Article, Hematology

Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy

a b s t r a c t

Introduction: Coagulopathy due to warfarin in patients with major bleeding was traditionally reversed with fresh frozen plasma and intravenous (IV) vitamin K, but prothrombin complex concentrates (PCC) are increasingly used in the treatment of these patients. Factor Eight Inhibitor Bypassing Activity is an activated four- factor PCC most commonly used in patients with hemophilia. We aimed to evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major bleeding, by measuring the percentage of patients who achieved target INR <= 1.5 and the incidence of Thrombotic adverse events (TAE).

Methods: In this prospective observational study, we enrolled patients presenting to the Emergency Department (ED) with warfarin associated coagulopathy (INR N 1.5) and major bleeding. Patients received FEIBA using an INR based dosing strategy and IV vitamin K.

Results: In 43 patients, median initial INR was 4.0 (2.7, 7.3 interquartile range (IQR)). Median time to result the second INR was 45 min (38, 55 IQR) and the median INR was 1.4 (1.3, 1.6 IQR). Out of the 43 patients, 93% achieved the target INR of <=1.5. In-hospital mortality was 40% (17 patients). There were 11 TAEs in 6 patients (14%); 4 events in 2 patients (5%) were attributed to FEIBA. Conclusion: A protocolized use of FEIBA and IV vitamin K resulted in the efficacious reversal of warfarin-induced coagulopathy in patients with major bleeding. TAEs occurred in 14% of patients and were attributed to FEIBA in 5% of patients.

(C) 2019

Introduction

Warfarin is a commonly prescribed oral anticoagulant for the treat- ment of a wide range of thromboembolic disorders, and patients on Warfarin therapy have an increased bleeding risk [1-4]. The risk of bleeding depends on age, co-morbid conditions, acute illnesses, stability of INR control and medication interactions, along with many other mod- ifiable and non-modifiable risk factors [2]. Rates of major bleeding vary among recent studies [5-8], but remain as high as 4% per person-year [3]. These hemorrhage-related adverse events lead to significant patient morbidity and mortality.

Traditionally, fresh frozen plasma and vitamin K have been used to reverse warfarin associated major bleeding. In 2012, the American College of Chest physicians recommended the use of four-

* Corresponding author at: Washington Hospital, 2000 Mowry Ave, Fremont, CA 94538.

E-mail addresses: [email protected] (N.N. Htet), [email protected] (D. Barounis), [email protected] (M. Hormese), [email protected] (E. Lovell).

factor prothrombin complex concentrate (PCC) and IV vitamin K rather than plasma for the treatment of these patients [9]. The latest guideline for reversal of antithrombotic agents in intracranial hemorrhage by the Neurocritical care Society and Society of Critical Care Medicine recom- mends administering 3-factor or 4-factor PCC rather than FFP to pa- tients with vitamin K antagonist-associated intracranial hemorrhage and INR >= 1.4 [10].

Three-factor PCCs contain factors II, IX, and X, and potentially low levels of factor VII. Four-factor PCCs contain II, VII, IX, and X, and have been increasingly used in the rapid reversal of warfarin associated coag- ulopathy [11-13]. Activated 4-factor PCC includes activated factor VII, along with non-activated factors II, IX, and X. In the United States, the only activated PCC is a freeze-dried sterile human plasma fraction with factor eight (VIII) inhibitor bypassing activity (FEIBA), made by Baxter [14].

FEIBA has been used for over 30 years to control bleeding in patients with hemophilia. It is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding associated with surgical in- terventions in these patients [15,16]. Recent data have reported off-

https://doi.org/10.1016/j.ajem.2019.05.047

0735-6757/(C) 2019

label use of FEIBA as an Anticoagulant reversal agent [17-20], and FEIBA has been found to achieve a faster normalization of INR compared with FFP [18].

In 2013, our institution developed a standard treatment algorithm for reversal of warfarin induced coagulopathy using FEIBA and IV vita- min K. The objective of this study was to evaluate the efficacy and safety of this protocol. Specifically, we sought to determine the percentage of patients who achieved INR <= 1.5 as well as the adverse thrombotic event rate.

Methods

We conducted a prospective observational study at a tertiary care suburban level I trauma center with N100,000 ED visits annually. The in- stitutional review board approved the study of all patients who received FEIBA for warfarin reversal after initiation of the institutional protocol in 2013. This approval was granted both as a prospective study and analy- sis of patients who provided consent, as well as a retrospective chart re- view of all patients who received FEIBA. When possible, informed consent was obtained to allow prospective evaluation of outcomes in- cluding thrombotic adverse events until time of hospital discharge. Pa- tients with warfarin associated coagulopathy and major bleeding received 1000 units of FEIBA IV over 15 min if their INR was >=5.0, and 500 units of FEIBA IV over 15 min if their INR was b5.0 (Fig. 1). All pa- tients also received IV vitamin K 10 mg over 30 min contemporaneously with the infusion of FEIBA. The protocol included an order for a second INR to be drawn 30 min after the FEIBA infusion, and if the INR remained N1.5 an additional 500 units of FEIBA could be given based on patient’s clinical status and physician judgment. The INR was then repeated at 4 h and daily thereafter as clinically necessary.

All patients who presented to the ED and received FEIBA between

February 7, 2013 and December 5, 2013 were identified via the

electronic Order entry for FEIBA. Study duration was determined to be ten months, based on availability of study investigators. ED pharmacists generated a report of potentially eligible subjects every Monday, Wednesday, and Friday with email alerts provided to study investiga- tors, who then evaluated patients for study eligibility. Patients were in- cluded if they were 18 years or older and received FEIBA for treatment of major hemorrhage secondary to warfarin associated coagulopathy with an INR N 1.5. We defined major bleeding based on the criteria used by the International Society of Thrombosis and Haemostasis: po- tentially life threatening bleed; symptomatic bleeding in a critical loca- tion such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial or intramuscular with compartment syn- drome; bleeding causing a 2 g/dL fall in hemoglobin, or bleeding leading to transfusion of 2 or more units of whole blood or red blood cells [21]. Patients were excluded if coagulopathy was present but not induced by warfarin, if the patient was taking warfarin but did not have coag- ulopathy (INR <= 1.5), if criteria for major hemorrhage were not met, if reversal agents were given prior to presentation in the ED or if re- versal agents besides FEIBA and IV Vitamin K were given in the ED (e.g. FFP, aFactor VII, PCCs, vitamin K via oral, subcutaneous or intra- muscular routes), or if patients did not receive vitamin K. Pregnant patients and prisoners were excluded. When possible, informed con- sent was obtained from the patient if competent, or from the patient's next of kin or durable power of attorney in the ED or within 24 h of hospital stay.

Data collected via chart review for all patients included patient age, sex, race, medical indication for warfarin, indication for warfarin reversal, initial dose of FEIBA administered, pretreatment INR, post- treatment INR at 30 min and subsequent INR, time between drug ad- ministration and INR <= 1.5, length of stay in hospital, in-hospital mortal- ity, cause of death, thrombotic adverse events, and location of thrombus.

Fig. 1. Institutional protocol for coagulopathy reversal in patients with major bleeding on warfarin. FEIBA = Factor Eight Inhibitor Bypassing Activity. U = units.

The primary outcome of the study was to evaluate the efficacy of FEIBA in lowering INR to <=1.5 in patients with major bleeding on warfa- rin. Secondary outcomes were in-hospital mortality as well as throm-

Table 1

Characteristics of patients treated with FEIBA (Factor Eight Inhibitor Bypassing Activity). LVAD = left ventricular assist device. GI = gastrointestinal. GU = genitourinary. ICH = in- tracranial hemorrhage. IQR = interquartile range.

botic Adverse event rates through hospital discharge. Thrombotic

adverse events (TAEs) included stroke, myocardial infarction, deep vein thrombosis, pulmonary embolism or arterial thromboembolism, but excluded superficial venous thromboses. Study investigators per- formed a chart review and reached a consensus decision based on clin- ical features and a time frame of TAEs occurring within 7 days of FEIBA administration, whether TAEs were attributable to FEIBA.

Descriptive statistics were used to summarize patient demographics and outcomes. Data are presented as mean and standard deviation or median and interquartile range or percentages as appropriate.

Results

Between February 7th 2013 and December 5th 2013, all 77 emer- gency department patients who received FEIBA were assessed for study eligibility. 33 patients were excluded: 11 received FFP; 12 did not receive IV vitamin K; 11 did not have major hemorrhage and 3 had INR <= 1.5. Four patients met more than one reason for exclusion. One patient's consent was withdrawn. For 13 patients, consent was un-

Patient characteristics FEIBA n =

43

Age in years, medium (IQR) 78 (42-91)

Male sex, n (%) 20 (46.5%)

Ethnicity

Caucasian 70%

African American 25.6%

Other 4.65%

Indication for anticoagulation, n (%)

Atrial fibrillation 28 (65.1%)

Thromboembolism 15 (34.9%)

Mechanical device (valve or LVAD) 4 (9.3%)

N1 indication 5 (11.6%)

Indication for warfarin reversal, n (%)

Intracranial hemorrhage 23 (53.4%)

GI bleeding 15 (34.9%)

Abdominal hematoma/retroperitoneal bleeding 2 (4.7%)

Genitourinary bleeding 1 (2.3%)

Pulmonary hemorrhage 1 (2.3%)

GI bleeding & GU bleeding 1 (2.3%)

Mortality, n (%) 17 (40%)

Causes of death, n (%)

Withdrawal of care due to ICH 11 (64.7%)

able to be obtained for prospective follow up, and therefore only their data obtained from chart review were included. Forty-three patients

Withdrawal of care due to poor clinical status secondary to retroperitoneal bleed

1 (5.9%)

were included in the study (Fig. 2).

Patient characteristics are listed in Table 1. The most common indi- cation for anticoagulation was atrial fibrillation followed by thrombo- embolism and mechanical valve (Table 1). Intracranial hemorrhage was the most common indication for warfarin reversal, followed by gas- trointestinal (GI) bleeding.

Dosing of FEIBA

Seventeen patients with INR >= 5 received FEIBA at a dose of 1000 units. Twenty-six patients with INR b 5 received FEIBA at a dose of 500 units. A second dose of 500 units of FEIBA was administered to 7 patients (16.3%) as guided by hospital protocol, to 2 patients (11.8%)

Cardiac arrest 3 (15.6%)

Multi-factorial (sepsis, hyperkalemia) 2 (11.8%)

who received 1000 units initially and to 5 patients (19.2%) who received 500 units initially.

Effect of FEIBA on INR reversal

Forty of 43 patients (93%) achieved the target INR of <=1.5 (Table 2), including the 6 patients who received the second dose of FEIBA and sur- vived to third INR draw. Three patients died before achieving target INR. Median initial INR was 4.0 (2.7, 7.3 IQR). Median time to result the

Fig. 2. Patients given FEIBA in ED during study period. FEIBA = Factor Eight Inhibitor Bypassing Activity. FFP = fresh frozen plasma. ED = emergency department.

Table 2

Reversal of coagulopathy in patients treated with FEIBA (Factor Eight Inhibitor Bypassing Activity). IQR = interquartile range. Time to initiate therapy equals the time from patient’s initial INR result to the time FEIBA infusion begins.

addition, the balance between procoagulant and anticoagulant activity plays a large role in the likelihood for thrombosis with PCC products. Heparin or a combination of anticoagulant proteins is found in FFP, in

some 3-factor and 4-factor PCC products, but not in activated PCCs

Coagulation profiles

Initial INR (median, IQR)

4.0 (2.7-7.3)

Patients achieving target INR <= 1.5, n (%)

40 (93%)

INR at second draw (median, IQR)

1.4 (1.3-1.6)

Time to second INR result (median, IQR)

45 min (38-55)

Time to initiate therapy (h:min), (median, IQR)

1:50 (1:07-2:21)

INR at third draw (median, IQR)

1.3 (1.2-1.4)

second INR was 45 min (IQR 38, 55) and the median second INR was 1.4 (IQR 1.3, 1.6). Median INR at third draw was 1.3 (1.2, 1.4).

Patient outcomes

Seventeen of 43 patients (40%) died in the ED or during their hospi- talization (Table 1). Of the patients who did not survive, 12 patients had care withdrawn; 11 out of 12 of these patients had Intracranial bleeding as the indication for FEIBA, and 1 had retroperitoneal bleeding. Three patients died due to cardiac arrest; all had GI bleeding. Two patients died due to multiple factors, such as hyperkalemia, bleeding and sepsis. In those two patients, FEIBA was given for GI bleeding or genitourinary (GU) bleeding.

In the 17 patients who died, 14 patients achieved INR <= 1.5. Three pa- tients had INR N 1.5 at second check. Among those three patients, two died prior to receiving additional doses of FEIBA. One patient received a repeat dose of FEIBA but died before collection of third INR.

Adverse events of FEIBA

Eleven thrombotic adverse events (TAEs) occurred in 6 patients (14%). Four TAEs in 2 patients (5%) were attributed to FEIBA by consen- sus of study investigators, given the time frame and description of the events surrounding the TAE. One patient developed a cyanotic hand ac- companied by an arm Deep venous thrombosis at the site of FEIBA administration as well as bilateral leg DVTs on hospital day 1. The other patient developed a leg deep venous thrombosis on hospital day 3.

Seven TAEs not attributed to FEIBA in 4 patients (9%) occurred N7 days after FEIBA administration, or were superficial thromboses. Since these TAEs were temporally remote to FEIBA administration, they were considered not attributable to FEIBA. One patient developed an ischemic stroke on hospital day 8 and a superficial arm venous thrombosis on hospital day 15. Another patient had an ischemic stroke on day 17. One patient had a superficial arm venous thrombosis on day 31 and a leg DVT on day 31. Bilateral arm DVTs were diagnosed on day 12 in 1 patient.

Discussion

In this study, we investigated whether the introduction of a stan- dardized protocol to guide the reversal of coagulopathy in patients on warfarin with major hemorrhage would provide safe and efficacious anticoagulation reversal. We demonstrated that an institutional proto- col consisting of a fixed dose of activated 4-factor PCC (FEIBA) and IV vi- tamin K resulted in a consistent INR reversal of warfarin-induced coagulopathy in patients presenting with major bleeding. These results are comparable to other published studies [18,19,22].

Regarding safety, thrombogenicity due to patients’ preexisting Thromboembolic risk factors as well as the risk of augmenting procoagulant factors with reversal products is a major concern in pa- tients requiring anticoagulation reversal [23,24]. Since FEIBA contains activated factor VII, there is a possibility of a higher incidence of throm- botic adverse events compared with non-activated 4-factor PCCs [18]. In

[11]. Thrombotic adverse events attributable to FEIBA occurred in 5% of patients in our study.

FEIBA has a long record of safety in patients with hemophilia with an estimated rate of 4 thrombotic events out of 100,000 FEIBA infusions. Of those reported thrombotic events, 81% were associated with FEIBA doses exceeding usual doses of 200 units/kg/day in this patient popula- tion [16,25]. FEIBA dosing reported for warfarin reversal is considerably lower than that used for indications related to hemophilia, with a max- imum dose of 1500 units [18,19]. Unlike in hemophilia however, pa- tients on warfarin are receiving anticoagulation for underlying pro- thrombotic conditions, and therefore these patient populations are at unequal baseline risk for thrombotic events.

In patients who received FEIBA for warfarin reversal, TAE rates ranged from 0% [19] and 7% [18] in studies using fixed low-dose FEIBA dosing of 500 to 1000 units based on admission INR, to 12% in a study of patients with intracranial hemorrhage which used a higher FEIBA dose of 15 or 25 units/kg based on admission INR [22]. In addition to the dose of FEIBA, these studies have wide variations in the timing of FEIBA administration, patient characteristics, and the type of major bleeding. As in these studies, we did not record whether our subjects were on chemical venous thromboembolism prophylaxis [18,19,22]. In clinical practice, the decision to start the patients with major bleeding on VTE prophylaxis occurs on a case-by-case basis [26,27]. Nationwide, mechanical rather than chemical VTE prophylaxis is used in patients with intracranial hemorrhage [26]. In a study evalu- ating the effect of VTE prophylaxis in patients admitted for GI bleeding, the use of VTE prophylaxis did not affect the rate of thrombotic events [27].

The reported TAE rate for non-activated PCCs also varies across stud- ies, reflecting differences in dosing, hospital protocols, and patients’ un- derlying procoagulant risk factors. Other non-activated 4-factor PCCs

{Human Prothrombin Complex (Beriplex(R) P/N), Human Prothrombin Complex (Octaplex(R)), Human Prothrombin Complex (PPSB-HT Nichiyaku), & Human Prothrombin Complex (Cofact)} have been asso- ciated with TAE rates ranging from 0 to 18% and a combined TAE of 2.7% (61 TAEs out of 2262 patients in 9 studies) [28].

Since FEIBA contains activated factor VII, it may lead to more throm- botic risk. However, the reported thrombotic rates of recombinant acti- vated factor VII (rFVIIa) vary widely across studies. The incidence of thrombosis has been reported at 24.6 per 105 infusions of rfVIIa [29], and a thromboembolic complication rate of 27.9% was found in a proto- col combining 3-factor PCCs, recombinant factor VIIa, and vitamin K30 for warfarin reversal. However, no thrombotic adverse events were found in another study where 3-factor PCC was compared to rFVIIa and FFP [31].

In 2013, the FDA approved a non-activated 4-factor prothrombin complex concentrate (Human) (Kcentra(R)). In a retrospective case se- ries of 26 patients that received Kcentra for warfarin reversal due to a traumatic injury, Kcentra reversed elevated INR rapidly compared to FFP without associated reported thrombosis [32]. Of studied patients, 84.6% had INR b 2 within 45 min after administration of Kcentra [32]. In a secondary post hoc analysis on safety data acquired during the two prospective, randomized, phase 3b trials including 388 patients, Thromboembolic events occurred in 7.3% of patients who received 4- factor PCCs (Kcentra and Beriplex) [33]. Since the size and methodology of existing studies on Kcentra vary, it is even more challenging to com- pare TAEs rates of Kcentra to FEIBA.

In a comparison between a 3-factor PCC (Profilnine(R)) added to acti- vated Factor VII and a 4 factor PCC (Kcentra(R)) for warfarin reversal after traumatic hemorrhage, the use of the 4 factor-PCC was associated with a significant reduction in DVT rates but also a less effective decrease in INR [34]. Although this study evaluated recombinant factor VII added

to a 3 factor PCC, the composition of the factors in the combination are still distinct from FEIBA, limiting the potential to generalize conclusions about activated versus non-activated PCCs.

Another area of debate is whether weight based versus fixed dosing is more appropriate for PCC reversal of warfarin induced coagulopathy. We found that, similar to other studies [18,19], a protocolized fixed dose of FEIBA based on initial INR was effective in reversing elevated INR. This also provided simplicity and low total dosing compared with previous weight-adjusted protocols [35]. The need for additional dosing of FEIBA was only 16.3% in our study, and repeat INR measurements after 30 min were important to monitor appropriate reversal of elevated INR.

In terms of clinical outcomes, we observed a high in-hospital mortal- ity (40%), consistent with a critically ill patient population. Twelve of the total 43 patients (28%), and 11 out of 23 patients with ICH (48%) had care withdrawn due to poor prognosis.

Historically, patients with Oral anticoagulant therapy-associated ICH have been reported to have mortality rates as high as 42% [36]. Our ob- served mortality was still higher than other studies in which FEIBA was given for warfarin reversal (22% [18], 13% [19], 9% [22]). We suspect that patient characteristics may vary across these single-center studies. For example, patients that died within 24 h of admission or had withdrawal of care were excluded in one study [22].

As warfarin is indicated as an anticoagulant in patients with prothrombotic conditions, reversing this anticoagulation returns pa- tients to their baseline thrombotic risk. Although FEIBA contains acti- vated factor VII, it is uncertain how much additional thrombotic risk can be attributed to this activated factor. Literature on recombinant fac- tor VIIa contains conflicting conclusions on its thrombotic potential [29- 31]. Given the small number of studies comparing PCCs, and the vari- ability in dosing protocols and patient co-morbidities, the question of thrombosis risk of FEIBA compared to a non-activated 4-factor PCC is unresolved. Currently, hospitals across the United States reverse warfa- rin associated major bleeding using internal protocols, based on avail- ability of products, and Clinician judgment. Larger multi-center studies would be needed to compare the thrombotic risk of various prothrom- bin complex concentrates.

Limitations

Our study has several limitations. It was a single center observational study, and we reported outcomes of the Prospective analysis of a protocolized reversal strategy using FEIBA and IV Vitamin K without a comparison group. Lack of treatment standardization of warfarin in- duced coagulopathy in our institution prior to the initiation of the FEIBA protocol precluded a direct comparison of outcomes to alterna- tive therapies such as FFP. However, treatment with FFP has previously been demonstrated to be prolonged when compared to FEIBA [18,22].

We had a small sample size and enrolled patients over a limited time frame of 10 months. We also analyzed a disease-oriented outcome, effi- cacy of INR reversal, rather than a patient-oriented outcome such as clinical reversal of bleeding identified by CT scans in intracranial hemor- rhage or resolution of GI bleeding identified via endoscopy. Study inves- tigators were also responsible for attributing TAEs to FEIBA, which may have led to bias.

Conclusion

A reversal protocol using a fixed low dose of FEIBA and IV vitamin K based on initial INR appears to be an efficacious strategy for normalizing INR values in patients on warfarin presenting to the emergency depart- ment with major bleeding. Protocolized use of FEIBA and IV vitamin K was found to provide an effective INR reversal. A 5% thrombotic adverse event rate attributable to FEIBA was demonstrated.

Disclosure

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Presentations at meetings

  • Society of Academic Emergency Medicine Regional Conference, Springfield, Illinois, Sept 28th 2013.
  • Illinois College of Emergency Physicians Spring Symposium, Chicago,

May 1st 2014.

  • Society of Academic Emergency Medicine Annual Meeting, Dallas, May 14th 2014.

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