Exploring Hematoma Expansion Shift with Recombinant Factor VIIa: A Pooled Analysis of Four Randomized Controlled Trials.

Background: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study we applied HES analysis to individual patient data from four randomized controlled trials evaluating recombinant Factor VIIa (rFVIIa) 80 μg/kg to placebo. Methods: We generated polychotomous strata of HES using absolute growth thresholds (≤0mL/<6mL/≥6mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL) and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. Results: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa treated patients exhibited no hematoma expansion as compared to 25% of placebo (88/352) treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa (acOR:0.57, 95% CI:0.43-0.75). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR: 0.61, 95% CI: 0.47-0.80). In both groups, mild to moderate expansion was observed in 38 to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR 0.48, 95% CI: 0.30-0.76 versus <20 mL: acOR:0.67, 95% CI:0.47-0.95, p interaction = 0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR:0.42, 95% CI:0.19-0.91 versus >2 hours: acOR:0.59, 95% CI:0.44-0.79, p interaction =0.30). Conclusions: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.