhagic events occurred in 6 patients (4.6%) and thrombotic events in 1 patient (0.8%) within 30 days. Mortality was observed in 22 patients (16.9%), with 13 of these deaths (59.1%) caused by intracranial hemorrhage. Regarding redosing requirements, a total of 15 patients required redosing of 4F-PCC across both warfarin and factor Xa inhibitors. Twelve patients required 1 additional dose, and 3 patients required 2 additional doses. Approximately 53% of those who required additional doses were on factor Xa inhibitors.

Secondary outcomes for warfarin patients are shown in Table 3. Of this population, 7 (29.2%) required repeat 4F-PCC dosing, including 5 (20.8%) who required 1 additional dose and 2 (8.3%) who required 2 additional doses. The mean INR decreased from 6.1 prior to administration to 1.65 following the initial 4F-PCC dose. After initial administration, 20 patients (83.3%) achieved an INR <2, and 10 patients (41.7%) achieved an INR ≤1.4.

Outcomes related to workflow processes can be seen in the Figure. The mean time from order to administration was approximately 46 minutes, from verification to administration was approximately 37 minutes, and from order to verification was approximately 10 minutes.

Discussion

This study found that the use of a fixed-dose 4F‑PCC protocol is a viable alternative to weight-based dosing at our institution. The findings are consistent with prior studies and meta-analyses demonstrating that fixed-dose strategies reduce total 4F‑PCC utilization while maintaining comparable efficacy and safety outcomes.¹

In our study, a majority of warfarin-treated patients achieved meaningful INR reduction. This aligns with available studies showing that approximately 80% to 90% of patients reach an INR below 2 following fixed-dose 4F‑PCC, with a lower percentage achieving stricter INR goals.^1,2 Although repeat dosing was required in a subset of patients in both the warfarin and factor Xa inhibitor groups, this finding has been described in prior studies and represents a known limitation of fixed-dose regimens. Overall, evidence on clinical outcomes related to INR reduction in patients on VKAs across different bleeding events remains mixed and was not evaluated in this study.^1,2

This study also demonstrated favorable safety outcomes in the assessment of both thrombotic and hemorrhagic event rates. There was a low rate of thrombotic events (0.8%) at 30 days following 4F‑PCC administration, which is lower than the approximately 3% reported in other studies evaluating fixed dosing in patients on both warfarin and factor Xa inhibitors.³The rate of hemorrhagic events (4.6%) observed in this study was also comparable to previously published data, where bleeding or hemorrhagic complications have been reported in approximately 10% to 15% of patients.^4,5 Although this study lacked a comparator arm using weight-based dosing, the observed thrombotic and hemorrhagic event rates with fixed dosing are comparable to, and in some cases lower than, rates reported in the current literature.^4,5

Mortality observed in this study was also lower than or similar to reported literature. Fixed-dose 4F‑PCC regimens have demonstrated mortality rates ranging from approximately 15% to 20%, depending on the underlying patient population and severity of bleeding.³ This is particularly evident in intracranial hemorrhage, which remains associated with a high baseline risk of death. In our study, most deaths (59.1%) were attributable to complications of intracranial hemorrhage, suggesting a population that may benefit from further exploration of dosing strategies and relation to cost savings.⁶

From an operational standpoint, fixed-dose protocols have been associated with improved efficiency and reduced time to administration compared with weight-based approaches because of simplification with preparation. Although there is not a comparison arm with weight-based dosing, the order-to-administration times observed in this study support these findings and highlight the workflow advantages of simplified dosing strategies in emergency settings.^6,7

Limitations

This study is limited by its retrospective, single-center design, and the absence of a direct comparator group using weight-based dosing. Variability in redosing practices may have occurred based on provider preference, particularly in settings such as the emergency department, where patient volume is greater and monitoring practices may differ. Additionally, hemostatic effectiveness was not assessed using standardized criteria. Different criteria or guidelines for assessing rates of hemorrhagic, thrombotic, or mortality events may have been used across the studies used for comparison. Cost savings were estimated based on modeled historical dosing and did not account for the potential of repeat dosing. Furthermore, these cost estimates may not be generalizable, as they can vary across health systems depending on local acquisition costs, hospital size, and patient volume.

Conclusion

Use of a fixed-dose 4F-PCC protocol was associated with significant cost savings, timely medication administration, and a low incidence of thrombotic, hemorrhagic, and mortality events. The simplified dosing approach likely contributed to improved workflow efficiency, particularly in emergent settings. Despite study limitations, these results further support fixed-dose 4F-PCC as a practical and efficient option for anticoagulation reversal in patients receiving warfarin or factor Xa inhibitors.

REFERENCES

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