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• W2011576600 abstract "Dr Levy discloses a financial relationship with CSL Behring.Pharmacologic agents are routinely used to modulate the coagulation system, a strategy that is an important component of patient blood management [1Goodnough L.T. Shander A. Current status of pharmacologic therapies in patient blood management.Anesth Analg. 2013; 116: 15-34Crossref PubMed Scopus (64) Google Scholar]. Multiple procoagulant therapies are available for clinicians, including desmopressin acetate, tranexamic acid, aminocaproic acid, fibrinogen concentrates and prothrombin complex concentrates. In perioperative surgical management with use of procoagulants, reports have focused on cardiac surgical patients but continue to expand to other surgical patients. For example, tranexamic acid has long been approved and available for clinical use as a hemostatic agent but more recently a large scale clinical trial was able to demonstrate both efficacy and safety for its prophylactic use in trauma patients [2Roberts I. Shakur H. Afolabi A. et al.CRASH-2 collaborators1The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.Lancet. 2011; 377: 1096-1101Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar]. The role of antifibrinolytic therapy in trauma emerged from earlier studies in cardiac and other surgical patients [3Levy J.H. Antifibrinolytic therapy: new data and new concepts.Lancet. 2010; 376: 3-4Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. One additional prohemostatic agent, recombinant human factor VIIa (rFVIIa), has undergone an ever-increasing off-label use within the first 10 years of its approval for treatment of hemophilia patients with inhibitors (Fig 1) [4Logan A.C. Yank V. Stafford R.S. Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records.Ann Intern Med. 2011; 154: 516-522Crossref PubMed Scopus (115) Google Scholar]. Postapproval, inpatient use of rFVIIa from 2000 to 2008 increased 143-fold for off-label indications compared with a fourfold increase for use in patients with hemophilia.For related article, see page 618In this issue of The Annals of Thoracic Surgery, Alfirevic and colleagues [5Alfirevic A. Duncan A. You J. Lober C. Soltesz E. Recombinant factor VII is associated with worse survival in complex cardiac surgical patients.Ann Thorac Surg. 2014; 98: 618-624Google Scholar] report a single institution, retrospective 5-year analysis of nearly 28,000 cardiac surgery patients with perioperative coagulopathy, of whom 164 (0.6%) received rFVIIa. They matched 144 of these to 359 control patients using propensity techniques for comorbidities and intraoperative red blood cell transfusions, and analyzed for mortality as a primary outcome, with thrombosis, renal, and neurologic complications as secondary outcomes. They report 40% of patients treated with rFVIIa died, compared with 18% of controls (odds ratio [OR] 2.82, 1.64 to 4.87, p < 0.001). Renal morbidity was significantly greater at 31% in the rFVIIa cohort compared with 17% of controls (OR 2.07, 1.19 to 3.62, p < 0.002). Neurologic and thrombotic complications were not different compared with controls, and no dose effect of rFVIIa was found. The authors conclude that caution is advised in the off-label administration of rFVIIa to cardiac surgical patients.Retrospective, observational studies like this are often fraught with potential confounding issues from patients who receive “last ditch” therapies like rFVIIa. Patients are already destined to have adverse outcomes that, despite propensity matching, bleed for uncontrollable and under-recognized reasons that may include retrocardiac surgical tears that are exceedingly difficult to fix or other potential complications that may not be predictable. As in the case of other therapies, retrospective database analysis is helpful in identifying the critically ill, problematic patients who may have adverse events, and thus worse outcomes. All prohemostatic agents in these circumstances will potentially be associated with adverse effects because they are administered for patients having these complications. Placebo, controlled randomized study data are critical for interpreting risk versus benefit considerations in such “last ditch” therapies.Of note is a 2012 Cochrane review [6Simpson E. Lin Y. Stanworth S. Birchall J. Doree C. Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia.Cochrane Database Syst Rev. 2012; 3: CD005011PubMed Google Scholar] of 29 randomized controlled trials, 16 of which involve 1,361 participants with prophylactic use of rFVIIa in 729 subjects and 13 trials involve 2,929 participants that examined the therapeutic use of rFVIIa in 1,878 subjects. There was a trend in favor of rFVIIa for reducing mortality (relative risk [RR] 0.91; 95% confidence interval [CI] 0.78 to 1.06). However, there was also a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47). The authors of this Cochrane review concluded that the use of rFVIIa as a hemostatic drug, either prophylactically or therapeutically, remains unproven and that its use should be restricted to clinical trials. This position has been echoed by the Canadian National Advisory Council (NAC) on blood and blood products; the NAC recommends that rFVIIa no longer be used off-label for prevention and treatment in patients without hemophilia [7Lin Y. Moltzan C.J. Anderson D.R. The evidence for the use of recombinant factor VIIa in massive bleeding: revision of the transfusion policy framework.Transfus Med. 2012; 22: 383-394Crossref PubMed Scopus (21) Google Scholar].However, current guidelines from the Society for Thoracic Surgery and Society of Cardiovascular Anesthesiologists recommend use of rFVIIa in open heart surgical patients with refractory microvascular bleeding [8Ferraris V.A. Brown J.R. Despotis G.J. et al.2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.Ann Thorac Surg. 2011; 91: 944-982Abstract Full Text Full Text PDF PubMed Scopus (981) Google Scholar]. This is in part based on an important rFVIIa study in cardiac surgery evaluating the safety and efficacy of recombinant activated factor VII in a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery that was a dose-escalation study in high-risk patients after cardiac surgery and were bleeding greater than 200 mL/hour [9Gill 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: 21-27Crossref PubMed Scopus (212) Google Scholar]. The primary endpoints were critical serious adverse events, and secondary endpoints included rates of reoperation, amount of blood loss, and transfusion. Return to the operating room for reexploration was approximately 25% for placebo, compared with approximately 12% to 15% in the rFVIIa groups. There were more critical serious adverse events in the rFVIIa groups which did not reach statistical significance [9Gill 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: 21-27Crossref PubMed Scopus (212) Google Scholar]. We and others have followed the off-label use of rFVIIa based on this report and other published experience [10Goodnough L.T. Lublin D.M. Zhang L. Despotis G. Eby C. Transfusion medicine service policies for recombinant factor VIIa administration.Transfusion. 2004; 44: 1325-1331Crossref PubMed Scopus (120) Google Scholar, 11Sheikh A.Y. Hill C.C. Goodnough L.T. Leung L.L. Fischbein M.P. Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding.Transfusion. 2014; 54: 300-305PubMed Google Scholar].As the authors suggest, additional data from placebo-controlled randomized trials is not available nor will likely in the foreseeable future, primarily because of feasibility issues (eg, difficulty in obtaining informed consent in a timely manner, ethical concern of administering a placebo to patients with refractory blood loss, and lacking standardized alternative therapies), but also because further clinical development of rFVIIa or its analogs will be for licensed indications. Therefore, it would be ill advised to use rFVIIa outside of approved indications without considering its risk–benefit profile in the specific setting of refractory hemorrhage in cardiac surgical patients. As has been noted, clinicians need to carefully scrutinize data from randomized trials for applicability and data from observational studies for selection bias (for or against the drug) [12Karkouti K. Levy J.H. Recombinant activated factor VII: the controversial conundrum regarding its off-label use.Anesth Analg. 2011; 113: 711-712PubMed Google Scholar]. Other considerations include that patients are increasingly receiving irreversible antiplatelet agents (eg, clopidogrel, prasugrel, and ticagrelor) which also increase the potential for refractory bleeding. As there is no specific antidote for the P2Y12 receptor inhibitors, we have shown that rFVIIa can significantly reduce the platelet defect associated with these agents [13Mazzeffi M. Szlam F. Jakubowski J.A. Tanaka K.A. Sugidachi A. Levy J.H. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.Thromb Res. 2013; 132: 106-111Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 14Szlam F. Tanaka K.A. Rumph B. Bolliger D. Levy J.H. In vitro effects of recombinant activated factor VIIa (NovoSeven) on clopidogrel-induced platelet inhibition.Thromb Haemost. 2009; 103: 863-865Crossref Scopus (14) Google Scholar]. Further prospective clinical studies are needed for these patients who are at high risk for refractory blood loss and may benefit from novel prohemostatic therapies, including rFVIIa and prothrombin complex concentrates.In the meantime, it is important when to consider rFVIIa as a therapeutic off-label agent to treat refractory bleeding after major surgery or trauma in view of randomized clinical trial data showing it to be ineffective and possibly harmful in various other clinical settings. When presented with a patient who continues to bleed despite administration of all available therapies, clinicians have only two choices; they can keep administering the same interventions that have been unsuccessful, or they can administer a procoagulant agent such as rFVIIa or prothrombin complex concentrates [12Karkouti K. Levy J.H. Recombinant activated factor VII: the controversial conundrum regarding its off-label use.Anesth Analg. 2011; 113: 711-712PubMed Google Scholar]. We believe that in the setting of refractory blood loss, clinicians are justified in choosing procoagulant agents for several reasons. Patients with ongoing refractory bleeding will have dismal outcomes unless the blood loss is controlled in a timely manner, and are already subject to adverse outcomes that may not be adequately matched with propensity scoring [15Karkouti K. Beattie W.S. Wijeysundera D.N. et al.Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis.Transfusion. 2005; 45: 26-34Crossref PubMed Scopus (158) Google Scholar]. Even if the safety data from randomized trials apply as previously reported, which indicate that rFVIIa increases the risk of thrombotic complications by several percent [16Levi M. Levy J.H. Andersen H.F. Truloff D. Safety of recombinant activated factor VII in randomized clinical trials.N Engl J Med. 2010; 363: 1791-1800Crossref PubMed Scopus (526) Google Scholar], this risk may be dwarfed by uncontrolled hemorrhage that is commonly fatal. Dr Levy discloses a financial relationship with CSL Behring. Dr Levy discloses a financial relationship with CSL Behring. Dr Levy discloses a financial relationship with CSL Behring. Pharmacologic agents are routinely used to modulate the coagulation system, a strategy that is an important component of patient blood management [1Goodnough L.T. Shander A. Current status of pharmacologic therapies in patient blood management.Anesth Analg. 2013; 116: 15-34Crossref PubMed Scopus (64) Google Scholar]. Multiple procoagulant therapies are available for clinicians, including desmopressin acetate, tranexamic acid, aminocaproic acid, fibrinogen concentrates and prothrombin complex concentrates. In perioperative surgical management with use of procoagulants, reports have focused on cardiac surgical patients but continue to expand to other surgical patients. For example, tranexamic acid has long been approved and available for clinical use as a hemostatic agent but more recently a large scale clinical trial was able to demonstrate both efficacy and safety for its prophylactic use in trauma patients [2Roberts I. Shakur H. Afolabi A. et al.CRASH-2 collaborators1The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.Lancet. 2011; 377: 1096-1101Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar]. The role of antifibrinolytic therapy in trauma emerged from earlier studies in cardiac and other surgical patients [3Levy J.H. Antifibrinolytic therapy: new data and new concepts.Lancet. 2010; 376: 3-4Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. One additional prohemostatic agent, recombinant human factor VIIa (rFVIIa), has undergone an ever-increasing off-label use within the first 10 years of its approval for treatment of hemophilia patients with inhibitors (Fig 1) [4Logan A.C. Yank V. Stafford R.S. Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records.Ann Intern Med. 2011; 154: 516-522Crossref PubMed Scopus (115) Google Scholar]. Postapproval, inpatient use of rFVIIa from 2000 to 2008 increased 143-fold for off-label indications compared with a fourfold increase for use in patients with hemophilia. For related article, see page 618 For related article, see page 618 For related article, see page 618 In this issue of The Annals of Thoracic Surgery, Alfirevic and colleagues [5Alfirevic A. Duncan A. You J. Lober C. Soltesz E. Recombinant factor VII is associated with worse survival in complex cardiac surgical patients.Ann Thorac Surg. 2014; 98: 618-624Google Scholar] report a single institution, retrospective 5-year analysis of nearly 28,000 cardiac surgery patients with perioperative coagulopathy, of whom 164 (0.6%) received rFVIIa. They matched 144 of these to 359 control patients using propensity techniques for comorbidities and intraoperative red blood cell transfusions, and analyzed for mortality as a primary outcome, with thrombosis, renal, and neurologic complications as secondary outcomes. They report 40% of patients treated with rFVIIa died, compared with 18% of controls (odds ratio [OR] 2.82, 1.64 to 4.87, p < 0.001). Renal morbidity was significantly greater at 31% in the rFVIIa cohort compared with 17% of controls (OR 2.07, 1.19 to 3.62, p < 0.002). Neurologic and thrombotic complications were not different compared with controls, and no dose effect of rFVIIa was found. The authors conclude that caution is advised in the off-label administration of rFVIIa to cardiac surgical patients. Retrospective, observational studies like this are often fraught with potential confounding issues from patients who receive “last ditch” therapies like rFVIIa. Patients are already destined to have adverse outcomes that, despite propensity matching, bleed for uncontrollable and under-recognized reasons that may include retrocardiac surgical tears that are exceedingly difficult to fix or other potential complications that may not be predictable. As in the case of other therapies, retrospective database analysis is helpful in identifying the critically ill, problematic patients who may have adverse events, and thus worse outcomes. All prohemostatic agents in these circumstances will potentially be associated with adverse effects because they are administered for patients having these complications. Placebo, controlled randomized study data are critical for interpreting risk versus benefit considerations in such “last ditch” therapies. Of note is a 2012 Cochrane review [6Simpson E. Lin Y. Stanworth S. Birchall J. Doree C. Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia.Cochrane Database Syst Rev. 2012; 3: CD005011PubMed Google Scholar] of 29 randomized controlled trials, 16 of which involve 1,361 participants with prophylactic use of rFVIIa in 729 subjects and 13 trials involve 2,929 participants that examined the therapeutic use of rFVIIa in 1,878 subjects. There was a trend in favor of rFVIIa for reducing mortality (relative risk [RR] 0.91; 95% confidence interval [CI] 0.78 to 1.06). However, there was also a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47). The authors of this Cochrane review concluded that the use of rFVIIa as a hemostatic drug, either prophylactically or therapeutically, remains unproven and that its use should be restricted to clinical trials. This position has been echoed by the Canadian National Advisory Council (NAC) on blood and blood products; the NAC recommends that rFVIIa no longer be used off-label for prevention and treatment in patients without hemophilia [7Lin Y. Moltzan C.J. Anderson D.R. The evidence for the use of recombinant factor VIIa in massive bleeding: revision of the transfusion policy framework.Transfus Med. 2012; 22: 383-394Crossref PubMed Scopus (21) Google Scholar]. However, current guidelines from the Society for Thoracic Surgery and Society of Cardiovascular Anesthesiologists recommend use of rFVIIa in open heart surgical patients with refractory microvascular bleeding [8Ferraris V.A. Brown J.R. Despotis G.J. et al.2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines.Ann Thorac Surg. 2011; 91: 944-982Abstract Full Text Full Text PDF PubMed Scopus (981) Google Scholar]. This is in part based on an important rFVIIa study in cardiac surgery evaluating the safety and efficacy of recombinant activated factor VII in a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery that was a dose-escalation study in high-risk patients after cardiac surgery and were bleeding greater than 200 mL/hour [9Gill 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: 21-27Crossref PubMed Scopus (212) Google Scholar]. The primary endpoints were critical serious adverse events, and secondary endpoints included rates of reoperation, amount of blood loss, and transfusion. Return to the operating room for reexploration was approximately 25% for placebo, compared with approximately 12% to 15% in the rFVIIa groups. There were more critical serious adverse events in the rFVIIa groups which did not reach statistical significance [9Gill 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: 21-27Crossref PubMed Scopus (212) Google Scholar]. We and others have followed the off-label use of rFVIIa based on this report and other published experience [10Goodnough L.T. Lublin D.M. Zhang L. Despotis G. Eby C. Transfusion medicine service policies for recombinant factor VIIa administration.Transfusion. 2004; 44: 1325-1331Crossref PubMed Scopus (120) Google Scholar, 11Sheikh A.Y. Hill C.C. Goodnough L.T. Leung L.L. Fischbein M.P. Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding.Transfusion. 2014; 54: 300-305PubMed Google Scholar]. As the authors suggest, additional data from placebo-controlled randomized trials is not available nor will likely in the foreseeable future, primarily because of feasibility issues (eg, difficulty in obtaining informed consent in a timely manner, ethical concern of administering a placebo to patients with refractory blood loss, and lacking standardized alternative therapies), but also because further clinical development of rFVIIa or its analogs will be for licensed indications. Therefore, it would be ill advised to use rFVIIa outside of approved indications without considering its risk–benefit profile in the specific setting of refractory hemorrhage in cardiac surgical patients. As has been noted, clinicians need to carefully scrutinize data from randomized trials for applicability and data from observational studies for selection bias (for or against the drug) [12Karkouti K. Levy J.H. Recombinant activated factor VII: the controversial conundrum regarding its off-label use.Anesth Analg. 2011; 113: 711-712PubMed Google Scholar]. Other considerations include that patients are increasingly receiving irreversible antiplatelet agents (eg, clopidogrel, prasugrel, and ticagrelor) which also increase the potential for refractory bleeding. As there is no specific antidote for the P2Y12 receptor inhibitors, we have shown that rFVIIa can significantly reduce the platelet defect associated with these agents [13Mazzeffi M. Szlam F. Jakubowski J.A. Tanaka K.A. Sugidachi A. Levy J.H. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.Thromb Res. 2013; 132: 106-111Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 14Szlam F. Tanaka K.A. Rumph B. Bolliger D. Levy J.H. In vitro effects of recombinant activated factor VIIa (NovoSeven) on clopidogrel-induced platelet inhibition.Thromb Haemost. 2009; 103: 863-865Crossref Scopus (14) Google Scholar]. Further prospective clinical studies are needed for these patients who are at high risk for refractory blood loss and may benefit from novel prohemostatic therapies, including rFVIIa and prothrombin complex concentrates. In the meantime, it is important when to consider rFVIIa as a therapeutic off-label agent to treat refractory bleeding after major surgery or trauma in view of randomized clinical trial data showing it to be ineffective and possibly harmful in various other clinical settings. When presented with a patient who continues to bleed despite administration of all available therapies, clinicians have only two choices; they can keep administering the same interventions that have been unsuccessful, or they can administer a procoagulant agent such as rFVIIa or prothrombin complex concentrates [12Karkouti K. Levy J.H. Recombinant activated factor VII: the controversial conundrum regarding its off-label use.Anesth Analg. 2011; 113: 711-712PubMed Google Scholar]. We believe that in the setting of refractory blood loss, clinicians are justified in choosing procoagulant agents for several reasons. Patients with ongoing refractory bleeding will have dismal outcomes unless the blood loss is controlled in a timely manner, and are already subject to adverse outcomes that may not be adequately matched with propensity scoring [15Karkouti K. Beattie W.S. Wijeysundera D.N. et al.Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis.Transfusion. 2005; 45: 26-34Crossref PubMed Scopus (158) Google Scholar]. Even if the safety data from randomized trials apply as previously reported, which indicate that rFVIIa increases the risk of thrombotic complications by several percent [16Levi M. Levy J.H. Andersen H.F. Truloff D. Safety of recombinant activated factor VII in randomized clinical trials.N Engl J Med. 2010; 363: 1791-1800Crossref PubMed Scopus (526) Google Scholar], this risk may be dwarfed by uncontrolled hemorrhage that is commonly fatal. Recombinant Factor VII Is Associated With Worse Survival in Complex Cardiac Surgical PatientsThe Annals of Thoracic SurgeryVol. 98Issue 2PreviewRecombinant activated factor VII (rFVIIa) decreases requirements for allogeneic blood transfusion and chest reexploration in patients undergoing cardiac surgery. Whether rFVIIa increases the risk of postoperative adverse events is unclear. We tested whether rFVIIa administration was associated with increased mortality and neurologic and renal morbidity in patients undergoing cardiac surgery. Risk of thromboembolic complications and the dose-response of rFVIIa on mortality and morbidity were also evaluated. Full-Text PDF" @default.
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• W2011576600 title "Off-Label Use of Recombinant Human Factor VIIa" @default.
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