FAST Trial Published: No Benefit of Factor VII in Treatment of ICH

Susan Jeffrey

May 16, 2008

May 16, 2008 — Disappointing phase 3 results failed to confirm promising phase 2b findings, showing that although hemostatic therapy with recombinant activated factor VII (rFVIIa) reduced hematoma growth in patients with acute intracerebral hemorrhage (ICH), it did not improve survival or functional outcomes.

"In summary, rFVIIa reduced hematoma growth but did not reduce the rate of death or severe disability after intracerebral hemorrhage," the researchers, with first author Stephan A. Mayer MD, from Columbia University College of Physicians and Surgeons, in New York, conclude. "Whether this hemostatic effect can translate into clinical benefit in a subgroup of patients at high risk for active bleeding, whether by treatment within an earlier time window or by demonstration of intrahematomal contrast extravasation after CT angiography, deserves further study."

The results, from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, are published in the May 15 issue of the New England Journal of Medicine. The findings were presented at the European Stroke Conference 2007, in Glasgow, Scotland, and reported by Medscape Neurology & Neurosurgery at that time. The FAST trial was supported by Novo Nordisk.

Most Devastating, Least Treatable

Intracerebral hemorrhage is the most devastating and least treatable form of stroke, the authors write. Given its prognostic significance, hematoma expansion is "an attractive therapeutic target," they note. Factor VIIa acts locally at sites of tissue and vascular wall disruption by binding to tissue factor, generating small amounts of thrombin sufficient to activate platelets, Dr. Mayer and colleagues explain. At pharmacologic doses, rFVIIa directly activates factor X on the surface of activated platelets, resulting in a thrombin burst and acceleration of coagulation.

"We previously found that rFVIIa reduced the growth of intracerebral hemorrhage when administered within 4 hours after the onset of symptoms," the authors write (Mayer SA et al. N Engl J Med 2005;352:777-785). Treatment also resulted in improved clinical and functional outcomes at 90 days in that phase 2b study.

The current phase 3 trial was meant to confirm those results. The researchers randomly assigned 841 patients with intracerebral hemorrhage to receive 1 of 2 doses of rFVIIa or placebo within 4 hours of the onset of stroke. Of these, 268 patients received placebo and 276 received 20 µg/kg and 297 received 80 µg/kg of rFVIIa.

The primary end point for the trial was poor outcome, defined as severe disability or death, measured by the modified Rankin scale 90 days after the stroke.

They found that the 80-µg/kg dose was associated with a significant reduction in growth of the volume of the hemorrhage. Despite this, though, the proportion of patients with poor clinical outcome did not differ between the groups.

FAST Trial Results by Treatment Group

End Point Placebo 20 µg/kg 80 µg/kg
Mean estimated increase in hemorrhage volume at 24 hours (%) 26 18 11a
Reduction in volume of ICH growth (mL [95% CI]) Reference 2.6 (-0.3 to 5.5) 3.8 (0.9 to 6.7)b
Proportion of patients with poor clinical outcome (%) 24 26 29

a. P < .001 vs placebo
b. P = .009 vs placebo

Mortality at 3 months was about 20% in all 3 groups, they note.

The overall frequency of thromboembolic serious adverse events was similar in the 3 groups, but arterial events were more common in the 80-µg/kg group (9% vs 4%; P = .04).

"In this study, rFVIIa given within 4 hours after the onset of symptoms of intracerebral hemorrhage significantly reduced growth of the hematoma but failed to improve survival or functional outcome at 90 days," the authors conclude. "This result contrasts with the clinical benefit demonstrated in our phase 2b trial, in which rFVIIa treatment produced a relative reduction in mortality of 38%."

Possible explanations for the discrepant findings include randomization imbalances, an increase in thromboembolic events with treatment, the inclusion of very elderly patients at high risk for nonneurologic causes of death, and substantially better outcomes in the placebo group in this trial vs the phase 2b trial, the authors speculate.

Future Research Directions

In an editorial accompanying the paper, Stanley Tuhrim, MD, from the Mount Sinai School of Medicine, in New York, discusses some of the lessons of these disappointing results. The results, for example, "emphasize 2 other principles that have emerged from other trials of stroke treatments: a single treatment approach may accomplish its physiological goal but may be insufficient to produce clinical benefit, and an intervention may be helpful to a well-defined subgroup but not to all those who have a particular disease," Dr. Tuhrim writes.

In this case, for example, the effects of advanced age, large volumes of intracerebral hemorrhage at baseline, and intraventricular blood may blunt the modest effect of limiting hematoma growth, he points out. "Conversely, treatment closer to the onset of symptoms, when enlargement is more likely to occur, may have a greater effect.

"In summary," he concludes, "although failing to show a clinical benefit, the trials of rFVIIa in the treatment of acute cerebral hemorrhage have demonstrated the ability of rFVIIa to limit hematoma growth while increasing the risk of arterial thrombosis only minimally, suggesting several other avenues for further investigation."

Other promising approaches to limiting hematoma growth or reducing hematoma volume are now under investigation, he notes. "Alone or in combination, these approaches may show a benefit. Proper selection of the patient group in which to apply these therapies may hold the key to these advances."

The study was supported by Novo Nordisk, Denmark. Dr. Mayer reports receiving research support from Novo Nordisk, receiving lecture fees and consulting fees from Astellas Pharma and PDL BioPharma, and receiving lecture fees from and holding stock options in Medivance. Disclosures for other authors appear in the paper. Dr. Tuhrim reports no potential conflict of interest relevant to this article.

N Engl J Med 2008:358:2127-2137 Abstract, 2174-2176. Abstract

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