Off-Label Use of Recombinant Factor VIIa in the Treatment of Major Haemorrhage Following Cardiothoracic Surgery: Experience in the North East of England

Background: Recombinant factor VIIa (rVIIa) is licensed for the prevention and treatment of bleeding episodes in patients with congenital haemophilia with inhibitors, acquired haemophilia and Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leucocyte antigen. It is also licensed for the prevention and treatment of bleeding in congenital factor VII deficiency. There has been much interest in the off-label use of rVIIa in the treatment of intractable haemorrhage but data remains limited on its safety and efficacy. In the North East of England, a regional protocol was developed to guide the use of rVIIa in major haemorrhage. Following correction of coagulopathy and optimal surgical management to achieve haemostasis, a dose of 90 mcg/kg rVIIa is recommended if bleeding continues (up to a maximum of 2 doses, the second dose given after an interval of 3 hours). Bilateral lower limb Doppler ultrasound is performed 7 days post treatment to monitor for thrombotic complications.

Aims: To assess the safety and efficacy of rVIIa in the treatment of major haemorrhage following cardiothoracic surgery.

Methods: Retrospective analysis of case records of all cardiothoracic patients receiving rVIIa for intractable haemorrhage in the North East of England between August 2001 and June 2007. Two tertiary referral cardiothoracic units exist in the region.

Results: Twenty-five patients in total received rVIIa. Median age: 41 years (range: 1 day-77 years). 36% (n=9) were below the age of 18 years. 80% male (n=20). Type of surgery: cardiac valve replacement 40% (n=10), cardiac transplant 20% (n=5), repair of cardiac defect in congenital heart disease 20% (n=5), lung transplant 8% (n=2), coronary artery bypass graft 8% (n=2), dissecting thoracic aortic aneurysm 4% (n=1). 76% (n=19) received the recommended dose, 12% (n=3) received higher doses (range: 120–300 mcg/kg) and 12% (n=3) received suboptimal doses (range: 9–60 mcg/kg). Two patients were given a second dose, one of whom had received a suboptimal dose initially. Median time to administration was 12.6 hours (range: 1–41 hours). A response was seen in 72% (n=18), defined as reduction or cessation of bleeding 1 hour after administration as assessed by the attending surgeon or anaesthetist. In those who had a response, there was a significant reduction in the number of red cell units transfused (median number of units transfused: pre rVIIa 9.5; post rVIIa 1.4; p<0.001). In the 7 patients who showed no response, the difference was less marked (median number of units transfused: pre rVIIa 11.7; post rVIIa 5; p=0.05). Of those who had a response, 67% (12/18) survived to discharge, 33% (6/18) died (none directly due to bleeding). Of those who had no response, 29% (2/7) survived to discharge, 71% (5/7) died (2 due to exsanguination). Arterial thrombosis occurred in 2 patients within 8 hours of rVIIa administration. However, both patients had identifiable pre-existing vascular risk factors. No venous thromboses were reported. 20% (n=5) had negative bilateral lower limb Doppler ultrasound. 32% (n=8) died within 7 days of receiving rVIIa, before scans could be performed (no deaths were due to thrombosis); 48% (n=12) had no documented scan results.

Conclusion: The majority of patients receiving rVIIa responded to treatment. Of those who responded, blood product usage was significantly reduced and the majority of patients survived. Thrombotic complications appear to be uncommon. This study suggests that rVIIa is both effective and safe when used to treat major haemorrhage in cardiothoracic patients. Randomised controlled trials are needed to confirm these results in this subgroup of patients.