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Recombinant Activated Factor VII: The Controversial Conundrum Regarding Its Off-Label Use

Karkouti, Keyvan MD, MSc, FRCPC*; Levy, Jerrold H. MD, FAHA

doi: 10.1213/ANE.0b013e318228c6a9
Cardiovascular Anesthesiology: Commentary
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Published ahead of print July 25, 2011 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology and Health Policy, Management, and Evaluation, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; and Department of Anesthesiology, Emory University School of Medicine, Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia.

Funding: Funded by the Department of Anesthesiology, Toronto General Hospital, University of Toronto, and the Emory University School of Medicine.

Recuse Note: Jerrold H. Levy is section Editor of Hemostasis and Transfusion Medicine for the Journal. This manuscript was handled by Steve Shafer, Editor-in-Chief, and Dr. Levy was not involved in any way with the editorial process or decision.

Conflict of Interest: See Disclosures at the end of the article.

Address correspondence to Keyvan Karkouti, MD, Toronto General Hospital, 200 Elizabeth St., 3EN-402, Toronto, Ontario, Canada M5G 2C4. Address e-mail to keyvan.karkouti@uhn.on.ca.

Accepted June 7, 2011

Published ahead of print July 25, 2011

Recombinant factor VIIa (rFVIIa; NovoSeven®, Novo Nordisk A/S, Bagsværd, Denmark) is a widely used recombinant protein currently licensed for treating bleeding episodes or preventing bleeding in surgical interventions or invasive procedures in patients with hemophilia A or B who have antibody inhibitors to factors VIII or IX or in patients with congenital factor VII deficiency. Since its original approval, rFVIIa has also been extensively reported and evaluated in a number of off-label uses. Over recent years, the off-label use of rFVIIa has turned out to be an increasingly controversial issue. Initially, rFVIIa was thought to potentially represent a “universal hemostatic agent” without serious safety issues.1 Controversy arose after recent studies demonstrated that its efficacy varies depending on the clinical setting and that it may increase the risk of thromboembolic complications in some clinical settings.2,3 Adding to the controversy was the observation that clinicians are increasingly using the drug off-label to treat life-threatening refractory bleeding after major surgery or trauma,4 a practice that has not been studied by randomized controlled trials and has recently been criticized in an editorial as being unhelpful, dangerous, and costly.5

In this context, what then can we learn from the phase I study published in this issue of the Journal?6 Surprisingly, a lot! Skolnick et al. reported a randomized, placebo-controlled study that assessed the effect of low-dose rFVIIa on blood loss (using a punch biopsy-induced bleeding model) in 40 healthy male volunteers who were treated with, and responded to, oral clopidogrel (300 mg loading, followed by 75 mg for 2 additional days). Importantly, to obtain 40 responders to clopidogrel (defined liberally as a >30% platelet inhibition as measured by VerifyNow® [Accumetrics, San Diego, CA] after 3 days of therapy), the investigators had to treat 104 patients, which means that the nonresponse rate was 56%. This illustrates the wide variability in responsiveness to clopidogrel that has often been reported,7 and highlights the need for individualized transfusion management when patients who are on clopidogrel therapy present for urgent surgery. More specifically, it clearly illustrates that the decision to preemptively transfuse platelets to patients receiving clopidogrel therapy on the basis of the expectation of excessive blood loss is inappropriate, because many of them may not have excessive blood loss owing to variability of its effect.

In the 37 clopidogrel responders who were evaluated, 10 and 20 mcg/kg of rFVIIa (n = 6 and 12, respectively) significantly improved ex vivo measures of whole blood clot dynamics, as measured by thromboelastography performed about 3 hours after administration of rFVIIa. This, by itself, does not necessarily translate into clinical benefit, because the authors illustrated this in a previous study that used the same human bleeding model to assess the effects of rFVIIa in the setting of warfarin therapy.8 In that study, despite causing robust improvements in ex vivo measures of clot dynamics, rFVIIa had no effect on blood loss or bleeding duration in a human model of reversing warfarin therapy,8 which is not surprising because agents that contain factors II, VII, IX, and X are more appropriate for reversing the effects of warfarin.9,10 In the current trial, however, subjects who received 10 and 20 mcg/kg of rFVIIa had an approximately 50% reduction in blood loss and 20% reduction in bleeding duration in comparison with those who received placebo (although the difference in bleeding duration did not reach the threshold of statistical significance). These clinical data support other data suggesting that rFVIIa may be effective for reversing thienopyridine-induced platelet dysfunction.11

The differing efficacy results of these 2 early-stage volunteer studies are emblematic of what numerous clinical and nonclinical trials have clearly illustrated in the last decade, which is that rFVIIa is not a universal hemostatic agent. Rather, it is a drug that seems to improve clot formation by enhancing the rate of thrombin generation on thrombin-activated platelet surfaces, thereby increasing the activation of platelets, thrombin-activatable fibrinolysis inhibitor, and factor XIII.12 Thus, rather than being a universal hemostatic agent, rFVIIa is a potent but specific prohemostatic agent that requires the presence of adequate amounts of hemostatic substrates to be effective. In other words, it is a drug that could potentially be considered to be a “clot-booster.”

Regarding rFVIIa as a clot booster rather than a universal hemostatic agent has important practical implications for the clinician. First, it highlights its potential safety risks. Just as we would not consider using a fibrinolytic agent or clot buster without considering its risk for bleeding complications, we should not consider using a potent prohemostatic clot booster without considering its risk for thromboembolic complications, which may outweigh its benefits in certain scenarios. Second, it highlights the fact that rFVIIa is not the correct choice for all bleeding problems. In some scenarios, such as the massively bleeding patient whose coagulation proteins have been depleted, it will likely be ineffective as a sole therapy, and in other scenarios, such as warfarin reversal, it will likely not be the best treatment option.

Considering rFVIIa as a prohemostatic clot booster may also help explain the discordance between the increasing off-label use of rFVIIa 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.2,9 When presented with a patient who continues to bleed despite administration of all available therapies, clinicians have only 2 choices: they can keep administering the standard interventions that have failed to work in that patient, or they can administer a potent clot-booster like rFVIIa. We believe that in the setting of refractory blood loss, clinicians are justified in choosing the latter course of action for several reasons. First, it is clinically evident that patients with massive refractory bleeding will have dismal outcomes unless the blood loss is controlled in a timely manner.13 Second, persisting with standard interventions will likely not achieve this goal and will unnecessarily expose patients to the risks of these interventions. Third, the efficacy and safety data from most randomized trials are not applicable to this scenario because they did not study patients with refractory blood loss. Fourth, even if the safety data from randomized trials do apply, which indicate that rFVIIa doubles the risk of thrombotic complications,3 this risk is likely dwarfed by the risk of allowing blood loss to continue unabated. Fifth, there is an expanding body of observational data,14 and some randomized trial data in bleeding patients,15 that suggest that rFVIIa is an effective therapy for refractory blood loss. Sixth and perhaps most important, this is a scenario for which additional applicable data from placebo-controlled randomized trials will not be forthcoming in the foreseeable future, primarily because of feasibility issues (e.g., 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 by Novo Nordisk will be for licensed indications.6

Does this mean that the controversy surrounding the off-label use of rFVIIa is unwarranted? Probably not, for it is an expensive drug with the potential for serious adverse responses that is increasingly being used off-label for indications for which its risk–benefit profile has not been fully elucidated. Nevertheless, we believe that blanket criticisms of the off-label use of this drug are at best unhelpful, and at worst harmful. At the same time, it would also be harmful to use this drug outside of approved indications without first fully considering its risk–benefit profile in the specific setting where its use is being considered. In this regard, clinicians need to carefully scrutinize data from randomized trials for applicability and data from observational studies for selection bias (for or against the drug). It would be most harmful if we resign ourselves to the current state of knowledge about this drug specifically, and refractory blood loss in general. New, potent, and irreversible antiplatelet agents (e.g., clopidogrel, prasugrel) and anticoagulant agents (e.g., dabigatran) are being introduced into clinical practice, which will likely increase the burden of refractory blood loss. We believe, therefore, that clinical studies (randomized where possible, well-designed observational where not) for patients who are at high risk for refractory blood loss and may benefit from novel pro-hemostatic therapies such as rFVIIa are urgently needed.

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DISCLOSURES

Name: Keyvan Karkouti, MD, MSc, FRCPC.

Contribution: Wrote first draft of manuscript and added additional information and references.

Conflicts of Interest: Serves on a steering committee for Novo Nordisk regarding recombinant factor XIII; received funding from Novo Nordisk for a rFVIIa registry.

Name: Jerrold H. Levy, MD, FAHA.

Contribution: Reviewed and revised manuscript and oversaw ongoing revisions and corrections.

Conflict of Interest: Serves on a steering committee for Novo Nordisk regarding recombinant factor XIII.

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© 2011 International Anesthesia Research Society