Outcomes of 4-factor Prothrombin Complex Concentrate in Patients With Liver Disease and Nonvitamin K Antagonist-Related Coagulopathy: A Retrospective Study

Abstract

The administration of 4-factor prothrombin complex concentrate (4F-PCC) has expanded beyond its Food and Drug Administration (FDA)-approved indication for the emergent reversal of vitamin K antagonists (VKAs). Therefore, this study aimed to evaluate the risks and benefits associated with the expanded use of 4F-PCC. We conducted a single-center retrospective review of 4F-PCC administrations at our university hospital. Of the 159 patients who received 4F-PCC, 76% (n = 121) and 24% (n = 38) received it for the FDA-approved indication in the vitamin K-related coagulopathy (VKA) group and for expanded use in the nonvitamin K-related coagulopathy (nVKA) group, respectively. The expanded use of 4F-PCC was associated with a less robust reduction in the international normalized ratio (INR) (INR of −0.7 ± 1.3 vs INR of −1.6 ± 1.8, P = .002), and fewer patients in the nVKA group achieved a postadministration INR of less than1.5 (11% vs 79%, P = .001) than those in the VKA group. Furthermore, the 30-day mortality rate was significantly higher in the nVKA cohort than in the VKA cohort (42% vs 20%, P = .04). Notably, based on our data, underlying differences in the patient’s comorbidities, particularly advanced liver disease, may have contributed to the observed outcome variations, including mortality rate. Therefore, factors, including comorbidities and the underlying etiology of coagulopathy, should be considered when deciding on the expanded use of 4F-PCC. Further research is needed to better understand the potential risks and benefits of 4F-PCC in expanded use scenarios, and the clinical decision to use 4F-PCC outside its FDA-approved indication should be made carefully, considering this information.

Introduction

Prothrombin complex concentrates (PCCs) provide an immediate source of non-activated clotting factors.^1,2 They are derived from donor-pooled plasma and can be quickly reconstituted and administered in a low volume. Prothrombin complex concentrate is classified into 2 broad categories as follows: 4-factor PCC (4F-PCC) and 3-factor PCC (3F-PCC). 4F-PCC, containing consistent amounts of factors II, VII, IX, and X and proteins C and S, is more commonly used than 3F-PCC, which does not contain factor VII.^3,4

The Food and Drug Administration (FDA)-approved indication for 4F-PCC usage is limited to adult patients receiving vitamin K antagonist (VKA) with active major bleeding or need for an urgent surgery/invasive procedure. 4F-PCC has been available in the United States since 2013 (Kcentra, CSL Behring). ⁵ As an urgent VKA reversal agent, 4F-PCC is currently recommended over plasma transfusion due to its rapidity in international normalized ratio (INR) correction, as well as the low volume of fluid required for infusion. ⁶

Apart from the specific FDA-approved indication, 4F-PCC has been used to promote thrombin generation in various clinical conditions, including acute coagulopathy of trauma,^7,8 as adjunctive therapy during massive blood transfusion, ⁹ correcting coagulopathy prior to urgent surgery, ¹⁰ and to manage the coagulopathy of chronic liver disease. ¹¹ Furthermore, few cardiopulmonary bypass protocols currently incorporate the use of 4F-PCC to reduce postoperative blood loss. ¹² The administration of 4F-PCC has also been incorporated into protocols to nonspecifically reverse several direct oral anticoagulants (DOACs).^13,14

Despite the enthusiasm for the expanded or off-label use of 4F-PCC clinically, data regarding its safety and efficacy in reversing coagulopathies that are unrelated to the administration of VKAs are limited. Moreover, the effectiveness of the expanded use of 4F-PCC is challenging to predict because of this knowledge gap. Therefore, this retrospective study aimed to evaluate the expanded use of 4F-PCC to address this knowledge gap and gain insights that may influence the use of 4F-PCC. The primary objective of the study was to evaluate the patient outcomes, safety profile, and efficacy of 4F-PCC when administered to patients receiving VKAs compared to those not receiving VKAs. At our academic medical center, many patients not receiving VKAs have coagulopathies associated with liver disease. Since 4F-PCC is specifically designed for vitamin K antagonism, we hypothesized that 4F-PCC would be less effective when used outside of its FDA-approved indication. The clinical significance of such an evaluation is essential, and if its efficacy is demonstrated, expanded use could offer significant benefits over the administration of plasma. Conversely, if ineffective, avoiding the use of 4F-PCC for non-approved indications would lower costs and eliminate potential adverse effects. Therefore, this study aimed to evaluate the expanded use of 4F-PCC in our university hospital. We evaluated patient outcomes in various clinical settings and the safety and efficacy of 4F-PCC for the reversal of nonvitamin K-related antagonists.

Methods

We performed a single-center, retrospective cohort analysis of all 4F-PCC administrations at our university hospital over 3 years. Pharmacy and patient electronic medical records were queried, and we reviewed the patients’ clinical courses throughout their index hospitalizations.

Study Population

We collected data on patient demographics, medical comorbidities, laboratory values, all diagnostic and therapeutic procedures performed, inpatient complications, and discharge disposition. For patients taking anticoagulants, the specific type and dose of outpatient anticoagulants were confirmed as part of our preadmission pharmacist-driven medicine reconciliation process. All patients who received 4F-PCC at our facility during the study period were included in the analysis. Patients who received VKAs and 4F-PCC for coagulopathy reversal were assigned to the VKA group; Patients not receiving VKAs but received 4F-PCC for coagulopathy reversal were assigned to the nonvitamin K-related coagulopathy (nVKA) group. Patients who had been prescribed VKAs but had not taken their VKA for more than 6 days prior to admission were included in the nVKA cohort. Patients with coagulopathies related to trauma, liver failure, massive hemorrhage, outpatient low-molecular-weight heparin administration, and the use of DOACs were all included in the nVKA cohort. FDA-approved use of 4F-PCC was defined as administration for reversing VKA due to active hemorrhage or prior to emergent surgery or procedure. Administration for any other purpose was defined as an expanded use.

Patients with a diagnosis of liver disease had the model for end-stage liver disease (MELD) scores calculated based on laboratory data obtained within 12 h of 4F-PCC administration. ¹⁵ Outcome data were derived from medical records and included the length of hospital stay, thromboembolic events, and any other documented complications. 4F-PCC was administered intravenously according to the following weight-based protocol: 25 U/kg 4F-PCC for INR < 4; 35 U/kg 4F-PCC for INR 4-6; 50 U/kg 4F-PCC for INR > 6 per package prescribing information. ⁵

Statistical Analysis

Patients who received 4F-PCC were identified using the hospital pharmacy administration record, and electronic medical records were reviewed. The data collected was entered into an Excel spreadsheet. Statistical comparisons were performed between patients who were administered 4F-PCC for VKA and nVKA. Categorical variables are reported as counts and percentages. Parametric and nonparametric continuous variables are reported as means and standard deviations and median interquartile ranges, respectively. We used χ² and Fisher exact tests to determine differences between cohorts for categorical variables. Conversely, we used the Mann-Whitney U test and Student t test to detect the differences in nonparametric and parametric continuous variables, respectively. All P values were 2-tailed, with statistical significance set at .05. Statistical analyses were performed using the IBM SPSS software for Windows, version 25.0 (IBM Corp.).

Study Approval

This study was approved by the University of Minnesota Institutional Review Board (IRB 1311E45523).

Results

We identified 159 discrete administrations of 4F-PCC; of these, 121 received 4F-PCC for VKA reversal for active hemorrhage or prior to an urgent procedure and 38 received 4F-PCC for non-VKA indications (Figure 1). Patients receiving 4F-PCC for VKA reversal were significantly older (66.5 vs 52.8 years, P = .001) and had more preexisting cardiac comorbidities than those receiving 4F-PCC for nVKA reversal (Table 1). Chronic and acute hepatic failure were more prevalent in the nVKA cohort than in the VKA cohort (57.9% vs 6.6%, P = .001).

Figure 1.

Schematic of the study design and patient cohorts. 4F-PCC, 4-factor prothrombin complex concentrate; VKA, vitamin K antagonists; nVKA, nonvitamin K-related coagulopathy.

Table 1.

Patient Demographics and Medical Comorbidities in the nVKA Versus VKA Groups.

Variables	nVKA (n = 38)	VKA (n = 121)	P Value
Age	53 ± 13	67 ± 15	.001a
Sex (Female)	20 (53%)	45 (37%)	.091
BMI	29 ± 6	29 ± 6	.698
Hypertension	18 (47%)	86 (71%)	.001a
Atrial fibrillation	6 (7%)	78 (93%)	.001a
Coronary artery disease	4 (11%)	48 (40%)	.001a
Heart failure	8 (10%)	72 (90%)	.001a
Liver failure	22 (58%)	8 (7%)	.001a
History of deep vein thrombosis	9 (24%)	37 (31%)	.414
History of pulmonary embolism	5 (13%)	22 (18%)	.472

Abbreviations: BMI, body mass index; nVKA, nonvitamin K antagonist coagulopathy; VKA, vitamin K antagonist.

^aStatistically significant.

In the nVKA group, 68% of the patients (n = 25/38) received 4F-PCC to reverse coagulopathy in the setting of an active hemorrhage, which was comparable to the VKA group (70%, n = 85/121) (Table 2). When evaluating specific indications, in the nVKA group, a significantly greater percentage of patients had coagulopathy of liver disease (nVKA = 22, 58%; VKA = 8, 6.6%, P = .001) and bleeding in the context of DOACs (nVKA: n = 8, 21% vs VKA: n = 1, 0.8%; P = .001) compared to the VKA cohort. Other specific indications for 4F-PCC administration in the nVKA cohort included patients with gastrointestinal hemorrhage (n = 14, 37%), cardiac surgery (n = 5, 13%), and trauma (n = 5, 13%). In the VKA group, 70% of the patients (n = 85/121) received 4F-PCC to reverse coagulopathy in the setting of active hemorrhage. A significantly greater number of patients in the VKA group had intracranial hemorrhage (nVKA: n = 6, 16% vs VKA: n = 45, 37%; P = .029). Other statistics for specific indications for 4F-PCC administration in patients with VKA included gastrointestinal hemorrhage (17%, n = 21/121), and additional conditions associated with clinically significant active hemorrhage as mentioned in Table 2.

Table 2.

Indications for 4F-PCC Administration in the nVKA and VKA Groups.^a

Total Study Patients (n = 159)	nVKA (24%, n = 38)	VKA (76%, n = 121)	P Value
Hemorrhage (any)	25 (68%, n = 25/38)	85 (70%, n = 85/121)	.604
ICH	6 (16%, n = 6/38)	45 (37%, n = 45/121)	.029b
GI hemorrhage	14 (37%, n = 14/38)	21 (17%, n = 21/121)	.698
Coagulopathy of liver disease	22 (58%, n = 22/38)	8 (6.6%, n = 8/121)	.001b
Direct oral anticoagulants	8 (21%, n = 8/38)	1 (0.8%, n = 1/121)	.001b
Trauma	5 (13%, n = 5/38)	19 (16%, n = 19/121)	.702
Cardiac surgery	5 (13%, n = 5/38)	17 (14%, n = 17/121)	.812

Abbreviations: ICH, intracranial hemorrhage; GI, gastrointestinal; nVKA, nonvitamin K antagonist coagulopathy; 4F-PCC, 4-factor prothrombin complex concentrate; VKA, vitamin K antagonist.

^aPatients were only evaluated for the subgroups listed; patients may be included in multiple subgroups or none of the subgroups if the indication was not among those evaluated.

^bStatistically significant.

Patients in the nVKA cohort had lower preadministration INR values than those in the VKA cohort (2.4 ± 1.4 vs 3.0 ± 1.8, P = .04) (Table 3). Although INR-based dosing was used in our protocol, the mean weight-based dosing of 4F-PCC was not statistically different between the 2 cohorts (nVKA = 31 ± 12 U/kg vs VKA = 28 ± 8.9 U/kg, P = .08). Postadministration INR values were higher in the nVKA cohort (2.1 ± 0.8 vs 1.39 ± 0.5, P = .001) than in the VKA cohort, demonstrating a significantly reduced effectiveness of 4F-PCC in improving or normalizing INR values (INR of −0.7 ± 1.28 vs INR of −1.6 ± 18) in this patient group. Additionally, significantly fewer patients in the nVKA group achieved an INR of <1.5 than those in the VKA cohort (11% vs 79%, P = .001).

Table 3.

Laboratory and Clinical Outcomes of 4F-PCC Administration in the nVKA Versus VKA Groups.

Variable	nVKA (n = 38)	VKA (n = 121)	P Value
Pre 4F-PCC INR	2.4 ± 1.4	3.0 ± 1.8	.04a
Post 4F-PCC INR	2.1 ± 0.8 (N = 36)	1.4 ± 0.5 (N = 116)	.001a
4F-PCC dosage (U/kg)	31 ± 12	28 ± 8.9	.08
INR corrected to <1.5	4 (11%) (N = 36)	92 (79%) (N = 116)	.001a
Change in INR	−0.7 ± 1.3	−1.6 ± 1.8	.002a
Resolution of hemorrhage	15 (54%) (N = 28)	56 (55%) (N = 84)	.891

Abbreviations: 4F-PCC, 4 factor prothrombin complex; INR, international normalized ratio; nVKA, nonvitamin K antagonist coagulopathy; VKA, vitamin K antagonist.

^aStatistically significant.

The incidence of thrombotic events for all patients in this study was not significantly different between the 2 cohorts (nVKA: n = 2, 5% vs VKA: n = 13, 11%, n = 13; P = .490). The 30-day mortality rate for all study patients was significantly higher in the nVKA cohort than in the VKA cohort (nVKA: n = 15, 42% vs VKA: n = 23, 20%; P = .040) (Table 4). However, when analyzed separately, the 30-day mortality rate for patients with advanced liver disease was not significantly different between the nVKA and VKA groups (nVKA: n = 13, 60% vs VKA: n = 3, 38%; P = .301) (Table 5).

Table 4.

Thirty-Day Mortality and Morbidity Rates for Patients Receiving 4F-PCC in Both the FDA-Indicated and Expanded Use.

Variable	nVKA (n = 38)	VKA (n = 121)	P Value
30-day mortality rate	15 (42%)	23 (20%)	.040a
Thromboembolic event	2 (5%)	13 (11%)	.490

Abbreviations: FDA, Food and Drug Administration; nVKA, non-vitamin K antagonist; 4F-PCC, 4-factor prothrombin complex concentrate; VKA, vitamin K antagonist.

^a Statistically significant.

Table 5.

Patient Characteristics, Laboratory Outcome, Clinical Outcomes, and Mortality Rate for 30 Patients With Liver Disease Who Received 4F-PCC in the nVKA Versus VKA Groups.

Variable	nVKA (n = 22)	VKA (n = 8)	P value
MELD score	31 ± 8	23 ± 7	.025a
INR corrected to <1.5	2 (9%)	4 (50%)	.013a
Control of bleeding in patients with hemorrhage	8/16 (47%)	4/7 (57%)	.428
30-day mortality	13 (60%)	3 (38%)	.301
90-day mortality	13 (60%)	3 (38%)	.301
Predicted 90-day MELD score mortality rate	53%	20%	.293
Thromboembolism	2 (9%)	1 (13%)	.623

Abbreviations: MELD, model for end-stage liver disease ¹⁵ ; INR, international normalized ratio; nVKA, nonvitamin K antagonist; 4F-PCC, 4-factor prothrombin complex concentrate; VKA, vitamin K antagonist.

^a Statistically significant.

Discussion

The use of 4F-PCC at our university hospital typically falls within its approved indications, and 76% (n = 121) of the 4F-PCC administration at our institution is for the reversal of VKA. Overall, of the patients in the VKA cohort, 70% (n = 85) received 4F-PCC for acute hemorrhage control and 18% (n = 22) for VKA reversal prior to urgent surgery or procedure. The expanded use of 4F-PCC in the nVKA group at our institution varied but fell into several distinct subgroups. The predominant groups were patients with liver failure (n = 22, 58%), gastrointestinal hemorrhage (n = 14, 37%), intracranial hemorrhage (n = 6, 16%), those taking DOAC medications (n = 8, 21%), and those undergoing cardiac surgery on cardiopulmonary bypass (n = 5, 13%).

We noted several differences in the impact of 4F-PCC between the patients in the VKA and nVKA groups. Although each group received a similar dose of 4F-PCC per our weight-based protocol, its effectiveness in reducing INR was less profound among patients in the nVKA group. This was confirmed by the limited change in INR values after 4F-PCC administration and the observation that only 11% of these patients achieved an immediate postinfusion INR of <1.5. The 30-day mortality rate was significantly higher in the nVKA group than in the VKA group.

These differences in the efficacy between the FDA-approved- and expanded-use groups may be partly due to the higher number of patients with advanced liver disease within the expanded-use group. The use of 4F-PCC in liver failure has been shown to have less impact on INR values than when used for warfarin reversal. ¹⁶ The observed mortality rate differences between these groups likely reflect the differences in the patient comorbidities. Given that 58% of the expanded-use cohort had advanced liver disease with an average MELD score of 31, which predicts a 90-day mortality rate of 53%, expanded-use patients were expected to have a higher mortality rate. ¹⁵ This observation is supported by a previous study that suggested that 4F-PCC is not sufficiently effective to correct coagulopathy in patients with liver disease, given the high mortality and morbidity rates arising from liver disease. ¹⁰ Because of the limitations of this retrospective study, we could not determine whether 4F-PCC administration had a causative impact on the high mortality rate of patients in the nVKA-expanded use cohort.

However, the use of 4F-PCC in liver failure remains controversial because severe hemorrhage in patients with cirrhosis is associated with high mortality. This is reflected in our data, which demonstrate a 60% (n = 13) mortality rate observed in our nVKA group with liver disease. Coagulopathy in liver disease is complex and involves many aspects of the clotting system, including platelet number and function and clotting factor activity. Although the loss of procoagulant factors may lead to derangements in traditional clotting tests, such as an elevated INR, this is frequently offset by a reciprocal loss of anticoagulant factors, which are not reflected in such laboratory values. Viscoelastic whole blood testing, including thromboelastography, for patients with liver disease has repeatedly shown that elevations in INR do not correlate with hypocoagulable state. ¹⁷ Therefore, relying on INR to determine the need for 4F-PCC administration in a patient with liver failure may expose more patients to harm than benefit.

The benefits of 4F-PCC in managing hemorrhage in patients receiving DOACs are unclear. Additionally, since the number of patients on DOACs has increased, clinicians have had to develop various methods to achieve hemostasis in these patients in the emergency setting, including the use of 4F-PCCs. ¹⁸ During this 3-year study period, we observed a few patients on DOACs who were treated with 4F-PCC. The recent approval of specific reversal agents for DOACs has provided new opportunities for rapid anticoagulant reversal.

This study has several limitations. Although we identified the administration of 4F-PCC based on pharmacy administration records, some clinical administration of 4F-PCC may have been unintentionally excluded from our data set. Another significant limitation of this study is its retrospective nature. Conclusions can rarely be made from retrospective studies performed at a single center. Given that this was a retrospective review, we could only infer correlations, not causality. Continued education and investigation regarding the use of 4F-PCC is necessary to maximize its clinical applications and effectiveness while maintaining patient safety, similar to the case with other agents for VKA reversal, such as vitamin K. ¹⁹

It is not uncommon for hemostatic medications, such as tranexamic acid ²⁰ and activated factor VII,^21,22 to be administered in uncontrolled hemorrhage settings. Despite the known risks of these medications, which are predominately thromboembolic events, ²³ they have been increasingly incorporated into daily clinical practice.^24,25 Given that managing an unstable patient with hemorrhage presents extreme challenges to the clinician, many have begun to favor the use of such medications in the acute setting despite insufficient evidence of their safety or efficacy. Other groups have reported thromboembolic complications of PCC use in patients with life-threatening hemorrhage. ²⁶ However, in our study, we did not observe a significant difference in thromboembolic events in patients who received 4F-PCC in the nVKA and VKA groups. Although the efficacy and safety of the expanded use of 4F-PCC in off-label settings remain uncertain, this expanded use of 4F-PCC should be carefully considered.

In conclusion, the administration of 4F-PCC was associated with higher rates of successful reversal of coagulopathy in patients receiving VKAs than in those not receiving VKAs. Following the administration of 4F-PCC, correction of the INR to <1.5 was achieved in only 11% (n = 4/38) and 79% (n = 92/121) of patients in the nVKA and VKA groups, respectively. The resolution of hemorrhage was not significantly different between the 2 groups; however, the 30-day mortality rate was significantly higher (P = .04) in the nVKA group (42%, n = 15/38) compared to the VKA group (20%, n = 23/121). Future randomized prospective studies regarding the expanded use of 4F-PCC would be required to revise existing guidelines.