Michael Parr

Intensive care Unit, Liverpool Hospital, University of New South Wales

Recombinant FVIIa is approved for the treatment of bleeding episodes and prevention of bleeding during surgery in patients with haemophilia and inhibitors, in patients with FVII deficiency and in patients with acquired haemophilia. In addition, rFVIIa is registered in many regions for treatment of Glanzmann's thrombasthenia. Recombinant FVIIa has been on the market for more than a decade and the toxicology and pharmacology within the approved indications are widely understood.

Clinical and experimental data show that rFVIIa exerts its haemostatic effect locally at the site of injury via interactions with elements of the coagulation system. At pharmacological doses, rFVIIa increases the generation of thrombin on the surface of activated platelets at the site of injury to the vessel wall, promoting the formation of a tight, stable fibrin plug. This mechanism of action makes rFVIIa a potential candidate for treatment of bleeding in patients without pre-existing coagulation abnormalities. The original trauma case report from Kenetwas followed by numerous case series in diverse patient groups. There have now been 15 randomised controlled trials, 9 where rFVIIa was administered before any blood and 6 after the administration of blood in patients with intracerebral haemorrhage, trauma, traumatic brain injury, cardiac surgery, spinal surgery, prostate and burn surgery. Most of these trials have had disappointing results, notably including the phase 3 study on intracerebral haemorrhage that followed a promising phase 2 study. Several large trials are ongoing. Following a phase 2 study of rFVIIa in trauma by Boffard, Australian and New Zealand hospitals are among 93 hospitals world wide that are performing a phase 3, multi-centre, randomised, double-blind, placebo controlled trial to evaluate the efficacy and safety of rFVIIa in severely injured trauma patients with bleeding refractory to standard treatment (CONTROL study). The trial aims to recruit 1500 patients and currently >520 patients have been randomised.
Haemostasis Registries including one at Monash University in Australia have been established to collect data on 'off-label' use of rFVIIa. The registry contains data on usage in a variety of clinical situations and has recently reported initial data. These registries however are no substitute for good clinical trials.

Many questions remain including:
What is the real evidence of efficacy?
What is the potential for benefit?
How can patients who will benefit be identified?
What is the optimal dose?
What are the safety concerns?

The evidence is accumulating but rFVIIa is not superglue.

References:
Kenet G. Walden R. Eldad A. Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999;354:1879
Boffard KD et al. Recombinant Factor VIIa as Adjunctive Therapy for Bleeding Control in Severely Injured Trauma Patients: Two Parallel Randomized, Placebo-Controlled, Double-Blind Clinical Trials. J Trauma 2005;59:8-15.

Cameron P, Phillips L, Balogh Z, Joseph A, Pearce A, Parr M, Jankelowitz G. The use of recombinant activated factor VII in trauma patients: experience from the Australia and New Zealand haemostasis registry. Injury 2007;38:1030-1038.

Isbister J, Phillips L, Dunkley S, Janeklowitz G, McNeil J, Cameron P. Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register. Internal Medicine Journal 2008;38:156-165

Dunkley S, Phillips L, McCall P, Brereton J, Lindeman R, Jankelowitz G, Cameron P.Recombinant Activated Factor VII in cardiac surgery: experience from the Australian and New Zealand Haemostasis Register. Annals of Thoracic Surgery 2008;85:836-44.

O'Connell KA. Wood JJ. Wise RP. Lozier JN. Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa.JAMA 2006;295:293-8