Marc Fisher MD Kennedy Lees MD Section Editors
A proven and effective treatment for intracerebral hemorrhage (ICH) remains an elusive goal. Results of recent clinical trials have been bitterly disappointing. Neither a surgical approach focusing on evacuation of the hematoma1 nor a medical approach focusing on neuroprotective strategies2,3 have shown any clinically relevant benefit.
The hematoma in ICH is a dynamic expanding mass. An increase in hematoma volume of >33% is seen in 38% of patients scanned within 3 hours of symptoms onset.4 In two-thirds of patients this increase in volume is seen within 1 hour.4 Because volume of the hematoma has been shown to be an important predictor of mortality and functional outcome,5 an approach focusing on preventing further bleeding is worth investigating.
In a recent phase 2 trial, a role for ultra-early hemostatic therapy with recombinant activated factor VII (rFVIIa) was identified.6 In this study, 399 patients with ICH were randomly assigned to receive placebo or 40, 80, or 160 μg of rFVIIa per kg of body weight. Treatment was given within 1 hour of the baseline CT scan and no later than 4 hours of symptoms onset. The primary efficacy endpoint for the study was the percent change in the volume of ICH. Global outcomes at 90 days were assessed using modified Rankin scale and the extended Glasgow Outcome scale. Of note, death and complete dependence on others was defined as modified Rankin Scale scores of 4 to 6. The study was conducted between August 2002 and March 2004 in 73 hospitals and 20 countries. In this study, rFVIIa was found to limit the expansion of the hematoma. At 24 hours, the mean increase in hematoma volume was 29% in the placebo group as compared with 16%, 14%, and 11% in the groups given 40, 80, and 160 μg, respectively, of rFVIIa per kg of body weight. Mortality at 90 days was 29% in the placebo group and 18% in the 3 treatment group.
Based on the positive phase 2 trial results, a definitive trial was initiated. The Factor Seven for Acute Hemorrhagic Stroke (FAST) trial was a double-blinded placebo-controlled study conducted between May 2005 and February 2007 at 122 sites in 22 countries.7 The patients were randomized to placebo, 20 μg/kg, and 80 μg/kg of rFVIIa; 8886 patients were screened, 841 underwent randomization, and 821 received study drug. In contrast to the phase 2 trial, the primary efficacy endpoint in FAST was severe disability or death defined as modified Rankin scale score of 5 or 6 at day 90. Treatment with 80 μg of rFVIIa was associated with a significant reduction in the growth in volume of the hematoma (26% in placebo group, 18% and 11% in the group receiving 20 μg and 80 μg, respectively). These results were not associated with any significant difference among the groups in the proportion of patients with poor clinical outcome (24% in placebo group, 26% in the 20-μg group, and 29% in the 80-μg group). Mortality at 3 month was ≈20% in the three groups. Further exploratory post hoc analyses identified a subset of patients that may clinically benefit from rFVIIa treatment: (1) subjects 70 years of age or younger with a baseline volume of ICH of ≤60 mL; (2) an intraventricular volume of ≤5 mL; and (3) a time from onset of symptoms of ≤2.5 hours. This group of patients constituted only 19% of the original study population.
The results of FAST were in contrast to the clinical benefit demonstrated in the phase 2 trial. The investigators attributed this discrepancy to randomization imbalances, an increase in arterial thromboembolic events with rFVIIa treatment, inclusion of very elderly patients, and better outcome in the placebo group compared to the previous trial. The randomization imbalances are in part related to the increased frequency of intraventricular hemorrhage in the treatment group compared to placebo. Intraventricular hemorrhage at baseline was present in 29% of placebo and 41% receiving 80 μg (opposite to what was seen in the first phase 2 trial). Although this increased frequency of intraventricular hemorrhage in the treatment group could have played a role in affecting the final results of the study, it is definitely not the only randomization imbalance. It is important to note that although patients were enrolled in 122 sites and 22 countries, 11 sites enrolled 32% of the patients. One site in particular enrolled 73 patients (9% of the total patients recruited into the study). This site was not part of the phase 2 trial. The clustering of patients recruitment in very few sites if not accounted for in the analysis could result in significant bias because the management of ICH patients could be slightly different among sites.
Mortality rate was another point that the investigators thought could explain the discrepancy between the 2 rFVIIa studies. The mortality rate in the placebo group was markedly lower in FAST compared to the phase 2 trial (19% vs 29%, respectively). It is not clear why the mortality rate in the placebo group in phase 2 trial was elevated. CHANT3 and GAIN2 are 2 recent ICH randomized clinical trials that enrolled patients very similar to those in the rFVIIa trials. They both reported a 20% mortality rate in the placebo arm, which is very close to the 19% reported in FAST. So the positive clinical effect seen in the phase 2 trial could be attributable to some confounding unknown variables that led to this unexplained increased in mortality in the placebo group rather than an actual effect of rFVIIa.
Although both rFVIIa studies recommended using the 1999 American Heart Association guidelines for management of ICH patients, the systolic blood pressure at the time of treatment was higher in the FAST trial compared to that in the phase 2 trial. Furthermore, left ventricular hypertrophy was more common in the treated group in FAST compared to placebo. This certainly brings to the forefront the importance of blood pressure control in the expansion of the hematoma. Is it possible that the increase in blood pressure may have blunted the effect of rFVIIa? In FAST we observed a 3.8-mL reduction in volume of ICH between the placebo group and 80-μg treated group compared to 4.5 mL in the initial phase 2 trial. A post hoc analysis looking at the combined effect of rFVIIa and systolic blood pressure may shed some lights on this issue.
So far every completed ICH clinical trial failed to show any clinically relevant improvement in neurological outcome. Most probably this is attributable to the complexity of ICH pathophysiology and the multitude of factors involved. Although hematoma volume is a predictor of poor outcome, it is not the only predictor. Others predictors for example include intraventricular hemorrhage, blood pressure, and HbA1C. So if we approach this disease addressing only 1 predictor, the chance of success is small. As it stands now we have a drug (rFVIIa) that has proven in 2 clinical trials that it will limit the expansion of the hematoma. The next step should follow an approach similar to the Interventional Management of Stroke study. We should study paradigms of treatments rather than a single drug or procedure. This could include rFVIIa in combination with either open or stereotaxic surgery, blood pressure control, glucose control, intensive care unit management, or other neuroprotective drugs.
In summary, ultra-early hemostatic therapy did limit hematoma expansion in ICH patients, but this was not enough to improve clinical outcome. Future trials should consider a more comprehensive approach to management of ICH.
- Received August 28, 2008.
- Accepted August 29, 2008.
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