This editorial was developed for AAN.com, which is publishing expert opinions on a variety of hot topics in neurology.
By J. Claude Hemphill III, MD, MAS (Department of Neurology, San Francisco General Hospital)
The results of the FAST (Factor Seven for Acute Hemorrhagic Stroke) trial were published in the May 15, 2008, issue of The New England Journal of Medicine (NEJM). FAST was an international, multicenter, randomized, double-blind, placebo-controlled, phase III trial of recombinant Factor VIIa (rFVIIa) in the treatment of spontaneous, nontraumatic intracerebral hemorrhage (ICH).
Overall, 841 patients with acute ICH diagnosed by CT scan within three hours of symptom onset were randomized to treatment with placebo or one of two doses of rFVIIa (20 µg/kg or 80 µg/kg) within one hour of completion of the CT.1 The hypothesis was that rFVIIa would limit hematoma expansion, which is now recognized as common early after acute ICH, and that this would lead to improved clinical outcome. A similar phase IIb study was published in 2005 in NEJM and had demonstrated both limitation of hematoma expansion and improved clinical outcome with rFVIIa.2
FAST once again demonstrated that rFVIIa decreases hematoma expansion, but there was no effect on mortality or functional outcome. There was an increase in thromboembolic events with rFVIIa treatment, principally subendocardial myocardial infarctions. As a consequence of this study, the study sponsor and maker of rFVIIa, Novo Nordisk, is not seeking FDA approval for rFVIIa in ICH treatment. What happened, and where does this leave ICH research?
The experiences with recent ICH trials have helped raise a number of key questions related to rFVIIa specifically, as well as ICH trial design in general, which are important to review.
Is there any reason to continue to study rFVIIa or other hemostatic agents for ICH?
Given the reproducible biological effect of rVIIa, and clear evidence from these and other studies that hematoma expansion worsens outcome after ICH, it is hard to dismiss the idea of hemostasis as a relevant intervention. Post-hoc analysis suggesting benefit to a "target population" for rFVIIa and new imaging methods of identifying ICH patients at particular risk of hematoma expansion (e.g., contrast CT "spot-sign") have already provided rational approaches to studying more narrow populations of patients that might be hypothesized to benefit from treatment. One size does not fit all.
Is hematoma expansion really a target for intervention in ICH and, if so, how does this affect trial design?
This is the crucial issue clarified by FAST. Certainly, hematoma expansion remains a target for study. But it remains to be seen whether hematoma expansion can be limited quickly and definitively enough to provide clinical outcome benefit. The modest absolute volumes of hematoma reduction in FAST (approximately 3.8 ml) might be insufficient to translate into meaningful clinical benefit.
Also, it should be obvious that "only patients who could benefit from limiting hematoma expansion will derive benefit." Coma, large hematoma and intraventricular hemorrhage volumes, and advanced aged are predictors of poor outcome after ICH, and patients with these characteristics may be less likely to respond to decreasing expansion of hematomas. No amount of hematoma expansion limitation is going to help a patient who was going to have a poor outcome anyway. These lessons are inherent aspects of all ICH hematoma expansion studies, regardless of the intervention being tested. Studies of blood pressure control, subgroup targeted rFVIIa, CT spot-sign directed treatment, warfarin-related ICH, or antiplatelet-related ICH should take heed.
What is the difference between a "surrogate endpoint" and "disease pathology" in acute stroke research?
Did FAST fail because rFVIIIa acted on a surrogate endpoint (hematoma expansion) that is not actually relevant to the disease? Probably not. Hematoma expansion is the disease and rFVIIa is a disease-modifying therapy. It is interesting to consider this question in the context of recent new interventions for acute ischemic stroke. Two clot-removal devices (the Merci® and Penumbra System™ retrievers) have been approved by the FDA because they are able to open occluded arteries. However, because the clinical studies using these devices were single-arm and lacked a control group, it is not known whether they actually improve patient outcome. In acute ischemic stroke, arterial occlusion could certainly be considered "the disease" and, at least for device approval, this was sufficient for FDA approval. Is the effect of rFVIIa on limiting hematoma expansion in the FAST trial different than the effect of the Merci and Penumbra retrievers opening occluded large arteries in acute ischemic stroke? FAST is an important reminder for all stroke investigations that "disease modifying" is really not enough. Our patients want to get better.
Experts may differ in their unpublished comments about this contentious issue, but here is my take. We know that in acute ICH, rFVIIa reliably decreases hematoma expansion, definitely increases thromboembolic complications and, in the broad group of patients studied in FAST, does not improve clinical outcome. While post-hoc analysis suggested benefit from rFVIIa in a "target population" of younger patients with smaller hematoma volumes and less intraventricular hemorrhage who were treated earlier, this has not been tested prospectively. I leave to the reader whether to consider off-label rFVIIa in patients who meet this "target population."
I wish I could write that FAST was positive and we now have a treatment for ICH. Even so, the study of ICH treatment has broken a barrier. This is a compelling time to be involved in ICH research. Let’s do it, and do it right.
Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785.
Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 2005;365:387-397.
Within the past 24 months, the author has received personal compensation as a consultant for Novo Nordisk, Astra Zeneca, and Medivance. He has also served on a scientific advisory board for Innercool Therapies and Ornim. In this period, the author served on the editorial board of Neurocritical Care. He has also served as an expert witness consultant regarding neurocritical care and stroke. Within the past five years, the author has received research support from NIH/NINDS and Novo Nordisk.