What literature supports flat dosing of Balfaxar (not Kcentra) for anticoagulation reversal?

Comment by InpharmD Researcher

Available evidence supports fixed-dose Balfaxar (Octaplex; 4-factor prothrombin complex concentrate [4F-PCC]) for anticoagulation reversal, although dosing varies by anticoagulant and clinical setting. For factor Xa inhibitor-associated major bleeding, guidelines and clinical studies support a fixed dose of 2,000 units, with repeat dosing if hemostasis is suboptimal, while warfarin reversal guidance supports a fixed dose of 1,500 units for intracranial hemorrhage-related major bleeding and 1,000 units for non-intracranial hemorrhage-related major bleeding. Across studies, fixed-dose strategies have generally demonstrated effective anticoagulation reversal and hemostasis and clinical outcomes broadly comparable to weight-based dosing without a notable increase in thrombotic or other adverse events, although the evidence is largely observational. Overall, fixed-dose Balfaxar may be a reasonable anticoagulation reversal strategy for both warfarin and factor Xa inhibitors, although an optimal fixed-dose regimen has not yet been established.
Background

The 2020 American College of Cardiology guidelines for management of bleeding during oral anticoagulation provide guidance on warfarin-related bleeding reversal using 4-factor prothrombin complex concentrate (4F-PCC) as a class and do not specifically mention Balfaxar. For vitamin K antagonist (VKA) reversal, 4F-PCC may be dosed using international normalized ratio (INR)-based weight-adjusted protocols or a fixed-dose approach of 1,000 units for non-intracranial major bleeding and 1,500 units for intracranial hemorrhage, with intravenous vitamin K co-administration. The guidelines do not provide fixed-dose prothrombin complex concentrate (PCC) protocols for direct oral anticoagulant-associated bleeding; instead, specific reversal agents are preferred, with PCC or activated PCC recommended as alternatives when targeted reversal agents (e.g., antidotes) are unavailable. [1]

The 2025 Thrombosis and Haemostasis Society of Australia and New Zealand (THANZ) guidelines provide guidance on direct oral anticoagulant (DOAC)-related bleeding using 4F-PCC and similarly do not specifically mention Balfaxar. The guidelines state that 4F-PCC can be administered either at a weight-based dose of 25-50 units/kg or as a fixed dose of 2,000 units, citing a recent meta-analysis of 25 studies that demonstrated no difference in bleeding reduction, thromboembolic rates, or mortality between weight-based and fixed-dose approaches. Importantly, these PCC-based strategies are positioned as second-line options; the guidelines preferentially recommend specific reversal agents when available. It is further specified that DOAC-specific reversal agents and hemostatic agents are unlikely to improve outcomes in patients with dabigatran levels below 50 ng/mL or apixaban/rivaroxaban levels below 75 ng/mL, underscoring the value of rapid drug-level measurement in guiding reversal decisions. [2]

A 2023 meta-analysis evaluated the effectiveness and safety of 4F-PCC for the treatment of major bleeding associated with oral factor Xa inhibitors. Involving data from 25 studies with a total of 1,760 patients, the analysis compared fixed versus variable dosing strategies. The primary outcomes measured were hemostatic effectiveness, mortality, and thromboembolic events, while secondary outcomes included 4F-PCC usage, length of stay in hospital and intensive care, and time to 4F-PCC administration. The findings revealed no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between fixed and variable dosing strategies. However, the average hospital stay was notably longer in patients receiving fixed doses. Additionally, the initial 4F-PCC dose was higher with variable dosing compared to fixed dosing. The analysis presented compelling evidence that fixed-dose 4F-PCC might be a viable and cost-effective alternative to variable dosing, with reduced product usage. Of note, use of Balfaxar specifically was not detailed within this analysis. [3]

A 2024 systematic review and meta-analysis examined the safety and efficacy of fixed versus variable-dose 4F-PCC for the reversal of VKA. A total of 23 studies (N= 2,055 patients) were included, comparing fixed-dose and weight-based dosing strategies. Notably, several included studies evaluated Octaplex, the international brand name for Balfaxar, with fixed doses ranging from 1,000 to 2,000 units depending on the indication and study protocol. The findings revealed that fixed dosing was less likely to achieve an INR <1.6 compared with weight-based dosing but showed similar efficacy for a target INR <2.0, with no significant differences in hospital mortality or thrombotic events between strategies. Overall, while fixed-dose protocols may reduce time to administration and potential costs, they may be insufficient for patients with lower INR goals as a surrogate for hemostasis or higher body weights, warranting cautious application until further confirmatory studies are available. [4]

Background References: [1] Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(5):594-622. doi:10.1016/j.jacc.2020.04.053
[2] Tran HA, Merriman E, Baker R, et al. 2025 Guidelines for direct oral anticoagulants: a practical guidance on the prescription, laboratory testing, peri-operative and bleeding management. Intern Med J. 2025;55(7):1174-1183. doi:10.1111/imj.70103
[3] Chiasakul T, Crowther M, Cuker A. Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing. Res Pract Thromb Haemost. 2023;7(2):100107. Published 2023 Mar 10. doi:10.1016/j.rpth.2023.100107
[4] Condeni MS, Weant KA, Neyens RR, Eriksson EA, Miano TA. Safety and efficacy of fixed versus variable-dose prothrombin complex concentrate for emergent reversal of vitamin K antagonists: A systematic review and meta-analysis. Am J Emerg Med. 2024;77:91-105. doi:10.1016/j.ajem.2023.11.066
Literature Review

A search of the published medical literature revealed 10 studies investigating the researchable question:

What literature supports flat dosing of Balfaxar (not Kcentra) for anticoagulation reversal?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-10 for your response.

Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors
Design

Prospective cohort study

N= 20
Objective To evaluate whether, in patients with therapeutic levels of oral anti-factor Xa inhibitors (XaI), pre-operative prothrombin complex concentrate (PCC) prevents excessive bleeding during and after emergency surgery and is not associated with thrombotic complications
Study Groups All patients (N= 20)
Inclusion Criteria Eligible patients were ≥18 years of age, receiving treatment with apixaban, rivaroxaban, or edoxaban, and in need of surgery/invasive procedure that could not be delayed for ≥8 hours and required normal hemostasis because of an expected blood loss of ≥50 mL
Exclusion Criteria Refusal to provide informed consent and surgery or invasive procedures that could safely be performed without discontinuation of anticoagulant therapy
Methods A fixed 2000 IU dose of 4-factor PCC (Octaplex, the Canadian brand of Balfaxar) was given to patients taking oral XaI with plasma XaI levels of at least 75 ng/mL before emergency surgery with expected blood loss of at least 50 mL. Patients were followed for 30 days. The primary efficacy outcome was the incidence of normal or mildly abnormal surgical hemostasis, as assessed by the surgeon; primary safety outcome was the incidence of thromboembolic events within 7 days.
Duration September 2018 to February 2024
Outcome Measures

Primary: Proportion of patients with normal or mildly abnormal surgical hemostasis

Secondary: Blood products used during and after surgery, decrease in hemoglobin from before surgery to nadir after PCC administration, estimated blood loss during surgery 
Baseline Characteristics   All patients (N= 20)
Age, y 74 (8.7)
Male sex, n (%) 10 (50)
Weight, kg 75 (15.5)
Body mass index, kg/m2 26.5 (4.7)
Creatinine clearance, mL/min 62 (32)
CrCl <30, n (%) 3 (15)
CrCl 30 to <60, n (%) 6 (30)
Indication for anticoagulation, n (%) - Atrial fibrillation 13 (65)
Indication for anticoagulation, n (%) - Venous thromboembolism 4 (20)
Indication for anticoagulation, n (%) - Both indications 2 (10)
Indication for anticoagulation, n (%) - Other 1 (5)
Anticoagulant treatment - Rivaroxaban daily dose 10 mg 1 (5)
Anticoagulant treatment - Rivaroxaban daily dose 20 mg 4 (20)
Anticoagulant treatment - Apixaban daily dose 5 mg 4 (20)
Anticoagulant treatment - Apixaban daily dose 10 mg 11 (55)
Baseline anti-Xa level, ng/mL, median (range) 128 (77-497)
Baseline hemoglobin, g/L 113 (28.8)
PCC dose, IU/kg 27 (6.1)
Interval last dose XaI to PCC 26 h 23 min (11 h 58 min)
Results   All patients (N = 20)
Primary efficacy outcome, n (%) - Normal or mildly abnormal hemostasis 16 (80)
Normal hemostasis 10 (50)
Mildly abnormal 6 (30)
Secondary efficacy outcomes - Blood products used after PCC, during and after surgery  
Patients transfused with red cells, n (%) 8 (40)
Red cell units given, median (range) 3.5 (1-14)
Patients transfused with plasma, n (%) 6 (30)
Plasma units given 2.5 (1-9)
Patients transfused with platelets, n (%) 4 (20)
Number of adult platelet units given 2 (1-3)
Hemoglobin decrease (from before PCC to nadir), g/L 29 (19)
Estimated surgical blood loss, mL, median (range) 155 (0-2000)
Primary safety outcome - Thromboembolism within 7 d, n (%) 1 (5)
Secondary safety outcomes - Thromboembolism between days 8 and 30, n (%) 0
All-cause mortality, n (%)* 4 (20)
*Causes of death were necrotizing fasciitis, prolonged respiratory failure, and COVID-19 infection; ruptured abdominal aortic aneurysm; pneumonia and chronic obstructive pulmonary disease and coronary artery disease; and recurrent sepsis and pancytopenia.
Adverse Events One thromboembolic event: incidental segmental pulmonary embolism in a patient with cancer and proximal deep vein thrombosis diagnosed just before the surgery.
Study Author Conclusions A fixed dose of PCC appears to control hemostasis in patients with therapeutic plasma levels of apixaban or rivaroxaban requiring emergency surgery.
Critique The study's strengths include the inclusion of patients needing reversal as defined by anti-Xa levels ≥75 ng/mL and the use of a fixed dose of PCC, which simplifies reversal. Limitations include the small sample size, nonrandomized design, and lack of independent adjudication of the severity of surgical bleeding. Additionally, the study lacked patients taking edoxaban, which was rarely prescribed during the study period.



Table 1 References:
[5] Schulman S, Bhagirath V, Chan N, et al. Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors. J Thromb Haemost. 2024;22:2761-2766. doi:10.1016/j.jtha.2024.07.002

Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study

Design

Multicenter, prospective study 

N= 84

Objective

To assess the efficacy and safety of 4-factor prothrombin complex concentrates (PCCs) for the reversal of the anticoagulant effect of rivaroxaban and apixaban

Study Groups

Apixaban (n= 39)

Rivaroxaban (n= 45) 

Inclusion Criteria

Patients on rivaroxaban or apixaban who required a PCC to manage acute and active major bleeding (defined by the International Society of Thrombosis and Hemostasis); administration of the last dose of either rivaroxaban or apixaban was within 24 hours

Exclusion Criteria

Patients with a drop of hemoglobin without an evident source of bleeding; preoperative reversal of rivaroxaban or apixaban; acute coronary syndrome or ischemic stroke within the past 30 days; received other hemostatic agents

Methods

Patients were recruited from 25 hospitals in Sweden and referred to the Coagulation Unit at Karolinska University Hospital. According to the hospital protocol, a flat dose of 1,500 IU of 4-factor PCCs was given to patients < 65 kg and 2,000 IU to patients ≥ 65 kg. A second dose of a PCC could be administered at the treating physician's discretion if patients were still bleeding. Patients' medical interventions, laboratory results, and outcomes were retrieved from their medical records. 

Two coagulation specialists assessed the effectiveness of bleeding management in each case and reached an agreement by discussion. 

Duration

Study enrollment: January 1, 2014, and October 1, 2016

Follow-up: 30 days post-treatment 

Outcome Measures

Duration of hospital stay, discharge destinations, and effectiveness of bleeding management

For non-intracranial hemorrhage (ICH): changes in the hemoglobin level, transfusion of blood products, intervention or surgery to stop the bleeding, and the administration of other hemostatic agents

For ICH: follow-up computed tomography (CT) within 24 hours, change in neurological status, and surgical intervention

Safety outcome: occurrence of arterial or venous thromboembolism and death

Baseline Characteristics

  

Apixaban (n= 39)

Rivaroxaban (n= 45) 

 p-value  

Median age, years (interquartile range [IQR])

77 (7 to 81)

 73 (68 to 84) 0.52  

Female

 17 (43.4%) 19 (42.2%) 1  

Median body weight, kg

75 (67 to 89)

75 (65 to 80)

 0.97  

Indication for anticoagulation

SPAF

VTE

Both

 

34 (87.2%)

2 (5.1%)

3 (7.7%)

 

29 (64.4%)

1 (2.2%)

15 (33.3%)

0.01

--

--

--

  

History of stroke

11 (28.2%)

 10 (22.2%) 0.62  

Concomitant medications 

Antiplatelet 

NSAID

 

7 (17.9%)

2 (5.1%)

 

3 (6.7%)

0

 

0.22

0.21

  

Baseline laboratory results

INR 

APTT

Creatinine

 

1.2 (1.1 to 1.3)

35 (32 to 39)

77 (61 to 83)

 

1.3 (1.1 to 1.5)

41 (36 to 49)

79.5 (63.5-99.5)

 

0.04

0.01

0.39

  

Bleeding location

ICH 

GI bleeding 

Visceral 

Genitourinary 

Musculoskeletal 

 

29 (74.4%)

5 (12.8%)

2 (5.1%)

2 (5.1%)

1 (2.6%)

 

30 (66.7%)

8 (17.8%)

3(6.7%)

2 (4.4%)

2 (4.4%)

0.95

--

--

--

--

--

  

Octaplex (Balfaxar; Octapharma) was given to 46.4% of patients, and Confidex/Beriplex (Kcentra; CSL Behring) was given to 52.4% of patients

SPAF, stroke prevention in patients with atrial fibrillation; VTE, venous thromboembolism; NSAID, nonsteroidal anti-inflammatory drug; INR, international normalized ratio; APTT, activated partial thromboplastin time; GI, gastrointestinal 

Results

Management given

Apixaban (n= 39)

Rivaroxaban (n= 45) 

p-value

  

Median PCC dose, IU factor IX

Total dose

Dose, IU/kg 

 

2000 (2000 to 2000)

26.7 (22 to 29.9)

 

2000 (1500 to 2000)

26.7 (20.8 to 29.4)

 

0.26

0.62

  

Transfusions given

Red blood cell concentrate

Plasma

Platelet

 

9 (23.1%)

2 (5.1%)

2 (5.1%)

 

11 (24.4%)

8 (17.8%)

8 (17.8%)

 

1

0.1

0.1

  

Outcome of management

 Apixaban (n= 39) Rivaroxaban (n= 45)
Effective  Ineffective Effective Ineffective

Bleeding location

ICH

GI

Visceral

Genitourinary

Musculoskeletal

 

21 (72.4%)

3 (60%)

0 

1 (50%)

1 (100%)

 

8 (27.6%)

2 (40%)

2 (100%)

1 (50%)

0 

 

22 (73.3%)

5 (62.5%)

1 (33.3%)

2 (100%)

2 (100.0%)

 

8 (26.7%)

3 (37.5%)

2 (66.7%)

0 

0 

Hemoglobin drop  

2 (33.3%)

 4 (66.7%)

3 (37.5%)

5 (62.5%)

Any invasive procedure 

None

Craniotomy

Gastroscopy

Embolization

Fasciotomy

Laparotomy

Thoracotomy

 

17 (68%)

5 (71.4%)

3 (75.1%)

0 

1 (100%)

0 

0 

 

8 (32%)

2 (28.6%)

1 (25%)

2 (100%)

0

0

0

 

23 (74.2%)

6 (100%)

1 (33.3%)

1 (50%)

0 

1 (50%)

0

 

1 (25%)

0 

2 (66.7%)

1 (50%)

0

1 (50%)

1 (100%)

Median length of hospital stay, days 

7 (3 to 15)

 4.5 (2 to 7)

9 (4 to 16)

2.5 (2 to 5)

Discharge destination

Home

Rehabilitation facility

Other hospital

Deceased

 

14 (93.3%)

7 (63.6%)

2 (66.7%)

3 (33.3%)

 

1 (6.7%)

4 (36.4%)

1 (33.3%)

6 (66.7%)

 

10 (90.9%)

13 (92.9%)

1 (100%)

5 (35.7%)

 

1 (9.1%)

1 (7.1%)

0 

9 (64.3%)

PCCs were administered 6 hours after the estimated bleeding time (2 to 10 hours). 

Most patients with ineffective hemostasis with PCC had ICH (n = 16; 61.5%).

Adverse Events

Occurrence of arterial or venous thromboembolism: ischemic stroke (n= 2) and pulmonary embolism (n= 1)

Study Author Conclusions

The study found that the majority of patients treated with PCCs for the management of major bleeding events (MBEs) on rivaroxaban or apixaban achieved effective bleeding control, with few observed thromboembolic events.

Based on the study results, the authors would suggest giving patients with MBEs on rivaroxaban or apixaban an initial PCC dose of 2000 IU, which may be repeated if the effect is suboptimal. Such an approach seems to be associated with an acceptable balance between efficacy and safety of PCCs.

Critique

The use of flat dosing of PCCs in this study led to an overall effective anticoagulant reversal when administered within a couple of hours of bleeding onset with a low risk of thromboembolism. However, the applicability of the study results of using flat doses of PCCs as reversal agents for rivaroxaban or apixaban may be limited by the absence of a control group.
Table 2 References:
[6] Majeed A, gren A, Holmstrm M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. doi:10.1182/blood-2017-05-782060

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

Design

Prospective observational multicenter cohort study

N= 66

Objective

To evaluate the use of prothrombin complex concentrate (PCC) at a dose of 2,000 units for the management of factor Xa-inhibitor–associated major bleeds

Inclusion Criteria

Received infusion of PCC (2,000 units) for major bleeding while on treatment with rivaroxaban or apixaban and not received other hemostatic agents, including plasma, platelets, activated PCC, or recombinant factor VIIa (antifibrinolytic drugs and local hemostatic agents were permitted) prior to administration of PCC

Exclusion Criteria

Established 'do not resuscitate' (DNR) orders, drop of hemoglobin without evidence of a source of bleeding, acute coronary syndrome, or ischaemic stroke in past 30 days

Methods

Patients were given 2,000 units PCC for reversal of rivaroxaban or apixaban and were followed up after PCC treatment, with information acquired using medical records and from patients directly. Treating physicians assessed the effectiveness of PCC treatment at 24 hours using all lab/testing results and imaging. Approximately 90% of the PCC used in Canada at the time of this study was Octaplex [Balfaxar], with the rest being Beriplex [Kcentra].

Rating categories included 'good,' 'moderate,' or 'poor,' with each category having preset criteria:

  • Good: bleeding stopped ≤1-hour post-infusion without an additional coagulation intervention
  • Moderate: bleeding stopped >1 to 4 hours post-infusion without an additional coagulation intervention
  • Poor: bleeding stopped >4 hours post-infusion with an additional coagulation intervention (plasma, whole blood, or coagulation factors)

Duration

Enrollment: July 2014 to July 2017

Follow-up: 30 ± 2 days

Outcome Measures

Primary: proportion of patients with effective PCC (as assessed by physicians)

Secondary: use of other blood products, decrease in hemoglobin from admission, length of stay in intensive care unit/hospital

Safety: thromboembolic events (including symptomatic DVT or pulmonary embolism, ischaemic stroke, heart valve or cardiac chamber thrombosis, symptomatic peripheral arterial thrombosis or myocardial infarction) within 7 days after PCC, 30-day event rate of thromboembolic events, deaths

Baseline Characteristics

  

All patients (N= 66)

Age, years

 76.9 ± 10.4

Male

 42 (67%)

Weight, kg (interquartile range [IQR])

 81 (68 to 90)

Anticoagulant treatment:

  

Patients on rivaroxaban

Daily dose, mg (IQR)

Time from last dose to PCC, hours

37 (56%) 

20 (15 to 20)

18.1 ± 10.3

Patients on apixaban

Daily dose, mg (IQR)

Time from last dose to PCC, hours

29 (44%)

10 (5 to 10)

17.8 (9.3) 

Treatment with PCC:

  

Time from onset of bleed to PCC, hours (IQR)

Time from arrival to PCC, hours (IQR)

First dose of PCC, IU

First dose of PCC, IU/kg

8.6 (4.8 to 18.1)

5.4 (3.3 to 7.8) 

2,072 ± 464

26.4 ± 7.7

Results

Endpoint

All patients (N= 66)

Effectiveness rating

Good

Moderate

Poor

 

43 (65%)

13 (20%)

10 (15%) 

Use of other blood products

Second dose of PCC (1,000 U and 2,000 U)

Red cells (1-8 U)

Platelets (1-3 apheresis or pooled U)

Cryoprecipitate

 

2 (3%)

13 (20%)

8 (12%)

1 (2%)

Decrease in hemoglobin from admission after PCC, g/L (IQR)

 18 (3 to 34)

Length of stay, days (IQR)

Hospital

Intensive care unit

 

16 (5.3 to 30)

0 (0 to 6) 

Thromboembolic events

Days 0-7

Days 8-30

 

2 (3%)

3 (5%)

Deaths

 9 (14%)

Adverse Events

In addition to adverse events listed in results section above, eight serious adverse events were reported: gastrointestinal bleeding (n= 3), gross hematuria (n= 2), cellulitis (n= 1), infection/hypernatremia/delirium (n= 1), neurological deterioration due to expansion of previously evacuated subdural hematoma (n= 1).

Study Author Conclusions

Management of oral factor Xa-inhibitor–associated major bleeding using PCC to achieve initial hemostasis was assessed by the treating physician as good in 65% of the cases, with 67% for intracranial and 69% for gastrointestinal bleeding. For another 20% of the cases, it was assessed as moderate.

Despite these ratings, patients still had significant morbidity and mortality, mainly after intracranial bleeding on anticoagulation. The risk of thromboembolism after reversal must be remembered and anticoagulation with at least a prophylactic dose should be started when bleeding has been controlled.

Critique

This was a Canadian study done without a control group, making it difficult to assess if the results were clinically significant. Additionally, patients were recruited after PCC treatment had already been administered; selection bias in deciding whether to treat with PCC may have excluded certain groups of patients. Notably, this study was funded by Octapharma, the manufacturer of Octaplex/Balfaxar; however, the grant was unrestricted and likely did not influence medication use during the study.
Table 3 References:
[7] Schulman S, Gross PL, Ritchie B, et al. Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study [published correction appears in Thromb Haemost. 2018 Dec;118(12):2188]. Thromb Haemost. 2018;118(5):842-851. doi:10.1055/s-0038-1636541
Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal
Design

Single-center, comparative, retrospective review

N= 226
Objective To report our experience with fixed-dose 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal
Study Groups

CNS bleed (n= 54)

Non-CNS bleed with INR ≤6 (n= 153)

Non-CNS bleed with INR ≥6.1 (n= 19)
Inclusion Criteria Patients ≥18 years of age, documented administration of 4F-PCC, currently taking warfarin, received institutional recommended 4F-PCC dose for bleeding or emergent surgery
Exclusion Criteria No INR drawn pre or post 4F-PCC administration, INR ≤1.3 at presentation, 4F-PCC given for non-warfarin reversal, institutional guidelines not followed
Methods

Retrospective analysis of patients receiving 4F-PCC for warfarin reversal. Fixed-dose regimen of 1000 or 2000 units based on indication. Data collected included INR values, 4F-PCC dose, patient weight, concurrent vitamin K administration, and clinical signs of bleeding.
Duration January 2015 to December 2016, and November 2017 to November 2018
Outcome Measures

Primary: Achievement of target INR

Secondary: Median INR after first dose of 4F-PCC, clinical signs of bleeding
Baseline Characteristics   Weight based (n = 102) Fixed (n = 124)
Male, n (%) 69 (67.6%) 69 (55.6%)
Age in years (SD) 69.9 (±17.2) 70 (±13.6)
Weight (kg), median (IQR) 85.5 (73.9-100.0) 87.1 (74.0-103.6)
Results   Weight based (n = 102) Fixed (n = 124) p-value
Achievement of goal INR 87 (85.3%) 75 (60.5%) <0.0001
Clinical signs of bleeding 34 (33.3%) 28 (23.0%) 0.09
Time to repeat INR (hours), median (95% CI) 2.39 (2.13, 2.73) 1.56 (1.32, 2.00) 0.01
Adverse Events Clinical signs of bleeding were similar between groups, with no significant differences noted
Study Author Conclusions

An FD strategy of 2000 units for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. However, an FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Higher doses may be needed to achieve target INR.
Critique

The study's retrospective design and lack of power calculation may limit the findings. Initial INRs were higher in the FD group, potentially affecting results. The study's generalizability is limited due to specific institutional practices and patient demographics.

 

Table 4 References:
[8] McMahon C, Halfpap J, Zhao Q, Bienvenida A, Rose AE. Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal. Ann Pharmacother. 2021;55(10):1230-1235. doi:10.1177/1060028021992142
Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage
Design

Retrospective, observational, multicentered, pre-post study

N= 90
Objective To validate the efficacy of a novel fixed-dose 4PCC protocol among patients with warfarin-associated intracranial hemorrhage (ICH)
Study Groups

Standard-dose (n= 48)

Fixed-dose (n= 42)
Inclusion Criteria Patients 18 years or older, received 4PCC for warfarin reversal in the setting of ICH, had an INR result >2 in the preceding 12 hours prior to receipt of 4PCC, and had a repeat INR drawn within 24 hours of 4PCC administration
Exclusion Criteria Pregnant, received FFP within six hours prior to 4PCC, baseline INR <2, received massive transfusion protocol within six hours of 4PCC, received FFP after 4PCC prior to first repeat INR result, received 4PCC for non-warfarin reversal indications, received an additional 4PCC dose prior to first repeat INR result, or received an incorrect 4PCC dose
Methods

Patients received either standard-dose 4PCC based on total body weight and initial INR or a fixed-dose of 2000 units. The primary outcome was the achievement of a target INR ≤1.4 on the first post-4PCC INR result. Data were collected via electronic medical record chart review.
Duration Standard-dose cohort: July 2016 to June 2017 Fixed-dose cohort: September 2017 to April 2019
Outcome Measures

Primary: Achievement of a target INR ≤1.4 on the first post-4PCC INR result

Secondary: Target INR achievement within 4 hours of 4PCC, thromboembolic complications within 7 days
Baseline Characteristics   Standard-dose (n= 48) Fixed-dose (n= 42)
Age (years), median (IQR) 79 (60.5–84.5) 79.5 (72–86)
Sex (male), no. (%) 29 (60.4) 22 (52.3)
Weight (kg), median (IQR) 74 (70–82.1) 77.6 (65.8–93.8)
Baseline INR, median (IQR) 2.7 (2.3–3.5) 2.8 (2.2–3.5)
Results   Standard-dose (n= 48) Fixed-dose (n= 42) p-Value
Post-4PCC INR ≤1.4, no. (%) 40 (83.3) 37 (88.1) 0.52
Post-4PCC INR, median (IQR) 1.26 (1.2–1.36) 1.16 (1.06–1.3) 0.004
Change in INR, median (IQR) 1.5 (1.1–2.3) 1.6 (1.1–2.3) 0.71
Adverse Events Thromboembolic complications were observed in 4.2% of the standard-dose group and 0% in the fixed-dose group
Study Author Conclusions

A fixed-dose 4PCC regimen of 2000 units for ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.
Critique

The study demonstrated that fixed-dose 4PCC is as effective as standard dosing for INR reversal in ICH patients, offering a simplified dosing regimen. However, the retrospective design and the fact that fixed-dose patients sometimes received higher doses than standard dosing may limit the generalizability of the findings. Additionally, the study did not enroll many patients with a TBW > 100 kg or a baseline INR > 5, which may be indications for increased dosing.

 

Table 5 References:
[9] Dietrich SK, Mixon MA, Rech MA. Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage. Am J Emerg Med. 2021;49:326-330. doi:10.1016/j.ajem.2021.06.032
High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage
Design

Retrospective cohort study

N= 31
Objective To compare the efficacy of high (4000 IU) versus low (2000 IU) fixed-dose four-factor prothrombin complex concentrate (4F-PCC) for warfarin reversal in patients with intracranial hemorrhage (ICH)
Study Groups

High dose 4F-PCC (n= 16)

Low dose 4F-PCC (n= 15)
Inclusion Criteria Patients on warfarin who received either low or high dose 4F-PCC for reversal and had both pre and post-brain imaging after 4F-PCC infusion
Exclusion Criteria Patients not on VKA therapy, did not receive 4F-PCC, did not have an ICH, or did not have adequate pre- and post-4F-PCC brain imaging
Methods Retrospective chart review comparing high (4000 IU) versus low (2000 IU) dose 4F-PCC. Patients also received 5 mg IV vitamin K for three days. Brain imaging was assessed pre- and post-4F-PCC infusion
Duration 2014 through 2018
Outcome Measures

Primary: Correction of INR to ≤1.5, improved or stable brain imaging post-4F-PCC

Secondary: Thrombotic events within three days of 4F-PCC infusion, 28-day mortality
Baseline Characteristics   High dose PCC (n= 16) Low dose PCC (n= 15) p-value
Patient weight, median (range), kg 86.5 (34.8–120.2) 80.0 (44.7–176.0) 0.29
INR pre-PCC, median (range) 4.4 (1.8–9.7) 3.9 (1.5–15) 0.90
Time from presentation to PCC infusion, median (range), hours 4.6 (0.2–12.6) 4.3 (0.4–20.8) 0.16
INR post-PCC, median (range) 1.2 (0.9–2.6) 1.4 (1.0–3.3) 0.20
INR correction (≤1.5) post-PCC, n (%) 14 (88%) 11 (73%) 0.39
INR at 24 h, median (range) 1.1 (0.9–1.2) 1.3 (1.0–1.5) 0.07
Received IV vitamin K upon presentation, n (%) 14 (88%) 15 (100%) 0.48
28-day mortality, n (%) 2 (0.1%) 1 (0.1%) 1.0
Thrombotic event within 3 days of PCC, n (%) 0 (0%) 0 (0%) 1.0
Results Change in brain imaging, all patients, n = 31 (%) Change in brain imaging, surgical cases excluded, n = 23
2000 IU PCC 12/15 (80%) improved/stable 9/11 (82%) improved/stable
4000 IU PCC 14/16 (88%) improved/stable 10/12 (83%) improved/stable
p-value 0.65 1.0
Relative risk of 2000 compared to 4000 1.6 1.09
Adverse Events No patients in either group had evidence of thrombosis within 3 days of receiving 4F-PCC
Study Author Conclusions

There was no significant difference between INR correction and brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal. A low-fixed dose 4F-PCC can be used in ICH patients with the added benefit of lower healthcare cost.
Critique

The study's strengths include the inclusion of a neuroradiology colleague for consistent brain imaging assessment and the economic analysis showing cost savings. Limitations include the small sample size, lack of randomization, and potential confounding from including neurosurgical patients. A larger randomized-control study is necessary for definitive conclusions.

 

Table 6 References:
[10] Compton F, Hall J, De Simone N, Usmani A, Sarode R, Burner J. High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage. Transfusion and Apheresis Science. 2022;61(5):103444. doi:10.1016/j.transci.2022.103444
Fixed vs Weight-Based Dosing of Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Patients With a Non-Neurologic Hemorrhage
Design Multi-center, retrospective chart review N= 59
Objective To evaluate the rate of hemostatic efficacy of weight-based (50 units/kg) vs fixed dose (2000 units) 4F-PCC for FXaI reversal in patients presenting with a non-neurologic hemorrhage
Study Groups Weight-based (n= 29) Fixed dose (n= 30)
Inclusion Criteria Patients greater than or equal to 18 years of age who received one dose of 4F-PCC for FXaI reversal for a non-neurologic bleed
Exclusion Criteria Patients who received 4F-PCC for indications other than FXaI reversal for a non-neurologic bleed and patients who received more than one dose of 4F-PCC
Methods

Retrospective chart review from January 21, 2020, to January 21, 2022, across a multi-center health system. Hemostatic efficacy was defined as the absence of hemorrhagic progression confirmed with imaging, >2 g/dl decrease in Hgb within 6 hours of 4F-PCC administration, reports of further significant bleeding within 48 hours, and a maintained or increased anti-factor Xa level from baseline.
Duration January 21, 2020, to January 21, 2022
Outcome Measures

Primary: Rate of hemostatic efficacy

Secondary: Mean hospital length of stay, administration of supplemental blood products within 24 hours, rate of thrombotic events within 7 days
Baseline Characteristics   Fixed Dose (n= 30) Weight Based (n= 29) P-value
Average age in years 73 ± 12.2 71.5 ± 13.1 0.65
Male, n (%) 14 (46.7) 18 (62.1) 0.3
Average weight. (kg) 88.1 ± 28.4 95.7 ± 37.5 0.56
Hypertension 21 (70) 22 (75.9) 0.77
Hyperlipidemia 12 (40) 19 (65.5) 0.07
Diabetes mellites 9 (30) 11 (37.9) 0.59
Atherosclerosis (Aortic or carotid) 0 (0) 4 (13.8) 0.05
Tobacco dependance 4 (13) 2 (6.8) 0.67
Alcohol abuse 2 (6.7) 3 (10.3) 0.67
Liver disease 1 (3.3) 2 (6.8) 0.61
Apixaban 24 (80) 17 (58.6) 0.09
Rivaroxaban 6 (20) 12 (41.4) 0.09
P2Y12 inhibitors 2 (6.7) 2 (6.8) 1
NSAID 2 (6.7) 2 (6.8) 1
Aspirin ≥325 mg 0 (0) 1 (3.4) 0.49
Results   Fixed Dose (n = 30) Weight-Based (n = 29) P-value
Hemostatic efficacy 28 (93.3) 27 (93.1) 1
Length of stay, days 5.93 ± 10.67 4.93 ± 3.6 0.21

Blood products administered within 24 hours

Fresh frozen plasma

Packed red blood cells

Platelets

Cryoprecipitate

 

3 (10)

16 (53.3)

1 (3.3)

0

 

1 (3.4)

22 (75.9)

1 (3.4)

0

  
Adverse Events Thrombotic events were similar between groups at 3.3% fixed vs 3.4% weight-based (P= 1)
Study Author Conclusions This study adds to current evidence suggesting that a fixed dose 4F-PCC is both safe and efficacious for FXaI reversal in non-neurologic bleeds
Critique The study's retrospective nature and small patient population are limitations. Hemostasis confirmation with imaging was not completed in a significant portion of patients, and hemoglobin levels were not available within 6 hours for many. No Factor Xa levels were drawn at baseline or post 4F-PCC administration. These factors may have contributed to low rates of lab and imaging data. Future large-scale prospective randomized controlled studies are necessary to confirm these results.

 

Table 7 References:
[11] Stokes T, Johnson C, Fish T, Mishler A. Fixed vs Weight-Based Dosing of Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Patients With a Non-Neurologic Hemorrhage. J Pharm Pract. 2025;38(6):499-506. doi:10.1177/08971900251319378
Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal
Design

Retrospective cohort study

N= 173
Objective To compare fixed versus weight-based PCC dosing for reversal of Factor Xa Inhibitor (FXaI) effects
Study Groups

Fixed-dose (n= 72)

Weight-based (n= 101)
Inclusion Criteria Patients aged ≥18 years who received PCC to reverse hemorrhage associated with apixaban or rivaroxaban
Exclusion Criteria Subjects receiving PCC for hemorrhage unassociated with apixaban or rivaroxaban
Methods

Retrospective chart review comparing fixed-dose PCC (5000 units for ICH, 2000 units for non-ICH) to weight-based PCC (50 units/kg). Data collected included time from order entry to administration, average PCC dose, hemostasis, and adverse events.
Duration April 26, 2021 to December 31, 2022
Outcome Measures

Primary: Time between order entry and medication administration

Secondary: Average PCC dose, hemostasis, 30-day mortality, hospital length of stay, adverse drug events
Baseline Characteristics   Fixed (n= 72) Weight-Based (n= 101) p-value
Age (years), mean (SD) 75.4 (11.3) 77.3 (11.1) 0.26
Gender, female, N (%) 29 (40.3) 47 (46.5) 0.41
Actual weight (kg), mean (SD) 82.2 (21.6) 79.0 (19.2) 0.33
Baseline SCr (mg/dL), mean (SD) 0.95 (0.54) 0.91 (0.61) 0.71
FXaI, N (%) - Apixaban 53 (73.6) 78 (77.2) 0.58
FXaI indication, N (%) - A. Fib/A. Flutter 58 (80.6) 79 (78.2) 0.19
Type of hemorrhage, N (%) - Intracranial 49 (68.1) 65 (64.4) 0.65
Results   Fixed (n= 72) Weight-Based (n= 101) p-Value
Average dose of PCC (units), mean (SD) 3898.9 (1338.7) 3821 (984.1) 0.68
Time from PCC order entry to administration (minutes), Median (IQR) 34.5 (26.25-42) 39 (26.25-55.75) 0.10
Achieved hemostasis, Yes (%) 57 (79.2) 72 (71.3) 0.24
Surgeries/interventions, Yes (%) 21 (29.2) 37 (36.7) 0.31
30-Day mortality (%) 19 (26.4) 36 (35.6) 0.18
Adverse Events There were zero adverse drug events reported. Rates of thrombosis were 2.8% in the fixed-dose group and < 1% in the weight-based group (p= 0.57)
Study Author Conclusions

The fixed-dosing strategy did not reduce time to PCC administration nor impact hemostasis or mortality. These data support that the fixed-dosing method is a viable option.
Critique

The study's retrospective design and single-site setting may limit external validity. The lack of a power calculation raises the possibility of a type II error. However, the study's consistent data collection and low missing data rate are strengths. Further research is needed to evaluate cost, safety, and efficacy of dosing strategies.

 

Table 8 References:
[12] Brett S, Taylor M, Pamela M, Michael G. Comparison of Fixed Versus Weight-Based Prothrombin Complex Concentrate Dosing Strategies for Factor Xa Inhibitor Reversal. Clin Appl Thromb Hemost. 2024;30:10760296241243368. doi:10.1177/10760296241243368

Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department
Design

Retrospective cohort study

N= 314
Objective To compare the efficacy and safety of frozen plasma with that of Octaplex (the Canadian brand name for Balfaxar), the available 4-factor prothrombin complex concentrate, in emergency departments during the study period
Study Groups

Frozen Plasma (n= 149)

Octaplex (n= 165)
Inclusion Criteria Patients who were ≥18 years of age, taking warfarin with an INR of ≥1.5, and received either frozen plasma or Octaplex in the ED for active bleeding or before an emergency procedure
Exclusion Criteria Patients <18 years of age, no documentation of warfarin use, administration without an initial INR check, or received both frozen plasma and Octaplex within 7 days
Methods Retrospective analysis comparing frozen plasma and Octaplex for warfarin reversal in two tertiary EDs. Octaplex doses were 1500 IU for intracranial hemorrhage and 1000 IU for other cases. Data were collected from health records, discharge summaries, and laboratory reports
Duration

September 2006 to August 2008: Plasma 

September 2008 to August 2010: Octaplex
Outcome Measures

Primary: Incidence of serious adverse events (death, ischemic stroke, myocardial infarction, heart failure, venous thromboembolism, peripheral arterial thromboembolism) within 7 days

Secondary: Time to INR reversal, hospital length of stay, red blood cells transfused within 48 hours
Baseline Characteristics   Frozen Plasma (n= 149) Octaplex (n= 165) p-value
Age (mean, SD), yr 76 (11.2) 77 (10.8) 0.664
Male (%) 81 (54.4) 99 (60) 0.313
Heart Failure (%) 50 (33.6) 32 (19.4) 0.004
Venous Thromboembolism (%) 10 (6.7) 22 (13.3) 0.053
Ischemic Heart Disease (%) 62 (41.6) 52 (31.5) 0.063
Gastrointestinal Bleed (%) 15 (10.1) 12 (7.3) 0.379
Hemodialysis (%) 4 (2.7) 6 (3.6) 0.753
Ischemic Stroke (%) 31 (20.8) 33 (20.0) 0.860
Peripheral Vascular Disease (%) 13 (8.7) 8 (4.8) 0.170
Anti-platelet (%) 33 (22.1) 40 (24.2) 0.661
Initial INR (Median, Q1-Q3) 2.9 (2.2–5.2) 3.0 (2.3–4.5) 0.432
Results Adverse Event (%) Frozen Plasma (N=149) Octaplex (N=165) p-value
Any Adverse Event 29 (19.5) 16 (9.7) 0.014
Death 22 (14.8) 15 (9.1) 0.120
Ischemic Stroke 0 (0) 0 (0) -
Myocardial Infarction 2 (1.3) 1 (0.6) 0.606
Heart Failure 4 (2.7) 0 (0) 0.0496
Pulmonary Embolism 0 (0) 0 (0) -
Deep Venous Thrombosis 1 (0.7) 0 (0) 0.475
Arterial Thromboembolism 0 (0) 0 (0) -
Any Adverse Event Excluding Death 7 (4.7) 1 (0.6) 0.029
Secondary Outcomes   
Time to INR reversal (hours) (Median, Q1-Q3) 11.8 (8.3–17.5) 5.7 (3.4–11.0) <0.0001
Hospital length of stay (days) (Median, Q1-Q3) 5 (2–12) 4 (2–11) 0.245
Mean units of packed red blood cells (Mean, SD) 3.2 (1.8) 1.4 (1.7) <0.0001
Adverse Events

Any Adverse Event: 19.5% in frozen plasma group vs. 9.7% in Octaplex group (p= 0.014)

Heart Failure: 2.7% in frozen plasma group vs. 0% in Octaplex group (p= 0.0496)

Any Adverse Event Excluding Death: 4.7% in frozen plasma group vs. 0.6% in Octaplex group (p= 0.029)
Study Author Conclusions Octaplex for urgent reversal of warfarin resulted in faster reversal and lower red cell transfusion requirement with fewer adverse events than frozen plasma.
Critique The study's retrospective design may introduce selection bias, and the lack of standardized timing for interventions could affect results. Despite these limitations, the study provides valuable insights into the efficacy and safety of Octaplex compared to frozen plasma for warfarin reversal. The findings are significant, but further prospective studies are needed to confirm these results and determine optimal dosing.
Table 9 References:
[13] Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013;128(4):360-364. doi:10.1161/CIRCULATIONAHA.113.001875

 

The effectiveness and safety of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of warfarin
Design

Retrospective case series

N= 103
Objective To investigate both the effectiveness and the safety of fixed low-dose prothrombin complex concentrates (PCCs) in patients requiring urgent reversal of warfarin
Study Groups All patients (N= 103)
Inclusion Criteria Patients aged 18 and older, taking a vitamin K antagonist, and either presented with major bleeding or required an urgent invasive procedure
Exclusion Criteria Patients with acquired coagulopathy due to cirrhosis or other known bleeding diathesis such as hemophilia
Methods Retrospective chart review of patients who received PCC for warfarin reversal. PCC (Octaplex, Canadian brand name for Balfaxar) was administered at a fixed dose of 1000 IU of FIX activity. Subsequent doses were given if the INR response or clinical response was insufficient. Data were collected on INR before and after PCC administration and clinical outcomes were evaluated
Duration January 2009 to October 2009
Outcome Measures

Primary: INR response
Baseline Characteristics   All patients (N= 103)
Median age, years (range) 78 (37-95)
Male 57 (55.3%)
Female 46 (44.7%)
Results   Clinical Response
INR ≤1.5 50 patients (48.5%)
INR 1.6 – 2.0 45 patients (43.7%)
INR 2.1 – 3.0 7 patients (6.8%)
INR 3.1 – 5.0 1 patient (0.97%)
Among 103 patients, 17 (16.5%) received more than one dose (>1000 IU) of PCC. After a second dose, 64.7% achieved an INR ≤1.5 and all achieved an INR ≤2.0; bleeding was successfully controlled without further intervention in 13 of 17 patients.
Adverse Events Five thrombotic events were reported within the 30-day follow-up period, including deep vein thrombosis (DVT) and non-ST elevation myocardial infarctions (NSTEMIs).
Study Author Conclusions At a fixed dose of 1000 IU of FIX activity, PCC seems to be effective and safe, but randomized controlled trials are required to confirm these observations.
Critique The study provides valuable real-world data on the use of fixed low-dose PCCs, demonstrating effectiveness and safety. However, the retrospective design and lack of a control group limit the ability to draw definitive conclusions. The small sample size may not capture rare adverse events, and variable timing of INR measurements post-treatment introduces potential bias.
Table 10 References:
[14] 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. Transfusion. 2013;53(7):1451-1450. doi:10.1111/j.1537-2995.2012.03924.x