a b s t r a c t

Purpose: Prior to the Food and Drug Administration approval of 4-factor prothrombin complex concentrate (4F- PCC), only 3-factor PCC (3F-PCC) products were available in the US. There is limited data comparing the safety and efficacy of 3F-PCC versus 4F-PCC. The purpose of our study, therefore, was to compare the safety and efficacy profiles of 3F-PCC versus 4F-PCC for the emergent reversal of warfarin.

Methods: A single-center, retrospective cohort analysis compared patients who received 3F-PCC or 4F-PCC for the

emergent reversal of warfarin due to life-threating bleeding from January 2013 to September 2015. The primary objective of this study was the percentage of patients whose International normalized ratio reversed to

<=1.5 within 8 h of PCC administration. The secondary safety objective was incidence of Thromboembolic events at 7 days post PCC.

Results: A total of 137 patients were included. The median baseline INR was 3.15 in the 3F-PCC group and 3.1 in the 4F-PCC group. The median post-PCC INR was 1.4 in the 3F-PCC group and 1.3 in the 4F-PCC group. INR <=1.5 was achieved in 45/58 (78%) patients in the 3F-PCC group and 46/58 (79%) patients in the 4F-PCC group (p = 0.61). The thromboembolic event rate between the two groups at 7 days was similar, 4/68 (5.9%) for 3F-PCC ver- sus 4/69 (5.8%) for 4F-PCC (p = 1.0).

Conclusions: There was no significant difference in the percentage of patients who achieved an INR <=1.5 between the 3F-PCC and 4F-PCC groups for emergent reversal of warfarin.

(C) 2017

Introduction

Patients presenting with life threating bleeding in the setting of the vitamin K antagonist (VKA) warfarin, may require emergent anticoagulation reversal. therapeutic options for emergent warfarin re- versal include administration of vitamin K, fresh frozen plasma , and prothrombin complex concentrates . There may be disadvan- tages, however, with the use of FFP and vitamin K, making PCC’s a favor- able option. For instance, FFP requires matching and thawing, which may delay therapy. Patients may also require large volumes of FFP for adequate reversal, with the potential to cause fluid overload and an increased risk for transfusion-related acute lung injury [1]. In regards to vitamin K, its delayed onset of action, despite its prolonged reversal, may make it a less favorable option for monotherapy compared to FFP and PCC.

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

* Corresponding author at: Department of Pharmacy, Hillcrest Hospital, 6780 Mayfield Rd, Mayfield Heights, OH 44124, United States.

E-mail addresses: [email protected], [email protected] (J.E. Kuroski), [email protected] (S. Young).

The 9th edition of the American College of Chest Physicians practice guidelines for the use of oral anticoagulants recommends the use of 4- factor PCC (4F-PCC) in combination with intravenous vitamin K over the use of FFP for the rapid reversal of warfarin [1]. However, this rec- ommendation for the use of 4F-PCC is based on limited data at the time of its publication. While 4F-PCC is recommended in the aforemen- tioned clinical practice guidelines, multiple PCC products exist and are classified as either 3-factor PCC (3F-PCC) or 4F-PCC. Contents of each PCC product available in the United States are listed in Table 1 [2].

While, 4F-PCC was approved in 2013 by the Food and Drug Admin- istration (FDA) for the urgent reversal of VKAs in acute major bleeding and has been available in Europe and Canada since 1996, none of the 3F-PCC products available in the US contain FDA approved labeling for this indication. Unfortunately, data is limited for recommending 4F- PCC over the use of 3F-PCC for this indication.

PCC products are not without their risk for adverse events. The most concerning adverse event associated with these products is the in- creased risk for thromboembolic events. The thromboembolic event rate in a phase III trial for 4F-PCC was 7.8% at 45 days compared to 6.4% in the FFP group [3]. The rate of thromboembolic events for 3F- PCC has been reported up to 8% [4-9].

http://dx.doi.org/10.1016/j.ajem.2017.01.049

0735-6757/(C) 2017

872 J.E. Kuroski, S. Young / American Journal of Emergency Medicine 35 (2017) 871-874

Table 1

Components of factor products [2].

Factor contentsa	Factor II	Factor VII	Factor IX	Factor X	Protein C	Protein S	Protein Z	Anti-thrombin III	Heparin
Bebulin(R) VH	100	b 5	100	100	-	-	-	-	b 0.15
Profilnine(R) SD	150	35	100	100	-	-	-	-	-
Kcentra(R)	106	55.1	100	141.4	120.7	86.2	124.1	2.1	1.7

^a IU per 100 IU of Factor IX.

The purpose of our study was to compare the safety and efficacy of 3F-PCC and 4F-PCC for the emergent reversal of warfarin for life- threating bleeding.

Methods

Data collection and study variables

This was a single-center, retrospective cohort study at a large tertiary care hospital. Patients greater than or equal to 18 years old, who received 3F-PCC from January 1, 2013 to May 31, 2014 or 4F-PCC from June 1, 2014 to September 15, 2015 for the emergent reversal of warfarin, were includ- ed. Only patients who received PCC at our hospital, either in the Emergen- cy Department or during their inpatient stay were included. Prisoners, pregnant patients, or patients who received 4F-PCC prior to Heart transplantation were excluded. This study was approved by the investigational review board of Allegheny-Singer Research Institute within Allegheny General Hospital in Pittsburgh, Pennsylvania.

Patients were identified through PCC dosing sheets that were com- pleted by a pharmacist at the time of PCC dispensing and then filed after dispensing was complete. These sheets were required for all pa- tients who were ordered either 3F-PCC or 4F-PCC.

The dose of 3F-PCC and 4F-PCC administered was based on our insti- tutional PCC dosing protocols approved by the Pharmacy and Therapeu- tics Committee within the hospital (Table 2). During January 1, 2013 to May 31, 2014, 3F-PCC was the hospital’s formulary approved PCC prod- uct. Starting from June 1, 2014 until present, 4F-PCC was the formulary PCC product that patients received. Patients in the 3F-PCC group re- ceived Bebulin(R) VH (Baxter Healthcare Corporation, Westlake Village, CA) [10]. Patients in the 4F-PCC group received Kcentra(R) (CSL Behring, Marburg, Germany) [11].

The PCC dosing strategy per our institutional protocols are listed in Table 2. Adherence to the institutional PCC dosing protocol was defined as patients meeting each of the following: baseline INR of >= 2.5, 2 units of FFP administered to patients who only received 3F-PCC with a baseline INR >= 4, received the correct PCC dose based on weight and baseline INR, received PCC for emergent bleeding only, follow-up INR drawn within 30 min after PCC administration, and received 10 mg of intravenous Vi- tamin K. Our institutional 3F-PCC dosing protocol recommended that FFP be administered in patients who were to receive 3F-PCC with an INR >= 4, as 3F-PCC has very low amounts of Factor VII.

The primary objective of this study was the percentage of patients achieving an INR reversed to <= 1.5 within 8 h of PCC administration. Sec- ondary objectives included the incidence of thromboembolic events at 7 days post PCC, in-hospital all-cause mortality, percentage of patients who received additional blood products within 48 h of PCC administra- tion, discharge disposition, and rate of adherence to PCC protocols.

Statistical analysis

All analyses began with assessment of the normality of the data using the Shapiro-Wilk test. Patients’ demographic, clinical and proce- dural data were reported as mean +- standard deviation if they were continuous variables and counts and percentages if they were categori- cal variables. Non-normally distributed data were reported as the medi- an and range. The chi-square test or Fisher’s exact test was used to determine the relationship between nominal variables. The indepen- dent samples t-test or the Mann-Whitney rank sum test was used to compare continuous variables between the 3F-PCC and 4F-PCC groups. The rates of all types of adverse events were summarized using counts and percentages. A value of p b 0.05 on two-tailed testing was consid- ered statistically significant. Statistical analyses were performed using IBM-SPSS Statistics, version 20.0 (IBM-SPSS Inc., Armonk, NY).

Results

A total of 144 patients were screened. Seven patients were excluded and 137 patients were included in the final analysis (Fig. 1). Baseline characteristics are listed in Table 3. patient weights were significantly higher in the 4F-PCC group. The most common indications for warfarin were atrial fibrillation and venous thromboembolism in both groups, with significantly more patients with diagnosed VTE in the 3F- PCC group. The most common indication for PCC in each group was in- tracranial hemorrhage, 70.6% of the patients in the 3F-PCC group and 78.3% of patients in the 4F-PCC group. The median baseline INR was

3.15 and 3.1 (p = 0.15) for the 3F-PCC and 4F-PCC groups, respectively. The results for the primary and secondary objectives are summa- rized in Tables 4 and 5. There were a total of 6 patients in each group who did not receive a repeat INR after PCC administration and 4 patients in the 3F-PCC group and 5 patients in the 4F-PCC group who did not re- ceive their repeat INR within 8 h of PCC administration. Of the remain- der analyzed patients, 45 of the 58 patients (78%) in the 3F-PCC group

Table 2

PCC dosing per protocol.

Baseline INR 2.5-4 4-6 N 6

3F-PCC dosing^a 25 units/kg 35 units/kg (actual body weight) PLUS 2 units of FFP 4F-PCC dosing 25 units/kg 35 units/kg 50 units/kg

^a 3F-PCC doses were rounded to nearest vial size; INR, international normalized ratio;

PCC, prothrombin complex concentrate. Fig. 1. Patient inclusion and exclusion.

J.E. Kuroski, S. Young / American Journal of Emergency Medicine 35 (2017) 871-874 873

INR, international normalized ratio; PCC, prothrombin complex concentrate.

Table 3					Table 5
Baseline characteristics.					Secondary endpoint results.
	3F-PCC	4F-PCC				3F-PCC	4F-PCC
	(n = 68)	(n = 69)	p		Dosing and administration	(n = 68)	(n = 69)	p
Sex, male, no. (%)	36 (53)	37 (53.6)	0.79		Patients received Vitamin K, no. (%)	64 (94.1)	68 (98.6)	0.17
Age, mean (years)	74.5	76.2	0.7		Vitamin K dose (mg), median (range)	10 (0-10)	10 (0-10)	0.14
Weight, mean (kg)	78.7	85.7	0.02		Time to PCC administration (minutes),	37.9 (+-28.3)	42.7 (+-27)	0.30
Primary service, no. (%)					mean (SD)
Trauma	35 (51.5)	44 (63.8)	0.13		Blood product administration
Neurosurgery	18 (26.5)	15 (21.7)	0.32		FFP, no. of patients (%)	41/68 (60.3)	20/69 (29)	b0.05
Other Warfarin indicationa, no. (%)	15 (22)	10 (14.5)	0.017		FFP before post-PCC INR, no. (%) FFP appropriate per PCC protocol, no. (%)	32/68 (47) 19/32a (59.4)	5/69 (7.2) 0/5a (0)	b0.05 0.01
Atrial fibrillation	47 (69.1)	45 (65.2)	0.63		FFP total units, median (range)	3 (1-15)	2 (2-10)	0.42
Venous thromboembolism	14 (20.6)	11 (15.9)	0.48		PRBC total, no. (%)	17/68 (25)	13/69 (18.8)	0.38
Valve replacement	8 (11.8)	15 (21.7)	0.12		PRBC total units, median (range)	3 (1-26)	2 (1-5)	0.45
Other	6 (8.8)	8 (11.6)	0.59		Recombinant Factor VIIa, no. (%)	2 (2.9)	0	0.15
PCC indication, no. (%)					Disposition
Intracranial hemorrhage	48 (70.6)	54 (78.3)	0.3		In-hospital all-cause mortality, no. (%)	24 (35.3)	13 (18.8)	0.03
Gastrointestinal bleed	4 (5.9)	2 (2.9)	0.39		Day to death, mean (SD)	4.0 (4.7)	6.4 (5.3)
Retroperitoneal bleed	2 (2.9)	2 (2.9)	0.99		Home	15 (22.1)	19 (27.5)	0.46
Emergent surgery	2 (2.9)	1 (1.4)	0.55		Skilled nursing facility	17 (25)	16 (23.2)	0.80
Other	12 (17.6)	10 (14.5)	0.62		Long term acute care	1 (1.5)	3 (4.3)	0.32
PCC dose (units/kg), median (range)	28.9 (22.5-40.1)	25 (12-50)	0.41		Inpatient rehab	9 (13.2)	12 (17.4)	0.50
Baseline INR, median (range)	3.15 (1.6-19b)	3.1 (2-19b)	0.15		Hospice	2 (2.9)	6 (8.7)	0.15

^a May have had >=1 indication.

^b Lab maximum N 19.

^a Of the patients who received FFP prior to post-PCC INR; PCC, prothrombin complex concentrate; FFP, fresh frozen plasma; PRBC, Packed red blood cells; INR, international normalized ratio; SD, standard deviation.

reached an INR of <=1.5 within 8 h of PCC administration compared to 46 of 58 patients (79%) in the 4F-PCC group (p = 0.61). The median post- PCC INR was 1.4 in the 3F-PCC group compared to 1.3 in the 4F-PCC group (p = 0.21). The mean time to follow-up INR was 191 min and 169 min in the 3F-PCC and 4F-PCC groups, respectively. Of the patients who did not achieve reversal, the INRs ranged from 1.6 to 2.6 in the 3F- PCC group and from 1.6 to 1.8 in the 4F-PCC group. Table 6 shows the stratification of INR reversal based on baseline INR.

Within 7 days of PCC administration there were a total of 4 patients

in each group who experienced a thromboembolic event, 5.9% versus 5.8% in the 3F-PCC and 4F-PCC groups, respectively (Table 7). A total of 24 patients (35.3%) in the 3F-PCC group compared to 13 patients (18.8%) in the 4F-PCC group died in the hospital (0.03). The most com- mon discharge disposition for each of the groups was either to home, 22.1% in 3F-PCC group versus 27.5% in 4F-PCC group, or to a skilled nurs- ing facility, 25% in 3F-PCC group versus 23.2% in 4F-PCC group.

A total of 41 patients (60.3%) received FFP in the 3F-PCC group com- pared to 29% in the 4F-PCC group. Thirty-two patients (47%) received the FFP prior to the follow-up INR compared to 5 patients (7.2%) in the 4F-PCC group. Of those 32 patients who received FFP prior to the fol- low-up INR in the 3F-PCC group, 19 (59.4%) patients were correctly ad- ministered FFP based on our institution’s 3F-PCC dosing protocol.

There was a low rate of the institutional PCC dosing protocol adher- ence in each of the groups, 7.4% versus 8.7% in the 3F-PCC and 4F-PCC groups respectively. The various reasons for non-adherence to the dos- ing protocol are listed in Table 8. The most common reason for non-ad- herence was time to follow-up INR, with a majority of patients having follow-up INRs N 60 min after the end of the PCC infusion.

Discussion

Main findings

There was no difference observed in the percentage of patients who achieved an INR of <= 1.5 within 8 h of PCC administration between the 3F-PCC and 4F-PCC groups. Each group had similar baseline INRs and re- ceived similar doses of PCC. There was a comparable thromboembolic event rate between each of the groups as well. Of the 8 total patients who did have a thromboembolic event, 4 of these patients had a history of thrombosis, suggesting an increase in baseline risk for thromboem- bolic events. Specifically, of the patients in the 3F-PCC group who had a thromboembolic event, one patient did receive a higher dose of PCC as the dose received was based on the transferring hospital's INR value. A second patient received FFP when it was not indicated based our institutional PCC dosing protocol. Of the patients in the 4F-PCC group with a thromboembolic event, none of the patients received addi- tional FFP or received a PCC dose that was not within the dosing protocol.

The results of our study showed that patients who received 4F-PCC had significantly lower in-hospital all-cause mortality compared to pa- tients who received 3F-PCC for warfarin reversal. This was an interest- ing finding considering that our results did not show any difference in the percentage of patients who reached an INR of <= 1.5 between the groups. When evaluating the relationship between mortality and pa- tients who did not reach the target INR, there was the same number of patients who did not reverse in each of the groups. Of the patients in the 3F-PCC group who died during their hospital admission, there was a total of 3 patients whose INR did not reverse after receiving

Table 4

Primary endpoint results.

INR results	3F-PCC (n = 58)	4F-PCC (n = 58)	p
Post-PCC INR, median (range)	1.4 (1.1-2.6)	1.3 (1-1.8)	0.21
Patients <= 1.5 at first post-PCC INR within 8 h, no. (%)	45/58 (77.6)	46/58 (79.3)	0.61
All patients <= 1.5 at first post-PCC INR, no. (%)	49/62 (79)	51/63 (81)	0.79
Patients <= 1.3 at first post-PCC INR within 8 h, no. (%)	24/58 (41.1)	30/58 (51.7)	0.26
Time to follow-up INR (minutes), mean (SD)	191 (+-195)	169 (+-230)	0.57

INR, international normalized ratio; PCC, prothrombin complex concentrate.

874 J.E. Kuroski, S. Young / American Journal of Emergency Medicine 35 (2017) 871-874

Table 6

Stratification of INR reversal to <=1.5 based on baseline INR.

Baseline INR range 3-F PCC (n = 58) 4F PCC (n = 58)

Table 8

Reasons for PCC dosing protocol non-adherence.

3F-PCC

4F-PCC

Reason for non-adherence^a

<= 4, no./n (%)	32/40 (80)	35/44 (79.5)
N 4-6, no./n (%)	6/9 (67.7)	6/6 (100)
N 6, no./n (%)	7/9 (77.8)	5/8 (62.5)

(n = 63) [n (%)]

(n = 63)

[n (%)] p

INR, international normalized ratio; PCC, prothrombin complex concentrate.

PCC. Their follow-up INRs ranged from 1.6 to 2. Of the patients in the 4F- PCC group who died during their hospital admission, there was also a total of 3 patients whose INR did not reverse after receiving PCC. Their follow-up INRs ranges from 1.7 to 1.8.

The only statistically significant difference seen been the groups, was more patients receiving FFP in the 3F-PCC group compared to the 4F- PCC group. However, the median number of FFP units that the patients received was not significantly different between the groups. This differ- ence in mortality between the groups may have been due to several confounding factors. One includes that there were a higher percentage of patients who were discharged to hospice in the 4F-PCC group com- pared to the 3F-PCC group, possibly skewing the mortality results. There was a non-significant difference in the percentage of patients who were admitted to our neurosurgical service for their intracranial hemorrhages in the 3F-PCC group compared to 4F-PCC. Our neurosurgi- cal service admits patients to their service with non-traumatic intracra- nial hemorrhages such as Aneurysmal subarachnoid hemorrhages or non-traumatic hemorrhagic strokes, which are typically of high acuity, possibly causing the difference in mortality.

Our institutional PCC dosing protocol recommends that patients

should have a baseline INR >= 2.5 for PCC administration because of our historical usage and history of adverse effects when given to patients with baseline INR values b 2.5. There are no current recommendations published in the United States for a target INR when emergent reversal of warfarin is required. We choose an INR goal <= 1.5, as this is our stan- dard institutional practice. In a recently published single-center obser- vational study that compared the use of 3F-PCC versus 4F-PCC, the investigators also used a target INR of <= 1.5 [12]. Similarly, this study found no significant difference in the percentage of patients who achieved their target INR. Their results, however did suggest that there was a Mortality benefit in patients who received 4F-PCC and an in- creased mortality rate in patients who did not reverse to <= 1.5.

Limitations

There are several limitations to our study, first including that this was a single center, retrospective review. The patient groups, 3F-PCC and 4F-PCC, were from two separate time periods. Also, some patients may have received PCC dosing based on INRs from outside facilities’ Lab- oratory results if they were admitted through our Emergency Depart- ment. There was variation in the timing of the follow-up INRs after the PCC had been administered in each of the groups. However, by only including INRs within 8 h of PCC administration, the INR would have been reflective of the PCC, not Vitamin K. Lastly, given that this study was completed retrospectively; it is difficult to assess the impact

Table 7

Thromboembolic event rate.

Baseline INR b 2.5	2 (3.2)	4 (6.3)	0.41
FFP at time of PCC administration	13 (20.6)	5 (7.9)	0.04
Non-protocol PCC dosing	3 (4.8)	2 (3.2)	0.64
No active bleeding	5 (7.9)	3 (4.8)	0.45
Incorrect FFP dose	10 (15.9)	0 (0)	0.001
Time to follow-up NR	56 (89)	59 (93.7)	0.62
No IV Vitamin K administered	6 (9.5)	2 (3.2)	0.14

^a May have had >=1 reason for non-adherence; PCC, prothrombin complex concentrate; FFP, fresh frozen plasma.

PCC has on hemostasis. By reversing the INR, an assumption is made that is will prevent an intracranial bleed from expanding or decrease the bleeding and improve hemodynamics in patients with gastrointesti- nal bleeds.

Conclusion

There was no significant difference in INR reversal in patients who received either 3F-PCC or 4F-PCC for the emergent reversal of warfarin in life threating bleeding. There was a similar thromboembolic event rate between each of the groups. Larger, prospective, randomized trials are needed to confirm these results.

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   3F-PCC (n = 68)

   4F-PCC

   (n = 69) p

   Baxter Healthcare Corporation. Bebulin VH Package Insert. Westlake Village, CA; 2012.

10. CSL Behring GmbH. Kcentra Package Insert. Marburg, Germany; 2013.

    Thromboembolic events at 7 days, no (%) 4 (5.9) 4 (5.8) 1.0

    Deep vein thrombosis 1 1 -

    Pulmonary embolism 1 2

    Stroke 1 1

    Foot ischemia 1 0

    PCC, prothrombin complex concentrate.

    Voils SA, Holder MC, Premraj S, Catlin JR, Allen BR. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for Emergent warfarin reversal. Thromb Res 2015;136(3):595-8 PubMed PMID: 26233569.