Open-label, multicenter, randomized clinical trial

Reversal of vitamin K antagonists

N= 159

Fixed-dose (n= 79)

Variable dose (n= 79)

4F-PCC 1,000 IU

vs

4F-PCC variable dose

Effective hemostasis:

87.3% in the fixed-dose group versus 89.9% in the variable group (risk difference 2.5%; 95% CI -13.3% to 7.9%; p= 0.27)

Median door-to-needle time:

109 min in the fixed-dose group versus 142 min in the variable group (p= 0.027)

The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.

Retrospective study

Reversal of vitamin K antagonist (warfarin)

N= 265

Fixed-dose (n= 90)

Variable-dose (n= 175)

4F-PCC 1,000 IU

vs

4F-PCC variable dose

Effective hemostasis:

37.8% in the fixed-dose group versus 21.7% in the variable group (p= 0.005)

INR ≤ 1.5:

62.5% in the fixed-dose group versus 69.4% in the variable group (p= 0.26)

In-hospital mortality: no difference

Time to administration was 20 minutes faster and cost was reduced using fixed-dosing

Retrospective study

Reversal of vitamin K antagonist (warfarin) with intracranial hemorrhage

N= 31

Low fixed-dose (n= 15)

High fixed-dose (n= 16)

4F-PCC 2,000 IU

vs

4F-PCC 4,000 IU

Improved or stable brain imaging:

80% in the low fixed-dose group versus 88% in the high fixed-dose group

There was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.

Retrospective study

Reversal of vitamin K antagonist (warfarin)

N= 154

Fixed-dose activated 4F-PCC (n= 29)

Fixed-dose 4F-PCC (n= 53)

Standard dose 4F-PCC (n= 72)

Activated 4F-PCC 500 IU if INR < 5 and 1000 IU if INR ≥ 5

vs

4F-PCC 1,500 to 2,000 IU

vs

4F-PCC standard dose per the package insert

Achievement of target INR ≤ 1.4:

58.6% in the activated group versus 69.8% in the fixed-dose group versus 79.2% in the standard dose group (p= 0.103)

Retrospective study

Reversal of vitamin K antagonist (warfarin) in three different bleeding indications

N= 54

CNS bleeds regardless of INR (n= 54)

Non-CNS bleeds with an initial INR ≤ 6 (n= 153)

Non-CNS bleeds with an initial INR ≥ 6.1 (n= 19)

4F-PCC 2,000 IU (1,000 IU if INR ≤ 6)

vs

Weight-based 4F-PCC dosing

Achievement of target INR:

CNS bleeds: 70.0% in the fixed-dose group vs 79.4% in the weight-based group (p= 0.52)

Non-CNS bleeds with initial INR ≥ 6: 70% in the fixed-dose group vs 100% in the weight-based group (p= 0.21)

Non-CNS bleeds with initial INR ≤ 6.1: 57.5% in the fixed-dose group vs 86.4% in the weight-based group (p= 0.0002)

Retrospective study

Reversal of vitamin K antagonist (warfarin) in obese patients (≥ 100 kg)

N= 44

Fixed-dose (n= 19)

Weight-based dose (n= 25)

4F-PCC 2,000 IU

vs

Weight-based 4F-PCC dosing

Achievement of target INR < 2 (< 1.5 INR for intracranial hemorrhage):

90% in the fixed-dose group versus 84% in the weight-based group (p= 0.68)

Median post-treatment INR:

1.6 (IQR 1.5 to 1.9) in the fixed-dose group vs 1.3 (IQR 1.2 to 1.5) in the weight-based group (p< 0.01)

Retrospective, observational study

Reversal of vitamin K antagonist (warfarin) with intracranial hemorrhage

N= 90

Fixed-dose (n= 42)

Standard-dose (n= 48)

4F-PCC 2,000 IU

vs

Standard dose 4F-PCC ranging from 25 to 50 units/kg based on total body weight

Achievement of target INR ≤ 1.4:

81.5% in the fixed-dose group versus 82.6% in the standard-dose group (p= 0.14)

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

Retrospective, single-arm study

Reversal of vitamin K antagonist 

N= 145

Fixed-dose (N= 145)

Achievement of target INR ≤ 1.5:

70.3% achieved target INR (p< 0.0001)

One patient experienced thromboembolic complication possibly related to 4F-PCC

Retrospective, single-arm study

Reversal of vitamin K antagonist

N= 113

Fixed-dose (n= 63)

Variable-dose (n= 50)

4F-PCC 2,000 or 2,500 IU (some received 1,000 IU based on the original recommendations)

vs

Variable-dose 4F-PCC

Achievement of target INR < 1.5:

43% in the fixed-dose group versus 46% in the variable-dose group (p= 0.83)

Prospective, open-label, randomized, controlled trial

Reversal of vitamin K antagonist (warfarin)

N= 71

Fixed-dose (n= 34)

Variable dose (n= 37)

Fixed-dose 4F-PCC 1,500 IU

vs

Variable-dose 4F-PCC

Achievement of target INR ≤ 1.5:

61.8% in the fixed-dose group versus 89.2% in the variable-dose group (p= 0.011)

CI, confidence interval; INR, international normalized ratio; CNS, central nervous system; IQR, interquartile range 

Prospective Evaluation of a Fixed-Dose 4-Factor Prothrombin Complex Concentrate Protocol for Urgent Vitamin K Antagonist Reversal

Design

Multicenter, interventional, quasi-experimental (pre-post), noninferiority, cohort study

N=54

Objective

Study Groups

Weight-based (n=30)

Fixed-dose (n=24)

Inclusion Criteria

Exclusion Criteria

Received 4F-PCC for reversal of a direct-acting oral anticoagulant (DOAC) or parenteral anticoagulant (e.g., heparin); received 4F-PCC for reversal of a coagulopathy not caused by an anticoagulant

Methods

This was a pre-post study that compared a prospective fixed-dose 4F-PCC protocol to a historical (retrospective) cohort who received weight-based 4F-PCC. 

The retrospective cohort was administered 4F-PCC with weight-based dosing that is dependent on initial INR per the package insert (25 units/kg if the baseline INR was 1.5–3.9, 35 units/kg if the baseline INR was 4–6, or 50 units/kg if the baseline INR was >6).

The prospective cohort was administered a fixed dose of 4F-PCC 1,500 IU over 25 minutes. The dose could be given without first assessing the patient's INR or weight. If baseline INR or weight information was already available and the subject weighed >100 kg or had an INR >7.5, the fixed-dose was increased to 4F-PCC 2,000 IU over 25 min.

All prospective subjects received IV vitamin K 10 mg, and a post-infusion INR was collected 1 h after the 4F-PCC infusion was completed.

Duration

Weight-based (historical cohort): October 2017 to June 2018

Outcome Measures

Primary: achievement of a post-infusion INR <2

Secondary: achievement of a post-infusion INR <1.5; 7-day mortality; 7-day venous thromboembolic events (VTEs)

Baseline Characteristics

Weight-based (n=30)

Fixed-dose (n=24)

Age, years

Female

Weight, kg

Baseline INR

Within the fixed-dose group, 6 (25%) subjects received the 2,000 IU dose because of baseline weight or INR.

Results

Weight-based (n=30)

Fixed-dose (n=24)

Mean post-infusion INR

After 24 hours

1.33

1.32

1.38

1.31

Post-infusion INR <2.0

Post-infusion INR <1.5

29 (96.7%)

27 (90%)

23 (95.8%)

18 (75%)

0.0035

>0.45

7-day mortality

4 (13.3%)

2 (8.3%)

0.009

Adverse Events

No patients experienced VTE within 7 days of 4F-PCC administration.

Study Author Conclusions

The use of a fixed-dose 4F-PCC protocol is safe and effective for the rapid reversal of vitamin K antagonist-associated anticoagulation.

InpharmD Researcher Critique

This study included a retrospective cohort which may be subject to incomplete or inaccurate documentation. Although this study compared two dosing schemes, it was not a randomized study. Additionally, this study was conducted at a single center in North Carolina.

The noninferiority margin of 15% was chosen at the investigators’ discretion and driven by the use of an INR-based endpoint as the primary outcome measure, which does not always accurately reflect hemostasis and clinical outcomes.

Emergent warfarin reversal with fixed-dose 4-factor prothrombin complex concentrate

Design

Retrospective, multicenter, chart review

N=64

Objective

To evaluate the efficacy, safety, and cost-savings of a fixed-dose four-factor prothrombin complex concentrate (4F-PCC) protocol

Study Groups

Fixed-dose 4F-PCC (N=64)

Inclusion Criteria

Exclusion Criteria

Baseline INR < 2; pregnant; 4F-PCC used for DOAC reversal; 

Methods

This was a retrospective chart review of patients who fixed-dose 4F-PCC for urgent warfarin reversal in five hospitals (two health systems) in the United States. All patients received a 4F-PCC 1500 Units and had a repeat INR drawn within 8 hours of 4F-PCC administration. 

Duration

Outcome Measures

Co-primary: patients who achieved a post-administration INR ≤1.5 and ≤2.0

Secondary: thrombotic events within 7 days of 4F-PCC; survival to discharge; hospital length of stay

Baseline Characteristics

Fixed-dose 4F-PCC (N=64)

Age, years (interquartile range)

Male

Weight, kg (interquartile range)

BMI, kg/m² (interquartile range)

83.9 (68.0-99.9)

27.1 (24.2-31.3)

Concomitant antiplatelet use

Additional therapies

Fresh frozen plasma

Vitamin K

11 (17.2%)

57 (89.1%)

Results

Fixed-dose 4F-PCC (N=64)

INR (interquartile range)

Baseline

Post-treatment

3.0 (2.4-3.9)

1.4 (1.3-1.6)

Target INR achieved

≤1.5

≤2.0

44 (68.8%)

61 (95.3%)

Required repeat 4F-PCC dose

Survival to discharge

Length of hospital stay, days (interquartile range)

Cost analysis

Dose if weight-based, units (interquartile range)

Difference between fixed- and weight-based dose, units (interquartile range)

Cost avoidance per treatment*, $

2,350 (1,762-2,500)

850 (263-1,000)

$1,199 ($370-$1,410)

The median time between INR after 4F-PCC administration was 1.3 hours.

*Based on an average wholesale price (AWP) of $1.41/unit

Adverse Events

There were no thrombotic events seen within 7 days of 4F-PCC administration.

Study Author Conclusions

A fixed-dose of 1500 units of 4F-PCC successfully achieved a target INR of ≤1.5 in the majority of patients and resulted in no thrombotic events. This study adds to the data evaluating alternative 4F-PCC dosing regimens in comparison to package insert recommended dosing.

InpharmD Researcher Critique

This study is limited by its retrospective and small, single-cohort nature. The pricing data is also an extrapolation based on AWP and did not account for patients who required repeat dosing. Additionally, other baseline characteristics (e.g., CHA₂DS₂VASc, HAS-BLED) were not collected. 

Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal

Design

Multi-center, observational, pre-post comparison

N=191

Objective

Study Groups

Standard-dose (n=116)

Fixed-dose (n=75)

Inclusion Criteria

Age > 18 years, received 4PCC warfarin reversal, INR result 12 hours prior to receipt of 4PCC, repeat INR drawn within 24 hours of 4PCC administration.

Exclusion Criteria

Pregnancy, received fresh frozen plasma (FFP) within 6 hours prior to 4PCC, arrived to hospital with trauma-team activation, baseline INR < 2, received massive transfusion protocol within six hours of 4PCC (> 4 units of packed red blood cells infused within one hour), FFP after 4PCC but prior to first post-4PCC INR result, received 4PCC for non-warfarin reversal indications, received additional 4PCC dose prior to first post-4PCC INR result, received incorrect 4PCC dose in either group.

Methods

Patients between July 1, 2016 and June 30, 2017 received standard dose of 4PCC (25 to 50 units/kg; dose-capped at maximum TBW of 100 kg). Patients between September 1, 2017 to August 31, 2018 received fixed-dose of 1500 units or 2000 units depending on if baseline INR is > 7.5, TBW is > 100 kg, or for neurological bleeding indications.

Duration

Outcome Measures

Primary outcome: Achievement of target INR < 1.4 on first post-4PCC INR result

Secondary outcomes: Achievement of target INR < 1.4 in subgroup of patients, patients who achieved target INR within 4 hours of PCC administration, patients with post-4PCC INR < 2, patients requiring additional doses within 12 hours, mean cost of therapy, thromboembolic complications observed, 30-day in-hospital mortality, hospital length of stay.

Baseline Characteristics

Standard dose (n=116)

Fixed-dose (n=75)

Age, years

Male

Warfarin

Atrial fibrillation

Peripheral edema/deep vein thrombosis

Mechanical heart valve

Other

59%

28%

4%

14%

48%

29%

19%

4%

0.63

0.98

0.002

0.05

4PCC indication

Intracranial hemorrhage

Gastrointestinal bleeding

Intra-abdominal hemorrhage/intra-thoracic hemorrhage

Surgical

Other

32%

14%

1%

25%

28%

11%

21%

11%

31%

25%

0.002

0.36

0.005

0.37

0.86

Baseline INR

3.5

4.3

4PCC dose, units FIX

2174

1772

4PCC units FIX/kg

27.4

21.3

Vitamin K received

83%

73%

Vitamin K dose, mg

9.21

9

Results

Endpoint

Standard dose (n=116)

Fixed-dose (n=75)

p-Value

Primary outcome, INR results (standard deviation or percentage)

Post-4PCC INR < 1.4

Mean post-4PCC INR levels

Time from 4PCC to first INR, hours

Change in INR 

76 (65%)

1.38 (0.33)

4.81 (3.94)

2.12 (2.02)

43 (57%)

1.5 (0.63)

5.9 (5.8)

2.8 (2.9)

0.32

0.09

0.12

0.06

Post-4PCC INR < 1.4 in subgroup population:

Baseline INR > 7.5

TBW > 100 kg

Intracranial hemorrhage

50% (3/6)

72% (13/18)

90% (36/40)

25% (2/8)

50% (5/10)

88% (7/8)

0.68

0.44

0.83

Target INR < 1.4 within 4 hours of PCC

Post-4PCC INR < 2

Additional doses of 4PCC within 12 hours

Cost of 4PCC therapy

Thromboembolic complications

30-day in-hospital mortality

Hospital length of stay, days

Adverse Events

Common Adverse Events: N/A

Study Author Conclusions

InpharmD Researcher Critique

Comparison of Hemostatic Outcomes in Patients Receiving Fixed-Dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate

Design

Single-center, retrospective, cohort study

N=72

Objective

To evaluate the efficacy and safety of 4F-PCC administration using a fixed dose of approximately 2000 factor IX units to achieve hemostasis in anticoagulated patients, compared with weight-based therapy.

Study Groups

Weight-based dosing (n=38)

Fixed-dosing (n=34)

Inclusion Criteria

Exclusion Criteria

On direct thrombin inhibitor (e.g. dabigatran), history of heparin-induced thrombocytopenia, history of disseminated intravascular coagulation, death within 24 hours of hospitalization, included in a vulnerable population.

Methods

Before January 1, 2018, patients received weight-based dosing of 4F-PCC which ranged from 35 to 50 factor IX units/kg. The amount administered depended on bleed severity at the time. After January 1, 2018, the fixed-dosing of 2000 factor IX units of 4F-PCC was adopted. An additional 2000 units was available if deemed appropriate.

Duration

Outcome Measures

Primary outcome: clinically effective hemostasis after administration of 4F-PCC.

Effective hemostasis is defined as: no further reports of significant bleeding, stabilization of bleeding noted on serial computed tomography scans, no further significant drop in repeat hemoglobin measurements defined as a drop of > 2 g/dL within 2 to 6 hours post PCC administration.

Secondary outcome: Inpatient all-cause mortality, hospital length of stay, need for repeat dose, need for fresh frozen plasma (FFP) or packed red blood cells, safety, acquisition cost savings.

Baseline Characteristics

Weight-based (n=38)

Fixed-dose (n=34)

Age, years

Male

White

Total dose given, units

Total dose given, units/kg

Comorbidities

Diabetes mellitus

Hypertension

Myocardial infarction

Congestive heart failure

Cerebrovascular accident

Peripheral vascular disease

42.1%

97.4%

36.8%

44.7%

42.1%

47.4%

44.1%

91.2%

23.5%

52.9%

41.2%

38.2%

0.863

0.338

0.221

0.487

0.936

0.435

Charlson Comorbidity Index score

Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.

Results

Endpoint

Weight-based (n=38)

Fixed-dose (n=34)

p-value

Effective hemostasis after administration

Subgroup analysis of warfarin patients

Subgroup analysis of factor Xa-inhibitor patients

78.9%

83.3%

76.9%

91.2%

84.6%

95.0%

0.150

0.930

0.091

Mortality

4 (10.5%)

5 (14.7%)

0.592

Hospital length of stay, days

7.8 ± 5.9

8.7 ± 7.8

0.901

Repeat dose given

3 (7.9%)

3 (8.8%)

Need for fresh frozen plasma

7 (18.4%)

8 (23.5%)

Need for packed red blood cells

17 (44.7%)

6 (17.6%)

Total acquisition cost savings were calculated to be $91,029 or approximately $2,677 per patient when switching to a fixed-dose regimen based on cost of one factor IX unit of $1.58

Adverse Events

Fixed-dose group: n=0

Weight-based group: n=2 (5.3%)

Study Author Conclusions

A fixed-dose regimen of approximately 2000 factor IX units of 4F-PCC may be a reasonable approach to achieve hemostasis in patients receiving warfarin or factor Xa inhibitors. Additionally, utilization of a fixed-dose regimen may lead to significant acquisition cost savings for facilities.

InpharmD Researcher Critique

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

Design

Prospective observational multicenter cohort study

N= 66

Objective

Inclusion Criteria

Exclusion Criteria

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. 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

Baseline Characteristics

All patients (N= 66)

Age, years

Male

Weight, kg (interquartile range [IQR])

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)

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

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

InpharmD Researcher 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. 

Evaluation of Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal in Patients with Intracranial Hemorrhage

Design

Retrospective cohort study

N=61

Objective

To evaluate whether a fixed dose of 1,000 IU of four-factor prothrombin complex concentrate (4FPCC) achieves International Normalized Ratio (INR) reversal similar to weight-based dosing in patients with intracranial hemorrhage (ICH) who were anticoagulated with warfarin

Study Groups

Weight-based dosing (n=31)

Fixed dosing (n=30)

Inclusion criteria

Age ≥ 18 years, received 4FPCC for ICH, on chronic warfarin therapy

Baseline INR < 2, lab values unavailable

Methods

This was a historical cohort study of a single institution. Patients prior to April 2015 received weight-based 4FPCC doing, and after April 2015 the protocol changed to give a 1,000 U fixed dose repeated as necessary to reach goal INR.

Outcome Measures

Baseline Characteristics

Weight-based dosing (n=31)

Fixed dosing (n=30)

Age, years

Female

Weight, kg

Aspirin use

Baseline INR

Results

Weight-based dosing (n=31)

Fixed dosing (n=30)

p-value

Reached goal INR

INR <1.6

INR <1.5

25 (81%)

22 (71%)

22 (73%)

16 (53%)

0.49

0.15

Required repeat 4FPCC dosing

Total 4FPCC dose received, IU

Additional reversal agents given

Vitamin K

Fresh frozen plasma

28 (91%)

6 (20%)

28 (94%)

2 (7%)

0.67

0.14

Adverse Events

Not reported

Study Author Conclusions

A fixed dose of 1000 IU of PCC4 did not differ significantly in reaching goal INR in this population. It is likely that the optimal dosing strategy for PCC4 has not yet been elucidated and may involve accounting for both weight and initial INR.

InpharmD Researcher Critique

Although this was a retrospective study from a single center, there was a historical comparison group included. However, this study was insufficiently powered to avoid a type II error.

Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis

Design

Retrospective chart review

N=37

Objective

To determine the efficacy of fixed-dose 4-factor prothrombin complex concentrate (4FPCC; Kcentra) in reducing the International Normalized Ratio (INR) to ≤1.5 among warfarin patients with the need for urgent or emergent anticoagulation reversal

Study Groups

Fixed-dose 4FPCC (n=37)

Inclusion criteria

Patients on warfarin who received 4FPCC for the reversal of warfarin

Received repeat dosing before INR was drawn, INR drawn >3 hours post-dose

Methods

This was a retrospective chart review of patients who received a fixed dose of 1,500 units of 4FPCC for warfarin reversal at a level I academic trauma center over eight months.

Outcome Measures

Baseline Characteristics

Fixed-dose 4FPCC (n=37)

Age, years

Male

Weight, kg

Indication for reversal

Intracranial hemorrhage

Gastrointestinal bleed

Urgent surgery

Other

17 (46%)

5 (14%)

7 (19%)

8 (21%)

Results

Fixed-dose 4FPCC (n=37)

INR values (interquartile range)

Initial

Post 4FPCC dose

3.06 (2.17-5.21)

1.32 (1.15-1.50)

Additional 4FPCC dose given

Additional reversal agents given

Vitamin K

Desmopressin

Fresh frozen plasma

30 (81.1%)

5 (13.5%)

9 (24.3%)

Died before discharge

Adverse Events

N/A

Study Author Conclusions

Based on this evaluation, the administration of a fixed dose of 1,500 units 4FPCC, was shown to be effective in adequately reversing the INR in the majority of patients with minimal thrombotic risks.

InpharmD Researcher Critique

Limitations of this review are related to the retrospective, single-cohort study design. Additionally, all patients received at least one other reversal agent along with 4FPCC. The authors use no comparison group for fixed-dose efficacy, but they conducted a "what-if" cost analysis that favors fixed-dosing by saving $982 a patient versus variable dosing.

Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis

Design

Single center, retrospective, before-and-after analysis

N=53

Objective

To compare the achievement of target International Normalized Ratio (INR) ≤ 1.5 with the fixed dosing strategy versus the variable dosing strategy of prothrombin complex concentrate (PCC) in patients presenting with a vitamin K antagonist (VKA)-associated intracranial hemorrhage (ICH)

Study Groups

Variable dosing (n=25)

Fixed dosing (n=28)

Inclusion criteria

Age ≥ 18 years, presented with ICH while on VKA therapy, was given PCC therapy

Treated during the protocol transition month (November 2013)

Methods

Patients treated with PCC prior to November 2013 received variable dosing based on manufacturer recommendations, and after November 2013 received a fixed dose of 1,000 IU factor IX PCC, followed by follow-up INR-assessment (if the target INR of ≤1.5 was not achieved, another 500 IU of PCC was administered).

Duration

January 2013 to 1 August 2014

Outcome Measures

Baseline Characteristics

Variable dosing (n=25)

Fixed dosing (n=28)

Age, years

Female

Weight, kg

Baseline INR (range)

Results

Variable dosing (n=25)

Fixed dosing (n=28)

p-value

INR after initial dose (range)

Patients with INR≤1.5 after initial dose

1.3 (1.0-1.9)

24 (96%)

1.4 (1.2-2.0)

19 (68%)

0.001

0.013

Median total PCC dose used, IU (range)

Need for additional doses

Mortality

At discharge

At 30-days post-PCC treatment

3 (12%)

4 (16%)

6 (22%)

7 (25%)

0.474

0.509

Duration of hospital stay, days (range)

Door-to-needle time, mins

Adverse Events

N/A

Study Author Conclusions

This retrospective study shows that an initial fixed dose of 1000 IU factor IX PCC is inferior in achieving the target INR of ≤1.5 in comparison to the variable dose calculated from bodyweight, baseline INR, and target INR.

InpharmD Researcher Critique

A limitation of this study is the small sample size, which lacks the power to draw conclusions from data of the secondary endpoints. The sample size was, however, sufficient to demonstrate a significant difference in the primary outcome (achievement of target-INR). Another limitation is the retrospective nature of the study, resulting in the absence of parameters necessary for comparison of clinical outcome. A strength is that it used real-world data.

Design

Multicenter, prospective study 

N= 84

Objective

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

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) 

Median age, years (interquartile range [IQR])

Female

Median body weight, kg

0.01

--

--

--

History of stroke

Concomitant medications 

Antiplatelet 

NSAID

0.22

0.21

Baseline laboratory results

INR 

APTT

Creatinine

0.04

0.01

0.39

Bleeding location

ICH 

GI bleeding 

Visceral 

Genitourinary 

Musculoskeletal 

0.95

--

--

--

--

--

Results

Management given

Apixaban (n= 39)

Rivaroxaban (n= 45) 

p-value

0.26

0.62

1

0.1

0.1

Outcome of management

Bleeding location

8 (27.6%)

2 (40%)

2 (100%)

1 (50%)

0 

Hemoglobin drop  

Any invasive procedure 

None

8 (32%)

2 (28.6%)

1 (25%)

2 (100%)

0

0

0

Median length of hospital stay, days 

Discharge destination

1 (6.7%)

4 (36.4%)

1 (33.3%)

6 (66.7%)

Adverse Events

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

Study Author Conclusions

InpharmD Researcher 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.

Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal

Design

Post hoc analysis of randomized controlled trials

N=388

Objective

To analyze predictors of volume overload based on data collected during two completed randomized controlled trials (RCTs) that evaluated the efficacy of four-factor prothrombin complex concentrate (4FPCC) versus plasma in patients requiring urgent VKA reversal for acute major bleeding or before an urgent surgical or invasive procedure

Study Groups

Plasma (n=197)

4FPCC (n=191)

Inclusion criteria

vitamin K antagonist (VKA)-treated patients with major bleeding or requiring an urgent surgical invasion procedure

Methods

The two RCTs evaluated the efficacy of 4FPCC versus plasma in patients requiring urgent VKA reversal for acute major bleeding or before an urgent surgical or invasive procedure. The 4FPCC dose was based on baseline INR and body weight infused at a rate no more than 3 IU/kg/min. The infusion rate of plasma was at the discretion of the clinical team.

Duration

51 Days

Outcome Measures

Fluid overload

Baseline Characteristics

4FPCC (n=191)

Plasma (n=197)

Age, years

Female

Male

White

History of chonic heart failure

History of coronary artery disease

History of renal disease

Results

4FPCC (n=191)

Plasma (n=197)

Volume overload events

The mean 4FPCC infusion rate for patients with volume overload events was 170.0 IU/min versus 143.4 IU/min without volume overload.

Adverse Events

Most common volume overload event

4FPCC group: cardiac failure congestive (54.5%)

Plasma group: acute pulmonary edema (34.5%)

Study Author Conclusions

This study shows that the use of plasma (vs. 4FPCC), history of CHF, and history of renal disease appear to be independently predictive of volume overload. Careful consideration should be given to the use of plasma for urgent VKA reversal and alternative VKA reversal therapies, such as 4FPCC, should be considered.

InpharmD Researcher Critique

This was a well-designed post hoc analysis. However, the RCTs analyzed were efficacy trials, not safety. Safety outcomes between groups could not be powered.

Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal

Design

Retrospective chart review

N=39

Objective

To examine a protocol of 1500 IU fixed doses of four-factor prothrombin complex concentrate (4FPCC; Kcentra) in the setting of emergent warfarin reversal at a single institution

Study Groups

Fixed-dose 4FPCC (n=39)

Inclusion criteria

Patients who were administered 4FPCC per the fixed dose protocol for the purpose of emergent oral anticoagulation reversal for any clinical indication

No post administration INR available (due to death, transfer, or other reason)

Methods

All patients were administered a fixed dose of 1,500 IU of 4FPCC at a single level I trauma center.

Duration

March 2014 to January 2015

Outcome Measures

Baseline Characteristics

Fixed-dose 4FPCC (n=39)

Median age, years

Weight, kg

Chronic anticoagulant

Warfarin

Rivaroxaban

38 (97%)

1 (3%)

Indication for treatment

Intracranial hemorrhage

Gastrointestinal hemorrhage

Emergency surgery

Other

28 (72%)

4 (10%)

2 (5%)

5 (13%)

Results

Fixed-dose 4FPCC (n=39)

INR values (interquartile range)

Baseline

Aftere a single 4FPCC dose

3.3 (2.5-4.0)

1.4 (1.2-1.6)

Successful reversal after a single dose

Target INR <2.0

Target INR ≤1.5

36 (92%)

28 (72%)

Additional 4FPCC dose given

1 (3%)

Additional reversal agents given

Vitamin K

Fresh frozen plasma

36 (92%)

11 (28%)

Died before discharge

Adverse Events

Two of the three treatment failures (INR >2.0 after a single fixed-dose) presented initially with an INR >10

Study Author Conclusions

These findings suggest good efficacy and safety when utilizing a fixed-dose of 1,500 IU of 4FPCC for emergent warfarin reversal.

InpharmD Researcher Critique

This study was limited by the retrospective design, small sample size, and lack of a comparator group. Another important limitation is that several patients who received fresh frozen plasma and vitamin K in addition to the 4FPCC were included.