Hemostatic treatment in the early stage of intracerebral hemorrhage: the recombinant factor VIIa experience.

The treatment of intracerebral hemorrhage (ICH) has been a largely neglected item. In contrast to literally dozens of clinical trials of treatment of ischemic stroke, only a handful have addressed treatment of ICH with either medical (steroids,1 osmotic diuretics2) or surgical3 interventions. The medical intervention trials, primarily aimed at reducing brain edema surrounding the ICH, have shown lack of benefit of treatment with dexamethasone1 or glycerol solutions.2 Although some pilot data suggested a potential benefit of early surgical drainage of the hematoma,4,5 the recent publication of neutral results in the large, prospective, and randomized international Surgical Trial in Intracerebral Hemorrhage (STICH) study6 has been a disappointment. Mendelow and colleagues went for 8 years of enrollment and follow up of over 500 subjects in each treatment group, one managed “conservatively,” the other subjected to surgical drainage of the hematoma within a maximum of 4 days from symptom onset. The final results showed no benefit of one mode of treatment over the other, because a favorable outcome occurred as frequently in the “conservative” (24%) as in the surgical (26%) group when they were evaluated at 6 months. Although a prespecified subgroup analysis suggested a possible advantage of surgical treatment for superficially located ( 1 cm from the cortical surface) lobar hematomas, the overall trial results showed that only one fourth of patients with ICH can be expected to have a good clinical outcome, which cannot be improved on by surgical treatment. In the wake of the neutral STICH trial results, it is refreshing to see some hope for the treatment of this devastating stroke subtype with the publication of the results of the phase IIB trial of recombinant activated factor VIIa (rFVIIa) in ICH.7 Mayer et al assessed the value of different doses of rFVIIa (NovoSeven; Novo Nordisk) on decreasing the early enlargement of the hematoma (primary outcome) and compared this effect with clinical secondary outcomes measured at 90 days. The results were encouraging, because each of the 3 doses of rFVIIa (40, 80, 160 g/kg) given within 4 hours of symptom onset to close to 100 patients per group were followed by a reduction in hematoma growth in comparison with placebo; the mean relative increase in ICH volume was 11% for the highest rFVIIa dose (160 g/kg), which was significantly lower than the 29% observed in the placebo group, whereas the intermediate doses (40 and 80 g/kg) showed a trend toward lower volume increases as well (16% and 14%, respectively). The 3 rFVIIa groups combined had a significant reduction of absolute ICH growth (4.2 mL) in comparison with placebo (8.7 mL; P 0.01). These beneficial effects on early hematoma growth were correlated with survival and with favorable clinical outcomes (defined as 0 to 1 in the modified Rankin Scale, 7 to 8 in the Extended Glasgow Outcome Scale, 95 to 100 in the Barthel Index, and 0 to 1 in the National Institutes of Health Stroke Scale score) at 90 days. Both outcomes favored rFVIIa-treated subjects, who had an 18% mortality for the 3 groups combined in comparison with 29% for the placebo group (P 0.02). Similarly, death and severe disability combined occurred in 69% of placebo patients and in 53% of those treated with rFVIIa, an absolute risk reduction of 16% (P 0.004). This clinical effect translated into a number needed to treat of approximately 6 to prevent one unfavorable outcome. The enthusiasm generated by these preliminary results has to be tempered, however, by some of the findings reported. The most important one relates to the observed increased frequency of thromboembolic complications in the subjects treated with rFVIIa (7%, in comparison with 2% for the placebo group). Although this difference was not significant (P 0.12), it raises a concern about the range of patients likely to derive a net benefit from this therapy. The thromboembolic complications in the rFVIIa-treated group were predominantly arterial (16, for a total of 21 events), whereas the 2 events in the placebo group were venous, thus amounting to a rate of 5% of arterial events (7 myocardial and 9 cerebral infarcts) in the rFVIIa group versus none in the placebo group (P 0.01). Because one half of the 16 arterial events in the rFVIIa group occurred in the highest-dose (160 g/kg) group (a dose twice as high as that recommended for the treatment of bleeding in patients with hemophilia8), it is possible that the use of lower doses may result in a reduction of risk for this complication. This approach is being tested in the ongoing phase III FAST (rFVIIa in Acute