Science Selections March 2004

Introduction We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma. Methods Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate. Results Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIatreated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00). Conclusion Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy. Page 1 of 11 (page number not for citation purposes) aPTT = activated partial thromboplastin time; ARDS = acute respiratory distress syndrome; CI = confidence interval; FFP = fresh frozen plasma; ICU = intensive care unit; MOF = multiple organ failure; NNT = numbers needed to treat; PT = prothrombin time; RBC = red blood cell; RCT = randomized controlled trial; rFVIIa = recombinant activated factor VII; RRR = relative risk reductions; TBI = traumatic brain injury. Critical Care Vol 10 No 6 Rizoli et al. Introduction Trauma is the leading cause of mortality up to the fifth decade of life [1,2] and uncontrolled hemorrhage is responsible for approximately 40% of these fatalities [2-5]. Diffuse coagulopathy is one of the most challenging situations faced by physicians treating these patients and is associated with high morbidity and mortality. Coagulopathy is common, affecting as many as 25% to 36% of trauma victims, and may develop early after injury [6,7]. It results from factors such as dilution and consumption of coagulation factors and platelets, fibrinolysis, acidosis, and hypothermia. Although coagulopathy correlates with the severity of trauma, it is also an independent risk factor of mortality [7]. There is little agreement in the contemporary literature as to the precise definition of coagulopathy in trauma (Table 1) [6-11]. Because objective measurement of coagulopathy is often unattainable in the clinical setting, current guidelines recommend empirical replacement therapy for the coagulopathic patient with diffuse microvascular bleeding [8,12]. Current management involves replacing coagulation factors (fresh frozen plasma [FFP], platelets, and cryoprecipitate) and correcting acidosis and hypothermia, steps that often are insufficient to stop the bleeding and prevent death. Recombinant activated factor VII (rFVIIa) (NovoSeven®; Novo Nordisk A/S, Bagsværd, Denmark) is a hemostatic agent that acts at the site of injury to enhance thrombin generation, leading to a stable fibrin clot [13,14]. A growing number of case series and reports have described the safe and effective hemostatic properties of rFVIIa in trauma patients with uncontrolled hemorrhage refractory to conventional therapy [9,15]. These publications have described impressive results with the use of rFVIIa as a treatment option to control bleeding in highrisk, actively bleeding patients in various situations, including trauma [9,15,16], severe postpartum hemorrhage [17,18], and cardiac surgery [19-21]. Recently, our group published the first multi-center, international, randomized, placebo-controlled, double-blind study of rFVIIa in trauma and demonstrated that it is a safe and efficacious adjunctive therapy in controlling hemorrhage [22]. Considering that the majority of the patients in this study had evidence of being coagulopathic at the time of rFVIIa administration, we hypothesized that rFVIIa might have a particularly beneficial role in the treatment of diffuse coagulopathy that results from severe trauma. To test this hypothesis, we carried out a post-hoc analysis of a subgroup of patients from the randomized prospective trial, who based on the clinical requirement for replacement therapy were identified as having coagulopathy. Materials and methods The study protocol was approved by the ethics committee of each participating institution (see Appendix), and the trial was conducted according to Good Clinical Practice standards and the Helsinki Declaration. Written informed consent was obtained from all patients or, where applicable, from a legally authorized representative. Due to the emergency conditions and the possible absence of relatives at enrolment in the trial, ethics committees authorized waived informed consent. However, whenever a patient was included without written informed consent, such consent was promptly solicited from a legally authorized representative and subsequently from the patient.