Targeting hematoma expansion in ICH Illusions of hope or hope to disillusion
ABSTRACT Several variables are associated with poor outcome and mortality after intracerebral hemorrhage (ICH).(1) Among modifiable factors, hematoma expansion may have a predominant role, and has been the target of recent therapeutic trials in ICH. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) and Antihypertensive Treatment of Acute Cerebral Hemorrhage Study (ATACH-1) showed that intensive blood pressure (BP) lowering is associated with reduced hematoma expansion during the first 24 hours of ICH(2,3); the clinical effectiveness of this strategy is undergoing evaluation in phase III trials.
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ABSTRACT: Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. Hematoma growth is an independent determinant of both mortality and functional outcome after intracerebral hemorrhage. Attenuation of growth is an important therapeutic strategy.Neurology 04/2006; 66(8):1175-81. DOI:10.1212/01.wnl.0000208408.98482.99 · 8.30 Impact Factor
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ABSTRACT: There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. National Health and Medical Research Council of Australia.The Lancet Neurology 05/2008; 7(5):391-9. DOI:10.1016/S1474-4422(08)70069-3 · 21.82 Impact Factor
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ABSTRACT: In the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, 80 microg/kg of recombinant activated factor VII (rFVIIa) significantly reduced intracerebral hemorrhage (ICH) expansion when given within 4 hours of onset. However, in contrast to an earlier Phase 2b study, rFVIIa did not improve survival or functional outcome. In this exploratory analysis, we hypothesized that earlier treatment and exclusion of patients with a poor prognosis at baseline might enhance the benefit of rFVIIa treatment. Using the FAST data set, the impact of rFVIIa (80 microg/kg) on poor outcome at 3 months (modified Rankin Score of 5 or 6) was systematically evaluated within subgroups using clinically meaningful cut points in onset-to-treatment time, age, and baseline ICH and intraventricular hemorrhage volume. The effect of treatment on outcome was analyzed using logistic regression, and ICH volume was analyzed with linear mixed models. A subgroup (n=160, 19% of the FAST population) was identified comprising patients <or=70 years with baseline ICH volume <60 mL, intraventricular hemorrhage volume <5 mL, and time from onset-to-treatment <or=2.5 hours. The adjusted ORs for poor outcome with rFVIIa treatment was 0.28 (95% CI, 0.08 to 1.06), whereas the reduction in ICH growth was almost doubled (7.3+/-3.2 versus 3.8+/-1.5 mL, P=0.02). The improved effect was confirmed in an analysis of similar Phase 2 patients. A prospective trial would be needed to determine whether younger patients with ICH without extensive bleeding at baseline can benefit from 80 mug/kg of rFVIIa given within 2.5 hours of symptom onset.Stroke 02/2009; 40(3):833-40. DOI:10.1161/STROKEAHA.108.524470 · 6.02 Impact Factor