Recombinant activated Factor VII for acute intracerebral hemorrhage

N Engl J Med 2005,352:777-785

Introduction

Intracerebral hemorrhage is a devastating disorder with only 20% of victims regaining functional independence. The volume of the expanding hematoma is a critical determinant of mortality and functional outcome. The current study investigated whether the early administration of rFVIIa can reduce hematoma growth and improve outcome.

Study

The trial was a double blind, placebo controlled multicentre study in patients 18 years of age with a spontaneous intracerebral hemorrhage within three hours after the onset of symptoms. Exclusion criteria included GCS < 6, planned surgical evacuation, secondary hemorrhage, use of oral anticoagulants, thrombocytopenia or a history of coagulopathy, disseminated intravascular coagulation, sepsis, crush injury, pregnancy, pre-existing disability (modified Rankin score > 2) and symptomatic thrombotic or vaso-occlusive disease within 30 days. Patients were randomly assigned to receive a single intravenous dose of 40, 80, 160 g/kg rFVIIa or placebo. Treatment was given no later than 4 hours after the start of symptoms. Follow-up CT scanning was performed 24 and 72 hours after treatment. Clinical assessments were performed at enrollment, at the start of the study drug infusion, after 1 and 24 hours and on day 2, 3, 15 and 90 (modified Rankin scale, extended Glasgow-outcome scale, Barthel Index and NIHSS). Death and complete dependence were combined as a single poor outcome category. Safety assessment was an important part of the study. The primary outcome measure was the increase in volume of the intracerebral hemorrhage in the first 24 hours. All analyses were based on the intention-to-treat principle.

A total of 399 patients were enrolled. Baseline characteristics for the 4 study groups were similar. The mean time from onset to treatment was 167  ± 32 minutes. The mean percent increase in the volume of intracerebral hemorrhage was significantly lower in the group given 160  µg/kg rFVIIa than in the placebo group (p = 0.02). The effect was also significant when the three treatment groups were combined. There was a clear dose-response effect. The effect of rFVIIa was only evident when given within 3 hours after the start of symptoms. Mortality at 3 months was 29 percent in the placebo group and 18% in the combined treatment groups (p = 0.02). All four outcome scales showed a more favourable outcome for rFVIIa treated patients. Death and complete dependence were reduced from 69 percent in the placebo group to 53% in the combined treatment groups. This means that 6.2 (3.7 - 20) patients need to be treated with rFVIIa to prevent one unfavourable outcome. Unfortunately, concomitant treatment for the four treatment groups is not provided. There was a small increase in the number of serious thromboembolic events in the rFVIIa group (7 versus 2%, p = 0.12).

Discussion

The results of this study are impressive and clearly establish the efficacy of rFVIIa in a highly selected group of patients with spontaneous intracerebral hemorrhage. However, due to the long list of exclusion criteria, effectiveness in the real world should still be confirmed. Especially the increase in the number of serious thromboembolic events is worrisome and may reduce the overall benefit if applied in a more diverse group of patients. Future studies should also focus on the optimal dose and include a formal cost-effectiveness analysis. Until than, rFVIIa for intracerebral hemorrhage should only be given within the context of a rigorously controlled clinical trial.

M. van Iperen, Fellow Intensive Care
J.G. van der Hoeven, Internist-Intensivist