Update: What is the optimal dosing of 4-factor prothrombin complex concentrate in patients with warfarin-associated bleeding?

Introduction
In the setting of major bleeding or urgent surgery, rapid reversal of anticoagulation is critical. The 2020 American College of Cardiology (ACC) guideline on management of bleeding in patients on oral anticoagulants recommends the use of 4-factor prothrombin complex concentrate (4F-PCC) in addition to vitamin K for patients on warfarin who require rapid anticoagulation reversal.1 The use of plasma is suggested as an alternative when 4F-PCC is not available. Two dosing strategies for 4F-PCC are recommended by the guideline. The standard dose (also referred to as variable dose) is based on patient weight and current international normalized ratio (INR) as recommended by the manufacturer. The alternative option is a fixed dose strategy of 1000 units (U) for non-intracranial bleeding and 1500 U for intracranial hemorrhage (ICH) that would typically lead to using a lower dose compared to standard dosing. Fixed dosing has potential benefits including reduction of the administration of prothrombotic factors that can lead to thromboembolism, shortened time to administration, and decrease in cost, while still maintaining efficacy.2,3

Literature review
In a previous 2016 frequently asked question (FAQ), a review of the available literature comparing fixed to standard dosing of 4F-PCC demonstrated conflicting outcomes with respect to efficacy of fixed dosing. As described in the 2016 FAQ, many of the earlier studies utilized fixed doses less than 1000 U. It was concluded that these lower doses were not adequate in achieving rapid INR reversal. Therefore, more recent studies evaluated doses of 1000 U or higher and were summarized in the previous review. Since then, more studies have been published and this review provides a summary of additional literature published since 2016 that evaluates fixed dosing strategies in patients requiring reversal of warfarin.

Several observational studies describing outcomes with fixed dose 4F-PCC have been published.4-7 These retrospective, single-center studies describe use of 1500 U of 4F-PCC with sample sizes ranging from 37 to 145 patients. Bleeding was the indication for 4F-PCC in at least 50% of patients in each study. The achievement of INR of 1.5 or less was observed in about 70% of patients. Reports of thromboembolism were rare.

Studies comparing standard to fixed dose are summarized in the Table.8-15 All studies were retrospective in design, with the exception of the study by Bitonti and colleagues12 which prospectively used a fixed dose strategy and compared outcomes to a historical control that received the standard dose. The most common indications for 4F-PCC across studies included central nervous system (CNS) bleeding, gastrointestinal (GI) bleeding, and need for urgent surgery.8-15 The definition of fixed dose 4F-PCC varied slightly between studies. Typically, doses of 1000, 1500 and/or 2000 U (with an option for additional doses in some studies) were used depending on the indication, baseline INR and patient weight. The higher dose was used for patients with ICH, high INR and weight ≥ 100 kg. Achievement of a target INR was the most frequently evaluated outcome. In all studies, the standard 4F-PCC dose was found to have a greater or similar percentage of patients achieving the target INR compared to the fixed dose with inconsistency across studies with respect to statistical significance between the 2 groups. In the study by Bitonti and colleagues, fixed dosing was found to be noninferior to standard dosing for target INR < 2; however, noninferiority could not be established when evaluating the percentage of patients who achieved an INR < 1.5 after an initial dose of 4F-PCC.12

The INR level achieved across the studies was either similar or lower in patients who received standard versus fixed dosing.8-15 Although mortality was not statistically significantly different between groups in studies that evaluated this outcome, there was numerically higher mortality in the standard dose group in most reports. Thromboembolic complications were reported in both groups in some studies while others reported no events.

Two small, retrospective studies specifically evaluated patients requiring warfarin reversal due to ICH.14,15 In the fixed dose group, patients initially received 1000 U 4F-PCC and repeated doses if needed. The percentage of patients who achieved the target INR of 1.5 or less was greater in the standard dose compared to the fixed dose in both studies; however, statistical significance was established in only 1 study.15 Interestingly, the study that did not find statistical significance between groups had a higher mean dose of 2150 U in the standard dose group14 while the standard dose group in the other study received a mean dose of 1750 U.15

Table. Efficacy of fixed dose compared to standard dose 4F-PCC for patients requiring warfarin reversal.8-15
Study and designPopulationExposureMain resultsConclusion
McMahon 20218
 
SC, Retrospective cohort
Adult patients who received 4F-PCC (Kcentra®) for warfarin reversal for:
 
CNS bleed (n=54): 20 fixed dose; 34 standard dose
 
Non-CNS bleed + INR ≤ 6 (n=153): 94 fixed dose; 59 standard dose
 
Non-CNS bleed + INR ≥ 6.1 (n=19): 10 fixed dose; 9 standard dose
Fixed dose (n=124)
1000 or 2000 Ua
 
Standard dose (n=102)

Median baseline INR:
2.5 standard dose
3.0 fixed dose; p=0.003
 
 
 
 
 
Percentage of patients achieving target INRb with standard vs. fixed dose:
CNS bleed: 79.4% vs. 70%; p=NS
Non-CNS bleed + INR ≤ 6: 86.4% vs. 57.5%; p=0.0002
Non-CNS bleed + INR ≥ 6.1: 100% vs. 70%; p=NS
 
Median dose of standard vs. fixed regimen (U):
CNS bleed: 2147 vs. 2148; p=NS
Non-CNS bleed + INR ≤ 6: 2184 vs. 1057; p<0.0001
Non-CNS bleed + INR ≥ 6.1: 3337 vs. 2101; p=0.003
 
Post-dose median INR of standard vs. fixed dose:
CNS bleed: 1.3 vs. 1.3; p=NS
Non-CNS bleed + INR ≤ 6: 1.3 vs. 1.5; p<0.0001
Non-CNS bleed + INR ≥ 6.1: 1.2 vs. 1.5; p=0.03
 
Mortality of standard vs. fixed dose (p=NS for all):
CNS bleed: 17.7% vs. 26.3%
Non-CNS bleed + INR ≤ 6: 6.8% vs. 15.2%
Non-CNS bleed + INR ≥ 6.1: 0% vs. 40%
Fixed dose of 2000 U for CNS bleeds or INR ≥ 6.1 is comparable to standard dose.
 
Fixed dose of 1000 U for INR ≤ 6.1 did not achieve a similar outcome to standard dose.
 
1000 U may not be sufficient to achieve target INR.
Dietrich 20209
 
MC, retrospective cohort		Adult patients who received either aPCC or 4F-PCC (Kcentra®) for warfarin reversal for (most common indications listed):
 
ICH:
82.8% fixed dose aPCC
39.6% fixed dose 4F-PCC
8.9% standard dose 4F-PCC
 
Emergent surgery:
3.5% fixed dose aPCC 
17% fixed dose 4F-PCC
37.5% standard dose 4F-PCC
 
GI hemorrhage:
10.3% fixed dose aPCC
20.8% fixed dose 4F-PCC
13.9% standard dose 4F-PCC		Fixed dose aPCC:
500 U for INR < 5 OR
1000 U for INR ≥ 5 (n=29)
 
Fixed dose 4F-PCC:
1500 U OR
2000 U for INR ≥ 7.5 or TBW ≥ 100 kg (n=53)
 
Standard dose 4F-PCC (n=72): median dose 2000 U
 
Median baseline INR:
2.9 fixed dose aPCC
3.4 fixed dose 4F-PCC
2.8 standard dose 4F-PCC		Percentage of patients achieving target INR ≤ 1.4:
58.6% fixed dose aPCC vs.
69.8% fixed dose 4F-PCC vs. 79.2% standard dose 4F-PCC; p=NS
 
Percentage of patients achieving target INR ≤ 1.4 within 4 hours:
52.4% fixed dose aPCC vs.
72.7% fixed dose 4F-PCC vs. 86.5% standard dose 4F-PCC; p=0.0179 for aPCC compared to standard dose
 
Percentage of patients achieving target INR ≤ 1.4 within 8 hours:
52% fixed dose aPCC vs.
51.2% fixed dose 4F-PCC vs. 78.9% standard dose 4F-PCC; p=0.0092 for aPCC and fixed dose 4F-PCC compared to standard dose
 
In-hospital mortality:
13.8% fixed dose aPCC vs.
11.3% fixed dose 4F-PCC vs. 20.8% standard dose 4F-PCC; p=NS
 
Thromboembolic complications: 4 patients in fixed dose 4F-PCC vs. 1 patient aPCC group		No significant difference between fixed and standard 4F-PCC in achieving target INR. However, patients receiving the standard dose were more likely to reach target INR within 4 and 8 hours compared to those receiving the fixed dose.
Dietrich 2020b10
 
MC observational
Adult patients who received 4F-PCC (Kcentra®) for warfarin reversal for (most common indications listed):
ICH:
32% standard dose
11% fixed dose

GI hemorrhage:
14% standard dose
21% fixed dose

Surgery:
25% standard dose
32% fixed dose

IAH/ITH:
1% standard dose
11% fixed dose
Fixed dose:
1500 U OR
2000 U for INR ≥ 7.5, TBW ≥ 100 kg or ICH (n=75)

Standard dose (n=116)
 
Mean baseline INR:
3.5 standard dose
4.3 fixed dose
Percentage of patients achieving target INR ≤ 1.4 (p=NS for all groups):
Overall: 65% standard dose vs. 57% fixed dose
Baseline INR ≥ 7.5: 50% (3/6) standard dose vs. 25% (2/8) fixed dose
TBW ≥ 100 kg: 72% (13/18) standard dose vs. 50% (5/10) fixed dose
ICH: 90% (36/40) standard dose vs. 88% (7/8) fixed dose
 
Post-dose mean INR:
1.38 standard dose vs.1.5 fixed dose
 
In-hospital mortality at 30 d:
16.4% standard dose vs. 9% fixed dose; p=NS
 
Thromboembolic complications: 2 patients in standard dose vs. 0 patients in fixed dose
A fixed dose of 1500 U was similar to standard dose 4F-PCC in achieving target INR.
 
A higher fixed dose of 2000 U was statistically not different in achieving target INR compared to a standard dose in patients with INR ≥ 7.5, ICH or TBW ≥ 100 kg; however, the sample size in these subgroups was likely too small to detect a difference.
Gilbert 202011
 
SC, Retrospective cohort
Adult patients who received 4F-PCC (Kcentra®) for warfarin reversal for:
ICH:
36.7% standard dose
50% fixed dose
 
GI hemorrhage:
20% standard dose
23.3% fixed dose

Surgery:
36.7% standard dose
20% fixed dose
Fixed dose (n=30):
1500 U for ICH OR
1000 U for other major bleeding with option to add another 500 U if INR > 10 or TBW > 100 kg
 
Standard dose (n=30)

Median baseline INR:
3.25 standard dose
2.95 fixed dose
Percentage of patients achieving target INR < 1.6:
90% standard dose vs. 86.7% fixed dose; p=NS
 
Percentage of patients achieving target INR < 1.4:
73.3% standard dose vs. 50% fixed dose; p=NS

Median dose (U):
2551 standard dose vs. 1521 U fixed dose; p=0.004
 
Post-dose median INR:
1.3 standard dose vs.1.35 fixed dose; p=NS
 
Mortality:
26.7% standard dose vs. 13.3% fixed dose; p=NS
 
Thromboembolic complications: 0 standard dose vs. 1 patient in fixed dose
Results suggest similar efficacy between fixed (1500 U for ICH and 1000 U for other major bleeding) and standard dose 4F-PCC. Efficacy should be further evaluated in larger RCTs.
Bitonti 202012
 
MC, NI, interventional cohort
Prospective cohort: adult patients receiving fixed dose 4F-PCC (Kcentra®) for warfarin reversal
 
Historical cohort:  adult patients who received standard 4F-PCC for warfarin reversal
 
Indications for reversal:
ICH:
63.3% standard dose
37.5% fixed dose
 
GI hemorrhage:
26.7% standard dose
50% fixed dose
 
Surgery:
3.3% standard dose
4.2% fixed dose
Fixed dose (prospective cohort; n=24):
1500 U (n=16) OR
2000 U for INR ≥ 7.5 or TBW ≥ 100 kg (n=8)
 
Standard dose (historical cohort; n=30)
 
Baseline INR:
3.83 standard dose
4.58 fixed dose
Percentage of patients achieving target INR < 2:
96% standard dose vs. 95% fixed dose; p=0.0035 for NI
 
Percentage of patients achieving target INR < 1.5:
90% standard dose vs. 75% fixed dose; p=NS for NI

Mean dose (U):
2591 standard dose vs. 1721 U fixed dose; p=0.001

Post-dose mean INR:
1.32 standard dose vs. 1.38 fixed dose; p=NS

7-day mortality:
13.3% standard dose vs. 8.3% fixed dose; p<0.009 for noninferiority
 
No thromboembolic complications reported in either group
A fixed dose of either 1500 U or 2000 U is noninferior to standard dose 4F-PCC in achieving a target INR < 2 in most patients.
The higher dose of 2000 U was effective for patients with a higher baseline weight or INR.
 
Larger studies are needed to evaluate clinical outcomes.
Zemrak 201913
 
SC, Retrospective cohort
Adult patients who received 4F-PCC (Kcentra®) for warfarin reversal for:
 
CNS bleed: 59% in both groups
 
Non-CNS bleed: 26.2% standard dose vs. 20.5% low-dose
 
Surgery: 14.8% standard dose vs. 20.5% low-dose
Low-dosed (n=83)
15 Units/kg (max 1500 U) or 25 Units/kg (2500 U) depending on INR and type of bleed
 
Standard dose (n=122)
 
Baseline INR:
72% between 1.6 and 3.9
26% 4 or greater
Percentage of patients achieving target INRc and effective clinical responsee:
75.4% standard dose vs. 61.4% low dose; p=0.033
 
Effective clinical response:
79.5% standard dose vs. 74.7% low dose; p=NS
 
Percentage of patients achieving target INRc:
95.9% standard dose vs. 84.3% low dose; p=0.005
 
Mean dose (U):
2132 standard dose vs. 1530 U low dose; p<0.001
 
Thromboembolic events (p=NS):
72 h: 4.1% standard dose vs. 1.2% low dose
30 d: 8.2% standard dose vs. 4.8% low dose
 
Death or transfer to hospice care: 21.3% standard dose vs. 9.6% low-dose; p=0.027
Maximum doses of 1500 or 2500 U (low-dose) compared to standard dose 4F-PCC demonstrated no significant difference in effective clinical response despite significantly fewer patients in the low dose group achieving target INR.
 
Mortality was significantly higher with the standard dose and numerically a higher percentage of patients had thromboembolic events in the standard dose group.
Scott 201814
 
SC, Retrospective chart review
Adult patients who received 4F-PCC (Kcentra®) for warfarin reversal for ICH
 
Fixed dose:
1000 U repeated as necessary to achieve target INR (n=30)

Standard dose (n=31)
 
Mean baseline INR:
2.98 standard dose
2.84 fixed dose
Percentage of patients achieving target INR < 1.5:
71% standard dose vs. 53% fixed dose; p=NS

Mean dose (U):
2120 standard dose vs. 1045 U fixed dose; p<0.001
 
Required repeat dose:
16% standard dose vs. 17% fixed dose, p=NS

Fixed dose of 1000 U was similar to standard dose 4F-PCC in achieving target INR.
 
Impact in patients with higher baseline INR or body weight and impact on clinical outcomes overall requires further study.
Abdoellakhan 201715
 
SC, Retrospective chart review
Adult patients who received 4F-PCC (Cofact®) for warfarin reversal for ICH
 
Fixed dose:
1000 U
Additional 500 U given if necessary to achieve target INR (n=28)

Standard dose (n=25)

Median baseline INR:
3.1 standard dose
3.3 fixed dose
Percentage of patients achieving target INR ≤ 1.5:
98% standard dose vs. 68% fixed dose; p=0.013

Mean dose (U):
1750 standard dose vs. 1000 U fixed dose; p<0.005
 
Required repeat dose:
8% standard dose vs. 32% fixed dose, p=0.043
 
Post-dose mean INR:
1.3 standard dose vs. 1.4 fixed dose; p=0.001
 
30-day mortality:
16% standard dose vs. 25% fixed dose; p=NS
 
Thromboembolic events: 2 cases standard dose vs. 0 cases fixed dose
Significantly fewer patients achieved target INR with fixed dose compared to standard dose 4F-PCC requiring significantly greater additional doses.
 
Impact on clinical outcome needs further study.
a1000 U for non-CNS bleed + INR ≤ 6 OR 2000 U for CNS bleed or INR ≥ 6.1
b target INR < 1.4 for CNS bleeds, ≤ 1.5 for other indications
c target INR < 1.6 for CNS bleed, < 2 for non-CNS bleeding
d although weight-based like the standard dose, overall max doses that were given were lower than the standard dose (see results)
e effective clinical response as defined by the International Society of Thrombosis and Haemostasis is dependent on the type of bleed and can include evaluation of hemoglobin levels, need for additional hemostatic agents, ability to safely undergo a surgical procedure, degree of hematoma expansion (in the case of CNS bleed) and patient symptoms
Abbreviations: 4F-PCC, 4 factor prothrombin complex concentrate; aPCC, activated prothrombin complex concentrate; CNS, central nervous system; GI, gastrointestinal; IAH, intra-abdominal hemorrhage; ICH, intracranial hemorrhage; INR, international normalized ratio; ITH, intra-thoracic hemorrhage; MC, multicenter; NI, non-inferiority; NS, not significant; RCT, randomized controlled trial; SC, single-center; TBW, total body weight.

Considerations
Current evidence to date comparing efficacy of fixed 4F-PCC dosing to standard dosing is limited to retrospective or single-center observational studies with small sample sizes.4-15 The varied definitions of fixed dosing, which ranged from 1000 U to 2500 U, further limits the ability to determine the optimal fixed dose. Differences between groups in achieving target INR did not reach statistical significance despite numerical differences likely due to small sample size. Additionally, target INR goals differed across studies. Significant reduction in thromboembolic complications with use of a fixed dose compared to the standard dose could not be established, again, likely due to small sample size and inconsistencies across studies in duration of follow-up.

Currently, 5 brands of 4F-PCC are available globally including Cofact®, Octaplex®, Beriplex®, Kcentra® and PPSB-HT®.2 In the US, only Kcentra is available. These products vary with respect to quantity of clotting factors II, VII, IX, and X, protein C and S, and heparin. It has been suggested that differences in outcomes may also be attributed to varying product brands used in the studies. However, in this review, Kcentra was the most common 4F-PCC product used. Only 2 studies were conducted in Europe in which an alternate product was used.5,15

The use of a target INR as a primary outcome for patients experiencing bleeding is a surrogate marker that may not indicate resolution in bleeding. Furthermore, the optimal target INR to correlate with adequate reversal of anticoagulation is unknown. Of the studies summarized, only Zemrak and colleagues used both INR and clinical response as a primary outcome.13 Although the lower dose of 4F-PCC was not similar to standard dose in achieving target INR levels, there was not a significant difference in clinical response between the groups. Additionally, thromboembolic complications and mortality were higher with standard versus low-dose.

To address these limitations in the current literature, prospective, multicenter, randomized controlled trials are needed with clinical outcomes such as hemostatic effectiveness as defined by the International Society on Thrombosis and Hemostasis (ISTH) criteria. One such trial, the PROPER 3, was prematurely stopped due to unknown reasons.16,17 An open-label, randomized trial comparing a fixed, 1500 U 4F-PCC dose to standard dose for achieving a target INR of 1.5 or less has been conducted, according to Clinicaltrials.gov.18 However, results of the study are yet to be published.

Conclusion
According to the ACC consensus on management of bleeding due to oral anticoagulants, standard dose 4F-PCC is recommended for patients who require warfarin reversal due to major bleeding or urgent surgery.1 A lower, fixed dose of 1000 or 1500 U is an alternative dosing option. Evidence supporting this fixed dosing strategy is limited to retrospective and observational studies. A fixed dose strategy may be considered for patients with lower pre-treatment INR levels and for patients with non-CNS bleeding.2,3 Prospective, larger randomized controlled trials evaluating hemostatic effectiveness and thromboembolic complications are needed to provide clarity on the optimal dosing of 4F-PCC in patients requiring warfarin reversal.

References

  1. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(5):594-622. doi: 10.1016/j.jacc.2020.04.05
  2. Schwebach AA, Waybright RA, Johnson TJ. Fixed-dose four-factor prothrombin complex concentrate for vitamin K antagonist reversal: does one dose fit all? Pharmacotherapy. 2019;39(5):599-608. doi: 10.1002/phar.226
  3. Denise H. Rhoney DH, Chester KW, Darsey DA. Optimal dosage and administration practices for vitamin K antagonist reversal with 4-Factor prothrombin complex concentrate. Clin Appl Thromb Hemost.2020; 26: doi: 1177/1076029620947474
  4. Fuh L, Goldstein JN, Hayes BD. Initiation of a fixed-dose four-factor prothrombin complex concentrate protocol. J Thromb Thrombolysis. 2020;50(1):217-220. doi: 10.1007/s11239-019-01984-w
  5. Sobrino Jiménez C, Romero-Garrido JA, García-Martín Á, et al. Safety and effectiveness of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal following a fixed-dose strategy. Eur J Hosp Pharm. 2020 Jun 26:ejhpharm-2019-002114. doi: 10.1136/ejhpharm-2019-002114
  6. Jansma B, Montgomery J, Dietrich S, Mixon MA, Peksa GD, Faine B. Emergent warfarin reversal with fixed-dose 4-factor prothrombin complex concentrate. Ann Pharmacother. 2020;54(11):1090-1095. doi: 10.1177/1060028020920855
  7. Astrup G, Sarangarm P, Burnett A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. J Thromb Thrombolysis. 2018;45(2):300-305. doi: 10.1007/s11239-017-1586-x
  8. McMahon C, Halfpap J, Zhao Q, Bienvenida A, Rose AE. Evaluation of a fixed-dose regimen of 4-Factor prothrombin complex concentrate for warfarin reversal. Ann Pharmacother. 2021 Feb 1:1060028021992142. doi: 10.1177/1060028021992142
  9. Dietrich SK, Rowe S, Cocchio CA, Harmon AJ, Nerenberg SF, Blankenship PS. Comparison of 3 different prothrombin complex concentrate regimens for emergent warfarin reversal: PCCWaR Study. Ann Pharmacother. 2020 Dec 11:1060028020978568. doi: 10.1177/1060028020978568
  10. Dietrich SK, Mixon M, Holowatyj M, Werth JC, Delgado SA, Mascolo NE, Meister ER, Zoucha SM, Trujillo TC. Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal. Am J Emerg Med. 2020b;38(10):2096-2100. doi: 10.1016/j.ajem.2020.06.017
  11. Gilbert BW, Morton L, Huffman JB, et al. Modified version of the American College of Cardiology’s recommendation for low-dose prothrombin complex concentrate is effective for warfarin reversal. Am J Emerg Med. 2020;38(4):806-809. doi: 10.1016/j.ajem.2019.12.005
  12. Bitonti MT, Rumbarger RL, Absher RK, Curran LM. Prospective evaluation of a fixed-dose 4-factor prothrombin complex concentrate protocol for urgent vitamin K antagonist reversal. J Emerg Med. 2020;58(2):324-329. doi: 10.1016/j.jemermed.2019.10.013
  13. Zemrak W, Manuel F, Smith KE, et al. Low-dose compared to manufacturer-recommended dose four-factor prothrombin complex concentrate for acute warfarin reversal. J Thromb Thrombolysis. 2019;47(2):263-271. doi: 10.1007/s11239-018-1768-1
  14. Scott R, Kersten B, Basior J, Nadler M. Evaluation of fixed-dose four-factor prothrombin complex concentrate for emergent warfarin reversal in patients with intracranial hemorrhage. J Emerg Med. 2018 ;54(6):861-866. doi: 10.1016/j.jemermed.2018.01.030
  15. Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed versus variable dosing of prothrombin complex concentrate in vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocrit Care. 2017;26(1):64-69. doi: 10.1007/s12028-016-0248-8.
  16. Abdoellakhan RA, Khorsand N, Van Hest RM, et al. Randomised controlled trial protocol to evaluate a fixed dose prothrombin complex concentrate against the variable dose in vitamin K antagonist related bleeding (PROPER3). BMJ Open. 2018;8(3):e020764. doi: 10.1136/bmjopen-2017-020764
  17. EU Clinical Trials Register. Accessed April 27, 2021. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000392-33/NL
  18. Fixed versus variable dosing of 4-factor prothrombin complext concentrate for emergent warfarin reversal. U.S. National Library of Medicine: Clinicaltrials.gov. Updated June 10, 2019. Accessed April 27, 2021. https://clinicaltrials.gov/ct2/show/NCT03064035?term=4+factor+prothrombin+complex+concentrate&draw=6&rank=1

Prepared by:
Rita Soni, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

May 2021

The information presented is current as of April 6, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.