- Email: [email protected]
Comparing Factor Concentrates for Post-Bypass Coagulopathy: Is There One Best Option?
Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
Contents lists available at ScienceDirect
journal homepage: www.jcvaonline.com
Editorial
Comparing Factor Concentrates for Post-Bypass Coagulopathy: Is There One Best Option? TRADITIONAL MANAGEMENT of post-bypass coagulopathy often relies on the transfusion of fresh frozen plasma and platelets in order to achieve acceptable hemostasis. However, this can often be detrimental to both cardiac function and hemodynamic stability due to the volume overload from excessive transfusion. Furthermore, an increase in red blood cell transfusion is common due to dilution. The rising use of factor concentrates for factor repletion has aided in providing therapy that can be given in much smaller volumes, along with more concentrated amounts of coagulation factors.1 These concentrates include recombinant activated Factor VII (rFVIIa), fibrinogen concentrates, and prothrombin complex concentrates (PCC).2 Certainly, the off-label use of these concentrates in cardiac surgery has demonstrated sufficient clinical benefits leading to their inclusion in blood management guidelines; however, their use does not come without safety concerns and thrombosis risk.3,4 Additionally, each of these concentrates has been well studied against standard transfusion approaches described above, but there are far fewer direct comparisons of the effectiveness of factor concentrates when compared with other factor concentrates in the cardiac surgery setting. As we continue to explore these therapies for optimal dosing, timing of administration, and safety profiles, we must keep in mind that each of these targetspecific agents works differently with different intended goals, and therefore, any direct comparisons of factor concentrates may not be as straightforward as we would like. Initial comparisons of one factor concentrate to another actually date back to more than a decade ago, although studies did not involve cardiac surgical patients directly. In the setting of sustained anticoagulation (ie, vitamin K antagonist), 4-factor PCC (Factors II, VII, IX, X) compared to rFVIIa, an animal model demonstrated that PCC was more effective in restoring hemostatic function.5 Interestingly, a comparison of 3-factor PCC (Factors II, IX, X) and low-dose rFVIIa in patients requiring emergent warfarin reversal revealed that 1.0 to 1.2 mg of rFVIIa was more effective at achieving an international normalized ratio (INR) less than 1.5 when compared with 3-factor PCC (average dose 20 U/kg).6 Next, a direct comparison of 4-factor PCC to 3-factor PCC in an http://dx.doi.org/10.1053/j.jvca.2017.09.009 1053-0770/& 2017 Elsevier Inc. All rights reserved.
animal model also demonstrated superiority of 4-factor PCC for the reversal of anticoagulation with a vitamin K antagonist. In this study, both bleeding times and prothrombin times were more fully decreased to normal with the 4-factor PCC.7 A similar recent comparison in warfarin-anticoagulated patients revealed that 4-factor PCC was more effective in INR reversal (r 1.5) than 3-factor PCC (87.5% v 45.6%, p o 0.001).8 While there was no difference in blood product transfusion, 4-factor PCC also was demonstrated to be a more costeffective option. These head-to-head comparisons alone should not be used to determine the one best option, but they should be used to emphasize the important relationship between Factor VII and INR values. With significantly elevated INR values, Factor VII activity may drop below levels needed for adequate hemostasis. However, in cases of mildly elevated INR, 10% to 15% Factor VII is still sufficient for hemostasis when given 3-factor PCC.9 Therefore, 3-factor PCC may still be an efficacious option to choose in this setting, but the starting INR levels should be considered when picking the optimal factor concentrate. In the setting of coagulopathy after cardiac surgery, off-label use of factor concentrates continues to increase. Compared with standard therapy, both rFVIIa and PCC have been shown to be more effective at decreasing blood loss and/or transfusion.10–13 However, there is little direct comparison of factor concentrates in this particular setting. Outside of post-bypass bleeding, PCC and rFVIIa have been studied in intracranial hemorrhage patients, but again, this is in the setting of warfarin.14 In nonanticoagulated patients undergoing cardiac surgery, Tanaka and colleagues have compared the efficacy of 3-factor PCC with that of rFVIIa.15 In a retrospective analysis of 50 patients receiving 3-factor PCC after cardiac surgery, they found that compared with a group of 100 patients receiving rFVIIa (matched for age, gender, and bypass duration), 3-factor PCC decreases further need for blood product transfusion (p o 0.001), decreases 12-hour chest tube output (p o 0.001), and decreases overall costs, including that of blood products and factor concentrates ($8,962 v $16,442, p o 0.001). Also, no acute thrombotic complications or differences in 30-day mortality were noted in the 2 groups.
2
Editorial / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
Given the limited data on direct comparisons of any of the factor concentrates, Harper and colleagues look to further expand our understanding of the efficacy and adverse outcomes associated with PCC and rFVIIa.16 In this current issue of the Journal of Cardiothoracic and Vascular Anesthesia, they perform a retrospective analysis of 3-factor PCC (Bebulin, Baxalta US Inc, Westlake Village, CA) and rFVIIa (NovoSeven RT, Novo Nordisk A/S, Bagsvaerd, Denmark) in patients undergoing cardiac surgery with cardiopulmonary bypass. Review of medical records from January 2003 to April 2015 revealed 72 patients that received 3-factor PCC and 263 patients that received rFVIIa. In a propensity-matched analysis, 53 patients for each factor concentrate were then investigated for 30-day mortality, as well as complications, bleeding, transfusion, lengths of stay, and need for additional procedures. While they found no difference in death within 30 days (p ¼ 1.0), intensive care unit length of stay (p ¼ 0.554), or hospital (p ¼ 0.113) length of stay, the authors did observe the PCC group to have a decreased need for intraoperative and postoperative transfusion, decreased 24-hour chest tube output (p ¼ 0.009), and decreased incidence of postoperative renal failure requiring dialysis (odds ratio 0.3, confidence interval 0.1–0.7). They conclude that the use of rFVIIa after cardiac surgery may be associated with need for dialysis and increased transfusion for bleeding when compared with 3-factor PCC. The Harper study is valuable, given the paucity of data comparing PCC and rFVIIa, especially in cardiac surgery. Given the many unanswered questions regarding safety profiles, dosing, and timing of administration, the information provided here will add to the ongoing investigations of factor concentrates. The finding of renal failure related to rFVIIa has been suggested before, but still remains uncertain. This study has additional strengths in its direct comparison, as well as the use of laboratory data throughout the perioperative period. Furthermore, the addition of a propensity-matched comparison should be commended; however, the inclusion of STS (Society of Thoracic Surgeons)-risk score, preoperative cardiac function, preoperative antiplatelet/anticoagulant use, and case complexity would aid in risk stratifying for potential postoperative coagulopathy. As the authors acknowledge, it is difficult to control the timing of the chosen factor concentrate, particularly in a retrospective analysis. As such, it was noted that timing of rFVIIa may have been later in the post-bypass period given that rFVIIa is often given as a “rescue” option after massive transfusion and ongoing bleeding.3 This is similar to the Tanaka study above where some patients did not receive rFVIIa until after arrival to the intensive care unit rather than in the operating room.15 In the current era of factor concentrate use, the use of PCC has become more accepted, and at many institutions, PCC is administered not as a last M.F. has no disclosures to report. P.A.P. is a speaker for Edwards Lifesciences. 1 Address reprint requests to Prakash A. Patel, MD, Assistant Professor, Department of Anesthesiology and Critical Care, University of Pennsylvania, Perelman School of Medicine, 3400 Spruce Street; Dulles 6, Philadelphia, PA 19104.
resort option, but rather after a preset quantity of plasma, platelet, and cryoprecipitate transfusion. Thus, direct comparisons in this retrospective nature will continue to have these limitations. Similarly, the dosing of factor concentrates varies when not controlled in an algorithmic approach, and again, the authors acknowledge this limitation. In the Harper study, the mean total dose of rFVIIa was 106 μg/kg, which is rather high compared with reported average doses of rFVIIa for this off-label indication.10,11 Similarly, the average dose of 3-factor PCC in the current study was 30 IU/kg, which may be only a modest dose for the degree of bleeding, but again, dosing for this off-label use in post-bypass coagulopathy has not been established. Moving forward, the use of factor concentrates will increase in cardiac surgery, despite a current lack of safety profiles for these agents. Future studies that compare specific agents will ideally be prospective, randomized trials. Likewise, these investigations should include 4-factor PCC, which has an approved indication for reversal of warfarin-related bleeding and is also more commonly recommended in current guidelines.17 Also, the incorporation of point-of-care testing into the decision-making process should be included in future studies. While there is no rapid thrombin generation assay available to us clinically, pointof-care tests such as the CT EXTEM (ROTEM, Tem International GmbH, Germany) have been applied as a guide to administering PCC, and they may possibly help choose between PCC and rFVIIa.18 These potential future investigations may be very helpful in learning more about outcomes, but it is also very important to keep in mind that any direct comparisons of factor concentrates may not really answer the question of which factor concentrate is the best one to choose after cardiac surgery. Each of these options works differently in the coagulation cascade with different mechanisms for achieving hemostasis. Similarly, given that dosing of individual factor concentrates varies significantly, it is unlikely that dosing “equivalents” can be applied when looking at different concentrates. Therefore, any direct comparisons will still not be comparing apples to apples. However, this should not prevent these much-needed future investigations from taking place as the role of factor concentrates continues to grow in the cardiac operating room. Michael Fabbro II, DOn Prakash A. Patel, MD† n Department of Anesthesiology, University of Miami Miller School of Medicine Miami, FL † Department of Anesthesiology and Critical Care University of Pennsylvania, Perelman School of Medicine Philadelphia, PA
References 1 Patel PA, Fabbro M. CON: Factor concentrates should not have an expanded role in the routine management of the bleeding cardiac surgical patient. J Cardiothorac Vasc Anesth 2017[Epub ahead of print]. 2 Ghadimi K, Welsby IJ. PRO - Factor concentrates are essential for hemostasis in complex cardiac surgery. J Cardiothorac Vasc Anesth 2017. [Epub ahead of print]. 3 Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists
Editorial / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
4
5
6
7
8
9
10
blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91: 944–82. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology 2015;122:241–75. Dickneite G. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res 2007;119: 643–51. Chapman SA, Irwin ED, Abou-Karam NM, et al. Comparison of 3-factor prothrombin complex concentrate and low-dose recombinant factor VIIa for warfarin reversal. World J Emerg Surg 2014;9:27. Herzog E, Kaspereit F, Krege W, et al. Four-factor prothrombin complex concentrate (Beriplexs P/N) is superior to three-factor prothrombin complex concentrate for reversal of coumarin anticoagulation. Crit Care 2015;19:P347. DeAngelo J, Jarrell D, Cosgrove R, et al. Comparison of 3-factor versus 4-factor prothrombin complex concentrate with regard to warfarin reversal, blood product use, and costs. Am J Ther 2017. [Epub ahead of print]. Makris M, van Veen J. Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 2011;9:117–9. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: A randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation 2009;120:21–7.
3
11 Andersen ND, Bhattacharya SD, Williams JB, et al. Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations. Ann Thorac Surg 2012;93:1921–8; discussion 1928–9. 12 Cappabianca G, Mariscalco G, Biancari F, et al. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. Crit Care 2016;20:5. 13 Arnékian V, Camous J, Fattal S, et al. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg 2012;15:382–9. 14 Pinner NA, Hurdle AC, Oliphant C, et al. Treatment of warfarin-related intracranial hemorrhage: A comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg 2010;74: 631–5. 15 Tanaka KA, Mazzeffi MA, Grube M, et al. Three-factor prothrombin complex concentrate and hemostasis after high-risk cardiovascular surgery. Transfusion 2013;53:920–1. 16 Harper PC, Smith MM, Brinkman NJ, et al. Outcomes following threefactor inactive prothrombin complex concentrate vs recombinant activated factor VII administration during cardiac surgery. J Cardiothorac Vasc Anesth 2017. [Epub ahead of print]. 17 Ghadimi K, Levy JH, Welsby IJ. Prothrombin complex concentrates for bleeding in the perioperative setting. Anesth Analg 2016;122: 1287–300. 18 Tanaka KA, Mazzeffi M, Durila M. Role of prothrombin complex concentrate in perioperative coagulation therapy. J Intensive Care 2014;2:60.
Contents lists available at ScienceDirect
journal homepage: www.jcvaonline.com
Editorial
Comparing Factor Concentrates for Post-Bypass Coagulopathy: Is There One Best Option? TRADITIONAL MANAGEMENT of post-bypass coagulopathy often relies on the transfusion of fresh frozen plasma and platelets in order to achieve acceptable hemostasis. However, this can often be detrimental to both cardiac function and hemodynamic stability due to the volume overload from excessive transfusion. Furthermore, an increase in red blood cell transfusion is common due to dilution. The rising use of factor concentrates for factor repletion has aided in providing therapy that can be given in much smaller volumes, along with more concentrated amounts of coagulation factors.1 These concentrates include recombinant activated Factor VII (rFVIIa), fibrinogen concentrates, and prothrombin complex concentrates (PCC).2 Certainly, the off-label use of these concentrates in cardiac surgery has demonstrated sufficient clinical benefits leading to their inclusion in blood management guidelines; however, their use does not come without safety concerns and thrombosis risk.3,4 Additionally, each of these concentrates has been well studied against standard transfusion approaches described above, but there are far fewer direct comparisons of the effectiveness of factor concentrates when compared with other factor concentrates in the cardiac surgery setting. As we continue to explore these therapies for optimal dosing, timing of administration, and safety profiles, we must keep in mind that each of these targetspecific agents works differently with different intended goals, and therefore, any direct comparisons of factor concentrates may not be as straightforward as we would like. Initial comparisons of one factor concentrate to another actually date back to more than a decade ago, although studies did not involve cardiac surgical patients directly. In the setting of sustained anticoagulation (ie, vitamin K antagonist), 4-factor PCC (Factors II, VII, IX, X) compared to rFVIIa, an animal model demonstrated that PCC was more effective in restoring hemostatic function.5 Interestingly, a comparison of 3-factor PCC (Factors II, IX, X) and low-dose rFVIIa in patients requiring emergent warfarin reversal revealed that 1.0 to 1.2 mg of rFVIIa was more effective at achieving an international normalized ratio (INR) less than 1.5 when compared with 3-factor PCC (average dose 20 U/kg).6 Next, a direct comparison of 4-factor PCC to 3-factor PCC in an http://dx.doi.org/10.1053/j.jvca.2017.09.009 1053-0770/& 2017 Elsevier Inc. All rights reserved.
animal model also demonstrated superiority of 4-factor PCC for the reversal of anticoagulation with a vitamin K antagonist. In this study, both bleeding times and prothrombin times were more fully decreased to normal with the 4-factor PCC.7 A similar recent comparison in warfarin-anticoagulated patients revealed that 4-factor PCC was more effective in INR reversal (r 1.5) than 3-factor PCC (87.5% v 45.6%, p o 0.001).8 While there was no difference in blood product transfusion, 4-factor PCC also was demonstrated to be a more costeffective option. These head-to-head comparisons alone should not be used to determine the one best option, but they should be used to emphasize the important relationship between Factor VII and INR values. With significantly elevated INR values, Factor VII activity may drop below levels needed for adequate hemostasis. However, in cases of mildly elevated INR, 10% to 15% Factor VII is still sufficient for hemostasis when given 3-factor PCC.9 Therefore, 3-factor PCC may still be an efficacious option to choose in this setting, but the starting INR levels should be considered when picking the optimal factor concentrate. In the setting of coagulopathy after cardiac surgery, off-label use of factor concentrates continues to increase. Compared with standard therapy, both rFVIIa and PCC have been shown to be more effective at decreasing blood loss and/or transfusion.10–13 However, there is little direct comparison of factor concentrates in this particular setting. Outside of post-bypass bleeding, PCC and rFVIIa have been studied in intracranial hemorrhage patients, but again, this is in the setting of warfarin.14 In nonanticoagulated patients undergoing cardiac surgery, Tanaka and colleagues have compared the efficacy of 3-factor PCC with that of rFVIIa.15 In a retrospective analysis of 50 patients receiving 3-factor PCC after cardiac surgery, they found that compared with a group of 100 patients receiving rFVIIa (matched for age, gender, and bypass duration), 3-factor PCC decreases further need for blood product transfusion (p o 0.001), decreases 12-hour chest tube output (p o 0.001), and decreases overall costs, including that of blood products and factor concentrates ($8,962 v $16,442, p o 0.001). Also, no acute thrombotic complications or differences in 30-day mortality were noted in the 2 groups.
2
Editorial / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
Given the limited data on direct comparisons of any of the factor concentrates, Harper and colleagues look to further expand our understanding of the efficacy and adverse outcomes associated with PCC and rFVIIa.16 In this current issue of the Journal of Cardiothoracic and Vascular Anesthesia, they perform a retrospective analysis of 3-factor PCC (Bebulin, Baxalta US Inc, Westlake Village, CA) and rFVIIa (NovoSeven RT, Novo Nordisk A/S, Bagsvaerd, Denmark) in patients undergoing cardiac surgery with cardiopulmonary bypass. Review of medical records from January 2003 to April 2015 revealed 72 patients that received 3-factor PCC and 263 patients that received rFVIIa. In a propensity-matched analysis, 53 patients for each factor concentrate were then investigated for 30-day mortality, as well as complications, bleeding, transfusion, lengths of stay, and need for additional procedures. While they found no difference in death within 30 days (p ¼ 1.0), intensive care unit length of stay (p ¼ 0.554), or hospital (p ¼ 0.113) length of stay, the authors did observe the PCC group to have a decreased need for intraoperative and postoperative transfusion, decreased 24-hour chest tube output (p ¼ 0.009), and decreased incidence of postoperative renal failure requiring dialysis (odds ratio 0.3, confidence interval 0.1–0.7). They conclude that the use of rFVIIa after cardiac surgery may be associated with need for dialysis and increased transfusion for bleeding when compared with 3-factor PCC. The Harper study is valuable, given the paucity of data comparing PCC and rFVIIa, especially in cardiac surgery. Given the many unanswered questions regarding safety profiles, dosing, and timing of administration, the information provided here will add to the ongoing investigations of factor concentrates. The finding of renal failure related to rFVIIa has been suggested before, but still remains uncertain. This study has additional strengths in its direct comparison, as well as the use of laboratory data throughout the perioperative period. Furthermore, the addition of a propensity-matched comparison should be commended; however, the inclusion of STS (Society of Thoracic Surgeons)-risk score, preoperative cardiac function, preoperative antiplatelet/anticoagulant use, and case complexity would aid in risk stratifying for potential postoperative coagulopathy. As the authors acknowledge, it is difficult to control the timing of the chosen factor concentrate, particularly in a retrospective analysis. As such, it was noted that timing of rFVIIa may have been later in the post-bypass period given that rFVIIa is often given as a “rescue” option after massive transfusion and ongoing bleeding.3 This is similar to the Tanaka study above where some patients did not receive rFVIIa until after arrival to the intensive care unit rather than in the operating room.15 In the current era of factor concentrate use, the use of PCC has become more accepted, and at many institutions, PCC is administered not as a last M.F. has no disclosures to report. P.A.P. is a speaker for Edwards Lifesciences. 1 Address reprint requests to Prakash A. Patel, MD, Assistant Professor, Department of Anesthesiology and Critical Care, University of Pennsylvania, Perelman School of Medicine, 3400 Spruce Street; Dulles 6, Philadelphia, PA 19104.
resort option, but rather after a preset quantity of plasma, platelet, and cryoprecipitate transfusion. Thus, direct comparisons in this retrospective nature will continue to have these limitations. Similarly, the dosing of factor concentrates varies when not controlled in an algorithmic approach, and again, the authors acknowledge this limitation. In the Harper study, the mean total dose of rFVIIa was 106 μg/kg, which is rather high compared with reported average doses of rFVIIa for this off-label indication.10,11 Similarly, the average dose of 3-factor PCC in the current study was 30 IU/kg, which may be only a modest dose for the degree of bleeding, but again, dosing for this off-label use in post-bypass coagulopathy has not been established. Moving forward, the use of factor concentrates will increase in cardiac surgery, despite a current lack of safety profiles for these agents. Future studies that compare specific agents will ideally be prospective, randomized trials. Likewise, these investigations should include 4-factor PCC, which has an approved indication for reversal of warfarin-related bleeding and is also more commonly recommended in current guidelines.17 Also, the incorporation of point-of-care testing into the decision-making process should be included in future studies. While there is no rapid thrombin generation assay available to us clinically, pointof-care tests such as the CT EXTEM (ROTEM, Tem International GmbH, Germany) have been applied as a guide to administering PCC, and they may possibly help choose between PCC and rFVIIa.18 These potential future investigations may be very helpful in learning more about outcomes, but it is also very important to keep in mind that any direct comparisons of factor concentrates may not really answer the question of which factor concentrate is the best one to choose after cardiac surgery. Each of these options works differently in the coagulation cascade with different mechanisms for achieving hemostasis. Similarly, given that dosing of individual factor concentrates varies significantly, it is unlikely that dosing “equivalents” can be applied when looking at different concentrates. Therefore, any direct comparisons will still not be comparing apples to apples. However, this should not prevent these much-needed future investigations from taking place as the role of factor concentrates continues to grow in the cardiac operating room. Michael Fabbro II, DOn Prakash A. Patel, MD† n Department of Anesthesiology, University of Miami Miller School of Medicine Miami, FL † Department of Anesthesiology and Critical Care University of Pennsylvania, Perelman School of Medicine Philadelphia, PA
References 1 Patel PA, Fabbro M. CON: Factor concentrates should not have an expanded role in the routine management of the bleeding cardiac surgical patient. J Cardiothorac Vasc Anesth 2017[Epub ahead of print]. 2 Ghadimi K, Welsby IJ. PRO - Factor concentrates are essential for hemostasis in complex cardiac surgery. J Cardiothorac Vasc Anesth 2017. [Epub ahead of print]. 3 Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists
Editorial / Journal of Cardiothoracic and Vascular Anesthesia ] (]]]]) ]]]–]]]
4
5
6
7
8
9
10
blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91: 944–82. American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology 2015;122:241–75. Dickneite G. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation. Thromb Res 2007;119: 643–51. Chapman SA, Irwin ED, Abou-Karam NM, et al. Comparison of 3-factor prothrombin complex concentrate and low-dose recombinant factor VIIa for warfarin reversal. World J Emerg Surg 2014;9:27. Herzog E, Kaspereit F, Krege W, et al. Four-factor prothrombin complex concentrate (Beriplexs P/N) is superior to three-factor prothrombin complex concentrate for reversal of coumarin anticoagulation. Crit Care 2015;19:P347. DeAngelo J, Jarrell D, Cosgrove R, et al. Comparison of 3-factor versus 4-factor prothrombin complex concentrate with regard to warfarin reversal, blood product use, and costs. Am J Ther 2017. [Epub ahead of print]. Makris M, van Veen J. Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 2011;9:117–9. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: A randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation 2009;120:21–7.
3
11 Andersen ND, Bhattacharya SD, Williams JB, et al. Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations. Ann Thorac Surg 2012;93:1921–8; discussion 1928–9. 12 Cappabianca G, Mariscalco G, Biancari F, et al. Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. Crit Care 2016;20:5. 13 Arnékian V, Camous J, Fattal S, et al. Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery. Interact Cardiovasc Thorac Surg 2012;15:382–9. 14 Pinner NA, Hurdle AC, Oliphant C, et al. Treatment of warfarin-related intracranial hemorrhage: A comparison of prothrombin complex concentrate and recombinant activated factor VII. World Neurosurg 2010;74: 631–5. 15 Tanaka KA, Mazzeffi MA, Grube M, et al. Three-factor prothrombin complex concentrate and hemostasis after high-risk cardiovascular surgery. Transfusion 2013;53:920–1. 16 Harper PC, Smith MM, Brinkman NJ, et al. Outcomes following threefactor inactive prothrombin complex concentrate vs recombinant activated factor VII administration during cardiac surgery. J Cardiothorac Vasc Anesth 2017. [Epub ahead of print]. 17 Ghadimi K, Levy JH, Welsby IJ. Prothrombin complex concentrates for bleeding in the perioperative setting. Anesth Analg 2016;122: 1287–300. 18 Tanaka KA, Mazzeffi M, Durila M. Role of prothrombin complex concentrate in perioperative coagulation therapy. J Intensive Care 2014;2:60.