22 Sep 07

Safety of rFVIIa in hemodynamically unstable polytrauma patients with traumatic brain injury

Posted in rFVIIa, Trauma at 18:03 by Laci

By Yoram Kluger, Bruno Riou, Rolf Rossaint, Sandro B Rizoli, Kenneth David Boffard, Philip Iau Tsau Choong, Brian Warren and Michael Tillinger

Critical Care 2007, 11:R85

Trauma is a leading cause of mortality and morbidity, with traumatic brain injury (TBI) and uncontrolled hemorrhage responsible for the majority of these deaths. Recombinant activated factor VIIa (rFVIIa) is being investigated as an adjunctive hemostatic treatment for bleeding refractory to conventional replacement therapy in trauma patients. TBI is a common component of polytrauma injuries. However, the combination of TBI with polytrauma injuries is associated with specific risk factors and treatment modalities somewhat different from those of polytrauma without TBI. Although rFVIIa treatment may offer added potential benefit for patients with combined TBI and polytrauma, its safety in this population has not yet been assessed. We conducted a post hoc sub analysis of patients with TBI and severe blunt polytrauma enrolled into a prospective, international, double-blind, randomized, placebo-controlled study.

Methods
A post hoc analysis of study data was performed for 143 patients with severe blunt trauma enrolled in a prospective, randomized, placebo-controlled study, evaluating the safety and efficacy of intravenous rFVIIa (200 + 100 + 100 μg/kg) or placebo, to identify patients with a computed tomography (CT) diagnosis of TBI. The incidences of ventilator-free days, intensive care unit-free days, and thromboembolic, serious, and adverse events within the 30-day study period were assessed in this cohort.

Results
Thirty polytrauma patients (placebo, n = 13; rFVIIa, n = 17) were identified as having TBI on CT. No significant differences in rates of mortality (placebo, n = 6, 46%, 90% confidence interval (CI): 22% to 71%; rFVIIa, n = 5, 29%, 90% CI: 12% to 56%; P = 0.19), in median numbers of intensive care unit-free days (placebo = 0, rFVIIa = 3; P = 0.26) or ventilator-free days (placebo = 0, rFVIIa = 10; P = 0.19), or in rates of thromboembolic adverse events (placebo, 15%, 90% CI: 3% to 51%; rFVIIa, 0%, 90% CI: 0% to 53%; P = 0.18) or serious adverse events (placebo, 92%, 90% CI: 68% to 98%; rFVIIa, 82%, 90% CI: 60% to 92%; P = 0.61) were observed between treatment groups.

Conclusion
The use of a total dose of 400 (200 + 100 + 100) μg/kg rFVIIa in this group of hemodynamically unstable polytrauma patients with TBI was not associated with an increased risk of mortality or with thromboembolic or adverse events.

25 Aug 06

Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding

Posted in Bleeding, rFVIIa at 8:59 by Laci

By T Klitgaard, RT y Palacios, KD Boffard, PTC Iau, B Warren et al for the NovoSeven® Trauma Study Group

Critical Care 2006, 10:R104

Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown.

Methods
In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 µg.kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 µg.kg-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)).

Results
Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml.kg-1.h-1; central volume of distribution 89 (32% CV) ml.kg-1; inter-compartmental clearance 24 ml.kg-1.h-1; and peripheral compartment volume 31 ml.kg-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U.ml-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters.

Conclusion
A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.

Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding

Posted in Bleeding, rFVIIa at 8:42 by Laci

By J-L Vincent, R Rossaint, B Riou, Y Ozier, D Zideman and DR Spahn

Critical Care 2006, 10:R120  http://ccforum.com/content/10/4/R120

Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage.

Methods
A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A-E according to the strength of evidence available. Consensus was sought among the committee for each recommendation.

Results

A recommendation for use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E) and bleeding following cardiac surgery (grade D). rFVIIa could not be recommended for use: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child-Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child-Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team.

Conclusions
There is a rationale for using rFVIIa to treat massive bleeding in certain indications; however, only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.

06 Jun 06

Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: Two parallel randomized, placebo-controlled, double-blind clinical trials

Posted in Bleeding, rFVIIa, Trauma at 17:31 by Laci

By KD Boffard, B Riou, B Warren, PIT Choong, S Rizoli, et al

J Trauma 2005;59:8–18

Background
Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma.

Methods
Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 ug/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose.

Results
Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p=0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p=0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p=0.10) and massive transfusion (7% vs. 19%; p=0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups.

Conclusion
Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.

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