UMEM Educational Pearls

Category: Critical Care Literature Update

Title: recombinant Factor VIIa for ICH

Keywords: intracerebral hemorrhage, recombinant factor VIIa (PubMed Search)

Posted: 7/6/2008 by Mike Winters, MD (Updated: 9/29/2023)
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Recent Articles from the Critical Care Literature

Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage.

Mayer SA, Brun NC, Begtrup MSc, Broderick J, Davis S, et al. NEJM 2008;358:2127-37.

Intracerebral hemorrhage (ICH) accounts for approximately 10% to 15% of all strokes, yet has the highest morbidity and mortality, with up to 40% of patients dying within 30 days. Aside from age, size, location, intraventricular extension, and GCS, hematoma expansion is an independent determinant of morbidity and mortality. Hematoma expansion is reported to occur in up to 70% of patients within the first several hours of the ICH. Recent research has focused on therapies to limit hematoma expansion. One such therapy is recombinant human activated Factor VII (rFVIIa). Excitement regarding this expensive drug came from a single phase 2 trial (Mayer SA, et al. NEJM 2005:352:777-85.) that demonstrated rFVIIa significantly reduced hematoma expansion and improved patient mortality.

The FAST trial (Factor Seven for Acute Hemorrhagic Stroke), was a manufacture sponsored, phase 3 trial performed by the same investigators to confirm the findings of their previous phase 2 study. The FAST trial was a multi-center, randomized, double-blind, placebo-controlled trial conducted at 122 sites in 22 countries. Patients had to be at least 18 years of age with a spontaneous ICH documented by CT within 3 hours of symptom onset. Important exclusion criteria included GCS < 5 at presentation, secondary ICH (trauma, AVM), current anticoagulant therapy, thrombocytopenia, DIC, previous disability from CVA, or a thromboembolic event < 30 days prior to symptom onset. The primary end-point was disability or death defined by a modified Rankin score of 5 or 6 at day 90. The modified Rankin score evaluates global disability and handicap and ranges from 0 to 6. A score of 5 indicates a patient who is bed-bound and incontinent, whereas a score of 6 indicates death.

Of 8,886 patients screened, 821 underwent randomization and received placebo, 20 mcg/kg of rFVIIa, or 80 mcg/kg of rFVIIa. Treatment had to start within 1 hour of the baseline CT and no more than 4 hours after the onset of symptoms. Patients then underwent a repeat CT at 24 hours and 72 hours to evaluate for hematoma expansion. Of note, the majority of the patients in this study were Caucasian males, older than 65 year of age who had deep gray matter ICHs.

As reported by the trial investigators, rFVIIa did reduce hematoma expansion at 24 hours compared to placebo. In the placebo arm, 26% of patients had hematoma growth, whereas only 11% of patients who received 80 mcg/kg of rFVIIa had hematoma expansion. In addition, the investigators report that the reduction in hematoma growth was even greater in those treated in less than 2 hours from onset of symptoms. However, when you look at the data for 72 hours, there was no significant difference in total hematoma volume or edema volume. More importantly, mortality at 90 days did not differ between placebo and the treatment groups. In fact, a higher percentage of patients who received 80 mcg/kg of rFVIIa had a worse outcome than compared with placebo. Furthermore, there was an absolute increase of 5% in the frequency of arterial thromboembolic serious events (MI, ischemia CVA) in the group receiving 80 mcg/kg of rFVIIa.

Take Home Point: This phase 3 trial failed to demonstrate improved 90 day mortality in patients with spontaneous ICH who received rFVIIa. Although hematoma expansion was reduced at 24 hours in the rFVIIa groups, total lesion volume and edema volume at 72 hours remained unchanged. Although rFVIIa has been used in a variety of clinical settings, the results of this study indicate that it does improve mortality in patients with spontaneous ICH. Given the expense of the drug and lack of benefit, this should not be a drug we are using in the ED to treat patients with spontaneous ICH.