Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

International Stroke Society-Joint World Congress on Stroke

Cape Town, South Africa / October 26-29, 2006

According to Dr. Alan Bryer, Head, Stroke Unit, Groote Schuur Hospital, and Professor, University of Cape Town, South Africa, intracerebral hemorrhage (ICH) is the pathological stroke type with the worst prognosis and carries a case fatality of 35 to 52%. Risk factors include hypertension, which is found in 70 to 80% of patients with ICH; excess alcohol use; amyloid angiopathy; use of anticoagulants, which increase the risk by about 8 to 11 times; and genetic predisposition. Morbidity and mortality are directly related to the size of the ICH. Secondary deterioration occurs in about 20 to 38% of presenting patients. This deterioration is associated with hematoma expansion and cerebral edema. The age-standardized incidence is about 30 to 120 per 100,000 person-years. The proportion of all strokes caused by ICH varies between populations with Asians, Hispanics and people of African origin having a higher proportion. In Sub-Saharan Africa, ICH accounts for about 26 to 33% of strokes.

Until recently, little available treatment other than stroke unit care was available for ICH patients, noted Dr. Stephen Davis, Director, Division of Neurosciences and Department of Neurology, and Professor, The Royal Melbourne Hospital and University of Melbourne, Australia. Hematoma evacuation was not found to be beneficial in the STICH (Surgical Trial in Intracerebral Hemorrhage); medical therapies to reduce brain edema and intracranial pressure in patients with ICH are unproven; and corticosteroids are contraindicated. The management of hypertension in these patients remains controversial.

Hematoma size appears to be an important prognostic predictor of outcome. Hematoma size or volume <10 mL is not associated with a particularly poor outcome but a volume of >60 mL is, and indeed, a good outcome is rare if the volume exceeds 30 mL. In a pooled meta-analysis of 218 patients with ICH allocated to placebo from recombinant factor VIIa (rFVIIa) studies, hematoma growth was frequent, occurring in 72.9% of patients at 24 hours’ follow-up. For each 10% increase in hematoma growth, there was a 5% increased hazard of death and a 16% greater likelihood of worsening by 1 point on the modified Rankin Scale (mRS). Like ischemic stroke, ICH grows in the first few hours. According to Dr. Davis, “Dynamic hematoma growth is a critical clinical target” and “provides an opportunity to intervene.”

A proof of concept study with rFVIIa was carried out in 20 countries. “We were particularly struck that the percentage and absolute change in hematoma growth were influenced in a highly significant manner,” Dr. Davis observed. The use of rFVIIa resulted in an overall 50% reduction in the volume of the hematoma and positive secondary outcomes of mortality and clinical scores.

Dr. Thorsten Steiner, Professor of Neurology and Neurointensive Care, University of Heidelberg, Germany, described this study in more detail. Nearly 400 patients with ICH were randomized to receive rFVIIa at doses of 40, 80 or 160 µg/kg within three hours of symptom onset and 60 minutes of computed tomography (CT) confirmation.

The primary outcome confirmed that active treatment halved the risk of hematoma growth, which in turn effectively reduced mortality and resulted in improved clinical outcome. Recently, more clinical outcome data are available from this study. The proportion of patients with an excellent outcome of mRS 0 or 1 was greater in the active treatment groups compared to the placebo group. The two higher doses trialled were also associated with a lower Barthel Index on follow-up than was found in the placebo group. The number of patients needed to treat (NNT) to achieve a good outcome with rFVIIa was five to seven across the different doses used.

In a post-hoc analysis of the proof of concept study, Dr. Michael Diringer, Professor and Neurosurgery ICU Director, Washington University in St. Louis, Missouri, and colleagues found that for all rFVIIa doses combined compared with placebo, both mortality (18% vs. 29%; P=0.02) and severe disability (mRS 4-6, 53% vs. 69%; P=0.004) were reduced. The mRS utility scores indicated that rFVIIa was associated with significantly better health-related quality of life (P<0.006 for all).

Dr. Stephan Mayer, Associate Professor of Clinical Neurology and Neurosurgery, Columbia University, New York, and colleagues presented data on time to treatment in the rFVIIa proof of concept study. Mean baseline ICH volume in the combined factor rFVIIa group was 24 ± 26 mL. Mean absolute increase in ICH volume between baseline and 24 hours later was 8.7 mL in placebo vs. 4.2 mL in the active treatment cohort (P=0.01). The efficacy of rFVIIa depended on the time to treatment: for each 30-minute reduction in onset-to-treatment time, mean ICH was smaller in rFVIIa vs. placebo by 3.6 mL. However, shorter onset-to-treatment time was not associated with an odds reduction in poor outcome (adjusted odds ratio 0.98 per 30-minute decrease in onset-to-treatment time [P=0.88]) after controlling for treatment assignment, age, gender, Glasgow Coma Scale score, baseline ICH volume, hemorrhage location and intraventricular bleeding. From this initial study, it appears that treatment within four hours of symptom onset reduces the hematoma size.

Intracerebral Hemorrhage with Other Complications

According to Dr. Steiner, intraventricular hemorrhage (IVH) occurs in about 40 to 50% of patients with ICH and is associated with an increase in mortality of up to 50%. A post-hoc analysis of data from the proof of concept study revealed that treatment with rFVIIa reduced the increase in IVH. Forty-three per cent of patients randomized to placebo developed IVH and 36% of those on rFVIIa. Predictors of the development of IVH include increasing age, the volume of ICH on admission, mean arterial blood pressure (BP) of >120 mm Hg and hemorrhage located in the thalamus. For every 10mL increase in parenchymal hemorrhage, there was an increase of 2.3 mL in intraventricular volume.

Treatment with rFVIIa is aimed at reducing further hemorrhage in patients presenting with ICH, but there is a potential risk for other thromboembolic events. According to Dr. Steiner, thromboembolic events (defined as occurring within 15 days of treatment—beyond that the investigators deemed rFVIIa treatment unlikely to be the cause) were not more frequent in patients treated with rFVIIa compared to placebo.

Investigators here this week addressed the issue of whether there is a role for rFVIIa in the reversal of anticoagulant therapy in ICH patients. Although this has not been directly answered by clinical trials (and patients on anticoagulants were excluded from the proof of concept study), there are encouraging results from small case series. Dr. Steiner explained that in three retrospective reviews of patient records, rFVIIa was associated with faster normalization of the international normalized ratio (INR) following anticoagulation-associated ICH. Previous research found that the INR normalized within 6.78 ± 2.68 hours when rFVIIa was added to therapy with vitamin K and fresh-frozen plasma (FFP) in 29 patients compared to 47.44 ± 9.88 hours in 24 control patients treated with only FFP (Roitberg et al. Neurosurgery 2005;57(5):832-6). While normalization of the INR is likely to translate into clinical benefit, this remains to be shown in prospective, randomized clinical trials.

Ongoing Clinical trials and Future Research

According to Dr. Davis, the FAST (rFVIIa in Acute Intracerebral Hemorrhage) study has almost been completed, with results anticipated in early 2007. The confirmatory study of its use in ICH differs from the earlier proof of concept study in outcome measures. In FAST, the outcome measures are disability measures and clinical outcome after three months; reduction in hematoma growth and mortality are secondary outcome measures. Patients with ICH will be randomized within four hours to placebo or one of two doses of rFVIIa (20 or 80 µg/kg).

The use of rFVIIa in patients with high blood glucose or in those with renal failure has also demonstrated efficacy. As reported by Dr. Davis, increased blood glucose does add to a poorer prognosis in ICH but does not appear to reduce the treatment effect of rFVIIa. The FAST study will add to the available information on this effect. Additionally, renal dysfunction is not a contraindication to the use of rFVIIa.

STICH showed that surgery was only beneficial for superficial bleeds and not in patients with IVH. STICH 2 has just begun and is investigating the role of early surgery for lobar hemorrhage. Dr. Davis suggested that further studies are needed to guide the management of BP in ICH and the role of intraventricular thrombolysis in patients with IVH. Dr. Steiner also suggested that the future management of ICH may involve combination therapy; for example, surgery in combination with rFVIIa use and the use of rFVIIa combined with standard therapy, such as FFP, in patients who develop ICH while on anticoagulants.