- Email: [email protected]
Off-Label Use of Recombinant Human Factor VIIa
EDITORIAL
Off-Label Use of Recombinant Human Factor VIIa Lawrence Tim Goodnough, MD, and Jerrold H. Levy, MD, FCCM Stanford University Medical Center, Stanford University, Stanford, California; and Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina
P
harmacologic agents are routinely used to modulate the coagulation system, a strategy that is an important component of patient blood management [1]. 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 [2]. The role of antifibrinolytic therapy in trauma emerged from earlier studies in cardiac and other surgical patients [3]. 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) [4]. 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 In this issue of The Annals of Thoracic Surgery, Alfirevic and colleagues [5] 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 Address correspondence to Dr Goodnough, 300 Pasteur Dr, Rm H-1402, 5626, Stanford, CA 94305-5626; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
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 [6] 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 [7]. 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 [8]. 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 placebocontrolled 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 [9]. 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
Dr Levy discloses a financial relationship with CSL Behring.
Ann Thorac Surg 2014;98:393–5 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.06.007
394
EDITORIAL GOODNOUGH AND LEVY OFF-LABEL USE OF rFVIIa
Fig 1. Estimated annual in-hospital cases of rFVIIa use for hemophilia and off-label indications. Cases signify the number of hospitalizations during which rFVIIa was used. The graph depicts all cases for each year. The width of each segment represents the number of cases for each category as indicated by differential shading. (CV ¼ cardiovascular; hemophilia ¼ hemophilia A and B; ICH ¼ nontraumatic intracranial hemorrhage; trauma ¼ body and brain trauma.)
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 [9]. We and others have followed the off-label use of rFVIIa based on this report and other published experience [10,11]. As the authors suggest, additional data from placebocontrolled 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) [12]. 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 [13,14]. Further prospective clinical studies are needed for these patients who are at high risk for refractory blood loss and may benefit from novel
Ann Thorac Surg 2014;98:393–5
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 [12]. 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 [15]. 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 [16], this risk may be dwarfed by uncontrolled hemorrhage that is commonly fatal.
References 1. Goodnough LT, Shander A. Current status of pharmacologic therapies in patient blood management. Anesth Analg 2013;116:15–34. 2. CRASH-2 collaborators1 Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377: 1096–101. 3. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet 2010;376:3–4. 4. Logan AC, Yank V, Stafford RS. Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records. Ann Intern Med 2011;154:516–22. 5. Alfirevic 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: 618–24. 6. Simpson 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:CD005011. 7. Lin Y, Moltzan CJ, Anderson DR. The evidence for the use of recombinant factor VIIa in massive bleeding: revision of the transfusion policy framework. Transfus Med 2012;22: 383–94. 8. Ferraris VA, Brown JR, Despotis GJ, 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;91:944–82. 9. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebocontrolled trial in the setting of bleeding after cardiac surgery. Circulation 2009;120:21–7. 10. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion 2004;44:1325–31. 11. Sheikh AY, Hill CC, Goodnough LT, Leung LL, Fischbein MP. Open aortic valve replacement in a patient
Ann Thorac Surg 2014;98:393–5
with Glanzmann’s thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion 2014;54:300–5. 12. Karkouti K, Levy JH. Recombinant activated factor VII: the controversial conundrum regarding its off-label use. Anesth Analg 2011;113:711–2. 13. Mazzeffi M, Szlam F, Jakubowski JA, Tanaka KA, Sugidachi A, Levy JH. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel. Thromb Res 2013;132:106–11.
EDITORIAL
GOODNOUGH AND LEVY OFF-LABEL USE OF RFVIIA
395
14. Szlam F, Tanaka KA, Rumph B, Bolliger D, Levy JH. In vitro effects of recombinant activated factor VIIa (NovoSeven) on clopidogrel-induced platelet inhibition. Thromb Haemost 2009;103:863–5. 15. Karkouti K, Beattie WS, Wijeysundera DN, et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005;45:26–34. 16. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791–800.
Off-Label Use of Recombinant Human Factor VIIa Lawrence Tim Goodnough, MD, and Jerrold H. Levy, MD, FCCM Stanford University Medical Center, Stanford University, Stanford, California; and Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina
P
harmacologic agents are routinely used to modulate the coagulation system, a strategy that is an important component of patient blood management [1]. 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 [2]. The role of antifibrinolytic therapy in trauma emerged from earlier studies in cardiac and other surgical patients [3]. 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) [4]. 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 In this issue of The Annals of Thoracic Surgery, Alfirevic and colleagues [5] 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 Address correspondence to Dr Goodnough, 300 Pasteur Dr, Rm H-1402, 5626, Stanford, CA 94305-5626; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
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 [6] 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 [7]. 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 [8]. 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 placebocontrolled 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 [9]. 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
Dr Levy discloses a financial relationship with CSL Behring.
Ann Thorac Surg 2014;98:393–5 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.06.007
394
EDITORIAL GOODNOUGH AND LEVY OFF-LABEL USE OF rFVIIa
Fig 1. Estimated annual in-hospital cases of rFVIIa use for hemophilia and off-label indications. Cases signify the number of hospitalizations during which rFVIIa was used. The graph depicts all cases for each year. The width of each segment represents the number of cases for each category as indicated by differential shading. (CV ¼ cardiovascular; hemophilia ¼ hemophilia A and B; ICH ¼ nontraumatic intracranial hemorrhage; trauma ¼ body and brain trauma.)
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 [9]. We and others have followed the off-label use of rFVIIa based on this report and other published experience [10,11]. As the authors suggest, additional data from placebocontrolled 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) [12]. 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 [13,14]. Further prospective clinical studies are needed for these patients who are at high risk for refractory blood loss and may benefit from novel
Ann Thorac Surg 2014;98:393–5
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 [12]. 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 [15]. 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 [16], this risk may be dwarfed by uncontrolled hemorrhage that is commonly fatal.
References 1. Goodnough LT, Shander A. Current status of pharmacologic therapies in patient blood management. Anesth Analg 2013;116:15–34. 2. CRASH-2 collaborators1 Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377: 1096–101. 3. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet 2010;376:3–4. 4. Logan AC, Yank V, Stafford RS. Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records. Ann Intern Med 2011;154:516–22. 5. Alfirevic 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: 618–24. 6. Simpson 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:CD005011. 7. Lin Y, Moltzan CJ, Anderson DR. The evidence for the use of recombinant factor VIIa in massive bleeding: revision of the transfusion policy framework. Transfus Med 2012;22: 383–94. 8. Ferraris VA, Brown JR, Despotis GJ, 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;91:944–82. 9. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebocontrolled trial in the setting of bleeding after cardiac surgery. Circulation 2009;120:21–7. 10. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion 2004;44:1325–31. 11. Sheikh AY, Hill CC, Goodnough LT, Leung LL, Fischbein MP. Open aortic valve replacement in a patient
Ann Thorac Surg 2014;98:393–5
with Glanzmann’s thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion 2014;54:300–5. 12. Karkouti K, Levy JH. Recombinant activated factor VII: the controversial conundrum regarding its off-label use. Anesth Analg 2011;113:711–2. 13. Mazzeffi M, Szlam F, Jakubowski JA, Tanaka KA, Sugidachi A, Levy JH. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel. Thromb Res 2013;132:106–11.
EDITORIAL
GOODNOUGH AND LEVY OFF-LABEL USE OF RFVIIA
395
14. Szlam F, Tanaka KA, Rumph B, Bolliger D, Levy JH. In vitro effects of recombinant activated factor VIIa (NovoSeven) on clopidogrel-induced platelet inhibition. Thromb Haemost 2009;103:863–5. 15. Karkouti K, Beattie WS, Wijeysundera DN, et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005;45:26–34. 16. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791–800.