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Coagulation Disorders


Table 1: Randomised Clinical Trials Concerning Recombinant Activated Factor VII in Haemophilia Patients with Inhibitors


Study Type


Shapiro et al., Double-blind 199811


RCT


Lusher et al., Double-blind 19988


RCT


Santagostino Multicentre et al., 200612


open-label


Kavakli et al., Multicentre 200613


Astermark et al., 200714 Intervention


rFVIIa 35 versus 90µg/kg prior to incision, then every 2 hours or as needed for 48 hours, then every 2–6 hours for 3 days, thereafter 90µg/kg as needed


rFVIIa 35 versus 70µg/kg to treat joint, muscle and mucocutaneous bleedings rFVIIa 270 versus 90µg/kg within 6 hours of joint bleed every 3 hours.


Treated (n) Response to Treatment 29


Thrombotic AE


Treatment successful: low dose 67% versus 1 in the high dose 93%, being significant from day 3 35µg/kg group post-operatively; p<0.05


66 18


cross-over RCT If not haemostasis at 9 hours continue 90µg/kg up to 24 hours, then other options rFVIIa 270µg/kg + 0 + 0 at 3-hour intervals 22 versus 3x90µg/kg at 3-hour intervals at


double-blind


cross-over RCT first and second joint bleeding or vice versa Multicentre open-label


1 dose FEIBA (75–100IU/kg) versus 2 doses rFVIIa 90–120µg/kg


cross-over RCT


Konkle et al., Double-blind 200715


rFVIIa 270 versus 90µg/kg


cross-over RCT daily prophylaxis for 3 months compared with 3 months pre- and post-prophylactic period


Pruthi et al., Open-label 200716


Pre-operative bolus 90µg/kg and then BI multicentre RCT every 2 hours during surgery to POD 5 and


then every 4 hours to POD 10 versus CI 50µg/kg/hour to POD 5 and then 25µg/kg/hour to POD 10


Young et al., Multicentre 200817


double-blind cross-over RCT


270µg/kg + 0 + 0 every 3 hours versus 3x90µg/kg versus 75IU/kg FEIBA at time 0


27


Rescue medication needed within 9 hours was 8.3% (rFVIIa 270µg/kg), 9.3% (3x90µg/kg)


and 36.4% (FEIBA), respectively. rFVIIa 270 and 3x90µg/kg versus FEIBA; p=0.032 and p=0.069, respectively. No difference between rFVIIa dose groups


AE = adverse event; BI = bolus infusion; CI = continuous infusion; FEIBA = factor eight inhibitor bypassing agent; NS = not significant; POD = post-operative day; RCT = randomised controlled trial; rFVIIa = recombinant activated factor VII.


Results of the Studies


Eight RCTs involving 256 haemophilia patients with inhibitors receiving rFVIIa were identified (see Table 1). Shapiro et al.11


performed a RCT


comparing rFVIIa (3,590 versus 90µg/kg) during and after elective surgery. Patients received rFVIIa immediately prior to incision: intra- operatively as needed, every two hours for the first 48 hours and every two to six hours for the following three days. Intraoperative haemostasis was achieved in 28 out of 29 patients. All high-dose patients and 12 out of 15 low-dose patients had satisfactory haemostasis during the first 48 hours. One patient, who had received the 35µg/kg dose, developed thrombosis of the right internal jugular vein after central venous catheter placement. A statistically significant difference was reported in efficacy from days three to five post-operatively in favour of the high-dose group compared with the low-dose group.


Lusher et al. investigated the effect of rFVIIa 35 versus 70µg/kg on haemostatic efficacy in patients with and without inhibitors having joint, muscle and mucocutaneous bleeds.8


This RCT demonstrated no


significant difference between groups. Santagostino et al.12


reported on a multicentre, randomised, open-label cross-over trial comparing the efficacy and safety of standard (90µg/kg every three hours as needed) and high-dose (single dose of 270µg/kg) rFVIIa for home treatment of haemarthroses. Eighteen haemophiliacs


72 A similar study was performed by Kavakli et al.13 Study compared one


high dose of rFVIIa + two placebo doses with 3 medium doses of rFVIIa. In this multicentre RCT, patients were randomised to treatment of a first joint bleeding episode with one 270µg/kg rFVIIa dose followed by two doses of placebo at three-hourly intervals. Treatment of a second joint bleed was with three single doses of 90µg/kg rFVIIa at three-hourly intervals. The results showed a similar efficacy for both regimens.


Astermark and colleagues14 compared one dose of FEIBA (target dose,


85IU/kg) or two doses of rFVIIa (target dose, 105µg/kg x two), with the second dose of rFVIIa administered two hours after the first dose. The haemostatic effect of the treatment was evaluated by the patients up to 48 hours after administration. No significant differences were identified between groups. Efficacy at six hours – the primary outcome measured – was 80.9% in FEIBA patients versus 78.7% in the rFVIIa group (p=0.059).


conducted a RCT using rFVIIa for secondary prophylaxis in inhibitor patients. Twenty-two patients were randomised 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270µg/kg for three months. Bleeding frequency was reduced by 45 and 59% during


Konkle et al.15 EUROPEAN ONCOLOGY & HAEMATOLOGY


with inhibitors were included and similar success rates for standard- and high-dose regimens were reported.


None 24 22


Reduced bleeding frequency by 45% (90µg/kg) and 59% (270µg/kg), both p<0.001. No difference between dose groups


Haemostatic efficacy was 73% in BI versus 75% in CI; p=NS


None 48


Treatment rated excellent in 61% (35µg/kg None group) versus 57% (70µg/kg group); p=NS Haemostasis at 9 hours 25% (high dose) versus 31% low dose; p=NS. Number of boluses needed in the high-dose (n=1)


None


versus standard-dose (n=3) groups; p=0.0001 65% (270µg/kg) versus 70% (3 x 90µg/kg) achieved haemostasis; p=NS


FEIBA (80.9%) and rFVIIa (78.7%) exhibit similar effects on joint bleeds; p=0.059


None None


1 in the BI group


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