Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation

Abstract

Summary. Background: Bleeding is a common complication following hematopoietic stem cell transplantation (HSCT) and standard hemostatic treatment is often ineffective. We conducted a multicentre, randomized trial of the efficacy and safety of activated recombinant factor VII (rFVIIa, NovoSeven Ò ) in the treatment of bleeding following HSCT. Methods: 100 patients with moderate or severe bleeding (52 gastrointestinal; 26 hemorrhagic cystitis; seven pulmonary; one cerebral; 14 other) were included from days +2 to +180 post-transplant (97 allogeneic; three autologous) to receive seven doses of rFVIIa (40, 80 or 160 lg kg )1) or placebo every 6 h. The primary efficacy endpoint was the change in bleeding score between the first administration and 38 h. Results: No significant effect of increasing rFVIIa dose was observed on the primary endpoint. A post hoc analysis comparing each rFVIIa dose with placebo showed that 80 lg kg )1 rFVIIa improved the bleeding score at the 38 h time point (81% vs. 57%, P ¼ 0.021). This effect was not seen at 160 lg kg )1. There were no differences in transfusion requirements across dose groups. There was no trend in the type or number of severe adverse events observed. Six thromboembolic events were observed in the active treatment groups: three during, and three following the 96-h observation period. Conclusions: Despite no overall effect of rFVIIa treatment on primary endpoint, post hoc analysis showed an improvement in the control of bleeding for 80 lg kg )1 rFVIIa vs. standard hemostatic treatment. The heterogeneity of the population may have contributed to the lack of an increasing effect with increased dose. Further trials should focus upon identifying the patient populations that may benefit from treatment with rFVIIa.

Use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without hemophilia: a systematic review and meta-analysis

“…[20][21][22][23]27 Twelve RCTs were of the therapeutic use of recombinant factor VIIa, with sample sizes ranging from 28 to 400 patients ( Table 2). The clinical settings included trauma, 14 cirrhosis with upper gastrointestinal bleeding, 29,30 bleeding after cardiac surgery, 31 dengue hemorrhagic fever, 32 bleeding after hemato poietic stem-cell transplant, 33 spontaneous intracranial hemorrhage 3,34−36 and traumatic intracranial hemorrhage. 37 Dosing regimens varied from a single dose of 5 µg/kg 36 to multiple doses totalling 1120 µg/kg.…”

“…37 Dosing regimens varied from a single dose of 5 µg/kg 36 to multiple doses totalling 1120 µg/kg. 33 The primary outcomes included control of bleeding, 29,30,32,33,35 transfusion requirements, 14 adverse events 31,34,36,37 and, in one study of intracranial hemorrhage, a clinical com-bined outcome of severe disability or death. 3 Common exclusion criteria were history of clotting and hemorrhagic dia thesis.…”

The role of recombinant factor VIIa in on-pump cardiac surgery: Proceedings of the Canadian Consensus Conference

“…The routine use of rFVIIa in bleeding patients has been assessed by RCTs in trauma (n = 301), 24 gastrointestinal (n = 245), 25 and post-transplant (n = 100) 26 bleeding scenarios. Although there are several case reports of its successful use in other clinical scenarios, these had limited influence on the panel's recommendations.…”

Challenges in the Therapeutic Use of a “So-Called” Universal Hemostatic Agent: Recombinant Factor VIIa

“…Another RCT of rFVIIa in a non-hemophilia/non-FVII deficient cohort was reported recently by Pihusch et al 30 In this trial 100 patients who had undergone a hematopoetic stem cell transplantation (HSCT) with moderate or severe bleedings were randomized to receive either 7 doses of rFVIIa at 40, 80 or 160 µg/kg per dose) or placebo every 6 hours. The primary efficacy endpoint was the change in a pre-established bleeding score between first administration and hour 38.…”