Commentary: recombinant activated factor VII: the controversial conundrum regarding its off-label use.

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. 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. 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, 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. In this context, what then can we learn from the phase I study published in this issue of the Journal? Surprisingly, a lot! Skolnick et al. reported a randomized, placebocontrolled 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, 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. 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, which is not surprising because agents that contain factors II, VII, IX, and X are more appropriate for reversing the effects of warfarin. 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. 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 thrombinactivated platelet surfaces, thereby increasing the activation of platelets, thrombin-activatable fibrinolysis inhibitor, and factor XIII. 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 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.