Hemostatic Efficacy and Safety of Weight-Based Versus Fixed-Dose 4F-PCC for Vitamin K Antagonist Reversal

Abstract

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P = .229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P = .181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results.

Keywords

anticoagulation prothrombin complex concentrate warfarin anticoagulation reversal factor stewardship

Introduction

Vitamin K antagonists (VKA) such as warfarin are used for many indications including atrial fibrillation and venous thromboembolism (VTE) treatment. The most common complication associated with VKA therapy is bleeding which has been reported at annual rates of 1.7%–3.4%.¹ Major, life-threatening bleeding is correlated with high morbidity and mortality which necessitates an effective and quick reversal strategy. Four-factor prothrombin complex concentrate (4F-PCC) in combination with vitamin K has become a mainstay for reversal.

4F-PCC is a coagulation factor replacement product that contains inactivated factors II, VII, IX and X, proteins C and S, antithrombin III, and heparin. It is approved by the Food and Drug Administration (FDA) for the reversal of acquired coagulation factor deficiency induced by VKA in patients with a major bleed or when an urgent procedure is necessary.² The use of 4F-PCC in combination with vitamin K is recommended first line for VKA-associated major bleeding by the American College of Cardiology.³ The package labeling recommends individualized dosing based on body weight and baseline international normalized ratio (INR).²

A previous internal, retrospective cohort study was conducted to determine the incidence of thrombotic events (TE) and to identify independent risk factors for thromboembolism after 4F-PCC for all indications. Rates of TE in the first 14 days following 4F-PCC were found to be 15.5%, which is significantly higher than initially reported rates of 4%–7% in previous literature.⁴ Multiple combinations of TE were seen, with the majority developing deep vein thrombosis (DVT). Approximately one-third of these patients also experienced pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accidents (CVA), transient ischemic attacks (TIA) and/or other arterial thromboses. Since initial studies, several others have also reported higher TE incidences up to 14.8%.^5,6

Thus, several recent studies have investigated the use of a low, fixed-dosing regimen of 4F-PCC for VKA reversal to identify more ideal dosing schemes.^7-14 These studies had various strategies for employing fixed-dosing of 4F-PCC, which ranged from 500 to 1500 units. Overall, the studies with lower fixed-doses were less successful in obtaining target INR; however, a fixed-dose of 1500 units appeared to be effective for INR reversal. Benefits of factor stewardship (using lower, fixed doses of 4F-PCC) include potential reduction in TE, reduced time to administration, and reduced hospital costs, while maintaining similar efficacy.

Given the high TE rate seen at our institution and newer literature supporting a fixed-dosing strategy, institutional guidelines were updated in February 2018 to recommend a low, fixed-dose 4F-PCC of 1500 units for patients requiring urgent VKA reversal. Previous studies using fixed-dose regimens evaluated hemostatic efficacy solely based on surrogate markers of bleeding, such as INR. The purpose of this study is to evaluate hemostatic efficacy using INR and other clinical measures of bleeding, and to assess the rate of TE when utilizing INR and weight-based vs fixed-doses of 4F-PCC.

Methods

This was a single-center, retrospective, quasi-experimental study conducted at a 763-bed level I trauma center, tertiary care facility. The study protocol was submitted for review by the Carilion Clinic Institutional Review Board prior to commencement and determined as a quality assurance/quality improvement project, not human subjects research. All adult patients who received 4F-PCC between January 2014 through May 2016 (weight-based cohort) or April through October 2018 (fixed-dose cohort) for the indication of urgent reversal of VKA therapy were included. In the weight-based cohort, 4F-PCC dosing was determined using baseline INR and actual body weight, as per the package labeling. In the fixed-dose cohort, patients received 1500 units of 4F-PCC. An additional 500-unit dose of 4F-PCC could be considered if the INR after the first dose was still greater than 1.7 and the patient was experiencing signs of clinically significant bleeding per provider discretion. Doses were rounded to nearest vial size based on factor IX component per hospital policy in both groups. No changes occurred to hospital policies, clinical practice, or the electronic medical record during the 2 time periods, except for recommended dosing. The 4F-PCC doses were prepared in the pharmacy for administration by the nurse in both cohorts. Patients were excluded if they were under the age of 18 years, received 4F-PCC for an alternative indication, refused blood products, or had hemophilia or a clotting disorder.

The primary endpoint was hemostatic efficacy in patients receiving 4F-PCC for VKA associated bleeding, as defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. Clinical outcomes for hemostasis were defined as less than 20% growth in hematoma within 24 hours on imaging for intracerebral hemorrhages (ICH) or 20% drop in hemoglobin in 24 hours for all other hemorrhages. All repeat imaging and hemoglobin values obtained within the first 24 hours were assessed for this endpoint. The INR cut off of 1.7 was selected based on our institution’s protocol requiring an INR of ≤1.7 to proceed with non-emergent procedures and a supplemental dose of 4F-PCC being permitted above this value with signs of bleeding given that INR value alone is a surrogate marker of bleeding. Clinical hemostatic efficacy lacks a standard definition and was defined in this study largely based on expert opinion from a compilation of the above literature and the Sarode criteria for ICH.¹⁵ Secondary endpoints included rates of TE (ie, DVT/PE, arterial thrombosis, MI, CVA) within 14 days of 4F-PCC administration, additional doses of 4F-PCC, concomitant reversal agents and blood products, time from order entry to administration of 4F-PCC, hospital and ICU length of stay, and all-cause mortality. Several post-hoc analyses were conducted including hemostatic efficacy based on diagnosis of ICH, weight, and INR value, as well as VTE prophylaxis rate and cost savings.

Continuous, non-parametric data were represented as medians with interquartile ranges (IQR) and categorical data were represented as frequencies. All continuous data were analyzed utilizing Mann Whitney U and categorical data were analyzed using Chi-squared. Level of significance was set at .05. Statistical analysis was performed utilizing IBM® SPSS version 17.

Results

Baseline Characteristics

A total of 478 patients who received 4F-PCC were screened for eligibility during the study period and 208 met the inclusion criteria (Figure 1). One hundred and sixty-three patients were included in the weight-based group and 45 patients in the fixed-dose group. A total of 155 patients (74.5%) received 4F-PCC for active bleeding and were evaluated for hemostatic efficacy. The most common site of bleeding was intracranial bleeding, followed by trauma-related and gastrointestinal bleeding. The remaining 53 patients (25.5%) received 4F-PCC for an urgent procedure. At baseline, the presenting INR values were similar between groups, with a median INR of 2.7 (IQR 2.1-3.8) and 2.6 (IQR 2.2-3.5) in weight-based and fixed-dose groups, respectively (P = .524). The only baseline characteristics that differed between treatment arms were thrombosis within the past 3 months (28.8% vs 8%; P = .031) and trauma in the previous 30 days (22.7% vs 6.7%; P = .016), both of which were higher in the weight-based cohort (Table 1).

Table 1.

Baseline Characteristics.

	Weight-Based (N = 163)	Fixed-Dose (N = 45)	P-Value
Age, years, median (IQR)	74 (64-81)	73 (63-80.5)	.886
Sex, male, n (%)	83 (50.9)	21 (46.7)	.613
Weight, kg, median (IQR)	87.2 (71.7-103.9)	85.2 (76.6-103.1)	.718
BMI, kg/m², median (IQR)	29.1 (24.5-36.3)	29.2 (26.1-35.4)	.572
Race, Caucasian, n (%)	147 (90.2)	37 (82.2)	.139
PMH, n (%)
History of TE	97 (59.5)	25 (55.6)	.634
Previous VTE^a	37 (38.1)	8 (32)	.927
Recent thrombosis^a	28 (28.8)	2 (8)	.031
Cancer history	46 (28.2)	11 (24.4)	.615
Trauma	37 (22.7)	3 (6.7)	.016
Tobacco use	24 (14.7)	4 (8.9)	.310
Recent surgery	11 (6.7)	2 (4.4)	.572
Indication for anticoagulation, n (%)
Atrial fibrillation/flutter	94 (57.7)	29 (64.4)	.413
VTE	39 (23.9)	8 (17.8)	.383
Heart valve	11 (6.7)	4 (8.9)	.623
Atrial fibrillation + VTE	8 (4.9)	1 (2.2)	.433
Atrial fibrillation + valve	3 (1.8)	0 (0)	.359
Other/unknown	8 (4.9)	3 (6.7)	.641
Antiplatelet use PTA, n (%)	76 (46.6)	16 (35.6)	.186
Medication use with increased risk of VTE, n (%)	5 (3.1)	2 (4.4)	.650
GCS, median (IQR)	15 (13-15)	15 (13.5-15)	.721
APACHE II, median (IQR)	18 (12-22)	19 (16-25)	.211
Bleeding site, n (%)^b			.009^c
ICH	41 (33.9)	20 (58.8)
Trauma	34 (28.1)	3 (8.8)
GIB	20 (16.5)	5 (14.7)
Other	26 (21.5)	6 (17.6)

Abbreviations: CAD, coronary artery disease; GCS, Glasgow Coma Score; GIB, gastrointestinal bleed; HLD, hyperlipidemia; HTN, hypertension; ICH, intracerebral hemorrhage; PTA, prior to admission; PVD, peripheral vascular disease; TE, thrombotic event; VTE, venous thromboembolism.

^aPatients with history of thrombosis (weight based, n = 97; fixed dose, n = 25).

^bPatients with an active bleed (weight based, n = 121; fixed dose, n = 34).

^cICH vs all other bleeding sites.

Hemostatic Efficacy

The median 4F-PCC dose was 2349 units (25.7 units/kg) in the weight-based cohort and 1584 units (18.1 units/kg) in the fixed-dose cohort (P < .001). When evaluating the primary endpoint in bleeding patients, there was no difference seen between the 2 cohorts with 76.9% achieving hemostatic efficacy in the weight-based group compared to 77.4% in the fixed-dose group (P = .229; Table 2). Both cohorts had a reduction in INR to a median of 1.3 (IQR 1.2-1.6 weight-based; IQR 1.2-1.5 fixed-dose) after 4F-PCC (P = .748). When evaluating surrogate markers of bleeding alone, an INR of ≤1.4 was achieved in 66.1% of the weight-based group and 67.7% of the fixed-dose group (P = .86).

Table 2.

Efficacy Results.

	Weight-Based (N = 163)	Fixed Dose (N = 45)	P-Value
Primary endpoint: hemostatic efficacy, n (%)^a	93 (76.9)	24 (77.4)	.229
INR ≤1.4, n (%)^a	80 (66.1)	21 (67.7)	.860
INR <1.7 with hemostasis, n (%)^b	12 (29.3)	4 (40)	.220
Secondary endpoints
Thromboembolic events, n (%)	22 (13.5)	3 (6.7)	.181
Additional doses 4F-PCC	4 (2.5)	2 (4.4)	.480
Administration time from order entry, min, median (IQR)	40 (29-62)	41 (34-55)	.395
Hospital LOS, days, median (IQR)	6.4 (3.5-13)	7 (4.1-10.8)	.599
ICU LOS, days, median (IQR)	3.2 (1.7-5.6)	3 (1.5-6.5)	.618
Mortality, n (%)	45 (27.6)	12 (26.7)	.9

^aPatients with an active bleed (weight-based, n = 121; fixed-dose, n = 31).

^bPatients who did not achieve an INR of ≤1.4 (weight-based, n = 41; fixed-dose, n = 10).

Patients who received 4F-PCC for an urgent procedure were only evaluated for reduction of the INR to 1.4 or lower. This was achieved in 19 out of 42 patients (45.2%) in the weight-based arm and 8 out of 14 patients (57.1%) in the fixed-dose arm.

Thrombotic Events

New onset thromboembolic events were seen in 22 patients (13.5%) in the weight-based cohort compared to 3 patients (6.7%) in the fixed-dose cohort (P = .181; Table 2). In those who received weight-based dosing, DVT was reported in 13 patients, arterial thrombus in 3 patients, and PE, MI, and CVA were each reported in 2 patients. There were 3 different TE in the fixed-dose group, including a DVT, MI, and CVA. The median time to TE was 7.3 (3.2-11.7) and 8.5 (1.5-12.3) days in the weight-based and fixed dosed groups, respectively (P = .841).

Additional Secondary Endpoints

Additional 4F-PCC doses were administered to 4 patients (2.5%) in the weight-based group and 2 patients (4.4%) in the fixed-dose group (P = .48, Table 2). All received an additional dose for bleeding except for 1 of the weight-based patients who was undergoing a procedure. One of the patients in the fixed-dose group received an inappropriately low first-dose of 4F-PCC which subsequently led to a 1500-unit dose being ordered. There were no statistical differences regarding use of additional reversal agents, except for protamine (Table 3). Protamine was only utilized in 8.6% of the patients receiving weight-based 4F-PCC (P = .042). The majority of patients in both treatment arms received concomitant vitamin K at a rate of 94% and 91% (P = .409). The median dosage of vitamin K was 10 mg given intravenously.

Table 3.

Additional Reversal Agent and Blood Product Administration.

	Weight-Based (N = 163)	Fixed-Dose (N = 45)	P-Value
Additional reversal agents
Vitamin K, n (%)	154 (94.5)	41 (91.1)	.409
Tranexamic acid, n (%)	4 (2.5)	0 (0)	.289
Aminocaproic acid, n (%)	10 (6.1)	0 (0)	.089
Desmopressin, n (%)	9 (5.5)	2 (4.4)	.775
Factor VIIa, n (%)	1 (.6)	0 (0)	.598
Protamine, n (%)	14 (8.6)	0 (0)	.042
Blood product administration pre 4F-PCC
Total blood product administration, n (%)	40 (24.5)	4 (8.9)	.023
FFP, n (%)	27 (16.6)	3 (6.7)	.094
FFP, units, median (IQR)	2 (2-4)	2 (2-2)	.509
Cryoprecipitate, n (%)	1 (.6)	1 (2.2)	.328
Cryoprecipitate, units, median (IQR)	1 (1-1)	1 (1-1)	1
PRBC, n (%)	23 (14.1)	3 (6.7)	.181
PRBC, units, median (IQR)	2 (1-4)	2 (2-3)	.928
Platelets, n (%)	4 (2.5)	1 (2.2)	.4
Platelets, units, median (IQR)	1 (1-1)	2 (2-2)	.183
Blood product administration post 4F-PCC
Total blood product administration, n (%)	53 (32.5)	10 (22.2)	.183
FFP, n (%)	27 (16.6)	2 (4.4)	.038
FFP, units, median (IQR)	2 (1-2)	4 (2-6)	.148
Cryoprecipitate, n (%)	1 (.6)	1 (2.2)	.328
Cryoprecipitate, units, median (IQR)	2 (2-2)	2 (2-2)	1
PRBC, n (%)	39 (23.9)	8 (17.8)	.383
PRBC, units, median (IQR)	2 (2-3)	2 (1-3)	.495
Platelets, n (%)	7 (4.3)	2 (4.4)	.965
Platelets, units, median (IQR)	1 (1-2)	2 (1-2)	.667

Abbreviations: FFP, fresh frozen plasma; PRBC, packed red blood cells.

Eight-seven patients (41.8%) received blood products, with only 2 categories achieving statistically significant differences (Table 3). Forty patients (24.5%) received any type of blood product prior to 4F-PCC in the weight-based cohort compared to 4 (8.9%) in the fixed-dose cohort (P = .023). After 4F-PCC was administered, total blood product use was similar between groups except fresh frozen plasma (FFP), which was used in 27 patients (16.6%) in the weight-based group and 2 (4.4%) in the fixed-dose group (P = .038).

There was no difference regarding time from order entry to pharmacist verification, which was 8 minutes (IQR 5-15) in the weight-based group and 9 minutes (IQR 5-12) in the fixed-dose group (P = .811). Time from order entry to administration was similar at 40 (IQR 29-62) and 41 (IQR 34-55) minutes (P = .395; Table 2). There was no difference for the additional secondary endpoints of in-hospital mortality, ICU or hospital length of stay (Table 2).

Post-Hoc Analyses

Several post-hoc analyses were conducted to evaluate the effectiveness in certain subgroups of patients, including those with an ICH, weight of ≥100 kg, and baseline INR of ≥4 (Table 4). Patients identified as having an ICH achieved hemostatic efficacy in 63.4% of the weight-based group and 55% of the fixed-dose group (P = .849). For all other indications, hemostatic efficacy was achieved in 73.8% and 90.9% in the weight-based and fixed-dose groups, respectively (P = .701).

Table 4.

Post-Hoc Analyses.

	Weight-Based (N = 163)	Fixed-Dose (N = 45)	P-Value
Hemostatic efficacy
Bleeding site
ICH, n (%)^a	26 (63.4)	11 (55)	.849
Other, n (%)^b	59 (73.8)	10 (90.9)	.701
Weight ≥100 kg, n (%)^c	28 (77.8)	4 (50)	.453
INR ≥4, n (%)^d	21 (80.7)	2 (66.7)	NR
DVT prophylaxis
Mechanical PPX, n (%)	143 (87.7)	39 (86.7)	.849
Pharmacologic PPX, n (%)	75 (46)	23 (51.1)	.544
No PPX, n (%)	17 (10.4)	2 (4.4)	.217
Time to pharmacologic PPX, days, median (IQR)	2 (.9-4.8)	1.5 (.6-4.6)	.546

Abbreviations: ICH, intracranial hemorrhage; NR, not reported; PPX, prophylaxis; TE, thrombotic event.

^aPatients with an ICH (weight-based, n = 41; fixed-dose, n = 20).

^bPatients with a bleeding site other than ICH (weight-based, n = 80; fixed-dose, n = 11).

^cPatients with a body weight ≥100 kg (weight-based, n = 36; fixed-dose, n = 8).

^dPatients with an INR ≥4 (weight-based, n = 26; fixed-dose, n = 3).

Of the patients who received 4F-PCC for a bleeding indication, there were 36 patients (22.1%) in the weight-based cohort and 8 patients (17.8%) in the fixed-dose cohort who weighed at least 100 kg (P = .819). The median weight in this subset of patients was 116 kg (IQR 106-144) and 118 kg (IQR 110-142) in the 2 groups, respectively. Twenty-eight (77.8%) of those patients receiving weight-based doses achieved hemostatic efficacy, as did 4 patients (50%) in the fixed-dose arm (P = .453). There were 4 patients in each group for which efficacy was unable to be assessed due to incomplete data such as lack of measurements on repeat brain imaging. No patient in either group received an additional dose of 4F-PCC.

A total of 29 bleeding patients presented with an INR of ≥4. Of these patients, the median INR at presentation was similar (5.8 weight-based vs 6.1 fixed-dose). Twenty-six of these patients were in the weight-based group, where 21 patients (80.7%) achieved hemostatic efficacy. Of the 5 remaining patients, 2 did not achieve efficacy and the remainder were unable to be assessed (Table 4). There were only 3 bleeding patients with INR of ≥4 in the fixed-dose cohort. Two of these patients achieved hemostasis and 1 patient was unable to be assessed. No patient in either group received an additional dose of 4F-PCC.

There were no statistical differences in proportion of patients who received mechanical or pharmacologic VTE prophylaxis. Seventeen patients (10.4%) who received weight-based dosing and 2 patients (4.4%) in the fixed-dose arm received neither mechanical nor pharmacologic prophylaxis; however, none of those patients experienced a TE. Additionally, there was no difference in time to TE or time to pharmacologic prophylaxis (Table 4).

Utilizing patient weight and baseline INR in the fixed-dose group, the median dose per package labeling was calculated at 2251 units resulting in a median of 751 units more than the administered fixed-dose. Doses are commonly rounded to the nearest 500-unit vial size, resulting in a reduction of 1-2 vials per patient dose. With an average wholesale cost of $3.26 per unit of 4F-PCC in the United States, an estimated $1630 was saved per 500-unit vial using a low, fixed dose of 1500 units.

Discussion

4F-PCC, in combination with vitamin K, has become the standard of care for urgent reversal of VKA therapy. While the FDA approved dosing of 4F-PCC considers weight and INR, concern for thrombotic complications has led clinicians to identify more ideal dosing strategies to optimize hemostasis and minimize risk.

This study is 1 of many that has sought to identify a preferable 4F-PCC dosing strategy for VKA-associated bleeding reversal. In 1 retrospective cohort study, 1500 units of 4F-PCC given for emergent VKA reversal was associated with INR reversal and showed no thrombotic complications within 7 days of 4F-PCC administration. Reduction of the INR to less than 2 was achieved in 92.3% of patients, reduction of the INR to 1.5 or less was achieved in 71.8% of patients, and the median INR achieved was 1.4.⁷ Additionally, a retrospective chart review showed that 1500 units of 4F-PCC given for warfarin reversal achieved the target INR of ≤1.5 after a single dose in almost 75% of patients. No patients required an additional dose of 4F-PCC, and there were no thrombotic complications.⁸ Another study retrospectively examined the effects of implementing a fixed-dose protocol consisting of 1500 units of 4F-PCC with the option to supplement the remainder of the package insert dosing if the target INR was not achieved. The study found that 17% of patients were eligible to receive a supplemental dose; however, only 2 of them required it, suggesting most patients had adequate hemostasis with the fixed-dose 4F-PCC.⁹ Recently, a multicenter, quasi-experimental study compared a prospective, fixed-dose 1500-unit 4F-PCC cohort to a historic, weight-based cohort. The fixed-dose 4F-PCC was found to be non-inferior to traditional weight-based dosing for achieving an INR of <2.¹⁰

However, not all fixed dosing regimens studied have proven to be efficacious at reversing the INR in VKA associated bleeding. A systematic review found that doses lower than 1000 units were often associated with inability to obtain target INR and that patients with higher baseline INR, higher body weight, and ICH may need higher doses.¹¹ Additionally, a retrospective cohort study compared variable dose 4F-PCC to a fixed-dose of 1000 units. An INR of ≤1.5 was achieved in 96% of the variable dose cohort compared with 68% of the fixed-dose cohort. More patients in the fixed-dose cohort required an additional dose. A post-hoc analysis in this study revealed that for patients with a baseline INR of ≤4, there was no difference in target INR achievement.¹² In a retrospective cohort study including 61 patients exclusively with ICH, weight-based dosing was compared to a fixed 1000-unit dose of 4F-PCC. The primary endpoint of achieving an INR of <1.5 was obtained in 71% of the weight-based group compared with 53% of the fixed-dose group. The study also found no difference in the number of patients discharged to home or in-hospital mortality.¹³ In a systematic review, 28 prospective studies utilizing various dosing regimens were analyzed for INR reversal. Studies using a fixed-dose of 500 units were found to be insufficient for successful reversal. Fixed dosing of 1500 units was, however, associated with good outcomes including success of INR achievement and hemostatic efficacy.¹⁴

While this study also sought to evaluate a fixed dose of 1500 units 4F-PCC vs traditional 4F-PCC dosing, 1 factor that differentiates it from others is the method used for determining hemostatic efficacy. Prior studies have evaluated only surrogate markers of bleeding, specifically INR values, to indirectly identify patients who have achieved hemostasis. While it is believed that a reduction in INR is associated with bleeding cessation, there is still concern that it is an indirect marker of bleeding and reduction may not always be indicative of hemostasis. Likewise, slight INR elevations from baseline may not be associated with clinically relevant bleeding and should not be further reversed due to risk of adverse sequelae, such as TE. In this study, clinical outcomes of hemostasis were evaluated based on change in hematoma growth for ICH and changes in hemoglobin values for other types of bleeding, in addition to considering INR value. When using these criteria, hemostatic efficacy rates appear similar to what has been reported in prior studies and adds to the literature suggesting that low, fixed-dose 4F-PCC is as effective as traditionally dosed 4F-PCC. With the limited data available in this retrospective review and few patients receiving extra doses, no trends were noted in the patients who received an additional dose to suggest that a specific patient population may require higher doses of 4F-PCC.

Regarding additional agents utilized in the management of bleeding reversal, most of the patients in each treatment arm received intravenous vitamin K, which aided in long term hemostasis. Protamine was used in more patients in the weight-based group, the reason for which could not be determined in this retrospective review. Patients in the weight-based group received more FFP after 4F-PCC administration which may have added to lowering of the INR. Despite the lower FFP usage, the fixed-dose group had equivalent efficacy.

While its use is critical in many life-threatening bleeding scenarios, 4F-PCC is not a benign medication and may also lead to significant adverse events, as evidenced by the TE rate of 15.5% observed at this institution in all patients receiving 4F-PCC. The high TE rate is likely multifactorial and may also be affected by the relatively low rates of pharmacologic VTE prophylaxis initiated after administration of 4F-PCC, which was seen in both treatment arms. Despite this, a non-statistically, but clinically significant reduction from 13.5% to 6.7% was seen in those patients receiving 1500 units 4F-PCC for VKA reversal.

Additional factors that may have led to higher TE rates in the weight-based treatment arm are the larger number of trauma patients and those who experienced recent TE prior to admission. Trauma related injuries are often associated with hypercoagulable states and patients with recent TE may also have been at higher risk for developing additional TE.

Another potential benefit of utilizing fixed-dose 4F-PCC is faster pharmacist order verification leading to shorter administration times. While no difference was noted in this study, this may have been impacted by the presence of a clinical pharmacist in the emergency department to expedite ordering and processing. Lastly, a significant cost savings is realized when utilizing the fixed-dose strategy, reducing the dose by a minimum of 1 vial per patient and aids in factor stewardship. This extrapolates to an annual minimum cost savings at this institution of at least $125,510. Given the significant reduction in TE noted, this also results in additional indirect cost savings of reduced thrombotic complications. Incident VTE was associated with an annual cost of $12,000-15,000 per patient in a recent literature review.¹⁶

As mentioned previously, some studies have suggested that those patients who have ICH bleeding, a higher baseline INR, or those with a higher body weight may not achieve hemostasis goals with a fixed-dose 4F-PCC regimen.¹¹ In a post-hoc analysis, patients who had a diagnosis of ICH, an INR of ≥4, or who had a body weight of ≥100 kilograms were evaluated for the primary endpoint of hemostasis. ICH patients had lower hemostatic efficacy than the patients with other types of bleeding; however, it was similar between both treatment arms and to what is currently reported in literature.¹³ A small number of patients weighing at least 100 kg or with INR values 4 or higher were evaluated for hemostatic efficacy and rates were found to be similar between cohorts. However, given the limited number of patients in this study, these patients should be monitored carefully and re-dosed as appropriate based on clinical markers of bleeding. Hemostatic efficacy utilizing low dose 4F-PCC has not been well described in these subgroups and should be evaluated in future studies.

Limitations

There were several limitations associated with this study, including its small sample size. This limited the ability to detect a statistical difference between the 2 groups. Due to the retrospective nature of this study, several data points were unavailable which led some patients to be unevaluable for the primary endpoint. Furthermore, there may have been additional differences between the 2 groups that were unable to be elicited through chart review. As a retrospective review, all patients that met inclusion criteria were included which may have resulted in nonmatched study groups. When evaluating baseline characteristics, there were slight differences between the 2 groups which may have increased rates of TE in the weight-based group. Lastly, in this study we sought to determine hemostatic efficacy not just with objective measures such as changes in INR, but in addition to other markers of clinical hemostasis. Hemostatic efficacy is a subjective endpoint and is difficult to determine when retrospectively evaluated. In order to mitigate the subjectivity with this data point, specific objective endpoints were defined, but these may not have been able to capture a complete picture of hemostasis. Protamine use was not defined as an exclusion criterion and the imbalanced use in the 2 groups may have impacted the results.

Conclusions

In this study evaluating both indirect and clinical markers of hemostatic efficacy, there was no difference between INR plus weight-based doses and fixed-doses of 1500 units of 4F-PCC for VKA reversal. A clinically significant reduction in thrombotic complications was demonstrated in the fixed-dose cohort. Future studies are needed to validate the findings of this study and to determine if utilizing a lower, fixed-dose of 4F-PCC reduces thrombotic complications associated with the medication while maintaining efficacy.

Footnotes

Declaration of Conflicting Iinterests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Ashley E. Milkovits

David Sugrue

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