Trial results on the use of recombinant activated factor VII in acute intracerebral haemorrhage

Feb 24 2005

The New England Journal of Medicine (NEJM) today reports positive results from the recently completed clinical trial of recombinant activated factor VII (NovoSeven/rFVIIa) in intracerebral haemorrhage (ICH).

ICH is the deadliest, most disabling type of stroke. The current unmet medical need for a treatment of ICH is recognised by neurologists around the world as a serious medical emergency. The volume of bleeding into the brain is an important predictor of neurological and clinical outcomes after 30 days and it has been well documented that such bleeding continues over the early hours following symptom onset. As such early treatment should aim to reduce haematoma growth to improve clinical outcome.

The NEJM article, 'Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage', presents the results of the largest pharmacologic therapy trial conducted in ICH to date. The trial was designed to determine if a reduction in haematoma growth might be achieved by administration of the haemostatic agent rFVIIa and to evaluate whether limiting haemorrhage growth had significant impact on improving patient clinical outcomes.

The NEJM article reports encouraging results from the trial demonstrating that early administration of rFVIIa was associated with reduced haematoma growth and improved clinical outcome.

Dr Stephan Mayer, chairman of the Steering Committee and associate professor from the departments of Neurology and Neurosurgery, Columbia University College of Physicians and Surgeons, New York, says: "I was thinking maybe if we reduced bleeding, we could improve the lives of the patients a little, but what we found was better; we reduced bleeding and had significant reductions in poor outcome."

The results of the trial look promising for healthcare professionals who are searching for a treatment option for ICH.

Trial data:

The trial included 399 patients, all diagnosed by a CT scan within three hours of ICH onset. Patients were randomly assigned to receive placebo (N=96), 40 (N=108), 80 (N=92), or 160 (N=103) micro g/kg doses of rFVIIa within one hour of the baseline scan. The primary outcome measure was the percentage change in ICH volume at 24 hours after treatment. Clinical and neurological outcomes were assessed at 90 days after treatment.

Key findings included:

• Primary end point: Statistically significant reduction in haematoma growth
  • Compared to 29% growth in placebo-treated patients, ICH volume growth in the 40, 80, and 160 micro g/kg treatment groups was 16%, 14%, and 11% respectively (corresponding to a relative reduction of 45%, 52% and 62%)
• Secondary end points: Statistically significant improvement in neurological and clinical outcome
  • 69% of placebo-treated patients died or were severely disabled at 90 days after dosing (modified Rankin Scale (mRS) score 4-6), compared to 55%, 49%, and 54% of the rFVIIa-treated patients. Receiving rFVIIa more than doubled a patient's chances of improving one level on the mRS. These results were consistent with the results shown by other standard stroke scales. These outcomes scales include the outcome of adverse events.
  • This led to a 16% absolute reduction in the risk of death or severe disability at three months according to the mRS.
  • Mortality was 38% lower (statistically significant p=0.02) in the combined rFVIIa-treated groups compared to placebo.
• Safety end-points:
  • The overall frequency of fatal or disabling thromboembolic serious adverse events did not differ between the rFVIIa (2.0%) and the placebo (2.1%) groups. However, arterial thromboembolic serious adverse events occurred statistically significantly more frequently with rFVIIa treatment (5%) than with placebo (0%), manifesting in the form of myocardial ischemic events and cerebral infarction. The majority of patients recovered from these complications.

Overall, the trial results indicate that early administration of rFVIIa to patients with ICH may limit haematoma growth, reduce mortality and improve neurological and clinical outcomes without significantly raising the risk of fatal or disabling thromboembolic complications.