Real-World Reversal of Factor Xa Inhibition in the Setting of Major Life-Threatening Bleeding or Urgent Surgery

Abstract

Background: Management of major life-threatening bleeding with factor Xa (FXa) inhibition poses complex challenges involving novel direct reversal agents competing with non-specific preexisting strategies. The recent availability of andexanet alfa (AA) led to a health-system guideline incorporating its use alongside the most commonly used historic agent, four-factor prothrombin complex concentrate (4F-PCC). Objectives: The objective was to characterize the use and efficacy of AA and 4F-PCC for reversal of FXa inhibition after implementation of the health-system guideline. Methods: This multi-hospital, retrospective cohort study included patients aged >18 years administered either AA or 4F-PCC between October 2018 to June 2020 with the indication for urgent reversal of FXa inhibitor-induced coagulopathy. The primary outcome assessed hemostatic efficacy between treatment groups. Secondary outcomes evaluated adjunct blood product administration, incidence of repeat pharmacologic reversal, incidence of thromboembolism, intensive care unit and hospital length of stays, and in-hospital mortality. Results: Eighty-five patients were included; 33 patients received AA and 52 patients received 4F-PCC. Effective hemostasis was achieved at similar rates in both treatment groups (84.8% vs 76.9%; P = .373). Thrombotic events occurring during the observed hospitalization were more frequent among the AA treated group (18% vs 3.8%, P = .027). No differences were observed for other secondary outcomes. Conclusion: Guideline use resulted in similar rates of effective hemostasis with a higher incidence of VTE in patients receiving AA. Further exploration with a larger, prospective study to evaluate these findings is warranted.

Keywords

apixaban rivaroxaban anticoagulation life-threatening bleeding trauma

Background

Over the past decade, the use of direct oral anticoagulants (DOACs) has increased within the United States.¹ As compared to warfarin, growing evidence demonstrates decreased rates of thromboembolism and a similar to decreased bleeding risk with DOAC use.^2-5 Prior to the approval of andexanet alfa (AA), the management of major life-threatening bleeding with select DOAC use posed complex challenges involving non-specific reversal strategies.⁶ Non-specific agents, such as four-factor prothrombin complex concentrate (4F-PCC), demonstrate variable efficacy in achieving hemostasis in this population.^7,8 Approved in 2018 by the Food and Drug Administration (FDA), AA, a recombinant modified human factor Xa (FXa) protein, is the first targeted reversal agent indicated for life-threatening or uncontrolled bleeding in patients treated with apixaban or rivaroxaban.⁹ The Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) trial was a prospective, multicenter, open-label, single-cohort study, evaluating the effect of AA in 352 patients with acute major bleeding within 18 hours after administration of a FXa inhibitor.¹⁰ While good or excellent hemostatic efficacy at 12 hours was achieved in the majority of patients, an increase in anti-FXa activity four hours after infusion cessation was observed. A relationship between hemostatic efficacy and reduction in anti-factor Xa activity was not demonstrated. Thrombotic complications were observed in 10% of patients within 30 days. Based on the trial results, guidelines suggest the use of AA for apixaban- or rivaroxaban-related life-threatening bleeding. However, factors such as medication cost and safety concerns likely limit widespread institutional adoption.^6,11

Due to formulary availability of AA in October 2018, a clinical guideline at our health system was created, incorporating its use in addition to the most frequently used historic reversal agent, 4F-PCC (KCentra®). A multidisciplinary group considered available literature, clinical experience, and operational concerns. While AA is the only agent approved for the treatment of life-threatening bleeding associated with FXa inhibitors, previous clinical experience and literature supports the use of 4F-PCC.^7,8 The guideline outlines the appropriate agent with respect to clinical scenario and timing of last FXa inhibitor dose. AA is indicated in intracranial, immediate life- or limb-threatening bleeding (physician discretion), whereas a single dose of 4F-PCC 50 units/kg (U/kg) is recommended for an urgent surgery or procedure. The AA high-dose (800 mg IV bolus, followed by 8 mg/min for up to 120 minutes) or low-dose (400 mg IV bolus, followed by 4 mg/min for up to 120 minutes) regimen is recommended based on the timing of the last dose of apixaban or rivaroxaban.⁹ Adjunct blood product use may be prescribed at the discretion of the provider. The purpose of this study was to characterize the use, efficacy, and safety of AA and 4F-PCC for reversal of FXa inhibition.

Methods

This multi-hospital, retrospective, observational cohort study included adult patients aged >18 years administered either AA or 4F-PCC between October 2018 and June 2020 with the indication for reversal of FXa inhibitor-induced coagulopathy. This health-system based study included two hospitals containing level one trauma and comprehensive stroke centers with an urban, university base. Patients administered AA or 4F-PCC for indications other than FXa inhibitor-induced coagulopathy were excluded. Patients were also excluded if pharmacologic reversal was administered but FXa inhibitor-induced coagulopathy was not suspected thereafter. The primary outcome evaluated hemostatic efficacy, assessed by a single reviewer based on the definition from the Scientific Standardization Subcommittee of the International Society of Thrombosis and Haemostasis.(12) Objective criteria, including stabilization of hemoglobin levels at 48 hours after initial treatment; stabilization of hematoma volume or increase by <35% as compared to baseline volume (assessed by computed tomography scan) within 12 hours; absence of further hemostatic or blood product transfusion(s); and absence of neurologic dysfunction or limb loss at discharge were utilized where applicable. Secondary outcomes evaluated adjunct blood product use, incidence of repeat pharmacologic reversal, incidence of thromboembolism, intensive care unit (ICU) and hospital length of stay (LOS) and in-hospital mortality between reversal agents. Protocol driven routine prophylactic screening was not performed during the study period. A drug utilization report was obtained to screen prospective patients. All data points were collected from the electronic medical record, including baseline characteristics, past medical history, indication for anticoagulation reversal, last dose of anticoagulant, imaging, documentation of surgical procedures or interventions, vital signs and laboratory values, and the medication administration record, including receipt of AA and 4F-PCC and timing of anticoagulation re-initiation.

Variables are expressed as values and percentages or median and interquartile range (IQR) where applicable. Categorical variables were compared using a Pearson chi-square test and continuous variables were compared using a Mann-Whitney U test. P values less than .05 were considered statistically significant. All analyses were conducted using Stata (Version 16; StataCorp, College Station, TX). This quality improvement study was considered exempt by the institutional review board.

Results

A total of 85 patients were included for analysis; 33 patients received AA and 52 patients received 4F-PCC. Baseline characteristics were comparable between the two treatment groups, including median age (73 vs 70 years; P = .528), gender (female, 54.5% vs 44.2%; P = .354) and BMI (25.8 vs 29.9 kg/m²; P = .392) (Table 1). The primary indication for anticoagulation among AA and 4F-PCC treatment groups was atrial fibrillation (60.6% vs 55.8%; P = .66), followed by venous thromboembolism (VTE) (27.2% vs 48.1%; P = .016), which was more prevalent in the 4F-PCC group. The indication for reversal due to limb- or life-threatening bleeding was more prevalent in the AA treated group (87.9% vs 69.2%; P = .048) with neurologic most common. Common surgeries and procedures between the two groups included exploratory laparotomy (4.7%), laminectomy (3.5%) and emergent pericardiocentesis (2.4%). Prior to admission, receipt of apixaban was common in both AA and 4F-PCC groups (69.8% vs 57.7%; P = .002). Patients receiving rivaroxaban more frequently received 4F-PCC (24.2% vs 42.3%; P = .002), as well as those patients with an unknown time since last anticoagulant dose (12.1% vs 48.1%; P = .002). Two patients (6%) received AA after protamine administration failed to achieve hemostatic efficacy.

Table 1.

Baseline Characteristics (N = 85).

	AA (n = 33)	4F-PCC (n = 52)	P-Value
Age, years	73 (64 – 79)	70 (61 – 79)	.528
Gender, female	18 (54.5%)	23 (44.2%)	.354
BMI, kg/m²	25.8 (21.9 – 31.9)	29.9 (24.7 – 34.5)	.392
Anticoagulation indication
Atrial fibrillation	20 (60.6%)	27 (55.8%)	.66
Venous thromboembolism	9 (27.2%)	28 (48.1%)	.016
Cerebrovascular accident	2 (6%)	6 (11.5%)	.399
Patent foramen ovale	2 (6%)	1 (1.9%)	.314
Peripheral vascular disease	0	1 (1.9%)	.423
Present on admission
Acute kidney injury	7 (21.2%)	20 (38.5%)	.096
Chronic kidney disease	2 (6%)	8 (15.4%)	.4
Cirrhosis	2 (6%)	5 (9.6%)	.561
Indication for therapy
Limb- or life-threatening bleed	29 (87.9%)	36 (69.2%)	.048
Neurologic	15 (45.4%)	15 (28.8%)	.041
Cardiovascular	5 (15.2%)	4 (7.7%)
Gastrointestinal	7 (21.2%)	16 (30.8%)
Reversal for urgent or emergent surgery/Procedure	4 (11.1)	12 (23%)
Hemodynamic instability*	4 (12.1%)	23 (44.2%)	.002
Medication reversed
Apixaban	23 (69.8%)	30 (57.7%)	.002
Rivaroxaban	8 (24.2%)	22 (42.3%)
Enoxaparin	2 (6%)	0
Timing since last dose
<8 hours	6 (18.2%)	3 (5.8%)	.002
≥8 hours	23 (69.7%)	24 (46.1%)
Unknown	4 (12.1%)	25 (48.1%)

Defined as an initial mean arterial pressure < 65 mmHg.

Effective hemostasis was achieved at similar rates in both treatment groups (84.8% vs 76.9%; P = .373) (Table 2). The proportion of patients receiving packed red blood cells (PRBCs) (36.4% vs 48.1%; P = .288) and fresh frozen plasma (FFP) (27.3% vs 19.2%; P = .386) administered peri-reversal were not different between groups. Patients with gastrointestinal- (27.2% vs 36.5%) and cardiovascular-related (21.2% vs 15.3%) bleeding, including pericardial tamponade, effusion, or aortic dissection, received the highest amount of blood products. Patients who received 4F-PCC as the initial reversal agent were more likely to receive a second dose of a hemostatic agent (3% vs 9.6%; P = .248) (Table 3). Observed guideline deviations included utilization of AA for an urgent surgery or procedure (12.1%) or alternative dosing regimens for both AA (18.1%) and 4F-PCC (15.3%). Of the 6 AA patients administered alternative regimens, three (50%) patients received subtherapeutic and three (50%) patients received supratherapeutic dosing. Of the 4F-PCC patients administered alternative regimens, 8/8 (100%) patients received subtherapeutic dosing. Thrombotic events occurring during the observed hospitalization were more frequent among the AA treated group (18% vs 3.8%; P = .027) (Table 4). Time to thrombosis occurred at 4 days (1.5 – 9.5) as compared to 9 days (7.5 – 10.5) for AA and 4F-PCC treated groups, respectively. Median time to VTE prophylaxis initiation occurred one day after reversal in both treatment groups. No differences were observed with ICU LOS (2.5 vs 2.5 days; P = .516), hospital LOS (6.2 vs 5.4 days; P = .577), and in hospital mortality (18.1% vs 17.3%; P = .918) (Table 5).

Table 2.

Outcomes (N = 85).

	AA (n = 33)	4F-PCC (n = 52)	P-Value
Effective hemostasis achieved	28 (84.8%)	40 (76.9%)	.373
Adjuncts to reversal
Packed red blood cells	12 (36.4%)	25 (48.1%)	.288
Within 24 hours prior to reversal, units	4 (3 – 5.5)	2 (2 – 2.75)
Within 24 hours after reversal, units	1 (1 – 2.5)	2 (1 – 3)
Total (LOS), units	4 (2 – 7)	3.5 (2 – 4.75)
Fresh frozen plasma	9 (27.3%)	10 (19.2%)	.386
Within 24 hours prior to reversal, units	2 (2 – 5)	2 (1 – 2)
Within 24 hours after reversal, units	2 (1.75 – 2)	2 (2 – 2.5)
Total (LOS), units	4 (2 – 5)	2 (2 – 2.5)
Repeat reversal agent ordered	1 (3%)	5 (9.6%)	.248
Thromboembolism after reversal	6 (18%)	2 (3.8%)	.027
Thrombosis	4 (66.7%)	2 (100%)
Pulmonary embolism	2 (33.3%)	0
Timing after reversal, days	4 (1.5 – 9.5)	9 (7.5 – 10.5)
Timing to restart VTE prophylaxis, days	1 (1 – 2)	1
ICU LOS, days	2.5 (.8 – 5.5)	2.5 (.9 – 4.4)	.516
Hospital LOS, days	6.2 (4.6 – 14.8)	5.4 (3.6 – 10.9)	.577
In-hospital mortality	6 (18.1%)	9 (17.3%)	.918

Table 3.

Case Series of Patients Administered a Second Reversal Agent.

Patient	Indication	Anticoagulant	Initial Strategy		Subsequent Strategy		Evidence of Continued Bleeding	Notes	Hemostasis Achieved
Patient	Indication	Anticoagulant	Drug	Dose	Drug	Dose	Evidence of Continued Bleeding	Notes	Hemostasis Achieved
1	Intracranial hemorrhage	Apixaban	AA	Low	4F-PCC	35U/kg	No	Both agents ordered simultaneously	No
2	Hemoptysis	Rivaroxaban	4F-PCC	50U/kg	AA	Low	Yes	Still bleeding 5 hours after 4F-PCC	Yes
3	Intracranial hemorrhage	Apixaban	4F-PCC OSH*	Unknown	AA	Low	No	Unclear 4F-PCC dose at OSH	Yes
4	Intracranial hemorrhage	Apixaban	4F-PCC OSH	14U/kg	AA	Low	No	Ordered after hematology consult	Yes
5	Subarachnoid hemorrhage	Apixaban	4F-PCC OSH	50U/kg	AA	Low	No	Ordered after hematology consult	Yes
6	GI bleed	Apixaban	4F-PCC	25U/kg	4F-PCC	50U/kg	No	N/A	Yes

*Outside hospital

Table 4.

Case Series of Thromboembolic Events Occurring After Pharmacologic Reversal^a.

Patient	Indication	Reversal agent	Dosing regimen administered	VTE	Timing after reversal (days)
1	Intraparenchymal hemorrhage	AA	Appropriate	Subsegmental PE	12
2	Intraparenchymal hemorrhage	AA	Appropriate	Left cephalic upper extremity DVT	9
3	Right MCA infarct with hemorrhagic conversion	AA	Appropriate	Segmental PE	4
4	Intraventricular hemorrhage	AA	Inappropriate (supratherapeutic)	Left occlusive gastrocnemius DVT	14
5	Procedural reversal	AA	Appropriate	Left cephalic upper extremity DVT	11
6	GI bleed	AA	Appropriate	Renal artery thrombosis	2
7	Procedural reversal	4F-PCC	Appropriate	Left cephalic upper extremity DVT	6
8	Intraparenchymal and subarachnoid hemorrhage, subdural hematoma	4F-PCC	Appropriate	Left common femoral DVT	12

^aA second reversal agent was not administered in any case.

Table 5.

Summary of Outcomes with Initial AA and 4F-PCC Administration.

Discussion

This observational study describes the real-world utilization of a therapeutic guideline to aid clinical decision making when emergently reversing FXa induced coagulopathy. While comparisons of reversal strategies have been described in the available literature, many of the published analyses focus on the outcomes for a specific subset of patients.^13-15 This analysis uniquely analyzes the outcomes of FXa patients with diverse medical and surgical emergencies.

The combination of the pharmacokinetic and pharmacodynamic properties of each FXa inhibiting anticoagulant, available reversal agents, and patient specific factors (such as underlying indication for the anticoagulation and risk of thrombosis) can significantly complicate decisions regarding anticoagulant reversal. Our analysis demonstrates the effective implementation of a clinical decision-making tool to aid in the management of coagulopathy and bleeding emergencies related to DOAC use. The guideline was implemented in an attempt to mitigate risk of adverse events associated with agents used for reversal, ensure appropriate dosing of reversal agents, and decrease the amount of time spent deliberating optimal reversal strategies. An analysis comparing medication utilization and patient outcomes in the absence of such a tool could prove useful in evaluating the effectiveness of the tool in achieving these goals.

The incidence of patients requiring the administration of repeat reversal agents was low, but more prevalent in the 4F-PCC group (3% vs 9.6%). Interestingly, no VTE events were observed in patients receiving repeat reversal. These scenarios were all unique and reflect the heterogeneity of the patient population being evaluated. However, several instances were the result of a reversal agent being administered at an outside hospital prior to presentation at the included study institutions. Timing between repeat doses varied among these patients; current literature does not address the effect of repeat dosing or the temporal relationship between repeat doses and clinical outcomes. Reviewing outcomes specific to this subset of patients could prove insightful.

A gap in literature exists in analyzing outcomes with respect to the location of bleeding or type of procedure performed. A higher number of patients were observed to have hemodynamic instability at the time of anticoagulation reversal in the 4F-PCC group (12.1% vs 44.2%) despite similar requirements for adjunctive blood products. This could be attributable to recommendations made in the guideline (e.g. preferentially administering 4F-PCC prior to emergent procedure or preference given to andexanet for intracranial hemorrhage). The rates of effective hemostasis achieved in this retrospective analysis correlate with similar analyses that have been previously published.^14,16,17 The individual rates of effective hemostasis between groups are difficult to compare as the indications for anticoagulant reversal were different within the cohort. While the number of patients described in this analysis is larger than some published retrospective analyses, our numbers still do not allow for the type of detailed subgroup analysis that would provide clarity on this issue. Further prospective studies in this area, such as analyzing the optimal pharmacologic agent in specific disease states, both medical and surgical, would be helpful in determining the optimal therapy for each indication.

Rates of thrombotic events also correlated to previously published literature evaluating the respective reversal strategies individually.^10,16,17 However, it should be noted that the VTE events were not fully adjudicated in terms of ensuring they were not present on admission. Timing of VTE prophylaxis after reversal was similar between the two treatment groups. Each patient with a VTE event after reversal was initiated on prophylactic subcutaneous heparin. All subjects receiving appropriate dosing and the median time to VTE prophylaxis was one day after pharmacologic reversal. It is unknown if an increased VTE risk solely lies with the reversal agent, while modifiable and/or non-modifiable patient-specific characteristics likely represent concomitant factors.

The retrospective nature of our study carries inherent limitations relating to the documentation of information within the patient’s chart. Many ordering providers routinely practice at both study sites, suggesting practice patterns are consistent between institutions. A potential bias may have existed in the selection of pharmacologic anticoagulation and associated cost. Compared to AA, 4F-PCC provides a significant cost advantage. At the time of current writing, the average wholesale price (AWP) of 4F-PCC with dosing based on 100 kg patient (5,000 IU) is $6,582.¹⁸ Conversely, the AWP of the AA low-dose and high-dose regimens is $15,000 and $27,000, respectively. Adjunct blood product use between the two treatment groups may have confounded the association of hemostatic efficacy with specific reversal agents. Further, there are significant differences in patient characteristics between the AA and 4F-PCC groups in terms of bleeding type, which likely interferes with comparison and may explain the lack of differences seen in the outcomes such as LOS and mortality.

Conclusion

This study highlights the real-world challenges associated with the urgent or emergent reversal of FXa inhibiting anticoagulants. The availability of multiple reversal strategies with limited clinical experience or evidence to support one therapy over another makes choosing the optimal agent for each case extremely complex. Similar rates of hemostatic efficacy were observed between the two treatment groups. A greater incidence of thromboembolic events was observed in AA treated patients despite appropriate dosing and timing of VTE prophylaxis after reversal. The data collected herein does not allow for the evaluation of which patients specifically would derive more benefit from one therapy or an alternative. Therefore, it remains critically important to continuously evaluate evidence and real-world experiences to optimize patient outcomes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NDM is a consultant for Alexion Pharmaceuticals. No other conflicts of interest exist.

Funding

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

ORCID iDs

Lauren E. Schmidt

Niels D. Martin

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