Comparison of 4F-PCC and aPCC time to administration and outcomes for oral anticoagulant-related ICH

a b s t r a c t

Introduction: intracranial hemorrhages (ICHs) are associated with increased morbidity and mortality. Use of oral anticoagulants are a potential risk factor for ICH, and reversal of the anticoagulant with agents such as Four-Factor prothrombin complex concentrate (4F-PCC) or Activated Prothrombin Complex Concentrate (aPCC) is vital to prevent hematoma expansion. The objective of the study was to the compare the Time to administration and out- comes of 4F-PCC or aPCC in patients with ICH taking an oral anticoagulant.

Methods: This was a multicenter, retrospective cohort chart review of patients with ICH taking an oral anticoag- ulants who received 4F-PCC or aPCC over a two year period. The primary outcome of the study was to the com- pare the time to administration of 4F-PCC or aPCC in patients with ICH on an oral anticoagulant. Secondary outcomes included evaluating mortality rate, Modified Rankin scale (mRs) score, presence of worsening bleed volume on first computed tomography (CT) six hours after the initial reading, and hospital and intensive care unit (ICU) length of stay. The tertiary outcome was to evaluate the effect of risk factors for delay on time to ad- ministration, with delay being greater than 60 min.

Results: A total of 350 patient charts were reviewed and 193 patients (4F-PCC [n = 99] and aPCC [n = 94]) were included in the study. There was no significant difference in the primary outcome of median time to administra- tion for the 4F-PCC group (141 min, IQR [93-185]) compared to aPCC (121 min, IQR [107-194]; p = 0.08). No difference was identified between the two groups for all secondary outcomes. Only time to CT results was found to be a risk factor for administration delay (OR, 1.160; 95% CI, 1.073-1.255; p < 0.001).

Discussion: In patients with ICH taking oral anticoagulants, there was no significant difference in the time to ad- ministration between 4F-PCC and aPCC. More prospective randomized controlled trials are warranted to deter- mine an ideal reversal time to improve patient outcomes.

(C) 2022

  1. Introduction

Intracranial Hemorrhage may be spontaneous or traumatic in nature, occurring within the intracerebral, subdural, or subarachnoid spaces. Risk factors for ICH include hypertension, smoking, alcohol consumption, male sex, and the use of antiplatelet or anticoagulant medications [1]. Available oral anticoagulants include vitamin K antag- onists (VKA; warfarin), factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), and the direct thrombin inhibitor (DTI; dabigatran). Patients who are taking a VKA have an increased risk of ICH [2]. Factor Xa

* Corresponding author at: Department of Pharmacy, Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH 44307, USA.

E-mail address: [email protected] (S. Lin).

inhibitors and direct thrombin inhibitors reduce incidences of ICH by about 50% compared to warfarin [3]. Individually, landmark trials such as ROCKET-AF, ARISTOTLE, and RELY report an ICH risk of 0.57%, 0.33%, and 0.30% per year for rivaroxaban, apixaban, and dabigatran, re- spectively [4-6]. Additionally, major bleeding risk are also reduced in patients on factor Xa inhibitors and direct thrombin inhibitors by 17% compared to patients on warfarin [3].

ICHs are associated with increased morbidity and mortality [1]. Prognostic factors include age, weight and glucose level at admission, intracerebral hemorrhage Volume expansion, Glasgow Coma Scale score, and chronic kidney disease [1]. It has also been shown that hematoma expansion greater than or equal to 30 cm3 is associ- ated with a poor prognosis [1]. Hematoma expansion can be further exacerbated by the degree of coagulaopathy, as each 1.0 increase in

0735-6757/(C) 2022

INR from 1.1 demonstrated a 2.4 mL increase in Hematoma volume [7]. Thus, it is imperative for healthcare providers to reverse the anti- coagulant to inhibit further hematoma expansion. Available intrave- nous reversal agents include Four-factor prothrombin complex concentrate (4F-PCC), Activated Prothrombin Complex Concentrate (aPCC), idarucizumab, and andexanet alfa.

With recent literature regarding fixed dose compared to INR dosing for 4F-PCC, the optimal dosing strategy and timing remains controver- sial. One study found reductions in hematoma enlargement up until 4 h and 13 min, but do not include their reversal strategy [8]. The PROPER3 trial demonstrated a significantly shorter door-to-needle when implementing the fixed dose strategy compared to INR dosing (109 min vs 142 min; diff -33 min; 95% CI -56 to -4 min) and achieved effective hemostasis in 87.3% of their fixed dose patients [9]. However, another study also utilized a fixed dosing strategy, but reported ineffec- tive hemostasis in 27% of patients with ICH on apixaban and rivaroxa- ban after receiving 4F-PCC within 6 h of bleeding [10].

Currently, there is limited data regarding the optimal time to admin- istration for individual reversal agents and even less literature compar- ing efficacy of 4F-PCC and aPCC against each other. Furthermore, there are no Guideline recommendations for door to reversal time, despite there being data surrounding ideal Door-to-needle time for ischemic stroke (within 60 min) [11].To our knowledge, this is the first study to evaluate time to administration across the two different reversal agents and its impact on patient outcomes. The primary objective of the study was to compare the time to administration of 4F-PCC or aPCC in patients with ICH taking an oral anticoagulant.

  1. Methods
    1. Study design

This was a multicenter, retrospective cohort chart review of patients with ICH receiving Anticoagulant reversal with 4F-PCC (Kcentra(R)) or aPCC (FEIBA(R)) over a two year period. This study was approved by the Institutional Review Board and the requirement for informed con- sent was waived. The health system includes 19 hospitals, including one level 1 trauma center and three level 2 trauma centers, and 5895 beds system-wide. Eligible patients were those who presented to the emergency department (ED) with an ICH, on an oral anticoagulant prior to admission, and received an appropriate dose and regimen of ei- ther 4F-PCC or aPCC for reversal. Patients were excluded if they were less than 18 years of age, pregnant, received a reversal agent outside of the ED, were administered desmopressin for any indication during the same admission, were transferred into or out of the health-system, or received idarucizumab.

Last doses of oral anticoagulants were confirmed with the patients or family prior to reversal. If the patient or family members were ineli- gible to confirm the last dose and there was a recent fill history as re- ported by insurance claims on the electronic medical record (EMR), it was assumed by the medical team that the patient recently took their medication and would require reversal. INR levels were evaluated for patients on warfarin, but no additional levels or labs were collected for Factor Xa inhibitors.

Appropriate dose and regimen of reversal agents was determined based on the health-system ICH reversal protocol. Per this protocol, pa- tients on warfarin are reversed with INR-based dosing of 4F-PCC along with the co-administration of 10 mg of intravenous vitamin K. Dosing for 4F-PCC is as follows: 4F-PCC 10 units/kg for INR 1.5 to 1.9 (max dose 1000 units), 4F-PCC 25 units/kg for INR 2 to 3.9 (max dose

2500 units), 4F-PCC 35 units/kg for INR 4 to 6 (max dose 3500 units), 4F-PCC 50 units/kg for INR >6 (max dose 5000 units). Factor Xa inhibi- tors, apixaban and rivaroxaban, are reversed with 50 units/kg of aPCC. Per the institutional guidelines, the dosing weight is actual body weight unless the patient has an actual body weight greater than 140% of their ideal body weight for which the adjusted body weight is recommended.

Each regional hospital ED and main campus ED store both reversal agents in the central pharmacy, whereas freestanding EDs keep their products in automated dispensing cabinets (ADS). After the reversal agent is ordered and verified, each IV room will begin compounding the medication while freestanding EDs will retrieve the medication from their ADS and start the compounding process. Of note, reversal agents from central pharmacy are compounded by pharmacy techni- cians while reversals at freestanding EDs are compounded by nurses. Each medication vial is connected to a diluent vial by a Mix2Vial(R) Set and swirled to dissolve the product. The solution is removed from the vial and placed in an empty IV bag. If the reversal agent was compounded by central pharmacy, the bag is then delivered the emer- gency department. Lastly, the medication is connected to an infusion pump and administered to the patient. When available, emergency medicine (EM) pharmacists help by assisting with oral anticoagulant fill history identification, reversal agent dosing, order placement, or co- ordinating with central pharmacy for medication preparation and deliv- ery. All facilities have the ability to contact a hospital pharmacist at all hours of the day.

    1. Study population

Baseline demographics collected include age, biological sex, race, body mass index, comorbidities, smoker status, admission labs, and GCS from the EMR. Prior to admission, anticoagulant or Antiplatelet therapy was determined by documented Medication lists on the admis- sion history and physical. Mode of arrival, location of hemorrhage, mechanism of bleed, administration of fresh frozen plasma , and discharge location were determined based on documentation in the EMR.

The primary outcome of the study was to compare the time to ad- ministration of 4F-PCC to aPCC in patients with ICH taking an oral anti- coagulant prior to admission. Secondary outcomes included the mortality rate, mRs score, hematoma expansion, hospital length of stay , and ICU LOS between 4F-PCC and aPCC. The mRs score was determined by the last physical and occupational therapist notes and calculated by two investigators. The tertiary outcome was to evaluate the impact of risk factors on delay of time to administration. Risk factors included time to CT results, time to INR result reported, and time to re- versal agent administration from Order entry. A delay in time to admin- istration was defined as administration greater than 60 min. This was based on extrapolated literature for acute ischemic stroke, as there is no available literature regarding optimal time to reversal for ICH [11]. The time for risk factor delay was defined as time between order entry to result time. Blood is frequently drawn upon admission to the ED; therefore, in these instances time was collected as time from Blood draw to results time. Additional subgroup analyses were performed for mortality rate and GCS.

    1. Statistical analysis

Due to the retrospective nature of this study and lack of available lit- erature on this topic, a power analysis was not performed and a conve- nience sample was utilized. Continuous variables are reported as mean with standard deviation or median with interquartile range (IQR) de- pendent on the normality of the data distribution and analyzed by stu- dent’s t-test or Mann-Whitney U test as appropriate. Normality was determined by Shapiro-Wilks test. Categorical variables are reported as n (%) and analyzed by chi-square or Fisher’s exact test as appropriate dependent upon expected cell counts. The primary outcome was ana- lyzed by Mann-Whitney U test. The tertiary outcome was analyzed by logistic regression. Post-hoc testing was performed for significant differ- ences between groups using adjusted post-hoc residuals and Bonferroni correction as appropriate. Statistical analyses were performed using IBM SPSS statistics version 24.0. The level of significance of 0.05 (two- sided) was assumed for all tests.

  1. Results
    1. Demographic characteristics of study population

A total of 350 patient charts were reviewed for eligibility and 164 pa- tients were excluded. The majority of patients excluded were due to ad- ministration of the reversal agent outside of the ED (n = 72) and not presenting to the ED with an ICH (n = 24). A total of 186 patients were included in the study (4F-PCC [n = 93] and aPCC [n = 93]) (Fig. 1). Demographic data are presented in Table 1. The study population was primarily male (n = 96 [52%]), Caucasian (n = 155 [83%]), with a median age of 79 years (IQR 69-85). The most common comorbidity requiring need for anticoagulation was atrial fibrillation (n = 137 [74%]), followed by deep vein thrombosis (n = 29 [16%]). There was no difference in an- tiplatelet therapy prior to admission (aspirin, n = 58 [31%]; clopidogrel, n = 10 [5%]; ticagrelor, n = 1[1%]). In the 4F-PCC group, the median dose received was 2000 units (1500-2500) whereas the median dose in the aPCC group was 3950 units (3377-4500). There were no significant dif- ferences in baseline characteristics with the exception of atrial fibrillation (4F-PCC [n = 58, 62%] vs aPCC [n = 79, 85%]; p < 0.001), median INR

(4F-PCC [2.8 (IQR 2.1-3.8)] vs aPCC [1.1 (IQR1.0-1.2)]; p < 0.001), me-

dian prothrombin (4F-PCC [27 (IQR 22-37)] vs aPCC [11 (IQR 11-12)]; p < 0.001), location of hemorrhage, and administration of FFP (4F-PCC [n = 8, 9%] vs aPCC [n = 1, 1%, p = 0.035]). A post-hoc analysis identified a significant difference in location of hemorrhage for subarachnoid (4F-PCC [n = 5, 5%] vs aPCC [n = 13, 14%]) and subdural hemorrhages (4F-PCC [n = 40, 43%] vs aPCC [n = 22, 24%]).

    1. Outcomes

There was no significant difference in the primary outcome of median time to administration for the 4F-PCC group (141 min, IQR [108-193]) compared to aPCC (119 min, IQR [80-175]; difference, 22 min; p = 0.08) (Table 2). Further, the secondary outcomes did not differ significantly be- tween the two groups (Table 2). The mortality rate was 12%, the median mRS was 4 (IQR 3-5), and median hospital LOS was 5 (IQR 3-8) for the 4F-PCC group. ICU LOS for both groups was two days (IQR 1-4).

    1. Effects of time-delaying risk factors on administration time

Time to administration was categorized into two different groups: patients who received the reversal agent within 60 min (n = 19) and those greater than 60 min (n = 167). There was a significant difference in median time to lab between the two administration groups (within 60 min [36 min (IQR 29-45)] vs greater than 60 min [51 min (IQR

40-66)]; p = 0.002). Median time to CT results was significantly differ- ent between to the two administration groups (within 60 min [10 min (IQR 7-15)] vs greater than 60 min [34 min IQR (26-47)]; p < 0.001). Time to medication was also significantly different between the two groups (within 60 min [26 min IQR (16-29)] vs greater than 60 min [34 min (IQR 26-47)]; p < 0.001). Of the three risk factors that were evaluated, only time to CT results was found to be a significant risk fac- tor where patients were 16% more likely to be delayed for every minute increase in time to CT results (OR, 1.160; 95% CI, 1.073-1.255; P < 0.001) (Table 3).

    1. Subgroup analysis

Subgroup analysis for time to administration was performed for pa- tients with in-hospital mortality (n = 24) and a GCS score <= 8 (n = 30). There was no difference in time to administration between the reversal agents for either subgroup. Median time to administration was 67 min (IQR 63-133) in those receiving 4F-PCC vs 92 min (IQR 53-128) aPCC in the mortality subgroup (p = 0.713). Median time to administration was 76 min (IQR 62-119) in those receiving 4F-PCC vs. 76 min (IQR 50-106) aPCC in the GCS subgroup (p = 0.267).

  1. Discussion
    1. Outcomes

In this retrospective study of patients with ICH that received antico- agulant reversal agents, an overall difference in time to administration was not detected between reversal agents. There was also no difference between the two groups with regard to mortality rate, mRs score, hema- toma expansion, hospital LOS, or ICU LOS. Additionally, there was no re- lationship observed between time to administration and patient outcomes. When evaluating risk factors for delay, only time to CT result was an independent risk factor for delayed time to administration.

Interestingly, the median time to administration for both groups to- gether was 137 min (IQR 93-185) after presentation. While it would have been expected to be within 120 min, the time to administration seen in this study was corroborated by the administration time reported in Rhoney et al., which was a mean administration time of 144 min. While our study median time was slightly faster than what was demon- strated in Rhoney et al., both are significant amounts of time given the severity of ICHs [12]. This may be attributed to the fact that many pa- tients were transferred between hospitals within the health-system, as some patients may have received the reversal agent in the second facility’s ED, thus prolonging time to administration. Another possibility

Fig. 1. Population Assessed for Eligibility.

Table 1

Baseline characteristics of the patients at ED presentation.

Table 2



N = 186






N = 186

4F-PCC n= 93


n = 93


n = 93

n= 93

Mortality a

23 (12)

11 (12)

12 (13)



79 (69-85)

77 (67-85)

79 (72-84)


mRS b

4 (3-5)

4 (2-5)

4 (3-5)


Male sexb

96 (52)

43 (46)

53 (57)


Volume expansion at 6 h a,

35/166 (21)

12/84 (14)

23/82 (28)




n = 166


155 (83)

73 (79)

82 (88)

Hospital LOS b, n = 185

5 (3-8)

5 (3-9)

5 (3-8)



23 (12)

15 (16)

8 (9)

ICU LOS b, n = 170

2 (1-4)

2 (1-4)

2 (1-4)



8 (4)

5 (5)

3 (3)

Mortality a

23 (12)

11 (12)

12 (13)


U), length of stay (LOS), modified Rankin


28 (25-33)

27 (24-33)

29 (25-33)




median [IQR].

b n(%). Abbreviations: intensive care unit (IC


138 (74)

70 (75)

68 (73)



32 (17)

21 (23)

11 (12)



46 (25)

24 (26)

22 (23)



29 (16)

20 (22)

9 (10)



19 (10)

12 (13)

7 (8)


Atrial fibrillation

137 (74)

58 (62)

79 (85)


Current smokerb

15 (8)

6 (7)

9 (10)


scale (mRs).

Admission Labsa Blood glucose (mg/dL)








In this study, time to CT results was an independent risk factor for delay. This was an expected finding based on the nature of the ED and the health-system protocol. For critical patients, blood draw, order time, and time to lab, may occur simultaneously. The setting of where labs may be drawn can also help facilitate a reduction in time, as this can be performed in either triage or

INR, n = 177 1.6 (1.1-2.9) 2.8 (2.1-3.8) 1.1 (1.0-1.2) <0.001

immediately when the patient is brought to a room. Additionally,

Prothrombin (sec),

n = 178

Platelets (103/cm2),

n = 185

Location of hemorrhageb


68 (37)

30 (32)

38 (41)



18 (10)

5 (5)

13 (14)


62 (33)

40 (43)

22 (24)


38 (20)

18 (19)

20 (22)

Mechanism of bleedb


93 (50)

44 (47)

49 (53)



86 (46)

46 (50)

40 (43)


4 (2)

1 (1)

3 (3)


Antiplatelet PTA b

3 (2)

2 (2)

1 (1)



58 (31)

32 (34)

26 (28)



10 (5)

5 (5)

5 (5)



1 (1)

1 (1)

0 (0)


16 (11-28) 27 (22-37) 11 (11-12) <0.001

208 216 203 0.423

(164-254) (163-254) (171-254)

the difference between 4-FPCC and aPCC is expected, as there is no need to wait for an INR when dosing aPCC in contrast to 4F-PCC.

As for time to medication, per the health-system protocol, orders for reversal agent are entered once there is a confirmed hemorrhage on CT. CT order entry time can vary and is dependent on triage assessment of patients and need for stabilization. Immediate CT order entry can occur for critically ill patients or can be delayed for non-critical patients who arrive as a self-check-in patient. Additionally, delays from medica- tion order entry to medication administration would be dependent upon pharmacy compounding and delivery, which were not collected in this study. This study also did not evaluate preparation differences of the medications as this outside of the scope of this study. While differ- ences between delayed administration and dose utilized was not con- ducted in this study, it has been determined by the authors that this

Admission, n = 184 15 (14-15) 15 (14-15) 15 (14-15) 0.468

Discharge, n = 184 15 (12-15) 15 (13-15) 15 (11-15) 0.474



23 (12)

0 (0)

23 (25)



70 (38)

0 (0)

70 (75)



93 (50)

93 (100)

0 (0)


Administration of FFP b 9 (5) 8 (9) 1 (1) 0.035

would be an insignificant delay as it would require an additional two or three vials to be compounded.

    1. Limitations

This study is limited by its retrospective design where information is

Mode of arrival b, n =



126/181 (70)

58/89 (65)

68/92 (74)


4/181 (2)

3/89 (3)

1/92 (1)


51/181 (28)

28/89 (31)

23/92 (25)

Discharge location a 0.185


55 (30)

31 (33)

24 (26)


41 (21)

23 (23)

18 (19)


41 (22)

14 (15)

27 (29)



11 (12)

12 (13)


27 (15)

15 (16)

12 (13)


not collected in real-time, such as time to CT results was reported as the read time from the radiologist, but there may have been a provider in the room during the scan to interpret the initial findings. Additionally, the radiologist reported read time is based on the assumption that they immediately made contact with the provider after discovering the findings. Next, there is potential for this study to be underpowered as no power or sample size calculation was completed due to lack of prior research on this topic. Also, lack of information regarding symp- tom onset for some patients was not reported in admission histories

Presented as amedian (IQR), bn (%). Abbreviations: body mass index (BMI), chronic kidney disease (CKD), Deep vein thrombosis , emergency medical services (EMS), fresh fro- zen plasma (FFP), Glasgow Coma Scale (GCS), International normalized ratio , prior to admission (PTA), pulmonary embolus (PE).

for delay in administration may be that patients who presented to the ED with a higher GCS may have been triaged differently than those with lower scores and therefore they did not take precedence to be given a room or sent to CT.

Despite not finding significance in the secondary outcomes, there is a noted similarity between ICU LOS. This may be due to the fact that our patients have similar baseline GCS. Since GCS is used to reflect the sever- ity of an ICH, the ICU admission may have served as an observation pe- riod for these patients.

and therefore not included in data collection. This may have influenced secondary outcomes for this cohort, as patients without reversal may have continual hematoma expansion and worse prognosis. Further- more, the Mode of transport and length of Transfer time between hospi- tals, as well as which patients received the reversal agent at the second facility was not be evaluated in this study. While 4F-PCC and aPCC are known to cause thrombosis, this study did not collect and evaluate thrombosis risk between groups. Lastly, while patients were excluded if they received antiplatelet reversal during their admission or ED pre- sentation, they were not excluded solely for having antiplatelet therapy on their medication lists. Antiplatelet reversal was determined at the discretion of the provider based on clinical judgement. As such, this an- tiplatelet therapy poses as a confounder and may affect patient out- comes due to the impact of delayed platelet aggregation on hematoma expansion.

Table 3

Regression Analysis for Covariates Associated with Delayed Time to Administration

Predictor Variables

Not Delayed Time to Administration 60 min n = 21

Delayed Time to Administration >60 min n = 165

Adjusted OR (95% CI)


Time to Lab

36 (29-45)

52 (40-67)

0.996 (0.987-1.006)


Time to CT

11 (8-15)

48 (30-71)

1.161 (1.075-1.255)


Time to medication

26 (13-28)

34 (26-46)

1.064 (1.001-1.131)


Presented as median (IQR). Abbreviations: computed tomography (CT).

  1. Conclusion

This was the first study to evaluate the time to administration of 4F-PCC and aPCC and the impact of administration time on patient out- comes. There was no difference in time to administration or secondary outcomes. However, more prospective randomized controlled trials are warranted to determine if an ideal reversal time improves patient outcomes.

CRediT authorship contribution statement

Stacy Lin: Writing – review & editing, Writing – original draft, Valida- tion, Supervision, Resources, Project administration, Methodology, In- vestigation, Formal analysis, Data curation, Conceptualization. Brittany Cunningham: Writing – review & editing, Writing – original draft, Vali- dation, Supervision, Methodology, Investigation, Formal analysis, Con- ceptualization. Chanda Mullen: Writing – review & editing, Writing – original draft, Validation, Supervision, Software, Methodology, Investiga- tion, Formal analysis, Data curation, Conceptualization. Erin Simon: Writing – review & editing, Writing – original draft, Validation, Supervi- sion, Methodology, Investigation, Conceptualization. Deanna Bice: Writ- ing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Data curation, Conceptualization. Jenna Garlock: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Conceptualization.

Declaration of Competing Interest

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


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