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Evidence Supporting the Use of Recombinant Activated Factor VII in Congenital Bleeding Disorders


prophylaxis with 90 and 270µg/kg rFVIIa, respectively (both p<0.0001). Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis compared with the pre-prophylaxis period.


Pruthi et al.16


investigated the efficacy of bolus infusion (BI) versus continuous infusion (CI) of rFVIIa in inhibitor patients undergoing major surgery. All patients received an initial bolus of 90µg/kg rFVIIa and were then randomly assigned to BI (n=12) or CI (n=12). The BI group received 90µg/kg rFVIIa every two hours during surgery through day five, then every four hours for days six to 10. The CI group received 50µg/kg/hour rFVIIa through day five, then 25mg/kg/hour for days six to 10. The haemostatic efficacy of rFVIIa was similar in the BI and CI arms (73 and 75%, respectively).


evaluated rFVIIa and FEIBA for controlling joint bleeds in a home treatment setting. Patients received each of three treatments in one of six possible sequences: 270µg/kg rFVIIa at hour 0 plus placebo at three and six hours, 90µg/kg rFVIIa at 0, three and six hours, and 75IU/kg FEIBA at 0 hours. Efficacy was assessed as the need for rescue treatment within nine hours of administration of the trial drugs. The percentage of rFVIIa 270µg/kg patients requiring additional haemostatics within nine hours was lower than for the FEIBA group (8 versus 36%, p=0.032).


Young et al.17


However, it should be noted that the three RCTs performed to date only involved 67 patients in total. This makes it difficult to exclude the possibility that a clinically significant difference between the treatment regimes may actually exist.


No RCT conducted in patients with Glanzmann’s thrombastenia, Bernard-Soulier syndrome or in patients with acquired FVII deficiency were identified.


Discussion


This article found eight randomised clinical studies evaluating the haemostatic efficacy of rFVIIa in patients with haemophilia A and B with inhibitors. These studies included a total of 256 patients, with the majority of studies enrolling <30 patients. This limits conclusions on the efficacy and safety of rFVIIa in these patients.


Haemostatic Efficacy


When comparing studies evaluating the haemostatic efficacy of rFVIIa in patients undergoing surgery, Shapiro et al.11


reported the effect of


rFVIIa at 35 and 90µg/kg, where the high-dose patients had 93% haemostatic efficacy versus 67% in the 35µg/kg dose group. The results were significantly different from day three post-operatively. This study concluded that 90µg/kg was appropriate for surgical interventions. This thinking was recently challenged by Obergfell et al.18


In terms of CI of rFVIIa versus BI doses, data indicate that CI at a dose of 50µg/kg/hour after a standard BI dose of rFVIIa results in acceptable haemostatic efficacy. These results suggest that it may be beneficial to consider adjunctive treatment with tranexamic acid, although a RCT is warranted.


When comparing the haemostatic efficacy of a standard dose (90µg/kg) of rFVIIa infused two14


or three times17 versus a single


dose of FEIBA at 75–100IU/kg, different results emerge. Astermark et al.14


reported similar haemostatic efficacy (81% for FEIBA versus 79% for rFVIIa); whereas Young et al.17


reported a successful response in


only 54% of the FEIBA-treated patients compared with 91–92% in the rFVIIa patients.


The difference in rFVIIa response between the two studies may, at least in part, be explained by different dosing schedules. The patients in the study by Young et al.17


intervals compared to only two doses in the Astermark study.14


received three doses at three-hourly With


an estimated half-life of approximately 120 minutes for rFVIIa, three doses would result in a higher peak thrombin generation, maintaining a high thrombin generation for a longer period of time, compared with only two doses.


who reviewed published data on elective orthopaedic surgical procedures in haemophilia patients with inhibitors. These authors found that increasing the dose or administering an extra dose, i.e. related to the inadequate amount of rFVIIa, could resolve most bleeding complications.


Therefore, they concluded that the optimal rFVIIa bolus dose for orthopaedic surgery might be higher than 90µg/kg. A minimum initial dose of 120µg/kg, followed every two hours by a similar dose or a 90µg/kg dosing regimen for BI was suggested.18


Four RCTs have been reported in the home-treatment setting. The percentage of patients reporting a successful response to rFVIIa treatment varied from 31 to 66%, which is well below the 80–90% efficacy rating often reported in the literature from non-randomised trials.7,19


EUROPEAN ONCOLOGY & HAEMATOLOGY


However, the different haemostatic responses to FEIBA reported in the two studies reviewed is less obvious.14,17


When comparing efficacy


between rFVIIa and FEIBA, it could be argued that since the standard recommended dose of FEIBA is 50–100IU/kg every four to six hours and that of rFVIIa is 90µg/kg every two to three hours until haemostasis is achieved, the dose in the FEIBA and rFVIIa arms were markedly unmatched. This is a strong argument because it is assumed that the treatment efficacy depends on the dose of FEIBA administered at each infusion.22


This was illustrated in a study of six haemophiliac patients with inhibitors experiencing 61 bleeds treated with FEIBA. There was definite cessation of bleeding in 93% of cases with a cumulative median dose of 205IU/kg per event.22


The reason for this discrepancy is unclear, since RCTs and


One study evaluated the effect of rFVIIa in two doses (90 versus 270µg/kg) for secondary prophylaxis. This study demonstrated that bleeding frequency was halved during the three months of


73


However, the higher haemostatic efficacy of rFVIIa reported from the non-randomised observational studies may be due to the fact that observational studies can include a wide spectrum of disease severity, with treatment tailored to the individual patient thereby introducing confounding by indication. Furthermore, the low number of subjects included in the RCTs8,12,13,17


observational studies in general are expected to yield similar efficacy.20,21


may also explain the


finding of broader, and hence less precise, efficacy ranges compared to the larger observational studies.7,19


No significant differences in haemostatic efficacy following rFVIIa treatment12,13,17


and/or need for rescue medication13,17 were found


between repeated standard dosing versus single high-dose rFVIIa administration in the RCTs reported here. Based on the evidence, high-dose rFVIIa (270µg/kg) was approved by the EMEA in 2007.


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