Hemostatic treatment with recombinant activated factor vIIa (rFVIIa) failed to reduce death or disability in a phase 3 trial of patients with intracerebral hemorrhage (ICH), according to results presented during the AAN 59th annual meeting.
Hemostatic treatment with recombinant activated factor vIIa (rFVIIa) failed to reduce death or disability in a phase 3 trial of patients with intracerebral hemorrhage (ICH), said Stephan Mayer, MD, associate professor of clinical neurology and neurosurgery, Columbia University, New York, New York. The results from the Factor VIIa for Acute Hemorrhagic Stroke Treatment (FAST) study were presented at the American Academy of Neurology 59th Annual Meeting. These results are in opposition to those of an earlier phase 2b trial that measured the same end points.
Currently, rFVIIa is FDA-approved as treatment for bleeding in patients with hemophilia who have antibodies to factor VIII or IX.
The FAST study was conducted in 160 centers in 26 countries and included 821 patients with ICH documented by computed tomography (CT) scan within 3 hours after symptom onset. Patients were randomly assigned to either rFVIIa 20 or 80 mcg/kg or placebo, administered within 1 hour after the baseline CT scan was performed.
The hemostatic benefit with rFVIIa did not translate into a clinical benefit. The primary study outcome was the proportion of patients who died or were severely disabled (score of 5 or 6 on the modified Rankin scale, which is used to assess global outcome after a stroke). There was no significant difference in this outcome among groups (24% of patients receiving placebo, 26% of those receiving rFVIIa 20 mcg/kg, and 29% of those receiving rFVIIa 80 mcg/kg).
Deep vein thrombosis or pulmonary embolism occurred in 6% of the placebo recipients compared with 5% of patients receiving rFVIIa 80 mcg/kg, a nonsignificant difference. "Recombinant FVIIa did cause an absolute 5% increase in arterial thromboembolic events, which were split evenly between minor troponin leaks and somewhat more disabling cerebral infarction as detected on follow-up brain imaging within 3 days of dosing. Most of these infarcts were asymptomatic but some had major neurologic deficits," Dr Mayer said.
The phase 2b study of rFVIIa had the same study design as the phase 3 study; however, those earlier phase 2b results demonstrated a significant decrease in hematoma volume among patients assigned to rFVIIa compared with those assigned to placebo. Although this phase 2b study was not designed to detect differences in clinical outcomes, the rate of mortality and severe disability (as defined by the modified Rankin scale) was also significantly lower in the patients randomized to rFVIIa.
According to Dr Mayer, several potential explanations could account for the discordant clinical findings in the FAST study and the earlier phase 2b trial, including a randomization imbalance that resulted in an excess of patients with ventricular bleeding being assigned to rFVIIa 80 mcg/kg versus those assigned to placebo (41% vs 29%, respectively). "Intraventricular hemorrhage is a well-established determinant of poor outcome after ICH," Dr Mayer said.
In addition, the proportion of patients with left ventricular hypertrophy was also greater for those randomized to rFVIIa compared with those randomized to placebo.
Furthermore, although the median scores on the Glasgow Coma Scale were similar in all 3 groups (14 in the placebo group compared with 13 in the rFVIIa groups), 6% of patients assigned to rFVIIa 80 mcg/kg were in a deep coma compared with 3% of patients assigned to placebo.
"These randomization imbalances indicated that sicker people were randomized to active treatment, which may have affected outcome," Dr Mayer said.
Ninety-day mortality rates among patients receiving placebo were 29% in the phase 2b trial compared with 19% in the FAST study. An excess number of deaths occurred between Day 15 and Day 90 among patients randomized to rFVIIa, and most of these deaths were related to medical comorbidities rather than neurologic problems.
Liberal inclusion criteria may have resulted in a significant number of patients who had little chance of benefiting from treatment being enrolled in the FAST study, according to Dr Mayer. "When trying to measure a drug's ability to minimize a brain lesion and promote recovery, you want people who are more resilient and have an easier time bouncing back up the Rankin scale," Dr Mayer said.
Dr Mayer said that future trials of rFVIIa should probably restrict enrollment to patients aged <70 years who have active bleeding but a reasonable hematoma volume, and the time window for treatment should be narrowed to <3 hours from symptom onset.