CLINICAL
USE
FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IN THE EMERGENCY DEPARTMENT: A REVIEW
OF
Authors: Courtney M. Willis, BS, PharmD(c), and A. Brad Hall, PharmD, Gainesville and Lakeland, FL
W
arfarin, a vitamin K antagonist (VKA), is the mainstay for the prevention and treatment of arterial and venous thrombosis. The complication associated with VKA therapy that causes the most concern is the risk of major bleeding events, particularly anticoagulantassociated intracranial hemorrhage. 1 A variety of approaches may be used to assist with reversal of the anticoagulation effects of VKAs; these approaches often combine vitamin K with prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or recombinant factor VIIa. Human 4-factor PCC (4 F-PCC [Kcentra], CSL Behring, King of Prussia, PA) was the first treatment approved by the Food and Drug Administration for the rapid reversal of VKA therapy. 2 4 F-PCC restores clotting factors II, VII, IX, and X, protein C, and protein S, which are needed for blood hemostasis and are depleted with VKA therapy. Further studies will likely evaluate the role of 4 F-PCC in the management of trauma-related massive bleeding, as well as for reversal of the new oral factor Xa and direct thrombin inhibitors. This review provides an updated assessment of the use of 4 F-PCC in the management of VKA reversal in the emergency department. In the past, options for VKA reversal included FFP, recombinant factor VIIa, or PCC with vitamin K supplementation. Reversal of the international normalized ratio (INR) to normal levels occurs approximately 12 to 24 hours after administration of vitamin K, necessitating the administration of adjunct agents when rapid reversal is required. 3 An inherent limitation of FFP is the large volumes required for administration (15 to 20 mL/kg), which can be a concern Courtney Willis is 2015 PharmD Candidate, University of Florida College of Pharmacy, Gainesville, FL. Brad Hall is Clinical Pharmacy Specialist–Emergency Medicine and PGY2 Emergency Medicine Pharmacy Director, Lakeland Regional Medical Center, Lakeland, FL. For correspondence, write: Courtney M. Willis, BS, PharmD(c); E-mail: cwillis16@ufl.edu. J Emerg Nurs 2015;41:9-12. Available online 9 July 2014 0099-1767 Copyright © 2015 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jen.2014.04.016
January 2015
VOLUME 41 • ISSUE 1
in patients at risk for fluid overload, including patients with renal and heart failure. 4 The large volumes and extensive infusion times associated with FFP may also lead to an increased risk for transfusion-related acute lung injury (TRALI), increasing the risk for transfusion-related deaths. 5 Additional concerns with FFP administration include delays associated with the time to thaw the plasma, lengthy administration times, and blood type matching. FFP is derived from human plasma and therefore carries a small risk of the transmission of microbes and viruses. Reversal with 4 F-PCC may offer significant advantages compared with reversal with FFP. 4 F-PCC does not require thawing and is available as a powder for reconstitution. 4 F-PCC does not require ABO compatibility testing and contains more concentrated factors, which allows for lower infusion volume requirements compared with FFP. 6 Additionally, 4 F-PCC undergoes viral inactivation through nanofiltration, eliminating the risk of the transmission of viruses. 7 The most recent (9th) edition of the American College of Chest Physicians’ Antithrombotic Therapy and Prevention of Thrombosis Guidelines, 4 published in 2012, recommends the use of 4 F-PCC rather than FFP for the urgent reversal of VKA-associated major bleeding. This recommendation is based on a number of studies that have shown that 4 F-PCC is as efficacious as FFP for rapid INR reversal and the improvement of blood hemostasis. Results from a multinational, phase IIIb clinical trial by Sarode et al 8 demonstrated that when compared with FFP, 4 F-PCC achieved similar effective homeostasis within 24 hours (72.4% vs 65.4%), thus showing that 4 F-PCC is not inferior to FFP. The trial revealed that 4 F-PCC lowered the INR to less than or equal to 1.3 by 30 minutes after the end of infusion in 62.2% of patients, versus only 9.6% in patients receiving FFP. 8 Utilization of 4 F-PCC in Trauma Care and Surgery
Traumatically injured patients are at a high risk for severe anticoagulant-associated intracranial hemorrhage and intractable bleeding. 9 The potential role of 4 F-PCC in coagulopathy related to major trauma is that theoretically it can promptly secure blood hemostasis while reducing transfusion requirements. 10 Currently the literature does
WWW.JENONLINE.ORG
9
CLINICAL/Willis and Hall
not include any randomized controlled trials that assess the efficacy and safety of 4 F-PCC in patients with massive bleeding. 11 A retrospective study comparing VKA reversal using FFP and PCC in traumatically injured patients revealed that the mean time to achieve INR was more rapid when PCC was used. However, the improvement in clinical outcomes such as hospital length of stay was not statistically different between the groups. 9 4 F-PCC has been used for a number of years in European countries for preoperative VKA reversal but has just recently gained acceptance in the United States for this indication. A small Belgium trial with 40 patients that compared 4 F-PCC (Cofact; Sanquin, The Netherlands) with FFP for reversal of VKA in patients undergoing cardiopulmonary bypass revealed that 15 minutes after cardiopulmonary bypass, more patients reached the target INR of less than or equal to 1.5 with 4 F-PCC (7/16 patients with 4 F-PCC vs 0/15 patients with FFP). 12 In December 2013, the Food and Drug Administration extended its approval of 4 F-PCC for the reversal of VKA prior to urgent surgical or invasive procedures. The results from a recent randomized trial involving 168 participants revealed effective blood homeostasis in 89.7% of patients in the 4 F-PCC group versus 75.3% in the FFP group, demonstrating the superiority of 4 F-PCC over FFP (a 14.4% difference). Rapid INR reduction was also achieved in 55.2% of patients in the 4 F-PCC group versus 9.9% in the FFP group, demonstrating the superiority of 4 F-PCC over FFP. Therefore 4 F-PCC was found to be a suitable alternative to FFP for rapid VKA reversal in patients who require urgent surgery or invasive procedures. 13
promising candidate for the reversal of the effects of dabigatran, rivaroxaban, and apixaban; however, the data supporting its clinical utilization have not been robust, with most of the data from preclinical animal trials 21,22 and studies that include healthy volunteers. 23 Initial evidence from Eerenberg et al 23 revealed that in a small sample of healthy males, 50 units/kg of 4 F-PCC (Cofact) immediately and completely reversed the anticoagulant effects in subjects who received rivaroxaban, but no impact on the anticoagulation activity was noticed in subjects who received dabigatran. 23 Thromboembolic Complications
A concern with 4 F-PCC use is the potential for the introduction of a prothrombotic state and resulting thromboembolic events. A patient’s recent underlying disease state (eg, myocardial infarction, transient ischemic attack, antithrombin deficiency, and a history of thromboembolic events) may potentially expose the patient to this risk regardless of the methods used to reverse the coagulopathy. Sarode et al 8 found no statistical difference in thromboembolic risk associated with 4 F-PCC compared with FFP (4% vs 3%). However, the study excluded patients who had a history of thromboembolic events within the prior 3 months. Additionally, the authors state that the trial was underpowered in establishing statistically significant differences between interventions for safety outcomes. 8 Thromboembolic complications with use of 4 F-PCC have been reported in the literature, with a higher incidence in patients who have underlying thrombotic risk. 24 Nursing Considerations
Reversal of the New Oral Anticoagulant Agents
The newer anticoagulant agents have been the topic of discussion during the past several years because of some of their potential advantages compared with warfarin. The metabolism of the newer anticoagulant agents is unaffected by food, they are affected by fewer drug-drug interactions, they exhibit rapid onset of action, and routine INR monitoring is unnecessary. Clinical trials have shown that the newer oral anticoagulants (e.g., dabigatran, rivaroxaban, and apixaban) are not inferior to warfarin therapy in the prevention of ischemic stroke in patients with atrial fibrillation, 14–16 as well as for the treatment of venous thromboembolism. 17–19 The newer oral anticoagulants were also associated with less risk of intracranial hemorrhage relative to warfarin. 14–16 Despite these benefits, the reversal of factor Xa and direct thrombin inhibitor anticoagulant effects have not been established and are clinical concerns. 20 The literature suggests that 4 F-PCC may be the most
10
JOURNAL OF EMERGENCY NURSING
Dosing for 4 F-PCC is performed according to the pretreatment INR of the patient and the patient’s actual body weight. The precise dosing for 4 F-PCC is described in the Figure. Because 4 F-PCC is a blood product, a varying concentration of factors may be present from one product to another. When calculating the 4 F-PCC dose, it is important to consider the exact factor content in each vial. In preparation for 4 F-PCC administration, each vial should be reconstituted in 20 mL of sterile water for injection and administered within 4 hours of reconstitution. The vials are for single use only, and any unused portions should be discarded. 4 F-PCC should be administered at room temperature through a peripheral infusion line that is separate from all other intravenous medications. According to the Kcentra package insert, it should be infused at a rate of 0.12 mL/kg/min up to a maximum rate of 8.4 mL/kg/min (210 units/min), making sure that blood does not enter the syringe, because there may be a risk of fibrin clot formation. 2 The peripheral intravenous catheter should be flushed with
VOLUME 41 • ISSUE 1
January 2015
Willis and Hall/CLINICAL
phytonadione (vitamin K), 10 mg /50 mL D5W via IV administered over 30 min x 1 dose; may repeat in 12 hours if necessary
PLUS Fresh thawed plasma, 15 mL/ kg IV
Transfuse each unit over 30 to 60 minutes
OR Pre-treatment INR 2 to 6
4F-PCC 50 units/kg IV x 1 dose at 210 units/min
FIGURE Reversal orders for life-threatening/major bleeding or for urgent surgery/an urgent procedure that requires an international normalized ratio less than 1.5. aD5W, 5% dextrose in water; 4 F-PCC, 4-factor prothrombin complex concentrate; INR, international normalized ratio; IV, intravenous. aSome procedures, including central venous cannulation, have been shown to be performed safely at international normalized ratios greater than 1.5. The dosing for vitamin K was verified and gathered from Chapman SA, Irwin ED, Beal AL, Kulinski KM, Hutson KE, Thorson, MA. Prothrombin complex concentrate versus standard therapy for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45:869-75. The dosing for FFP were verified and gathered from Nitzki-George D, Wozniak I, Caprini JA. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Annals of Pharmacother 2013;47:841-55. The doses and infusion rates for 4F-PCC were verified and gathered from the Kcentra package insert 2.
normal saline solution before and after administration of 4 F-PCC to maintain catheter patency. 4 F-PCC may induce hypersensitivity reactions and should be avoided if the patient has ever experienced a severe reaction to any of the factor components, human albumin, or antithrombin III. 2 Patients should be carefully monitored for signs and symptoms of hypersensitivity such as flushing, hives, wheezing, bronchospasm, angioedema, and hypotension. In the event a patient exhibits signs of severe allergic reaction, administration of 4 F-PCC should be discontinued immediately. 4 F-PCC formulations incorporate small amounts of heparin and therefore cannot be administered in patients with a history of heparin-induced thrombocytopenia. 1 In the event of warfarin-induced coagulopathy, baseline pretreatment INR should be assessed and rechecked 30 minutes after the administration of 4 F-PCC. If the patient’s INR is greater than or equal to 1.3, additional coagulation factors may be administered. Once the normalization of INR is obtained, it may be reassessed after 3 to 6 hours. This interval reflects the
January 2015
VOLUME 41 • ISSUE 1
short circulating half-life of factor VII and the onset of action of vitamin K. Data are insufficient to recommend the use of 4 F-PCC in women who are pregnant or lactating. It is not known if 4 F-PCC can cause fetal harm or if it is excreted in human milk, and therefore administration of 4 F-PCC to pregnant or lactating women is recommended only if the benefit outweighs the risk. 2
Conclusion
A rapid process of reversal is often necessary for patients who present to the emergency department with lifethreatening bleeding or who may require an urgent surgery or invasive procedure. Several years of clinical experience with 4 F-PCC (Kcentra) have been achieved outside the US, where the product is known as Beriplex P/N (CSL Behring), and 4 F-PCC recently gained acceptance in the
WWW.JENONLINE.ORG
11
CLINICAL/Willis and Hall
US as an effective alternative to FFP to rapidly reverse the effects of VKA and to successfully lower INR in patients with acute major bleeding or who require urgent surgery. 8,13 The literature has proposed a potentially important role of 4 F-PCC for reversal in trauma-induced coagulopathy, as well as for the reversal of the newer oral anticoagulant factor Xa and direct thrombin inhibitors. However, clinical evidence to justify 4 F-PCC use in these indications is insufficient. 4 F-PCC reversal has been linked with a low but clinically concerning risk of thromboembolic complications. It is unclear whether these complications are directly associated with 4 F-PCC treatment or with a patient’s previous underlying risk of thrombosis. The efficacy of 4 F-PCC has been demonstrated by laboratory measurements of INR normalization and homeostatic efficacy, but it is uncertain whether 4 F-PCC improves clinical outcomes. 6 REFERENCES 1. Hanger HC, Geddes AA, Wilkinson TJ, Lee M, Baker AE. Warfarin related intracerebral heamorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J. 2012;43:308-16.
10. Sorensen B, Fries D. Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg. 2012;99:40-50. 11. Pham HP, Shaz BH. Update on massive transfusion. Br J Anaesth. 2013;111(S1):i71-82. 12. Demeyere R, Gillardin S, Arnout J, Strengers PFW. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251-60. 13. Randomized phase IIIb study of rapid vitamin K antagonist reversal in patients requiring an urgent surgical procedure: four-factor prothrombin complex concentrate is superior to plasma. http://bloodjournal. hematologylibrary.org/content/122/21/3588. Accessed February 16, 2014. 14. Connolly SJ, Ezekowitz MD, Yusuf S. Dabigatran versus Warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. 15. Granger CB, Alexander JH, McMurray JJ. Apixaban versus Warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92. 16. Patel MR, Mahaffey KW, Garg J. rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91. 17. Schulman S, Kearon C, Kakkar AK. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
2. Kcentra [package insert]. CSL Behring LLC; 2013.
18. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510.
3. Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates-evaluation of safety and thrombogenicity. Crit Care. 2011;15:201-9.
19. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
4. Holbrook A, Schulman S, Witt DM. Antithrombotic therapy and prevention of thrombosis (9th edition). American College of Chest Physicians evidencebased clinical practice guidelines. Chest. 2012;141(2 Suppl):152S-84S. 5. Holness L, Knippen MA, Simmons L. Fatalities caused by TRALI. Transfus Med Rev. 2004;18:184-8. 6. Quinlan DJ, Eikelboom JW, Weitz JI, Weitz E. Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. Circulation. 2013;128:1179-81. 7. Cada DJ, Levien TL, Baker DE. Prothrombin complex concentrate. Hosp Pharm. 2013;48(11):951-7. 8. Sarode R, Milling TJ, Refaai MA. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding. Circulation. 2013;128:1234-43. 9. Chapman SA, Irwin ED, Beal AL, Kulinski KM, Hutson KE, Thorson MA. Prothrombin complex concentrate versus standard therapy for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45:869-75.
12
JOURNAL OF EMERGENCY NURSING
20. Dickneitee G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrate (PCCs): what is the evidence? Thromb Haemost. 2014;111:189-98. 21. Martin AC, Bonniec BL, Fischer A. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168:4228-33. 22. Grottke O, Ryn JV, Spronk HM, Rossaint R. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care. 2014;18:R27-36. 23. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2012;124:1573-9. 24. Rodgers G. Prothrombin complex concentrates in emergency bleeding disorders. Am J Hematol. 2012;87:898-902.
VOLUME 41 • ISSUE 1
January 2015
USE
FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IN THE EMERGENCY DEPARTMENT: A REVIEW
OF
Authors: Courtney M. Willis, BS, PharmD(c), and A. Brad Hall, PharmD, Gainesville and Lakeland, FL
W
arfarin, a vitamin K antagonist (VKA), is the mainstay for the prevention and treatment of arterial and venous thrombosis. The complication associated with VKA therapy that causes the most concern is the risk of major bleeding events, particularly anticoagulantassociated intracranial hemorrhage. 1 A variety of approaches may be used to assist with reversal of the anticoagulation effects of VKAs; these approaches often combine vitamin K with prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or recombinant factor VIIa. Human 4-factor PCC (4 F-PCC [Kcentra], CSL Behring, King of Prussia, PA) was the first treatment approved by the Food and Drug Administration for the rapid reversal of VKA therapy. 2 4 F-PCC restores clotting factors II, VII, IX, and X, protein C, and protein S, which are needed for blood hemostasis and are depleted with VKA therapy. Further studies will likely evaluate the role of 4 F-PCC in the management of trauma-related massive bleeding, as well as for reversal of the new oral factor Xa and direct thrombin inhibitors. This review provides an updated assessment of the use of 4 F-PCC in the management of VKA reversal in the emergency department. In the past, options for VKA reversal included FFP, recombinant factor VIIa, or PCC with vitamin K supplementation. Reversal of the international normalized ratio (INR) to normal levels occurs approximately 12 to 24 hours after administration of vitamin K, necessitating the administration of adjunct agents when rapid reversal is required. 3 An inherent limitation of FFP is the large volumes required for administration (15 to 20 mL/kg), which can be a concern Courtney Willis is 2015 PharmD Candidate, University of Florida College of Pharmacy, Gainesville, FL. Brad Hall is Clinical Pharmacy Specialist–Emergency Medicine and PGY2 Emergency Medicine Pharmacy Director, Lakeland Regional Medical Center, Lakeland, FL. For correspondence, write: Courtney M. Willis, BS, PharmD(c); E-mail: cwillis16@ufl.edu. J Emerg Nurs 2015;41:9-12. Available online 9 July 2014 0099-1767 Copyright © 2015 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jen.2014.04.016
January 2015
VOLUME 41 • ISSUE 1
in patients at risk for fluid overload, including patients with renal and heart failure. 4 The large volumes and extensive infusion times associated with FFP may also lead to an increased risk for transfusion-related acute lung injury (TRALI), increasing the risk for transfusion-related deaths. 5 Additional concerns with FFP administration include delays associated with the time to thaw the plasma, lengthy administration times, and blood type matching. FFP is derived from human plasma and therefore carries a small risk of the transmission of microbes and viruses. Reversal with 4 F-PCC may offer significant advantages compared with reversal with FFP. 4 F-PCC does not require thawing and is available as a powder for reconstitution. 4 F-PCC does not require ABO compatibility testing and contains more concentrated factors, which allows for lower infusion volume requirements compared with FFP. 6 Additionally, 4 F-PCC undergoes viral inactivation through nanofiltration, eliminating the risk of the transmission of viruses. 7 The most recent (9th) edition of the American College of Chest Physicians’ Antithrombotic Therapy and Prevention of Thrombosis Guidelines, 4 published in 2012, recommends the use of 4 F-PCC rather than FFP for the urgent reversal of VKA-associated major bleeding. This recommendation is based on a number of studies that have shown that 4 F-PCC is as efficacious as FFP for rapid INR reversal and the improvement of blood hemostasis. Results from a multinational, phase IIIb clinical trial by Sarode et al 8 demonstrated that when compared with FFP, 4 F-PCC achieved similar effective homeostasis within 24 hours (72.4% vs 65.4%), thus showing that 4 F-PCC is not inferior to FFP. The trial revealed that 4 F-PCC lowered the INR to less than or equal to 1.3 by 30 minutes after the end of infusion in 62.2% of patients, versus only 9.6% in patients receiving FFP. 8 Utilization of 4 F-PCC in Trauma Care and Surgery
Traumatically injured patients are at a high risk for severe anticoagulant-associated intracranial hemorrhage and intractable bleeding. 9 The potential role of 4 F-PCC in coagulopathy related to major trauma is that theoretically it can promptly secure blood hemostasis while reducing transfusion requirements. 10 Currently the literature does
WWW.JENONLINE.ORG
9
CLINICAL/Willis and Hall
not include any randomized controlled trials that assess the efficacy and safety of 4 F-PCC in patients with massive bleeding. 11 A retrospective study comparing VKA reversal using FFP and PCC in traumatically injured patients revealed that the mean time to achieve INR was more rapid when PCC was used. However, the improvement in clinical outcomes such as hospital length of stay was not statistically different between the groups. 9 4 F-PCC has been used for a number of years in European countries for preoperative VKA reversal but has just recently gained acceptance in the United States for this indication. A small Belgium trial with 40 patients that compared 4 F-PCC (Cofact; Sanquin, The Netherlands) with FFP for reversal of VKA in patients undergoing cardiopulmonary bypass revealed that 15 minutes after cardiopulmonary bypass, more patients reached the target INR of less than or equal to 1.5 with 4 F-PCC (7/16 patients with 4 F-PCC vs 0/15 patients with FFP). 12 In December 2013, the Food and Drug Administration extended its approval of 4 F-PCC for the reversal of VKA prior to urgent surgical or invasive procedures. The results from a recent randomized trial involving 168 participants revealed effective blood homeostasis in 89.7% of patients in the 4 F-PCC group versus 75.3% in the FFP group, demonstrating the superiority of 4 F-PCC over FFP (a 14.4% difference). Rapid INR reduction was also achieved in 55.2% of patients in the 4 F-PCC group versus 9.9% in the FFP group, demonstrating the superiority of 4 F-PCC over FFP. Therefore 4 F-PCC was found to be a suitable alternative to FFP for rapid VKA reversal in patients who require urgent surgery or invasive procedures. 13
promising candidate for the reversal of the effects of dabigatran, rivaroxaban, and apixaban; however, the data supporting its clinical utilization have not been robust, with most of the data from preclinical animal trials 21,22 and studies that include healthy volunteers. 23 Initial evidence from Eerenberg et al 23 revealed that in a small sample of healthy males, 50 units/kg of 4 F-PCC (Cofact) immediately and completely reversed the anticoagulant effects in subjects who received rivaroxaban, but no impact on the anticoagulation activity was noticed in subjects who received dabigatran. 23 Thromboembolic Complications
A concern with 4 F-PCC use is the potential for the introduction of a prothrombotic state and resulting thromboembolic events. A patient’s recent underlying disease state (eg, myocardial infarction, transient ischemic attack, antithrombin deficiency, and a history of thromboembolic events) may potentially expose the patient to this risk regardless of the methods used to reverse the coagulopathy. Sarode et al 8 found no statistical difference in thromboembolic risk associated with 4 F-PCC compared with FFP (4% vs 3%). However, the study excluded patients who had a history of thromboembolic events within the prior 3 months. Additionally, the authors state that the trial was underpowered in establishing statistically significant differences between interventions for safety outcomes. 8 Thromboembolic complications with use of 4 F-PCC have been reported in the literature, with a higher incidence in patients who have underlying thrombotic risk. 24 Nursing Considerations
Reversal of the New Oral Anticoagulant Agents
The newer anticoagulant agents have been the topic of discussion during the past several years because of some of their potential advantages compared with warfarin. The metabolism of the newer anticoagulant agents is unaffected by food, they are affected by fewer drug-drug interactions, they exhibit rapid onset of action, and routine INR monitoring is unnecessary. Clinical trials have shown that the newer oral anticoagulants (e.g., dabigatran, rivaroxaban, and apixaban) are not inferior to warfarin therapy in the prevention of ischemic stroke in patients with atrial fibrillation, 14–16 as well as for the treatment of venous thromboembolism. 17–19 The newer oral anticoagulants were also associated with less risk of intracranial hemorrhage relative to warfarin. 14–16 Despite these benefits, the reversal of factor Xa and direct thrombin inhibitor anticoagulant effects have not been established and are clinical concerns. 20 The literature suggests that 4 F-PCC may be the most
10
JOURNAL OF EMERGENCY NURSING
Dosing for 4 F-PCC is performed according to the pretreatment INR of the patient and the patient’s actual body weight. The precise dosing for 4 F-PCC is described in the Figure. Because 4 F-PCC is a blood product, a varying concentration of factors may be present from one product to another. When calculating the 4 F-PCC dose, it is important to consider the exact factor content in each vial. In preparation for 4 F-PCC administration, each vial should be reconstituted in 20 mL of sterile water for injection and administered within 4 hours of reconstitution. The vials are for single use only, and any unused portions should be discarded. 4 F-PCC should be administered at room temperature through a peripheral infusion line that is separate from all other intravenous medications. According to the Kcentra package insert, it should be infused at a rate of 0.12 mL/kg/min up to a maximum rate of 8.4 mL/kg/min (210 units/min), making sure that blood does not enter the syringe, because there may be a risk of fibrin clot formation. 2 The peripheral intravenous catheter should be flushed with
VOLUME 41 • ISSUE 1
January 2015
Willis and Hall/CLINICAL
phytonadione (vitamin K), 10 mg /50 mL D5W via IV administered over 30 min x 1 dose; may repeat in 12 hours if necessary
PLUS Fresh thawed plasma, 15 mL/ kg IV
Transfuse each unit over 30 to 60 minutes
OR Pre-treatment INR 2 to 6
4F-PCC 50 units/kg IV x 1 dose at 210 units/min
FIGURE Reversal orders for life-threatening/major bleeding or for urgent surgery/an urgent procedure that requires an international normalized ratio less than 1.5. aD5W, 5% dextrose in water; 4 F-PCC, 4-factor prothrombin complex concentrate; INR, international normalized ratio; IV, intravenous. aSome procedures, including central venous cannulation, have been shown to be performed safely at international normalized ratios greater than 1.5. The dosing for vitamin K was verified and gathered from Chapman SA, Irwin ED, Beal AL, Kulinski KM, Hutson KE, Thorson, MA. Prothrombin complex concentrate versus standard therapy for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45:869-75. The dosing for FFP were verified and gathered from Nitzki-George D, Wozniak I, Caprini JA. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Annals of Pharmacother 2013;47:841-55. The doses and infusion rates for 4F-PCC were verified and gathered from the Kcentra package insert 2.
normal saline solution before and after administration of 4 F-PCC to maintain catheter patency. 4 F-PCC may induce hypersensitivity reactions and should be avoided if the patient has ever experienced a severe reaction to any of the factor components, human albumin, or antithrombin III. 2 Patients should be carefully monitored for signs and symptoms of hypersensitivity such as flushing, hives, wheezing, bronchospasm, angioedema, and hypotension. In the event a patient exhibits signs of severe allergic reaction, administration of 4 F-PCC should be discontinued immediately. 4 F-PCC formulations incorporate small amounts of heparin and therefore cannot be administered in patients with a history of heparin-induced thrombocytopenia. 1 In the event of warfarin-induced coagulopathy, baseline pretreatment INR should be assessed and rechecked 30 minutes after the administration of 4 F-PCC. If the patient’s INR is greater than or equal to 1.3, additional coagulation factors may be administered. Once the normalization of INR is obtained, it may be reassessed after 3 to 6 hours. This interval reflects the
January 2015
VOLUME 41 • ISSUE 1
short circulating half-life of factor VII and the onset of action of vitamin K. Data are insufficient to recommend the use of 4 F-PCC in women who are pregnant or lactating. It is not known if 4 F-PCC can cause fetal harm or if it is excreted in human milk, and therefore administration of 4 F-PCC to pregnant or lactating women is recommended only if the benefit outweighs the risk. 2
Conclusion
A rapid process of reversal is often necessary for patients who present to the emergency department with lifethreatening bleeding or who may require an urgent surgery or invasive procedure. Several years of clinical experience with 4 F-PCC (Kcentra) have been achieved outside the US, where the product is known as Beriplex P/N (CSL Behring), and 4 F-PCC recently gained acceptance in the
WWW.JENONLINE.ORG
11
CLINICAL/Willis and Hall
US as an effective alternative to FFP to rapidly reverse the effects of VKA and to successfully lower INR in patients with acute major bleeding or who require urgent surgery. 8,13 The literature has proposed a potentially important role of 4 F-PCC for reversal in trauma-induced coagulopathy, as well as for the reversal of the newer oral anticoagulant factor Xa and direct thrombin inhibitors. However, clinical evidence to justify 4 F-PCC use in these indications is insufficient. 4 F-PCC reversal has been linked with a low but clinically concerning risk of thromboembolic complications. It is unclear whether these complications are directly associated with 4 F-PCC treatment or with a patient’s previous underlying risk of thrombosis. The efficacy of 4 F-PCC has been demonstrated by laboratory measurements of INR normalization and homeostatic efficacy, but it is uncertain whether 4 F-PCC improves clinical outcomes. 6 REFERENCES 1. Hanger HC, Geddes AA, Wilkinson TJ, Lee M, Baker AE. Warfarin related intracerebral heamorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J. 2012;43:308-16.
10. Sorensen B, Fries D. Emerging treatment strategies for trauma-induced coagulopathy. Br J Surg. 2012;99:40-50. 11. Pham HP, Shaz BH. Update on massive transfusion. Br J Anaesth. 2013;111(S1):i71-82. 12. Demeyere R, Gillardin S, Arnout J, Strengers PFW. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251-60. 13. Randomized phase IIIb study of rapid vitamin K antagonist reversal in patients requiring an urgent surgical procedure: four-factor prothrombin complex concentrate is superior to plasma. http://bloodjournal. hematologylibrary.org/content/122/21/3588. Accessed February 16, 2014. 14. Connolly SJ, Ezekowitz MD, Yusuf S. Dabigatran versus Warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. 15. Granger CB, Alexander JH, McMurray JJ. Apixaban versus Warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92. 16. Patel MR, Mahaffey KW, Garg J. rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91. 17. Schulman S, Kearon C, Kakkar AK. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
2. Kcentra [package insert]. CSL Behring LLC; 2013.
18. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510.
3. Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: prothrombin complex concentrates-evaluation of safety and thrombogenicity. Crit Care. 2011;15:201-9.
19. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
4. Holbrook A, Schulman S, Witt DM. Antithrombotic therapy and prevention of thrombosis (9th edition). American College of Chest Physicians evidencebased clinical practice guidelines. Chest. 2012;141(2 Suppl):152S-84S. 5. Holness L, Knippen MA, Simmons L. Fatalities caused by TRALI. Transfus Med Rev. 2004;18:184-8. 6. Quinlan DJ, Eikelboom JW, Weitz JI, Weitz E. Four-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. Circulation. 2013;128:1179-81. 7. Cada DJ, Levien TL, Baker DE. Prothrombin complex concentrate. Hosp Pharm. 2013;48(11):951-7. 8. Sarode R, Milling TJ, Refaai MA. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding. Circulation. 2013;128:1234-43. 9. Chapman SA, Irwin ED, Beal AL, Kulinski KM, Hutson KE, Thorson MA. Prothrombin complex concentrate versus standard therapy for INR reversal in trauma patients receiving warfarin. Ann Pharmacother. 2011;45:869-75.
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20. Dickneitee G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrate (PCCs): what is the evidence? Thromb Haemost. 2014;111:189-98. 21. Martin AC, Bonniec BL, Fischer A. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol. 2013;168:4228-33. 22. Grottke O, Ryn JV, Spronk HM, Rossaint R. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care. 2014;18:R27-36. 23. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2012;124:1573-9. 24. Rodgers G. Prothrombin complex concentrates in emergency bleeding disorders. Am J Hematol. 2012;87:898-902.
VOLUME 41 • ISSUE 1
January 2015
