Recombinant Activated Factor VIIa: Phase III Trial Fails to Show Clinical Benefit
Abstract & Commentary
By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College, Attending Neurologist, NewYork-Presbyterian Hospital. Dr. Segal reports no financial relationships relevant to this field of study. This article originally appeared in the July 2008 issue of Neurology Alert. It was edited by Michael Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Vice Chairman, Professor of Neurology, Weill Cornell Medical College; Chief of Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital, and Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College. Drs. Fink and Beal report no financial relationships relevant to this field of study.
Synopsis: Even though rFVIIa reduced hematoma growth, it did not reduce mortality in patients with ICH.
Source: Mayer SA, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127-2137.
Randomized studies of neuroprotective agents for ischemic stroke have resulted in a series of failures, as multiple agents, promising in animal models, have failed when applied to human subjects. By contrast, intracerebral hemorrhage (ICH) has been somewhat a "neglected stepsister" when compared to ischemic stroke; it has been studied minimally, despite its high morbidity and mortality. It was this backdrop that made the positive results of the Phase II trial of recombinant activated Factor VII (rFVIIa or Novo-Seven) so tantalizing. This procoagulant medication appeared to ameliorate the damage from ICH by limiting early hematoma growth. There might finally be a drug for stroke besides intravenous thrombolysis, if only for so-called "red stroke" rather than for a bland infarct.
rFVIIa is indicated for treatment of hemorrhage in hemophiliacs, and is a powerful pro-coagulant, acting at sites of tissue injury to promote platelet activation and generation of thrombin. While it was previously thought that ICH was a monophasic event, more recent evidence, using serial CT scans, indicates that hematomas undergo significant early expansion. In the initial Phase II study, it was shown that, at doses of 80 m, rFVIIa not only produced a significant decrease in hematoma growth compared to placebo but also, more importantly, produced a significant decrease in mortality.1
In the current Phase III study, Factor Seven for Acute Hemorrhagic Stroke (FAST), 841 patients were included and were randomized to rFVIIa 80 m/kg, 20 m/kg, or placebo. Nearly 9000 patients were screened to generate these 841, with the majority being excluded due to presentations beyond a required hyperacute four-hour time window. Baseline characteristics were comparable between the groups, though intraventricular hemorrhage (IVH) was more common in both drug treatment groups, most notably in the high-dose rFVIIa subjects.
rFVIIa did significantly reduce hematoma expansion, with volume growth being 18% and 11%, respectively, in the low- and high-dose rFVIIa groups compared to 26% in placebo patients (p < 0.001). There were 2.6 mL and 3.8 mL reductions in absolute hematoma volumes in the low and high rFVIIa treatment groups, compared with placebo; however, these reductions were more modest than in the Phase II trial, where there was a 4.5 mL reduction in the 80 m group. Most importantly, the groups did not differ in the primary study endpoint, with poor clinical outcomes in 24% of placebo patients compared with 26% among low-dose and 29% in high-dose rFVIIa treated patients. In fact, the overall trend favored placebo and an inverse dose-response relationship for rFVIIa. Furthermore, a 5% absolute increase in serious thromboembolic complications was seen in high-dose rFVIIa treated patients, including myocardial infarctions. In a subgroup analysis, among subjects younger than age 70, with baseline ICH volumes of less than 60 mL, and who were treated within 2.5 hours of symptom onset, rFVIIa did have a favorable effect, with an odds ratio for a poor outcome of 0.28 (p = 0.03).
As Mayer et al note, the results may have been influenced by imbalances in randomization, since there was a significantly larger proportion of intraventricular hemorrhage (IVH) in the high-dose rFVIIa group. IVH is known to contribute to poor outcomes in ICH patients. Interestingly, in the Phase II trial, placebo patients had more IVH at baseline and more IVH growth, suggesting that rFVIIa had a beneficial effect on IVH, in addition to parenchymal clot. In the current study, placebo patients also demonstrated significant IVH progression compared to treated patients, nearly doubling from a mean of 2.7 mL to 4.6 mL at 24 hours. Even with this increase, however, high-dose rFVIIa patients still had greater IVH volumes (5.4 mL at 24 hours).
Commentary
As has become typical of stroke treatment trials, the FAST trial failed in part due to the favorable outcomes of its placebo patients. As Mayer et al note, the mortality rate in the placebo group was 19% in the FAST trial compared with 29% in the Phase II trial. While intraventricular hemorrhage, a known poor prognostic factor, was more prevalent in Phase II placebo patients, the reverse occurred in FAST, placing a handicap on the drug-treated cohort. Intraventricular hemorrhage may respond to rFVIIa, but is best treated with external ventricular drainage and, possibly, with infusion of intraventricular thrombolytics; the latter therapy will be tested in the planned Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) trial. Interestingly, IVH also was a complicating factor in the negative study STICH (Surgical Trial in Intracerebral Haemorrhage), with post-hoc analysis of this trial suggesting a benefit for surgical hematoma evacuation when patients with IVH were excluded.
Mayer et al's exploratory post-hoc analyses identified three additional factors that may have skewed results: patient age, hematoma volume, and time to treatment. The study had no upper age limit, and included a subset of quite elderly patients, the oldest being 97. Age, rather than any study drug effect, may be a much stronger determinant of outcome among elderly patients. Hematoma size also was important, since massive hematomas (> 60 mL) are associated with uniformly poor outcomes, especially if initial GCS (Glasgow Coma Score) is < 8. It would be difficult to detect a treatment effect for rFVIIa among such patients, since most would be severely disabled even in the best of circumstances. Conversely, small hematomas < 30 mL do well regardless and, therefore, also might be excluded from studies such as this. Finally, the FAST data suggest that earlier treatment, such as at 2-3 hours, portends a better outcome, since the number of patients with ongoing active bleeding rapidly declines during these early hours. This is not unlike the situation in ischemic stroke and IV rtPA, since even within the 3-hour time window from thrombolysis, there is likely an earlier time range (eg, 0-90 minutes) in which potential benefits can be much more marked.
Like other stroke trials, FAST likely failed due to weaknesses in patient selection, particularly regarding patient age and hematoma volume, and also due to unexpectedly favorable outcomes among its placebo patients. Closer attention to the presence or absence of IVH also is crucial as we move forward in the study of hemorrhagic stroke.
Reference
1. Mayer SA, et al; Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352:777-785.
Randomized studies of neuroprotective agents for ischemic stroke have resulted in a series of failures, as multiple agents, promising in animal models, have failed when applied to human subjects. By contrast, intracerebral hemorrhage (ICH) has been somewhat a "neglected stepsister" when compared to ischemic stroke; it has been studied minimally, despite its high morbidity and mortality.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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